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<?xml version="1.0" encoding="utf-8"?><feed xmlns="http://www.w3.org/2005/Atom" ><generator uri="https://jekyllrb.com/" version="3.9.3">Jekyll</generator><link href="https://transfemscience.org/feed.xml" rel="self" type="application/atom+xml" /><link href="https://transfemscience.org/" rel="alternate" type="text/html" /><updated>2023-10-17T14:30:18-07:00</updated><id>https://transfemscience.org/feed.xml</id><title type="html">Transfeminine Science | Articles</title><subtitle>Transfeminine Science is a site for information on hormone therapy for transfeminine people.</subtitle><author><name>Transfeminine Science</name></author><entry><title type="html">Puberty Blockers: A Review of GnRH Analogues in Transgender Youth</title><link href="https://transfemscience.org/articles/puberty-blockers/" rel="alternate" type="text/html" title="Puberty Blockers: A Review of GnRH Analogues in Transgender Youth" /><published>2022-01-30T15:04:00-08:00</published><updated>2022-01-31T00:00:00-08:00</updated><id>https://transfemscience.org/articles/puberty-blockers</id><content type="html" xml:base="https://transfemscience.org/articles/puberty-blockers/"><h1 id="puberty-blockers-a-review-of-gnrh-analogues-in-transgender-youth">Puberty Blockers: A Review of GnRH Analogues in Transgender Youth</h1>
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<p>By
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<!-- First author --><a href="/about/#mitzi">Mitzi</a><!-- Second author --><!-- Third author --><!-- Fourth author --> | First published January 30, 2022
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| Last modified January 31, 2022</p>
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<h2 id="abstract--tldr">Abstract / TL;DR</h2>
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<p>Puberty blockers are medications used to pause puberty in both cisgender and transgender youth. For the latter, significant evidence suggests that they improve well-being, psychological functioning, and risk of suicidality, both during puberty and in later life. Their effects are reversible upon discontinuation. Current evidence does not suggest any negative impact on cognitive development, IQ, or fertility. A minor impact on bone density may exist, affecting primarily transgender girls, but little high quality data is available. Based on limited data, prescribers may wish to consider calcium supplementation in transgender teens receiving puberty blockers, and may wish to prefer transdermal delivery over oral estrogens in transgender girls starting hormone therapy in order to optimise bone density outcomes. There is a lack of evidence supporting the common belief that most children grow out of gender dysphoria (“desistance”), as widely cited data describing the rate at which this happens appears highly unreliable. Puberty blockers are difficult to access, and many Western countries have sharply restricted their use recently, in a trend condemned by numerous medical associations. Randomised controlled trials on puberty blockers can likely never be performed, but nonetheless, there is clear evidence they offer significant benefit, and have relatively minor risks.</p>
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<h2 id="introduction">Introduction</h2>
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<p>Puberty blockers, also known as <a href="https://en.wikipedia.org/wiki/Gonadotropin-releasing_hormone">gonadotropin-releasing hormone</a> (GnRH) <a href="https://en.wikipedia.org/wiki/Gonadotropin-releasing_hormone_analogue">analogues</a>, were introduced for medical use in the 1980s (<a href="https://doi.org/10.1146/annurev.me.34.020183.002423">Swerdloff &amp; Heber, 1983</a>). Originally developed to supersede other therapies in the treatment of prostate cancer, they were soon adapted for paediatric use, revolutionising the treatment of <a href="https://en.wikipedia.org/wiki/Precocious_puberty">precocious puberty</a>: a rare condition in which puberty begins before the age of 8 (in natal girls) or 9 (in natal boys). Precocious puberty is associated with several negative consequences, such as short stature, teasing, bullying, and worse mental health outcomes. By reversibly pausing puberty for several years in children with this condition, outcomes are often significantly improved, and puberty blockers remain the mainstay treatment for this condition several decades later.</p>
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<p>In the 1990s, puberty blockers began to be used in transgender adolescents, as a way of pausing their unwanted puberty, and giving them more time to consider their future (<a href="https://doi.org/10.1007/s007870050073">Cohen-Kettenis &amp; van Goozen, 1998</a>). The protocol for this, originally develped by the Dutch <a href="https://en.wikipedia.org/wiki/VU_University_Medical_Center">VUmc clinic</a>, has sometimes been referred to as the “Dutch Method.” <a href="https://doi.org/10.1007/s10508-011-9758-9">Cohen-Kettenis et al. (2011)</a> published a study following one such Dutch patient 22 years later. Since then, the use of puberty blockers has increased tremendously with the increase in patients seeking transgender healthcare.</p>
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<p>Recently, puberty blockers have been the subject of controversy, with legal proceedings seeking to prohibit their use across several countries. Notably, their use was temporarily stopped in the United Kingdom in December 2020 following a ruling in the <em><a href="https://en.wikipedia.org/wiki/Bell_v_Tavistock">Bell v. Tavistock</a></em> case, which was appealed in 2021. Also in 2021, Arkansas became the first U.S. state to make it illegal for doctors to prescribe puberty blockers, with several other states pursuing similar legislation. Critics express concern about the safety of puberty blockers, their reversibility, and effectiveness.</p>
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<p>This article seeks to review the literature on the use and safety of puberty blockers in transgender youth, examining their safety, and arguments for and against their use in a comprehensive way. While rarely, alternative medications like the progestin <a href="https://en.wikipedia.org/wiki/Medroxyprogesterone_acetate">medroxyprogesterone acetate</a> have been used for this, this article mainly focuses on <a href="https://en.wikipedia.org/wiki/Gonadotropin-releasing_hormone_agonist">GnRH agonists</a>: by far the most widely used class of medication for puberty blockade, and what’s most commonly colloquially referred to as “puberty blockers.”</p>
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<h2 id="mechanism-of-action">Mechanism of Action</h2>
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<p>GnRH is a naturally occurring hormone in humans responsible for the release of <a href="https://en.wikipedia.org/wiki/Follicle-stimulating_hormone">follicle-stimulating hormone</a> (FSH) and <a href="https://en.wikipedia.org/wiki/Luteinizing_hormone">luteinizing hormone</a> (LH) from the <a href="https://en.wikipedia.org/wiki/Pituitary_gland">pituitary gland</a>. Through this mechanism, the body produces its gonadal estrogen and testosterone. GnRH agonists bind to the <a href="https://en.wikipedia.org/wiki/Gonadotropin-releasing_hormone_receptor">GnRH receptor</a> and activate it, causing it to be continuously stimulated. This causes an initial increase of LH and FSH, then over the course of several weeks, causes the pituitary gland to become desensitised, pausing the natural sex hormone production for the duration the medication is taken. When the medication is stopped, its effect is reversed, with normal sex hormone production resuming about a week after the medication clears the body (<a href="https://doi.org/10.1093/humrep/15.5.1009">Cedrin-Durnerin et al., 2000</a>).</p>
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<p>GnRH agonists are prescribed as an injection administered every one to six months, a surgically implanted pellet once per year, or a nasal spray administered two to three times per day. A short-acting daily injection exists, but is not used for puberty blockade in clinical practise. Common examples of GnRH agonists include <a href="https://en.wikipedia.org/wiki/Leuprorelin">leuprorelin</a> (Lupron; Eligard), <a href="https://en.wikipedia.org/wiki/Triptorelin">triptorelin</a> (Decapeptyl), <a href="https://en.wikipedia.org/wiki/Goserelin">goserelin</a> (Zoladex), <a href="https://en.wikipedia.org/wiki/Histrelin">histrelin</a> (Supprelin LA), <a href="https://en.wikipedia.org/wiki/Nafarelin">nafarelin</a> (Synarel) and <a href="https://en.wikipedia.org/wiki/Buserelin">buserelin</a> (Suprefact).</p>
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<p>Like GnRH agonists, <a href="https://en.wikipedia.org/wiki/Gonadotropin-releasing_hormone_antagonist">GnRH antagonists</a> bind to the GnRH receptor, however, they do not stimulate it. Instead, they compete with the body’s own GnRH, rendering it ineffective. As a result, they achieve similar effects without causing an initial increase in hormone levels. Also unlike GnRH agonists, oral formulations of GnRH antagonists exist, allowing some of them to be taken as a daily pill. Common examples include <a href="https://en.wikipedia.org/wiki/Elagolix">elagolix</a> (Orilissa), <a href="https://en.wikipedia.org/wiki/Degarelix">degarelix</a> (Firmagon), <a href="https://en.wikipedia.org/wiki/Cetrorelix">cetrorelix</a> (Cetrotide), <a href="https://en.wikipedia.org/wiki/Ganirelix">ganirelix</a> (Orgalutran; Antagon) and <a href="https://en.wikipedia.org/wiki/Relugolix">relugolix</a> (Orgovyx; Relumina). Unfortunately, being much newer drugs, GnRH antagonists are not normally used as puberty blockers at the moment.</p>
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<p>In gender dysphoric youth, GnRH agonists are prescribed after the onset of puberty. GnRH agonists are not prescribed to children who have not yet started puberty, but may be started at any point during puberty to pause further changes (<a href="https://doi.org/10.1210/jc.2017-01658">Hembree et al., 2017</a>).</p>
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<h2 id="quality-of-evidence">Quality of Evidence</h2>
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<p>In medicine, the gold standard for evidence is the <a href="https://en.wikipedia.org/wiki/Randomized_controlled_trial">randomised controlled trial</a>, or RCT. In a nutshell, participants are randomly assigned into two or more treatment groups (arms), such that the only difference between arms is the treatment they receive. Commonly, one group receives a placebo, while another receives the treatment being studied. The ideal RCT is blinded, meaning neither participants nor investigators of the study know which group is receiving which treatment. No such trials have been performed with puberty blockers, giving rise to concerns that there could be insufficient evidence available for their use.</p>
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<p>Unfortunately, RCTs may not be practically possible for puberty blockers, and are unlikely to ever be performed. A good summary of the reasons for this is provided by <a href="https://doi.org/10.1080/26895269.2020.1747768">Giordano &amp; Holm (2020)</a>:</p>
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<blockquote>
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<p>There are two main practical problems that preclude conducting a RCT.</p>
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<p>First, patients who approach clinics for help because of distress caused by the first signs of puberty will be unlikely to accept to be a part of a RCT. Medications are needed within a relatively short period of time, at pain of treatment being less effective or ineffective. Recruitment would thus be hard if not impossible.</p>
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<p>Second, the ideal RCT is either double blind, i.e. neither researchers nor participants know who gets the active drug, or it assesses outcomes using blinded observers when treatment allocation cannot be hidden from participants. Blinding is necessary in order to reduce bias in outcome assessments. But, a RCT of puberty delay could not maintain blinding. Because GnRHa are effective in delaying puberty it would soon become evident to participants, researchers and outcome assessors who was in the active treatment arm and who was not. This breakdown of blinding would mean that there would be potential bias in the outcome assessments, both in relation to biological and psychological outcomes. It would also mean that participants allocated to the non-treatment arm of the study would be likely to either withdraw from the study at a much higher rate than in the treatment arm introducing potential bias, and/or be more likely not to adhere to the trial but seek puberty delaying treatment outside of the trial thereby adding a confounder.</p>
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</blockquote>
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<p><a href="https://doi.org/10.1080/080352501316978011">Mul et al. (2001)</a> ran into this problem conducting a similar study on teens with precocious puberty:</p>
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<blockquote>
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<p>In the original study design a third arm with untreated children was scheduled as a control group. It was decided to omit this control group from the study design after it appeared that the parents of all patients who were randomized in the untreated control group refused further participation in the study as GnRHa treatment could be obtained elsewhere.</p>
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</blockquote>
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<p>Besides practical limitations, such RCTs are likely to be unethical. Evidence suggests withholding puberty blockers may cause lasting harm in itself. To knowingly cause such harm to the control group of an RCT is likely to be morally unacceptable, and such an RCT would be unlikely to receive approval from an ethical review board.</p>
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<p>This is not to say that studies evaluating such outcomes don’t exist at all: for example, while not randomised or blinded, <a href="https://doi.org/10.1111/jsm.13034">Costa et al. (2015)</a> compares 101 patients receiving psychological support and puberty blockers to 100 patients receiving psychological support alone. The results of this study are further outlined below.</p>
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<p>As a result of these limitations, this article mainly cites <a href="https://en.wikipedia.org/wiki/Cohort_study">cohort studies</a>, making the argument that sufficient other high-quality studies exist to reach well-supported conclusions: a practise sometimes required in other areas of medicine as well. Because this is the only way we can practically evaluate puberty blockers and RCTs are likely impossible, it seems disingenuous to make the claim that lack of RCTs equate to lack of evidence around puberty blockers, as this standard of evidence can never be met, and the claim ignores a substantial existing body of literature.</p>
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<h2 id="suicidality-and-well-being">Suicidality and Well-being</h2>
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<p>A significant body of evidence associates the use of puberty blockers in those who want such treatment with improved psychological well-being: the primary argument for their use.</p>
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<p>While different studies use different methodologies, three standardised psychological questionnaires are typically used to evaluate well-being: the <a href="https://en.wikipedia.org/wiki/Children%27s_Global_Assessment_Scale">Children’s Global Assessment Scale</a> (CGAS), the <a href="https://en.wikipedia.org/wiki/Child_Behavior_Checklist">Child Behavior Checklist</a> (CBCL), and the <a href="https://en.wikipedia.org/wiki/Youth_Self-Report">Youth Self-Report</a> (YSR). All three are aimed at evaluating psychological functioning and problematic behaviour: typically, the CGAS is administered by a clinician, the CBCL is filled out by a parent or guardian, and the YSR is filled out by a child themselves. It’s important to note that scores in these assessments are known to markedly worsen in adolescence in general, with the onset of psychological difficulties and self-harm often appearing during puberty (<a href="https://doi.org/10.1176/appi.ajp.160.8.1479">Verhuist et al., 2003</a>; <a href="https://doi.org/10.1001/2013.jamapsychiatry.55">Nock et al., 2013</a>; <a href="https://doi.org/10.1093/pubmed/fdw010">Morey et al., 2017</a>; <a href="https://doi.org/10.3346/jkms.2018.33.e191">Jung et al., 2018</a>).</p>
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<p>One of the largest studies to investigate well-being to date has been <a href="https://doi.org/10.1542/peds.2019-1725">Turban et al. (2020)</a>. It surveyed 20,619 American transgender adults. 3,494 (16.9%) reported that they ever wanted to receive puberty blockers. Of those, only 89 received them. In total, 75.3% of those who received puberty blockers reported ever experiencing suicidal thoughts, compared to 90.2% of those who did not. After controlling for demographic variables like income, family support, and education level, puberty blockers remained significantly associated with decreased odds of lifetime suicidal ideation.</p>
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<p>A similarly large survey by <a href="https://doi.org/10.1016/j.jadohealth.2021.10.036">Green et al. (2021)</a> included 11,914 Americans aged 13–24 who identified as transgender or nonbinary. The study compares those who received hormone therapy or puberty blockers to those who wished to receive them, but didn’t. It finds that in those who received treatment, rates of depression, suicidal ideation, and suicide attempts were significantly lower. This remained true of those aged 13–17, who were significantly more likely to receive puberty blockers specifically.</p>
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<p><a href="https://doi.org/10.1111/jsm.13034">Costa et al. (2015)</a> studied 201 gender dysphoric adolescents who presented at the British <a href="https://en.wikipedia.org/wiki/NHS_Gender_Identity_Development_Service">Tavistock and Portman NHS Gender Identity Development Service</a>. Of them, half were considered eligible for puberty blockers immediately, receiving them in addition to psychological support. The other half were not considered immediately eligible for puberty blockers, citing reasons such as psychiatric problems or conflicts with parents and siblings. These patients received only psychological support for the following 18 months. All patients’ global psychological functioning was assessed using the CGAS questionnaire. Both groups showed significantly improved psychological functioning with psychological support, but the group receiving only psychological support stalled and showed no further improvement towards the end of the study, while those receiving puberty blockers continued to show greater improvement. The authors point out that the eventual CGAS score of the group receiving puberty blockers coincided almost perfectly with those found in a sample of children/adolescents without observed psychological/psychiatric symptoms.</p>
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<table>
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<thead>
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<th><img src="/assets/images/puberty-blockers/costa2015.png" alt="" /></th>
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<td><strong>Figure 1:</strong> CGAS scores of psychological functioning in transgender teens receiving puberty blockers and psychological support, compared to those receiving psychological support alone in <a href="https://doi.org/10.1111/jsm.13034">Costa et al. (2015)</a>.</td>
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<p>A later study at the same British gender identity clinic, <a href="https://doi.org/10.1371/journal.pone.0243894">Carmichael et al. (2021)</a>, received widespread media coverage in the United Kingdom following its mixed findings. It followed 44 gender dysphoric adolescents who received puberty blockers. CGAS scores were higher than the 2015 study at baseline, and showed slower and more modest improvement. The study reached contradictory conclusions, with improvements reported in some questionnaires, but not others, even for comparable measurements. Interestingly, in some of the researchers’ measures of well-being, social acceptance, and self-perception, adolescents themselves reported significant improvements, while their parents reported almost no improvement. The study characterises participants’ overall experiences with puberty blockers as positive, but is difficult to draw any conclusions from.</p>
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<p><a href="https://doi.org/10.1111/j.1743-6109.2010.01943.x">De Vries et al. (2011)</a> and <a href="https://doi.org/10.1542/peds.2013-2958">de Vries et al. (2014)</a> investigate the psychological outcomes of the same cohort of transgender adolescents receiving puberty blockers at the VUmc gender clinic in the Netherlands. Both investigate psychological outcomes in a range of tests, with the 2014 study providing long-term follow-up many years after puberty blockers, and after gender reassignment surgery. In the studied cohort, psychological functioning improves and depression decreases over time, as evidenced by standardised tests, including CGAS scores. Significant improvements in well-being are reported both during treatment with puberty blockers, and in the years after, with hormone therapy and surgery. Unlike Carmichael et al., CBCL and YSR scores improve.</p>
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<p><a href="https://doi.org/10.1016/j.jadohealth.2019.12.018">Van der Miesen et al. (2020)</a> charts psychological well-being across 3 groups of Dutch adolescents: 272 transgender adolescents who haven’t yet received puberty blockers, 178 adolescents receiving puberty blockers, and 651 cisgender adolescents from the general population. The study finds poorer psychological functioning in those before treatment, while psychological functioning and well-being is similar to cisgender adolescents in those receiving pubertal suppression. These findings are in line with <a href="https://doi.org/10.1111/jsm.13034">Costa et al. (2015)</a>, which noted that those receiving puberty blockers reached CGAS scores comparable to the general (age-matched) population.</p>
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<th><img src="/assets/images/puberty-blockers/vandermiesen2020.png" alt="" /></th>
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<td><strong>Figure 2:</strong> Percentages of teens who report suicidality in <a href="https://doi.org/10.1016/j.jadohealth.2019.12.018">van der Miesen et al. (2020)</a>. Suicidality was defined as endorsing the statement “I deliberately try to hurt or kill myself” or “I think about killing myself.” Suicidality among Dutch transgender youth has not significantly changed over time, making cohort differences unlikely (<a href="https://doi.org/10.1007/s00787-019-01394-6">Arnoldussen et al., 2020</a>).</td>
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<p>In addition to the studies listed above, several smaller, less focused studies have also assessed the well-being of transgender adolescents receiving puberty blockers and reported overall positive experiences (<a href="https://doi.org/10.1016/j.jpeds.2013.10.068">Khatchadourian et al., 2014</a>; <a href="https://doi.org/10.1186/s13633-020-00078-2">Achille et al., 2020</a>; <a href="https://doi.org/10.1542/peds.2019-3006">Kuper et al., 2020</a>). No studies report a decline in psychological functioning or notably negative psychological outcomes with the use of puberty blockers.</p>
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<p>In combination, this strongly suggests that puberty blockers improve well-being and psychological functioning in children who experience gender dysphoria. In addition, it suggests that inappropriately withholding them may lead to worse later-life outcomes, such as increased suicidality.</p>
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<p>Counterintuitively, several of the studies listed do note that puberty blockers don’t reduce gender dysphoria (<a href="https://doi.org/10.1111/j.1743-6109.2010.01943.x">de Vries et al., 2011</a>; <a href="https://doi.org/10.1371/journal.pone.0243894">Carmichael et al., 2021</a>). It’s important to be aware that this finding refers to the wish to transition, rather than psychological well-being. The finding is based on the Utrecht Gender Dysphoria Scale questionnaire (<a href="https://doi.org/10.1300/J485v09n03_04">de Vries et al., 2006</a>). To illustrate, the version for transmasculine youth asks patients whether they endorse such statements as “I prefer to behave like a boy”, “I wish I had been born as a boy”, “I hate having breasts”, and “every time someone treats me like a girl, I feel hurt.”</p>
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<p>When studies note that puberty blockers don’t reduce gender dysphoria, this means children don’t stop identifying as transgender after receiving puberty blockers. They continue to want to transition. <a href="https://doi.org/10.1111/j.1743-6109.2010.01943.x">De Vries et al. (2011)</a> points out this is the expected outcome:</p>
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<blockquote>
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<p>As expected, puberty suppression did not result in an amelioration of gender dysphoria. Previous studies have shown that only gender reassignment consisting of cross-sex hormone treatment and surgery may end the actual gender dysphoria. None of the gender dysphoric adolescents in this study renounced their wish for gender reassignment during puberty suppression. This finding supports earlier studies showing that young adolescents who had been carefully diagnosed show persisting gender dysphoria into late adolescence or young adulthood</p>
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</blockquote>
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<h2 id="fertility">Fertility</h2>
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<p>Unlike hormone therapy, no risk of permanent infertility is believed to exist with the use of puberty blockers. Several long-term follow-up studies of patients treated with puberty blockers have found normal fertility. Among others, <a href="https://doi.org/10.1210/jcem.84.1.5409">Feuillan et al. (1999)</a>, <a href="https://doi.org/10.1210/jcem.84.12.6203">Heger et al. (1999)</a>, <a href="https://doi.org/10.1016/j.mce.2006.04.012">Heger et al. (2006)</a> and <a href="https://doi.org/10.1111/cen.12319">Lazar et al. (2014)</a> find no indication of impaired fertility in patients treated with puberty blockers for precocious puberty. In the years and decades following their treatments, the several hundred patients in these studies are found to conceive normally without an increased need for assisted reproductive technology, and with uneventful pregnancies. Despite several decades of use, no reports exist in literature of permanent infertility linked to puberty blockers. Interestingly, transgender populations do have higher rates of sperm abnormalities than cisgender populations, before any medical treatment has taken place (<a href="https://doi.org/10.1111/andr.12527">Li et al., 2018</a>; <a href="https://doi.org/10.1111/andr.12999">Rodriguez-Wallberg et al., 2021</a>).</p>
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<p>In contrast, hormone therapy may cause permanent infertility (<a href="https://doi.org/10.1210/jc.2017-01658">Hembree et al., 2017</a>; <a href="https://doi.org/10.21037/tau.2019.05.09">Cheng et al., 2019</a>). If fertility preservation has not been accessed before beginning treatment, puberty blockers must be stopped to do so, ideally before hormone therapy begins. When puberty blockers are stopped, unwanted sex characteristics continue to develop. Transgender people may find this extremely distressing, which may be one reason for them to not pursue fertility preservation.</p>
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<p>No data exists on the exact length of time for which puberty blockers need to be stopped before full fertility is restored, and it likely varies depending on the age puberty blockers were initiated. <a href="https://doi.org/10.1007/s004310051289">Bertelloni et al. (2000)</a> found spermarche took place between 0.7 to 3 years after discontinuation of puberty blockers in boys treated for precocious puberty. <a href="https://doi.org/10.1542/peds.2018-3943">Barnard et al. (2019)</a> report on the case of a single transgender patient who had been receiving puberty blockers for 6 months, from the age of 17. Three months after the last dose of monthly leuprorelin, no viable sperm sample could be produced. Five months after, their sample was viable.</p>
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<p>Regardless of this, transgender individuals are extremely unlikely to use fertility preservation, with some estimates suggesting utilisation rates below 5% in North America (<a href="https://doi.org/10.1016/j.jadohealth.2017.01.022">Chen et al., 2017</a>; <a href="https://doi.org/10.1016/j.jadohealth.2016.12.012">Nahata et al., 2017</a>). In one piece of research, <a href="https://doi.org/10.1001/jamapediatrics.2020.0264">Pang et al. (2020)</a> questioned 102 transgender Australian teens on their reasons for declining fertility preservation. The following statistics were gathered:</p>
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<th><img src="/assets/images/puberty-blockers/pang2020.png" alt="" /></th>
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<td><strong>Figure 3:</strong> Australian transgender teens’ reasons for declining fertility preservation in <a href="https://doi.org/10.1001/jamapediatrics.2020.0264">Pang et al. (2020)</a>.</td>
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<p>As such, there is no evidence-based reason to believe puberty blockers could cause infertility, with fertility returning when they are discontinued. However, due to low discontinuation rates for puberty blockers and low fertility preservation rates, those who start puberty blockers and persist are unlikely to have biological children. Clinical guidelines recommend that adolescents seeking puberty blockers should be counselled on options for fertility preservation, and parents should be involved in this (<a href="https://doi.org/10.1210/jc.2017-01658">Hembree et al., 2017</a>).</p>
|
||
|
||
<h2 id="bone-density">Bone Density</h2>
|
||
|
||
<p><a href="https://en.wikipedia.org/wiki/Bone_mineral_density">Bone density</a> is a measure of the amount of <a href="https://en.wikipedia.org/wiki/Bone_mineral">bone mineral</a> present in bone tissue. Bone density is measured using imaging techniques, such as <a href="https://en.wikipedia.org/wiki/Dual-energy_X-ray_absorptiometry">DEXA scans</a>: a type of X-ray. It is used to predict patients’ risk of breaking bones. The clinical terms for low bone density are <a href="https://en.wikipedia.org/wiki/Osteopenia">osteopenia</a>, and in more severe cases, <a href="https://en.wikipedia.org/wiki/Osteoporosis">osteoporosis</a>, which is common among the elderly. For the purposes of this review, the most relevant measurement of bone density is the <a href="https://en.wikipedia.org/wiki/Bone_density#Z-score">z-score</a>, which expresses a patient’s bone density in comparison to other people of the same age and sex. A z-score of 0 indicates bone density equal to the general population. Small deviations, such as -0.2, may not always be relevant, but z-scores below -1 may be cause for concern.</p>
|
||
|
||
<p>There are concerns around the effects of puberty blockers on bone health. Puberty is a critical time for the accrual of bone density: a process largely driven by sex hormones. This process is delayed in those receiving puberty blockers, leading to temporary lower bone density and z-scores compared to peers going through puberty normally. While these short-term z-scores are not particularly relevant, long-term outcomes are very important: the question becomes what z-scores look like in the long term, into adulthood, and whether the use of puberty blockers has any impact on later-life fracture risk. Literature on this is uncertain.</p>
|
||
|
||
<p><a href="https://doi.org/10.1210/jc.2014-2439">Klink et al. (2015)</a> finds that in both trans girls and trans boys, z-scores are lower both before treatment, and after long-term follow-up. The study suggests a small negative effect on final bone density from the use of puberty blockers, although many measurements fail to reach statistical significance. The study records notably lower final z-scores for trans girls than trans boys.</p>
|
||
|
||
<p><a href="https://doi.org/10.1016/j.bone.2016.11.008">Vlot et al. (2017)</a> finds that 2 years after beginning hormone therapy, z-scores were returning towards normal. In trans boys, final z-scores were negligibly lower, while in trans girls, the effect was much more pronounced, with meaningfully lower z-scores both before and after treatment.</p>
|
||
|
||
<p>In line with this, <a href="https://doi.org/10.1210/clinem/dgaa604">Schagen et al. (2020)</a> finds that in its cohort, final z-scores normalised after 3 years of hormone therapy for trans boys, while they remained meaningfully low both before and after treatment for trans girls.</p>
|
||
|
||
<table>
|
||
<thead>
|
||
<tr>
|
||
<th><htmlprotect><a href="/assets/images/puberty-blockers/bone-density.png" target="_blank" style="background-image: none;"><img src="/assets/images/puberty-blockers/bone-density.png" /></a></htmlprotect></th>
|
||
</tr>
|
||
</thead>
|
||
<tbody>
|
||
<tr>
|
||
<td><strong>Figure 4:</strong> Bone Mineral Apparent Density (BMAD) of the <a href="https://en.wikipedia.org/wiki/Lumbar_vertebrae">lumbar spine</a> across multiple studies, relative to sex assigned at birth. Three measurements are taken in each study: the initiation of puberty blockers, the initiation of hormone therapy, and one measurement after several years of hormone therapy. A z-score below -1 is commonly considered to be clinically relevant osteopenia, while a score below -2.5 is considered to be osteoporosis. The figure illustrates that trans girls tend to have significantly lower bone density before, during, and after treatment, while this is not the case for trans boys. Trans girls also tend to receive puberty blockers for a longer time.</td>
|
||
</tr>
|
||
</tbody>
|
||
</table>
|
||
|
||
<p><a href="https://doi.org/10.1530/eje-15-0590">Guaraldi et al. (2016)</a> find in their literature review that in those receiving puberty blockers for precocious puberty, bone mineral density is lower than that of untreated peers during treatment with puberty blockers, then typically recovers when puberty is initiated, with long-term follow-up showing little difference to the general population. Combined with the results of trans boys, this suggests that not puberty blockers themselves, but rather, subsequent suboptimal hormone therapy in trans girls could potentially be to blame for their more pronounced negative outcomes.</p>
|
||
|
||
<p>The hormone therapy prescribed to trans girls in the listed studies may be suboptimal in several ways. To begin with, all three use very low adult maintenance dosages of no more than 2 mg oral estradiol in transfeminine patients. Such a dose is likely to produce serum estradiol levels of roughly 50 pg/ml on average: below the average estradiol exposure of cis women (<a href="/articles/transfem-intro/">Aly, 2018</a>; <a href="/articles/e2-equivalent-doses/">Aly, 2020</a>). Many clinical guidelines recommend higher levels, which some research suggests could have a small positive effect on final bone density compared to lower dosages (<a href="https://pubmed.ncbi.nlm.nih.gov/9513613/">Roux, 1997</a>; <a href="https://doi.org/10.1038/psp.2012.10">Riggs et al., 2012</a>). Indeed, the authors of all three studies themselves note their doses were low and may have been inadequate for optimal bone density.</p>
|
||
|
||
<p>Also significantly, all studies use oral estrogens. Oral estrogens significantly reduce <a href="https://en.wikipedia.org/wiki/Insulin-like_growth_factor_1">IGF-1</a> levels (<a href="https://doi.org/10.1530/eje-11-0560">Isotton et al., 2012</a>; <a href="https://doi.org/10.1016/j.ghir.2016.09.001">Southmayd &amp; De Souza, 2017</a>), which is thought to play a vital role in bone density accrual, and strongly correlates with bone density (<a href="https://doi.org/10.1210/jc.2013-3921">Barake, Klibanski &amp; Tritos, 2014</a>; <a href="https://doi.org/10.1155/2014/235060">Locatelli &amp; Bianchi, 2014</a>; <a href="https://doi.org/10.4103/2230-8210.167549">Ekbote et al., 2015</a>; <a href="https://doi.org/10.1016/j.mce.2015.09.017">Lindsey &amp; Mohan, 2016</a>; <a href="https://doi.org/10.1007/s12020-017-1440-0">Barake et al., 2018</a>). Some experts have recommended transdermal estrogens over oral estrogens to improve bone density outcomes in girls suffering from <a href="https://en.wikipedia.org/wiki/Turner_syndrome">Turner syndrome</a> (<a href="https://doi.org/10.1210/jc.2009-0926">Davenport, 2010</a>), and tentative evidence appears to support the practise (<a href="https://doi.org/10.4158/ep161622.or">Zaiem et al., 2017</a>). As such, while not currently discussed in most clinical guidelines, the prevalence of oral estrogens in transgender teens is a concern, and avoiding them in favour of transdermal estrogens could lead to improved final bone density.</p>
|
||
|
||
<p>As a final confounding factor, none of the studies control for lifestyle factors associated with lower bone density, such as exercise, smoking, vitamin D, and calcium intake. These factors have a significant effect on bone density. Transgender people are more likely to smoke, less likely to exercise, and less likely to consume adequate calcium, both as teens and as adults (<a href="https://doi.org/10.1123/jpah.2017-0298">Jones et al., 2018</a>; <a href="https://doi.org/10.1089/lgbt.2018.0103">Kidd, Dolezal &amp; Bockting, 2018</a>). This is believed to be the reason transgender people of all ages tend to have lower bone density before any treatment is initiated. Without controlling for these factors, which may distort the available data significantly, it’s difficult to draw confident conclusions from these studies, and a causal link between the use of puberty blockers and lower final bone density remains unproven. If such a link does exist, the effect seems unlikely to be dramatic, and unlikely to outweigh the benefits of puberty blockers.</p>
|
||
|
||
<p>In a noteworthy study, <a href="https://doi.org/10.1210/jc.2002-021154">Antoniazzi et al. (2003)</a> report that in those receiving puberty blockers for precocious puberty, bone mineral density is better preserved through calcium supplementation. Calcium intake is often inadequate in transgender youth (<a href="https://doi.org/10.1210/jendso/bvaa065">Lee et al., 2020</a>), and therefore warrants further study for improving their bone mineral density. Alongside calcium, lifestyle interventions, the use of transdermal instead of oral estrogens, and the avoidance of subphysiological adult dosages of estradiol could all potentially improve bone-related outcomes over current clinical practise.</p>
|
||
|
||
<h2 id="iq-and-cognitive-development">IQ and Cognitive Development</h2>
|
||
|
||
<p>One possible concern is the impact of puberty blockers on IQ and cognitive development. Very little research on the subject exists, with commonly cited critical studies investigating sheep rather than humans (<a href="https://doi.org/10.1016/j.psyneuen.2016.11.029">Hough et al., 2017</a>), or being case studies of a single patient (<a href="https://doi.org/10.3389/fnhum.2017.00528">Schneider et al., 2017</a>). Only two larger studies investigate this:</p>
|
||
|
||
<p><a href="https://doi.org/10.1016/j.psyneuen.2015.03.007">Staphorsius et al. (2015)</a>, the only study to investigate this in a transgender population, evaluated performance in the standardised <a href="https://en.wikipedia.org/wiki/Tower_of_London_test">Tower of London test</a>, as well as IQ scores. The study found no significant differences in executive functioning between the two groups. IQ was slightly lower in transgender girls receiving puberty suppression than the control group, but the same was not true in a statistically relevant way of transgender boys. Age differences, lifestyle factors, and a very low sample size may all explain these differences.</p>
|
||
|
||
<p><a href="https://doi.org/10.3389/fpsyg.2016.01053">Wojniusz et al. (2016)</a> assessed 15 girls suffering from precocious puberty and treated with a puberty blocker. The 15 girls were compared with 15 age-matched controls. Both groups showed similar IQ scores.</p>
|
||
|
||
<p>Neither study has very many participants, records baseline cognitive performance, or controls for confounding factors. As such, very few conclusions can be drawn from them. Decades of clinical experience with the use of puberty blockers in children suggests it’s unlikely any particularly dramatic effect on IQ exists, but without much larger, higher quality studies, no conclusion on this can be reached, and further research is needed.</p>
|
||
|
||
<h2 id="desistance">Desistance</h2>
|
||
|
||
<p>Discontinuation rates for patients on puberty blockers are very low, with fewer than 5% of teens typically stopping them without going on to hormone therapy (<a href="https://doi.org/10.1016/j.jsxm.2018.01.016">Wiepjes et al., 2018</a>; <a href="https://doi.org/10.1007/s10508-020-01660-8">Brik et al., 2020</a>; <a href="https://doi.org/10.1542/peds.2019-3006">Kuper et al., 2020</a>). A potential concern is that this could mean puberty blockers put children on an almost guaranteed path towards gender transition, when they might otherwise change their minds.</p>
|
||
|
||
<p>Surprisingly, while a commonly held belief suggests most gender dysphoric children will grow out of it without treatment at a later age, little convincing evidence supports this claim. While existing studies report desistance rates ranging from 43% (<a href="https://doi.org/10.1097/chi.0b013e31818956b9">Wallien &amp; Cohen-Kettenis, 2008</a>) to 88% (<a href="https://doi.org/10.1037/0012-1649.44.1.34">Drummond et al., 2008</a>), they often contain significant methodological issues.</p>
|
||
|
||
<p>Historically, in the 20th century, a transgender identity was viewed as a negative outcome: it was something for a patient to be cured of, for example through aversion therapy. Since then, a cultural shift towards transgender people has taken place. Older studies into desistance rates are often reflective of this. As an example, <a href="https://doi.org/10.5694/j.1326-5377.1987.tb120415.x">Kosky (1987)</a> describes eight boys who were hospitalised in a psychiatric unit for displaying effeminate behaviour and cross-dressing, where they received intensive treatment aimed at curing them. Today, these behaviours are more accepted, and they are not necessarily viewed as the same thing as a transgender gender identity. Clearly, a study like this cannot be used to estimate the desistance rates of today’s gender dysphoric children.</p>
|
||
|
||
<p>Other studies describing the 1960s through 1980s are similar (<a href="https://pubmed.ncbi.nlm.nih.gov/5641781/">Bakwin, 1968</a>; <a href="https://doi.org/10.1176/ajp.128.10.1283">Lebovitz, 1972</a>; <a href="https://doi.org/10.1016/0010-440x(78)90019-6">Zuger, 1978</a>; <a href="https://doi.org/10.1093/jpepsy/4.1.29">Money &amp; Russo, 1979</a>; <a href="https://doi.org/10.1007/bf01542316">Davenport, 1986</a>). Many predate the <a href="https://en.wikipedia.org/wiki/Diagnostic_and_Statistical_Manual_of_Mental_Disorders#DSM-III_(1980)">DSM-III</a>, and thus the existence of formal diagnostic criteria. Few studied self-reported gender identity: instead, they tend to study gender non-conforming behaviour, such as cross-dressing, that doesn’t necessarily constitute a transgender identity. Many of them try to discourage patients as a core part of their treatment, sometimes in ways that are now banned across much of the world as <a href="https://en.wikipedia.org/wiki/Conversion_therapy">conversion therapy</a>. Combined with a drastically changed society, extrapolating modern transgender desistance rates from these studies is unreasonable.</p>
|
||
|
||
<p>A small number of more recent studies do exist. The highest desistance rates found in modern literature are approximately 88%, reported by three frequently cited Canadian studies: <a href="https://doi.org/10.1037/0012-1649.44.1.34">Drummond et al. (2008)</a>, <a href="https://doi.org/10.1080/0092623x.2017.1340382">Drummond et al. (2018)</a>, and <a href="https://doi.org/10.3389/fpsyt.2021.632784">Singh, Bradley &amp; Zucker (2021)</a>. Unfortunately, these studies appear to be at a high risk of bias: calling their credibility into question, the clinic in which they took place was closed in 2015, amidst allegations of conversion therapy. An independent <a href="https://www.transadvocate.com/wp-content/uploads/GIC-Review-26Nov2015-TA1.pdf">review</a> found that it “cannot state that the clinic does not practice reparative approaches.” In the review, many children and their parents report feeling the clinic was invasive and intimidating to them. Some instances include:</p>
|
||
|
||
<blockquote>
|
||
<p>Assessments are described as intrusive and even traumatic by some, who described feeling “poked and prodded”. One way mirror and multiple observers create discomfort. Many questions were felt to be irrelevant, unnecessarily intrusive (particularly those regarding sexual fantasies), especially when asked without context, rationale, and what seems to be inadequate or even absent informed consent. Also, it is unclear whether any potential benefit of this line of questioning to the patient was explained. Parents of younger clients report their child appearing to be and later reporting feeling they were very uncomfortable with the way they were asked about their gender variance “as if my child was not okay as a person.” One parent described feeling “dismissed” when she spoke to clinicians about this.</p>
|
||
</blockquote>
|
||
|
||
<blockquote>
|
||
<p>Patients reported feeling intimidated to question Dr. Zucker regarding their concerns and were not offered the opportunity to decline. Multiple informants commented on this.</p>
|
||
</blockquote>
|
||
|
||
<blockquote>
|
||
<p>Chart documentation revealed statements reflecting that the diversity of gender expression and variance are not accepted equally. One example is of a child for whom all gender and body dysphoria had resolved and multiple informants indicated sustained good mood and satisfaction with social and academic functioning. Despite this, the parents of the child were advised at discharge to encourage the child to spend more time with cisgendered boys because he had effeminate speech and mannerisms. These were not goals of the client or family.</p>
|
||
</blockquote>
|
||
|
||
<p>This may explain why these studies find a much higher desistance rate than other modern literature, and makes them very unlikely to be representative figures. As an alternative possibility, <a href="https://doi.org/10.1080/15532739.2018.1468292">Steensma &amp; Cohen-Kettenis (2018)</a> suggest that differences in the local social climate regarding gender variance may have also been an important contributing factor.</p>
|
||
|
||
<p><a href="https://doi.org/10.1177/1359104510378303">Steensma et al. (2011)</a> and <a href="https://doi.org/10.1016/j.jaac.2013.03.016">Steensma et al. (2013)</a> set out to investigate factors that could contribute to the persistence or desistance of gender dysphoria in children. The 2011 study reports a desistance rate of 45%, while the 2013 study reports 73%. The figures have been criticised because all children lost to follow-up are assumed to have desisted, which may or may not have inflated their number. More importantly however, in <a href="https://doi.org/10.1080/15532739.2018.1468292">Steensma &amp; Cohen-Kettenis (2018)</a>, the authors themselves argue they’ve been cited out of context, and their figures can’t be used to extrapolate desistance rates:</p>
|
||
|
||
<blockquote>
|
||
<p>Unlike what is suggested, we have not studied the gender identities of the children. Instead we have studied the persistence and desistence of children’s distress caused by the gender incongruence they experience to the point that they seek clinical assistance.
|
||
[…]
|
||
Using the term desistence in this way does not imply anything about the identity of the desisters. The children could still be hesitating, searching, fluctuating, or exploring with regard to their gender experience and expression, and trying to figure out how they wanted to live. Apparently, they no longer desired some form of gender-affirming treatment at that point in their lives.</p>
|
||
</blockquote>
|
||
|
||
<blockquote>
|
||
<p>Again, because of the purpose and the design of this study we did not report prevalence numbers in the sample under study. Furthermore, the sample in the 2013 study did not include children in the younger age spectrum of the referred population to the Amsterdam clinic. Reporting prevalence of persistence and/or desistance in this sample would therefore not be reliable.</p>
|
||
</blockquote>
|
||
|
||
<p>The only other modern study into persistence rates has been <a href="https://doi.org/10.1097/chi.0b013e31818956b9">Wallien &amp; Cohen-Kettenis (2008)</a>. The study appears to be of higher quality and provides the most convincing estimate available: a 27% persistence rate and a 43% desistance rate over the course of (on average) 10 years. The remaining 30% of participants were lost to follow-up.</p>
|
||
|
||
<p>Several further problems cast doubt on the data presented in all of these studies, including <a href="https://doi.org/10.1097/chi.0b013e31818956b9">Wallien &amp; Cohen-Kettenis (2008)</a>. Firstly: children are diagnosed using DSM-III and DSM-IV criteria, which are dated by today’s standards. In these older criteria, gender identity was not a diagnostic requirement: a child could be diagnosed with a gender identity disorder for a range of gender non-conforming behaviours, without themselves identifying as a different gender, or experiencing distress with their gender role or sex characteristics (<a href="https://doi.org/10.1080/15532739.2018.1456390">Temple Newhook et al., 2018</a>).</p>
|
||
|
||
<p>Strikingly, with the exception of <a href="https://doi.org/10.1177/1359104510378303">Steensma et al. (2011)</a>, all studies include a significant number of children who never actually met then-current DSM diagnostic criteria for Gender Identity Disorder: in the case of <a href="https://doi.org/10.1097/chi.0b013e31818956b9">Wallien &amp; Cohen-Kettenis (2008)</a>, a quarter of all participants. These participants have been assumed to be transgender for the purposes of extrapolating desistance rates, but held a diagnosis of Gender Identity Disorder Not Otherwise Specified: a broad category described by the DSM as representing those who may not necessarily seek medical transition, but may transiently cross-dress, be preoccupied with castration, or be <a href="https://en.wikipedia.org/wiki/Intersex">intersex</a> and experience gender dysphoria. These participants’ exact circumstances are not described by the researchers, but both Wallien &amp; Cohen-Kettenis and Steensma et al. report in their studies that all, or nearly all persisters met DSM diagnostic criteria, while only about half of desisters did.</p>
|
||
|
||
<p>Outside of this, there is a lack of long-term follow-up. A gender dysphoric child might desist in transitioning during their teens, but go on to transition in adulthood, for example because of peer pressure or lack of parental acceptance. Whether this happens at any significant rate has not been studied.</p>
|
||
|
||
<p>The studies do suggest that for an unknown percentage of children, gender dysphoria will resolve over time, but the high desistance rates often cited as an established fact don’t appear to be supported by evidence. Concerns that puberty blockers cause children to transition when they otherwise would’ve aged out of gender dysphoria appear misplaced: children whose dysphoria persisted were much more likely to have met the diagnostic criteria to receive puberty blockers.</p>
|
||
|
||
<p>Current literature on this will likely soon be superseded by higher-quality data, with several very large, well-funded studies into gender dysphoric youth now underway the United States (<a href="https://doi.org/10.2196/14434">Olson-Kennedy et al., 2019</a>), Australia (<a href="http://doi.org/10.1136/bmjopen-2019-032151">Tollit et al., 2019</a>) and the United Kingdom (<a href="https://doi.org/10.1136/bmjopen-2020-045628">Kennedy et al., 2019</a>).</p>
|
||
|
||
<p>Desistance and persistence rates can suggest a binary view, and should be seen in a greater context. Because children’s needs change over time, a hypothetical child might feel uncertain about their gender, possibly even receive puberty blockers, and then later decide they do not wish to transition. In such a case, puberty blockers may have met their needs at the time, and were not automatically harmful or regrettable, particularly due to their reversible nature. Neither being transgender, nor being cisgender should be seen as a negative outcome. In their critical commentary, <a href="https://doi.org/10.1080/15532739.2018.1456390">Temple Newhook et al. (2018)</a> write that it is important to respect children’s wishes and autonomy, and move away from the question of, “How should children’s gender identities develop over time?” toward a more useful question: “How should children best be supported as their gender identity develops?”</p>
|
||
|
||
<h2 id="regret">Regret</h2>
|
||
|
||
<p>In light of persistence and desistance rates, it makes sense to ask how patients themselves feel about their treatment with puberty blockers, and whether they regret receiving them. Limited research exists on the subject:</p>
|
||
|
||
<p>A large retrospective review of the medical files of all 6,793 patients treated at the Dutch VUmc clinic between 1972 and 2015 found that 14 patients (0.2%) regretted their treatment in total. This included patients who received puberty suppression, hormone therapy, and/or surgery. Notably, 5 of them regretted their treatment because of a lack of social acceptance (<a href="https://doi.org/10.1016/j.jsxm.2018.01.016">Wiepjes et al., 2018</a>).</p>
|
||
|
||
<p><a href="https://doi.org/10.1542/peds.2013-2958">De Vries et al. (2014)</a>, found none of the 55 transgender patients they followed regretted receiving puberty blockers, hormone therapy, or surgery. Psychological well-being continued to improve in their cohort, both with puberty blockers, hormone therapy, and later gender reassignment surgery.</p>
|
||
|
||
<p><a href="https://doi.org/10.1007/s10508-016-0764-9">Vrouenraets et al. (2016)</a> interviewed 13 adolescents who had been seen at a Dutch gender identity clinic, twelve of whom had received puberty blockers. Asked about long-term risks, most responded that they were significantly outweighed by puberty blockers allowing them to live a more happy life. Quotes from the interviewed children in the study include:</p>
|
||
<blockquote>
|
||
<p>The possible long-term consequences are incomparable with the unhappy feeling that you have and will keep having if you don’t receive treatment with puberty suppression. (trans boy; age: 18)</p>
|
||
</blockquote>
|
||
|
||
<blockquote>
|
||
<p>It isn’t a choice, even though a lot of people think that. Well, actually it is a choice: living a happy life or living an unhappy life. (trans girl; age: 14)</p>
|
||
</blockquote>
|
||
|
||
<p>They also comment on the increasing attention to transgender people in media, with one child saying:</p>
|
||
<blockquote>
|
||
<p>Thanks to media coverage I learned that gender dysphoria exists; that someone can have these feelings and that you can get treatment for it. Beforehand I thought I was the only one like this. (trans boy; age: 18)</p>
|
||
</blockquote>
|
||
|
||
<h2 id="ease-of-access">Ease of Access</h2>
|
||
|
||
<p>While large geographic differences exist, on the whole, access to puberty blockers is often difficult.</p>
|
||
|
||
<p>In the United States, <a href="https://doi.org/10.1542/peds.2019-1725">Turban et al. (2020)</a> found that access to puberty blockers was associated with a greater household income, noting that the annual cost of them ranges from $4,000 to $25,000 and insurance coverage was unavailable to many. It also found that transgender teens were less likely to receive puberty blockers if they did not identify as heterosexual or binary. Of those who received puberty blockers, 60% reported traveling &lt;25 miles for gender-affirming care, 29% travelled between 25 and 100 miles, and 11% travelled &gt;100 miles. As of 2021, several states are pursuing regulation banning the use of puberty blockers, with Arkansas having become the first to pass such a law. Several large professional bodies representing thousands of medical experts have condemned this type of regulation (<a href="https://www.aacap.org/AACAP/Latest_News/AACAP_Statement_Responding_to_Efforts-to_ban_Evidence-Based_Care_for_Transgender_and_Gender_Diverse.aspx">American Academy of Child and Adolescent Psychiatry, 2019</a>; <a href="https://www.ama-assn.org/delivering-care/population-care/raft-bills-intrude-medical-practice-harm-transgender-people">American Medical Association, 2021</a>; <a href="https://www.endocrine.org/news-and-advocacy/news-room/2021/endocrine-society-condemns-efforts-to-block-access-to-medical-care-for-transgender-youth">Endocrine Society, 2021</a>).</p>
|
||
|
||
<p>In the United Kingdom, waiting lists as long as <a href="https://gic.nhs.uk/appointments/waiting-times/">4 years or more</a> exist for initial intake appointments for puberty blockers. Legislative changes in light of <em>Bell v. Tavistock</em> complicated access dramatically: in the nine months between the ruling and its reversal, <a href="https://inews.co.uk/news/health/transgender-young-people-nhs-hormone-treatment-puberty-blockers-transition-1205675">no under-17s</a> received puberty blockers under the public healthcare sytem, and <a href="https://inews.co.uk/news/gids-tavistock-gender-hormone-treatment-clinician-trans-800657">reports described</a> the care of adolescents over 16, who were not affected by the judgement, being discontinued as well. Restrictions in light of <em>Bell v. Tavistock</em> were condemned by WPATH, EPATH, USPATH, AsiaPATH, CPATH, AusPATH, and PATHA, the leading medical associations for transgender health, who released a statement saying they believe it will cause significant harm to the affected patients (<a href="https://www.wpath.org/media/cms/Documents/Public%20Policies/2020/FINAL%20Statement%20Regarding%20Informed%20Consent%20Court%20Case_Dec%2016%202020.docx.pdf">WPATH, 2020</a>), as well as Amnesty International UK and Liberty (<a href="https://www.amnesty.org.uk/press-releases/amnesty-international-uk-and-liberty-joint-statement-puberty-blockers">Amnesty International UK, 2020</a>).</p>
|
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|
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<p>In Sweden, the Astrid Lindgren Children’s Hospital, a part of the <a href="https://en.wikipedia.org/wiki/Karolinska_University_Hospital">Karolinska University Hospital</a>, has recently <a href="https://segm.org/Sweden_ends_use_of_Dutch_protocol">stopped prescribing puberty blockers</a>, citing the <em>Bell v. Tavistock</em> case as their motivation.</p>
|
||
|
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<p>In Finland, new prescriber guidelines for treating gender dysphoric teens were released in 2020 (<a href="https://segm.org/Finland_deviates_from_WPATH_prioritizing_psychotherapy_no_surgery_for_minors">Society for Evidence Based Medicine, 2021</a>). They broke with WPATH guidelines, instead recommending that gender dysphoric teens receive psychosocial support and psychotherapy as a first-line treatment, and discouraging the use of puberty blockers, with the addition of much stricter criteria for their use. The Finnish health authority has stated that these recommendations will not be revised until further research is available.</p>
|
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|
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<p>A similar trend of increasing wait times and difficult access holds in many other countries, with the process to receive puberty blockers sometimes taking up to several years. Because of their time-sensitive nature in preventing unwanted permanent changes, long-term outcomes are likely to be worse with slower treatment. Some evidence supports this: for example, one study found that reducing treatment wait times led to reduced depression and anxiety compared to historical controls (<a href="https://doi.org/10.1542/peds.2020-042762">Dahlgren Allen et al., 2021</a>).</p>
|
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|
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<h2 id="conclusion">Conclusion</h2>
|
||
|
||
<p>Unknowns exist around puberty blockers in transgender youth, but their risks seem to be relatively minor based on available research, while clear evidence associates their use with improved well-being, psychological functioning, and reduced suicidality.</p>
|
||
|
||
<p>Based on parallels from research in cisgender teens treated for precocious puberty, as well as limited studies and clinical experience with transgender teens, it’s unlikely that puberty suppression has a dramatic negative effect on children’s final bone density, lifetime fracture risk, IQ, or cognitive development when prescribed in line with medical guidelines. However, there is insufficient evidence to determine whether or not they have any impact at all.</p>
|
||
|
||
<p>Although not supported by conclusive evidence, the use of puberty blockers may have a modest negative impact on bone density. This could be related to the use of puberty blockers themselves, but could also be related to suboptimal hormone therapy regimens after their use, particularly in transgender girls, as well as lifestyle factors. Studies investigating this suffer from significant methodological issues, and a definitive causal link remains unproven. Based on limited evidence, prescribers may wish to consider calcium supplementation in transgender teens receiving puberty blockers, and may wish to avoid oral estrogens in transgender girls beginning hormone therapy.</p>
|
||
|
||
<p>Compared to their cisgender peers, transgender adolescents who take puberty blockers are less likely to choose to have biological children, but puberty blockers do not permanently affect fertility.</p>
|
||
|
||
<p>Widely cited statistics around children growing out of gender dysphoria (“desistance”) as they grow older are based on highly unreliable data. Surprisingly, based on current evidence, we cannot reasonably guess the rate at which this happens. Regardless, desistance rates are not an argument for or against the use of puberty blockers. It is important to respect children’s wishes and autonomy, and to find the best way to support them as their gender identity develops, without imposing the idea that either a transgender or a cisgender gender identity is a bad outcome.</p>
|
||
|
||
<p>Very few patients who receive puberty blockers experience regret. In broader context, for the small minority of adult transgender patients who report feeling regret after undergoing hormone therapy or surgery, a common reason for that is a lack of social acceptance.</p>
|
||
|
||
<p>More high-quality research is urgently needed in this field. In particular, the effects of puberty blockers on IQ and cognitive development, bone outcomes, and desistance remain understudied subjects. Randomised controlled trials on puberty blockers are not available, and likely cannot be performed for both practical and ethical reasons. This should not be seen as a reason to discard all other research on the subject, or to label their use as experimental, as it is a standard of evidence that can never be met.</p>
|
||
|
||
<p>Puberty blockers are extremely difficult for patients to access in many countries, including the United States, the United Kingdom, and parts of Europe. Several countries have recently banned their use, or further restricted it significantly. This review provides further evidence supporting WPATH, EPATH, USPATH, AsiaPATH, CPATH, AusAPTH, PATHA, the Endocrine Society, the American Academy of Child and Adolescent Psychiatry, and the American Medical Association in condemning recent attempts to bar transgender teens from receiving gender-affirming care, including puberty blockers. To better support gender dysphoric children, barriers of access should instead be reduced where possible.</p>
|
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|
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<h2 id="references">References</h2>
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||
|
||
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</ul></content><author><name>{"first_name"=>"Mitzi", "author-link"=>"/about/#mitzi", "articles-link"=>"/articles-by-author/mitzi/", "email"=>"mitzi@transfemscience.org"}</name><email>mitzi@transfemscience.org</email></author><category term="github" /><category term="workspace" /><summary type="html">Puberty Blockers: A Review of GnRH Analogues in Transgender Youth By Mitzi | First published January 30, 2022 | Last modified January 31, 2022</summary></entry><entry><title type="html">An Interactive Web Simulator for Estradiol Levels with Injectable Estradiol Esters</title><link href="https://transfemscience.org/articles/injectable-e2-simulator-release/" rel="alternate" type="text/html" title="An Interactive Web Simulator for Estradiol Levels with Injectable Estradiol Esters" /><published>2021-07-16T12:00:00-07:00</published><updated>2023-04-12T00:00:00-07:00</updated><id>https://transfemscience.org/articles/injectable-e2-simulator-release</id><content type="html" xml:base="https://transfemscience.org/articles/injectable-e2-simulator-release/"><h1 id="an-interactive-web-simulator-for-estradiol-levels-with-injectable-estradiol-esters">An Interactive Web Simulator for Estradiol Levels with Injectable Estradiol Esters</h1>
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<!-- Supports up to four authors per article currently (author, author2, author3, author4) -->
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<p>By
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<!-- First author --><a href="/about/#aly">Aly</a><!-- Second author --><!-- Third author --><!-- Fourth author --> | First published July 16, 2021
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| Last modified April 12, 2023</p>
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<p><strong>Links to go straight to the simulator: <a href="/misc/injectable-e2-simulator/">Original Simulator</a> and <a href="/misc/injectable-e2-simulator-advanced/">Advanced Simulator</a></strong></p>
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<p>Estradiol is frequently used in <a href="https://en.wikipedia.org/wiki/Injection_(medicine)">injectable</a> form in transfeminine hormone therapy. <a href="https://en.wikipedia.org/wiki/Injectable_estradiol_ester">Injectable estradiol</a> is employed in the form of <a href="https://en.wikipedia.org/wiki/Estrogen_ester">estradiol esters</a> such as <a href="https://en.wikipedia.org/wiki/Estradiol_valerate">estradiol valerate</a> and <a href="https://en.wikipedia.org/wiki/Estradiol_cypionate">estradiol cypionate</a>, which are <a href="https://en.wikipedia.org/wiki/Prodrug">prodrugs</a> of estradiol that are slowly released from a <a href="https://en.wikipedia.org/wiki/Depot_injection">depot</a> formed at the injection site. These esters are most commonly formulated as <a href="https://en.wikipedia.org/wiki/Oil_solution">oil solutions</a> and are administered via <a href="https://en.wikipedia.org/wiki/Intramuscular_injection">intramuscular</a> or <a href="https://en.wikipedia.org/wiki/Subcutaneous_injection">subcutaneous injection</a>. Injectable estradiol is a popular choice among transfeminine people as well as some clinical providers as it has a number of advantages over other estradiol routes and forms. For instance, it allows for easy and inexpensive attainment of higher estradiol levels that can be useful in transfeminine people for achieving better <a href="https://en.wikipedia.org/wiki/Pharmacodynamics_of_estradiol#Antigonadotropic_effects">testosterone suppression</a>. This is particularly true in the case of estradiol monotherapy, a therapeutic approach in which an antiandrogen isn’t employed.</p>
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<p>Clinically used injectable estradiol preparations were developed many decades ago and are not as commonly used in medicine as estradiol preparations like <a href="https://en.wikipedia.org/wiki/Oral_estradiol">oral</a> and <a href="https://en.wikipedia.org/wiki/Transdermal_estradiol">transdermal estradiol</a>. In fact, injectable estradiol has been discontinued in many countries in favor of non-injectable preparations. In relation to the preceding, research and review material on the <a href="https://en.wikipedia.org/wiki/Pharmacokinetics">pharmacokinetics</a> of these preparations are limited and are scattered throughout the scientific literature. For most of the published <a href="https://en.wiktionary.org/wiki/concentration-time_curve">concentration–time curves</a> of circulating estradiol with injectable estradiol esters, only a single injection has been administered and the different doses that have been employed have been few. The scarce and obscure information on the pharmacokinetics of these formulations presents challenges for transfeminine people and their clinicians when it comes to understanding the estradiol levels that may result with injectable estradiol preparations. This is particularly true in relation to repeated injections of injectable estradiol formulations at varying doses and injection intervals, which is how these preparations are used in transfeminine hormone therapy. A proper understanding of the estradiol levels with injectable estradiol is important for transfeminine people for avoiding estradiol levels that are too low—which can result in inadequate testosterone suppression and therapeutic efficacy—while also avoiding estradiol levels that are too high—which may produce unnecessary side effects and risks (e.g., <a href="/articles/estrogens-blood-clots/">Aly, 2020</a>).</p>
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<p>To help with overcoming these obstacles, I’ve developed an interactive web app for simulating estradiol levels with injectable estradiol preparations. This simulator can be found at the following page:</p>
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<ul>
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<li><a href="/misc/injectable-e2-simulator/">Injectable Estradiol Simulator - Transfeminine Science</a></li>
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</ul>
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<p>Here is a screenshot of the simulator that shows what it looks like and what it can do:</p>
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<style type="text/css">
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#simulator-screenie {
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content: url("https://transfemscience.org/assets/images/injectable-e2/simulator-screenie.png");
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}
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@media only screen {
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html[data-theme='dark'] #simulator-screenie {
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content: url("https://transfemscience.org/assets/images/injectable-e2/simulator-screenie-dark.png");
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}
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}
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</style>
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<table>
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||
<tbody>
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||
<tr>
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<td><a href="https://transfemscience.org/misc/injectable-e2-simulator/?e=all_e2&amp;d=7&amp;r=y&amp;di=10&amp;xm=60&amp;lh=bp" target="_blank"><img id="simulator-screenie" class="no-invert" /></a></td>
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</tr>
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</tbody>
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</table>
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<p>The app simulates estradiol levels with a selection of major injectable estradiol preparations. These preparations include injectable <a href="https://en.wikipedia.org/wiki/Estradiol_benzoate">estradiol benzoate</a> (EB) in oil, <a href="https://en.wikipedia.org/wiki/Estradiol_valerate">estradiol valerate</a> (EV) in oil, <a href="https://en.wikipedia.org/wiki/Estradiol_cypionate">estradiol cypionate</a> (EC) in oil and as a <a href="https://en.wikipedia.org/wiki/Microcrystalline">microcrystalline</a> <a href="https://en.wikipedia.org/wiki/Suspension_(chemistry)">aqueous suspension</a>, <a href="https://en.wikipedia.org/wiki/Estradiol_enanthate">estradiol enanthate</a> (EEn) in oil, <a href="https://en.wikipedia.org/wiki/Estradiol_undecylate">estradiol undecylate</a> (EU) in oil, and <a href="https://en.wikipedia.org/wiki/Polyestradiol_phosphate">polyestradiol phosphate</a> (PEP). Options are available in the simulator for specifying injectable estradiol dose (mg), single versus repeated injections, injection interval (days, weeks, or months), units for estradiol concentrations (pg/mL or pmol/L), x-axis maximum value (or time interval to graph) (days), and y-axis max value (or estradiol concentration interval to graph) (pg/mL or pmol/L). One preparation can be simulated at a time or all of the supported injectable estradiol preparations can be graphed together at the same time. When all injectable preparations are simulated at once, the legend can be interacted with to hide or show individual preparations.</p>
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<p>The estradiol curves produced by the app are simulations based on available data from published studies with the supported injectable estradiol preparations. The accuracy of the curves is limited by the quality and quantity of these data. In other words, the curves are only estimates, and true estradiol levels with a given preparation may be different than what is shown. It is notable in this regard that estradiol curves with a given injectable estradiol preparation vary considerably between studies, with different levels and curve shapes apparent. There are many potential factors which may contribute to this variability, such as <a href="https://en.wikipedia.org/wiki/Pharmaceutical_formulation">formulation</a>, injection specifics (like <a href="https://en.wikipedia.org/wiki/Injection_site">injection site</a>, volume, and technique), <a href="https://en.wikipedia.org/wiki/Analytical_technique">the type and calibration of blood test used</a>, differing subject characteristics (like age, weight, etc.), and research matters like <a href="https://en.wikipedia.org/wiki/Sampling_error">sampling error</a>. The simulator is not able to take into account these potential variables as data on their influences are scarce and not well-defined. An assumption of the simulator is that estradiol levels and curve shapes scale linearly with dose, which may or may not actually be the case. Lastly, it must be made clear that the estradiol curves correspond to the averages of many people, and individual estradiol levels and curve shapes vary substantially even with the same injectable estradiol preparation. For these varied reasons, the simulator cannot tell a given person what their exact estradiol levels with a given injectable estradiol regimen will be. It can only be used as a guide to roughly estimate where one’s estradiol levels most plausibly could be. In relation to this, estradiol levels, as well as testosterone suppression, should be monitored and verified with blood work to ensure that they are in desired ranges.</p>
|
||
|
||
<p>A literature review and informal <a href="https://en.wikipedia.org/wiki/Meta-analysis">meta-analysis</a> of available estradiol concentration–time data with injectable estradiol preparations was conducted to determine the appropriate estradiol curves for the different estradiol esters included in the simulator. Data were collected from the literature, processed, and <a href="https://en.wikipedia.org/wiki/Scientific_modelling">modeled</a> using <a href="https://en.wikipedia.org/wiki/Pharmacokinetic_model">pharmacokinetic models</a>. This work can be found at the following page:</p>
|
||
|
||
<ul>
|
||
<li><a href="/articles/injectable-e2-meta-analysis/">An Informal Meta-Analysis of Estradiol Curves with Injectable Estradiol Preparations (Aly, 2021)</a></li>
|
||
</ul>
|
||
|
||
<p>The meta-analysis was not able to derive a reasonable curve for injectable estradiol undecylate due to lack of adequate published data for this ester for modeling. Because of the historical and theoretical importance of estradiol undecylate as an injectable estradiol ester however, it was desirable to nonetheless construct a curve of some form for estradiol undecylate so that it could be included in the simulator. In order to do this, a curve was instead fit to a well-known study for injectable <a href="https://en.wikipedia.org/wiki/Testosterone_undecanoate">testosterone undecanoate</a> (testosterone undecylate; TU) (<a href="https://doi.org/10.1530/eje.0.1400414">Behre et al., 1999</a>) and <a href="https://en.wikipedia.org/wiki/Area_under_the_curve_(pharmacokinetics)">area-under-the-curve</a> estradiol levels were scaled to be appropriate for those with a given dose of estradiol undecylate based on data with other injectable estradiol preparations. This approach is reasonable as estradiol undecylate and testosterone undecanoate have fairly similar <a href="https://en.wikipedia.org/wiki/Lipophilicity">fat solubilities</a> (<a href="https://files.transfemscience.org/pdfs/docs/Sex%20Hormone%20Ester%20Lipophilicity%20(Log%20P)%20Tables.pdf">Table</a>) due to being very similar in chemical structure and as fat solubility is the key property dictating the release rates and curve shapes of these preparations. Accordingly, the resulting curve for estradiol undecylate roughly accords with the reported clinical durations of this ester (<a href="https://en.wikipedia.org/w/index.php?title=Template:Potencies_and_durations_of_natural_estrogens_by_intramuscular_injection&amp;oldid=964345939">Table</a>). In any case, it should be cautioned that the estradiol undecylate curve is not based on real data for this estradiol ester and is only hypothetical or “just for fun”.</p>
|
||
|
||
<p>The simulator and the curves for the different injectable preparations included may be updated in the future with improvements and new features. Extension of the simulator to other <a href="https://en.wikipedia.org/wiki/Sex-hormonal_agent">hormonal preparations</a> like <a href="https://en.wikipedia.org/wiki/Injectable_testosterone">injectable testosterone</a>, <a href="https://en.wikipedia.org/wiki/Sublingual_estradiol">sublingual estradiol</a>, and <a href="https://en.wikipedia.org/wiki/Subcutaneous_estradiol_pellets">estradiol pellets</a> would be fairly straightforward and could be done in the future. However, it would require additional meta-analysis and much further work.</p>
|
||
|
||
<p>A special thank you to Violet and Lila for their indispensable input and guidance on modeling topics during the work on this project. An additional thanks to Violet for deriving a special three-compartment pharmacokinetic model that was used in the simulator. Please also check out Violet’s own work-in-progress <a href="https://github.com/tiliaqt/transkit/">TransKit</a> and <a href="https://github.com/tiliaqt/">Tilia</a> projects—pharmacokinetic tools tailored for transgender hormone therapy.</p>
|
||
|
||
<h2 id="updates">Updates</h2>
|
||
|
||
<h3 id="update-1-new-advanced-simulator">Update 1: New Advanced Simulator</h3>
|
||
|
||
<p>Since the release of the injectable estradiol simulator, a more advanced version of the simulator with additional options and functionality has been developed. This advanced simulator was created by <a href="/about/#luna">Luna</a> via modification of <a href="/about/#aly">Aly</a>’s original simulator code. It uses the same data (i.e. injectable estradiol curves) as the original simulator, but has the following new features: (1) simulate multiple traces at once; (2) stop after X doses (dose limit); (3) start trace at steady state; and (4) show cis woman menstrual cycle (median, 5th percentile, and 95th percentile estradiol levels; data from <a href="https://web.archive.org/web/20200127014925/http://www.ilexmedical.com/files/PDF/Estradiol_ARC.pdf">Abbott (2009)</a>). The advanced injectable estradiol simulator was released on October 5, 2022 and can be found at the following page:</p>
|
||
|
||
<ul>
|
||
<li><a href="/misc/injectable-e2-simulator-advanced/">Injectable Estradiol Simulator Advanced - Transfeminine Science</a></li>
|
||
</ul>
|
||
|
||
<p>Here is a screenshot of the advanced simulator and its capabilities:</p>
|
||
|
||
<style type="text/css">
|
||
#simulator-advanced-screenie {
|
||
content: url("https://transfemscience.org/assets/images/injectable-e2/simulator-advanced-screenie.png");
|
||
}
|
||
@media only screen {
|
||
html[data-theme='dark'] #simulator-advanced-screenie {
|
||
content: url("https://transfemscience.org/assets/images/injectable-e2/simulator-advanced-screenie-dark.png");
|
||
}
|
||
}
|
||
</style>
|
||
|
||
<table>
|
||
<tbody>
|
||
<tr>
|
||
<td><a href="https://transfemscience.org/misc/injectable-e2-simulator-advanced/?r=5&amp;e=22226&amp;d1=5&amp;d2=5&amp;d3=7&amp;d4=7&amp;d5=200&amp;ra=33330&amp;i1=7&amp;dl1=&amp;i2=7&amp;dl2=4&amp;i3=5&amp;dl3=&amp;i4=5&amp;dl4=&amp;s=e&amp;h=0&amp;xm=56&amp;cc=1" target="_blank"><img id="simulator-advanced-screenie" class="no-invert" /></a></td>
|
||
</tr>
|
||
</tbody>
|
||
</table>
|
||
|
||
<h3 id="update-2-literature-mentions">Update 2: Literature Mentions</h3>
|
||
|
||
<p>Since Transfeminine Science’s injectable estradiol simulator was released in mid-2021, it has been mentioned and cited in the scientific literature in a number of publications (see <a href="/articles/injectable-e2-meta-analysis/#update-2-literature-mentions">Aly, 2021</a>).</p>
|
||
|
||
<h2 id="references">References</h2>
|
||
|
||
<ul>
|
||
<li>Abbott Laboratories. (2009). <em>Estradiol. Architect System.</em> Abbott Park, Illinois/Wiesbaden, Germany: Abbott Laboratories. [<a href="https://web.archive.org/web/20200127014925/http://www.ilexmedical.com/files/PDF/Estradiol_ARC.pdf">PDF</a>]</li>
|
||
<li>Behre, H. M., Abshagen, K., Oettel, M., Hubler, D., &amp; Nieschlag, E. (1999). Intramuscular injection of testosterone undecanoate for the treatment of male hypogonadism: phase I studies. <em>European Journal of Endocrinology</em>, <em>140</em>(5), 414–419. [DOI:<a href="https://doi.org/10.1530/eje.0.1400414">10.1530/eje.0.1400414</a>]</li>
|
||
</ul></content><author><name>{"first_name"=>"Aly", "last_name"=>"W.", "author-link"=>"/about/#aly", "articles-link"=>"/articles-by-author/aly/"}</name></author><category term="github" /><category term="workspace" /><summary type="html">An Interactive Web Simulator for Estradiol Levels with Injectable Estradiol Esters By Aly | First published July 16, 2021 | Last modified April 12, 2023</summary><media:thumbnail xmlns:media="http://search.yahoo.com/mrss/" url="https://transfemscience.org/assets/images/injectable-e2/simulator-screenie.png" /><media:content medium="image" url="https://transfemscience.org/assets/images/injectable-e2/simulator-screenie.png" xmlns:media="http://search.yahoo.com/mrss/" /></entry><entry><title type="html">An Informal Meta-Analysis of Estradiol Curves with Injectable Estradiol Preparations</title><link href="https://transfemscience.org/articles/injectable-e2-meta-analysis/" rel="alternate" type="text/html" title="An Informal Meta-Analysis of Estradiol Curves with Injectable Estradiol Preparations" /><published>2021-07-16T12:00:00-07:00</published><updated>2023-06-23T00:00:00-07:00</updated><id>https://transfemscience.org/articles/injectable-e2-meta-analysis</id><content type="html" xml:base="https://transfemscience.org/articles/injectable-e2-meta-analysis/"><h1 id="an-informal-meta-analysis-of-estradiol-curves-with-injectable-estradiol-preparations">An Informal Meta-Analysis of Estradiol Curves with Injectable Estradiol Preparations</h1>
|
||
|
||
<!-- Supports up to four authors per article currently (author, author2, author3, author4) -->
|
||
|
||
<p>By
|
||
<!-- First author --><a href="/about/#aly">Aly</a><!-- Second author --><!-- Third author --><!-- Fourth author --> | First published July 16, 2021
|
||
| Last modified June 23, 2023</p>
|
||
|
||
<h2 id="abstract--tldr">Abstract / TL;DR</h2>
|
||
|
||
<p>Injectable estradiol preparations such as estradiol valerate and estradiol cypionate in oil are frequently used as estrogens in transfeminine hormone therapy. However, there is little characterization of these preparations in transfeminine people and dosing recommendations by transgender health guidelines appear to be based on expert opinion rather than on clinical data. To help shed light on the properties of injectable estradiol and to better inform dosing considerations in transfeminine people, an informal meta-analysis of available clinical data on estradiol concentration–time curves with major injectable estradiol formulations was conducted. The included preparations were injectable estradiol benzoate in oil, estradiol valerate in oil, estradiol cypionate both in oil and as a suspension, estradiol enanthate in oil, estradiol undecylate in oil, and polyestradiol phosphate. The literature was searched for clinical concentration–time data with these injectable estradiol esters and these data were collected and analyzed. Meta-analysis consisted of data for each injectable estradiol preparation being processed and fit with pharmacokinetic models. Selected pharmacokinetic parameters were additionally determined and reported. The results of this work were discussed with regard to characteristics of injectable estradiol preparations like curve shapes, durations, estrogenic exposure, and variability between people and studies. Recommendations for injectable estradiol preparations by transgender health guidelines were also explored in light of the present results. Current guidelines recommend doses of these preparations that appear to be highly excessive with injection intervals that are too widely spaced. Based on the findings of the present meta-analysis, recommendations by guidelines should be reassessed. Finally, the fitted curves in this work were incorporated into an interactive web-based injectable estradiol simulator intended for use by transfeminine people and their medical providers to help guide therapeutic decisions.</p>
|
||
|
||
<h2 id="introduction">Introduction</h2>
|
||
|
||
<p>Estradiol is the main estrogen used in transfeminine hormone therapy and is available in a variety of different forms for use by different <a href="https://en.wikipedia.org/wiki/Route_of_administration">routes of administration</a>. The most commonly employed forms are <a href="https://en.wikipedia.org/wiki/Oral_estradiol">oral</a>, <a href="https://en.wikipedia.org/wiki/Sublingual_estradiol">sublingual</a>, <a href="https://en.wikipedia.org/wiki/Transdermal_estradiol">transdermal</a>, and <a href="https://en.wikipedia.org/wiki/Injectable_estradiol">injectable</a> preparations. Injectable estradiol preparations have been discontinued in many countries and hence are unavailable for use in transfeminine hormone therapy in many parts of the world, for instance in most of Europe (<a href="https://doi.org/10.1530/EJE-21-0059">Glintborg et al., 2021</a>). However, they are still used by many transfeminine people particularly in the United States and in the <a href="https://en.wikipedia.org/wiki/Self-medication">do-it-yourself</a> (DIY) community. The most commonly used forms include <a href="https://en.wikipedia.org/wiki/Estradiol_valerate">estradiol valerate</a>, <a href="https://en.wikipedia.org/wiki/Estradiol_cypionate">estradiol cypionate</a>, and <a href="https://en.wikipedia.org/wiki/Estradiol_enanthate">estradiol enanthate</a> all in oil. Injectable estradiol preparations have certain advantages over other estradiol forms that make them a popular choice for use in transfeminine hormone therapy. These include often lower cost, capacity to easily achieve higher estradiol levels that can be useful for <a href="https://en.wikipedia.org/wiki/Pharmacodynamics_of_estradiol#Antigonadotropic_effects">testosterone suppression</a>, less frequent administration, and theoretically reduced health risks relative to oral estradiol at equivalent doses due to the lack of the <a href="https://en.wikipedia.org/wiki/First_pass_effect">first pass</a> with this route (<a href="/articles/estrogens-blood-clots/">Aly, 2020</a>). The higher estradiol levels with injections are particularly useful for estradiol monotherapy, in which an antiandrogen is not used.</p>
|
||
|
||
<p>Clinically used injectable estradiol preparations are formulated not as estradiol but as <a href="https://en.wikipedia.org/wiki/Estrogen_ester">estradiol esters</a>. When <a href="https://en.wikipedia.org/wiki/Intramuscular_injection">injected into muscle</a> or <a href="https://en.wikipedia.org/wiki/Subcutaneous_injection">fat</a> in <a href="https://en.wikipedia.org/wiki/Oil_solution">oil solutions</a> or <a href="https://en.wikipedia.org/wiki/Aqueous_suspension">crystalline aqueous suspensions</a>, these estradiol esters form <a href="https://en.wikipedia.org/wiki/Depot_injection">depots</a> at the injection site from which they are slowly released. Subsequent to release, estradiol esters are rapidly <a href="https://en.wikipedia.org/wiki/Metabolism">metabolized</a> into estradiol and hence act as <a href="https://en.wikipedia.org/wiki/Prodrug">prodrugs</a>. When estradiol itself is given by intramuscular injection in an <a href="https://en.wikipedia.org/wiki/Aqueous_solution">aqueous solution</a> or oil solution, it is rapidly absorbed and has a very short duration. Due to having lipophilic <a href="https://en.wikipedia.org/wiki/Ester">esters</a>, most clinically used injectable estradiol esters are more <a href="https://en.wikipedia.org/wiki/Lipophilicity">fat-soluble</a> than estradiol (as measured by <a href="https://en.wikipedia.org/wiki/Octanol-water_partition_coefficient">oil–water partition coefficient</a> (P)) (<a href="https://en.wikipedia.org/wiki/Template:Structural_properties_of_selected_estradiol_esters">Table</a>). When these esters are administered as oil solutions by intramuscular or subcutaneous injection, their increased lipophilicity causes them to be released from the injection-site depot more slowly than estradiol and to therefore have longer durations. In the case of <a href="https://en.wikipedia.org/wiki/Fatty_acid">fatty acid</a> esters, the longer the chain length of the ester—as in e.g. <a href="https://en.wikipedia.org/wiki/Estradiol_valerate">estradiol valerate</a> (5 carbons) vs. <a href="https://en.wikipedia.org/wiki/Estradiol_enanthate">estradiol enanthate</a> (7 carbons) vs. <a href="https://en.wikipedia.org/wiki/Estradiol_undecylate">estradiol undecylate</a> (10 carbons)—the greater the fat solubility, the slower the rate of release from the depot, and the longer the time to peak levels and duration (<a href="https://doi.org/10.1111/j.2042-7158.1959.tb10412.x">Edkins, 1959</a>; <a href="https://scholar.google.com/scholar?cluster=12842077211931556704">Sinkula, 1978</a>; <a href="https://journal.pda.org/content/35/3/106.short">Chien, 1981</a>; <a href="https://doi.org/10.1080/13697130500148875">Kuhl, 2005</a>; <a href="https://dspace.library.uu.nl/handle/1874/348465">Kalicharan, 2017</a>; <a href="https://doi.org/10.1007/978-981-13-3642-3_7">Vhora et al., 2019</a>). The durations of both injectable oil solutions and aqueous suspensions depend on the ester and its particular <a href="https://en.wiktionary.org/wiki/physicochemical">physicochemical</a> properties, but the characteristics of these preparations are different and they work in distinct ways to produce their depot effects (<a href="https://doi.org/10.1016/0039-128X(83)90109-5">Enever et al., 1983</a>; <a href="/articles/aqueous-suspensions/">Aly, 2019</a>). The durations of oil solutions are dependent on the lipophilicity of the ester as well as oil vehicle, whereas the durations of aqueous suspensions depend on the properties of the ester <a href="https://en.wikipedia.org/wiki/Crystal_structure">crystal lattice</a> as well as <a href="https://en.wikipedia.org/wiki/Particle_size">crystal sizes</a> (<a href="https://journal.pda.org/content/35/3/106.short">Chien, 1981</a>; <a href="https://doi.org/10.1016/0039-128X(83)90109-5">Enever et al., 1983</a>; <a href="/articles/aqueous-suspensions/">Aly, 2019</a>). The <a href="https://en.wikipedia.org/wiki/Polymer">polymeric</a> estradiol ester <a href="https://en.wikipedia.org/wiki/Polyestradiol_phosphate">polyestradiol phosphate</a> is more <a href="https://en.wikipedia.org/wiki/Hydrophilicity">hydrophilic</a> (water-soluble) than estradiol and works differently than other injectable estradiol preparations. Ιt is composed of many estradiol molecules linked together via <a href="https://en.wikipedia.org/wiki/Phosphate_ester">phosphate esters</a> (on average 13 molecules of estradiol per one molecule of polyestradiol phosphate) and has a prolonged duration due to slow <a href="https://en.wikipedia.org/wiki/Bond_cleavage">cleavage</a> into estradiol following injection. Estradiol esters are able to substantially prolong the duration of estradiol when used as injectables and these preparations have durations ranging from days to months depending on the ester and how it is formulated (<a href="https://en.wikipedia.org/w/index.php?title=Template:Potencies_and_durations_of_natural_estrogens_by_intramuscular_injection&amp;oldid=964345939">Table</a>).</p>
|
||
|
||
<p>There is very little in the way of research and review on the <a href="https://en.wikipedia.org/wiki/Pharmacokinetics">pharmacokinetics</a> of injectable estradiol preparations in the <a href="https://en.wikipedia.org/wiki/Transgender_health">transgender health</a> literature. Transgender hormone therapy guidelines presently offer only brief descriptions and dosing recommendations that appear to be based mainly on expert opinion for this form of estradiol (e.g., <a href="https://transcare.ucsf.edu/guidelines">Deutsch, 2016a</a>; <a href="https://doi.org/10.1210/jc.2017-01658">Hembree et al., 2017</a>). Many studies assessing the pharmacokinetics and <a href="https://en.wiktionary.org/wiki/concentration-time_curve">concentration–time profiles</a> of injectable estradiol preparations have been published but are largely confined to cisgender women and men rather than transgender people. These studies are scattered throughout the literature and have not been comprehensively reviewed or analyzed. Some review material exists on the pharmacokinetics of injectable estradiol preparations for use in <a href="https://en.wikipedia.org/wiki/Hormonal_contraception">hormonal birth control</a> and <a href="https://en.wikipedia.org/wiki/Menopausal_hormone_therapy">menopausal hormone therapy</a> in cisgender women (e.g., <a href="https://doi.org/10.1016/0378-5122(82)90064-0">Düsterberg &amp; Nishino, 1982</a>; <a href="https://pubmed.ncbi.nlm.nih.gov/3817596/">Kuhl, 1986</a>; <a href="https://doi.org/10.1016/0378-5122(90)90003-O">Kuhl, 1990</a>; <a href="https://doi.org/10.1016/0010-7824(94)90032-9">Garza-Flores, 1994</a>; <a href="https://doi.org/10.1080/13697130500148875">Kuhl, 2005</a>) and <a href="https://en.wikipedia.org/wiki/Androgen_deprivation_therapy">androgen deprivation therapy</a> for <a href="https://en.wikipedia.org/wiki/Prostate_cancer">prostate cancer</a> in cisgender men (e.g., <a href="https://doi.org/10.1002/pros.2990130405">Gunnarsson &amp; Norlén, 1988</a>). However, these publications discuss only small selections of the available research. Data on repeated administration of injectable estradiol preparations are more rare but have also been published (e.g., <a href="https://doi.org/10.1016/0306-4530(84)90004-0">Gooren et al., 1984</a> [<a href="https://commons.wikimedia.org/wiki/File:Hormone_levels_with_twice-daily_injectable_estradiol_benzoate_in_transgender_women.png">Graph</a>]; various others). Multi-dose <a href="https://en.wikipedia.org/wiki/Simulation">simulation</a> has been done previously for polyestradiol phosphate (<a href="https://doi.org/10.1002/(SICI)1097-0045(19990701)40:2%3C76::AID-PROS2%3E3.0.CO;2-Q">Henriksson et al., 1999</a>; <a href="https://doi.org/10.1002/1097-0045(20000615)44:1%3C26::AID-PROS4%3E3.0.CO;2-P">Johansson &amp; Gunnarsson, 2000</a>). However, it has not been explored for other injectable estradiol preparations to date. In contrast to injectable estradiol, excellent review literature and simulation exists for injectable testosterone preparations (e.g., <a href="https://doi.org/10.1007/978-3-662-00814-0_6">Behre, Oberpenning, &amp; Nieschlag, 1990</a>; <a href="https://doi.org/10.1007/978-3-642-72185-4_11">Behre &amp; Nieschlag, 1998</a>; <a href="https://doi.org/10.1017/CBO9780511545221.015">Behre et al., 2004</a>; <a href="https://doi.org/10.1007/978-3-540-78355-8_21">Nieschlag &amp; Behre, 2010</a>; <a href="https://doi.org/10.1017/CBO9781139003353.016">Nieschlag &amp; Behre, 2012</a>).</p>
|
||
|
||
<p>In order to aid understanding of concentration–time profiles with injectable estradiol preparations, I’ve developed an interactive web-based <a href="/misc/injectable-e2-simulator/">injectable estradiol simulator</a> for transfeminine people and their medical providers. During work on this simulator, it became apparent that there is substantial <a href="https://en.wikipedia.org/wiki/Statistical_dispersion">variability</a> in estradiol levels and curve shapes between different studies even with the same injectable estradiol ester. The injectable estradiol simulator was originally designed to simulate curves from only a single well-known pharmacokinetic study that directly compared <a href="https://en.wikipedia.org/wiki/Estradiol_benzoate">estradiol benzoate</a>, <a href="https://en.wikipedia.org/wiki/Estradiol_valerate">estradiol valerate</a>, and <a href="https://en.wikipedia.org/wiki/Estradiol_cypionate">estradiol cypionate</a> in oil (<a href="https://doi.org/10.1016/S0010-7824(80)80018-7">Oriowo et al., 1980</a> [<a href="https://commons.wikimedia.org/wiki/File:Estradiol_levels_after_a_single_5_mg_intramuscular_injection_of_estradiol_esters.png">Graph</a>]). However, due to the considerable differences in estradiol levels and curves across studies, it was decided that relying on only one study for such a project would be untenable. Instead, for the simulations to be reasonably accurate to the available data, many studies would need to be incorporated. Including additional studies would also allow for inclusion of other injectable estradiol esters in the simulator. As a result, the present work—an informal <a href="https://en.wikipedia.org/wiki/Meta-analysis">meta-analysis</a> of estradiol curves with injectable estradiol formulations—was conducted for the simulator project.</p>
|
||
|
||
<h2 id="methods">Methods</h2>
|
||
|
||
<p>A literature search was performed to identify studies reporting clinical estradiol concentration–time data with major injectable estradiol formulations (Table 1). All of these preparations have been used in transfeminine hormone therapy at one time or another in different parts of the world, although only estradiol valerate in oil and estradiol cypionate in oil are widely used today. Some of the injectable preparations included have notably been discontinued. Acceptable data for the search included mean and individual estradiol concentration data and <a href="https://en.wikipedia.org/wiki/Cmax_(pharmacology)">C<sub>max</sub></a> estradiol levels (mean peak estradiol levels of individual subjects at time <a href="https://en.wikipedia.org/wiki/Tmax_(pharmacology)">T<sub>max</sub></a>). <a href="https://en.wikipedia.org/wiki/List_of_academic_databases_and_search_engines">Databases</a> like <a href="https://pubmed.ncbi.nlm.nih.gov/">PubMed</a>, <a href="https://scholar.google.com/">Google Scholar</a>, and <a href="https://www.worldcat.org/">WorldCat</a> were searched using relevant keywords (e.g., estradiol ester names and variations thereof as well as major brand names). Publications with relevant information were catalogued for data collection. Only single-dose data and multi-dose data that allowed estradiol levels to return to baseline between doses (as in e.g. repeated once-monthly <a href="https://en.wikipedia.org/wiki/Combined_injectable_birth_control">combined injectable contraceptives</a>) were included. Studies were included regardless of the <a href="https://en.wikipedia.org/wiki/Hypothalamic%E2%80%93pituitary%E2%80%93gonadal_axis">hypothalamic–pituitary–gonadal axis</a> (HPG axis) status of the participants. The study <a href="https://en.wikipedia.org/wiki/Inclusion_and_exclusion_criteria">selection criteria</a> aimed to maximize data inclusion due to scarcity of data for several preparations. If however there were many studies for a specific preparation, studies with only 1 or 2 subjects were generally skipped due to the limited additional value that they would provide. When data were in figures in papers—as was generally the case—they were extracted from the graphs using <a href="https://automeris.io/WebPlotDigitizer/">WebPlotDigitizer</a>.</p>
|
||
|
||
<p><strong>Table 1:</strong> Major injectable estradiol formulations (ordered roughly from shortest- to longest-acting):</p>
|
||
|
||
<table>
|
||
<thead>
|
||
<tr>
|
||
<th>Estradiol ester</th>
|
||
<th>Abbr.</th>
|
||
<th>Form</th>
|
||
<th>Major brand names</th>
|
||
</tr>
|
||
</thead>
|
||
<tbody>
|
||
<tr>
|
||
<td><a href="https://en.wikipedia.org/wiki/Estradiol_benzoate">Estradiol benzoate</a></td>
|
||
<td>EB</td>
|
||
<td>Oil solution</td>
|
||
<td>Progynon-B</td>
|
||
</tr>
|
||
<tr>
|
||
<td><a href="https://en.wikipedia.org/wiki/Estradiol_valerate">Estradiol valerate</a></td>
|
||
<td>EV</td>
|
||
<td>Oil solution</td>
|
||
<td>Delestrogen, Mesigyna,<sup>a</sup> Progynon Depot</td>
|
||
</tr>
|
||
<tr>
|
||
<td><a href="https://en.wikipedia.org/wiki/Estradiol_cypionate">Estradiol cypionate</a></td>
|
||
<td>EC</td>
|
||
<td>Oil solution</td>
|
||
<td>Depo-Estradiol</td>
|
||
</tr>
|
||
<tr>
|
||
<td> </td>
|
||
<td> </td>
|
||
<td>Aqueous suspension<sup>b</sup></td>
|
||
<td>Cyclofem,<sup>a</sup> Lunelle<sup>a</sup></td>
|
||
</tr>
|
||
<tr>
|
||
<td><a href="https://en.wikipedia.org/wiki/Estradiol_enanthate">Estradiol enanthate</a></td>
|
||
<td>EEn</td>
|
||
<td>Oil solution</td>
|
||
<td>Perlutal,<sup>a</sup> Topasel<sup>a</sup></td>
|
||
</tr>
|
||
<tr>
|
||
<td><a href="https://en.wikipedia.org/wiki/Estradiol_undecylate">Estradiol undecylate</a><sup>c</sup></td>
|
||
<td>EU</td>
|
||
<td>Oil solution</td>
|
||
<td>Delestrec, Progynon Depot 100</td>
|
||
</tr>
|
||
<tr>
|
||
<td><a href="https://en.wikipedia.org/wiki/Polyestradiol_phosphate">Polyestradiol phosphate</a><sup>c</sup></td>
|
||
<td>PEP</td>
|
||
<td>Aqueous solution</td>
|
||
<td>Estradurin</td>
|
||
</tr>
|
||
</tbody>
|
||
</table>
|
||
|
||
<p><small><sup>a</sup> As <a href="https://en.wikipedia.org/wiki/Combined_injectable_contraceptive">combined injectable contraceptives</a> also including a progestin (<a href="https://en.wikipedia.org/wiki/Norethisterone_enanthate">norethisterone enanthate</a> (NETE), <a href="https://en.wikipedia.org/wiki/Medroxyprogesterone_acetate">medroxyprogesterone acetate</a> (MPA), or <a href="https://en.wikipedia.org/wiki/Dihydroxyprogesterone_acetophenide">dihydroxyprogesterone acetophenide</a> (DHPA)). <sup>b</sup> <a href="https://en.wikipedia.org/wiki/Microcrystalline">Microcrystalline</a> <a href="https://en.wikipedia.org/wiki/Particle_size">particle size</a>. <sup>c</sup> No longer marketed.</small></p>
|
||
|
||
<p>Following their collection, data were processed, aggregated, and <a href="https://en.wikipedia.org/wiki/Scientific_modelling">modeled</a>. Data were adjusted for <a href="https://en.wikipedia.org/wiki/Endogeny_(biology)">endogenous</a> estradiol <a href="https://en.wikipedia.org/wiki/Biosynthesis">production</a> and were <a href="https://en.wikipedia.org/wiki/Normalization_(statistics)">normalized</a> by dose. Adjustment for endogenous estradiol production was generally done via subtraction of baseline estradiol levels. In a number of cases however, subtraction of <a href="https://en.wikipedia.org/wiki/Trough_level">trough</a> estradiol levels or of estradiol levels from a <a href="https://en.wikipedia.org/wiki/Control_group">control group</a> was required instead. Data were also <a href="https://en.wikipedia.org/wiki/Weighting">weighted</a> by <a href="https://en.wikipedia.org/wiki/Sample_size">sample size</a>. In a handful of instances, certain missing information (e.g., time to peak levels, baseline levels, subject body weights) was filled in with reasonable assumptions to help maximize data inclusion. Data were processed in the form of mean estradiol curve data rather than individual-subject data (except for rare n=1 studies). The combined processed data from all studies for each injectable estradiol preparation were <a href="https://en.wikipedia.org/wiki/Curve_fitting">fit</a> via <a href="https://en.wikipedia.org/wiki/Least_squares">least squares regression</a> to <a href="https://en.wikipedia.org/wiki/Pharmacokinetics#Compartmental_analysis">one-, two-, and three-compartment</a> <a href="https://en.wikipedia.org/wiki/Pharmacokinetic_model">pharmacokinetic models</a> with <a href="https://en.wikipedia.org/wiki/First-order_absorption">first-order absorption and elimination</a> that were obtained from the literature and other sources (e.g., <a href="https://doi.org/10.1007/bf01059272">Colburn, 1981</a>; <a href="https://books.google.com/books?id=gMuCDwAAQBAJ">Wagner, 1993</a>; <a href="https://web.archive.org/web/20210717084442if_/https://wiki.ucl.ac.uk/download/attachments/23206987/Shafer%20NONMEM.pdf">Fisher &amp; Shafer, 2007</a>; <a href="http://mlxtran.lixoft.com/wp-content/uploads/sites/2/2016/02/PKPDlibrary.pdf">Lixoft, 2008</a>; <a href="https://doi.org/10.1016/j.vascn.2015.03.004">Abuhelwa, Foster, &amp; Upton, 2015</a>; <a href="https://onlinehelp.certara.com/phoenix/8.3/topics/pkmodelcalc.htm">Certara, 2020</a>). These models fit most curves from individual studies very well. Fitting the combined curve fits of all individual studies (as opposed to fitting all of the combined processed data directly) was additionally evaluated for each injectable estradiol preparation, and if it was feasible for the preparation and allowed for better fitting results, was employed instead. Fitting directly to the combined processed data has the effect of weighting individual studies by quantity of time points, whereas fitting the combined curve fits of studies eliminates this. The <a href="https://en.wikipedia.org/wiki/Akaike_information_criterion">Akaike information criterion</a> (AIC) was used to help guide <a href="https://en.wikipedia.org/wiki/Model_selection">model selection</a> for fitting of the preparations. Curve fitting was performed using the <a href="https://en.wikipedia.org/wiki/Python_(programming_language)">Python</a> library <a href="https://lmfit.github.io/lmfit-py/">Lmfit</a> with the <a href="https://en.wikipedia.org/wiki/Levenberg%E2%80%93Marquardt_algorithm">Levenberg–Marquardt algorithm</a>. C<sub>max</sub> concentrations are a different form of data than mean curve estradiol concentration–time data, and for this reason, were not included in the fitting unless data were very limited for a given injectable estradiol preparation. <a href="https://en.wikipedia.org/wiki/Outlier">Outlying</a> data were also excluded from fitting in a number of instances and this allowed for improved curve fits with more uniform <a href="https://en.wikipedia.org/wiki/Area_under_the_curve_(pharmacokinetics)">area-under-the-curve levels</a>. The main criterion used for excluding curves was fit area-under-the-curve levels that deviated considerably from what was typical for the injectable estradiol preparations (generally less than about 50% of the average or greater than about 150% of the average).</p>
|
||
|
||
<p>A selection of <a href="https://en.wikipedia.org/wiki/Pharmacokinetic_parameter">pharmacokinetic parameters</a> were calculated for each injectable estradiol preparation using the single-dose fit curves and compartmental pharmacokinetic analyses. These parameters included <a href="https://en.wikipedia.org/wiki/Cmax_(pharmacology)">maximal or peak concentrations</a> of estradiol after a single dose scaled to 5 mg (C<sub>max</sub>), <a href="https://en.wikipedia.org/wiki/Tmax_(pharmacology)">time to maximal concentrations</a> of estradiol after a single dose (T<sub>max</sub>), total <a href="https://en.wikipedia.org/wiki/Area_under_the_curve_(pharmacokinetics)">area-under-the-curve concentrations</a> of estradiol after a single dose (AUC<sub>0–∞</sub>), <a href="https://en.wikipedia.org/wiki/Biological_half-life">terminal elimination half-life</a> after a single dose (t<sub>1/2</sub>), and the <a href="https://en.wikipedia.org/wiki/Biological_half-life#First-order_elimination">terminal 90% life</a> after a single dose (t<sub>90%</sub>) (calculated as t<sub>1/2</sub> × 3.322). In addition, selected pharmacokinetic parameters were calculated for simulated repeated administration of each injectable preparation at <a href="https://en.wikipedia.org/wiki/Steady_state_(pharmacokinetics)">steady state</a> with a dose and dose interval of 5 mg once every 7 days using the single-dose fit curves and compartmental pharmacokinetic analyses. These parameters included time to peak concentrations of estradiol (T<sub>max</sub>), peak and <a href="https://en.wikipedia.org/wiki/Cmin_(pharmacology)">trough</a> concentrations of estradiol (C<sub>max</sub> and C<sub>min</sub>, respectively), <a href="https://en.wikipedia.org/wiki/Peak–trough_difference">peak–trough difference</a> (PTD; C<sub>max</sub> – C<sub>min</sub>), <a href="https://en.wikipedia.org/wiki/Peak-to-trough_ratio">peak–trough ratio</a> (PTR; C<sub>max</sub> ÷ C<sub>min</sub>), and <a href="https://en.wikipedia.org/wiki/Integral">integrated</a> <a href="https://en.wikipedia.org/wiki/Cavg_(pharmacokinetics)">mean concentrations</a> of estradiol (C<sub>avg</sub>). Simulation of repeated administration was performed by stacking estradiol levels for multiple injections. C<sub>max</sub> and T<sub>max</sub> were defined and calculated in general as peak estradiol level and time to peak level of the fit mean curve as opposed to the mean peak level and mean time to peak level of individual subjects. This is because the latter would not be possible to compute as most studies reported only estradiol mean curve data. Pharmacokinetic parameters were calculated using relevant pharmacokinetic equations and, as a <a href="https://en.wikipedia.org/wiki/Sanity_check">sanity check</a>, were compared against those computed by <a href="https://doi.org/10.1016/j.cmpb.2010.01.007">PKSolver</a>, a <a href="https://en.wikipedia.org/wiki/Microsoft_Excel">Microsoft Excel</a> pharmacokinetics <a href="https://en.wikipedia.org/wiki/Microsoft_Excel_add-in">add-in</a> program (<a href="https://doi.org/10.1016/j.cmpb.2010.01.007">Zhang et al., 2010</a>).</p>
|
||
|
||
<h2 id="results">Results</h2>
|
||
|
||
<p>The figures in the subsequent sections show the original data from studies adjusted for endogenous estradiol levels and normalized to a common dose as well as the curve fits to the data (or alternatively the curve fits of the fits of the data depending on the preparation) for the included injectable estradiol preparations. Estradiol benzoate, estradiol cypionate in oil, and estradiol cypionate suspension were fit to the fits of all individual studies for these preparations, whereas estradiol enanthate, estradiol undecylate, and polyestradiol phosphate were fit directly to the combined processed data for these esters. In the case of estradiol valerate, the two fitting approaches gave nearly identical curves, and so fitting the combined processed original data was done for simplicity for this preparation. C<sub>m</sub><sub>ax</sub> studies were excluded in the fitting for all preparations except estradiol enanthate, for which available estradiol concentration–time data were otherwise very limited. The data for the injectable estradiol preparations were generally fit best by a three-compartment pharmacokinetic model (<a href="https://www.desmos.com/calculator/ndgvp2avhj">Desmos</a>). As a result, and for consistency, this model was used in the fitting of all preparations.</p>
|
||
|
||
<h3 id="estradiol-benzoate">Estradiol Benzoate</h3>
|
||
|
||
<p>Injectable estradiol benzoate has been extensively used in the past in scientific research, most notably in studies elucidating the function and dynamics of the HPG axis. One such use of estradiol benzoate has been the <a href="https://en.wikipedia.org/wiki/Estrogen_provocation_test">estrogen provocation test</a>, a diagnostic test of HPG axis function. Due to its use in research, substantial estradiol concentration–time data with injectable estradiol benzoate exists. A total of 26 publications and concentration–time data for 355 individual injections were identified (Table 2).</p>
|
||
|
||
<p><strong>Table 2:</strong> Studies of injectable estradiol benzoate (<a href="https://files.transfemscience.org/pdfs/docs/Injectable%20Estradiol%20Studies%20and%20Levels.xlsx">Spreadsheet</a>; <a href="https://files.transfemscience.org/pdfs/misc/Injectables%20Meta-Analysis%20Plotly%20Charts.zip">Plotly</a>):</p>
|
||
|
||
<table>
|
||
<thead>
|
||
<tr>
|
||
<th>Study</th>
|
||
<th>n<sup>a</sup></th>
|
||
<th>Subjects</th>
|
||
<th>Dose</th>
|
||
<th>Reference(s)</th>
|
||
</tr>
|
||
</thead>
|
||
<tbody>
|
||
<tr>
|
||
<td>G75</td>
|
||
<td>3</td>
|
||
<td>Gonadectomized/postmenopausal women</td>
|
||
<td>27.6 mg</td>
|
||
<td><a href="https://www.worldcat.org/title/untersuchungen-zur-pharmakokinetik-von-ostradiol-17-beta-ostradiol-benzoat-ostradiol-valerianat-und-ostradiol-undezylat-bei-der-frau-der-verlauf-der-konzentrationen-von-ostradiol-17-beta-ostron-lh-und-fsh-im-serum/oclc/311708827">Geppert (1975)</a>; <a href="https://pubmed.ncbi.nlm.nih.gov/1150068/">Leyendecker et al. (1975)</a></td>
|
||
</tr>
|
||
<tr>
|
||
<td>K75</td>
|
||
<td>10</td>
|
||
<td>Normal premenopausal women</td>
|
||
<td>~0.15 mg</td>
|
||
<td><a href="https://doi.org/10.1210/jcem-41-6-1003">Keye &amp; Jaffe (1975)</a></td>
|
||
</tr>
|
||
<tr>
|
||
<td>S75a</td>
|
||
<td>10</td>
|
||
<td>Amenorrheic premenopausal women</td>
|
||
<td>1 mg</td>
|
||
<td><a href="https://doi.org/10.1111/j.1365-2265.1975.tb01534.x">Shaw et al. (1975)</a></td>
|
||
</tr>
|
||
<tr>
|
||
<td>S75b1</td>
|
||
<td>5</td>
|
||
<td>Normal premenopausal women</td>
|
||
<td>0.5 mg</td>
|
||
<td><a href="https://doi.org/10.1111/j.1365-2265.1975.tb01537.x">Shaw, Butt, &amp; London (1975)</a></td>
|
||
</tr>
|
||
<tr>
|
||
<td>S75b2</td>
|
||
<td>5</td>
|
||
<td>Normal premenopausal women</td>
|
||
<td>1.5 mg</td>
|
||
<td><a href="https://doi.org/10.1111/j.1365-2265.1975.tb01537.x">Shaw, Butt, &amp; London (1975)</a></td>
|
||
</tr>
|
||
<tr>
|
||
<td>S75b3</td>
|
||
<td>5</td>
|
||
<td>Normal premenopausal women</td>
|
||
<td>2.5 mg</td>
|
||
<td><a href="https://doi.org/10.1111/j.1365-2265.1975.tb01537.x">Shaw, Butt, &amp; London (1975)</a></td>
|
||
</tr>
|
||
<tr>
|
||
<td>L76</td>
|
||
<td>3</td>
|
||
<td>Normal premenopausal women</td>
|
||
<td>3 mg</td>
|
||
<td><a href="https://doi.org/10.1007/BF00667679">Leyendecker et al. (1976)</a></td>
|
||
</tr>
|
||
<tr>
|
||
<td>C78</td>
|
||
<td>22</td>
|
||
<td>Infertile anovulatory premenopausal women</td>
|
||
<td>1 mg</td>
|
||
<td><a href="https://doi.org/10.1016/S0015-0282(16)43271-1">Canales et al. (1978)</a></td>
|
||
</tr>
|
||
<tr>
|
||
<td>S78</td>
|
||
<td>6</td>
|
||
<td>Normal premenopausal women</td>
|
||
<td>2.5 mg</td>
|
||
<td><a href="https://doi.org/10.1016/S0300-595X(78)80008-5">Shaw (1978)</a></td>
|
||
</tr>
|
||
<tr>
|
||
<td>T78</td>
|
||
<td>19</td>
|
||
<td>Premenopausal women with hyperprolactinemia (n=12) and after prolactin normalization (n=7) (2 injections per subject for 7 of 12 subjects)</td>
|
||
<td>1 mg</td>
|
||
<td><a href="https://doi.org/10.1007/BF03346769">Travaglini et al. (1978)</a></td>
|
||
</tr>
|
||
<tr>
|
||
<td>T79</td>
|
||
<td>18</td>
|
||
<td>Premenopausal women with hyperprolactinemia (n=9) given estradiol benzoate alone and then in combination with progesterone (2 injections per subject)</td>
|
||
<td>1 mg</td>
|
||
<td><a href="https://doi.org/10.1007/BF03349341">Travaglini et al. (1979)</a></td>
|
||
</tr>
|
||
<tr>
|
||
<td>O80</td>
|
||
<td>10</td>
|
||
<td>Premenopausal women on a combined birth control pill</td>
|
||
<td>5 mg</td>
|
||
<td><a href="https://doi.org/10.1016/S0010-7824(80)80018-7">Oriowo et al. (1980)</a></td>
|
||
</tr>
|
||
<tr>
|
||
<td>C81</td>
|
||
<td>14</td>
|
||
<td>Lactating postpartum women (n=7) (2 injections per subject)</td>
|
||
<td>3 mg</td>
|
||
<td><a href="https://doi.org/10.1016/0020-7292(81)90043-6">Canales et al. (1981)</a></td>
|
||
</tr>
|
||
<tr>
|
||
<td>W81</td>
|
||
<td>19</td>
|
||
<td>Premenopausal women with prolactinomas and hyperprolactinemia</td>
|
||
<td>1 mg</td>
|
||
<td><a href="https://doi.org/10.1016/S0140-6736(81)92571-X">White et al. (1981)</a></td>
|
||
</tr>
|
||
<tr>
|
||
<td>S82</td>
|
||
<td>2</td>
|
||
<td>Men with XX male syndrome</td>
|
||
<td>5 mg</td>
|
||
<td><a href="https://doi.org/10.1210/jcem-54-4-745">Schweikert et al. (1982)</a></td>
|
||
</tr>
|
||
<tr>
|
||
<td>B83</td>
|
||
<td>10</td>
|
||
<td>Normal premenopausal women (n=5) not on and then on danazol (2 injections per subject)</td>
|
||
<td>5 mg</td>
|
||
<td><a href="https://doi.org/10.1016/S0015-0282(16)47174-8">Braun, Wildt, &amp; Leyendecker (1983)</a></td>
|
||
</tr>
|
||
<tr>
|
||
<td>K84</td>
|
||
<td>22</td>
|
||
<td>Gonadectomized premenopausal women on oral combined hormone therapy</td>
|
||
<td>1 mg</td>
|
||
<td><a href="https://doi.org/10.1007/BF00570759">Kemeter et al. (1984)</a></td>
|
||
</tr>
|
||
<tr>
|
||
<td>V84</td>
|
||
<td>7</td>
|
||
<td>Premenopausal women with alcoholism and cirrhosis or fatty liver disease</td>
|
||
<td>5 mg</td>
|
||
<td><a href="https://doi.org/10.1210/jcem-59-1-133">Välimäki et al. (1984)</a></td>
|
||
</tr>
|
||
<tr>
|
||
<td>G85</td>
|
||
<td>10</td>
|
||
<td>Transfeminine people not on hormone therapy (n=5) and normal men (n=5)</td>
|
||
<td>2 mg</td>
|
||
<td><a href="https://doi.org/10.1007/BF01541659">Goodman et al. (1985)</a></td>
|
||
</tr>
|
||
<tr>
|
||
<td>A86</td>
|
||
<td>18</td>
|
||
<td>Infertile ovulatory premenopausal women with transient hyperprolactinemia (n=9) and normal premenopausal women (n=9)</td>
|
||
<td>~5 mg</td>
|
||
<td><a href="https://doi.org/10.1507/endocrine1927.62.5_662">Aisaka et al. (1986)</a></td>
|
||
</tr>
|
||
<tr>
|
||
<td>C86</td>
|
||
<td>27</td>
|
||
<td>Perimenopausal women with dysfunctional uterine bleeding</td>
|
||
<td>2 mg</td>
|
||
<td><a href="https://doi.org/10.1016/0028-2243(86)90125-5">Cano et al. (1986)</a></td>
|
||
</tr>
|
||
<tr>
|
||
<td>M87</td>
|
||
<td>5</td>
|
||
<td>Normal premenopausal women</td>
|
||
<td>10 mg</td>
|
||
<td><a href="https://doi.org/10.1111/j.1365-2265.1987.tb01173.x">Messinis &amp; Templeton (1987a)</a>; <a href="https://doi.org/10.1530/jrf.0.0790549">Messinis &amp; Templeton (1987b)</a></td>
|
||
</tr>
|
||
<tr>
|
||
<td>S87</td>
|
||
<td>11</td>
|
||
<td>Normal premenopausal women</td>
|
||
<td>1 mg</td>
|
||
<td><a href="https://doi.org/10.1507/endocrine1927.63.10_1289">Sumioki (1987)</a></td>
|
||
</tr>
|
||
<tr>
|
||
<td>B89</td>
|
||
<td>20</td>
|
||
<td>Infertile ovulatory premenopausal women (n=10) not on and then on a GnRH agonist (2 injections per subject)</td>
|
||
<td>2 mg</td>
|
||
<td><a href="https://doi.org/10.1016/S0015-0282(16)60602-7">Bider et al. (1989)</a></td>
|
||
</tr>
|
||
<tr>
|
||
<td>V93</td>
|
||
<td>49</td>
|
||
<td>Premenopausal women on a GnRH agonist with gynecological disorders (n=15) or undergoing fertility treatment (n=6) (2–3 injections per subject)</td>
|
||
<td>2.5 mg</td>
|
||
<td><a href="https://pubmed.ncbi.nlm.nih.gov/8506068/">Vizziello et al. (1993)</a></td>
|
||
</tr>
|
||
<tr>
|
||
<td>E06</td>
|
||
<td>25</td>
|
||
<td>Premenopausal women with premenstrual mood disturbances (n=13) and normal premenopausal women (n=12)</td>
|
||
<td>~2.5 mg</td>
|
||
<td><a href="https://doi.org/10.1016/j.psyneuen.2005.10.004">Eriksson et al. (2006)</a></td>
|
||
</tr>
|
||
</tbody>
|
||
</table>
|
||
|
||
<p><small><sup>a</sup> Total number of injections, not total number of subjects.</small></p>
|
||
|
||
<p>A number of studies were excluded from fitting due to much higher or lower area-under-the-curve levels than average. A couple of studies were omitted from the meta-analysis as they only reported total estrogen levels rather than estradiol levels with estradiol benzoate (<a href="https://doi.org/10.1111/j.1471-0528.1974.tb00383.x">Akande, 1974</a>; <a href="https://journals.lww.com/greenjournal/abstract/1976/04000/induction_of_an_lh_surge_with_estradiol_benzoate_.6.aspx">Weiss, Nachtigall, &amp; Ganguly, 1976</a>). Two studies were omitted due partly to being very old and using very early and inaccurate blood tests (<a href="https://pubmed.ncbi.nlm.nih.gov/13547587/">Varangot &amp; Cedard, 1957</a>; <a href="https://files.transfemscience.org/pdfs/translations/Ittrich%20&amp;%20Pots%20(1965)%20-%20Östrogenbestimmungen%20in%20Blut%20und%20Urin%20Nach%20Verabreichung%20von%20Östrogenen.pdf">Ittrich &amp; Pots, 1965</a> [<a href="https://commons.wikimedia.org/wiki/File:Estradiol_levels_with_a_single_intramuscular_injection_of_40_or_50_mg_estradiol,_estradiol_benzoate,_estradiol_valerate,_or_estrone_in_oil_in_ovariectomized_women.png">Graph</a>]). The processed original data and fit of fits curve for estradiol benzoate are shown in Figure 1.</p>
|
||
|
||
<table>
|
||
<thead>
|
||
<tr>
|
||
<th><img src="/assets/images/injectable-e2/eb_v3c.svg" alt="" /></th>
|
||
</tr>
|
||
</thead>
|
||
<tbody>
|
||
<tr>
|
||
<td><strong>Figure 1:</strong> Published estradiol concentration–time curves and fit of fit curves (thick black or white line) with a single intramuscular injection of estradiol benzoate in oil solution over a period of 7 days. Each curve was adjusted for endogenous estradiol levels, normalized to a dose of 5 mg, and fit with a compartmental pharmacokinetic model. Following this, the combined fit curves of the individual studies were fit using the same pharmacokinetic model. The original data from the studies for estradiol benzoate are also provided elsewhere (<a href="https://files.transfemscience.org/pdfs/docs/Injectable%20Estradiol%20Studies%20and%20Levels.xlsx">Spreadsheet</a>; <a href="https://files.transfemscience.org/pdfs/misc/Injectables%20Meta-Analysis%20Plotly%20Charts.zip">Plotly</a>).</td>
|
||
</tr>
|
||
</tbody>
|
||
</table>
|
||
|
||
<h3 id="estradiol-valerate">Estradiol Valerate</h3>
|
||
|
||
<p>Studies with curve data on injectable estradiol valerate come from its use in menopausal hormone therapy and other therapeutic indications for estrogens, its use in combined injectable contraceptives, and use in scientific research. A total of 28 publications and concentration–time data for 309 individual injections were identified for estradiol valerate (Table 3).</p>
|
||
|
||
<p><strong>Table 3:</strong> Studies of injectable estradiol valerate (<a href="https://files.transfemscience.org/pdfs/docs/Injectable%20Estradiol%20Studies%20and%20Levels.xlsx">Spreadsheet</a>; <a href="https://files.transfemscience.org/pdfs/misc/Injectables%20Meta-Analysis%20Plotly%20Charts.zip">Plotly</a>):</p>
|
||
|
||
<table>
|
||
<thead>
|
||
<tr>
|
||
<th>Study</th>
|
||
<th>n<sup>a</sup></th>
|
||
<th>Subjects</th>
|
||
<th>Dose</th>
|
||
<th>Reference(s)</th>
|
||
</tr>
|
||
</thead>
|
||
<tbody>
|
||
<tr>
|
||
<td>S7175</td>
|
||
<td>12</td>
|
||
<td>Premenopausal women with menstrual migraine (n=10) and amenorrheic/postmenopausal women with history of menstrual migraine (n=2)</td>
|
||
<td>5–20 mg</td>
|
||
<td><a href="http://hdl.handle.net/1959.4/66063">Somerville (1971)</a>; <a href="https://doi.org/10.1212/WNL.22.4.355">Somerville (1972a)</a>; <a href="https://doi.org/10.1111/j.1526-4610.1972.hed1203093.x">Somerville (1972b)</a>; <a href="https://doi.org/10.5694/j.1326-5377.1972.tb93039.x">Somerville (1972c)</a>; <a href="https://doi.org/10.1212/wnl.25.3.239">Somerville (1975)</a></td>
|
||
</tr>
|
||
<tr>
|
||
<td>G75</td>
|
||
<td>3</td>
|
||
<td>Gonadectomized/postmenopausal women</td>
|
||
<td>26.2 mg</td>
|
||
<td><a href="https://www.worldcat.org/title/untersuchungen-zur-pharmakokinetik-von-ostradiol-17-beta-ostradiol-benzoat-ostradiol-valerianat-und-ostradiol-undezylat-bei-der-frau-der-verlauf-der-konzentrationen-von-ostradiol-17-beta-ostron-lh-und-fsh-im-serum/oclc/311708827">Geppert (1975)</a>; <a href="https://pubmed.ncbi.nlm.nih.gov/1150068/">Leyendecker et al. (1975)</a></td>
|
||
</tr>
|
||
<tr>
|
||
<td>V75a</td>
|
||
<td>4</td>
|
||
<td>Unknown/not described</td>
|
||
<td>10 mg</td>
|
||
<td><a href="https://doi.org/10.1080/17843286.1975.11716973">Vermeulen (1975)</a></td>
|
||
</tr>
|
||
<tr>
|
||
<td>V75b</td>
|
||
<td>2</td>
|
||
<td>Unknown/not described</td>
|
||
<td>4 mg</td>
|
||
<td><a href="https://doi.org/10.1080/17843286.1975.11716973">Vermeulen (1975)</a></td>
|
||
</tr>
|
||
<tr>
|
||
<td>O80</td>
|
||
<td>9</td>
|
||
<td>Premenopausal women on a combined birth control pill</td>
|
||
<td>5 mg</td>
|
||
<td><a href="https://doi.org/10.1016/S0010-7824(80)80018-7">Oriowo et al. (1980)</a></td>
|
||
</tr>
|
||
<tr>
|
||
<td>R80</td>
|
||
<td>6</td>
|
||
<td>Gonadectomized/postmenopausal women</td>
|
||
<td>10 mg</td>
|
||
<td><a href="https://doi.org/10.1016/0378-5122(80)90060-2">Rauramo et al. (1980)</a>; <a href="https://doi.org/10.1016/0378-5122(81)90010-4">Rauramo, Punnonen, &amp; Grönroos (1981)</a></td>
|
||
</tr>
|
||
<tr>
|
||
<td>B82</td>
|
||
<td>10</td>
|
||
<td>Normal premenopausal women with bromocriptine administration</td>
|
||
<td>20 mg</td>
|
||
<td><a href="https://doi.org/10.1016/S0015-0282(16)46042-5">Blackwell, Boots, &amp; Potter (1982)</a></td>
|
||
</tr>
|
||
<tr>
|
||
<td>D83</td>
|
||
<td>3</td>
|
||
<td>Normal postmenopausal women</td>
|
||
<td>4 mg</td>
|
||
<td><a href="https://doi.org/10.1159/000179680">Düsterberg, &amp; Wendt (1983)</a></td>
|
||
</tr>
|
||
<tr>
|
||
<td>A85</td>
|
||
<td>7</td>
|
||
<td>Normal premenopausal women</td>
|
||
<td>5 mg</td>
|
||
<td><a href="https://doi.org/10.1016/0010-7824(85)90081-2">Aedo et al. (1985)</a></td>
|
||
</tr>
|
||
<tr>
|
||
<td>D85</td>
|
||
<td>2</td>
|
||
<td>Gonadectomized/postmenopausal women</td>
|
||
<td>4 mg</td>
|
||
<td><a href="https://doi.org/10.1016/0378-5122(82)90064-0">Düsterberg &amp; Nishino (1982)</a>; <a href="https://doi.org/10.1159/000180039">Düsterberg, Schmidt-Gollwitzer, &amp; Hümpel (1985)</a></td>
|
||
</tr>
|
||
<tr>
|
||
<td>R87</td>
|
||
<td>7</td>
|
||
<td>Normal young men</td>
|
||
<td>10 mg</td>
|
||
<td><a href="https://doi.org/10.1007/BF00544558">Reimann et al. (1987)</a></td>
|
||
</tr>
|
||
<tr>
|
||
<td>S87a</td>
|
||
<td>8</td>
|
||
<td>Normal premenopausal women</td>
|
||
<td>5 mg</td>
|
||
<td><a href="https://doi.org/10.13699/j.cnki.1001-6821.1987.01.002">Sang et al. (1987)</a></td>
|
||
</tr>
|
||
<tr>
|
||
<td>S87b</td>
|
||
<td>8</td>
|
||
<td>Normal premenopausal women</td>
|
||
<td>2.5 mg</td>
|
||
<td><a href="https://doi.org/10.13699/j.cnki.1001-6821.1987.01.002">Sang et al. (1987)</a></td>
|
||
</tr>
|
||
<tr>
|
||
<td>S87c</td>
|
||
<td>20</td>
|
||
<td>Gonadectomized/postmenopausal women</td>
|
||
<td>10 mg</td>
|
||
<td><a href="https://doi.org/10.1016/0002-9378(87)90295-X">Sherwin et al. (1987)</a>; <a href="https://doi.org/10.1016/0165-0327(88)90061-4">Sherwin (1988)</a></td>
|
||
</tr>
|
||
<tr>
|
||
<td>G88</td>
|
||
<td>54</td>
|
||
<td>Normally cycling transmasculine people not on hormone therapy (n=31), transfeminine people not on hormone therapy (n=14), and gonadally intact transfeminine people on oral estrogen therapy (n=9)</td>
|
||
<td>10 mg</td>
|
||
<td><a href="https://doi.org/10.3109/09513598809023624">Goh &amp; Ratnam (1988)</a></td>
|
||
</tr>
|
||
<tr>
|
||
<td>G90</td>
|
||
<td>12</td>
|
||
<td>Normally cycling transmasculine people not on hormone therapy</td>
|
||
<td>10 mg</td>
|
||
<td><a href="https://doi.org/10.1007/BF02442351">Goh &amp; Ratnam (1990)</a></td>
|
||
</tr>
|
||
<tr>
|
||
<td>G94a</td>
|
||
<td>8</td>
|
||
<td>Normal premenopausal women</td>
|
||
<td>5 mg</td>
|
||
<td><a href="https://doi.org/10.1016/0010-7824(94)90032-9">Garza-Flores (1994)</a></td>
|
||
</tr>
|
||
<tr>
|
||
<td>G94c</td>
|
||
<td>5</td>
|
||
<td>Normal premenopausal women</td>
|
||
<td>5 mg</td>
|
||
<td><a href="https://doi.org/10.1016/0010-7824(94)90032-9">Garza-Flores (1994)</a></td>
|
||
</tr>
|
||
<tr>
|
||
<td>J94</td>
|
||
<td>9</td>
|
||
<td>Normal young men</td>
|
||
<td>10 mg</td>
|
||
<td><a href="https://doi.org/10.1210/jcem.79.6.7527406">Jilma et al. (1994)</a></td>
|
||
</tr>
|
||
<tr>
|
||
<td>G98</td>
|
||
<td>5</td>
|
||
<td>Men with Klinfelter’s syndrome</td>
|
||
<td>10 mg</td>
|
||
<td><a href="https://doi.org/10.1159/000023266">Goh &amp; Lee (1998)</a></td>
|
||
</tr>
|
||
<tr>
|
||
<td>G02</td>
|
||
<td>17</td>
|
||
<td>Normal postmenopausal women</td>
|
||
<td>5 mg</td>
|
||
<td><a href="https://www.kup.at/journals/summary/1071.html">Göretzlehner et al. (2002)</a></td>
|
||
</tr>
|
||
<tr>
|
||
<td>K06</td>
|
||
<td>10</td>
|
||
<td>Normal menopausal women</td>
|
||
<td>2 mg</td>
|
||
<td><a href="https://www.nel.edu/short-term-changes-in-melatonin-and-cortisol-serum-levels-after-a-single-administration-of-estrogen-to-menopausal-women-1766/">Kerdelhué et al. (2006)</a></td>
|
||
</tr>
|
||
<tr>
|
||
<td>V11</td>
|
||
<td>32</td>
|
||
<td>Normal young men</td>
|
||
<td>5 mg</td>
|
||
<td><a href="https://repositoriodigital.ipn.mx/handle/123456789/12490">Valle Alvarez (2011)</a></td>
|
||
</tr>
|
||
<tr>
|
||
<td>S12</td>
|
||
<td>48</td>
|
||
<td>Normal postmenopausal women (n=24) given Estradiol-Depot 10 mg and then Progynon Depot-10 (2 injections per subject)</td>
|
||
<td>10 mg</td>
|
||
<td><a href="https://doi.org/10.5414/cp201589">Schug, Donath, &amp; Blume (2012)</a></td>
|
||
</tr>
|
||
</tbody>
|
||
</table>
|
||
|
||
<p><small><sup>a</sup> Total number of injections, not total number of subjects.</small></p>
|
||
|
||
<p>A few of these studies were excluded from fitting due generally to much higher or lower area-under-the-curve levels than average or due to being C<sub>max</sub> data. One study was omitted as it only reported estrone levels rather than estradiol levels (<a href="https://www.worldcat.org/oclc/722383126">Ibrahim, 1996</a>). Another study was not included due to being in pregnant women with concomitant pregnancy termination (<a href="https://doi.org/10.1016/0002-9378(77)90026-6">Garner &amp; Armstrong, 1977</a>). One last study was omitted due partly to being very old and using very early and inaccurate blood tests (<a href="https://files.transfemscience.org/pdfs/translations/Ittrich%20&amp;%20Pots%20(1965)%20-%20Östrogenbestimmungen%20in%20Blut%20und%20Urin%20Nach%20Verabreichung%20von%20Östrogenen.pdf">Ittrich &amp; Pots, 1965</a> [<a href="https://commons.wikimedia.org/wiki/File:Estradiol_levels_with_a_single_intramuscular_injection_of_40_or_50_mg_estradiol,_estradiol_benzoate,_estradiol_valerate,_or_estrone_in_oil_in_ovariectomized_women.png">Graph</a>]). The processed original data and fit curve for estradiol valerate are shown in Figure 2.</p>
|
||
|
||
<table>
|
||
<thead>
|
||
<tr>
|
||
<th><img src="/assets/images/injectable-e2/ev_v3c.svg" alt="" /></th>
|
||
</tr>
|
||
</thead>
|
||
<tbody>
|
||
<tr>
|
||
<td><strong>Figure 2:</strong> Published estradiol concentration–time curves and fit curve (thick black or white line) with a single intramuscular injection of estradiol valerate in oil solution over a period of 30 days. Curves were adjusted for endogenous estradiol levels, normalized to a dose of 10 mg, and fit with a compartmental pharmacokinetic model. Fitting of the combined fits of individual studies for this preparation was explored but gave a nearly identical overall curve, so the overall fit curve for the combined processed original data was used for simplicity for this preparation. The original data from the studies for estradiol valerate are also provided elsewhere (<a href="https://files.transfemscience.org/pdfs/docs/Injectable%20Estradiol%20Studies%20and%20Levels.xlsx">Spreadsheet</a>; <a href="https://files.transfemscience.org/pdfs/misc/Injectables%20Meta-Analysis%20Plotly%20Charts.zip">Plotly</a>).</td>
|
||
</tr>
|
||
</tbody>
|
||
</table>
|
||
|
||
<h3 id="estradiol-cypionate-oil">Estradiol Cypionate Oil</h3>
|
||
|
||
<p>Estradiol cypionate in oil is used in menopausal hormone therapy and for other estrogen indications. However, its use has been more limited relative to other injectable estradiol preparations, like estradiol valerate. Only a handful of studies with relevant data were identified for estradiol cypionate in oil. This included 4 publications and estradiol concentration–time data for 49 individual injections (Table 4).</p>
|
||
|
||
<p><strong>Table 4:</strong> Studies of injectable estradiol cypionate in oil (<a href="https://files.transfemscience.org/pdfs/docs/Injectable%20Estradiol%20Studies%20and%20Levels.xlsx">Spreadsheet</a>; <a href="https://files.transfemscience.org/pdfs/misc/Injectables%20Meta-Analysis%20Plotly%20Charts.zip">Plotly</a>):</p>
|
||
|
||
<table>
|
||
<thead>
|
||
<tr>
|
||
<th>Study</th>
|
||
<th>n<sup>a</sup></th>
|
||
<th>Subjects</th>
|
||
<th>Dose</th>
|
||
<th>Reference(s)</th>
|
||
</tr>
|
||
</thead>
|
||
<tbody>
|
||
<tr>
|
||
<td>R73</td>
|
||
<td>6</td>
|
||
<td>Hypogonadal adolescent girls</td>
|
||
<td>1–2 mg</td>
|
||
<td><a href="https://doi.org/10.1210/jcem-37-4-574">Rosenfield et al. (1973)</a>; <a href="https://doi.org/10.1016/S0022-3476(74)80355-0">Rosenfield &amp; Fang (1974)</a></td>
|
||
</tr>
|
||
<tr>
|
||
<td>B80</td>
|
||
<td>~5</td>
|
||
<td>Normal premenopausal women</td>
|
||
<td>10 mg</td>
|
||
<td><a href="https://doi.org/10.1016/0026-0495(80)90117-1">Buckman et al. (1980)</a></td>
|
||
</tr>
|
||
<tr>
|
||
<td>O80</td>
|
||
<td>10</td>
|
||
<td>Premenopausal women on a combined birth control pill</td>
|
||
<td>5 mg</td>
|
||
<td><a href="https://doi.org/10.1016/S0010-7824(80)80018-7">Oriowo et al. (1980)</a></td>
|
||
</tr>
|
||
<tr>
|
||
<td>L96</td>
|
||
<td>28</td>
|
||
<td>Postmenopausal women with history of hormonal migraine (n=16) and without (n=12) initially on oral estrogen therapy (discontinued upon injection)</td>
|
||
<td>5 mg</td>
|
||
<td><a href="https://doi.org/10.1046/j.1526-4610.1996.3606367.x">Lichten et al. (1996)</a></td>
|
||
</tr>
|
||
</tbody>
|
||
</table>
|
||
|
||
<p><small><sup>a</sup> Total number of injections, not total number of subjects.</small></p>
|
||
|
||
<p>No curves were excluded from fitting in the case of this preparation. The processed original data and fit of fit curves for estradiol cypionate in oil are shown in Figure 3.</p>
|
||
|
||
<table>
|
||
<thead>
|
||
<tr>
|
||
<th><img src="/assets/images/injectable-e2/ec_oil_v3c.svg" alt="" /></th>
|
||
</tr>
|
||
</thead>
|
||
<tbody>
|
||
<tr>
|
||
<td><strong>Figure 3:</strong> Published estradiol concentration–time curves and fit of fit curves (thick black or white line) with a single intramuscular injection of estradiol cypionate in oil solution over a period of 30 days. Each curve was adjusted for endogenous estradiol levels, normalized to a dose of 5 mg, and fit with a compartmental pharmacokinetic model. Following this, the combined fit curves of the individual studies were fit using the same pharmacokinetic model. The original data from the studies for estradiol cypionate in oil are also provided elsewhere (<a href="https://files.transfemscience.org/pdfs/docs/Injectable%20Estradiol%20Studies%20and%20Levels.xlsx">Spreadsheet</a>; <a href="https://files.transfemscience.org/pdfs/misc/Injectables%20Meta-Analysis%20Plotly%20Charts.zip">Plotly</a>).</td>
|
||
</tr>
|
||
</tbody>
|
||
</table>
|
||
|
||
<h3 id="estradiol-cypionate-suspension">Estradiol Cypionate Suspension</h3>
|
||
|
||
<p>Estradiol cypionate suspension has been used exclusively in combined injectable contraceptives. For this reason, many relatively high quality pharmacokinetic studies with this injectable preparation have been conducted. A total of 9 publications and estradiol concentration–time data for 131 individual injections were identified for estradiol cypionate suspension (Table 5).</p>
|
||
|
||
<p><strong>Table 5:</strong> Studies of injectable estradiol cypionate suspension (<a href="https://files.transfemscience.org/pdfs/docs/Injectable%20Estradiol%20Studies%20and%20Levels.xlsx">Spreadsheet</a>; <a href="https://files.transfemscience.org/pdfs/misc/Injectables%20Meta-Analysis%20Plotly%20Charts.zip">Plotly</a>):</p>
|
||
|
||
<table>
|
||
<thead>
|
||
<tr>
|
||
<th>Study</th>
|
||
<th>n<sup>a</sup></th>
|
||
<th>Subjects</th>
|
||
<th>Dose</th>
|
||
<th>Reference(s)</th>
|
||
</tr>
|
||
</thead>
|
||
<tbody>
|
||
<tr>
|
||
<td>F82</td>
|
||
<td>11</td>
|
||
<td>Normal premenopausal women</td>
|
||
<td>5 mg</td>
|
||
<td><a href="https://doi.org/10.1016/0010-7824(82)90049-X">Fotherby et al. (1982)</a></td>
|
||
</tr>
|
||
<tr>
|
||
<td>A85</td>
|
||
<td>8</td>
|
||
<td>Normal premenopausal women</td>
|
||
<td>5 mg</td>
|
||
<td><a href="https://doi.org/10.1016/0010-7824(85)90081-2">Aedo et al. (1985)</a></td>
|
||
</tr>
|
||
<tr>
|
||
<td>G87a</td>
|
||
<td>7</td>
|
||
<td>Normal premenopausal women</td>
|
||
<td>5 mg</td>
|
||
<td><a href="https://doi.org/10.1016/0010-7824(87)90093-X">Garza-Flores et al. (1987)</a>; <a href="https://doi.org/10.1016/0010-7824(94)90032-9">Garza-Flores (1994)</a></td>
|
||
</tr>
|
||
<tr>
|
||
<td>G87b</td>
|
||
<td>8</td>
|
||
<td>Normal premenopausal women</td>
|
||
<td>5 mg</td>
|
||
<td><a href="https://doi.org/10.1016/0010-7824(87)90093-X">Garza-Flores et al. (1987)</a>; <a href="https://doi.org/10.1016/0010-7824(94)90032-9">Garza-Flores (1994)</a></td>
|
||
</tr>
|
||
<tr>
|
||
<td>G87c</td>
|
||
<td>7</td>
|
||
<td>Normal premenopausal women</td>
|
||
<td>5 mg</td>
|
||
<td><a href="https://doi.org/10.1016/0010-7824(87)90093-X">Garza-Flores et al. (1987)</a>; <a href="https://doi.org/10.1016/0010-7824(94)90032-9">Garza-Flores (1994)</a></td>
|
||
</tr>
|
||
<tr>
|
||
<td>G87d</td>
|
||
<td>8</td>
|
||
<td>Normal premenopausal women</td>
|
||
<td>2.5 mg</td>
|
||
<td><a href="https://doi.org/10.1016/0010-7824(87)90093-X">Garza-Flores et al. (1987)</a>; <a href="https://doi.org/10.1016/0010-7824(94)90032-9">Garza-Flores (1994)</a></td>
|
||
</tr>
|
||
<tr>
|
||
<td>G87e</td>
|
||
<td>8</td>
|
||
<td>Normal premenopausal women</td>
|
||
<td>2.5 mg</td>
|
||
<td><a href="https://doi.org/10.1016/0010-7824(87)90093-X">Garza-Flores et al. (1987)</a>; <a href="https://doi.org/10.1016/0010-7824(94)90032-9">Garza-Flores (1994)</a></td>
|
||
</tr>
|
||
<tr>
|
||
<td>G87f</td>
|
||
<td>6</td>
|
||
<td>Normal premenopausal women</td>
|
||
<td>2.5 mg</td>
|
||
<td><a href="https://doi.org/10.1016/0010-7824(87)90093-X">Garza-Flores et al. (1987)</a>; <a href="https://doi.org/10.1016/0010-7824(94)90032-9">Garza-Flores (1994)</a></td>
|
||
</tr>
|
||
<tr>
|
||
<td>Z98</td>
|
||
<td>9</td>
|
||
<td>Normal premenopausal women</td>
|
||
<td>5 mg</td>
|
||
<td><a href="https://doi.org/10.1016/S0010-7824(98)00048-1">Zhou et al. (1998)</a></td>
|
||
</tr>
|
||
<tr>
|
||
<td>R99</td>
|
||
<td>14</td>
|
||
<td>Healthy surgically sterile premenopausal women</td>
|
||
<td>5 mg</td>
|
||
<td><a href="https://doi.org/10.1016/s0010-7824(99)00081-5">Rahimy &amp; Ryan (1999)</a>; <a href="https://doi.org/10.1016/S0010-7824(99)00086-4">Rahimy, Ryan, &amp; Hopkins (1999)</a></td>
|
||
</tr>
|
||
<tr>
|
||
<td>S11a</td>
|
||
<td>15</td>
|
||
<td>Normal premenopausal women</td>
|
||
<td>5 mg</td>
|
||
<td><a href="https://doi.org/10.1016/j.contraception.2011.03.014">Sierra-Ramírez et al. (2011)</a></td>
|
||
</tr>
|
||
<tr>
|
||
<td>S11b<sup>b</sup></td>
|
||
<td>15</td>
|
||
<td>Normal premenopausal women</td>
|
||
<td>5 mg</td>
|
||
<td><a href="https://doi.org/10.1016/j.contraception.2011.03.014">Sierra-Ramírez et al. (2011)</a></td>
|
||
</tr>
|
||
<tr>
|
||
<td>T13</td>
|
||
<td>15</td>
|
||
<td>Normal premenopausal women</td>
|
||
<td>5 mg</td>
|
||
<td><a href="https://doi.org/10.1016/j.contraception.2012.11.010">Thurman et al. (2013)</a></td>
|
||
</tr>
|
||
</tbody>
|
||
</table>
|
||
|
||
<p><small><sup>a</sup> Total number of injections, not total number of subjects. <sup>b</sup> By subcutaneous injection rather than intramuscular injection.</small></p>
|
||
|
||
<p>One of these studies used subcutaneous injection instead of the usual intramuscular injection but the resulting curve was very similar to the curve for intramuscular injection in the same study (<a href="https://doi.org/10.1016/j.contraception.2011.03.014">Sierra-Ramírez et al., 2011</a> [<a href="https://commons.wikimedia.org/wiki/File:Estradiol_levels_after_a_single_subcutaneous_or_intramuscular_injection_of_5_mg_estradiol_cypionate.png">Graph</a>]). Several C<sub>max</sub> studies were excluded from fitting for this preparation. One pharmacokinetic study only measured estradiol cypionate levels rather than estradiol levels and hence was not included (<a href="https://doi.org/10.1016/j.jpba.2019.03.053">Martins et al., 2019</a> [<a href="https://commons.wikimedia.org/wiki/File:Estradiol_cypionate_levels_after_a_single_intramuscular_injection_of_5_mg_microcrystalline_estradiol_cypionate_in_aqueous_suspension_in_women.png">Graph</a>]). The processed original data and fit of fit curves for estradiol cypionate suspension are shown in Figure 4.</p>
|
||
|
||
<table>
|
||
<thead>
|
||
<tr>
|
||
<th><img src="/assets/images/injectable-e2/ec_susp_v3c.svg" alt="" /></th>
|
||
</tr>
|
||
</thead>
|
||
<tbody>
|
||
<tr>
|
||
<td><strong>Figure 4:</strong> Published estradiol concentration–time curves and fit of fits curve (thick black or white line) with a single intramuscular (or in one case subcutaneous) injection of a microcrystalline aqueous suspension of estradiol cypionate over a period of 30 days. Each curve was adjusted for endogenous estradiol levels, normalized to a dose of 5 mg, and fit with a compartmental pharmacokinetic model. Following this, the combined fit curves of the individual studies were fit using the same pharmacokinetic model. The original data from the studies for estradiol cypionate suspension are also provided elsewhere (<a href="https://files.transfemscience.org/pdfs/docs/Injectable%20Estradiol%20Studies%20and%20Levels.xlsx">Spreadsheet</a>; <a href="https://files.transfemscience.org/pdfs/misc/Injectables%20Meta-Analysis%20Plotly%20Charts.zip">Plotly</a>).</td>
|
||
</tr>
|
||
</tbody>
|
||
</table>
|
||
|
||
<h3 id="estradiol-enanthate">Estradiol Enanthate</h3>
|
||
|
||
<p>Estradiol enanthate has been used exclusively in combined injectable contraceptives. Several pharmacokinetic studies have been conducted with it because of this. A total of 7 publications and concentration–time data for 270 individual injections were identified for estradiol enanthate (Table 6).</p>
|
||
|
||
<p><strong>Table 6:</strong> Studies of injectable estradiol enanthate (<a href="https://files.transfemscience.org/pdfs/docs/Injectable%20Estradiol%20Studies%20and%20Levels.xlsx">Spreadsheet</a>; <a href="https://files.transfemscience.org/pdfs/misc/Injectables%20Meta-Analysis%20Plotly%20Charts.zip">Plotly</a>):</p>
|
||
|
||
<table>
|
||
<thead>
|
||
<tr>
|
||
<th>Study</th>
|
||
<th>n<sup>a</sup></th>
|
||
<th>Subjects</th>
|
||
<th>Dose</th>
|
||
<th>Reference(s)</th>
|
||
</tr>
|
||
</thead>
|
||
<tbody>
|
||
<tr>
|
||
<td>R86a</td>
|
||
<td>1</td>
|
||
<td>Normal premenopausal woman</td>
|
||
<td>5 mg</td>
|
||
<td><a href="https://doi.org/10.1016/0010-7824(86)90046-6">Recio et al. (1986)</a></td>
|
||
</tr>
|
||
<tr>
|
||
<td>R86b</td>
|
||
<td>1</td>
|
||
<td>Normal premenopausal woman</td>
|
||
<td>10 mg</td>
|
||
<td><a href="https://doi.org/10.1016/0010-7824(86)90046-6">Recio et al. (1986)</a></td>
|
||
</tr>
|
||
<tr>
|
||
<td>W86</td>
|
||
<td>3</td>
|
||
<td>Normal postmenopausal women</td>
|
||
<td>10 mg</td>
|
||
<td><a href="https://pubmed.ncbi.nlm.nih.gov/3814225/">Wiemeyer et al. (1986)</a>; <a href="https://pesquisa.bvsalud.org/portal/resource/en/lil-42873">Wiemeyer et al. (1987)</a></td>
|
||
</tr>
|
||
<tr>
|
||
<td>S88</td>
|
||
<td>14</td>
|
||
<td>Normal premenopausal women</td>
|
||
<td>10 mg</td>
|
||
<td><a href="https://doi.org/10.1016/0010-7824(88)90005-4">Schiavon et al. (1988)</a></td>
|
||
</tr>
|
||
<tr>
|
||
<td>G89</td>
|
||
<td>10</td>
|
||
<td>Normal premenopausal women</td>
|
||
<td>10 mg</td>
|
||
<td><a href="https://doi.org/10.1016/0010-7824(89)90107-8">Garza-Flores et al. (1989)</a></td>
|
||
</tr>
|
||
<tr>
|
||
<td>G94a</td>
|
||
<td>9</td>
|
||
<td>Normal premenopausal women</td>
|
||
<td>10 mg</td>
|
||
<td><a href="https://doi.org/10.1016/0010-7824(94)90032-9">Garza-Flores (1994)</a></td>
|
||
</tr>
|
||
<tr>
|
||
<td>G94b</td>
|
||
<td>9</td>
|
||
<td>Normal premenopausal women</td>
|
||
<td>5 mg</td>
|
||
<td><a href="https://doi.org/10.1016/0010-7824(94)90032-9">Garza-Flores (1994)</a></td>
|
||
</tr>
|
||
<tr>
|
||
<td>G94c</td>
|
||
<td>7</td>
|
||
<td>Normal premenopausal women</td>
|
||
<td>10 mg</td>
|
||
<td><a href="https://doi.org/10.1016/0010-7824(94)90032-9">Garza-Flores (1994)</a></td>
|
||
</tr>
|
||
<tr>
|
||
<td>M95</td>
|
||
<td>216</td>
|
||
<td>Normal premenopausal women</td>
|
||
<td>10 mg</td>
|
||
<td><a href="https://doi.org/10.1007/BF02436100">Martinez (1995)</a></td>
|
||
</tr>
|
||
</tbody>
|
||
</table>
|
||
|
||
<p><small><sup>a</sup> Total number of injections, not total number of subjects.</small></p>
|
||
|
||
<p>Of the available data, 216 of the injections were from a single study and mainly included only C<sub>max</sub> levels. <a href="https://pubmed.ncbi.nlm.nih.gov/3814225/">Wiemeyer et al. (1986)</a> was excluded from fitting due to having unusually high area-under-the-curve levels with a small sample size (n=3). Because of the scarcity of estradiol concentration–time data available for estradiol enanthate, C<sub>max</sub> studies were included in the fitting for this preparation. The processed original data and fit curve for estradiol enanthate are shown in Figure 5.</p>
|
||
|
||
<table>
|
||
<thead>
|
||
<tr>
|
||
<th><img src="/assets/images/injectable-e2/een_v3c.svg" alt="" /></th>
|
||
</tr>
|
||
</thead>
|
||
<tbody>
|
||
<tr>
|
||
<td><strong>Figure 5:</strong> Published estradiol concentration–time curves and fit curve (thick black or white line) with a single intramuscular injection of estradiol enanthate in oil solution over a period of 30 days. Curves were adjusted for endogenous estradiol levels, normalized to a dose of 10 mg, and fit with a compartmental pharmacokinetic model. The original data from the studies for estradiol enanthate are also provided elsewhere (<a href="https://files.transfemscience.org/pdfs/docs/Injectable%20Estradiol%20Studies%20and%20Levels.xlsx">Spreadsheet</a>; <a href="https://files.transfemscience.org/pdfs/misc/Injectables%20Meta-Analysis%20Plotly%20Charts.zip">Plotly</a>).</td>
|
||
</tr>
|
||
</tbody>
|
||
</table>
|
||
|
||
<h3 id="estradiol-undecylate">Estradiol Undecylate</h3>
|
||
|
||
<p>Estradiol undecylate was formerly used in the treatment of prostate cancer and in menopausal hormone therapy as well as for other estrogen therapeutic indications. However, it was discontinued many years ago and is no longer used today. Nonetheless, estradiol undecylate is of significant historical interest as an injectable estradiol preparation. A total of 3 publications and estradiol concentration–time data for 7 individual injections were identified for estradiol undecylate (Table 7).</p>
|
||
|
||
<p><strong>Table 7:</strong> Studies of injectable estradiol undecylate (<a href="https://files.transfemscience.org/pdfs/docs/Injectable%20Estradiol%20Studies%20and%20Levels.xlsx">Spreadsheet</a>; <a href="https://files.transfemscience.org/pdfs/misc/Injectables%20Meta-Analysis%20Plotly%20Charts.zip">Plotly</a>):</p>
|
||
|
||
<table>
|
||
<thead>
|
||
<tr>
|
||
<th>Study</th>
|
||
<th>n<sup>a</sup></th>
|
||
<th>Subjects</th>
|
||
<th>Dose</th>
|
||
<th>Reference(s)</th>
|
||
</tr>
|
||
</thead>
|
||
<tbody>
|
||
<tr>
|
||
<td>G75</td>
|
||
<td>3</td>
|
||
<td>Gonadectomized/postmenopausal women</td>
|
||
<td>32.3 mg</td>
|
||
<td><a href="https://www.worldcat.org/oclc/632312599">Geppert (1975)</a>/<a href="https://pubmed.ncbi.nlm.nih.gov/1150068/">Leyendecker et al. (1975)</a> [<a href="https://commons.wikimedia.org/wiki/File:Estradiol_levels_after_injections_of_estradiol,_estradiol_benzoate,_estradiol_valerate,_and_estradiol_undecylate_in_women.png">Graph</a>]</td>
|
||
</tr>
|
||
<tr>
|
||
<td>V75</td>
|
||
<td>4</td>
|
||
<td>Unknown/not described</td>
|
||
<td>100 mg</td>
|
||
<td><a href="https://doi.org/10.1080/17843286.1975.11716973">Vermeulen (1975)</a>/<a href="https://scholar.google.com/scholar?cluster=5963522046259984312">Vermeulen (1977)</a> [<a href="https://commons.wikimedia.org/wiki/File:Estradiol_levels_after_a_single_intramuscular_injection_of_10_mg_estradiol_valerate_and_100_mg_estradiol_undecylate.png">Graph</a>]</td>
|
||
</tr>
|
||
</tbody>
|
||
</table>
|
||
|
||
<p><small><sup>a</sup> Total number of injections, not total number of subjects.</small></p>
|
||
|
||
<p>Unfortunately, the identified data were of very low quality, with small sample sizes and considerable variations in estradiol levels. Moreover, estradiol undecylate is a very long-acting injectable estradiol ester with a duration measured in months, and the follow up in these studies only went to about 2 weeks post-injection. For these reasons, it was not possible to fit the data for estradiol undecylate in a reasonably accurate way—as suggested by area-under-the-curve estradiol levels that were only around one-third those of the other non-polymeric injectable estradiol esters. Limited multi-dose hormone concentration–time data also exist for estradiol undecylate, but these data could not be incorporated (<a href="https://doi.org/10.1159/000280272">Jacobi &amp; Altwein, 1979</a> [<a href="https://commons.wikimedia.org/wiki/File:Estradiol,_testosterone,_and_prolactin_levels_during_therapy_with_100_mg_per_month_estradiol_undecylate_in_men_with_prostate_cancer.png">Graph</a>]; <a href="https://doi.org/10.1111/j.1464-410X.1980.tb02961.x">Jacobi et al., 1980</a> [<a href="https://commons.wikimedia.org/wiki/File:Testosterone_levels_with_300_mg_per_week_cyproterone_acetate_and_100_mg_per_month_estradiol_undecylate_by_intramuscular_injection.png">Graph</a>]; <a href="https://www.worldcat.org/oclc/774239518">Derra, 1981</a> [<a href="https://archive.is/JyLYj">Graph</a>]). The processed original data and fit curve for estradiol undecylate are shown in Figure 6.</p>
|
||
|
||
<table>
|
||
<thead>
|
||
<tr>
|
||
<th><img src="/assets/images/injectable-e2/eu_v3c.svg" alt="" /></th>
|
||
</tr>
|
||
</thead>
|
||
<tbody>
|
||
<tr>
|
||
<td><strong>Figure 6:</strong> Published estradiol concentration–time curves and fit curve (thick black or white line) with a single intramuscular injection of estradiol undecylate in oil solution over a period of 90 days. Curves were adjusted for endogenous estradiol levels, normalized to a dose of 50 mg, and fit with a compartmental pharmacokinetic model. The original data from the studies for estradiol undecylate are also provided elsewhere (<a href="https://files.transfemscience.org/pdfs/docs/Injectable%20Estradiol%20Studies%20and%20Levels.xlsx">Spreadsheet</a>; <a href="https://files.transfemscience.org/pdfs/misc/Injectables%20Meta-Analysis%20Plotly%20Charts.zip">Plotly</a>).</td>
|
||
</tr>
|
||
</tbody>
|
||
</table>
|
||
|
||
<h3 id="polyestradiol-phosphate">Polyestradiol Phosphate</h3>
|
||
|
||
<p>Polyestradiol phosphate has been used primarily in the treatment of prostate cancer but has also been used for estrogen therapeutic indications like treatment of breast cancer and menopausal hormone therapy. While this injectable estradiol preparation has been used widely in the past, it appears to have recently been discontinued. All of the identified studies with estradiol concentration–time data on polyestradiol phosphate were in men with prostate cancer. A total of 11 publications and concentration–time data for 114 individual injections were identified for polyestradiol phosphate (Table 8).</p>
|
||
|
||
<p><strong>Table 8:</strong> Studies of injectable polyestradiol phosphate (<a href="https://files.transfemscience.org/pdfs/docs/Injectable%20Estradiol%20Studies%20and%20Levels.xlsx">Spreadsheet</a>; <a href="https://files.transfemscience.org/pdfs/misc/Injectables%20Meta-Analysis%20Plotly%20Charts.zip">Plotly</a>):</p>
|
||
|
||
<table>
|
||
<thead>
|
||
<tr>
|
||
<th>Study</th>
|
||
<th>n<sup>a</sup></th>
|
||
<th>Subjects</th>
|
||
<th>Dose</th>
|
||
<th>Reference(s)</th>
|
||
</tr>
|
||
</thead>
|
||
<tbody>
|
||
<tr>
|
||
<td>J76</td>
|
||
<td>16</td>
|
||
<td>Men with prostate cancer</td>
|
||
<td>160 mg</td>
|
||
<td><a href="https://doi.org/10.1016/S0083-6729(08)60965-6">Jönsson (1976)</a></td>
|
||
</tr>
|
||
<tr>
|
||
<td>L79</td>
|
||
<td>10</td>
|
||
<td>Men with prostate cancer</td>
|
||
<td>80 mg</td>
|
||
<td><a href="https://pubmed.ncbi.nlm.nih.gov/571863/">Leinonen et al. (1979)</a></td>
|
||
</tr>
|
||
<tr>
|
||
<td>L80</td>
|
||
<td>8</td>
|
||
<td>Men with prostate cancer</td>
|
||
<td>80 mg</td>
|
||
<td><a href="https://doi.org/10.1016/0022-4731(80)90225-3">Leinonen (1980)</a></td>
|
||
</tr>
|
||
<tr>
|
||
<td>J82</td>
|
||
<td>4</td>
|
||
<td>Men with prostate cancer</td>
|
||
<td>80 mg</td>
|
||
<td><a href="https://scholar.google.com/scholar?cluster=5512908264284113489">Jacobi (1982)</a></td>
|
||
</tr>
|
||
<tr>
|
||
<td>N87a</td>
|
||
<td>3</td>
|
||
<td>Men with prostate cancer</td>
|
||
<td>80 mg</td>
|
||
<td><a href="https://doi.org/10.1159/000472772">Norlén (1987)</a>; <a href="https://doi.org/10.1002/pros.2990130405">Gunnarsson &amp; Norlén (1988)</a></td>
|
||
</tr>
|
||
<tr>
|
||
<td>N87b</td>
|
||
<td>3</td>
|
||
<td>Men with prostate cancer</td>
|
||
<td>160 mg</td>
|
||
<td><a href="https://doi.org/10.1159/000472772">Norlén (1987)</a>; <a href="https://doi.org/10.1002/pros.2990130405">Gunnarsson &amp; Norlén (1988)</a></td>
|
||
</tr>
|
||
<tr>
|
||
<td>N87c</td>
|
||
<td>3</td>
|
||
<td>Men with prostate cancer</td>
|
||
<td>240 mg</td>
|
||
<td><a href="https://doi.org/10.1159/000472772">Norlén (1987)</a>; <a href="https://doi.org/10.1002/pros.2990130405">Gunnarsson &amp; Norlén (1988)</a></td>
|
||
</tr>
|
||
<tr>
|
||
<td>N87d</td>
|
||
<td>4</td>
|
||
<td>Men with prostate cancer</td>
|
||
<td>80 mg</td>
|
||
<td><a href="https://doi.org/10.1159/000472772">Norlén (1987)</a>; <a href="https://doi.org/10.1002/pros.2990130405">Gunnarsson &amp; Norlén (1988)</a></td>
|
||
</tr>
|
||
<tr>
|
||
<td>N87e</td>
|
||
<td>4</td>
|
||
<td>Men with prostate cancer</td>
|
||
<td>160 mg</td>
|
||
<td><a href="https://doi.org/10.1159/000472772">Norlén (1987)</a>; <a href="https://doi.org/10.1002/pros.2990130405">Gunnarsson &amp; Norlén (1988)</a></td>
|
||
</tr>
|
||
<tr>
|
||
<td>N87f</td>
|
||
<td>4</td>
|
||
<td>Men with prostate cancer</td>
|
||
<td>240 mg</td>
|
||
<td><a href="https://doi.org/10.1159/000472772">Norlén (1987)</a>; <a href="https://doi.org/10.1002/pros.2990130405">Gunnarsson &amp; Norlén (1988)</a></td>
|
||
</tr>
|
||
<tr>
|
||
<td>S88a</td>
|
||
<td>9</td>
|
||
<td>Men with prostate cancer</td>
|
||
<td>160 mg</td>
|
||
<td><a href="https://doi.org/10.1097/00000421-198801102-00024">Stege et al. (1988)</a>; <a href="https://doi.org/10.1002/pros.2990140211">Stege et al. (1989)</a></td>
|
||
</tr>
|
||
<tr>
|
||
<td>S88b</td>
|
||
<td>9</td>
|
||
<td>Men with prostate cancer</td>
|
||
<td>240 mg</td>
|
||
<td><a href="https://doi.org/10.1097/00000421-198801102-00024">Stege et al. (1988)</a>; <a href="https://doi.org/10.1002/pros.2990140211">Stege et al. (1989)</a></td>
|
||
</tr>
|
||
<tr>
|
||
<td>S88c</td>
|
||
<td>9</td>
|
||
<td>Men with prostate cancer</td>
|
||
<td>320 mg</td>
|
||
<td><a href="https://doi.org/10.1097/00000421-198801102-00024">Stege et al. (1988)</a>; <a href="https://doi.org/10.1002/pros.2990140211">Stege et al. (1989)</a></td>
|
||
</tr>
|
||
<tr>
|
||
<td>S96</td>
|
||
<td>11</td>
|
||
<td>Men with prostate cancer</td>
|
||
<td>320 mg</td>
|
||
<td><a href="https://doi.org/10.1002/(SICI)1097-0045(199605)28:5%3C307::AID-PROS6%3E3.0.CO;2-8">Stege et al. (1996)</a></td>
|
||
</tr>
|
||
<tr>
|
||
<td>H99</td>
|
||
<td>17</td>
|
||
<td>Men with prostate cancer</td>
|
||
<td>240 mg</td>
|
||
<td><a href="https://doi.org/10.1002/(SICI)1097-0045(19990701)40:2%3C76::AID-PROS2%3E3.0.CO;2-Q">Henriksson et al. (1999)</a>; <a href="https://doi.org/10.1002/1097-0045(20000615)44:1%3C26::AID-PROS4%3E3.0.CO;2-P">Johansson &amp; Gunnarsson (2000)</a></td>
|
||
</tr>
|
||
</tbody>
|
||
</table>
|
||
|
||
<p><small><sup>a</sup> Total number of injections, not total number of subjects.</small></p>
|
||
|
||
<p>A few older and strongly outlying studies were excluded from the fitting. The processed original data and fit curve for polyestradiol phosphate are shown in Figure 7.</p>
|
||
|
||
<table>
|
||
<thead>
|
||
<tr>
|
||
<th><img src="/assets/images/injectable-e2/pep_v3c.svg" alt="" /></th>
|
||
</tr>
|
||
</thead>
|
||
<tbody>
|
||
<tr>
|
||
<td><strong>Figure 7:</strong> Published estradiol concentration–time curves and fit curve (thick black or white line) with a single intramuscular injection of an aqueous solution of polyestradiol phosphate over a period of 90 days. The graph was clipped to maximum estradiol levels of 600 pg/mL (~2,200 pmol/L) for better viewability. Curves were adjusted for endogenous estradiol levels, normalized to a dose of 160 mg, and fit with a compartmental pharmacokinetic model. The original data from the studies for polyestradiol phosphate are also provided elsewhere (<a href="https://files.transfemscience.org/pdfs/docs/Injectable%20Estradiol%20Studies%20and%20Levels.xlsx">Spreadsheet</a>; <a href="https://files.transfemscience.org/pdfs/misc/Injectables%20Meta-Analysis%20Plotly%20Charts.zip">Plotly</a>).</td>
|
||
</tr>
|
||
</tbody>
|
||
</table>
|
||
|
||
<h3 id="other-injectable-estradiol-preparations">Other Injectable Estradiol Preparations</h3>
|
||
|
||
<p>A number of clinical studies with estradiol concentration–time data for other injectable estradiol preparations were also identified during literature search:</p>
|
||
|
||
<ul>
|
||
<li><a href="https://en.wikipedia.org/wiki/Estradiol_(medication)">Estradiol</a> (unesterified) in oil (<a href="https://files.transfemscience.org/pdfs/translations/Ittrich%20&amp;%20Pots%20(1965)%20-%20Östrogenbestimmungen%20in%20Blut%20und%20Urin%20Nach%20Verabreichung%20von%20Östrogenen.pdf">Ittrich &amp; Pots, 1965</a> [<a href="https://commons.wikimedia.org/wiki/File:Estradiol_levels_with_a_single_intramuscular_injection_of_40_or_50_mg_estradiol,_estradiol_benzoate,_estradiol_valerate,_or_estrone_in_oil_in_ovariectomized_women.png">Graph</a>])</li>
|
||
<li>Estradiol (unesterified) in an “aqueous” preparation (type of aqueous preparation unspecified but probably a microcrystalline aqueous suspension) (<a href="https://doi.org/10.1210/jcem-47-6-1368">Jones et al., 1978</a> [<a href="https://commons.wikimedia.org/wiki/File:Estradiol_and_testosterone_levels_with_a_single_intramuscular_injection_of_2_mg_aqueous_estradiol_in_healthy_young_men.png">Graph</a>])</li>
|
||
<li>Estradiol (unesterified) in different <a href="https://en.wikipedia.org/wiki/Microsphere">microsphere</a> formulations (e.g., Juvenum-E) (<a href="https://doi.org/10.1016/0010-7824(94)90032-9">Garza-Flores, 1994</a> [<a href="https://archive.is/6U7aj">Graph</a>]; <a href="https://doi.org/10.5772/intechopen.82553">Espino y Sosa et al., 2019</a> [<a href="https://commons.wikimedia.org/wiki/File:Estradiol_levels_with_estradiol_and_progesterone_microspheres_by_intramuscular_injection_once_per_month_in_menopausal_women.png">Graph</a>])</li>
|
||
<li><a href="https://en.wikipedia.org/wiki/Estradiol/progesterone">Estradiol/progesterone</a> in a <a href="https://en.wikipedia.org/wiki/Macrocrystalline">macrocrystalline</a> aqueous suspension (<a href="https://doi.org/10.1016/0010-7824(91)90105-O">Garza-Flores et al., 1991</a>)</li>
|
||
<li><a href="https://en.wikipedia.org/wiki/Estradiol/megestrol_acetate">Estradiol/megestrol acetate</a> in a microcrystalline aqueous suspension (Mego-E) (a lesser-known combined injectable contraceptive used in China) (<a href="http://en.cnki.com.cn/Article_en/CJFDTOTAL-SHEI198702001.htm">Yan et al., 1987</a> [<a href="https://archive.is/iyDyF">Graphs</a>])</li>
|
||
<li><a href="https://en.wikipedia.org/wiki/Estradiol_dipropionate">Estradiol dipropionate</a> in oil (Agofollin) (<a href="https://doi.org/10.1051/rnd:19760314">Presl et al., 1976</a> [<a href="https://commons.wikimedia.org/wiki/File:Estradiol_levels_after_a_single_intramuscular_injection_of_50_%CE%BCg_per_kg_estradiol_dipropionate_in_pubertal_girls.png">Graph</a>])</li>
|
||
<li><a href="https://en.wikipedia.org/wiki/Estradiol_benzoate/estradiol_phenylpropionate">Estradiol benzoate/estradiol phenylpropionate</a> in oil (Dimenformon Prolongatum) (<a href="https://doi.org/10.1016/0378-5122(80)90060-2">Rauramo et al., 1980</a>; <a href="https://doi.org/10.1016/0378-5122(81)90010-4">Rauramo, Punnonen, &amp; Grönroos, 1981</a>)</li>
|
||
<li><a href="https://en.wikipedia.org/wiki/Estradiol_benzoate/estradiol_phenylpropionate/testosterone_propionate/testosterone_phenylpropionate/testosterone_isocaproate">Estradiol benzoate/estradiol phenylpropionate/testosterone propionate/testosterone phenylpropionate/testosterone isocaproate</a> in oil (Estandron Prolongatum) (<a href="https://doi.org/10.1080/17843286.1975.11716973">Vermeulen, 1975</a>)</li>
|
||
<li><a href="https://en.wikipedia.org/wiki/Estradiol_benzoate/estradiol_dienanthate/testosterone_enanthate_benzilic_acid_hydrazone">Estradiol benzoate/estradiol dienanthate/testosterone enanthate benzilic acid hydrazone</a> in oil (Climacteron) (<a href="https://doi.org/10.3109/01674828709016773">Sherwin &amp; Gelfand, 1987</a>; <a href="https://doi.org/10.1016/0002-9378(87)90295-X">Sherwin et al., 1987</a>; <a href="https://doi.org/10.1016/0165-0327(88)90061-4">Sherwin, 1988</a> [<a href="https://en.wikipedia.org/wiki/Template:Hormone_levels_with_estradiol_benzoate/estradiol_dienanthate/testosterone_enanthate_benzilic_acid_hydrazone_by_intramuscular_injection">Graphs</a>])</li>
|
||
</ul>
|
||
|
||
<p>These preparations were not included in the present meta-analysis due to their relative obscurity and the limited data available for them. In addition, there were concerns about fitting the used pharmacokinetic models to the formulations with multiple estradiol components and to the microsphere formulations.</p>
|
||
|
||
<p>No estradiol concentration–time data were identified for certain other injectable estradiol forms of interest, like unesterified estradiol in aqueous solution, estradiol benzoate as a microcrystalline aqueous suspension (Agofollin Depot; Ovocyclin M), or <a href="https://en.wikipedia.org/wiki/Estradiol_benzoate_butyrate/algestone_acetophenide">estradiol benzoate butyrate/dihydroxyprogesterone acetophenide</a> in oil (Redimen, Soluna, Unijab) (another lesser-known combined injectable contraceptive).</p>
|
||
|
||
<h3 id="all-injectable-estradiol-preparations-together">All Injectable Estradiol Preparations Together</h3>
|
||
|
||
<p>Figure 8 shows the curve fits for all of the injectable estradiol preparations scaled to a single dose of 5 mg (or equivalent) together in the same figure. The dose for polyestradiol phosphate was scaled to be about 6.5 times higher than the other injectable estradiol preparations in order to make it roughly equivalent to them in terms of total estradiol exposure. This was because polyestradiol phosphate was found to produce much lower area-under-the-curve estradiol levels than the other injectable estradiol preparations (see the <a href="#discussion">Discussion</a> section). Estradiol undecylate was not included in Figure 8 as a decent fit curve could not be obtained for it due to the very limited data available for this preparation.</p>
|
||
|
||
<table>
|
||
<thead>
|
||
<tr>
|
||
<th><img src="/assets/images/injectable-e2/all_v3c.svg" alt="" /></th>
|
||
</tr>
|
||
</thead>
|
||
<tbody>
|
||
<tr>
|
||
<td><strong>Figure 8:</strong> Curve fits of published estradiol concentration–time data with different injectable estradiol preparations by intramuscular injection scaled to equivalent doses and plotted over a period of 20 days in a single combined graph. Polyestradiol phosphate is scaled to a 6.5-fold higher dose that is roughly equivalent to that for the other esters as it gave total estradiol levels that were around 6 or 7 times lower than the other esters at the same dose. An alternative version of this figure without estradiol benzoate and with the x-axis spanning 30 days is also provided (<a href="/assets/images/injectable-e2/all_v3c_no_eb.svg">Graph</a>).</td>
|
||
</tr>
|
||
</tbody>
|
||
</table>
|
||
|
||
<p>Figure 9 shows simulated curves at steady state for repeated administration of all of the injectable estradiol preparations scaled to a dose of 5 mg (or equivalent) once every 7 days. As with the previous figure, the dose for polyestradiol phosphate was scaled to be about 6.5 times higher than the other injectable estradiol preparations and estradiol undecylate was not included in the figure.</p>
|
||
|
||
<table>
|
||
<thead>
|
||
<tr>
|
||
<th><img src="/assets/images/injectable-e2/all_v3c_repeated.svg" alt="" /></th>
|
||
</tr>
|
||
</thead>
|
||
<tbody>
|
||
<tr>
|
||
<td><strong>Figure 9:</strong> Simulated curves at steady state for repeated administration of different injectable estradiol preparations by intramuscular injection scaled to equivalent doses and plotted over three injection cycles. This simulation was based on the fit curves of the published single-dose estradiol concentration–time data reported in this meta-analysis. Polyestradiol phosphate is scaled to a 6.5-fold higher dose that is roughly equivalent to that for the other esters as it gave total estradiol levels that were around 6 or 7 times lower than the other esters at the same dose. An alternative version of this figure without estradiol benzoate is also provided (<a href="/assets/images/injectable-e2/all_v3c_repeated_no_eb.svg">Graph</a>).</td>
|
||
</tr>
|
||
</tbody>
|
||
</table>
|
||
|
||
<p>For more simulated estradiol concentration–time curves with repeated injections of these injectable estradiol preparations, please see the accompanying <a href="#interactive-web-simulator">interactive web simulator</a>.</p>
|
||
|
||
<h3 id="selected-pharmacokinetic-parameters">Selected Pharmacokinetic Parameters</h3>
|
||
|
||
<p>The table below shows selected pharmacokinetic parameters for the fit curves of the included injectable estradiol preparations (Table 9). Estradiol undecylate was not included in the table due to the lack of data needed to achieve a decent curve fit for this preparation and the uncertainty of its parameters.</p>
|
||
|
||
<p><strong>Table 9:</strong> Selected pharmacokinetic parameters for estradiol with injectable estradiol preparations following a single 5 mg dose by intramuscular injection:</p>
|
||
|
||
<table>
|
||
<thead>
|
||
<tr>
|
||
<th>Estradiol preparation</th>
|
||
<th>T<sub>max</sub><br />(d)</th>
|
||
<th>C<sub>max</sub><br />(pg/mL)</th>
|
||
<th>t<sub>1/2</sub><br />(d)</th>
|
||
<th>t<sub>90%</sub><br />(d)</th>
|
||
<th>AUC<sub>0–∞</sub><br />(pg•d/mL)</th>
|
||
</tr>
|
||
</thead>
|
||
<tbody>
|
||
<tr>
|
||
<td>Estradiol benzoate in oil</td>
|
||
<td>0.65</td>
|
||
<td>971</td>
|
||
<td>1.2</td>
|
||
<td>3.9</td>
|
||
<td>2410</td>
|
||
</tr>
|
||
<tr>
|
||
<td>Estradiol valerate in oil</td>
|
||
<td>2.1</td>
|
||
<td>295</td>
|
||
<td>3.0</td>
|
||
<td>9.9</td>
|
||
<td>1886</td>
|
||
</tr>
|
||
<tr>
|
||
<td>Estradiol cypionate oil</td>
|
||
<td>4.3</td>
|
||
<td>155</td>
|
||
<td>6.7</td>
|
||
<td>22.3</td>
|
||
<td>2150</td>
|
||
</tr>
|
||
<tr>
|
||
<td>Estradiol cypionate suspension</td>
|
||
<td>1.2</td>
|
||
<td>241</td>
|
||
<td>5.1</td>
|
||
<td>16.9</td>
|
||
<td>2096</td>
|
||
</tr>
|
||
<tr>
|
||
<td>Estradiol enanthate in oil</td>
|
||
<td>6.5</td>
|
||
<td>160</td>
|
||
<td>4.6</td>
|
||
<td>15.1</td>
|
||
<td>2183</td>
|
||
</tr>
|
||
<tr>
|
||
<td>Polyestradiol phosphate <sup>a</sup></td>
|
||
<td>18.0</td>
|
||
<td>34</td>
|
||
<td>28.4</td>
|
||
<td>94.2</td>
|
||
<td>2117</td>
|
||
</tr>
|
||
</tbody>
|
||
</table>
|
||
|
||
<p><small><sup>a</sup> Scaled instead to a single 32.5 mg injection (6.5 times higher dose than with the other esters).</small></p>
|
||
|
||
<p>The table below shows selected pharmacokinetic parameters for simulated curves at steady state with repeated administration of the included injectable estradiol preparations (Table 10). As with the previous table, estradiol undecylate was not included.</p>
|
||
|
||
<p><strong>Table 10:</strong> Selected pharmacokinetic parameters for estradiol with injectable estradiol preparations with simulated repeated administration of 5 mg once every 7 days by intramuscular injection:</p>
|
||
|
||
<table>
|
||
<thead>
|
||
<tr>
|
||
<th>Estradiol preparation</th>
|
||
<th>T<sub>max</sub><br />(d)</th>
|
||
<th>C<sub>max</sub><br />(pg/mL)</th>
|
||
<th>C<sub>min</sub><br />(pg/mL)</th>
|
||
<th>Peak–trough<br />diff. (pg/mL)</th>
|
||
<th>Peak–trough<br />ratio</th>
|
||
<th>C<sub>avg</sub><br />(pg/mL)</th>
|
||
</tr>
|
||
</thead>
|
||
<tbody>
|
||
<tr>
|
||
<td>Estradiol benzoate in oil</td>
|
||
<td>0.64</td>
|
||
<td>990</td>
|
||
<td>29</td>
|
||
<td>962</td>
|
||
<td>35</td>
|
||
<td>344</td>
|
||
</tr>
|
||
<tr>
|
||
<td>Estradiol valerate in oil</td>
|
||
<td>1.9</td>
|
||
<td>384</td>
|
||
<td>142</td>
|
||
<td>242</td>
|
||
<td>2.7</td>
|
||
<td>269</td>
|
||
</tr>
|
||
<tr>
|
||
<td>Estradiol cypionate oil</td>
|
||
<td>3.1</td>
|
||
<td>339</td>
|
||
<td>262</td>
|
||
<td>77</td>
|
||
<td>1.3</td>
|
||
<td>307</td>
|
||
</tr>
|
||
<tr>
|
||
<td>Estradiol cypionate suspension</td>
|
||
<td>1.0</td>
|
||
<td>404</td>
|
||
<td>189</td>
|
||
<td>214</td>
|
||
<td>2.1</td>
|
||
<td>299</td>
|
||
</tr>
|
||
<tr>
|
||
<td>Estradiol enanthate in oil</td>
|
||
<td>4.0</td>
|
||
<td>329</td>
|
||
<td>288</td>
|
||
<td>41</td>
|
||
<td>1.1</td>
|
||
<td>312</td>
|
||
</tr>
|
||
<tr>
|
||
<td>Polyestradiol phosphate <sup>a</sup></td>
|
||
<td>3.2</td>
|
||
<td>304</td>
|
||
<td>299</td>
|
||
<td>5</td>
|
||
<td>1.0</td>
|
||
<td>302</td>
|
||
</tr>
|
||
</tbody>
|
||
</table>
|
||
|
||
<p><small><sup>a</sup> Scaled instead to repeated injections of 32.5 mg every 7 days (6.5 times higher dose than with the other esters).</small></p>
|
||
|
||
<p>Terminal half-life (t<sub>1/2</sub>) is the time for the concentration of estradiol to decrease by 50% after <a href="https://en.wiktionary.org/wiki/pseudoequilibrium">pseudo-equilibrium</a> of <a href="https://en.wikipedia.org/wiki/Distribution_(pharmacology)">distribution</a> has been reached—<em>not the time required for half of an administered dose of the estradiol ester to be <a href="https://en.wikipedia.org/wiki/Elimination_(pharmacology)">eliminated</a></em> (<a href="https://doi.org/10.1111/j.1365-2885.2004.00600.x">Toutain &amp; Bousquet-Mélou, 2004</a>). It is calculated using only the terminal portion of a concentration–time curve, without the <a href="https://en.wikipedia.org/wiki/Absorption_(pharmacology)">absorption</a> or distribution phases influencing it (<a href="https://doi.org/10.1111/j.1365-2885.2004.00600.x">Toutain &amp; Bousquet-Mélou, 2004</a>). Due to <a href="https://en.wikipedia.org/wiki/Flip%E2%80%93flop_kinetics">flip–flop kinetics</a> with depot injectables and the very short blood half-life of estradiol (~0.5–2 hours), what is being described by the terminal half-life in the case of depot estradiol injectables is not actually elimination of estradiol from blood but rather is the absorption of estradiol from the injection-site depot (<a href="https://doi.org/10.1111/j.1365-2885.2004.00600.x">Toutain &amp; Bousquet-Mélou, 2004</a>; <a href="https://doi.org/10.4155/tde.11.19">Yáñez et al., 2011</a>).</p>
|
||
|
||
<h2 id="discussion">Discussion</h2>
|
||
|
||
<h3 id="data-quality-limitations-and-variability-between-studies">Data Quality, Limitations, and Variability Between Studies</h3>
|
||
|
||
<p>The accuracies of the curve fits for the different included injectable estradiol preparations are limited by the available data for these preparations. The quantity and quality of data are variable among these preparations. In some cases, such as with estradiol valerate in oil and estradiol cypionate in suspension, the data are overall quite good. In other instances, such as with estradiol cypionate in oil and estradiol enanthate in oil, the available data are more limited. There was undersampling of certain parts of the concentration–time curve with some preparations, for instance estradiol benzoate in oil (the early curve), estradiol enanthate in oil (much of the curve), and polyestradiol phosphate (the late curve). In the case of estradiol undecylate in oil, the available data for this preparation weren’t adequate to achieve a decent curve fit at all. The fit curves and calculated pharmacokinetic parameters of the included injectable estradiol preparations should be interpreted with the imperfect data in mind. For example, the curve shapes and pharmacokinetic parameters for the different preparations should not be taken as precise determinations in most cases but instead as rough estimates that would no doubt change with more and better data. Indeed, the fits and pharmacokinetic parameters were often noticeably sensitive to the influences of individual studies. Modeling decisions, such as the choice of pharmacokinetic model, or whether to fit directly to the combined processed data versus to the fits of individual studies, also yielded significantly different curve fits as well as calculated pharmacokinetic parameters.</p>
|
||
|
||
<p>Due to scarcity of data for several injectable estradiol preparations, the study selection criteria maximized data inclusion in order to allow for better curve fits at the risk of including potentially less reliable data. As examples, studies were included regardless of the status of the HPG axis of the participants, and C<sub>max</sub> data were included in the fitting if data were very limited. In the case of HPG axis state, studies with cycling women may result in greater error due to more variable levels of endogenous estradiol. Moreover, acute high levels of estradiol can induce a surge in <a href="https://en.wikipedia.org/wiki/Luteinizing_hormone">luteinizing hormone</a> levels after several days in gonadally intact women, and this may cause a delayed bump in estradiol levels (<a href="https://en.wikipedia.org/wiki/Estrogen_provocation_test">Wiki</a>). One of the more overt instances of this can be seen in a study of estradiol benzoate in such women (<a href="https://doi.org/10.1016/S0300-595X(78)80008-5">Shaw, 1978</a> [<a href="https://commons.wikimedia.org/wiki/File:Estrogen_provocation_test_and_gonadotropin_surge_with_a_single_injection_of_estradiol_benzoate_in_premenopausal_women.png">Graph</a>]). Many if not most of the included studies with estradiol benzoate involved women with intact HPG axes, whereas studies of this sort were uncommon with the other preparations. In the case of C<sub>max</sub> data, these data when C<sub>max</sub> corresponds to the mean of individual peaks are a different type of data than the peak of the mean curve of all individuals. C<sub>max</sub> levels can differ in both magnitude and timing compared to the mean curve peak (e.g., <a href="https://doi.org/10.1016/S0010-7824(80)80018-7">Oriowo et al., 1980</a> [<a href="https://commons.wikimedia.org/wiki/File:Estradiol_levels_after_a_single_5_mg_intramuscular_injection_of_estradiol_esters.png">Graph</a>]; <a href="https://doi.org/10.1016/S0010-7824(99)00086-4">Rahimy, Ryan, &amp; Hopkins, 1999</a>). This is because for instance not all individuals peak at the same time and this variability in time to peak normally serves to dilute peak levels for the mean curve when compared to individual maximal concentrations. However, C<sub>max</sub> levels are in any case generally in the vicinity of the mean curve peak. While C<sub>max</sub> levels were excluded in the fitting for most injectable estradiol preparations, they were included in the case of estradiol enanthate. This was because the available mean and individual estradiol curve data were very limited for this specific preparation, and inclusion of C<sub>max</sub> data allowed for improved fitting in spite of its limitations. Lastly, some of the included data was once-monthly multi-dose, and research with once-monthly estradiol enanthate-containing combined injectable contraceptives has found that the time to peak levels may shift with repeated long-term use (<a href="https://doi.org/10.1016/0010-7824(88)90005-4">Schiavon et al., 1988</a>; <a href="https://doi.org/10.1016/0010-7824(94)90032-9">Garza-Flores, 1994</a>).</p>
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<p>There was considerable variability between studies in terms of estradiol levels and concentration–time curve shapes with the same injectable estradiol preparation. The reasons for the large variability across studies are not fully clear. In any case, there are many potential factors that may contribute to this variability. These include preparation- and injection-related factors like <a href="https://en.wikipedia.org/wiki/Pharmaceutical_formulation">formulation</a> (e.g., <a href="https://en.wikipedia.org/wiki/Excipient#Vehicles">oil vehicle</a>, other components and <a href="https://en.wikipedia.org/wiki/Excipient">excipients</a>, concentration, <a href="https://en.wikipedia.org/wiki/Particle_size">particle size</a>), injection volume, <a href="https://en.wikipedia.org/wiki/Injection_site">site of injection</a> (e.g., <a href="https://en.wikipedia.org/wiki/Gluteal_muscles">buttocks</a>, <a href="https://en.wikipedia.org/wiki/Vastus_lateralis_muscle">thigh</a>, <a href="https://en.wikipedia.org/wiki/Deltoid_muscle">upper arm</a>), injection technique (e.g., force of injection—and resulting depot droplet dimensions), and <a href="https://en.wikipedia.org/wiki/Syringe_dead_space">syringe dead space</a>. They additionally include various subject- and research-related variables like differing <a href="https://en.wikipedia.org/wiki/Analytical_technique">blood-testing methodology</a>, differing <a href="https://en.wikipedia.org/wiki/Sample_(statistics)">sample</a> characteristics (e.g., age, weight, gender, ethnicity, physical activity, HPG axis state), and <a href="https://en.wikipedia.org/wiki/Sampling_error">sampling error</a> (<a href="https://scholar.google.com/scholar?cluster=12842077211931556704">Sinkula, 1978</a>; <a href="https://journal.pda.org/content/35/3/106.short">Chien, 1981</a>; <a href="https://jpet.aspetjournals.org/content/281/1/93.short">Minto et al., 1997</a>; <a href="https://doi.org/10.1208/s12248-009-9153-9">Larsen &amp; Larsen, 2009</a>; <a href="https://doi.org/10.1517/17425240903307431">Larsen et al., 2009</a>; <a href="https://books.google.com/books?id=5wcyP2OBPhoC&amp;pg=PA80">Florence, 2010</a>; <a href="https://doi.org/10.1007/978-1-4614-0554-2_7">Larsen, Thing, &amp; Larsen, 2012</a>; <a href="https://dspace.library.uu.nl/handle/1874/348465">Kalicharan, 2017</a>). Older studies, which used potentially less accurate blood tests and tended to have smaller numbers of subjects, seemed to particularly add to the variability between studies. These studies may represent less reliable data than more recent research with larger sample sizes. The exclusion criteria helped to remove <a href="https://en.wikipedia.org/wiki/Outlier">outliers</a> for the different injectable estradiol preparations however. This meta-analysis does not take into account the potential factors underlying the variability between studies. To do so would be difficult, as in many cases information on these variables is not provided in individual studies and research quantifying their precise influences and relative importances is limited.</p>
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<p>It is in any case known from other studies that different oil vehicles are absorbed at different rates from the injection site (<a href="https://doi.org/10.1111/j.1600-0773.1979.tb02404.x">Svendsen &amp; Aaes‐Jørgensen, 1979</a>; <a href="https://doi.org/10.1016/S0378-5173(98)00121-5">Schultz et al., 1998</a>; <a href="https://doi.org/10.1016/S0378-5173(01)00860-2">Larsen et al., 2001</a>) and can result in different concentration–time curve shapes (<a href="https://scholar.google.com/scholar?cluster=7643602853178335452">Ballard, 1978</a> [<a href="https://archive.is/PbwqF">Excerpt</a>]; <a href="https://doi.org/10.1111/j.1600-0447.1985.tb08535.x">Knudsen, Hansen, &amp; Larsen, 1985</a>). This is thought to be due to differences in oil lipophilicity and depot release rates. <a href="https://en.wikipedia.org/wiki/Viscosity">Viscosity</a> of oils has also been hypothesized to potentially influence rate of depot escape (<a href="https://doi.org/10.5414/cp201589">Schug, Donath, &amp; Blume, 2012</a>). However, research so far has not supported this hypothesis (<a href="https://doi.org/10.1208/s12248-009-9153-9">Larsen &amp; Larsen, 2009</a>; <a href="https://doi.org/10.1007/978-1-4614-0554-2_7">Larsen, Thing, &amp; Larsen, 2012</a>). Oil vehicles can vary with injectable estradiol preparations even for the same estradiol ester. For instance, pharmaceutical estradiol valerate is formulated in <a href="https://en.wikipedia.org/wiki/Sesame_oil">sesame oil</a>, <a href="https://en.wikipedia.org/wiki/Castor_oil">castor oil</a>, or <a href="https://en.wikipedia.org/wiki/Sunflower_oil">sunflower oil</a> depending on the preparation (<a href="https://files.transfemscience.org/pdfs/docs/Injectable%20Estradiol%20Vehicles%20and%20Their%20Compositions%20and%20Properties.pdf">Table</a>). It is notable however that these three oils have similar lipophilicities (<a href="https://files.transfemscience.org/pdfs/docs/Injectable%20Estradiol%20Vehicles%20and%20Their%20Compositions%20and%20Properties.pdf">Table</a>). On the other hand, <a href="https://en.wiktionary.org/wiki/homebrew">homebrewed</a> injectable estradiol preparations used by DIY transfeminine people often employ <a href="https://en.wikipedia.org/wiki/Medium-chain_triglyceride">medium-chain triglyceride (MCT) oil</a> as the oil vehicle. This oil (in the proprietary form of <a href="https://en.wikipedia.org/wiki/Viscoleo">Viscoleo</a>) has notably been found to be much more rapidly absorbed than conventional oils like sesame oil and castor oil in animals (<a href="https://doi.org/10.1111/j.1600-0773.1979.tb02404.x">Svendsen &amp; Aaes‐Jørgensen, 1979</a>; <a href="https://doi.org/10.1016/S0378-5173(98)00121-5">Schultz et al., 1998</a>; <a href="https://doi.org/10.1016/S0378-5173(01)00860-2">Larsen et al., 2001</a>). In addition, although based on very limited data, MCT oil has been found to give spikier and shorter-lasting depot injectable curves in humans (<a href="https://doi.org/10.1111/j.1600-0447.1985.tb08535.x">Knudsen, Hansen, &amp; Larsen, 1985</a>). As such, injectable estradiol preparations using MCT oil as the vehicle may have differing and less favorable concentration–time curve shapes than pharmaceutical injectable estradiol products. Other excipients, like <a href="https://en.wikipedia.org/wiki/Benzyl_alcohol">benzyl alcohol</a>, as well as factors like injection site and volume, have additionally been found to influence pharmacokinetic properties with depot injectables (<a href="https://jpet.aspetjournals.org/content/281/1/93.short">Minto et al., 1997</a>; <a href="https://doi.org/10.1016/j.ejps.2015.12.011">Kalicharan, Schot, &amp; Vromans, 2016</a>). Excipients besides oil vehicle also vary by formulation (<a href="https://files.transfemscience.org/pdfs/docs/Injectable%20Estradiol%20Vehicles%20and%20Their%20Compositions%20and%20Properties.pdf">Table</a>).</p>
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||
<p>An implication of the variability between studies is that there is not a single estradiol concentration–time curve for a given injectable estradiol preparation but rather there are many, with these curves determined by variables such as formulation, dose/administration, and subject characteristics, among others. Hence, the curve fits determined in this meta-analysis represent only an estimation of the most typical and hence likely case, but the true curve for a preparation in a given context may be quite different.</p>
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<p>Fitting all studies for a given injectable estradiol preparation individually first, and then fitting the fits of these studies, allowed for improved curve fits relative to directly fitting all of the combined processed original data for the preparation. The latter approach has limitations in that it has the effect of inherently weighting individual studies by quantity of time points (resulting in studies with greater time sampling having greater influence on the fit). Additionally, and more problematically, this approach can lead to distortions in curve shape due to different studies sampling different portions of the curve to differing extents in conjunction with systematic differences in curves between these studies. These are problems that fitting the fits of individual studies instead can solve. However, it is not possible to fit all individual studies, as some studies have limited time sampling and curve characterization which precludes fitting them appropriately. C<sub>max</sub> data are an example of this, which on their own cannot be fit properly. As such, it was not possible to fit the fits of the individual studies for all injectable estradiol preparations. Consequently, the fitting approach in this regard was not the same across esters, with some fit instead directly to the combined processed original data (e.g., estradiol enanthate, polyestradiol phosphate).</p>
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<p>In spite of the various limitations of this work, aggregated analysis and modeling with injectable estradiol preparations has not previously been done. This informal meta-analysis provides among the most detailed insight into estradiol levels and curve shapes with these preparations available to date.</p>
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<h3 id="durations-and-curve-shapes">Durations and Curve Shapes</h3>
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<p>The curve shapes of non-polymeric injectable estradiol esters in oil relate strongly to lipophilicity. The more lipophilic the ester, the lower the peak levels and the more protracted the estradiol concentration–time curve. Accordingly, estradiol benzoate, one of the least lipophilic estradiol esters, has one of the spikiest curves and shortest durations, whereas more lipophilic estradiol esters, like estradiol cypionate in oil and estradiol enanthate, have comparatively flatter curves with delayed peaks and longer durations.</p>
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<h4 id="duration-of-estradiol-valerate">Duration of Estradiol Valerate</h4>
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<p>The estradiol concentration–time curve for injectable estradiol valerate in the well-known <a href="https://doi.org/10.1016/S0010-7824(80)80018-7">Oriowo et al. (1980)</a> [<a href="https://commons.wikimedia.org/wiki/File:Estradiol_levels_after_a_single_5_mg_intramuscular_injection_of_estradiol_esters.png">Graph</a>] study is notably spikier and shorter-lasting than the overall curve for estradiol valerate in this meta-analysis. On the other hand, the overall curve for injectable estradiol valerate in this meta-analysis was similar to (and considerably influenced by) the curves from several relatively recent and presumably better-quality studies of this injectable estradiol ester (e.g., <a href="https://www.kup.at/journals/summary/1071.html">Göretzlehner et al., 2002</a>; <a href="https://repositoriodigital.ipn.mx/handle/123456789/12490">Valle Alvarez, 2011</a>; <a href="https://doi.org/10.5414/cp201589">Schug, Donath, &amp; Blume, 2012</a>). It’s noteworthy that <a href="https://doi.org/10.1016/S0010-7824(80)80018-7">Oriowo et al. (1980)</a> used a <a href="https://en.wikipedia.org/wiki/Peanut_oil">peanut oil</a>-based formulation of estradiol valerate that differed from pharmaceutical injectable estradiol valerate preparations, which generally use <a href="https://en.wikipedia.org/wiki/Sesame_oil">sesame oil</a> or <a href="https://en.wikipedia.org/wiki/Castor_oil">castor oil</a> as the carrier (as well as other excipients) (<a href="https://files.transfemscience.org/pdfs/docs/Injectable%20Estradiol%20Vehicles%20and%20Their%20Compositions%20and%20Properties.pdf">Table</a>). This may have influenced the curve shape of estradiol valerate in <a href="https://doi.org/10.1016/S0010-7824(80)80018-7">Oriowo et al. (1980)</a>. The study also had a small <a href="https://en.wikipedia.org/wiki/Sample_size">sample size</a> relative to the more recent studies (n=9 versus n=17, n=32, and n=24×2, respectively). Based on the newer and overall data, estradiol valerate appears to have a curve that is noticeably flatter and more prolonged than that suggested by <a href="https://doi.org/10.1016/S0010-7824(80)80018-7">Oriowo et al. (1980)</a>.</p>
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<h4 id="duration-of-estradiol-cypionate-in-oil-versus-estradiol-enanthate">Duration of Estradiol Cypionate in Oil versus Estradiol Enanthate</h4>
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<p>Available estradiol concentration–time data for injectable estradiol cypionate in oil and estradiol enanthate in oil are more limited than with several of the other injectable estradiol preparations, and no direct comparisons of these two preparations exist at present. Based on some of the available literature on these injectable estradiol esters, most notably discussion by <a href="https://doi.org/10.1016/S0010-7824(80)80018-7">Oriowo et al. (1980)</a> and a review of the pharmacokinetics of combined injectable contraceptives (<a href="https://doi.org/10.1016/0010-7824(94)90032-9">Garza-Flores, 1994</a> [<a href="https://commons.wikimedia.org/wiki/File:Idealized_curves_of_estradiol_levels_after_injection_of_different_estradiol_esters_in_women.png">Graph</a>]), it seemed that the duration of estradiol enanthate in oil was longer than that of estradiol cypionate in oil. However, this was based on limited research from separate and hence indirectly comparative studies of these esters. The estradiol cypionate in oil data from the relevant <a href="https://doi.org/10.1016/0010-7824(94)90032-9">Garza-Flores (1994)</a> figure was based on <a href="https://doi.org/10.1016/S0010-7824(80)80018-7">Oriowo et al. (1980)</a> [<a href="https://commons.wikimedia.org/wiki/File:Estradiol_levels_after_a_single_5_mg_intramuscular_injection_of_estradiol_esters.png">Graph</a>], and there are reasons to be cautious about relying on these data alone. The main concern is that curve shapes with the same injectable estradiol preparation can vary considerably across studies, as the present meta-analysis has shown. The reasons for this have yet to be fully clarified as already discussed, but among other factors may include varying formulations across studies of the same injectable estradiol ester. It is notable in this regard that <a href="https://doi.org/10.1016/S0010-7824(80)80018-7">Oriowo et al. (1980)</a> used a formulation of estradiol cypionate that differs from conventional pharmaceutical estradiol cypionate in oil preparations—specifically, the study used a <a href="https://en.wikipedia.org/wiki/Peanut_oil">peanut oil</a>-based formulation (with few other specifics) rather than the <a href="https://en.wikipedia.org/wiki/Cottonseed_oil">cottonseed oil</a>-based preparation employed in marketed pharmaceutical formulations (<a href="https://files.transfemscience.org/pdfs/docs/Injectable%20Estradiol%20Vehicles%20and%20Their%20Compositions%20and%20Properties.pdf">Table</a>). The study also had a somewhat small <a href="https://en.wikipedia.org/wiki/Sample_size">sample size</a> (n=10) and may have had significant <a href="https://en.wikipedia.org/wiki/Sampling_error">sampling error</a>. Hence, single studies, perhaps particularly <a href="https://doi.org/10.1016/S0010-7824(80)80018-7">Oriowo et al. (1980)</a>, should be interpreted cautiously.</p>
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<p>A small but interesting pharmacokinetic study which directly compared injectable <a href="https://en.wikipedia.org/wiki/Testosterone_cypionate">testosterone cypionate</a> (n=6) and <a href="https://en.wikipedia.org/wiki/Testosterone_enanthate">testosterone enanthate</a> (n=6) both in oil is relevant to the topic in question. This study found that equivalent doses of these testosterone esters using otherwise identical formulations produced virtually identical testosterone concentration–time curves (<a href="https://doi.org/10.1016/S0015-0282(16)44543-7">Schulte-Beerbühl &amp; Nieschlag, 1980</a> [<a href="https://commons.wikimedia.org/wiki/File:Testosterone_levels_with_a_single_intramuscular_injection_of_about_200_mg_testosterone_enanthate_or_testosterone_cypionate_in_oil_in_men.png">Graph</a>]). The findings of this study are consistent with the fact that the lipophilicities of testosterone cypionate and testosterone enanthate (as measured by predicted <a href="https://en.wikipedia.org/wiki/Octanol-water_partition_coefficient">log P</a>) are very similar when directly compared (e.g., 5.1 vs. 5.11 with <a href="http://www.vcclab.org/lab/alogps/">ALOGPS</a>, 6.29 vs. 6.11 with <a href="https://docs.chemaxon.com/display/docs/logp-plugin.md">ChemAxon logP</a>, and 6.4 vs. 6.3 with <a href="http://www.sioc-ccbg.ac.cn/skins/ccbgwebsite/software/xlogp3/">XLogP3</a>, respectively (<a href="https://files.transfemscience.org/pdfs/docs/Sex%20Hormone%20Ester%20Lipophilicity%20(Log%20P)%20Tables.pdf">Table</a>). This of course is of importance as lipophilicity is thought to be the key factor determining the release kinetics of oil-based depot injectables (<a href="https://scholar.google.com/scholar?cluster=12842077211931556704">Sinkula, 1978</a>; <a href="https://doi.org/10.1007/978-0-387-49785-3_9">Shah, 2007</a>; <a href="https://doi.org/10.1208/s12248-009-9153-9">Larsen &amp; Larsen, 2009</a>; <a href="https://doi.org/10.1007/978-1-4614-0554-2_7">Larsen, Thing, &amp; Larsen, 2012</a>; <a href="https://doi.org/10.1201/b22448-9">Shahiwala, Mehta, &amp; Momin, 2018</a>). Analogously similar lipophilicities can be seen when comparing estradiol cypionate and estradiol enanthate, which employ the same ester moieties (e.g., predicted log P values of 6.47 vs. 6.45 with ALOGPS and 7.1 vs. 7.0 with XLogP3, respectively) (<a href="https://files.transfemscience.org/pdfs/docs/Sex%20Hormone%20Ester%20Lipophilicity%20(Log%20P)%20Tables.pdf">Table</a>). Hence, on a theoretical level, injectable estradiol cypionate and estradiol enanthate, like injectable testosterone cypionate and testosterone enanthate, might be expected to produce very similar curves—at least provided all other variables, such as formulation, are held constant.</p>
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<p>The present meta-analysis found that the overall estradiol curve for estradiol cypionate in oil was significantly less spikey and more prolonged than that observed in <a href="https://doi.org/10.1016/S0010-7824(80)80018-7">Oriowo et al. (1980)</a>. It is noteworthy in this regard that all of the other studies included for estradiol cypionate in oil specifically employed pharmaceutical Depo-Estradiol and that the overall curve for this preparation appears to be more consistent with its licensed injection interval for use in menopausal hormone therapy (1–5 mg once every 3–4 weeks) (<a href="https://www.accessdata.fda.gov/drugsatfda_docs/label/2005/085470s015lbl.pdf">Depo-Estradiol Label</a>). Moreover, this meta-analysis found that injectable estradiol cypionate in oil and estradiol enanthate in oil had fairly similar and comparably flat and prolonged estradiol concentration–time curves. However, estradiol cypionate in oil appeared to peak earlier than estradiol enanthate, while estradiol enanthate was eliminated more rapidly than estradiol cypionate in oil in the terminal portion of the curve. In any case, the available concentration–time data for these preparations are limited, and the present work is not able to determine whether these estradiol esters have truly differing pharmacokinetic properties, as the apparent differences between the curves for these preparations may simply be due to statistical error. Taken together, estradiol cypionate in oil may have a less spikey and longer-lasting curve than that implied by <a href="https://doi.org/10.1016/S0010-7824(80)80018-7">Oriowo et al. (1980)</a>, and estradiol cypionate in oil and estradiol enanthate may have more similar curves than has been previously assumed.</p>
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<h4 id="curve-shape-of-estradiol-cypionate-suspension">Curve Shape of Estradiol Cypionate Suspension</h4>
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<p>While estradiol cypionate as an aqueous suspension is a relatively long-lasting injectable estradiol preparation similarly to estradiol cypionate in oil and estradiol enanthate in oil, it seems to differ in the shape of its estradiol concentration–time curve from these preparations. Estradiol cypionate as a suspension has a curve that appears to peak significantly earlier than estradiol cypionate in oil and other longer-acting oil-based injectable estradiol preparations. This might relate to the differing mechanisms of depot action and unique properties of injectable aqueous suspensions (<a href="/articles/aqueous-suspensions/">Aly, 2019</a>). In line with this notion, injectable <a href="https://en.wikipedia.org/wiki/Medroxyprogesterone_acetate">medroxyprogesterone acetate</a> suspension (Depo-Provera) also appears to peak rapidly despite having a very long duration (longer durations tending to be associated with delayed peaks in the case of oil-based depot injectables) (<a href="https://en.wikipedia.org/wiki/Medroxyprogesterone_acetate#Time%E2%80%93concentration_curves">Graphs</a>). Although aqueous suspensions generally last longer than oil solutions as injectables (<a href="https://doi.org/10.1016/0039-128x(83)90109-5">Enever et al., 1983</a>; <a href="/articles/aqueous-suspensions/">Aly, 2019</a>), this is not always the case, and estradiol cypionate suspension interestingly seems to be shorter-acting than estradiol cypionate in oil.</p>
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<h3 id="estradiol-exposure-and-potency">Estradiol Exposure and Potency</h3>
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<p>The average estradiol levels with the non-polymeric injectable estradiol esters when scaled to a dose and dosing interval of 5 mg every 7 days were around 300 pg/mL (~1,100 pmol/L). For comparison, in premenopausal cisgender women, estradiol production is on average about 200 μg/day (or 6 mg per month/cycle) and mean estradiol levels are around 100 pg/mL (~370 pmol/L) (<a href="/articles/transfem-intro/#normal-hormone-levels">Aly, 2019</a>). After adjusting for the <a href="https://en.wikipedia.org/wiki/Molecular_weight">molecular weight</a> of the ester, the estradiol levels for a given dose of non-polymeric injectable estradiol esters are in fairly close agreement with the estradiol levels for an equal quantity of estradiol produced endogenously by the ovaries in premenopausal cisgender women (very roughly around 1.2 mg estradiol per 7 days for injectable estradiol esters and 1.4 mg estradiol per 7 days for ovarian production to achieve average integrated estradiol levels of around 100 pg/mL). The preceding is in accordance with the fact that injectable estradiol valerate has been reported to have approximately 100% <a href="https://en.wikipedia.org/wiki/Bioavailability">bioavailability</a> (with this being less characterized but likely also the case for the other non-polymeric injectable estradiol esters) (<a href="https://doi.org/10.1016/0378-5122(82)90064-0">Düsterberg &amp; Nishino, 1982</a>; <a href="https://doi.org/10.1016/0010-7824(94)90030-2">Seibert &amp; Günzel, 1994</a>).</p>
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<p>Although non-polymeric injectable estradiol esters have differing estradiol concentration–time curve shapes, they all appear to achieve fairly similar area-under-the-curve levels of estradiol when compared to one another. This is in accordance with the fact that differences in molecular weight and hence estradiol content with the different estradiol esters are fairly minor (all of the assessed non-polymeric esters range from 62 to 76% of that of estradiol in terms of estradiol content, and all but estradiol undecylate are in the range of 69 to 76%) (<a href="https://en.wikipedia.org/wiki/Template:Structural_properties_of_selected_estradiol_esters">Table</a>). The appearance of differences in area-under-the-curve levels of estradiol in the present meta-analysis is probably just due to <a href="https://en.wikipedia.org/wiki/Statistical_error">statistical error</a>, and true differences cannot be established by this meta-analysis. An implication of the similar area-under-the-curve estradiol levels with the different non-polymeric injectable estradiol esters is that these preparations can all be expected to deliver a roughly comparable amount of estradiol for the same dose.</p>
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<p>On the other hand, the polymeric ester polyestradiol phosphate appears to produce around 6- to 7-fold lower area-under-the-curve and average estradiol levels than non-polymeric estradiol esters. This suggests that the estradiol in polyestradiol phosphate is not 100% bioavailable, and is supported by the fact that this ester is used clinically at substantially higher dosages than other injectable estradiol esters (40–320 mg/month), even for the same indications such as menopausal hormone therapy and treatment of prostate cancer (<a href="https://en.wikipedia.org/wiki/Polyestradiol_phosphate#Medical_uses">Wiki</a>; <a href="https://web.archive.org/web/20180102072958/http://pharmanovia.com/product/estradurin/">Estradurin Labels</a>). This does not seem to have been previously described in the literature, and the reasons for it are unknown. It seems possible that polyestradiol phosphate may be partially <a href="https://en.wikipedia.org/wiki/Excretion">excreted</a> before it can be cleaved into estradiol and thereby rendered partly <a href="https://en.wikipedia.org/wiki/Biological_activity">inactive</a>, in turn necessitating the use of higher doses to achieve the same estradiol levels and therapeutic effect.</p>
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|
||
<p>Although two given injectable estradiol preparations may produce equivalent total estradiol levels, this does not necessarily mean that they will always have the same estrogenic <a href="https://en.wikipedia.org/wiki/Potency_(pharmacology)">potency</a> (i.e., strength of effect at a given dose). It is plausible that spikier estradiol concentration–time curves, like with estradiol benzoate, may have overall lower estrogenic potency than more steady curves, like with estradiol enanthate. This is because <a href="https://en.wikipedia.org/wiki/Estrogen_receptor">estrogen receptors</a> for a given <a href="https://en.wikipedia.org/wiki/Tissue_(biology)">tissue</a> should become <a href="https://en.wikipedia.org/wiki/Binding_saturation">saturated</a> at a certain point due to the finite quantity of available <a href="https://en.wikipedia.org/wiki/Receptor_(biochemistry)">receptors</a> in the tissue. As a result, high peak estradiol levels with spikier curves may effectively be “wasted” to varying extents in different tissues. On the other hand, more spikey estradiol curves, due to higher peak estradiol levels, might have greater influence on tissues that require high estradiol levels for effect such as the liver (and by extension on coagulation and associated health risks) (<a href="/articles/estrogens-blood-clots/">Aly, 2020</a>). However, these possibilities are speculative and theoretical. Although some literature exists that is relevant to this issue (e.g., <a href="https://doi.org/10.1042/bj0310579">Parkes, 1937</a>; <a href="https://doi.org/10.1016/S0015-0282(16)31145-1">Bradbury, Long, &amp; Durham, 1953</a>), there is very little research in this area. Consequently, it is not currently possible to take into account time-related variations in estradiol levels or differing estradiol curve shapes when assessing the comparative estrogenic potency between injectable estradiol preparations (or between other estradiol forms/routes). It is also noteworthy that these variations depend on injection interval and may be reduced with shorter injection intervals that maintain steadier estradiol levels, which must also be considered.</p>
|
||
|
||
<h3 id="variability-between-individuals">Variability Between Individuals</h3>
|
||
|
||
<p>There is substantial variation in total estradiol levels and curve shapes between people with the same injectable estradiol preparation. Indicators of <a href="https://en.wikipedia.org/wiki/Interindividual_variability">interindividual variability</a> such as <a href="https://en.wikipedia.org/wiki/Standard_deviation">standard deviation</a> or 95% range have not been included in this meta-analysis at this time due to the large amount of additional time and work this would require (e.g., additional extraction of error bars from all studies and analysis). In any case, individual studies that were included show this marked interindividual variation (e.g., <a href="https://doi.org/10.1016/S0010-7824(80)80018-7">Oriowo et al., 1980</a>; <a href="https://www.worldcat.org/oclc/774239518">Derra, 1981</a> [<a href="https://archive.is/JyLYj">Graph</a>]; <a href="https://doi.org/10.1016/0010-7824(85)90081-2">Aedo et al., 1985</a> [<a href="https://archive.is/3zlVj">Graphs</a>]; <a href="https://doi.org/10.13699/j.cnki.1001-6821.1987.01.002">Sang et al., 1987</a> [<a href="https://archive.is/agwRs">Graphs</a>]; <a href="https://doi.org/10.1016/s0010-7824(99)00081-5">Rahimy &amp; Ryan, 1999</a> [<a href="https://commons.wikimedia.org/wiki/File:Estradiol_levels_with_a_single_intramuscular_injection_of_5_mg_estradiol_cypionate_in_aqueous_suspension_in_surgically_sterile_women.png">Graph</a>]; <a href="https://repositoriodigital.ipn.mx/handle/123456789/12490">Valle Alvarez, 2011</a> [<a href="https://commons.wikimedia.org/wiki/File:Estradiol_levels_with_a_single_intramuscular_injection_of_5_mg_estradiol_valerate_in_oil_in_32_men.png">Graph</a>]; <a href="https://doi.org/10.5414/CP201589">Schug, Donath, &amp; Blume, 2012</a> [<a href="https://archive.is/UAQdX">Graphs</a>]). Highly variable estradiol levels are already well-established with oral and transdermal estradiol (<a href="https://doi.org/10.1080/13697130500148875">Kuhl, 2005</a>; <a href="https://en.wikipedia.org/wiki/Pharmacokinetics_of_estradiol">Wiki</a>). Less variability might be expected with non-polymeric injectable estradiol esters since these preparations appear to have approximately complete bioavailability. However, it seems that even with injectable forms of estradiol, the variability between people is still quite substantial. An implication of this is that the appropriate dose and dosing interval of an injectable estradiol formulation for a given person will vary considerably. This emphasizes the importance of blood work to ensure that injectable estradiol preparations are neither overdosed—which can increase health risks such as blood clots (<a href="/articles/estrogens-blood-clots/">Aly, 2020</a>)—nor underdosed—which may result in suboptimal testosterone suppression and therapeutic efficacy.</p>
|
||
|
||
<h3 id="insights-for-clinical-guidelines-and-dosing-recommendations">Insights for Clinical Guidelines and Dosing Recommendations</h3>
|
||
|
||
<p>Clinical guidelines for transgender health (see also <a href="/articles/transfem-hormone-guidelines/">Aly (2020)</a>) provide recommendations on doses and dosing intervals of injectable estradiol valerate in oil and estradiol cypionate in oil (Table 11). Dosing recommendations are not given for other injectable estradiol preparations, which are much less commonly used in transgender medicine. The recommended doses for estradiol valerate and estradiol cypionate vary widely depending on the guidelines, whereas the recommended intervals are consistently once every 1 to 2 weeks. The doses for estradiol valerate range from 2 to 20 mg/week or 5 to 80 mg/2 weeks and the doses for estradiol cypionate range from &lt;1 to 10 mg/week or &lt;2 to 80 mg/2 weeks. For reference, the <a href="https://en.wikipedia.org/wiki/Endocrine_Society">Endocrine Society</a> guidelines and the <a href="https://en.wikipedia.org/wiki/University_of_California,_San_Francisco">University of California, San Francisco</a> (UCSF) guidelines are the most major clinical guidelines for transgender hormone therapy at present (<a href="/articles/transfem-hormone-guidelines/">Aly, 2020</a>). The Endocrine Society guidelines recommend 5 to 30 mg/2 weeks or 2 to 10 mg/week for either estradiol valerate or estradiol cypionate (<a href="https://doi.org/10.1210/jc.2017-01658">Hembree et al., 2017</a>). Conversely, the UCSF guidelines recommend &lt;20 to 40 mg/2 weeks for estradiol valerate and &lt;2 to 5 mg/2 weeks for estradiol cypionate (with the option to divide dose into weekly injections if cyclical side effects occur) (<a href="https://transcare.ucsf.edu/guidelines">Deutsch, 2016a</a>).</p>
|
||
|
||
<p><strong>Table 11:</strong> Recommended doses and injection intervals of injectable estradiol preparations (specifically estradiol valerate and estradiol cypionate) in transgender medicine clinical guidelines<sup>a</sup>:</p>
|
||
|
||
<table>
|
||
<thead>
|
||
<tr>
|
||
<th>Guidelines</th>
|
||
<th>Ester(s)</th>
|
||
<th>Dose ranges and intervals</th>
|
||
</tr>
|
||
</thead>
|
||
<tbody>
|
||
<tr>
|
||
<td><a href="https://doi.org/10.1210/jc.2017-01658">Endocrine Society / Hembree et al. (2017)</a></td>
|
||
<td>Estradiol valerate or cypionate</td>
|
||
<td>5–30 mg/2 weeks or 2–10 mg/week i.m.</td>
|
||
</tr>
|
||
<tr>
|
||
<td><a href="https://transcare.ucsf.edu/guidelines/feminizing-hormone-therapy">UCSF / Deutsch (2016b)</a></td>
|
||
<td>Estradiol valerate</td>
|
||
<td>Initial–low: &lt;20 mg/2 weeks i.m.<br />Initial: 20 mg/2 weeks i.m.<br />Maximum: 40 mg/2 weeks i.m.<br />Note: “May divide dose into weekly injections for cyclical symptoms”<br />Note: Specifically for transfeminine adults</td>
|
||
</tr>
|
||
<tr>
|
||
<td> </td>
|
||
<td>Estradiol cypionate</td>
|
||
<td>Initial–low: &lt;2 mg/2 weeks i.m.<br />Initial: 2 mg/2 weeks i.m.<br />Maximum: 5 mg/2 weeks i.m.<br />Note: “May divide dose into weekly injections for cyclical symptoms”<br />Note: Specifically for transfeminine adults</td>
|
||
</tr>
|
||
<tr>
|
||
<td><a href="https://web.archive.org/web/20220916063817/https://transcare.ucsf.edu/guidelines/youth">UCSF / Olson-Kennedy et al. (2016)</a></td>
|
||
<td>Estradiol valerate</td>
|
||
<td>5–20 mg/2 weeks<br />Maximum: 30–40 mg/2 weeks<br />Note: Specifically for transfeminine youth</td>
|
||
</tr>
|
||
<tr>
|
||
<td> </td>
|
||
<td>Estradiol cypionate</td>
|
||
<td>2–10 mg/week<br />Note: Specifically for transfeminine youth</td>
|
||
</tr>
|
||
<tr>
|
||
<td><a href="https://www.lgbthealtheducation.org/publication/transgender-sod/">Fenway Health / Cavanaugh et al. (2015)</a></td>
|
||
<td>Estradiol valerate</td>
|
||
<td>Initial: 5–10 mg/week i.m.<br />Usual: 20 mg/2 weeks i.m.<br />Maximum: 40 mg/2 weeks i.m.</td>
|
||
</tr>
|
||
<tr>
|
||
<td> </td>
|
||
<td>Estradiol cypionate</td>
|
||
<td>Initial: 2.5 mg/2 weeks i.m.<br />Usual: 5 mg/2 weeks i.m.<br />Maximum: 10 mg/2 weeks i.m.</td>
|
||
</tr>
|
||
<tr>
|
||
<td><a href="https://callen-lorde.org/transhealth/">Callen-Lorde (2018)</a></td>
|
||
<td>Estradiol valerate</td>
|
||
<td>Initial: 10–20 mg/2 weeks<br />Maximum: 20–40 mg/2 weeks</td>
|
||
</tr>
|
||
<tr>
|
||
<td> </td>
|
||
<td>Estradiol cypionate</td>
|
||
<td>Initial: 2.5 mg/2 weeks<br />Maximum: 5 mg/2 weeks</td>
|
||
</tr>
|
||
<tr>
|
||
<td><a href="https://www.sfdph.org/dph/comupg/oservices/medSvs/hlthCtrs/TransGendprotocols122006.pdf">Davidson et al. / Tom Waddell Health Center (2013)</a></td>
|
||
<td>Estradiol valerate or cypionate</td>
|
||
<td>Initial: 20–40 mg/2 weeks i.m.<br />Average: 40 mg/2 weeks i.m.<br />Maximum: 40–80 mg/2 weeks i.m.</td>
|
||
</tr>
|
||
<tr>
|
||
<td><a href="https://www.rainbowhealthontario.ca/product/4th-edition-sherbournes-guidelines-for-gender-affirming-primary-care-with-trans-and-non-binary-patients/">Bourns / Sherbourne Health / Rainbow Health Ontario (2019)</a></td>
|
||
<td>Estradiol valerate</td>
|
||
<td>Initial: 3–4 mg/week or 6–8 mg/2 weeks<br />Usual: Variable<br />Maximum: 10 mg/week</td>
|
||
</tr>
|
||
<tr>
|
||
<td><a href="http://www.phsa.ca/transcarebc/Documents/HealthProf/Primary-Care-Toolkit.pdf">Trans Care BC (2021)</a></td>
|
||
<td>Estradiol valerate</td>
|
||
<td>Initial: 5 mg/week i.m. or s.c.<br />Usual: 10–20 mg/week i.m. or s.c.<br />Every 2 weeks at 2x dose may be tolerated in some</td>
|
||
</tr>
|
||
<tr>
|
||
<td><a href="http://www.phsa.ca/transcarebc/Documents/HealthProf/BC-Trans-Adult-Endocrine-Guidelines-2015.pdf">Dahl et al. / Vancouver Coastal Health (2015)</a></td>
|
||
<td>Estradiol valerate</td>
|
||
<td>20–40 mg/2 weeks i.m.<br />Note: “Alternative estrogen therapy for 3–6 months only”</td>
|
||
</tr>
|
||
<tr>
|
||
<td><a href="https://doi.org/10.1016/j.jsxm.2020.01.012">European Society for Sexual Medicine / T’Sjoen et al. (2020)</a></td>
|
||
<td>Estradiol valerate</td>
|
||
<td>5–30 mg/1–2 weeks i.m.</td>
|
||
</tr>
|
||
<tr>
|
||
<td> </td>
|
||
<td>Estradiol cypionate</td>
|
||
<td>2–10 mg/week i.m.</td>
|
||
</tr>
|
||
<tr>
|
||
<td><a href="https://transline.zendesk.com/hc/en-us/articles/229373288-TransLine-Hormone-Therapy-Prescriber-Guidelines">TransLine (2019)</a></td>
|
||
<td>Estradiol valerate</td>
|
||
<td>Initial/Usual: 5–10 mg/week<br />Maximum: 20 mg/week</td>
|
||
</tr>
|
||
<tr>
|
||
<td> </td>
|
||
<td>Estradiol cypionate</td>
|
||
<td>Initial/Usual: 1.25–2.5 mg/week<br />Maximum: 5 mg/week</td>
|
||
</tr>
|
||
</tbody>
|
||
</table>
|
||
|
||
<p><small><sup>a</sup> Several other guidelines recommend doses and intervals that appear to be taken directly from the Endocrine Society or UCSF guidelines and thus are not listed here but can be found elsewhere (<a href="/articles/transfem-hormone-guidelines/">Aly, 2020</a>).</small></p>
|
||
|
||
<p>A number of concerns arise when the doses and intervals of injectable estradiol valerate and estradiol cypionate recommended by the major transgender clinical guidelines are considered in the context of the present informal meta-analysis and when they are compared between guidelines. Based on the present work, dosages of injectable preparations recommended by the major transgender clinical guidelines appear to result in estradiol exposure that is markedly higher than that with the recommended dosages for other routes and forms of estradiol (e.g., oral or transdermal). Whereas a dosage of 5 mg/week of any non-polymeric injectable estradiol ester appears to give average estradiol levels of around 300 pg/mL (~1,100 pmol/L), which are already <a href="https://en.wiktionary.org/wiki/supraphysiological">supraphysiological</a>, doses of injectable estradiol valerate or estradiol cypionate recommended by guidelines are as high as <em>15 to 20 mg</em> per week. The average estradiol concentrations that would be expected to result from such doses per this meta-analysis (e.g., ~600–1,200 pg/mL or 2,200–4,400 pmol/L at 10–20 mg/week) (Figure 10) would vastly exceed the ranges for estradiol levels in transfeminine people advised by the same guidelines (generally about 50–200 pg/mL or ~180–730 pmol/L) (<a href="https://en.wikipedia.org/wiki/Template:Target_ranges_for_hormone_levels_in_hormone_therapy_for_transgender_women">Table</a>). This is not merely theoretical; for example, a study that used 40 mg/week estradiol valerate by intramuscular injection in cisgender women with estrogen deficiency to produce “<a href="https://en.wikipedia.org/wiki/Pseudopregnancy_(hormone_therapy)">pseudopregnancy</a>” reported measured estradiol levels of about 2,500 pg/mL (~9,200 pmol/L) at 3 months and 3,100 pg/mL (~11,400 pmol/L) at 6 months of treatment (<a href="https://doi.org/10.1055/s-2007-1001723">Ulrich, Pfeifer, &amp; Lauritzen, 1994</a>). Moreover, highly supraphysiological estradiol levels with guideline-based injectable estradiol doses are not unexpected when normal production of estradiol in premenopausal cisgender women is considered (~1.4 mg per week or 6 mg per month/cycle giving mean estradiol levels of ~100 pg/mL or 370 pmol/L) (<a href="/articles/transfem-intro/#normal-hormone-levels">Aly, 2019</a>). Clinical safety data on high doses of injectable estradiol esters like estradiol valerate and estradiol cypionate are lacking at present, but excessive estrogenic exposure is known to increase the risk of health complications such as blood clots (<a href="/articles/estrogens-blood-clots/">Aly, 2020</a>). The very high doses of these preparations that are recommended by guidelines should raise considerable reservations about their safety.</p>
|
||
|
||
<table>
|
||
<thead>
|
||
<tr>
|
||
<th><img src="/assets/images/injectable-e2/ev_guidelines.svg" alt="" /></th>
|
||
</tr>
|
||
</thead>
|
||
<tbody>
|
||
<tr>
|
||
<td><strong>Figure 10:</strong> Simulated estradiol levels with injectable estradiol valerate at the doses and interval (5–40 mg/2 weeks) preferentially recommended by current major transgender care guidelines. Steady-state estradiol levels are reached by about the second or third injection with this injection interval and levels do not further accumulate. An alternative version of this figure with half-doses at a once-weekly interval (i.e., 2.5–20 mg/week) is also provided (<a href="/assets/images/injectable-e2/ev_guidelines_weekly.svg">Graph</a>).</td>
|
||
</tr>
|
||
</tbody>
|
||
</table>
|
||
|
||
<p>The present author elsewhere has listed doses of injectable estradiol preparations that are roughly comparable in terms of total estradiol exposure to doses for other estradiol forms and routes used in transfeminine people (<a href="/articles/e2-equivalent-doses/">Aly, 2020</a>). These doses range from about 1 to 6 mg per week for “low dose” to “very high dose” therapy with non-polymeric injectable estradiol esters (<a href="/assets/images/injectable-e2/ev_better_doses.svg">Graph</a>). This dose range for injectable estradiol is likely to be more appropriate for use in transfeminine people than current recommendations by many guidelines. Although high estradiol levels can be useful in transfeminine hormone therapy when antiandrogens are not used due to their greater efficacy than physiological levels in terms of testosterone suppression, only modestly supraphysiological estradiol levels (e.g., ~200–300 pg/mL or 730–1,100 pmol/L) appear to be required for strong testosterone suppression (<a href="/articles/transfem-intro/#gonadal-suppression">Aly, 2019</a>; <a href="https://doi.org/10.1016/S0140-6736(21)00100-8">Langley et al., 2021</a>; <a href="/articles/estrogens-blood-clots/#update-1-langley-et-al-2021-patch-study-results">Aly, 2020</a>). In relation to this, doses of injectable estradiol need not be excessive.</p>
|
||
|
||
<p>Some guidelines, such as the Endocrine Society guidelines, recommend the same doses and intervals for both estradiol valerate and estradiol cypionate, whereas other guidelines, such as the UCSF guidelines, recommend different doses for these two injectable estradiol esters. Concerningly, the doses for estradiol valerate and estradiol cypionate recommended by the UCSF guidelines differ by roughly an order of magnitude (&lt;20 to 40 mg/2 weeks for estradiol valerate and &lt;2 to 5 mg/2 weeks for estradiol cypionate). These estradiol esters appear to produce similar average estradiol levels (e.g., around 300 pg/mL or 1,100 pmol/L at a dosage of 5 mg/week) and have concentration–time curve shapes that are not extremely different, with estradiol cypionate being only somewhat flatter and more prolonged than estradiol valerate. As such, it would appear that similar doses should be appropriate for these esters. This is supported by the fact that the same doses of estradiol valerate and estradiol cypionate are used in combined injectable contraceptives in cisgender women (both 5 mg once per month) and that these doses were carefully determined during an intensive clinical development programme for these preparations (<a href="https://doi.org/10.1016/0010-7824(94)90032-9">Garza-Flores, 1994</a>; <a href="https://doi.org/10.3109/01443619409027641">Newton, d’Arcangues, &amp; Hall, 1994</a>; <a href="https://doi.org/10.1016/0010-7824(94)90033-7">Sang, 1994</a>; <a href="https://doi.org/10.1016/0010-7824(94)90029-9">Toppozada, 1994</a>). This programme notably included dose-ranging and direct-comparison studies. Based on the present analysis, the current recommendations by the UCSF guidelines may result in marked overdosage in the case of estradiol valerate and potential underdosage in the case of estradiol cypionate.</p>
|
||
|
||
<p>Transgender health guidelines recommend an injection interval for estradiol valerate and estradiol cypionate in oil of once every 1 to 2 weeks. Although an injection interval of 2 weeks seems technically feasible in the case of both of these preparations, such an interval would appear to result in substantial fluctuations in estradiol levels, with high peak levels and low troughs. This is particularly true in the case of the shorter-acting estradiol valerate (Figures 10, 11). Considering the wide fluctuations and unknown effects of this variability, as well as the fact that testosterone suppression when applicable may depend on sustained higher estradiol levels, it may be advisable that a once-weekly interval be preferentially recommended for these preparations. This would achieve steadier estradiol levels and would reduce potential problems due to high or low estradiol levels (Figure 11). Alternatively, a shorter interval of once every 5 days may be used with estradiol valerate to further reduce the variability in estradiol levels that occurs with this preparation (Figure 11). On the other hand, an injection interval of once every 10 days to 2 weeks may be practical and allowable in the case of the longer-acting estradiol cypionate in oil (as well as estradiol enanthate) (Figure 11)—provided that the injection cycles are well-tolerated and testosterone suppression remains adequate. When selecting different injection intervals, doses should be scaled by the interval to maintain equivalent total estradiol exposure (e.g., 3.5 mg/5 days, 5 mg/7 days, 7 mg/10 days, or 10 mg/14 days for high-dose non-polymeric injectable estradiol esters).</p>
|
||
|
||
<table>
|
||
<thead>
|
||
<tr>
|
||
<th><img src="/assets/images/injectable-e2/ev_ec_intervals.svg" alt="" /></th>
|
||
</tr>
|
||
</thead>
|
||
<tbody>
|
||
<tr>
|
||
<td><strong>Figure 11:</strong> Simulated estradiol levels with a high dosage of injectable estradiol valerate or estradiol cypionate in oil at different injection intervals (doses scaled by interval to be equivalent in total estradiol exposure).</td>
|
||
</tr>
|
||
</tbody>
|
||
</table>
|
||
|
||
<p>With the preceding concerns about the doses and intervals of injectable estradiol preparations recommended by transgender care guidelines considered, the question of how these recommendations were determined arises. Unfortunately, current guidelines do not generally describe how they arrived at their recommendations nor do they usually cite sources to support them. It is notable that the UCSF guidelines recommend doses and intervals for injectable estradiol preparations that are nearly identical to those advised by <a href="https://en.wikipedia.org/wiki/Christian_Hamburger">Christian Hamburger</a> and <a href="https://en.wikipedia.org/wiki/Harry_Benjamin">Harry Benjamin</a> in the late 1960s in the first medical textbook on transgender people (<a href="https://scholar.google.com/scholar?cluster=17287240145299798098">Hamburger &amp; Benjamin, 1969</a>). These authors recommended a dose of 10–40 mg/2 weeks for estradiol valerate and of 2–5 mg/2 weeks for estradiol cypionate (although Benjamin additionally stated that after 4–8 months, the same doses could be used at a longer injection interval of once every 4 weeks). These recommendations were notably made before estradiol blood tests became practicably available and were prior to the advent of modern pharmacokinetic studies. Hence, the recommendations for at least these guidelines appear to be based mainly on past expert opinion and long-standing historical precedent rather than on pharmacokinetic or clinical data. The same is likely to also be true for most other guidelines. High doses with certain injectable estradiol preparations (namely estradiol valerate) were probably originally employed for the purpose of achieving longer durations and more convenient injection intervals. This was notably prior to the risks of excessive estrogenic exposure like blood clots becoming known, and these doses may simply have never been revised.</p>
|
||
|
||
<p>The reasons that dose recommendations for injectable estradiol in transfeminine people have remained as they have for so long may be related to several factors. These include (1) a long-standing lack of research and funding in transgender health; (2) injectable estradiol not being widely available or as commonly used as other forms of estradiol; and (3) many clinicians only testing estradiol levels at trough (right before the next injection) with injectable estradiol preparations (e.g., <a href="https://doi.org/10.1055/s-0030-1255074">Mueller et al., 2011</a>; <a href="https://doi.org/10.4158/EP-2020-0414">Chantrapanichkul et al., 2021</a>; <a href="https://doi.org/10.1089/lgbt.2020.0249">Cirrincione et al., 2021</a>). The latter point is noteworthy as trough levels only describe the lowest point of the estradiol concentration–time curve with injectable estradiol preparations, and can give a very misleading impression of average or total estradiol exposure. In any case, the very high estradiol levels with currently recommended doses of injectable estradiol forms for transfeminine people have not gone unnoticed in the literature (e.g., <a href="https://doi.org/10.1159/000087751">Gooren, 2005</a>; <a href="https://doi.org/10.1001/jama.2012.165234">Spack, 2013</a>; <a href="https://books.google.com/books?id=EuB_AwAAQBAJ&amp;pg=PA241">Deutsch, 2014</a>; <a href="https://doi.org/10.1530/EJE-21-0059">Glintborg et al., 2021</a>; <a href="https://doi.org/10.3390/ijerph182312640">Tassinari &amp; Maranghi, 2021</a>; <a href="https://doi.org/10.1016/j.tips.2022.03.006">Le, Huang, &amp; Cirrincione, 2022</a>). Additionally, clinical studies in transfeminine people have reported high to very high estradiol levels with typical clinical doses of injectable estradiol (e.g., <a href="https://doi.org/10.1530/EJE-09-0265">Kronawitter et al., 2009</a> [<a href="https://archive.is/k2HTe">Table</a>]; <a href="https://doi.org/10.1055/s-0030-1255074">Mueller et al., 2011</a> [<a href="https://archive.is/1X4Co">Table</a>]; <a href="https://doi.org/10.1111/j.1447-0756.2011.01815.x">Sharula et al., 2012</a> [<a href="https://files.transfemscience.org/pdfs/docs/Sharula%20et%20al.%20(2012)%20Tables%201%20and%202%20Clinical%20Features%20+%20Laboratory%20Data.pdf">Data</a>]; <a href="https://doi.org/10.1089/trgh.2016.0016">Nelson et al., 2016</a> [<a href="https://archive.is/MlUU5">Table</a>]; <a href="https://doi.org/10.1016/j.fertnstert.2020.08.277">LaBudde, Craig, &amp; Spratt, 2020</a>; <a href="https://doi.org/10.4158/EP-2020-0414">Chantrapanichkul et al., 2021</a> [<a href="https://archive.is/arQvz">Table</a>]; <a href="https://doi.org/10.1089/lgbt.2020.0249">Cirrincione et al., 2021</a> [<a href="https://archive.is/Gk8Y5">Table</a>]).</p>
|
||
|
||
<p>Among the surveyed guidelines for transgender hormone therapy, only the UCSF guidelines (<a href="https://transcare.ucsf.edu/guidelines/feminizing-hormone-therapy">Deutsch, 2016b</a>) and the <a href="https://sherbourne.on.ca/">Sherbourne Health</a>/<a href="https://www.rainbowhealthontario.ca/">Rainbow Health Ontario</a> guidelines (<a href="https://www.rainbowhealthontario.ca/product/4th-edition-sherbournes-guidelines-for-gender-affirming-primary-care-with-trans-and-non-binary-patients/">Bourns, 2019</a>) referenced pharmacokinetic literature in their discussion of injectable estradiol. The specific publications cited by these guidelines were <a href="https://doi.org/10.1016/0378-5122(82)90064-0">Düsterberg &amp; Nishino (1982)</a>, <a href="https://doi.org/10.1016/j.contraception.2011.03.014">Sierra-Ramírez et al. (2011)</a>, and <a href="https://doi.org/10.1016/j.contraception.2012.11.010">Thurman et al. (2013)</a>. Although it is favorable to see guidelines considering published pharmacokinetic data for informing use of these preparations, there are a few concerns about the studies that were cited. <a href="https://doi.org/10.1016/0378-5122(82)90064-0">Düsterberg &amp; Nishino (1982)</a> in its study of injectable estradiol valerate had a very small sample size (n=2), and this study was excluded as an outlier in the present meta-analysis due to unusually high estradiol levels. The findings of <a href="https://doi.org/10.1016/0378-5122(82)90064-0">Düsterberg &amp; Nishino (1982)</a> also do not seem to have actually been used to guide dosing recommendations in the case of the UCSF guidelines, since if this were the case, the recommended doses should have been much lower. On the other hand, <a href="https://www.rainbowhealthontario.ca/product/4th-edition-sherbournes-guidelines-for-gender-affirming-primary-care-with-trans-and-non-binary-patients/">Bourns (2019)</a> cited the same study and recommended injectable estradiol valerate at doses of 3–4 mg/week or 6–8 mg/2 weeks. These doses are well below those recommended by other transgender care guidelines and appear to be more appropriate for use in transfeminine people in light of the present meta-analysis. <a href="https://doi.org/10.1016/j.contraception.2011.03.014">Sierra-Ramírez et al. (2011)</a> and <a href="https://doi.org/10.1016/j.contraception.2012.11.010">Thurman et al. (2013)</a>, although better-quality studies than <a href="https://doi.org/10.1016/0378-5122(82)90064-0">Düsterberg &amp; Nishino (1982)</a>, described injectable estradiol cypionate suspension rather than estradiol cypionate in oil. The oil-based version of estradiol cypionate is the form normally used in transfeminine hormone therapy, and there are important differences between these estradiol cypionate preparations such that pharmacokinetic studies for the suspension can’t necessarily be generalized to the oil solution. These preparations do in any case produce similar total estradiol levels however and hence doses should be comparable for them.</p>
|
||
|
||
<p>This meta-analysis is only informal and unpublished research. Nonetheless, based on the results of this work and the preceding discussion, current dosing recommendations for injectable estradiol preparations by most transgender clinical guidelines appear to be highly excessive and likely unsafe, with injection intervals that may additionally be too widely spaced. Transgender care guidelines should consider reassessing these recommendations, and the transgender medical community should make an effort to better characterize the pharmacokinetics and optimal dosing schemes of injectable estradiol preparations in transfeminine people in the future. Since clinical data on these preparations are scarce and will probably remain so in the near-term, use of published pharmacokinetic data may be further considered for guiding dosing recommendations for injectable estradiol. As identified and catalogued by this meta-analysis, there is a wealth of existing data that could be used to better inform transgender care guidelines in terms of the use of injectable estradiol preparations in transfeminine people.</p>
|
||
|
||
<h2 id="interactive-web-simulator">Interactive Web Simulator</h2>
|
||
|
||
<p>This informal meta-analysis of estradiol concentration–time data with injectable estradiol preparations was conducted for the purpose of deriving accurate and representative estradiol curves for incorporation into a web-based injectable estradiol simulator intended for use by transfeminine people and their clinicians. This web app is able to simulate both single-injection curves and repeated-injection curves with these preparations. An informational page for this simulator can be found at the following location:</p>
|
||
|
||
<ul>
|
||
<li><a href="/articles/injectable-e2-simulator-release/">An Interactive Web Simulator for Estradiol Levels with Injectable Estradiol Esters (Aly, 2021)</a></li>
|
||
</ul>
|
||
|
||
<p>And the injectable estradiol simulator itself can be found at the following page:</p>
|
||
|
||
<ul>
|
||
<li><a href="/misc/injectable-e2-simulator/">Injectable Estradiol Simulator - Transfeminine Science</a></li>
|
||
</ul>
|
||
|
||
<h2 id="future-possibilities">Future Possibilities</h2>
|
||
|
||
<p>There are various possibilities for further work on this project in the future. For example, assessment of <a href="https://en.wikipedia.org/wiki/Interindividual_variability">interindividual variability</a> for estradiol levels with injectable estradiol preparations could be included in the meta-analysis. As another example, it would be fairly straightforward and valuable to expand the meta-analysis as well as simulator to other <a href="https://en.wikipedia.org/wiki/Sex-hormonal_agent">hormonal preparations</a> such as <a href="https://en.wikipedia.org/wiki/Injectable_testosterone">injectable testosterone preparations</a> and other estradiol routes and forms like <a href="https://en.wikipedia.org/wiki/Oral_estradiol">oral estradiol</a>, <a href="https://en.wikipedia.org/wiki/Sublingual_estradiol">sublingual estradiol</a>, and <a href="https://en.wikipedia.org/wiki/Estradiol_pellets">estradiol pellets</a>. Pharmacokinetic literature for some of these preparations has already been collected by this author. However, these future possibilities would require much additional time and effort to complete.</p>
|
||
|
||
<h2 id="special-thanks">Special Thanks</h2>
|
||
|
||
<p>A special thank you to Violet and Lila for their indispensable input and guidance on modeling topics during the work on this project. An additional thanks to Violet for deriving a special three-compartment pharmacokinetic model that was used in this work. Please also check out Violet’s own projects <a href="https://github.com/tiliaqt/">Tilia</a>—an effort to empower trans people with tools to manage their hormonal transitions—and <a href="https://github.com/tiliaqt/transkit/">TransKit</a>—a work-in-progress pharmacokinetic simulation library specifically tailored for transgender hormone therapy. Lastly, thank you to all the peer reviewers who carefully reviewed this article prior to it being posted.</p>
|
||
|
||
<h2 id="updates">Updates</h2>
|
||
|
||
<h3 id="update-1-wpath-soc8-guidelines">Update 1: WPATH SOC8 Guidelines</h3>
|
||
|
||
<p>In September 2022, the <a href="https://en.wikipedia.org/wiki/World_Professional_Association_for_Transgender_Health">World Professional Association for Transgender Health</a> (WPATH) <a href="https://en.wikipedia.org/wiki/Standards_of_Care_for_the_Health_of_Transgender_and_Gender_Diverse_People">Standards of Care for the Health of Transgender and Gender Diverse People</a> Version 8 (SOC8) were published and made recommendations on transgender hormone therapy for the first time (<a href="https://doi.org/10.1080/26895269.2022.2100644">Coleman et al., 2022</a>). These guidelines are among the most highly regarded and consulted transgender care guidelines that exist. In terms of the recommended doses of hormonal medications for transgender people, the WPATH SOC8 appear to have largely copied the <a href="https://en.wikipedia.org/wiki/Endocrine_Society">Endocrine Society’s</a> 2017 guidelines on transgender hormone therapy (<a href="https://doi.org/10.1210/jc.2017-01658">Hembree et al., 2017</a>). More specifically, in the case of injectable estradiol preparations for transfeminine people, doses of 5–30 mg/2 weeks or 2–10 mg/week estradiol valerate or estradiol cypionate were recommended. There was no discussion of injectable estradiol in the guidelines besides the preceding doses and intervals being included in a table, and no literature citations were included to support these doses. As described in the present work, these recommendations include doses and intervals that appear to be highly excessive, too widely spaced, and likely unsafe. As such, major transgender care guidelines unfortunately continue to make uncited recommendations for injectable estradiol in transfeminine people that are out of step with insights available from abundant published pharmacokinetic data and are likely inadvisable, with the possibility of substantial safety risks.</p>
|
||
|
||
<h3 id="update-2-literature-mentions">Update 2: Literature Mentions</h3>
|
||
|
||
<p>The following publications in the literature have cited or mentioned Transfeminine Science’s injectable estradiol simulator and/or meta-analysis since the project was published in mid-2021:</p>
|
||
|
||
<h4 id="hughes-et-al-2022">Hughes et al. (2022)</h4>
|
||
|
||
<p>Hughes, J. H., Woo, K. H., Keizer, R. J., &amp; Goswami, S. (2022). Clinical Decision Support for Precision Dosing: Opportunities for Enhanced Equity and Inclusion in Health Care. <em>Clinical Pharmacology &amp; Therapeutics</em>, <em>113</em>(3), 565–574. [DOI:<a href="https://doi.org/10.1002/cpt.2799">10.1002/cpt.2799</a>]:</p>
|
||
|
||
<blockquote>
|
||
<p>Lastly, we recommend that developers of [clinical decision support software (CDSS)] for dosing take an iterative and participatory approach to designing systems. By involving stakeholders in the design process, they will develop solutions that best suit users’ needs and are more likely to be adopted and used correctly. This participatory approach should involve interviews and usability testing with clinicians. Formal usability testing and analysis with real end users can improve the quality and usefulness of a system.<sup>88</sup> Though patients themselves are not typically the end users of CDSS, their expertise (especially that of marginalized groups and organized patient advocacy organizations) can also inform CDSS developers. As an example, transgender people have compiled their own resources to understanding dosing regimens in the absence of clear clinical guidelines.<sup>89</sup> Developers of CDSS could provide a great deal of value to these patient populations, and improve their software’s utility, by working with them to understand their needs from a dosing tool.</p>
|
||
</blockquote>
|
||
|
||
<blockquote>
|
||
<p>89. Aly, W. An interactive web simulator for estradiol levels with injectable estradiol esters. <em>Transfeminine Science</em> &lt;https://transfemscience.org/articles/injectable-e2-simulator-release/&gt; (2021) Accessed November 1, 2022.</p>
|
||
</blockquote>
|
||
|
||
<h4 id="jaafar-et-al-2022">Jaafar et al. (2022)</h4>
|
||
|
||
<p>Jaafar, S., Torres-Leguizamon, M., Duplessy, C., &amp; Stambolis-Ruhstorfer, M. (2022). Hormonothérapie injectable et réduction des risques: pratiques, difficultés, santé des personnes trans en France. [Hormone replacement therapy injections and harm reduction: practices, difficulties, and transgender people’s health in France.] <em>Sante Publique</em>, <em>34</em>(HS2), 109–122. [<a href="https://scholar.google.com/scholar?cluster=7107598530477039727">Google Scholar</a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/37336724/">PubMed</a>] [DOI:<a href="https://doi.org/10.3917/spub.hs2.0109">10.3917/spub.hs2.0109</a>] [Translated]:</p>
|
||
|
||
<blockquote>
|
||
<p>With regard to feminizing [substitutive hormone therapy (HS)], there are no specialty injectables based on estrogens in the French pharmacopoeia. This makes it impossible to set up estrogen monotherapies which require high dosages that are more difficult to obtain with specialties with other galenic forms [5]. Faced with this lack of care, some trans women and transfeminine people obtain estradiol-based injectable solutions on the Internet or through other sources [6]. […]</p>
|
||
</blockquote>
|
||
|
||
<blockquote>
|
||
<p>5. Aly. An informal meta-analysis of estradiol curves with injectable estradiol preparations [Internet]. Transfem Sci. 2021 July 16. [Visited on 29/12/2022]. Online : https://transfemscience.org/articles/injectable-e2-meta-analysis/.</p>
|
||
</blockquote>
|
||
|
||
<h4 id="linet-2023">Linet (2023)</h4>
|
||
|
||
<p>Linet, T. (2023). Prise en charge endocrinologique d’une personne trans. [Endocrinological care of a trans person.] In Faucher, P., Hassoun, D., &amp; Linet, T. (Eds.). <em>Santé sexuelle et reproductive des personnes LGBT</em> [<em>Sexual and Reproductive Health of LGBT People</em>] (pp. 109–124). Issy-les-Moulineaux, France: Elsevier Masson. [<a href="https://books.google.com/books?id=g4-dEAAAQBAJ&amp;pg=PA116">Google Books</a>] [<a href="https://www.elsevier-masson.fr/sante-sexuelle-et-reproductive-des-personnes-lgbt-9782294778162.html">URL</a>] [<a href="https://worldcat.org/title/1368281171">WorldCat</a>] [<a href="https://archive.is/Nw3Jp">Excerpt</a>] [Translated]:</p>
|
||
|
||
<blockquote>
|
||
<p>Choice of estrogen.</p>
|
||
|
||
<p>Estradiol is generally the most prescribed estrogen. It is given orally or sublingually in transfeminine people with no significant cardiovascular risk factors. For others, the percutaneous form (patches, gel) is recommended.</p>
|
||
|
||
<p>The starting dose is 2 mg of estradiol orally with a step increase of 2 mg every 2 to 3 months until the optimal dose is reached [1]. For the patches, the initial dosage and the increments are 50 or 100 μg, and for the gel 2.5 g. This means that the optimal dose is generally 6 to 8 mg per day for the oral route, 3 to 4 mg for the sublingual route, and 300 to 400 μg for the patches (see table 11.1).</p>
|
||
|
||
<p>It may happen in consultation that the person does not wish to use the prescribed estrogens and wishes to continue the self-prescription of injectable estrogens. It is then possible to evaluate with them the most suitable dosage using the Transfem Science Injection Simulator (https://transfemscience.org/misc/injectable-e2-simulator/). Risk prevention related to injections (needles) can be done. Associations can help the person find 25 G needles of 40 mm useful this type of treatment.</p>
|
||
</blockquote>
|
||
|
||
<h3 id="update-3-herndon-et-al-2023">Update 3: Herndon et al. (2023)</h3>
|
||
|
||
<p>In March 2023, the following paper on injectable estradiol in transfeminine people was published online:</p>
|
||
|
||
<ul>
|
||
<li>Herndon, J. S., Maheshwari, A. K., Nippoldt, T. B., Carlson, S. J., Davidge-Pitts, C. J., &amp; Chang, A. Y. (2023). Comparison of Subcutaneous and Intramuscular Estradiol Regimens as part of Gender-Affirming Hormone Therapy. <em>Endocrine Practice</em>, <em>29</em>(5), 356–361. [DOI:<a href="https://doi.org/10.1016/j.eprac.2023.02.006">10.1016/j.eprac.2023.02.006</a>] [<a href="https://www.sciencedirect.com/science/article/abs/pii/S1530891X23000502">URL</a>]</li>
|
||
</ul>
|
||
|
||
<p>The study was a retrospective analysis of individualized injectable estradiol in adult transfeminine people who received hormone therapy at the <a href="https://en.wikipedia.org/wiki/Mayo_Clinic">Mayo Clinic</a>. Doses of injectable estradiol were adjusted by clinical providers based on estradiol levels, testosterone suppression, and feminization goals, and subsequently these clinical data were retrospectively studied by Mayo Clinic researchers. The primary aim of the study was to compare injectable estradiol by intramuscular versus subcutaneous routes. However, other general considerations for injectable estradiol, such as dosing, estradiol levels, testosterone suppression, type of injectable estradiol ester (estradiol valerate vs. estradiol cypionate), and estradiol monotherapy versus concomitant use of antiandrogens, were also assessed. The paper noted that the study was the largest to assess injectable estradiol in transfeminine people to date and was the first to directly compare intramuscular and subcutaneous injectable estradiol routes in transfeminine people.</p>
|
||
|
||
<p>Injectable estradiol doses were adjusted to achieve estradiol and testosterone levels within therapeutic ranges defined by the Endocrine Society 2017 guidelines (&gt;100 pg/mL [367 pg/mL] for estradiol and &lt;50 ng/dL [&lt;1.7 nmol/L] for testosterone). Estradiol levels were measured exclusively using <a href="https://en.wikipedia.org/wiki/Liquid_chromatography%E2%80%93tandem_mass_spectrometry">liquid chromatography–tandem mass spectrometry</a> (LC–MS/MS), while the assay method for measuring testosterone levels was not specified. In terms of when in the injection cycle estradiol levels were measured, the authors stated the following: (1) “Timing of estradiol blood draw in relation to injection was not protocolized” and (2) “In our practice, although estradiol concentrations were generally checked midway through the injection cycle, we were unable to document with certainty the timing of the estradiol lab testing which may have influenced the results and/or the outliers”. Only the most recent blood test for each individual was analyzed, with the results of earlier tests discarded. Doses were analyzed in per-week amounts, regardless of dosing frequency (either once weekly or once every two weeks).</p>
|
||
|
||
<p>There were a total of 130 transfeminine people on injectable estradiol who were analyzed in the study. Of these individuals, 56 received intramuscular (i.m.) injections and 74 received subcutaneous (s.c.) injections. The median duration of therapy for injectable estradiol was 3.0 years for both routes. The vast majority of people used weekly injections (91.1% for i.m., 98.6% for s.c.), whereas the small remainder (n=6) injected once every 2 weeks. Similarly, the great majority used injectable estradiol valerate (89.3% for i.m., 86.5% for s.c.), while a small subset (n=16) used injectable estradiol cypionate. The authors did not state the injectable vehicles, but they can be confidently assumed to have both been in oil. The treatment-individualized doses per week of injectable estradiol were median 4 mg (<a href="https://en.wikipedia.org/wiki/Interquartile_range">interquartile range</a> (IQR) 3–5.15 mg; <a href="https://en.wikipedia.org/wiki/Range_(statistics)">range</a> 1–8 mg) for the i.m. route and median 3.75 mg (IQR 3–4 mg; range 1–8 mg) for the s.c. route, with the differences in doses between groups being slightly but significantly different (p = 0.005). For the small number of people on two-week injection cycles, the doses for the combined i.m. and s.c. groups were median 8.5 mg (range 6–16 mg) every 2 weeks. Estradiol levels with injectable estradiol were median 189.5 pg/mL (IQR 126.8–252.5 or 122.5–257 pg/mL; range ~33–575 pg/mL] for i.m. and median 196 pg/mL (IQR 125.3–298.5 pg/mL; range ~23–581 pg/mL) for s.c., with the differences between groups not being significantly different (p = 0.70). The percentages of individuals with estradiol levels in target range (&gt;100 pg/mL) were 78.6% for i.m. and 82.4% for s.c. The estradiol doses and levels of individual patients for each route were also provided in the paper (<a href="https://archive.is/lQwjC">Graph</a>). It can be seen that more individuals clustered into the higher range of doses with i.m. than with s.c. injections.</p>
|
||
|
||
<p>In the case of estradiol valerate versus estradiol cypionate, dose per week for i.m. with estradiol valerate was median 4 mg (IQR 3–5.45 mg) and with estradiol cypionate was median 4 mg (IQR 2.25–5 mg). In the case of s.c., dose per week with estradiol valerate was median 4 mg (IQR 3–4 mg) and with estradiol cypionate was median 3 mg (IQR 2–3 mg). The doses between estradiol valerate and estradiol cypionate were not significantly different in the case of i.m. (p = 0.51), but were significantly different in the case of s.c. (p = 0.025). Estradiol levels with the two different injectable estradiol esters were not provided.</p>
|
||
|
||
<p>On <a href="https://en.wikipedia.org/wiki/Multiple_linear_regression">multiple regression analysis</a>, injectable estradiol dose was significantly positively associated with estradiol levels (p &lt; 0.001) following adjustment for several variables (injection route, <a href="https://en.wikipedia.org/wiki/Body_mass_index">body mass index</a> (BMI), antiandrogen use, gonadectomy status). Each 1 mg per week in dose was associated with estradiol levels that were increased by (estimate ± standard error) 57.42 ± 10.46 pg/mL. No other variable, including notably BMI, was significantly associated with estradiol levels. According to the authors, the dose-dependently higher estradiol levels with injectable estradiol suggested the need to start at lower doses that are gradually increased in conjunction with close monitoring of hormone levels.</p>
|
||
|
||
<p>Testosterone levels in those with gonads were 11 ng/dL (IQR 0–19.8 ng/dL) for i.m. and 11 ng/dL (0–20 ng/dL) for s.c., with levels not significantly different between groups (p = 0.92). Adequate testosterone suppression (&lt;50 ng/dL) in those with gonads was achieved in 84.6% with i.m. and 86.6% with s.c. In the small subset of individuals on injections every two weeks (n=6), 100% of individuals achieved target estradiol and testosterone levels. A majority of individuals on injectable estradiol in the study concomitantly used an antiandrogen, with this usually being <a href="https://en.wikipedia.org/wiki/Spironolactone">spironolactone</a> or <a href="https://en.wikipedia.org/wiki/Finasteride">finasteride</a>. In a minority of individuals, injectable estradiol monotherapy, without concomitant use of an antiandrogen, was employed and hormone levels were measured (n=17). In this subgroup, estradiol levels were median 220 pg/mL (IQR 180–264 pg/mL) at a dose per week of median 4 mg (IQR 3–6 mg), with estradiol levels noticeably higher than in the overall group. In terms of hormone levels for those on injectable estradiol monotherapy, 100% achieved therapeutic estradiol levels (&gt;100 pg/mL) and 88.2% achieved target testosterone levels (&lt;50 ng/dL). The authors noted that most individuals on injectable estradiol monotherapy were able to adequately suppress testosterone, but that higher doses and levels of estradiol may be needed for testosterone suppression in this context.</p>
|
||
|
||
<p>Herndon et al. (2023) noted that existing recommendations for injectable estradiol in transfeminine people suggest doses of 2 to 10 mg per week or 5 to 30 mg every 2 weeks, referencing the Endocrine Society 2017 guidelines (<a href="https://doi.org/10.1210/jc.2017-01658">Hembree et al., 2017</a>) and UCSF 2016 guidelines (<a href="https://transcare.ucsf.edu/guidelines">Deutsch, 2016a</a>). They also noted that the UCSF 2016 guidelines recommended lower doses of estradiol cypionate than estradiol valerate, which they attributed to pharmacokinetic differences between the esters (citing <a href="https://doi.org/10.1016/S0010-7824(80)80018-7">Oriowo et al. (1980)</a> for this claim). However, the authors noted that the differences between estradiol valerate and estradiol cypionate doses they observed were small, and questioned the clinical relevance of the differences. The authors also tactfully critiqued dosing recommendations by existing guidelines, and suggested their own data to guide dosing instead, with the following relevant excerpts:</p>
|
||
|
||
<blockquote>
|
||
<p>Prior studies used for development of guidelines for parenteral doses are suboptimal given their small sample sizes or pre-specificized [gender-affirming hormone therapy (GAHT)] protocols with no adjustment of estradiol doses or no information on hormone concentrations achieved. [Discussion of <a href="https://doi.org/10.1097/AOG.0000000000000692">Deutsch, Bhakri, &amp; Kubicek (2015)</a> and <a href="https://doi.org/10.1055/s-0030-1255074">Mueller et al. (2011)</a> …]</p>
|
||
</blockquote>
|
||
|
||
<blockquote>
|
||
<p>Overall, the studies used to support the current dosing recommendation guidelines for parenteral estradiol dosing are limited, incomplete with regards to hormone concentrations achieved, and do not provide SC as an available option. The doses of estradiol used in this study (with either SC or IM approach), were successful in achieving serum estradiol concentrations at the cisgender female range. Most importantly, as compared to current available guidelines and consensus statements [1, 2], these doses of estradiol valerate are less than half of what is recommended for both initial and maintenance dosing and achieved suppression of testosterone.</p>
|
||
</blockquote>
|
||
|
||
<blockquote>
|
||
<p>Lower doses of parenteral injections than previously described in clinical practice guidelines achieved therapeutic estradiol concentrations. Our data can serve as a dosing guide for initial and maintenance use of parenteral estradiol, which is different than what has been previously described.</p>
|
||
</blockquote>
|
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<p>Herndon et al. (2023) concluded that injectable estradiol by both i.m. and s.c. routes is effective in achieving therapeutic estradiol levels in transfeminine people. They noted that there were not meaningful differences between i.m. and s.c. in terms of dose, although i.m. may require slightly higher doses than s.c. to achieve therapeutic estradiol levels. The authors stated that doses of injectable estradiol to achieve therapeutic estradiol levels in transfeminine people were lower than previously recommended by guidelines and other publications. They concluded that clinical use of injectable estradiol in transfeminine people should include discussion of both i.m. and s.c. routes and invidiualization by patient. Finally, they called for more clinical studies on injectable estradiol in transfeminine people to evaluate clinical outcomes, feminization, and additional risks and benefits of this route compared to other routes.</p>
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<p>The findings of Herndon et al. (2023) are pleasingly consistent with the results of the present meta-analysis. Based on the findings of this meta-analysis, assuming a linear relationship between dose and estradiol levels, estradiol levels with non-polymeric injectable estradiol esters, like estradiol valerate and estradiol cypionate in oil via intramuscular injection, increase by around 60 pg/mL on average for each 1 mg per week in dose (with Herndon et al. (2023) finding a value of 57 pg/mL per 1 mg using a multiple linear regression model). In relation to this, mean integrated estradiol levels of around 250 pg/mL on average would be expected at a dosage of 4 mg once per week. Accordingly, Herndon et al. (2023) found median estradiol levels of 190 to 196 pg/mL at per-week median doses of 3.75 to 4 mg. Similarly, the present work recommended injectable estradiol doses with non-polymeric esters of 1 to 6 mg per week (to achieve mean integrated estradiol levels of roughly 50–300 pg/mL), which is comparable to the range of about 2 to 6 mg per week used in most transfeminine people in Herndon et al. (2023) (to achieve estradiol levels of at least 100 pg/mL, along with adequate testosterone suppression). Additionally, it was noted in this meta-analysis—based on clinical research in cisgender men with prostate cancer—that only modestly supraphysiological estradiol levels, of no more than approximately 200 to 300 pg/mL, are likely to be needed for strong testosterone suppression in transfeminine people. This has likewise been confirmed with solid clinical data in transfeminine people by Herndon et al. (2023), with 88% of those on injectable estradiol monotherapy having testosterone levels of &lt;50 ng/dL at a median injectable estradiol dose of 4 mg/week and with median estradiol levels of 220 pg/mL. It is the opinion of the present author that Herndon et al. (2023) is a very important and formative study, with clinical implications that go far beyond merely supporting the s.c. use of injectable estradiol. The study represents the first major step in the published literature to correcting the dosing and intervals of injectable estradiol in transgender care guidelines and in transgender health generally. I commend the researchers for their work.</p>
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<h2 id="supplementary-material">Supplementary Material</h2>
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<ul>
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<li><a href="https://files.transfemscience.org/pdfs/docs/Injectable%20Estradiol%20Studies%20and%20Levels.xlsx">Injectable Estradiol Studies and Levels - Spreadsheet</a></li>
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<li><a href="https://files.transfemscience.org/pdfs/misc/Injectables%20Meta-Analysis%20Plotly%20Charts.zip">Injectable Estradiol Studies and Levels - Plotly Charts</a></li>
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<li><a href="https://files.transfemscience.org/pdfs/docs/Injectable%20Estradiol%20Vehicles%20and%20Their%20Compositions%20and%20Properties.pdf">Injectable Estradiol Vehicles and Their Compositions and Properties - Doc</a></li>
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<li><a href="https://files.transfemscience.org/pdfs/docs/Sex%20Hormone%20Ester%20Lipophilicity%20(Log%20P)%20Tables.pdf">Sex Hormone Ester Lipophilicity (Log P) Tables - Doc</a></li>
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</ul>
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<li>Zhou, X. F., Shao, Q. X., Han, X. J., Weng, L. J., &amp; Sang, G. W. (1998). Pharmacokinetics of medroxyprogesterone acetate after single and multiple injection of Cyclofem<sup>®</sup> in Chinese women. <em>Contraception</em>, <em>57</em>(6), 405–411. [DOI:<a href="https://doi.org/10.1016/S0010-7824(98)00048-1">10.1016/S0010-7824(98)00048-1</a>]</li>
|
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</ul></content><author><name>{"first_name"=>"Aly", "last_name"=>"W.", "author-link"=>"/about/#aly", "articles-link"=>"/articles-by-author/aly/"}</name></author><category term="github" /><category term="workspace" /><summary type="html">An Informal Meta-Analysis of Estradiol Curves with Injectable Estradiol Preparations By Aly | First published July 16, 2021 | Last modified June 23, 2023</summary></entry><entry><title type="html">An Exploration of Sublingual Estradiol as an Alternative to Oral Estradiol in Transfeminine People</title><link href="https://transfemscience.org/articles/sublingual-e2-transfem/" rel="alternate" type="text/html" title="An Exploration of Sublingual Estradiol as an Alternative to Oral Estradiol in Transfeminine People" /><published>2021-06-11T20:26:25-07:00</published><updated>2021-09-06T00:00:00-07:00</updated><id>https://transfemscience.org/articles/sublingual-e2-transfem</id><content type="html" xml:base="https://transfemscience.org/articles/sublingual-e2-transfem/"><h1 id="an-exploration-of-sublingual-estradiol-as-an-alternative-to-oral-estradiol-in-transfeminine-people">An Exploration of Sublingual Estradiol as an Alternative to Oral Estradiol in Transfeminine People</h1>
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<p>By
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<!-- First author --><a href="/about/#sam">Sam</a><!-- Second author --><!-- Third author --><!-- Fourth author --> | First published June 11, 2021
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| Last modified September 6, 2021</p>
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<h2 id="abstract--tldr">Abstract / TL;DR</h2>
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<p>Despite being less well characterised in the medical literature than other formulations, sublingually administered estradiol has been used successfully by several gender clinics around the world. While there may be practical shortcomings associated with the sublingual route, clinical experience and best judgement would suggest it to be effective and affordable when dosed correctly. Sublingual administration of estradiol may be a useful alternative to oral administration for some transfeminine people and can be used for feminising hormone therapy instead.</p>
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<h2 id="introduction">Introduction</h2>
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<p>Although the most common way to administer medication in the form of pills or tablets is by the oral route, oral estradiol formulations can otherwise be taken sublingually or buccally (<a href="https://doi.org/10.1080/13697130500148875">Kuhl, 2005</a>). Sublingual administration refers to the placing of the pill or tablet under the tongue to dissolve and be absorbed into the bloodstream. Buccal administration is similar and refers to placing the medication between the cheek and gums, where it also quickly dissolves and is absorbed (<a href="https://doi.org/10.1016/j.maturitas.2003.12.004">Gass et al., 2004</a>; <a href="https://doi.org/10.1208/s12249-012-9839-7">Bartlett &amp; Maarschalk, 2012</a>).</p>
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<p>Many transfeminine people wonder or ask questions on online forums about the sublingual route of administration for estradiol. Some of the most common queries are “What doses of sublingual estradiol should I take?”, “How often should I take sublingual estradiol?”, “Is sublingual estradiol better than oral estradiol?” and so on.</p>
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<p>Previously, I reviewed the literature in a comparison of oral and transdermal estradiol (<a href="/articles/oral-vs-transdermal-e2/">Sam, 2020a</a>). Although many transfeminine people experiment with sublingual estradiol and its use appears to be commonplace among those who self-medicate with estrogens, I did not discuss sublingual or buccal routes of administration in this review. In part, the reason for this was because few studies exist concerning the use of sublingual estradiol compared to conventional and more widely used routes. This is likely also the reason that sublingual estradiol is not discussed in many clinical practice guidelines (<a href="/articles/transfem-hormone-guidelines/">Aly, 2020a</a>). Moreover, I wanted to focus specifically on oral estradiol. Since the time of publication of that article, however, several new studies of sublingual estradiol in transfeminine people have been published. In light of this new information, and on account of the many questions asked by transfeminine people online, I believe an in-depth look at this route of administration is warranted. So this is intended to be an overview of the published medical literature regarding sublingual estradiol, with a specific focus on its use in transgender care, aiming to answer some of these questions.</p>
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<p>It is of note that, although the sublingual and buccal administration are distinct routes of administration, they are very similar to each other in how they are performed and in their pharmacology (<a href="https://doi.org/10.1016/0002-9378(50)90390-5">Perloff, 1950</a>; <a href="https://doi.org/10.1016/S0015-0282(02)03639-7">Chandrasekhara et al., 2002</a>). As such, although I have ostensibly chosen to make use of the term “sublingual” in this literature review, much of the content here is applicable to buccal administration of estradiol as well.</p>
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<h2 id="pharmacology-of-sublingual-estradiol">Pharmacology of Sublingual Estradiol</h2>
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<p>While sublingual estradiol has not been as widely used in clinical practice as oral estradiol and other formulations, a number of studies have examined its pharmacology. These studies include both samples of postmenopausal cisgender women and transfeminine people as well as other patient populations (<a href="https://journals.lww.com/greenjournal/Abstract/1981/01000/Rapid_Absorption_of_Micronized_Estradiol_17_beta_.14.aspx">Casper &amp; Yen, 1981</a>; <a href="https://doi.org/10.1016/S0140-6736(89)92762-1">Serhal &amp; Craft, 1989</a>; <a href="https://doi.org/10.1097/AOG.0000000000000692">Deutsch, Bhakri, &amp; Kubicek, 2015</a>; <a href="https://doi.org/10.1089/lgbt.2020.0249">Cirrincione et al., 2021</a>). Both oral estradiol and oral estradiol valerate tablets can be taken sublingually (<a href="https://doi.org/10.1093/oxfordjournals.bmb.a072432">Serhal, 1990</a>).</p>
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<p>After the administration of a dose of oral estradiol, the medication is heavily metabolised and inactivated into estrogen conjugates by the liver (<a href="https://doi.org/10.1080/13697130500148875">Kuhl, 2005</a>). In turn, these metabolites are gradually converted back into estradiol, which serves to prolong its half life (to approximately 13–20 hours) (<a href="https://doi.org/10.1016/j.contraception.2012.12.011">Stanczyk, Archer, &amp; Bhavnani, 2013</a>). In contrast to oral estradiol, sublingual estradiol does not pass extensively through the liver and is not significantly deactivated by hepatic metabolism into estrogen metabolites. Instead, sublingually administered estradiol is rapidly absorbed into the bloodstream and directly enters circulation. Consequently, sublingual estradiol has greater bioavailability than oral estradiol, meaning that lower doses are needed to achieve similar AUC estradiol levels (<a href="https://doi.org/10.1080/13697130500148875">Kuhl, 2005</a>) (Figures 1 and 2). This is an advantage of sublingual estradiol over oral estradiol, as it allows for lower doses to be used and for reduced medication costs.</p>
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<table>
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<tbody>
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<tr>
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<td><img src="/assets/images/sublingual-e2-transfem/single-dose-oral-e2.png" /></td>
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<td><img src="/assets/images/sublingual-e2-transfem/single-dose-sl-e2.png" /></td>
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</tr>
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<tr>
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<td colspan="2"><strong>Figures 1 and 2:</strong> Pharmacokinetics in different studies of a single 0.25 to 2 mg dose of micronised estradiol with oral administration (left) and sublingual or buccal administration (right). Sources: <a href="https://doi.org/10.1016/0002-9378(81)90101-0">Burnier et al. (1981)</a>; <a href="https://journals.lww.com/greenjournal/Abstract/1981/01000/Rapid_Absorption_of_Micronized_Estradiol_17_beta_.14.aspx">Casper &amp; Yen (1981)</a>; <a href="https://doi.org/10.1530/acta.0.1010093">Fiet et al. (1982)</a>; <a href="https://pubmed.ncbi.nlm.nih.gov/8240460/">Kuhnz, Gansau, &amp; Mahler (1993)</a>; <a href="https://doi.org/10.1016/S0029-7844(96)00513-3">Price et al. (1997)</a>; <a href="https://doi.org/10.1055/s-2001-18223">Wiegratz et al. (2001)</a>; <a href="https://doi.org/10.1080/cmt.6.2.104.111">Wren et al. (2003)</a>; and <a href="https://doi.org/10.1097/GME.0000000000000467">Pickar et al. (2015)</a>. Dotted black lines represent approximately average integrated estradiol levels in premenopausal women (<a href="https://doi.org/10.1016/j.cca.2019.04.062">Verdonk et al., 2019</a>).
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</td>
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</tr>
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</tbody>
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</table>
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</htmlprotect>
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<p>Because accidental swallowing of some of the estradiol seems probable, the sublingual route is, most likely, actually a combination of sublingual and oral delivery of estradiol (<a href="https://doi.org/10.1016/S0889-8545(21)00577-5">Lobo, 1987</a>; <a href="https://doi.org/10.1080/13697130500148875">Kuhl, 2005</a>). A preliminary report from an ongoing study of transfeminine people reported that a single 1 mg dose of sublingual estradiol caused an average rise in the level of estradiol up to a maximum of at least 179 pg/mL (657 pmol/L) within one to two hours of administration. In contrast, a peak concentration of just 36 pg/mL (130 pmol/L) was found with the same 1 mg dose administered orally (<a href="https://doi.org/10.1210/jendso/bvaa046.2237">Doll et al., 2020</a>). Thereafter, estradiol levels decreased rapidly. This response has also been found in other studies of postmenopausal women where a wide range of peak concentrations have been observed (<a href="https://doi.org/10.1016/0002-9378(81)90101-0">Burnier et al., 1981</a>; <a href="https://doi.org/10.1016/S0029-7844(96)00513-3">Price et al., 1997</a>; <a href="https://doi.org/10.1080/cmt.6.2.104.111">Wren et al., 2003</a>). Estradiol levels are found to rapidly rise on the order of ten times that of the peak of oral estradiol, then rapidly decline with an elimination half-life of a few hours (<a href="https://doi.org/10.1080/13697130500148875">Kuhl, 2005</a>). Sublingual estradiol is somewhat analogous in this respect to intravenously administered estradiol, which also is associated with a rapid increase in estradiol levels and a very short elimination half-life following a dose (<a href="https://pubmed.ncbi.nlm.nih.gov/8240460/">Kuhnz, Gansau, &amp; Mahler, 1993</a>). Another route of administration that is similar in this regard is intranasal administration (<a href="https://doi.org/10.1007/BF03190030">Devissaguet et al., 1999</a>). Owing to the spikiness and short duration of sublingual estradiol, sublingual estradiol does not achieve as stable of concentrations as other formulations do. As such, this is a marked difference to other formulations of estradiol, such as oral estradiol, that produce much more stable hormone levels that do not fluctuate as much over the course of the day.</p>
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<p>A range of estimates have been reported for the relative bioavailability of sublingual estradiol. One small randomised study of postmenopausal women found approximately 2.5-fold higher area-under-the-curve (AUC) levels of estradiol with sublingual estradiol than with the same doses of oral estradiol (<a href="https://doi.org/10.1016/S0029-7844(96)00513-3">Price et al., 1997</a>). Other studies have reported relative bioavailability estimates for sublingual estradiol of up to five times that of oral estradiol (<a href="https://doi.org/10.1016/S0378-5122(99)00036-5">Pines et al., 1999</a>). A study in marmoset monkeys found that the absolute bioavailability of sublingual estradiol was 10%; approximately twice that of conventional absolute bioavailability estimates of oral estradiol (5%, though with a wide range of 0.1 to 12%) (<a href="https://doi.org/10.1007/978-3-642-60107-1_15">Kuhnz, Blode, &amp; Zimmermann, 1993</a>). Therefore, with respect to AUC levels of estradiol, the sublingual route appears to have between approximately two and five times higher estradiol levels compared to oral estradiol when given at the same doses. Based on these findings, approximate doses of sublingual estradiol for use in transfeminine hormone therapy can be derived (Table 1). It is of note that, at this time, the comparative potency of sublingual estradiol remains to be properly characterised due to a lack of research.</p>
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<p><strong>Table 1:</strong> Approximately comparable doses of estradiol (E2) and estradiol valerate (EV) administered by the oral and sublingual routes in terms of total estradiol exposure (<a href="https://doi.org/10.1016/S0029-7844(96)00513-3">Price et al., 1997</a>; <a href="https://doi.org/10.1016/S0378-5122(99)00036-5">Pines et al., 1999</a>):</p>
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<table>
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<thead>
|
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<th> </th>
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<th>Low Dose</th>
|
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<th>Moderate Dose</th>
|
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<th>High Dose</th>
|
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<th>Very-High Dose</th>
|
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<td><strong>Oral E2</strong></td>
|
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<td>2 mg/day</td>
|
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<td>4 mg/day</td>
|
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<td>8 mg/day</td>
|
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<td>10 mg/day</td>
|
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</tr>
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<td><strong>Sublingual E2</strong><sup>a</sup></td>
|
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<td>0.5–1 mg/day</td>
|
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<td>1–2 mg/day</td>
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<td>2–4 mg/day</td>
|
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<td>2.5–5 mg/day</td>
|
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</tr>
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<tr>
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<td><strong>Oral EV</strong></td>
|
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<td>3 mg/day</td>
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<td>6 mg/day</td>
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<td>10 mg/day</td>
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<td>12 mg/day</td>
|
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</tr>
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<td><strong>Sublingual EV</strong><sup>a</sup></td>
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<td>0.75–1.5 mg/day</td>
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<td>1.5–3 mg/day</td>
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<td>2.5–5 mg/day</td>
|
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<td>3–6 mg/day</td>
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<p><small><sup>a</sup> Range calculated by dividing oral doses by two and four to reflect differences in absolute bioavailability and rounding to the nearest 0.25 mg. <sup>*</sup> Bioidentical estradiol has wide interindividual variation in its pharmacology and the effects of doses may vary significantly between individuals. EV has greater molecular weight and therefore contains less medication for the same amount/dose by weight. It should be noted that estimates for the relative bioavailability of EV are extrapolated from formulations with no valeric ester attached (i.e., E2).</small></p>
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<h3 id="sublingually-administered-estradiol-and-feminisation">Sublingually Administered Estradiol and Feminisation</h3>
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<p>The very short half-life of sublingually and buccally administered estradiol relative to other forms raises a few questions for its potential use of sublingual estradiol in feminising hormone therapy. One of the most commonly asked questions on online forums is regarding which gender-affirming hormone therapy regimens might be most “effective” with respect to the feminising effects of estrogens. These include, but are not limited to, outcomes such as breast development and fat distribution.</p>
|
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|
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<p>In contrast to oral and trandermal estradiol, no data exist describing the extent of feminisation with sublingual estradiol (<a href="/articles/oral-vs-transdermal-e2/">Sam, 2020a</a>). However, as discussed previously, oral and non-oral estradiol have not been found to differ in their effects on breast development or other feminising outcomes in transfeminine people or cisgender hypogondal girls (<a href="https://doi.org/10.1210/jc.2005-1081">Rosenfield et al., 2005</a>; <a href="https://doi.org/10.1186/1687-9856-2014-12">Shah et al., 2014</a>; <a href="https://doi.org/10.1530/EJE-17-0496">Klaver et al., 2018</a>; <a href="https://doi.org/10.1210/clinem/dgaa841">de Blok et al., 2021</a>). In consideration of this, differences in efficacy might not be expected for sublingual estradiol either. The fact that several gender clinics have employed sublingual estradiol is also encouraging and suggests that sublingual estradiol is effective for inducing feminization (<a href="https://doi.org/10.1097/AOG.0000000000000692">Deutsch, Bhakri, &amp; Kubicek, 2015</a>; <a href="https://doi.org/10.5468/ogs.2019.62.1.46">Lim et al., 2019</a>; <a href="https://doi.org/10.1089/lgbt.2020.0249">Cirrincione et al., 2021</a>). Nevertheless, as no studies have been conducted comparing the feminising efficacy of sublingual estradiol with objective measures, it is not possible to say for certain whether or not there is any difference in feminisation outcomes between oral and sublingual estradiol. Hopefully, studies in the future will shed more light on this.</p>
|
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|
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<h3 id="testosterone-suppressing-efficacy-of-sublingually-administered-estradiol">Testosterone Suppressing Efficacy of Sublingually Administered Estradiol</h3>
|
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|
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<p>Another question that might be raised by the short half-life of sublingual estradiol is how it might compare to more conventional routes of administration in terms of its ability to suppress testosterone and other androgens.</p>
|
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<p>Estrogens were first characterised for their use as antigonadotrophic antiandrogens in the 1940s, in the form of oral synthetic estrogens, namely diethylstilbestrol (DES), to treat men with prostate cancer (<a href="https://cancerres.aacrjournals.org/content/1/4/293">Huggins &amp; Hodges, 1941</a>). Estrogens given in the form of oral ethinylestradiol (EE), long-acting estradiol esters, such as polyestradiol phosphate, and transdermal estradiol patches have been studied. Their efficacy for this indication is well established (<a href="https://doi.org/10.1002/(SICI)1097-0045(199605)28:5%3C307::AID-PROS6%3E3.0.CO;2-8">Stege et al., 1996</a>; <a href="https://doi.org/10.1002/cncr.21528">Kohli, 2006</a>; <a href="https://doi.org/10.1111/iju.12613">Sciarra et al., 2015</a>). As data are more limited for testosterone suppression with estrogens in transfeminine people, these data are valuable for informing transfeminine hormone therapy. Sublingual estradiol, on the other hand, has never been used as therapy for prostatic cancer and, consequently, no such data exist on the same scale to show the ability of sublingual estradiol in this capacity.</p>
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<p>Recent data from some studies have found that physiologic levels of estradiol (i.e., 100–200 pg/mL [367–734 pmol/L]) from non-sublingual estradiol alone result in rapid and near complete, if not complete, suppression of testosterone levels to the female range in many transfeminine people (<a href="https://doi.org/10.1089/trgh.2017.0035">Leinung, Feustel, &amp; Joseph, 2018</a>; <a href="https://doi.org/10.1210/clinem/dgaa884">Pappas et al., 2020</a>). Additionally, new data from around 900 men enrolled in the ongoing <a href="https://en.wikipedia.org/wiki/Prostate_Adenocarcinoma:_TransCutaneous_Hormones">Prostate Adenocarcinoma TransCutaneous Hormones</a> (PATCH) study, a multicentre randomised controlled trial in the United Kingdom, show that sustained median estradiol levels of between 215 to 250 pg/mL (789–918 pmol/L) from transdermal patches were similarly effective (~95%) to GnRH analogues in reducing testosterone levels to the castrate range (&lt;50 ng/dL [&lt;1.7 nmol/L]) (<a href="https://doi.org/10.1016/S0140-6736(21)00100-8">Langley et al., 2021</a>). However, because of the markedly different pharmacokinetics of sublingual estradiol, it is plausible that estradiol administered in this way might result in sub-par suppression at doses with similar AUC levels of estradiol. Put another way, sustained estradiol levels may be more efficacious with respect to testosterone suppression than the frequent and short-lived “spikes” in estradiol levels that occur with the sublingual route.</p>
|
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|
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<p>There is some weak evidence from pharmacological studies of estradiol that support this possibility. One line of evidence is that some studies of both sublingual and intravenous administration have reported rapid but limited suppression of the gonadotropins (follicle-stimulating hormone and luteinising hormone) in women despite sufficiently elevated estradiol levels for several hours (<a href="https://doi.org/10.1210/jcem-32-6-766">Tsai &amp; Yen, 1971</a>; <a href="https://doi.org/10.1016/0002-9378(81)90101-0">Burnier et al., 1981</a>; <a href="https://journals.lww.com/greenjournal/Abstract/1981/01000/Rapid_Absorption_of_Micronized_Estradiol_17_beta_.14.aspx">Casper &amp; Yen, 1981</a>; <a href="https://doi.org/10.1002/j.1552-4604.1993.tb01949.x">Hoon et al., 1993</a>). These studies are low quality and indirect since testosterone suppression itself was not measured and they were performed in cisgender women. Another problem is that all were single dose studies and their findings may not translate to multiple dosing. It may be the case that full gonadotropin suppression becomes apparent with repeated physiologic doses of sublingual estradiol. Nevertheless, these studies might suggest a limited effect of sublingual estradiol to fully suppress gonadal function in transfeminine people without the use of excessive doses that would lead to greater health risks or the additional use of other antiandrogens.</p>
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|
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<p>It could be the case that monotherapy with sublingual estradiol may not be as effective at comparable doses to the typically employed doses in studies of prostatic cancer (e.g., two to four 100 μg/24 hours transdermal patches). Transdermal patches, gels and parenteral estradiol esters, such as estradiol valerate, injected intramuscularly or subcutaneously might therefore be more reliable choices for monotherapy regimens. On the other hand, sublingual estradiol has been studied in transfeminine people in combination with and without the low-dose use of the progestin medroxyprogesterone acetate (MPA) (<a href="https://doi.org/10.1210/jc.2018-02253">Jain, Kwan, &amp; Forcier, 2019</a>). In this study, at least reasonably high rates of testosterone levels within the female range (&lt;50 ng/dL [&lt;1.7 nmol/L]) were achieved by the transfeminine people who took sublingual estradiol together with medroxyprogesterone acetate, showing that sublingual estradiol taken together with other antiandrogens (e.g., 10 mg/day cyproterone acetate) is very likely to be viable for achieving effective testosterone suppression (<a href="/articles/cpa-dosage/">Aly, 2019</a>).</p>
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<h3 id="monitoring-of-estradiol-levels-with-sublingual-administration">Monitoring of Estradiol Levels with Sublingual Administration</h3>
|
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|
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<p>A further consideration regarding the rapid changes in estradiol levels that occur with the use of sublingual estradiol is the relevance of monitoring of estradiol levels through bloodwork. Currently, consensus guidelines do not recommend a specific time for monitoring of the blood relative to the time of a last dose (<a href="https://transcare.ucsf.edu/guidelines">Deutsch, 2016</a>; <a href="https://doi.org/10.5694/mja2.50259">Cheung et al., 2019</a>; <a href="https://doi.org/10.1016/j.jsxm.2020.01.012">T’Sjoen et al., 2020</a>). This may be in part due to practical reasons, or because there is currently no robust data from randomised controlled trials to guide the specifics of dosing in transgender hormone therapy (<a href="https://doi.org/10.1002/14651858.CD013138.pub2">Haupt et al., 2020</a>). Nevertheless, because estradiol levels vary so significantly with sublingual estradiol, knowledge of how long after the last dose blood was drawn is important to ensure proper interpretation of laboratory results.</p>
|
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|
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<p>For instance, measuring hormone levels just after a dose of sublingual estradiol has been taken might lead to the misinterpretation that levels of estradiol are excessively high and that one’s dosage should be reduced to achieve a more sensible concentration of estradiol in the blood. In reality, this would be a misunderstanding caused by the pharmacology of sublingual estradiol as the point of measurement would be right around the time when estradiol levels are most likely to be at their highest. These estradiol levels would not be indicative of the average amount of exposure, which is the more accurate measure of overall estrogenicity. Similarly, on the opposite end of the scale, drawing blood just before the administration of a new dose might lead to the belief that estrogen levels are too low and, consequently, lead to the use of excessive doses of estrogens. The latter misinterpretation may be more common among people unfamiliar with the pharmacology of sublingual estradiol as levels of estradiol only remain very high in the first few hours after a dose of sublingual estradiol has been taken before falling rapidly.</p>
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|
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<p>This oversight may also have implications in studies of sublingual estradiol. For instance, in the previously mentioned respective analysis of the use of sublingual estradiol for gender-affirming hormone therapy, the frequency of administration and time of measurement relative to the last dose were not specified in their results (<a href="https://doi.org/10.1210/jc.2018-02253">Jain, Kwan, &amp; Forcier, 2019</a>). Although this data is much needed and is valuable to ongoing research to characterise sublingual estradiol in in transfeminine people, a significant problem is not knowing at what time estradiol levels were measured after the medication was administered. It is difficult to say much about the estradiol levels recorded in this study. Moreover, it is impossible to use this data to help derive equivalent doses of sublingual and oral estradiol.</p>
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|
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<p>A possible solution to the problem of rapidly changing hormone levels associated with the sublingual route might simply be to measure when estradiol levels are most likely to be closest to their average. In the case of sublingual estradiol, studies generally find this to be approximately four hours after the administration of a dose, although there is likely to be considerable variation between individuals (<a href="https://doi.org/10.1080/13697130500148875">Kuhl, 2005</a>). Nevertheless, this approach may give the most representative “snapshot” of overall estrogenic exposure and might help to avoid misleading laboratory data in users of sublingual estradiol.</p>
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<h3 id="administration-of-multiple-sublingual-doses-per-day">Administration of Multiple Sublingual Doses Per Day</h3>
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<p>In order to compensate for the short half-life of sublingually administered estradiol, multiple doses of estrogens can be administered in smaller quantities per day to maintain hormone levels that are somewhat more consistent (<a href="https://doi.org/10.1007/s002130051095">Ahokas, Kaukoranta, &amp; Aito, 1999</a>).</p>
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<p>In one study of premenopausal women with high-dose estrogen therapy, 2 mg of sublingual estradiol was administered three or four times per day (a total of 6–8 mg/day), resulting in significantly more stable hormone levels than would be expected with a single dose per day (<a href="https://doi.org/10.1016/S0140-6736(89)92762-1">Serhal &amp; Craft, 1989</a>). This was replicated in another study where estradiol was administered three to eight times per day (<a href="https://doi.org/10.4088/JCP.v62n0504">Ahokas et al., 2001</a>). Conversely, a third study investigating low-dose buccal estradiol found little difference between the “steady-state” estradiol concentrations with a once-daily and twice-daily 0.25 mg dose of buccal estradiol over a 12 hour observation period (<a href="https://doi.org/10.1080/cmt.6.2.104.111">Wren et al., 2003</a>). These findings may indicate that sublingual and buccal estradiol needs to be taken at least thrice per day in order to achieve concentrations of estradiol that are more stable.</p>
|
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|
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<p>For the reasons outlined in the subsections above, it would seem advantageous that transfeminine people using sublingual estradiol employ this approach and take sublingual estradiol in divided doses throughout the day; perhaps ideally at least three or four times per day. For instance, instead of taking a 2 mg dose every 24 hours, it would be better to take four 0.5 mg doses in the space of 24 hours (as evenly spaced as practical). Administering sublingual estradiol multiple times throughout the day might be less convenient, but is likely to provide at least somewhat more balanced estradiol levels and potentially better testosterone suppression. The administration of multiple doses every day could be regarded as optimal for the use of sublingually administered estradiol.</p>
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<h2 id="safety-and-tolerability">Safety and Tolerability</h2>
|
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|
||
<p>Unfortunately, as with the pharmacokinetics of sublingually and buccally estradiol, the published medical literature concerning the safety and tolerability of this route of administration leaves much to be desired. No long term safety data exist for sublingually administered estradiol in the same way that both oral and transdermal estradiol have been rigorously studied in menopausal women (<a href="https://doi.org/10.1016/j.thromres.2018.06.014">Rovinski et al., 2018</a>; <a href="https://doi.org/10.1016/S0140-6736(19)31709-X">CGHFBC, 2019</a>).</p>
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<h3 id="adverse-health-effects-of-estrogens">Adverse Health Effects of Estrogens</h3>
|
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|
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<p>With sufficient exposure, owing to their effects in the liver, estrogens are associated with an increased risk of blood clots (<a href="https://doi.org/10.1080/13697130500148875">Kuhl, 2005</a>; <a href="/articles/estrogens-blood-clots/">Aly, 2020b</a>). Additionally, under certain circumstances, estrogens can be associated with other cardiovascular complications (<a href="https://doi.org/10.1001/jama.291.14.1701">Anderson et al., 2004</a>; <a href="https://doi.org/10.1080/00365590510031228">Mikkola et al., 2005</a>). Although the absolute risk is low in the short-term, these are the most significant health concerns associated with gender-affirming hormone therapy.</p>
|
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<p>A limited number of studies have assessed the effects of sublingually administered estradiol on the liver (<a href="https://doi.org/10.1016/S0378-5122(99)00036-5">Pines et al., 1999</a>; <a href="https://doi.org/10.5468/ogs.2019.62.1.46">Lim et al., 2019</a>). These data found similar effects on lipids and cholesterol to other estrogens. One line of evidence that indicates sublingual estradiol has greater hepatic impact than other non-oral forms such as trandermal estradiol is the significantly greater quantities of estrone and estrone sulphate that are generated by this route; a marker of estrogenic exposure in the liver (<a href="https://doi.org/10.1016/0002-9378(81)90101-0">Burnier et al., 1981</a>; <a href="https://doi.org/10.1089/lgbt.2020.0249">Cirrincione et al., 2021</a>). Intense estrogenic activation in the liver is the mechanism by which non-oral estradiol induces a hypercoagulable state at high doses (<a href="/articles/vte-transfem-analysis/">Sam, 2020b</a>; <a href="/articles/pep-cardiovascular-analysis/">Sam, 2020c</a>).</p>
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<p>While a large body of research does exist concerning the short and long term health effects of estrogens, none of these studies have investigated sublingual or buccal estradiol (<a href="https://doi.org/10.1093/humupd/dmy039">Oliver-Williams et al., 2019</a>; <a href="https://doi.org/10.1111/1471-0528.16524">Mishra et al., 2021</a>). Given that oral estradiol has greater risks than non-oral estradiol, and that sublingual administration partially but not fully avoids first-pass metabolism, it may be the case that its own risk would be no higher than the risk observed with oral estradiol but no lower than the risk observed with non-oral routes. A retrospective cohort study in the United States found that the incidence of thromboembolism in transfeminine people with an average dose of 4 mg/day oral estradiol was approximately twice that of cisgender controls not taking hormone therapy after adjusting for confounders (HR 2.0, 95% CI 1.4–2.8 versus reference women) (<a href="https://doi.org/10.7326/M17-2785">Getahun et al., 2018</a>). These increases in risks are much lower compared to regimens in transfeminine people in the past that included high doses of synthetic estrogens, but it’s important to remember that even such increases can significantly increase morbidity and mortality (<a href="https://doi.org/10.1016/j.thromres.2020.08.006">Morimont, Dogné, &amp; Douxfils, 2020</a>). It would be advisable to limit doses of sublingual and buccal estradiol so that they are not excessive (i.e., &lt;6 mg/day) in the interest of harm reduction and the balancing of the risks and benefits of gender-affirming hormone therapy.</p>
|
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<h3 id="non-compliance">Non-compliance</h3>
|
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|
||
<p>A practical obstacle to the use of sublingual estradiol in transfeminine people is that it may be highly inconvenient to have to administer doses thrice, four times or perhaps even more often throughout the duration of a single day. It has been found in observational studies that, in general, the number of prescribed medications and doses per day are positively associated with patient non-compliance and the number of missed doses (<a href="https://doi.org/10.2147/TCRM.S1458">Jin et al., 2008</a>; <a href="https://doi.org/10.1016/j.pmedr.2014.10.001">Toh et al., 2014</a>). These findings are especially of relevance to transfeminine people as, in most cases, we require decades of hormone therapy. While missing one dose from time to time may be of little consequence, missing doses repeatedly could be more problematic.</p>
|
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|
||
<p>In contrast to sublingual estradiol, the half-life of oral estradiol and transdermal gel is long enough to enable once-daily administration (<a href="https://doi.org/10.1055/s-2001-18223">Wiegratz et al., 2001</a>; <a href="https://doi.org/10.1097/01.AOG.0000161958.70059.db">Potts &amp; Lobo, 2005</a>). In the case of transdermal patches and parenteral estradiol, these forms only have to be replenished every few days or after even longer intervals of time (<a href="https://doi.org/10.1016/j.contraception.2012.11.010">Thurman et al., 2013</a>; <a href="https://doi.org/10.1097/JCP.0000000000000351">Wisner et al., 2015</a>). Therefore, when considering the use of sublingual estradiol versus other forms, whether or not it would be practical or convenient to consistently take medication several times a day should probably also be an important consideration for transfeminine people. If not, then another formulation may be preferable for the person in question. This may be especially true for long term use.</p>
|
||
|
||
<h2 id="summary-and-conclusions">Summary and Conclusions</h2>
|
||
|
||
<p>There is much less research investigating sublingual and buccal estradiol than other forms of estrogen. These forms, namely oral and transdermal estrogens, are used in the alleviation of the menopause and for other indications that have historically been more widely used. As a result, they have received much more attention and characterisation than sublingual estradiol has for transfeminine hormone therapy. However, several recent studies have added to our knowledge of sublingual estradiol. Clinical practice guidelines for transgender care that have historically not discussed the use of sublingual estradiol may be adjusted accordingly if more information becomes available.</p>
|
||
|
||
<p>Sublingual estradiol is different in its pharmacology to other formulations. The main difference is that it is associated with a rapid rise and fall in estradiol levels. It has between two and four times the bioavailability of oral estradiol and hence provides the same total estradiol exposure at doses that are two to four times lower. This is a particular advantage because sublingual estradiol, therefore, is cheaper than oral estradiol, and the higher estradiol levels at the same dose may be helpful for testosterone suppression.</p>
|
||
|
||
<p>While no evidence exists to show or suggest that sublingual estradiol results in better or inferior feminisation to that experienced with other routes of administration, it is plausible that sublingual estradiol may to some degree result in less testosterone suppression at the same total estradiol exposure. Sublingual estradiol has, nonetheless, been shown to be effective with respect to testosterone suppression when paired with other antiandrogens. Care should be taken with sublingual estradiol when monitoring estradiol levels to ensure correct interpretation. In order to help minimise these potential problems, sublingual estradiol can be taken in multiple doses divided throughout the day.</p>
|
||
|
||
<p>The health risks of sublingual estradiol have not been quantified in large observational or randomised studies. Therefore, although the partial bypassing of the first pass through the liver is reassuring in this respect, its cardiovascular risk profile is unknown. Sublingual estradiol may be inconvenient and other formulations can be used instead if preferred, particularly for more long-term therapy.</p>
|
||
|
||
<p>Taken together, although much more research is clearly needed to properly characterise the route, sublingual estradiol may have a number of advantageous properties and may be a useful alternative to oral estradiol in transfeminine hormone therapy.</p>
|
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|
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<h2 id="references">References</h2>
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<li>Lobo, R. A. (1987). Absorption and metabolic effects of different types of estrogens and progestogens. <em>Obstetrics and Gynecology Clinics of North America</em>, <em>14</em>(1), 143–167. [<a href="https://pubmed.ncbi.nlm.nih.gov/3306517/]">PubMed</a>] [DOI:<a href="https://doi.org/10.1016/S0889-8545(21)00577-5">10.1016/S0889-8545(21)00577-5</a>] [<a href="https://www.obgyn.theclinics.com/article/S0889-8545(21)00577-5/fulltext">URL</a>] [<a href="https://files.transfemscience.org/pdfs/Lobo%20(1987)%20-%20Absorption%20and%20metabolic%20effects%20of%20different%20types%20of%20estrogens%20and%20progestogens.pdf">PDF</a>]</li>
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||
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<li>Mishra, S. R., Chung, H. F., Waller, M., &amp; Mishra, G. D. (2021). Duration of estrogen exposure during reproductive years, age at menarche and age at Menopause, and risk of cardiovascular disease events, all‐cause and cardiovascular mortality: a systematic review and meta‐analysis. <em>BJOG: An International Journal of Obstetrics &amp; Gynaecology</em>, <em>128</em>(5), 809–821. [DOI:<a href="https://doi.org/10.1111/1471-0528.16524">10.1111/1471-0528.16524</a>]</li>
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<li>Sciarra, A., Gentile, V., Cattarino, S., Gentilucci, A., Alfarone, A., D’Eramo, G., &amp; Salciccia, S. (2015). Oral ethinylestradiol in castration‐resistant prostate cancer: a 10‐year experience. <em>International Journal of Urology</em>, <em>22</em>(1), 98–103. [DOI:<a href="https://doi.org/10.1111/iju.12613">10.1111/iju.12613</a>]</li>
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<li>Serhal, P., &amp; Craft, I. (1989). Oocyte donation in 61 patients. <em>The Lancet</em>, <em>333</em>(8648), 1185–1187. [DOI:<a href="https://doi.org/10.1016/S0140-6736(89)92762-1">10.1016/S0140-6736(89)92762-1</a>]</li>
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<li>Shah, S., Forghani, N., Durham, E., &amp; Neely, E. K. (2014). A randomized trial of transdermal and oral estrogen therapy in adolescent girls with hypogonadism. <em>International Journal of Pediatric Endocrinology</em>, <em>2014</em>(1), 12. [DOI:<a href="https://doi.org/10.1186/1687-9856-2014-12">10.1186/1687-9856-2014-12</a>]</li>
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<li>Stanczyk, F. Z., Archer, D. F., &amp; Bhavnani, B. R. (2013). Ethinyl estradiol and 17β-estradiol in combined oral contraceptives: pharmacokinetics, pharmacodynamics and risk assessment. <em>Contraception</em>, <em>87</em>(6), 706–727. [DOI:<a href="https://doi.org/10.1016/j.contraception.2012.12.011">10.1016/j.contraception.2012.12.011</a>]</li>
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<li>Stege, R., Gunnarsson, P. O., Johansson, C. J., Olsson, P., Pousette, Å., &amp; Carlström, K. (1996). Pharmacokinetics and testosterone suppression of a single dose of polyestradiol phosphate (Estradurin®) in prostatic cancer patients. <em>The Prostate</em>, <em>28</em>(5), 307–310. [DOI:<a href="https://doi.org/10.1002/(SICI)1097-0045(199605)28:5%3C307::AID-PROS6%3E3.0.CO;2-8">10.1002/(SICI)1097-0045(199605)28:5&lt;307::AID-PROS6&gt;3.0.CO;2-8</a>]</li>
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<li>T’Sjoen, G., Arcelus, J., De Vries, A. L., Fisher, A. D., Nieder, T. O., Özer, M., &amp; Motmans, J. (2020). European Society for Sexual Medicine position statement “assessment and hormonal management in adolescent and adult trans people, with attention for sexual function and satisfaction”. <em>The Journal of Sexual Medicine</em>, <em>17</em>(4), 570–584. [DOI:<a href="https://doi.org/10.1016/j.jsxm.2020.01.012">10.1016/j.jsxm.2020.01.012</a>]</li>
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<li>Thurman, A., Kimble, T., Hall, P., Schwartz, J. L., &amp; Archer, D. F. (2013). Medroxyprogesterone acetate and estradiol cypionate injectable suspension (Cyclofem) monthly contraceptive injection: steady-state pharmacokinetics. <em>Contraception</em>, <em>87</em>(6), 738–743. [DOI:<a href="https://doi.org/10.1016/j.contraception.2012.11.010">10.1016/j.contraception.2012.11.010</a>]</li>
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</ul></content><author><name>{"first_name"=>"Sam", "last_name"=>"S.", "author-link"=>"/about/#sam", "articles-link"=>"/articles-by-author/sam/"}</name></author><category term="github" /><category term="workspace" /><summary type="html">An Exploration of Sublingual Estradiol as an Alternative to Oral Estradiol in Transfeminine People By Sam | First published June 11, 2021 | Last modified September 6, 2021</summary></entry><entry><title type="html">Clinical Guidelines with Information on Transfeminine Hormone Therapy</title><link href="https://transfemscience.org/articles/transfem-hormone-guidelines/" rel="alternate" type="text/html" title="Clinical Guidelines with Information on Transfeminine Hormone Therapy" /><published>2020-11-20T10:00:00-08:00</published><updated>2023-05-23T00:00:00-07:00</updated><id>https://transfemscience.org/articles/transfem-hormone-guidelines</id><content type="html" xml:base="https://transfemscience.org/articles/transfem-hormone-guidelines/"><h1 id="clinical-guidelines-with-information-on-transfeminine-hormone-therapy">Clinical Guidelines with Information on Transfeminine Hormone Therapy</h1>
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<!-- Supports up to four authors per article currently (author, author2, author3, author4) -->
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<p>By
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<!-- First author --><a href="/about/#aly">Aly</a><!-- Second author --><!-- Third author --><!-- Fourth author --> | First published November 20, 2020
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| Last modified May 23, 2023</p>
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<h2 id="abstract--tldr">Abstract / TL;DR</h2>
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<p>This article is a collection of clinical practice guidelines throughout the world with information on transfeminine hormone therapy. Examples of these clinical guidelines include the World Professional Association for Transgender Health (WPATH) Standards of Care for the Health of Transgender and Gender Diverse People, the Endocrine Society guidelines, and the University of California, San Francisco (UCSF) Center of Excellence for Transgender Health guidelines, among many others.</p>
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<h2 id="introduction">Introduction</h2>
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<p>Clinicians use <a href="https://en.wikipedia.org/wiki/Medical_guideline">clinical practice guidelines</a> (CPGs) to learn about and guide themselves in administering medical care for different indications. Clinical practice guidelines review and summarize the available scientific literature and research in a given medical area. They allow clinicians to competently administer care without necessarily having to delve into and develop their understanding via the primary scientific literature. <a href="https://en.wikipedia.org/wiki/Literature_review">Literature reviews</a> can serve a similar function. However, clinical practice guidelines are generally more substantial and are more founded in <a href="https://en.wikipedia.org/wiki/Evidence-based_medicine">evidence-based medicine</a>. They are also regularly updated. Clinical practice guidelines are developed and maintained by clinical organizations and societies, universities, government agencies, and sometimes even large medical clinics. They may be international/locationless or oftentimes region-specific.</p>
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<p>There are many clinical practice guidelines for transgender medicine (for review, <a href="https://dx.doi.org/10.1001%2Fjournalofethics.2016.18.11.stas1-1611">Deutsch, Radix, &amp; Reisner, 2016</a>; <a href="https://doi.org/10.1016/j.ucl.2019.07.001">Radix, 2019</a>; <a href="https://doi.org/10.1007/978-3-030-05683-4_4">Radix, 2019</a>; <a href="https://www.uptodate.com/contents/society-guideline-links-transgender-health">UpToDate</a>; <a href="https://doi.org/10.1210/jendso/bvab048.1609">Bewley et al., 2021</a>; <a href="https://doi.org/10.1136/bmjopen-2021-048943">Dahlen et al., 2021</a>; <a href="https://doi.org/10.1089/trgh.2020.0043">Ziegler, Carroll, &amp; Charnish, 2021</a>). These guidelines discuss topics such as psychotherapy, hormone therapy, voice therapy, and surgical management of transgender people, among others. In addition to educating and guiding clinicians, transgender clinical practice guidelines are useful materials for transgender people as they can help to inform them about their care.</p>
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<p>This page is a maintained list of known English clinical guidelines throughout the world that include information specifically on the subject of transfeminine hormone therapy. The most major guidelines on transgender hormone therapy are the <a href="https://en.wikipedia.org/wiki/World_Professional_Association_for_Transgender_Health">World Professional Association for Transgender Health</a> (WPATH) <a href="https://en.wikipedia.org/wiki/Standards_of_Care_for_the_Health_of_Transsexual,_Transgender,_and_Gender_Nonconforming_People">Standards of Care for the Health of Transgender and Gender Diverse People</a> (SOC) (<a href="https://doi.org/10.1080/26895269.2022.2100644">Coleman et al., 2022</a>), the <a href="https://en.wikipedia.org/wiki/Endocrine_Society">Endocrine Society</a> guidelines (<a href="https://doi.org/10.1210/jc.2009-0345">Hembree et al., 2017</a>), and the <a href="https://en.wikipedia.org/wiki/University_of_California,_San_Francisco">University of California, San Francisco</a> (UCSF) guidelines (<a href="https://transcare.ucsf.edu/guidelines">Deutsch, 2016</a>). The WPATH SOC and the Endocrine Society guidelines are international, while the UCSF guidelines are based in the United States.</p>
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<h2 id="international">International</h2>
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<table>
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<thead>
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<tr>
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||
<th>Title</th>
|
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<th>Author / Organization</th>
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<th>Year</th>
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<th>Form</th>
|
||
</tr>
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||
</thead>
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<tbody>
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<tr>
|
||
<td><a href="https://doi.org/10.1210/jc.2017-01658">Endocrine Treatment of Gender-Dysphoric/Gender-Incongruent Persons: An Endocrine Society Clinical Practice Guideline</a> [<a href="https://academic.oup.com/jcem/article-pdf/102/11/3869/21533864/jc.2017-01658.pdf">PDF</a>] [See also: <a href="https://doi.org/10.1210/jc.2009-0345">1st/2009 edition</a>]</td>
|
||
<td>Hembree et al. / Endocrine Society</td>
|
||
<td>2017</td>
|
||
<td>Published article</td>
|
||
</tr>
|
||
<tr>
|
||
<td><a href="https://doi.org/10.1080/26895269.2022.2100644">Standards of Care for the Health of Transgender and Gender Diverse People, Version 8</a> (<a href="https://www.wpath.org/publications/soc">Alt</a>; <a href="https://www.tandfonline.com/doi/pdf/10.1080/26895269.2022.2100644">PDF</a>) [See also: <a href="https://doi.org/10.1080/15532739.2011.700873">Version 7/2012 edition</a> ([<a href="https://www.wpath.org/media/cms/Documents/SOC%20v7/Standards%20of%20Care%20V7%20-%202011%20WPATH.pdf">PDF</a>])]</td>
|
||
<td>Coleman et al. / World Professional Association for Transgender Health (WPATH)</td>
|
||
<td>2022</td>
|
||
<td>Published article</td>
|
||
</tr>
|
||
<tr>
|
||
<td><a href="https://doi.org/10.1080/15532730903383757">Hormone Therapy in Adults: Suggested Revisions to the Sixth Version of the Standards of Care</a></td>
|
||
<td>Feldman &amp; Safer</td>
|
||
<td>2009</td>
|
||
<td>Published article</td>
|
||
</tr>
|
||
<tr>
|
||
<td><a href="https://www.ippf.org/resource/imap-statement-hormone-therapy-transgender-people">International Medical Advisory Panel (IMAP) Statement on Hormone Therapy for Transgender People</a> [<a href="https://www.ippf.org/sites/default/files/ippf_imap_transgender.pdf">PDF</a>]</td>
|
||
<td>International Planned Parenthood Federation (IPPF)</td>
|
||
<td>2015</td>
|
||
<td>Online document</td>
|
||
</tr>
|
||
<tr>
|
||
<td><a href="https://www.uptodate.com/contents/transgender-women-evaluation-and-management">Transgender Women: Evaluation and Management</a> [<a href="https://files.transfemscience.org/pdfs/Tangpricha%20&amp;%20Safer%20(2019)%20-%20Transgender%20Women_%20Evaluation%20and%20Management%20-%20UpToDate.pdf">PDF</a>]</td>
|
||
<td>Tangpricha &amp; Safer / UpToDate</td>
|
||
<td>2020</td>
|
||
<td>Online web page</td>
|
||
</tr>
|
||
</tbody>
|
||
</table>
|
||
|
||
<h2 id="united-states">United States</h2>
|
||
|
||
<table>
|
||
<thead>
|
||
<tr>
|
||
<th>Title</th>
|
||
<th>Author / Organization [Place]</th>
|
||
<th>Year</th>
|
||
<th>Form</th>
|
||
</tr>
|
||
</thead>
|
||
<tbody>
|
||
<tr>
|
||
<td><a href="https://transcare.ucsf.edu/guidelines">Guidelines for the Primary and Gender-Affirming Care of Transgender and Gender Nonbinary People</a> [<a href="https://transcare.ucsf.edu/sites/transcare.ucsf.edu/files/Transgender-PGACG-6-17-16.pdf">PDF</a>]</td>
|
||
<td>Deutsch / Center of Excellence for Transgender Health, University of California, San Francisco (UCSF) [San Francisco, California]</td>
|
||
<td>2016</td>
|
||
<td>Online document</td>
|
||
</tr>
|
||
<tr>
|
||
<td><a href="https://www.lgbtqiahealtheducation.org/publication/medical-care-of-trans-and-gender-diverse-adults-2021/">Medical Care of Trans and Gender Diverse Adults</a> [<a href="https://www.lgbtqiahealtheducation.org/wp-content/uploads/2021/07/Medical-Care-of-Trans-and-Gender-Diverse-Adults-Spring-2021.pdf">PDF</a>]</td>
|
||
<td>Thompson, et al. / Fenway Health [Boston, Massachusetts]</td>
|
||
<td>2021</td>
|
||
<td>Online document</td>
|
||
</tr>
|
||
<tr>
|
||
<td><a href="https://callen-lorde.org/transhealth/">Protocols for the Provision of Hormone Therapy</a> [<a href="https://web.archive.org/web/20221228055728if_/https://callen-lorde.org/graphics/2018/04/Callen-Lorde-TGNC-Hormone-Therapy-Protocols.pdf">PDF</a>]</td>
|
||
<td>Callen-Lorde Community Health Center [New York City, New York]</td>
|
||
<td>2018</td>
|
||
<td>Online document</td>
|
||
</tr>
|
||
<tr>
|
||
<td><a href="https://www.sfdph.org/dph/comupg/oservices/medSvs/hlthCtrs/TransGendprotocols122006.pdf">Protocols for Hormonal Reassignment of Gender</a></td>
|
||
<td>Davidson et al. / Tom Waddell Health Center / San Francisco Department of Public Health [San Francisco, California]</td>
|
||
<td>2013</td>
|
||
<td>Online document</td>
|
||
</tr>
|
||
<tr>
|
||
<td><a href="https://transline.zendesk.com/hc/en-us/articles/229373288-TransLine-Hormone-Therapy-Prescriber-Guidelines">TransLine Gender Affirming Hormone Therapy Prescriber Guidelines</a> [<a href="https://www.transhealthconsulting.com/s/TransLine-HRT-Guidelines-FINAL-9tsd.pdf">PDF</a>]</td>
|
||
<td>Gorton et al. / TransLine / Lyon-Martin Health Services [San Francisco, California]</td>
|
||
<td>2019</td>
|
||
<td>Online document</td>
|
||
</tr>
|
||
</tbody>
|
||
</table>
|
||
|
||
<h2 id="canada">Canada</h2>
|
||
|
||
<table>
|
||
<thead>
|
||
<tr>
|
||
<th>Title</th>
|
||
<th>Author / Organization</th>
|
||
<th>Year</th>
|
||
<th>Form</th>
|
||
</tr>
|
||
</thead>
|
||
<tbody>
|
||
<tr>
|
||
<td><a href="http://www.phsa.ca/transcarebc/Documents/HealthProf/Primary-Care-Toolkit.pdf">Gender-Affirming Care for Trans, Two-Spirit, and Gender Diverse Patients in BC: A Primary Care Toolkit</a></td>
|
||
<td>Trans Care BC [Vancouver, British Columbia, Canada]</td>
|
||
<td>2021</td>
|
||
<td>Online document</td>
|
||
</tr>
|
||
<tr>
|
||
<td><a href="http://www.phsa.ca/transcarebc/Documents/HealthProf/BC-Trans-Adult-Endocrine-Guidelines-2015.pdf">Endocrine Therapy for Transgender Adults in British Columbia: Suggested Guidelines: Physical Aspects of Transgender Endocrine Therapy</a></td>
|
||
<td>Dahl et al. / Vancouver Coastal Health [Vancouver, British Columbia, Canada]</td>
|
||
<td>2015</td>
|
||
<td>Online document</td>
|
||
</tr>
|
||
<tr>
|
||
<td><a href="https://www.rainbowhealthontario.ca/product/4th-edition-sherbournes-guidelines-for-gender-affirming-primary-care-with-trans-and-non-binary-patients/">Guidelines for Gender-Affirming Primary Care with Trans and Non-Binary Patients</a> [<a href="https://www.rainbowhealthontario.ca/wp-content/uploads/woocommerce_uploads/2019/12/Guidelines-FINAL-Dec-2019-iw2oti.pdf">PDF</a>]</td>
|
||
<td>Bourns / Sherbourne Health / Rainbow Health Ontario [Toronto, Ontario, Canada]</td>
|
||
<td>2019</td>
|
||
<td>Online document</td>
|
||
</tr>
|
||
</tbody>
|
||
</table>
|
||
|
||
<h2 id="europe">Europe</h2>
|
||
|
||
<table>
|
||
<thead>
|
||
<tr>
|
||
<th>Title</th>
|
||
<th>Author / Organization</th>
|
||
<th>Year</th>
|
||
<th>Form</th>
|
||
</tr>
|
||
</thead>
|
||
<tbody>
|
||
<tr>
|
||
<td><a href="https://doi.org/10.1016/j.jsxm.2020.01.012">European Society for Sexual Medicine Position Statement “Assessment and Hormonal Management in Adolescent and Adult Trans People, With Attention for Sexual Function and Satisfaction”</a></td>
|
||
<td>T’Sjoen et al. / European Society for Sexual Medicine</td>
|
||
<td>2020</td>
|
||
<td>Published article</td>
|
||
</tr>
|
||
</tbody>
|
||
</table>
|
||
|
||
<h2 id="united-kingdom">United Kingdom</h2>
|
||
|
||
<table>
|
||
<thead>
|
||
<tr>
|
||
<th>Title</th>
|
||
<th>Author / Organization</th>
|
||
<th>Year</th>
|
||
<th>Form</th>
|
||
</tr>
|
||
</thead>
|
||
<tbody>
|
||
<tr>
|
||
<td><a href="https://doi.org/10.1080/14681994.2014.883353">Good Practice Guidelines for the Assessment and Treatment of Adults with Gender Dysphoria</a> [<a href="https://www.rcpsych.ac.uk/docs/default-source/improving-care/better-mh-policy/college-reports/cr181-good-practice-guidelines-for-the-assessment-and-treatment-of-adults-with-gender-dysphoria.pdf">PDF</a>]</td>
|
||
<td>Wylie et al. / Royal College of Psychiatrists</td>
|
||
<td>2014</td>
|
||
<td>Published article</td>
|
||
</tr>
|
||
<tr>
|
||
<td>Various [<a href="https://web.archive.org/web/20201116155321/https://www.gpref.bedfordshire.nhs.uk/media/160288/Treatment%20of%20Gender_Dysphoria_in_Transwomen_(Male_to_Female_Transsexuals).pdf">PDF</a>] [<a href="https://medicines.blmkccg.nhs.uk/wp-content/uploads/2020/05/Treatment-of-Gender-Dysphoria-in-Transwomen-Male-to-Female-Transsexuals-Pt-Information-Leaflet-published-by-West-London-Mental-health-NHS-Trust-Information.pdf">PDF</a>] [<a href="https://web.archive.org/web/20210920002540/http://medicinesmanagement.doncasterccg.nhs.uk/wp-content/uploads/2018/06/Doncaster-and-Bassetlaw-Transgender-women-prescribing-guidance.pdf">PDF</a>] [<a href="http://www.sunderlandccg.nhs.uk/wp-content/uploads/2016/08/SCCG-Gender-Dysphoria-Feminising-Hormones-Dec-2015-DecX2016.pdf">PDF</a>] [<a href="https://web.archive.org/web/20210419204521/https://remedy.bnssgccg.nhs.uk/media/3218/the-laurels-transgender-prescribing-guideline.pdf">PDF</a>] [<a href="https://awttc.nhs.wales/files/guidelines-and-pils/endocrine-management-of-gender-dysphoria-in-adults-pdf/">PDF</a>]</td>
|
||
<td>Various / National Health Service (NHS) Trusts</td>
|
||
<td>Various</td>
|
||
<td>Online documents</td>
|
||
</tr>
|
||
</tbody>
|
||
</table>
|
||
|
||
<h2 id="italy">Italy</h2>
|
||
|
||
<table>
|
||
<thead>
|
||
<tr>
|
||
<th>Title</th>
|
||
<th>Author / Organization</th>
|
||
<th>Year</th>
|
||
<th>Form</th>
|
||
</tr>
|
||
</thead>
|
||
<tbody>
|
||
<tr>
|
||
<td><a href="https://doi.org/10.1007/s40618-021-01694-2">SIGIS–SIAMS–SIE Position Statement of Gender Affirming Hormonal Treatment in Transgender and Non‑Binary People</a></td>
|
||
<td>Fisher et al. / Italian Society of Gender, Identity and Health (SIGIS) / Italian Society of Andrology and Sexual Medicine (SIAMS) / Italian Society of Endocrinology (SIE)</td>
|
||
<td>2021</td>
|
||
<td>Published article</td>
|
||
</tr>
|
||
<tr>
|
||
<td><a href="https://doi.org/10.1007/BF03345758">SIAMS-ONIG Consensus on Hormonal Treatment in Gender Identity Disorders</a></td>
|
||
<td>Godano et al. / Società Italiana di Andrologia e Medicina della Sessualità (SIAMS) [Italian Society of Andrology and Sexual Medicine] / Osservatorio Nazionale sull’Identità di Genere (ONIG) [National Observatory of Gender Identity]</td>
|
||
<td>2009</td>
|
||
<td>Published article</td>
|
||
</tr>
|
||
</tbody>
|
||
</table>
|
||
|
||
<h2 id="australia">Australia</h2>
|
||
|
||
<table>
|
||
<thead>
|
||
<tr>
|
||
<th>Title</th>
|
||
<th>Author / Organization</th>
|
||
<th>Year</th>
|
||
<th>Form</th>
|
||
</tr>
|
||
</thead>
|
||
<tbody>
|
||
<tr>
|
||
<td><a href="https://doi.org/10.5694/mja2.50259">Position Statement on the Hormonal Management of Adult Transgender and Gender Diverse Individuals</a></td>
|
||
<td>Cheung et al.</td>
|
||
<td>2019</td>
|
||
<td>Published article</td>
|
||
</tr>
|
||
<tr>
|
||
<td><a href="https://www.rch.org.au/adolescent-medicine/gender-service/">Australian Standards of Care and Treatment Guidelines: For Trans and Gender Diverse Children and Adolescents</a> [<a href="https://www.rch.org.au/uploadedFiles/Main/Content/adolescent-medicine/australian-standards-of-care-and-treatment-guidelines-for-trans-and-gender-diverse-children-and-adolescents.pdf">PDF</a>]</td>
|
||
<td>Telfer et al. / Royal Children’s Hospital</td>
|
||
<td>2020</td>
|
||
<td>Online document</td>
|
||
</tr>
|
||
<tr>
|
||
<td><a href="https://equinox.org.au/resources/">Hormone Therapy Prescribing Guide for General Practitioners working with Trans, Gender Diverse and Non-Binary Patients</a> [<a href="https://equinoxdotorgdotau.files.wordpress.com/2021/07/ht-prescribing-guideline-v3-aug-2020.pdf">PDF</a>]</td>
|
||
<td>Cundill et al. / Equinox Gender Diverse Health Centre / Thorne Harbour Health</td>
|
||
<td>2020</td>
|
||
<td>Online document</td>
|
||
</tr>
|
||
<tr>
|
||
<td><a href="https://auspath.org.au/2022/03/31/auspath-australian-informed-consent-standards-of-care-for-gender-affirming-hormone-therapy/">Australian Informed Consent Standards of Care for Gender Affirming Hormone Therapy</a> [<a href="https://auspath.org.au/wp-content/uploads/2022/03/AusPATH_Informed-Consent-SoC_A4_2022_FINAL.pdf">PDF</a>]</td>
|
||
<td>AusPATH</td>
|
||
<td>2022</td>
|
||
<td>Online document</td>
|
||
</tr>
|
||
</tbody>
|
||
</table>
|
||
|
||
<h2 id="new-zealand">New Zealand</h2>
|
||
|
||
<table>
|
||
<thead>
|
||
<tr>
|
||
<th>Title</th>
|
||
<th>Author / Organization</th>
|
||
<th>Year</th>
|
||
<th>Form</th>
|
||
</tr>
|
||
</thead>
|
||
<tbody>
|
||
<tr>
|
||
<td><a href="https://researchcommons.waikato.ac.nz/handle/10289/12160">Guidelines for Gender Affirming Healthcare for Gender Diverse and Transgender Children, Young People and Adults in Aotearoa, New Zealand</a> [<a href="https://researchcommons.waikato.ac.nz/bitstream/handle/10289/12160/Guidelines%20for%20Gender%20Affirming%20Health%20low%20res.pdf">PDF</a>]</td>
|
||
<td>Oliphant et al. / Transgender Health Research Lab, University of Waikato</td>
|
||
<td>2018</td>
|
||
<td>Published article</td>
|
||
</tr>
|
||
</tbody>
|
||
</table>
|
||
|
||
<h2 id="south-africa">South Africa</h2>
|
||
|
||
<table>
|
||
<thead>
|
||
<tr>
|
||
<th>Title</th>
|
||
<th>Author / Organization</th>
|
||
<th>Year</th>
|
||
<th>Form</th>
|
||
</tr>
|
||
</thead>
|
||
<tbody>
|
||
<tr>
|
||
<td><a href="https://doi.org/10.4102/sajhivmed.v22i1.1299">Southern African HIV Clinicians’ Society Gender-Affirming Healthcare Guideline for South Africa</a> [<a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8517808/pdf/HIVMED-22-1299.pdf">PDF</a>]</td>
|
||
<td>Tomson et al. / Southern African HIV Clinicians Society (SAHCS)</td>
|
||
<td>2021</td>
|
||
<td>Published article</td>
|
||
</tr>
|
||
</tbody>
|
||
</table>
|
||
|
||
<h2 id="elsewhere">Elsewhere</h2>
|
||
|
||
<table>
|
||
<thead>
|
||
<tr>
|
||
<th>Title</th>
|
||
<th>Author / Organization [Place]</th>
|
||
<th>Year</th>
|
||
<th>Form</th>
|
||
</tr>
|
||
</thead>
|
||
<tbody>
|
||
<tr>
|
||
<td><a href="https://www.undp.org/asia-pacific/publications/blueprint-provision-comprehensive-care-trans-people-and-trans-communities-asia-and-pacific">Blueprint for the Provision of Comprehensive Care for Trans People and Trans Communities in Asia and the Pacific</a> [<a href="https://www.undp.org/sites/g/files/zskgke326/files/migration/asia_pacific_rbap/rbap-hhd-2015-asia-pacific-trans-health-blueprint.pdf">PDF</a>]</td>
|
||
<td>Health Policy Project / Asia Pacific Transgender Network / United Nations Development Programme [Asia and the Pacific]</td>
|
||
<td>2015</td>
|
||
<td>Online document</td>
|
||
</tr>
|
||
<tr>
|
||
<td><a href="https://iris.paho.org/handle/10665.2/31360">Blueprint for the Provision of Comprehensive Care for Trans Persons and their Communities in the Caribbean and Other Anglophone Countries</a> [<a href="https://web.archive.org/web/20210419205021/https://www.paho.org/hq/dmdocuments/2014/2014-cha-blueprint-comprehensive-anglo-countries.pdf">PDF</a>]</td>
|
||
<td>John Snow, Inc. / Pan American Health Organization / World Health Organization [Latin America and the Caribbean]</td>
|
||
<td>2014</td>
|
||
<td>Online document</td>
|
||
</tr>
|
||
<tr>
|
||
<td><a href="http://www.sapphokolkata.in/wp-content/uploads/2019/09/GAT-Revised-Updated_19.09.19.pdf">A Good Practice Guide to Gender-Affirmative Care</a></td>
|
||
<td>Sappho for Equality [India]</td>
|
||
<td>2019</td>
|
||
<td>Online document</td>
|
||
</tr>
|
||
<tr>
|
||
<td><a href="https://doi.org/10.4103%2Fijem.IJEM_593_19">IDEA Group Consensus Statement on Medical Management of Adult Gender Incongruent Individuals Seeking Gender Reaffirmation as Female</a></td>
|
||
<td>Majumder et al. / Integrated Diabetes and Endocrine Academy (IDEA) [India]</td>
|
||
<td>2020</td>
|
||
<td>Published article</td>
|
||
</tr>
|
||
<tr>
|
||
<td><a href="https://ihri.org/transgender-health/">The Thai Handbook of Transgender Healthcare Services</a> [<a href="https://ihri.org/wp-content/uploads/2021/09/The-Thai-Handbook-of-Transgender-Heatlhcare-Services.pdf">PDF</a>]</td>
|
||
<td>Vacharathit et al. / Center of Excellence in Transgender Health / Chulalongkorn University [Thailand]</td>
|
||
<td>2021</td>
|
||
<td>Online document</td>
|
||
</tr>
|
||
</tbody>
|
||
</table>
|
||
|
||
<h2 id="references">References</h2>
|
||
|
||
<ul>
|
||
<li>AusPATH. (2022). <em>Australian Informed Consent Standards of Care for Gender Affirming Hormone Therapy.</em> Australia: Australian Professional Association for Trans Health. [<a href="https://auspath.org.au/2022/03/31/auspath-australian-informed-consent-standards-of-care-for-gender-affirming-hormone-therapy/">URL</a>] [<a href="https://auspath.org.au/wp-content/uploads/2022/03/AusPATH_Informed-Consent-SoC_A4_2022_FINAL.pdf">PDF</a>]</li>
|
||
<li>Bewley, S., Dahlen, S., Connolly, D., Arif, I., Junejo, M., &amp; Catherine, M. (2021). International Clinical Practice Guidelines for Gender Minority/Trans People: Systematic Review &amp; Quality Assessment. How Does the Endocrine Society Fare? <em>Journal of the Endocrine Society</em>, <em>5</em>(Suppl 1), A791–A791. [DOI:<a href="https://doi.org/10.1210/jendso/bvab048.1609">10.1210/jendso/bvab048.1609</a>]</li>
|
||
<li>Bourns, A. (2019). <em>Guidelines for Gender-Affirming Primary Care with Trans and Non-Binary Patients, 4th Edition.</em> Toronto: Rainbow Health Ontario/Sherbourne Health. [<a href="https://www.rainbowhealthontario.ca/product/4th-edition-sherbournes-guidelines-for-gender-affirming-primary-care-with-trans-and-non-binary-patients/">URL</a>] [<a href="https://www.rainbowhealthontario.ca/wp-content/uploads/woocommerce_uploads/2019/12/Guidelines-FINAL-4TH-EDITION-n7ozcr.pdf">PDF</a>]</li>
|
||
<li>Callen-Lorde Community Health Center. (2018). <em>Protocols for the Provision of Hormone Therapy</em>. New York City: Callen-Lorde Community Health Center. [<a href="https://callen-lorde.org/transhealth/">URL</a>] [<a href="https://web.archive.org/web/20221228055728if_/https://callen-lorde.org/graphics/2018/04/Callen-Lorde-TGNC-Hormone-Therapy-Protocols.pdf">PDF</a>]</li>
|
||
<li>Cheung, A. S., Wynne, K., Erasmus, J., Murray, S., &amp; Zajac, J. D. (2019). Position Statement on the Hormonal Management of Adult Transgender and Gender Diverse Individuals. <em>Medical Journal of Australia</em>, <em>211</em>(3), 127–133. [DOI:<a href="https://doi.org/10.5694/mja2.50259">10.5694/mja2.50259</a>]</li>
|
||
<li>Coleman, E., Bockting, W., Botzer, M., Cohen-Kettenis, P., DeCuypere, G., Feldman, J., Fraser, L., Green, J., Knudson, G., Meyer, W. J., Monstrey, S., Adler, R. K., Brown, G. R., Devor, A. H., Ehrbar, R., Ettner, R., Eyler, E., Garofalo, R., Karasic, D. H., … &amp; Zucker, K. (2012). [World Professional Association for Transgender Health (WPATH)] Standards of Care for the Health of Transsexual, Transgender, and Gender-Nonconforming People, Version 7. <em>International Journal of Transgenderism</em>, <em>13</em>(4), 165–232. [DOI:<a href="https://doi.org/10.1080/15532739.2011.700873">10.1080/15532739.2011.700873</a>] [<a href="https://www.wpath.org/publications/soc">URL</a>] [<a href="https://www.wpath.org/media/cms/Documents/SOC%20v7/SOC%20V7_English2012.pdf">PDF</a>]</li>
|
||
<li>Coleman, E., Radix, A. E., Bouman, W. P., Brown, G. R., de Vries, A. L., Deutsch, M. B., Ettner, R., Fraser, L., Goodman, M., Green, J., Hancock, A. B., Johnson, T. W., Karasic, D. H., Knudson, G. A., Leibowitz, S. F., Meyer-Bahlburg, H. F., Monstrey, S. J., Motmans, J., Nahata, L., … &amp; Arcelus, J. (2022). [World Professional Association for Transgender Health (WPATH)] Standards of Care for the Health of Transgender and Gender Diverse People, Version 8. <em>International Journal of Transgender Health</em>, <em>23</em>(Suppl 1), S1–S259. [DOI:<a href="https://doi.org/10.1080/26895269.2022.2100644">10.1080/26895269.2022.2100644</a>] [<a href="https://www.wpath.org/publications/soc">URL</a>] [<a href="https://www.tandfonline.com/doi/pdf/10.1080/26895269.2022.2100644">PDF</a>]</li>
|
||
<li>Cundill, P., Wong, P., Cheung, A., &amp; Brownhill, A. (2020). <em>Hormone Therapy Prescribing Guide for General Practitioners working with Trans, Gender Diverse and Non-Binary Patients [Version 3.0].</em> Australia: Equinox Gender Diverse Health Centre/Thorne Harbour Health. [<a href="https://equinox.org.au/resources/">URL</a>] [<a href="https://equinoxdotorgdotau.files.wordpress.com/2021/07/ht-prescribing-guideline-v3-aug-2020.pdf">PDF</a>]</li>
|
||
<li>Dahl, M., Feldman, J. L., Goldberg, J., &amp; Jaberi, A. (2015). <em>Endocrine Therapy for Transgender Adults in British Columbia: Suggested Guidelines. Physical Aspects of Transgender Endocrine Therapy.</em> Vancouver: Vancouver Coastal Health. [<a href="https://scholar.google.com/scholar?cluster=10288793516023166968">Google Scholar</a>] [<a href="http://www.phsa.ca/transcarebc/Documents/HealthProf/BC-Trans-Adult-Endocrine-Guidelines-2015.pdf">PDF</a>]</li>
|
||
<li>Dahlen, S., Connolly, D., Arif, I., Junejo, M. H., Bewley, S., &amp; Meads, C. (2021). International Clinical Practice Guidelines for Gender Minority/Trans People: Systematic Review and Quality Assessment. <em>BMJ Open</em>, <em>11</em>(4), e048943. [DOI:<a href="http://dx.doi.org/10.1136/bmjopen-2021-048943">10.1136/bmjopen-2021-048943</a>]</li>
|
||
<li>Davidson, A., Franicevich, J., Freeman, M., Lin, R., Martinez, L., Monihan, M., Porch, M., Samuel, L., Stukalin, R., Vormohr, J., &amp; Zevin, B. (2013). <em>Protocols for Hormonal Reassignment of Gender.</em> San Francisco: San Francisco Department of Public Health/Tom Waddell Health Center. [<a href="https://scholar.google.com/scholar?cluster=3995032054574212445">Google Scholar</a>] [<a href="https://www.sfdph.org/dph/comupg/oservices/medSvs/hlthCtrs/TransGendprotocols122006.pdf">PDF</a>]</li>
|
||
<li>Deutsch, M. B. (Ed.). (2016). <em>Guidelines for the Primary and Gender-Affirming Care of Transgender and Gender Nonbinary People, 2nd Edition.</em> San Francisco: University of California, San Francisco/UCSF Transgender Care. [<a href="https://transcare.ucsf.edu/guidelines">URL</a>] [<a href="https://transcare.ucsf.edu/sites/transcare.ucsf.edu/files/Transgender-PGACG-6-17-16.pdf">PDF</a>]</li>
|
||
<li>Deutsch, M. B., Radix, A., &amp; Reisner, S. (2016). What’s in a Guideline? Developing Collaborative and Sound Research Designs that Substantiate Best Practice Recommendations for Transgender Health Care. <em>AMA Journal of Ethics</em>, <em>18</em>(11), 1098–1106. [DOI:<a href="https://dx.doi.org/10.1001%2Fjournalofethics.2016.18.11.stas1-1611">10.1001/journalofethics.2016.18.11.stas1-1611</a>]</li>
|
||
<li>Feldman, J., &amp; Safer, J. (2009). Hormone Therapy in Adults: Suggested Revisions to the Sixth Version of the <em>Standards of Care</em>. <em>International Journal of Transgenderism</em>, <em>11</em>(3), 146–182. [DOI:<a href="https://doi.org/10.1080/15532730903383757">10.1080/15532730903383757</a>]</li>
|
||
<li>Fisher, A. D., Senofonte, G., Cocchetti, C., Guercio, G., Lingiardi, V., Meriggiola, M. C., Mosconi, M., Motta, G., Ristori, J., Speranza, A. M., Pierdominici, M., Maggi, M., Corona, G., &amp; Lombardo, F. (2021). SIGIS–SIAMS–SIE position statement of gender affirming hormonal treatment in transgender and non-binary people. <em>Journal of Endocrinological Investigation</em>, <em>45</em>(3), 657–673. [DOI:<a href="https://doi.org/10.1007/s40618-021-01694-2">10.1007/s40618-021-01694-2</a>]</li>
|
||
<li>Godano, A., Maggi, M., Jannini, E., Meriggiola, M. C., Ghigo, E., Todarello, O., Lenzi, A., &amp; Manieri, C. (2009). SIAMS-ONIG Consensus on Hormonal Treatment in Gender Identity Disorders. <em>Journal of Endocrinological Investigation</em>, <em>32</em>(10), 857–864. [DOI:<a href="https://doi.org/10.1007/BF03345758">10.1007/BF03345758</a>]</li>
|
||
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</ul></content><author><name>{"first_name"=>"Aly", "last_name"=>"W.", "author-link"=>"/about/#aly", "articles-link"=>"/articles-by-author/aly/"}</name></author><category term="github" /><category term="workspace" /><summary type="html">Clinical Guidelines with Information on Transfeminine Hormone Therapy By Aly | First published November 20, 2020 | Last modified May 23, 2023</summary></entry><entry><title type="html">Spironolactone and Claims About Increased Visceral Fat in Transfeminine People</title><link href="https://transfemscience.org/articles/spiro-visceral-fat/" rel="alternate" type="text/html" title="Spironolactone and Claims About Increased Visceral Fat in Transfeminine People" /><published>2020-10-25T09:56:15-07:00</published><updated>2022-10-02T00:00:00-07:00</updated><id>https://transfemscience.org/articles/spiro-visceral-fat</id><content type="html" xml:base="https://transfemscience.org/articles/spiro-visceral-fat/"><h1 id="spironolactone-and-claims-about-increased-visceral-fat-in-transfeminine-people">Spironolactone and Claims About Increased Visceral Fat in Transfeminine People</h1>
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<p>By
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<p>A <a href="https://moderntranshormones.com/2018/01/01/whats-wrong-with-spironolactone/">claim has been originated by some in the online transgender community</a> that the antiandrogen <a href="https://en.wikipedia.org/wiki/Spironolactone">spironolactone</a> increases <a href="https://en.wikipedia.org/wiki/Visceral_fat">visceral fat</a> in transfeminine people and that this effect is irreversible. Visceral fat is a type of adipose tissue located in the intra-abdominal region which surrounds the internal organs (viscera) in that area. In excess, visceral fat causes the abdomen to look bloated and unattractive. The supposed phenomenon of visceral fat accumulation with spironolactone has sometimes been referred to by people in the transgender community as “spiro belly”. The claim is based on theory—specifically that spironolactone has been found to increase levels of the <a href="https://en.wikipedia.org/wiki/Corticosteroid">corticosteroid</a> hormone <a href="https://en.wikipedia.org/wiki/Cortisol">cortisol</a> due to its <a href="https://en.wikipedia.org/wiki/Antimineralocorticoid">antimineralocorticoid</a> activity and cortisol is known to increase visceral fat, which together imply that spironolactone might likewise be able to increase visceral fat. It is also based on claimed <a href="https://en.wikipedia.org/wiki/Anecdotal_evidence">anecdotal observations</a> of transfeminine people taking spironolactone, which are said to corroborate the hypothesis. Despite these claims owever, there is no actual direct scientific or medical literature to support the idea that spironolactone increases visceral fat, and there is considerable evidence contradicting it.</p>
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<p>The influence of spironolactone on cortisol levels in clinical studies is variable and the magnitude of effect is limited. Hence, the clinical significance of increased cortisol levels with spironolactone is uncertain. Moreover, cortisol is an <a href="https://en.wikipedia.org/wiki/Agonist">agonist</a> of the <a href="https://en.wikipedia.org/wiki/Glucocorticoid_receptor">glucocorticoid receptor</a> (thereby producing <a href="https://en.wikipedia.org/wiki/Glucocorticoid">glucocorticoid</a> effects) and of the <a href="https://en.wikipedia.org/wiki/Mineralocorticoid_receptor">mineralocorticoid receptor</a> (thereby producing <a href="http://en.wikipedia.org/wiki/Mineralocorticoid">mineralocorticoid</a> effects). As already touched on, spironolactone has potent antimineralocorticoid activity (that is, mineralocorticoid receptor <a href="https://en.wikipedia.org/wiki/Receptor_antagonist">antagonism</a>). Hence, even if spironolactone did increase cortisol levels enough to potentially increase visceral fat, its antimineralocorticoid activity could modify the capacity of cortisol to produce this effect. In relation to this, there is accumulating research to suggest that spironolactone may actually <em>decrease</em> visceral fat via its antimineralocorticoid activity. Antimineralocorticoids like spironolactone show <a href="https://en.wiktionary.org/wiki/antiadipogenic">antiadipogenic</a> (anti-fat-accumulation) effects <em>in vitro</em> (<a href="https://doi.org/10.1096/fj.06-7970com">Caprio et al., 2007</a>; <a href="https://doi.org/10.1210/en.2010-0674">Caprio et al., 2011</a>) and have been shown to decrease visceral fat in animals (<a href="https://doi.org/10.1007/s12325-008-0039-5">Karakurt, 2008</a>; <a href="https://doi.org/10.1096/fj.13-245415">Armani et al., 2014</a>; <a href="https://doi.org/10.1038/ijo.2016.13">Mammi et al., 2016</a>; <a href="https://doi.org/10.1139/cjpp-2018-0416">Olatunji et al., 2018</a>). It is possible that they may also be able to do so in humans. Here are some notable literature excerpts relevant to this topic (<a href="https://doi.org/10.1016/bs.vh.2018.10.005">Infante et al., 2019</a>; <a href="https://doi.org/10.1038/nrd.2016.31">Giordano, Frontini, &amp; Cinti, 2016</a>):</p>
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<blockquote>
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<p>A possible explanation for [MR antagonists reducing cardiovascular morbidity and mortality more in patients with abdominal obesity] may be that patients with heart failure and abdominal obesity have higher aldosterone concentrations due to excessive secretion of specific aldosterone-releasing factors from [visceral adipose tissue]. […] Several studies on murine models of genetic and diet-induced obesity have widely reported beneficial effects of MR antagonism in terms of metabolic outcomes, such as body weight, fat mass, adipose tissue inflammation, insulin sensitivity, and lipid metabolism (Armani, Cinti, et al., 2014; Armani, Marzolla, et al., 2014; Garg &amp; Adler, 2012; Guo et al., 2008; Hirata et al., 2009). Nevertheless, data on the outcomes of MR pharmacological blockade for prevention and treatment of obesity and metabolic syndrome are still scarce in humans (Tirosh et al., 2010). Of note, Tanko et al. demonstrated that the powerful MR antagonist drospirenone, in combination with estradiol, leads to a significant reduction of central fat mass and central fat mass/peripheral fat mass ratio in healthy post-menopausal women (Tankó &amp; Christiansen, 2005). Moreover, another study has reported that MR antagonists significantly reduce body mass index and visceral fat area in patients with primary aldosteronism after a 1-year treatment period (Karashima et al., 2016). […] In light of these data, MR antagonism may be a useful therapeutic tool for prevention and treatment of cardiometabolic derangements observed in metabolic syndrome, even though additional studies are deemed necessary to confirm its impact on larger clinical settings.</p>
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</blockquote>
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<blockquote>
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<p>An anti-obesity drug whose primary mode of action is to induce browning should act predominantly on visceral fat, thereby directly counteracting the major cause of obesity-associated metabolic disorders. Accumulation of abdominal visceral fat is, to some extent, linked to increased local levels and/or activity of androgen and glucocorticoid steroid hormones<sup>145,146</sup>. These hormones are also ligands of the mineralocorticoid receptors, which are found on white and brown adipocytes and could have a role in abdominal visceral fat accumulation and BAT to WAT conversion<sup>147–151</sup>.** […] **In this context, mineralocorticoid receptor antagonism has been shown to protect mice from the adverse obesogenic and metabolic effects of a high-fat diet via conversion of a substantial amount of visceral and subcutaneous WAT into BAT<sup>153</sup>. Given that mineralocorticoid receptor antagonists are widely prescribed diuretics, used to manage chronic heart failure, hyperaldosteronism and female hirsutism<sup>154</sup>, patients receiving such drugs should also be assessed for weight loss and metabolic parameters to establish whether these compounds have anti-obesity properties.</p>
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</blockquote>
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<p>A number of studies have assessed the influence of antimineralocorticoids like spironolactone and <a href="https://en.wikipedia.org/wiki/Eplerenone">eplerenone</a> (another antimineralocorticoid) on visceral fat in humans. Spironolactone (12.5–100 mg/day) and eplerenone (25–100 mg/day) decreased visceral fat in people with pathologically high levels of <a href="https://en.wikipedia.org/wiki/Aldosterone">aldosterone</a> (a major endogenous mineralocorticoid hormone) (<a href="https://doi.org/10.1038/hr.2015.129">Karashima et al., 2016</a>). A study of cisgender girls with <a href="https://en.wikipedia.org/wiki/Polycystic_ovary_syndrome">polycystic ovary syndrome</a> (PCOS) found that a combination of spironolactone (50 mg/day), <a href="https://en.wikipedia.org/wiki/Pioglitazone">pioglitazone</a>, and <a href="https://en.wikipedia.org/wiki/Metformin">metformin</a> decreased visceral fat (<a href="https://doi.org/10.1155/2018/4192940">Diaz et al., 2018</a>). However, this study was of course confounded by the other medications. In addition to the preceding studies, many other clinical studies (at least 10) have assessed and similarly found no indication of increased visceral or abdominal fat with spironolactone (25–200 mg/day) (as measured by visceral fat directly or by indirect related measures like <a href="https://en.wikipedia.org/wiki/Waist_circumference">waist circumference</a> or <a href="https://en.wikipedia.org/wiki/Waist–hip_ratio">waist–hip ratio</a>) (<a href="https://doi.org/10.1016/0010-7824(91)90112-S">Wild et al., 1991</a>; <a href="https://doi.org/10.1210/jcem.81.6.8964851">Lovejoy et al., 1996</a>; <a href="https://doi.org/10.1210/jc.2003-031780">Ganie et al., 2004</a>; <a href="https://doi.org/10.2337/dc06-0618">Meyer, McGrath, &amp; Teede, 2007</a>; <a href="https://doi.org/10.1007/s12325-008-0039-5">Karakurt et al., 2008</a>; <a href="https://doi.org/10.1016/j.contraception.2011.12.011">Vieira et al., 2012</a>; <a href="https://doi.org/10.1210/jc.2013-1040">Ganie et al., 2013</a>; <a href="https://doi.org/10.1111/j.1365-2265.2012.04466.x">Harmanci et al., 2013</a>; <a href="https://doi.org/10.1111/jog.12543">Leelaphiwat et al., 2015</a>; <a href="https://doi.org/10.1530/EJE-17-0516">Alpañés et al., 2017</a>). I was not able to identify any studies assessing visceral fat with higher doses of spironolactone (&gt;200 mg/day). Additional studies are also underway to assess the possibility that spironolactone could decrease visceral fat.</p>
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<p>With regard to the anecdotal claims of spironolactone increasing visceral fat in transfeminine people, it’s important to note that <a href="https://en.wikipedia.org/wiki/Anecdotal_evidence">anecdotes are unreliable</a> and are <a href="https://en.wikipedia.org/wiki/Hierarchy_of_evidence">considered to be the lowest form of evidence in medicine</a>. This is for well-founded reasons—succinctly, anecdotes very often don’t hold up when rigorous studies are conducted. It’s probable that excess abdominal fat—a problem which afflicts many—has been misattributed to spironolactone rather than to the real causes in transfeminine people. It’s notable in this regard that androgens are known to increase visceral fat and that men have twice as much visceral fat as women on average (<a href="https://doi.org/10.1016/j.jsbmb.2007.09.001">Blouin, Boivin, &amp; Tchernof, 2008</a>; <a href="http://doi.org/10.1007/s13679-014-0119-6">Zerradi et al., 2014</a>). It’s possible that many transfeminine people may have excess visceral fat due to prior androgen exposure and that this visceral fat may not fully reverse with hormone therapy. As we know, hormone therapy unfortunately isn’t able to reverse all established bodily sexual dimorphism.</p>
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<p>Besides increased visceral fat, <a href="https://moderntranshormones.com/2018/01/01/whats-wrong-with-spironolactone/">many other serious adverse effects with spironolactone have been claimed</a>. However, these claimed adverse effects are likewise based on anecdotes and theory, and there is a lack of direct clinical evidence to support such side effects. In actuality, spironolactone even at high doses appears to be well-tolerated per studies and systematic reviews. The claimed side effects of spironolactone may actually largely be due to phenomena like <a href="https://en.wikipedia.org/wiki/Nocebo">nocebo</a> and misattribution—which can be controlled for in systematic studies but not in the case of anecdotal observations.</p>
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<p>To summarize, no research, animal or clinical, has found increased visceral fat with spironolactone, and there is accumulating evidence that spironolactone may cause the very opposite effect. More studies are needed to further characterize this possible benefit of spironolactone in humans however.</p>
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<h2 id="references">References</h2>
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<ul>
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<li>Alpañés, M., Álvarez-Blasco, F., Fernández-Durán, E., Luque-Ramírez, M., &amp; Escobar-Morreale, H. F. (2017). Combined oral contraceptives plus spironolactone compared with metformin in women with polycystic ovary syndrome: a one-year randomized clinical trial. <em>European Journal of Endocrinology</em>, <em>177</em>(5), 399–408. [DOI:<a href="https://doi.org/10.1530/eje-17-0516">10.1530/eje-17-0516</a>]</li>
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</ul></content><author><name>{"first_name"=>"Aly", "last_name"=>"W.", "author-link"=>"/about/#aly", "articles-link"=>"/articles-by-author/aly/"}</name></author><category term="github" /><category term="workspace" /><summary type="html">Spironolactone and Claims About Increased Visceral Fat in Transfeminine People By Aly | First published October 25, 2020 | Last modified October 2, 2022</summary></entry><entry><title type="html">Estrogens and Their Influences on Coagulation and Risk of Blood Clots</title><link href="https://transfemscience.org/articles/estrogens-blood-clots/" rel="alternate" type="text/html" title="Estrogens and Their Influences on Coagulation and Risk of Blood Clots" /><published>2020-10-20T19:30:00-07:00</published><updated>2023-03-28T00:00:00-07:00</updated><id>https://transfemscience.org/articles/estrogens-blood-clots</id><content type="html" xml:base="https://transfemscience.org/articles/estrogens-blood-clots/"><h1 id="estrogens-and-their-influences-on-coagulation-and-risk-of-blood-clots">Estrogens and Their Influences on Coagulation and Risk of Blood Clots</h1>
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<p>By
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<!-- First author --><a href="/about/#aly">Aly</a><!-- Second author --><!-- Third author --><!-- Fourth author --> | First published October 20, 2020
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| Last modified March 28, 2023</p>
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<h2 id="abstract--tldr">Abstract / TL;DR</h2>
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<p>Estrogens increase coagulation by activating estrogen receptors in the liver and thereby modulating the production of a variety of circulating coagulation factors. With sufficiently high exposure, this can result in an increase in the risk of blood clots as well as coagulation-associated cardiovascular complications like heart attack and stroke. However, the degrees of risk vary depending on the estrogen type, route, and dose. Non-bioidentical estrogens like ethinylestradiol have greater strength in the liver due to their relative resistance to metabolism and increase blood clot risk more readily than bioidentical estradiol, while oral administration of estradiol results in a first pass through the liver and has greater impact on blood clot risk than non-oral estradiol. Physiological estradiol levels with non-oral estradiol appear to have minimal to no risk of blood clots, whereas oral estradiol has significant risk and at high doses may have risk similar to that of the doses of ethinylestradiol in modern birth control pills. Higher estradiol levels with non-oral estradiol seem to have significant risk of blood clots and cardiovascular problems as well, although the risks appear to be lower than with ethinylestradiol-containing birth control pills. Absolute risks of blood clots are low but accumulate with time and add up on a population scale. In addition, a variety of risk factors, such as age, physical inactivity, concomitant progestogen use, and often-unknown thrombophilic abnormalities, can substantially augment risk. Due to their higher risks of blood clots, oral estradiol as well as excessive doses of non-oral estradiol should ideally be avoided in transfeminine people. This is particularly applicable in those with risk factors for blood clots. In any case, therapeutic considerations for transfeminine people include not only safety but also effectiveness, other factors like cost and convenience, and the natures of the alternative therapeutic options.</p>
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<h2 id="introduction">Introduction</h2>
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<p><a href="https://en.wikipedia.org/wiki/Estrogen_(medication)">Estrogens</a> increase <a href="https://en.wikipedia.org/wiki/Coagulation">coagulation</a> (blood clotting) and the risk of <a href="https://en.wikipedia.org/wiki/Thrombosis">thrombosis</a>, a <a href="https://en.wikipedia.org/wiki/Cardiovascular_event">cardiovascular event</a> otherwise known as a <a href="https://en.wikipedia.org/wiki/Thrombus">blood clot</a>. There are two major types of blood clots, which are categorized depending on whether they happen in a <a href="https://en.wikipedia.org/wiki/Vein">vein</a> or in an <a href="https://en.wikipedia.org/wiki/Artery">artery</a>: (1) <a href="https://en.wikipedia.org/wiki/Venous_thrombosis">venous thrombosis or venous thromboembolism</a> (VTE); and (2) <a href="https://en.wikipedia.org/wiki/Arterial_thrombosis">arterial thrombosis</a>. VTE is a blood clot in a vein, a <a href="https://en.wikipedia.org/wiki/Blood_vessel">blood vessel</a> that carries blood towards the <a href="https://en.wikipedia.org/wiki/Heart">heart</a>. It comprises two different subtypes: (1) <a href="https://en.wikipedia.org/wiki/Deep_vein_thrombosis">deep vein thrombosis</a> (DVT), a clot in a vein of the leg or pelvic region; and (2) <a href="https://en.wikipedia.org/wiki/Pulmonary_embolism">pulmonary embolism</a> (PE), a clot that has <a href="https://en.wikipedia.org/wiki/Embolism">broken free and blocked</a> an artery in the lungs. Arterial thrombosis is a blood clot in an artery, a blood vessel that carries blood away from the heart. Arterial thrombosis can lead to <a href="https://en.wikipedia.org/wiki/Myocardial_infarction">myocardial infarction</a> (MI; also known as heart attack) or <a href="https://en.wikipedia.org/wiki/Stroke">cerebrovascular accident</a> (CVA; also known as stroke). Blood clots are major health problems that can cause serious complications and even death. Estrogens, via increased coagulation with sufficiently high exposure, have the potential to heighten the risk of both venous and arterial thrombosis and hence to increase all of the aforementioned risks. The risk of blood clots with estrogens serves as a limiting factor in their use due to the potential health consequences.</p>
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<p>Estrogens are <a href="https://en.wikipedia.org/wiki/Binding_selectivity">selective</a> <a href="https://en.wikipedia.org/wiki/Agonist">agonists</a> of the <a href="https://en.wikipedia.org/wiki/Estrogen_receptor">estrogen receptors</a> (ERs). They are thought to increase coagulation and hence blood clot risk by activating ERs. However, the impact on coagulation and risk of blood clots with estrogens varies due to factors like estrogen type, <a href="https://en.wikipedia.org/wiki/Route_of_administration">route</a>, and dose. In addition, other factors, like concomitant <a href="https://en.wikipedia.org/wiki/Progestogen_(medication)">progestogen</a> use and a variety of non-hormonal factors, are known to modify the risk. The purpose of this article is to review the risks of blood clots with estrogens, the <a href="https://en.wikipedia.org/wiki/Mechanism_of_action">mechanisms</a> underlying increased coagulation and blood clot risk with estrogens, and the reasons for differences among estrogens in terms of risk. Exploring these topics can inform estrogen dosing considerations in transfeminine people and help to minimize risks and optimize safety. Moreover, higher levels of estrogens are therapeutically useful for suppressing testosterone production in transfeminine people but may increase blood clot risk, and <a href="https://en.wikipedia.org/wiki/Risk–benefit_analysis">risk–benefit analysis</a> is warranted in this context.</p>
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<h2 id="blood-clot-risks-with-estrogens-and-progestogens">Blood Clot Risks with Estrogens and Progestogens</h2>
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<p>A variety of estrogens have been used in medicine. These include <a href="https://en.wiktionary.org/wiki/bioidentical">bioidentical</a> estrogens like <a href="https://en.wikipedia.org/wiki/Estradiol_(medication)">estradiol</a> as well as non-bioidentical estrogens like <a href="https://en.wikipedia.org/wiki/Conjugated_estrogens">conjugated estrogens</a> (CEEs; Premarin), <a href="https://en.wikipedia.org/wiki/Ethinylestradiol">ethinylestradiol</a> (EE), and <a href="https://en.wikipedia.org/wiki/Diethylstilbestrol">diethylstilbestrol</a> (DES). Estradiol is the major <a href="https://en.wikipedia.org/wiki/Natural_product">natural</a> estrogen in the human body. CEEs deliver primarily estradiol as the active estrogen, but also contain significant quantities of naturally occurring <a href="https://en.wikipedia.org/wiki/Equine_estrogen">equine (horse) estrogens</a> such as <a href="https://en.wikipedia.org/wiki/Equilin">equilin</a> (7-dehydroestrone) and <a href="https://en.wikipedia.org/wiki/17β-Dihydroequilin">17β-dihydroequilin</a> (7-dehydroestradiol). EE and DES are <a href="https://en.wikipedia.org/wiki/Synthetic_compound">synthetic</a> estrogens that were created by humans and do not occur naturally. DES was discontinued decades ago and is relatively little-known today, but has significant historical importance. Estradiol is used in both oral and non-oral forms (e.g., transdermal patches), while the non-bioidentical estrogens have typically been used orally. For context, the table below shows some approximate comparable doses of these estrogens in terms of general estrogenicity.</p>
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<p><strong>Table 1:</strong> Approximate or estimated comparable doses of estrogens in terms of general/systemic estrogenicity (<a href="/articles/e2-equivalent-doses/">Aly, 2020</a>; <a href="https://doi.org/10.1080/13697130500148875">Kuhl, 2005</a>; <a href="https://en.wikipedia.org/wiki/Template:Estrogen_dosages_for_menopausal_hormone_therapy">Table</a>; <a href="https://en.wikipedia.org/wiki/Template:Relative_oral_potencies_of_estrogens">Table</a>; <a href="https://en.wikipedia.org/wiki/Template:Oral_potencies_of_estrogens">Table</a>):</p>
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<table>
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<thead>
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<tr>
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<th>Estrogen type/route</th>
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<th>Very low dose <sup>a</sup></th>
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<th>Low dose <sup>a</sup></th>
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<th>Moderate dose <sup>b</sup></th>
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<th>High dose</th>
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</tr>
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</thead>
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<tbody>
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<tr>
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<td>Oral estradiol</td>
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<td>1 mg/day</td>
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<td>2 mg/day</td>
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<td>4 mg/day</td>
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<td>8 mg/day</td>
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</tr>
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<tr>
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<td>Transdermal estradiol<sup>c</sup></td>
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<td>25 μg/day</td>
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<td>50 μg/day</td>
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<td>100 μg/day</td>
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<td>200 μg/day</td>
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</tr>
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<tr>
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<td>Oral conjugated estrogens</td>
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<td>0.625 mg/day</td>
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<td>1.25 mg/day</td>
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<td>2.5 mg/day</td>
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<td>5 mg/day</td>
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</tr>
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<tr>
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<td>Oral ethinylestradiol</td>
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<td>7.5 μg/day</td>
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<td>15 μg/day</td>
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<td>30 μg/day</td>
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<td>60 μg/day</td>
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</tr>
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<tr>
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<td>Oral diethylstilbestrol</td>
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<td>0.375 mg/day</td>
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<td>0.75 mg/day</td>
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<td>1.5 mg/day</td>
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<td>3 mg/day</td>
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</tr>
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<tr>
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<td>Comparable estradiol level</td>
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<td>~25 pg/mL</td>
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<td>~50 pg/mL</td>
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<td>~100 pg/mL</td>
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<td>~200 pg/mL</td>
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</tr>
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</tbody>
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</table>
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<p><small><sup>a</sup> Menopausal replacement dosages. <sup>b</sup> Similar to normal mean/integrated estrogenic exposure during the menstrual cycle in premenopausal women (<a href="/articles/transfem-intro/#normal-hormone-levels">Aly, 2018</a>). <sup>c</sup> Specifically transdermal patches.</small></p>
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<p>Estrogens were first associated with blood clots and associated cardiovascular complications in the 1960s and 1970s. Significant to substantial increases in these risks were found in clinical trials of high-dose DES (5 mg/day) for prostate cancer in men (<a href="https://pubmed.ncbi.nlm.nih.gov/6022476/">VACURG, 1967</a>; <a href="https://doi.org/10.1002/1097-0142(197311)32:5&lt;1126::AID-CNCR2820320518&gt;3.0.CO;2-C">Byar, 1973</a>; <a href="https://doi.org/10.3109/21681805.2013.861508">Turo et al., 2014</a>), trials of moderate-dose CEEs (2.5–5 mg/day) for prevention of heart disease in men (<a href="https://doi.org/10.1001/jama.1970.03180070069012">Coronary Drug Project Research Group, 1970</a>; <a href="https://doi.org/10.1001/jama.1973.03230060030009">Coronary Drug Project Research Group, 1973</a>; <a href="https://doi.org/10.1016/0167-5273(89)90102-2">Luria, 1989</a>; <a href="https://doi.org/10.1210/jcem.84.10.5954">Sudhir &amp; Komesaroff, 1999</a>; <a href="https://doi.org/10.1016/j.maturitas.2019.08.010">Dutra et al., 2019</a>), and studies of early high-dose EE-containing <a href="https://en.wikipedia.org/wiki/Birth_control_pill">birth control pills</a> (50–150 μg/day) in premenopausal women (<a href="https://doi.org/10.1093/oxfordjournals.aje.a115799">Gerstman et al., 1991</a>; <a href="https://doi.org/10.1016/j.fertnstert.2016.09.027">PCASRM, 2017</a>; <a href="https://web.archive.org/web/20220222083101/https://en.wikipedia.org/wiki/Template:Dose_of_ethinylestradiol_in_birth_control_pills_and_risk_of_venous_thromboembolism">Table</a>). The increase in cardiovascular events with DES in men with prostate cancer was sufficiently great that it actually cancelled out the benefits of its effects against prostate cancer in terms of overall mortality. The large increases in blood clots and cardiovascular problems seen in these studies resulted in alarm and concern about the safety of estrogens. Consequent to these events, estrogen doses were lowered. DES for prostate cancer was decreased to 1 to 3 mg/day and EE in birth control pills was decreased to 20 to 35 μg/day. Estrogens were also reduced to lower doses for other indications, such as menopausal hormone therapy. The dose reductions helped to lower the risks, although it did not eliminate them.</p>
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<p>In the <a href="https://en.wikipedia.org/wiki/Women's_Health_Initiative">Women’s Health Initiative</a> (WHI) <a href="https://en.wikipedia.org/wiki/Randomized_controlled_trial">randomized controlled trials</a> (RCTs), low-dose oral CEEs alone (0.625 mg/day) were shown to slightly increase the risk of blood clots (<a href="https://doi.org/10.1001/jama.291.14.1701">Anderson et al., 2004</a>; <a href="https://doi.org/10.1001/archinte.166.7.772">Curb et al., 2006</a>; <a href="https://doi.org/10.1146/annurev.publhealth.29.020907.090947">Prentice &amp; Anderson, 2008</a>; <a href="https://doi.org/10.1055/s-0034-1384624">Prentice, 2014</a>; <a href="https://en.wikipedia.org/wiki/Template:Results_of_the_Women's_Health_Initiative_menopausal_hormone_therapy_randomized_controlled_trials">Table</a>). In addition, the increase was considerably augmented by concomitant use of a low dose (2.5 mg/day) of the progestogen <a href="https://en.wikipedia.org/wiki/Medroxyprogesterone_acetate">medroxyprogesterone acetate</a> (MPA) (<a href="https://doi.org/10.1001/jama.288.3.321">Rossouw et al., 2002</a>; <a href="https://doi.org/10.1001/jama.292.13.1573">Cushman et al., 2004</a>; <a href="https://doi.org/10.1146/annurev.publhealth.29.020907.090947">Prentice &amp; Anderson, 2008</a>; <a href="https://doi.org/10.1055/s-0034-1384624">Prentice, 2014</a>; <a href="https://en.wikipedia.org/wiki/Template:Results_of_the_Women's_Health_Initiative_menopausal_hormone_therapy_randomized_controlled_trials">Table</a>). Increased risk of blood clots with low-dose oral CEEs plus low-dose MPA was also shown in another large RCT, the <a href="https://www.acc.org/latest-in-cardiology/clinical-trials/2010/02/23/19/07/hers">Heart and Estrogen/Progestin Replacement Study</a> (HERS) (<a href="https://doi.org/10.1001/jama.280.7.605">Hulley et al., 1998</a>; <a href="https://doi.org/10.7326/0003-4819-132-9-200005020-00002">Grady et al., 2000</a>). Other progestogens besides MPA are also associated with augmentation of blood clot risk related to oral estrogens (<a href="https://doi.org/10.1016/j.thromres.2018.06.014">Rovinski et al., 2018</a>; <a href="https://doi.org/10.1080/13697137.2018.1446931">Scarabin, 2018</a>; <a href="https://doi.org/10.1093/humupd/dmy039">Oliver-Williams et al., 2019</a>; <a href="https://doi.org/10.1136/bmj.k4810">Vinogradova, Coupland, &amp; Hippisley-Cox, 2019</a>; <a href="https://en.wikipedia.org/wiki/Template:Risk_of_venous_thromboembolism_with_hormone_therapy_and_birth_control_pills_(QResearch/CPRD)">Table</a>). Large <a href="https://en.wikipedia.org/wiki/Observational_study">observational studies</a> have found low-dose oral estradiol (generally ≤2 mg/day) to be dose-dependently associated with increased risk of blood clots similarly to CEEs (<a href="https://doi.org/10.1097/MOH.0b013e32833c07bc">Olié, Canonico, &amp; Scarabin, 2010</a>; <a href="https://doi.org/10.1111/j.1538-7836.2010.03839.x">Renoux, Dell’Aniello, &amp; Suissa, 2010</a>; <a href="https://doi.org/10.1136/bmj.k4810">Vinogradova, Coupland, &amp; Hippisley-Cox, 2019</a>; <a href="https://doi.org/10.1016/B978-0-323-46202-0.00031-5">Konkle &amp; Sood, 2019</a>; <a href="https://en.wikipedia.org/wiki/Template:Risk_of_venous_thromboembolism_with_hormone_therapy_and_birth_control_pills_(QResearch/CPRD)">Table</a>). However, the risk with oral estradiol or with oral <a href="https://en.wikipedia.org/wiki/Esterified_estrogens">esterified estrogens</a> (a CEEs-like preparation with reduced equine estrogen content) appears to be lower than with oral CEEs (<a href="https://doi.org/10.1001/jama.292.13.1581">Smith et al., 2004</a>; <a href="https://doi.org/10.1001/jamainternmed.2013.11074">Smith et al., 2014</a>; <a href="https://doi.org/10.1136/bmj.k4810">Vinogradova, Coupland, &amp; Hippisley-Cox, 2019</a>; <a href="https://en.wikipedia.org/wiki/Template:Risk_of_venous_thromboembolism_with_hormone_therapy_and_birth_control_pills_(QResearch/CPRD)">Table</a>). On the other hand, in another large observational study, oral estradiol and oral CEEs both in combination with progestogens appeared to show similarly increased risk of blood clots (<a href="https://doi.org/10.1111/jth.12060">Roach et al., 2013</a>). As with oral CEEs, progestogens appear to augment the blood clot risk with oral estradiol (<a href="https://doi.org/10.1136/bmj.k4810">Vinogradova, Coupland, &amp; Hippisley-Cox, 2019</a>; <a href="https://en.wikipedia.org/wiki/Template:Risk_of_venous_thromboembolism_with_hormone_therapy_and_birth_control_pills_(QResearch/CPRD)">Table</a>).</p>
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<p>In contrast to oral estrogens, transdermal estradiol at low to moderate doses (50–100 μg/day) has generally not been associated with increased coagulation nor with increased risk of blood clots or associated cardiovascular complications (<a href="https://doi.org/10.1136/bmj.39555.441944.BE">Canonico et al., 2008</a>; <a href="https://doi.org/10.1016/j.fertnstert.2007.07.1298">Hemelaar et al., 2008</a>; <a href="https://doi.org/10.1097/MOH.0b013e32833c07bc">Olié, Canonico, &amp; Scarabin, 2010</a>; <a href="https://doi.org/10.1111/j.1538-7836.2010.03839.x">Renoux, Dell’Aniello, &amp; Suissa, 2010</a>; <a href="https://doi.org/10.1210/jc.2015-2237">Mohammed et al., 2015</a>; <a href="https://doi.org/10.1210/jc.2015-2236">Stuenkel et al., 2015</a>; <a href="https://doi.org/10.1089/jwh.2016.6151">Bezwada, Shaikh, &amp; Misra, 2017</a>; <a href="https://doi.org/10.1016/j.thromres.2018.06.014">Rovinski et al., 2018</a>; <a href="https://doi.org/10.1080/13697137.2018.1446931">Scarabin, 2018</a>; <a href="https://doi.org/10.1016/B978-0-323-46202-0.00031-5">Konkle &amp; Sood, 2019</a>; <a href="https://doi.org/10.1093/humupd/dmy039">Oliver-Williams et al., 2019</a>; <a href="https://doi.org/10.1136/bmj.k4810">Vinogradova, Coupland, &amp; Hippisley-Cox, 2019</a>; <a href="https://doi.org/10.1016/j.thromres.2020.05.008">Abou-Ismail, Sridhar, &amp; Nayak, 2020</a>; <a href="https://en.wikipedia.org/wiki/Template:Risk_of_venous_thromboembolism_with_hormone_therapy_and_birth_control_pills_(QResearch/CPRD)">Table</a>). Similarly, the <a href="https://en.wikipedia.org/wiki/Menopause,_Estrogen_and_Venous_Events">Menopause, Estrogen and Venous Events</a> (MEVE) study found that oral estradiol was associated with a large increase in risk of blood clots in women with previous history of blood clots whereas transdermal estradiol (mean dose 50 μg/day) was associated with no risk increase (<a href="https://doi.org/10.1097/gme.0b013e3181f9f7c3">Olié et al., 2011</a>). However, there are some exceptions on findings of transdermal estradiol and cardiovascular risks, for instance one observational study finding an increased risk of stroke with higher-dose (&gt;50 μg/day) transdermal estradiol patches in menopausal women (<a href="https://doi.org/10.1136/bmj.c2519">Renoux et al., 2010</a>; <a href="https://doi.org/10.1093/humupd/dmy039">Oliver-Williams et al., 2019</a>) and studies finding only small differences or no difference in coagulation between oral estradiol and transdermal estradiol in transfeminine people (<a href="https://doi.org/10.1210/clinem/dgaa262">Lim et al., 2020</a>; <a href="https://doi.org/10.1111/jth.15256">Scheres et al., 2021</a>). Studies are mixed on whether the combination of transdermal estradiol at menopausal doses with progestogens is associated with greater blood clot risk, with some finding no change and others finding increased risk (<a href="https://doi.org/10.1016/j.thromres.2018.06.014">Rovinski et al., 2018</a>; <a href="https://doi.org/10.1080/13697137.2018.1446931">Scarabin, 2018</a>; <a href="https://doi.org/10.1136/bmj.k4810">Vinogradova, Coupland, &amp; Hippisley-Cox, 2019</a>). It has been suggested that this may be related to the type of progestogen used (<a href="https://doi.org/10.1080/13697137.2018.1446931">Scarabin, 2018</a>).</p>
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<p>There is little quality clinical data at this time on the risk of blood clots with higher doses of oral or transdermal estradiol than those used in menopausal hormone therapy. In any case, risk of blood clots has been assessed limitedly in transfeminine hormone therapy with regimens containing oral estradiol (e.g., 2–8 mg/day) generally in combination with other agents (antiandrogens and/or progestogens). In these studies, blood clot risk has been reported to be increased to a greater extent than with the low doses of oral estradiol used in menopausal hormone therapy (<a href="https://doi.org/10.1530/EJE-13-0493">Wierckx et al., 2013</a>; <a href="https://doi.org/10.1016/j.jcte.2015.02.003">Weinand &amp; Safer, 2015</a>; <a href="https://doi.org/10.1016/j.jsxm.2016.09.001">Arnold et al., 2016</a>; <a href="https://doi.org/10.7326/M17-2785">Getahun et al., 2018</a>; <a href="https://doi.org/10.1007/s11154-018-9454-3">Irwig, 2018</a>; <a href="https://doi.org/10.1161/HYPERTENSIONAHA.119.13080">Connelly et al., 2019</a>; <a href="https://doi.org/10.1111/jth.14626">Connors &amp; Middeldorp, 2019</a>; <a href="https://doi.org/10.2147/JBM.S166780">Goldstein et al., 2019</a>; <a href="https://doi.org/10.1177/2042018819871166">Iwamoto et al., 2019</a>; <a href="https://doi.org/10.1373/clinchem.2018.288316">Khan et al., 2019</a>; <a href="https://doi.org/10.1016/B978-0-323-46202-0.00031-5">Konkle &amp; Sood, 2019</a>; <a href="https://doi.org/10.1136/bmj.l600">Quinton, 2019</a>; <a href="https://doi.org/10.3389/fendo.2019.00685">Swee, Javaid, &amp; Quinton, 2019</a>; <a href="https://doi.org/10.1016/j.thromres.2020.05.008">Abou-Ismail, Sridhar, &amp; Nayak, 2020</a>).</p>
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<p>Whereas the WHI demonstrated <a href="https://en.wikipedia.org/wiki/Causality">causation</a> for oral CEEs alone in terms of blood clot risk, no <a href="https://en.wikipedia.org/wiki/Statistical_power">adequately powered</a> RCTs have been conducted with oral or transdermal estradiol alone to establish causation in terms of blood clot risk at this time. Only very large and expensive trials would be able to show this due to the rarity of blood clots, and these studies have not been conducted to date. For similar reasons, RCTs demonstrating increased risk of blood clots with EE-containing birth control pills have also not been conducted at this time (<a href="https://doi.org/10.1016/j.ccm.2004.01.013">Moores, Bilello, &amp; Murin, 2004</a>). In any case, causation has clearly been demonstrated with estrogens in other contexts, and this can be assumed as likely in the case of oral estradiol similarly. In addition, the <a href="https://en.wikipedia.org/wiki/Estrogen_in_Venous_Thromboembolism_Trial">Estrogen in Venous Thromboembolism Trial</a> (EVTET), an RCT of low-dose (2 mg/day) oral estradiol plus the progestogen <a href="https://en.wikipedia.org/wiki/Norethisterone_acetate">norethisterone acetate</a> (NETA) versus placebo in postmenopausal women with history of previous blood clots, found that this hormone therapy regimen significantly increased coagulation and the incidence of blood clots (10.7% incidence with hormone therapy and 2.3% with placebo; <em>P</em> = 0.04) (<a href="https://doi.org/10.1055/s-0037-1614156">Høibraaten et al., 2000</a>; <a href="https://doi.org/10.1055/s-0037-1615717">Høibraaten et al., 2001</a>).</p>
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<p>Estradiol levels appear to not be associated with blood clot risk in premenopausal women (<a href="https://doi.org/10.1111/jth.12484">Holmegard et al., 2014</a>). The fact that transdermal estradiol patches at 100 μg/day in menopausal women haven’t been associated with a greater risk of blood clots is notable as this dose achieves estradiol levels of around 100 pg/mL on average, which are similar to the mean integrated levels of estradiol during the normal menstrual cycle in premenopausal women (<a href="/articles/transfem-intro/#normal-hormone-levels">Aly, 2018</a>; <a href="https://en.wikipedia.org/wiki/Pharmacokinetics_of_estradiol#Transdermal_patches">Wiki</a>). Rates of blood clots are also similar between men—who have relatively low estradiol levels—and women after controlling for atypical hormonal states like pregnancy and use of birth control pills in women (<a href="https://doi.org/10.1016/j.ccm.2004.01.013">Moores, Bilello, &amp; Murin, 2004</a>; <a href="https://pubmed.ncbi.nlm.nih.gov/16304352/">Rosendaal, 2005</a>; <a href="https://doi.org/10.1007/s11239-009-0365-8">Montagnana et al., 2010</a>; <a href="https://doi.org/10.1161/CIRCULATIONAHA.113.004768">Roach et al., 2013</a>). Interestingly however, men have a consistently higher incidence of recurrent blood clots than women (<a href="https://doi.org/10.1161/CIRCULATIONAHA.113.004768">Roach et al., 2013</a>). These findings suggest that physiological levels of estradiol and progesterone in premenopausal women may not meaningfully increase coagulation or blood clot risk. However, the available data are mixed, with some studies suggesting that estradiol and/or progesterone levels within physiological ranges may indeed influence coagulation (<a href="https://doi.org/10.1093/humrep/det092">Chaireti et al., 2013</a>) and blood clot risk in premenopausal and/or perimenopausal women (<a href="https://doi.org/10.1111/j.1538-7836.2005.01693.x">Simon et al., 2006</a>; <a href="https://doi.org/10.1097/GME.0b013e31829752e0">Canonico et al., 2014</a>; <a href="https://doi.org/10.1111/jth.14474">Scheres et al., 2019</a>).</p>
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<p>Modern combined birth control pills contain EE at moderately estrogenic doses (20–35 μg/day) and a physiological dose of a progestogen. They increase the risk of blood clots by several-fold (<a href="https://doi.org/10.1016/B978-0-323-46202-0.00031-5">Konkle &amp; Sood, 2019</a>; <a href="https://doi.org/10.1136/bmj.h2135">Vinogradova, Coupland, &amp; Hippisley-Cox, 2015</a>; <a href="https://en.wikipedia.org/wiki/Template:Risk_of_venous_thromboembolism_with_hormone_therapy_and_birth_control_pills_(QResearch/CPRD)">Table</a>). In addition, they are associated with about a 1.5- to 2-fold increase in risk of heart attack and stroke (<a href="https://doi.org/10.1517/14740338.2014.950654">Lidegaard, 2014</a>; <a href="https://doi.org/10.1016/B978-0-323-46202-0.00031-5">Konkle &amp; Sood, 2019</a>). However, overall mortality is not increased with birth control pills—at least in the relatively young women in whom they are used (<a href="https://doi.org/10.1136/bmj.c927">Hannaford et al., 2010</a>). Per studies of menopausal hormone therapy, it is likely that the progestogen in EE-containing birth control pills augments the risk of blood clots with EE. Early high-dose birth control pills (50–100 μg/day) had as much as twice the risk of blood clots of modern birth control pills (<a href="https://doi.org/10.1093/oxfordjournals.aje.a115799">Gerstman et al., 1991</a>; <a href="https://doi.org/10.1016/j.fertnstert.2016.09.027">PCASRM, 2017</a>; <a href="https://web.archive.org/web/20220222083101/https://en.wikipedia.org/wiki/Template:Dose_of_ethinylestradiol_in_birth_control_pills_and_risk_of_venous_thromboembolism">Table</a>). In contrast to the different blood clot risks between oral and transdermal estradiol, non-oral birth control forms containing EE, for instance transdermal birth control patches and vaginal birth control rings, are associated with similar increases in blood clot risk as EE-containing birth control pills (<a href="https://doi.org/10.1016/j.beem.2012.11.002">Plu-Bureau et al., 2013</a>; <a href="https://doi.org/10.1016/j.fertnstert.2016.09.027">PCASRM, 2017</a>; <a href="https://doi.org/10.1016/B978-0-323-46202-0.00031-5">Konkle &amp; Sood, 2019</a>; <a href="https://doi.org/10.1016/j.thromres.2020.05.008">Abou-Ismail, Sridhar, &amp; Nayak, 2020</a>). Hence, unlike with estradiol, route of administration does not appear to modify blood clot risk with EE based on available data.</p>
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<p><a href="https://en.wikipedia.org/wiki/High-dose_estrogen">High-dose estrogen therapy</a> using oral synthetic estrogens like DES and EE in people with breast or prostate cancer has been found to strongly increase the risk of blood clots and associated cardiovascular complications (<a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4052190/">Phillips et al., 2014</a>; <a href="https://doi.org/10.3109/21681805.2013.861508">Turo et al., 2014</a>; <a href="https://doi.org/10.1016/j.maturitas.2016.10.010">Coelingh Bennink et al., 2017</a>). This has also been the case with <a href="https://en.wikipedia.org/wiki/Estramustine_phosphate">estramustine phosphate</a> (EMP; estradiol normustine phosphate), an <a href="https://en.wikipedia.org/wiki/Estrogen_ester">estradiol ester</a> that is used at massive doses in prostate cancer (e.g., 140–1,400 mg/day orally) and that results in pregnancy levels of estradiol (<a href="https://doi.org/10.1046/j.1442-2042.2001.00254.x">Kitamura, 2001</a> [<a href="https://commons.wikimedia.org/wiki/File:Estradiol_and_testosterone_levels_with_280_mg_per_day_oral_estramustine_phosphate_in_men_with_prostate_cancer.png">Graph</a>]; <a href="https://doi.org/10.1111/j.1464-410X.2011.10201.x">Ravery et al., 2011</a>). In the 1980s however, it was found that high-dose non-oral estradiol did not have the same cardiovascular risks as high-dose estrogen therapy with oral synthetic estrogens or EMP (<a href="https://doi.org/10.1002/pros.2990140410">von Schoultz et al., 1989</a>; <a href="https://doi.org/10.5173/ceju.2009.03.art1">Ockrim &amp; Abel, 2009</a>). This included studies with <a href="https://en.wikipedia.org/wiki/Polyestradiol_phosphate">polyestradiol phosphate</a> (PEP), a long-lasting injectable <a href="https://en.wikipedia.org/wiki/Prodrug">prodrug</a> of estradiol, and with high-dose transdermal estradiol gel (<a href="https://doi.org/10.1002/pros.2990140410">von Schoultz et al., 1989</a>; <a href="/articles/high-dose-transdermal-e2/">Aly, 2019</a>). However, subsequent larger and higher-quality studies found that although the cardiovascular risks with PEP were much lower than with high-dose oral synthetic estrogen therapy, they were nonetheless still increased (<a href="https://doi.org/10.1080/00365590801943274">Hedlung et al., 2008</a>; <a href="https://doi.org/10.5173/ceju.2009.03.art1">Ockrim &amp; Abel, 2009</a>; <a href="https://doi.org/10.3109/00365599.2011.585820">Hedlund et al., 2011</a>; <a href="/articles/pep-cardiovascular-analysis/">Sam, 2020</a>). This includes an approximate 2-fold increase in the risk of blood clots with estradiol levels in the range of roughly 300 to 500 pg/mL (<a href="/articles/pep-cardiovascular-analysis/">Sam, 2020</a>). Studies using high-dose transdermal estradiol patches have not found significantly increased cardiovascular complications as of present (<a href="https://doi.org/10.1016/S1470-2045(13)70025-1">Langley et al., 2013</a>; <a href="/articles/pep-cardiovascular-analysis/">Sam, 2020</a>). However, these studies have been relatively <a href="https://en.wikipedia.org/wiki/Statistical_power">underpowered</a>, which limits their interpretation. In any case, increased coagulation has been observed with high-dose transdermal estradiol patches (achieving estradiol levels of 350 to 500 pg/mL) (<a href="https://doi.org/10.1002/cncr.20857">Bland et al., 2005</a>) similarly to PEP (<a href="https://pubmed.ncbi.nlm.nih.gov/10230677/">Mikkola et al., 1999</a>). More data on the risk of blood clots and cardiovascular issues with high-dose transdermal estradiol patches should come in the future with <a href="https://en.wikipedia.org/wiki/Prostate_Adenocarcinoma:_TransCutaneous_Hormones">PATCH</a> and <a href="https://en.wikipedia.org/wiki/Systemic_Therapy_in_Advancing_or_Metastatic_Prostate_Cancer:_Evaluation_of_Drug_Efficacy">STAMPEDE</a>—two large-scale clinical studies in the United Kingdom that are evaluating this form of estradiol for prostate cancer (<a href="https://doi.org/10.1111/bju.14153">Gilbert et al., 2018</a>; <a href="https://doi.org/10.1080/13543784.2019.1570130">Singla, Ghandour, &amp; Raj, 2019</a>).</p>
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<p>Injections of short-acting estradiol esters like <a href="https://en.wikipedia.org/wiki/Estradiol_valerate">estradiol valerate</a> and <a href="https://en.wikipedia.org/wiki/Estradiol_cypionate">estradiol cypionate</a> are notable in that they are often used by transfeminine people and are generally used at doses that achieve high estradiol levels. As with high-dose transdermal estradiol patches, little to no quality data on the risk of blood clots exists for these preparations at present. Pyra and colleagues found that the risk of blood clots with injectable estradiol valerate in transfeminine people was increased by around 2-fold, but the <a href="https://en.wikipedia.org/wiki/Confidence_interval">confidence intervals</a> were very wide and <a href="https://en.wikipedia.org/wiki/Statistical_significance">statistical significance</a> was not reached (<a href="https://doi.org/10.1089/trgh.2019.0061">Pyra et al., 2020</a>). The doses used in the whole population for the study were not provided, but in the actual VTE cases, the doses of injectable estradiol valerate were described and ranged from 4 to 20 mg once per week and 10 to 40 mg once every 2 weeks (<a href="https://doi.org/10.1089/trgh.2019.0061">Pyra et al., 2020</a>). Studies have also assessed and found increased coagulation with high doses of estradiol valerate by injection in the range of 10 to 40 mg once every 2 weeks in men with prostate cancer (<a href="https://files.transfemscience.org/pdfs/Kohli%20&amp;%20McClellan%20(2001)%20-%20Parenteral%20Estrogen%20Therapy%20in%20Advanced%20Prostate%20Cancer_%20Retrospective%20Analysis%20of%20Intra-Muscular%20Estradiol%20Valerate%20in%20Hormone%20Refractory%20Prostate%20Disease%20%5BIn%20Proceedings%20of%20ASCO%5D.pdf#page=3">Kohli &amp; McClellan, 2001</a>; <a href="https://doi.org/10.1200/jco.2004.22.90140.4726">Kohli et al., 2004</a>; <a href="https://doi.org/10.1002/cncr.21528">Kohli, 2005</a>). Increased coagulation has additionally been observed with the combination of 5 mg estradiol valerate and a progestogen once per month as a <a href="https://en.wikipedia.org/wiki/Combined_injectable_birth_control">combined injectable contraceptive</a> in premenopausal women (<a href="https://doi.org/10.1016/0010-7824(90)90052-W">Meng et al., 1990</a>; <a href="https://doi.org/10.1016/s0010-7824(03)00164-1">UN/WHO et al., 2003</a>). It is unclear whether the high peaks in estradiol levels associated with short-acting injectable forms of estradiol are harmful in terms of coagulation and blood clot risk (<a href="https://doi.org/10.1210/jc.2017-01658">Hembree et al., 2017</a>). However, the increased risk of <a href="https://en.wikipedia.org/wiki/Polycythemia">polycythemia</a> with short-acting injectable testosterone esters relative to other non-oral forms of testosterone (<a href="https://doi.org/10.1016/j.sxmr.2017.04.001">Ohlander, Varghese, &amp; Pastuszak, 2018</a>) is indirectly suggestive that this could be the case. Accordingly, a study found increased coagulation in premenopausal women with a combined injectable contraceptive containing estradiol valerate but not with one employing the more prolonged and stable estradiol cypionate at the same dose (<a href="https://doi.org/10.1016/s0010-7824(03)00164-1">UN/WHO et al., 2003</a>).</p>
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<p><a href="https://en.wikipedia.org/wiki/Selective_estrogen_receptor_modulator">Selective estrogen receptor modulators</a> (SERMs) such as <a href="https://en.wikipedia.org/wiki/Tamoxifen">tamoxifen</a> (Nolvadex) and <a href="https://en.wikipedia.org/wiki/Raloxifene">raloxifene</a> (Evista) increase the risk of blood clots similarly to estrogens (<a href="https://doi.org/10.1016/S1471-4914(02)02282-7">Park &amp; Jordan, 2002</a>; <a href="https://doi.org/10.1200/JCO.2005.11.005">Fabian &amp; Kimler, 2005</a>). The risk appears to be elevated a few-fold similarly to what might be expected with moderate doses of oral estradiol or CEEs (<a href="https://doi.org/10.1002/cncr.20347">Deitcher &amp; Gomes, 2004</a>; <a href="https://doi.org/10.1016/j.ctrv.2011.06.009">Iqbal et al., 2012</a>; <a href="https://doi.org/10.1016/B978-0-323-46202-0.00031-5">Konkle &amp; Sood, 2019</a>).</p>
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<p><a href="https://en.wikipedia.org/wiki/Pregnancy">Pregnancy</a> is a time when estradiol and progesterone levels increase to extremely high concentrations (<a href="https://en.wikipedia.org/wiki/Template:Hormone_levels_during_pregnancy_in_human_females">Graphs</a>). Estradiol levels increase progressively throughout pregnancy to around 2,000 pg/mL on average at the end of the first trimester, to about 10,000 pg/mL on average at the end of the second trimester, and to around 20,000 pg/mL on average at the end of the third trimester (<a href="https://doi.org/10.1111/j.1365-2265.1994.tb02478.x">Kerlan et al., 1994</a> [<a href="https://commons.wikimedia.org/wiki/File:Estrogen,_progesterone,_testosterone,_and_SHBG_levels_during_pregnancy_in_women.png">Graph</a>]; <a href="https://doi.org/10.1186/s12884-016-0937-5">Schock et al., 2016</a>). Coagulation is greatly increased during pregnancy, and the risk of blood clots is likewise strongly increased (<a href="https://doi.org/10.1001/archinte.160.6.809">Heit et al., 2000</a>; <a href="https://doi.org/10.1136/bmjopen-2015-008864">Abdul Sultan et al., 2015</a>; <a href="https://doi.org/10.1007/s11239-015-1311-6">Heit, Spencer, &amp; White, 2016</a>; <a href="https://en.wikipedia.org/wiki/Template:Venous_thromboembolism_incidence_during_pregnancy_and_the_postpartum_period">Table</a>). Estradiol and progesterone levels are strongly correlated with the increases in coagulation during pregnancy (<a href="https://doi.org/10.1016/j.thromres.2019.03.015">Bagot et al., 2019</a>). The risk of blood clots with modern birth control pills is similar to that with pregnancy as a whole (<a href="https://doi.org/10.1007/s11239-015-1311-6">Heit, Spencer, &amp; White, 2016</a>), while the increases in risk of blood clots with early high-dose EE-containing birth control pills and with high-dose oral synthetic estrogen therapy for breast and prostate cancer are comparable to the risk increase during late pregnancy. Estradiol levels also increase to very high concentrations during <a href="https://en.wikipedia.org/wiki/Controlled_ovarian_hyperstimulation">ovarian stimulation for <em>in-vitro</em> fertilization</a> in premenopausal women, and this has been associated with increased coagulation and risk of blood clots as well (<a href="https://doi.org/10.1016/j.thromres.2011.11.024">Westerlund et al., 2012</a>; <a href="https://doi.org/10.1016/j.fertnstert.2011.10.038">Rova, Passmark, &amp; Lindqvist, 2012</a>; <a href="https://doi.org/10.3109/09513590.2014.927858">Kasum et al., 2014</a>).</p>
|
||
|
||
<p>Due to their greater risks of cardiovascular problems as well as other concerns, DES has been virtually abandoned while EE has been discontinued for almost all indications except birth control. EE continues to be used in birth control because it is resistant to metabolism in the uterus and controls menstrual bleeding better than oral estradiol does (<a href="https://doi.org/10.1016/j.contraception.2012.12.011">Stanczyk, Archer, &amp; Bhavnani, 2013</a>). CEEs are also being increasingly superseded by estradiol in medicine, although significant use of CEEs for hormone therapy in cisgender women continues. Transdermal estradiol is gaining momentum over oral estradiol in menopausal hormone therapy as well. Major transgender hormone therapy guidelines (see also <a href="/articles/transfem-hormone-guidelines/">Aly, 2020</a>) recommend against the use of EE and CEEs in transfeminine people due to their greater risks and the inability to accurately monitor blood estrogen levels with these preparations (<a href="https://www.wpath.org/media/cms/Documents/SOC%20v7/Standards%20of%20Care%20V7%20-%202011%20WPATH.pdf#page=39">Coleman et al., 2012</a>; <a href="https://transcare.ucsf.edu/sites/transcare.ucsf.edu/files/Transgender-PGACG-6-17-16.pdf#page=26">Deutsch, 2016</a>; <a href="https://doi.org/10.1210/jc.2017-01658">Hembree et al., 2017</a>). Estradiol is the estrogen that is almost exclusively used in transfeminine people today. Besides estrogen type, it has been recommended that transdermal estradiol be used instead of oral estradiol in transfeminine people who are over 40 or 45 years of age or are otherwise at risk for blood clots (<a href="https://transcare.ucsf.edu/sites/transcare.ucsf.edu/files/Transgender-PGACG-6-17-16.pdf#page=26">Deutsch, 2016</a>; <a href="https://doi.org/10.1177/2042018819871166">Iwamoto et al., 2019</a>; <a href="https://doi.org/10.1530/EJE-21-0059">Glintborg et al., 2021</a>). Menopausal hormone therapy guidelines similarly recommend the use of transdermal estradiol over oral estrogens in cisgender women who are at higher risk for blood clots (e.g., <a href="https://doi.org/10.1210/jc.2015-2236">Stuenkel et al., 2015</a>).</p>
|
||
|
||
<p>As previously described, progestogens appear to augment the risk of blood clots with oral estrogens. Conversely, findings on the combination of non-oral estradiol and progestogens are mixed—with some studies finding increased risk and others finding no additional risk (<a href="https://doi.org/10.1016/j.thromres.2018.06.014">Rovinski et al., 2018</a>; <a href="https://doi.org/10.1080/13697137.2018.1446931">Scarabin, 2018</a>; <a href="https://doi.org/10.1136/bmj.k4810">Vinogradova, Coupland, &amp; Hippisley-Cox, 2019</a>). Progestogens by themselves do not usually increase coagulation (<a href="https://doi.org/10.1016/0378-5122(96)00994-2">Kuhl, 1996</a>; <a href="https://doi.org/10.1016/j.maturitas.2003.09.016">Schindler, 2003</a>; <a href="https://doi.org/10.1080/13625180600772741">Wiegratz &amp; Kuhl, 2006</a>; <a href="https://doi.org/10.1007/s11154-011-9182-4">Sitruk-Ware &amp; Nath, 2011</a>; <a href="https://doi.org/10.1016/j.beem.2012.09.004">Sitruk-Ware &amp; Nath, 2013</a>; <a href="https://doi.org/10.1515/hmbci-2018-0041">Skouby &amp; Sidelmann, 2018</a>) or blood clot risk (<a href="https://doi.org/10.1016/j.thromres.2012.02.042">Blanco-Molina et al., 2012</a>; <a href="https://doi.org/10.1136/bmj.e4944">Mantha et al., 2012</a>; <a href="https://doi.org/10.1016/j.contraception.2016.04.014">Tepper et al., 2016</a>; <a href="https://doi.org/10.1055/s-0039-1677806">Rott, 2019</a>). However, depot MPA alone at birth control doses has uniquely been associated with a few-fold increase in blood clot risk (<a href="https://doi.org/10.1161/ATVBAHA.110.211482">van Hylckama Vlieg, Helmerhorst, &amp; Rosendaal, 2010</a>; <a href="https://doi.org/10.1007/s11154-011-9178-0">DeLoughery, 2011</a>; <a href="https://doi.org/10.1016/j.thromres.2012.02.042">Blanco-Molina et al., 2012</a>; <a href="https://doi.org/10.1016/j.ando.2012.09.001">Gourdy et al., 2012</a>; <a href="https://doi.org/10.1136/bmj.e4944">Mantha et al., 2012</a>; <a href="https://doi.org/10.1055/s-0039-1677806">Rott, 2019</a>; <a href="https://doi.org/10.1097/AOG.0000000000003135">Tepper et al., 2019</a>). The reasons for this are unknown, but might relate to high peak MPA levels with depot injectables (<a href="https://doi.org/10.1136/bmj.e4944">Mantha et al., 2012</a>) or the weak <a href="https://en.wikipedia.org/wiki/Glucocorticoid">glucocorticoid</a> activity of MPA (<a href="https://doi.org/10.1080/09513590600717368">Kuhl &amp; Stevenson, 2006</a>; <a href="https://doi.org/10.1007/s11154-011-9182-4">Sitruk-Ware &amp; Nath, 2011</a>). Besides physiological-dose MPA alone, high-dose progestogen therapy with MPA, <a href="https://en.wikipedia.org/wiki/Megestrol_acetate">megestrol acetate</a> (MGA), and <a href="https://en.wikipedia.org/wiki/Cyproterone_acetate">cyproterone acetate</a> (CPA) has been associated with increased coagulation and blood clot risk (<a href="https://doi.org/10.1007/978-1-59259-152-7_15">Schröder &amp; Radlmaier, 2002</a>; <a href="https://doi.org/10.1016/j.maturitas.2003.09.016">Schindler, 2003</a>; <a href="https://doi.org/10.1111/j.1464-410X.2007.06859.x">Seaman et al., 2007</a>; <a href="https://doi.org/10.1002/14651858.CD004310.pub3">Garcia et al., 2013</a>; <a href="https://doi.org/10.1136/bmjspcare-2015-001041">Taylor &amp; Pendleton, 2016</a>). However, this was not the case with <a href="https://en.wikipedia.org/wiki/Chlormadinone_acetate">chlormadinone acetate</a> (CMA) in a small study in women with prior history of blood clots (<a href="https://doi.org/10.1016/j.contraception.2004.07.009">Conard et al., 2004</a>). Risk of blood clots may also be increased for CPA in combination with estrogen in transfeminine people (<a href="https://doi.org/10.1016/j.eprac.2022.08.012">Patel et al., 2022</a>). In contrast to progestins, addition of oral progesterone to estrogen therapy is not associated with augmentation of blood clot risk (<a href="https://doi.org/10.1080/13697137.2018.1446931">Scarabin, 2018</a>; <a href="https://doi.org/10.1093/humupd/dmy039">Oliver-Williams et al., 2019</a>; <a href="https://doi.org/10.1080/13697137.2021.2022644">Kaemmle et al., 2022</a>). However, this may simply be due to the fact that oral progesterone produces low progesterone levels and has relatively weak progestogenic effects (<a href="/articles/oral-p4-low-levels/">Aly, 2018</a>). Non-oral and fully potent progesterone has yet to be properly studied and hence its risk profile remains unknown (<a href="/articles/oral-p4-low-levels/">Aly, 2018</a>).</p>
|
||
|
||
<p>In a historically notable study conducted by the <a href="https://en.wikipedia.org/wiki/Center_of_Expertise_on_Gender_Dysphoria">Center of Expertise on Gender Dysphoria</a> (CEGD) at the <a href="https://en.wikipedia.org/wiki/VU_University_Medical_Center">Vrije Universiteit Medical Center</a> (VUMC) in Amsterdam, the Netherlands in the 1980s, it was reported that the risk of blood clots with high-dose EE and CPA in transfeminine people was increased by 45-fold relative to the expected incidence in the general population (<a href="https://doi.org/10.1016/0026-0495(89)90233-3">Asscheman, Gooren, &amp; Eklund, 1989</a>; <a href="https://doi.org/10.1111/and.12150">Asscheman et al., 2014</a>). Mortality also appeared to be elevated and other health risks were increased as well (<a href="https://doi.org/10.1016/0026-0495(89)90233-3">Asscheman, Gooren, &amp; Eklund, 1989</a>; <a href="https://doi.org/10.1007/s11154-018-9449-0">Gooren &amp; T’Sjoen, 2018</a>). A subsequent study in transfeminine people by the CEGD confirmed strongly increased coagulation with EE but much lower increases with oral or transdermal estradiol (<a href="https://doi.org/10.1210/jc.2003-030520">Toorians et al., 2003</a>). Upon the CEGD switching transfeminine people from high-dose EE to physiological doses of oral or transdermal estradiol (also usually in combination with CPA), the risks decreased considerably (<a href="https://doi.org/10.1046/j.1365-2265.1997.2601068.x">van Kesteren et al., 1997</a>; <a href="https://doi.org/10.1530/eje-10-1038">Asscheman et al., 2011</a>; <a href="https://doi.org/10.1111/and.12150">Asscheman et al., 2014</a>). These findings were of major importance in the replacement of EE with estradiol in transfeminine hormone therapy, and have surely contributed significantly to apprehension about the use of high doses of estrogens in transfeminine people.</p>
|
||
|
||
<p>Taken together, estrogens of all kinds have been shown to dose-dependently increase or be associated with increased risk of blood clots. These findings suggest that, provided of course sufficient exposure occurs, increased coagulation and blood clot risk are common properties of estrogens. However, synthetic and non-bioidentical estrogens have greater risk of blood clots than estradiol, and oral estradiol shows greater risk than non-oral estradiol. In fact, physiological estradiol levels in women and low to moderate doses of transdermal estradiol may have no significant risk of blood clots at all. Nonetheless, non-oral estradiol with sufficiently high exposure can increase blood clot risk just the same as other forms of estrogen. Concomitant therapy with progestogens appears to augment the risk of blood clots with estrogens and high doses may particularly amplify the risk.</p>
|
||
|
||
<h3 id="risks-with-different-hormonal-exposures">Risks with Different Hormonal Exposures</h3>
|
||
|
||
<p>The table below provides relative risk increases for blood clots with different types, routes, and doses of estrogens, as well as with SERMs, pregnancy, and high-dose CPA. It shows the greater risks of blood clots with (1) oral estradiol relative to non-oral estradiol; (2) estradiol compared to non-bioidentical estrogens; and (3) lower estrogen levels/doses relative to higher estrogen levels/doses.</p>
|
||
|
||
<p><strong>Table 2:</strong> Relative risks of blood clots with different hormonal exposures (see also <a href="https://doi.org/10.1016/j.trsl.2020.06.011">Machin &amp; Ragni, 2020</a>):</p>
|
||
|
||
<table>
|
||
<thead>
|
||
<tr>
|
||
<th>Estrogen</th>
|
||
<th>Blood clot risk</th>
|
||
<th>Source</th>
|
||
</tr>
|
||
</thead>
|
||
<tbody>
|
||
<tr>
|
||
<td>Oral E2 ≤1 mg/day</td>
|
||
<td>1.2×</td>
|
||
<td><a href="https://doi.org/10.1136/bmj.k4810">Vinogradova et al. (2019)</a> [<a href="https://en.wikipedia.org/wiki/Template:Risk_of_venous_thromboembolism_with_hormone_therapy_and_birth_control_pills_(QResearch/CPRD)">Table</a>]</td>
|
||
</tr>
|
||
<tr>
|
||
<td>Oral E2 &gt;1 mg/day<sup>a</sup></td>
|
||
<td>1.4×</td>
|
||
<td><a href="https://doi.org/10.1136/bmj.k4810">Vinogradova et al. (2019)</a> [<a href="https://en.wikipedia.org/wiki/Template:Risk_of_venous_thromboembolism_with_hormone_therapy_and_birth_control_pills_(QResearch/CPRD)">Table</a>]</td>
|
||
</tr>
|
||
<tr>
|
||
<td>Oral E2 ≤1 or &gt;1 mg/day<sup>a</sup> + P<sup>b</sup></td>
|
||
<td>1.4–1.8×</td>
|
||
<td><a href="https://doi.org/10.1136/bmj.k4810">Vinogradova et al. (2019)</a> [<a href="https://en.wikipedia.org/wiki/Template:Risk_of_venous_thromboembolism_with_hormone_therapy_and_birth_control_pills_(QResearch/CPRD)">Table</a>]</td>
|
||
</tr>
|
||
<tr>
|
||
<td>Transdermal E2 ≤50 μg/day</td>
|
||
<td>0.9×</td>
|
||
<td><a href="https://doi.org/10.1136/bmj.k4810">Vinogradova et al. (2019)</a> [<a href="https://en.wikipedia.org/wiki/Template:Risk_of_venous_thromboembolism_with_hormone_therapy_and_birth_control_pills_(QResearch/CPRD)">Table</a>]</td>
|
||
</tr>
|
||
<tr>
|
||
<td>Transdermal E2 &gt;50 μg/day<sup>a</sup></td>
|
||
<td>1.1×</td>
|
||
<td><a href="https://doi.org/10.1136/bmj.k4810">Vinogradova et al. (2019)</a> [<a href="https://en.wikipedia.org/wiki/Template:Risk_of_venous_thromboembolism_with_hormone_therapy_and_birth_control_pills_(QResearch/CPRD)">Table</a>]</td>
|
||
</tr>
|
||
<tr>
|
||
<td>Oral CEEs ≤0.625 mg/day</td>
|
||
<td>1.4×</td>
|
||
<td><a href="https://doi.org/10.1136/bmj.k4810">Vinogradova et al. (2019)</a> [<a href="https://en.wikipedia.org/wiki/Template:Risk_of_venous_thromboembolism_with_hormone_therapy_and_birth_control_pills_(QResearch/CPRD)">Table</a>]</td>
|
||
</tr>
|
||
<tr>
|
||
<td>Oral CEEs &gt;0.625 mg/day<sup>a</sup></td>
|
||
<td>1.7×</td>
|
||
<td><a href="https://doi.org/10.1136/bmj.k4810">Vinogradova et al. (2019)</a> [<a href="https://en.wikipedia.org/wiki/Template:Risk_of_venous_thromboembolism_with_hormone_therapy_and_birth_control_pills_(QResearch/CPRD)">Table</a>]</td>
|
||
</tr>
|
||
<tr>
|
||
<td>Oral CEEs ≤ or &gt;0.625 mg/day<sup>a</sup> + P<sup>b</sup></td>
|
||
<td>1.5–2.4×</td>
|
||
<td><a href="https://doi.org/10.1136/bmj.k4810">Vinogradova et al. (2019)</a> [<a href="https://en.wikipedia.org/wiki/Template:Risk_of_venous_thromboembolism_with_hormone_therapy_and_birth_control_pills_(QResearch/CPRD)">Table</a>]</td>
|
||
</tr>
|
||
<tr>
|
||
<td>Modern EE + P birth control<sup>c</sup></td>
|
||
<td>4.2×</td>
|
||
<td><a href="https://doi.org/10.1007/s11239-015-1311-6">Heit, Spencer, &amp; White (2016)</a></td>
|
||
</tr>
|
||
<tr>
|
||
<td>High-dose EE + P birth control<sup>c</sup></td>
|
||
<td>4–10×<sup>d</sup></td>
|
||
<td><a href="https://doi.org/10.2217/1745509X.2.5.771">Tchaikovski, Tans, &amp; Rosing (2006)</a>;<br /><a href="https://doi.org/10.1016/j.fertnstert.2016.09.027">PCASRM (2017)</a> [<a href="https://web.archive.org/web/20220222083101/https://en.wikipedia.org/wiki/Template:Dose_of_ethinylestradiol_in_birth_control_pills_and_risk_of_venous_thromboembolism">Table</a>]</td>
|
||
</tr>
|
||
<tr>
|
||
<td>High-dose PEP injections<sup>e</sup></td>
|
||
<td>2.1×</td>
|
||
<td><a href="/articles/pep-cardiovascular-analysis/">Sam (2020)</a></td>
|
||
</tr>
|
||
<tr>
|
||
<td>High-dose oral DES, EE, or EMP</td>
|
||
<td>5.7–10×</td>
|
||
<td><a href="https://doi.org/10.1111/j.1464-410X.2007.06859.x">Seaman et al. (2007)</a>; <a href="https://doi.org/10.1111/j.1464-410X.2011.10201.x">Ravery et al.<br />(2011)</a>; <a href="https://doi.org/10.1016/j.eururo.2015.06.022">Klil-Drori et al. (2015)</a></td>
|
||
</tr>
|
||
<tr>
|
||
<td>SERMs (tamoxifen, raloxifene)</td>
|
||
<td>~1.5–3×</td>
|
||
<td><a href="https://doi.org/10.1002/cncr.20347">Deitcher &amp; Gomes (2004)</a>; <a href="https://doi.org/10.1016/j.ctrv.2011.06.009">Iqbal et al.<br />(2012)</a>; <a href="https://doi.org/10.1016/B978-0-323-46202-0.00031-5">Konkle &amp; Sood (2019)</a></td>
|
||
</tr>
|
||
<tr>
|
||
<td>Pregnancy (overall)<sup>f</sup></td>
|
||
<td>4.0×</td>
|
||
<td><a href="https://doi.org/10.1007/s11239-015-1311-6">Heit, Spencer, &amp; White (2016)</a></td>
|
||
</tr>
|
||
<tr>
|
||
<td>Pregnancy (3rd trimester)</td>
|
||
<td>5.1–7.1×</td>
|
||
<td><a href="https://doi.org/10.1136/bmjopen-2015-008864">Abdul Sultan et al. (2015)</a> [<a href="https://en.wikipedia.org/wiki/Template:Venous_thromboembolism_incidence_during_pregnancy_and_the_postpartum_period">Table</a>]</td>
|
||
</tr>
|
||
<tr>
|
||
<td>High-dose CPA alone</td>
|
||
<td>3–5×</td>
|
||
<td><a href="https://doi.org/10.1111/j.1464-410X.2007.06859.x">Seaman et al. (2007)</a></td>
|
||
</tr>
|
||
</tbody>
|
||
</table>
|
||
|
||
<p><small><strong>Footnotes:</strong> <sup>a</sup> At typical menopausal replacement doses (i.e., not very high—probably no more than double the given dose). <sup>b</sup> MPA, <a href="https://en.wikipedia.org/wiki/Norethisterone">norethisterone</a>, <a href="https://en.wikipedia.org/wiki/Norgestrel">norgestrel</a>, or <a href="https://en.wikipedia.org/wiki/Drospirenone">drospirenone</a>. <sup>c</sup> Modern EE + P birth control contains 20–35 μg/day EE, while high-dose EE + P birth control used in the 1960s and 1970s contained 50–150 μg/day EE. <sup>d</sup> Risk around twice as high as modern birth control pills. <sup>e</sup> Unpublished original research/analysis with borderline <a href="https://en.wikipedia.org/wiki/Statistical_significance">statistical significance</a> (95% CI 0.99–4.22). <sup>f</sup> Excluding the <a href="https://en.wikipedia.org/wiki/Postpartum">postpartum</a> period. With the postpartum period included, the risk of blood clots with pregnancy is 5–10× (<a href="https://doi.org/10.1016/j.bpobgyn.2014.03.001">McLintock, 2014</a>). <strong>Abbreviations:</strong> E2 = Estradiol; CEEs = Conjugated estrogens; EE = Ethinylestradiol; DES = Diethylstilbestrol; EMP = Estramustine phosphate; PEP = Polyestradiol phosphate; SERMs = Selective estrogen receptor modulators; CPA = Cyproterone acetate; P = Progestogen.</small></p>
|
||
|
||
<p>Note that the values in the table are <a href="https://en.wikipedia.org/wiki/Correlation">associations</a> mostly from observational studies rather than from RCTs. Hence, in many cases, causation has not been definitively established. In addition, the values represent rough average values with often wide 95% <a href="https://en.wikipedia.org/wiki/Confidence_interval">confidence intervals</a>. As a result, precision and accuracy of the estimates may in some cases be low. Also note that quantified blood clot risk will vary depending on the study and its definitions and methodology (including factors like <a href="https://en.wikipedia.org/wiki/Sampling_error">sampling error</a>, approach to control of <a href="https://en.wikipedia.org/wiki/Confounding_variable">confounding variables</a>, and residual confounding influences).</p>
|
||
|
||
<h2 id="mechanisms-of-increased-coagulation-with-estrogens">Mechanisms of Increased Coagulation with Estrogens</h2>
|
||
|
||
<p>The ERs are expressed in the liver and estrogens exert effects in this part of the body through these receptors (<a href="https://pubmed.ncbi.nlm.nih.gov/400323/">Eisenfeld &amp; Aten, 1979</a>; <a href="https://doi.org/10.1016/0022-4731(87)90197-x">Eisenfeld &amp; Aten, 1987</a>; <a href="https://files.transfemscience.org/pdfs/Sahlin%20&amp;%20von%20Schoultz%20(1999)%20-%20Liver%20Inclusive%20Protein,%20Lipid%20and%20Carbohydrate%20Metabolism%20%5BIn%20Estrogens%20and%20Antiestrogens%20II%20(Lauritzen).pdf#page=2">Sahlin &amp; von Schoultz, 1999</a>; <a href="https://doi.org/10.1210/er.2018-00158">Grossmann et al., 2019</a>). Estrogens are thought to increase the risk of blood clots by activating liver ERs and thereby modulating the hepatic production of numerous different <a href="https://en.wikipedia.org/wiki/Coagulation_factor">coagulation factors</a>, both <a href="https://en.wikipedia.org/wiki/Procoagulant">procoagulant</a> and <a href="https://en.wikipedia.org/wiki/Anticoagulant">anticoagulant</a> (<a href="https://doi.org/10.1080/13697130500148875">Kuhl, 2005</a>; <a href="https://doi.org/10.1016/j.thromres.2010.01.045">Tchaikovski &amp; Rosing, 2010</a>; <a href="https://doi.org/10.1007/s11154-011-9178-0">DeLoughery, 2011</a>; <a href="https://doi.org/10.1016/B978-0-323-46202-0.00031-5">Konkle &amp; Sood, 2019</a>). Most coagulation factors and their inhibitors are synthesized in the liver (<a href="https://doi.org/10.1016/S0889-8588(18)30273-9">Mammen, 1992</a>; <a href="https://doi.org/10.1055/s-2002-23205">Amitrano et al., 2002</a>; <a href="https://doi.org/10.1111/j.1365-2036.2007.03509.x">Peck-Radosavljevic, 2007</a>). Following their synthesis, these coagulation factors are secreted by the liver into the bloodstream where they circulate and mediate their actions. Circulating levels of procoagulant factors like <a href="https://en.wikipedia.org/wiki/Fibrinogen">fibrinogen</a> (factor I), <a href="https://en.wikipedia.org/wiki/Prothrombin">prothrombin</a> (factor II), <a href="https://en.wikipedia.org/wiki/Factor_VII">factors VII</a>, <a href="https://en.wikipedia.org/wiki/Factor_VIII">VIII</a>, and <a href="https://en.wikipedia.org/wiki/Factor_X">X</a>, anticoagulant factors like <a href="https://en.wikipedia.org/wiki/Antithrombin">antithrombin</a>, <a href="https://en.wikipedia.org/wiki/Protein_C">protein C</a>, <a href="https://en.wikipedia.org/wiki/Protein_S">protein S</a>, and <a href="https://en.wikipedia.org/wiki/Tissue_factor_pathway_inhibitor">tissue factor pathway inhibitor</a> (TFPI), and <a href="https://en.wikipedia.org/wiki/Fibrinolysis">fibrinolytic</a> factors like <a href="https://en.wikipedia.org/wiki/Plasminogen">plasminogen</a>, <a href="https://en.wikipedia.org/wiki/Tissue_plasminogen_activator">tissue plasminogen activator</a> (t-PA), and <a href="https://en.wikipedia.org/wiki/Plasminogen_activator_inhibitor-1">plasminogen activator inhibitor-1</a> (PAI-1), are all influenced by estrogens (<a href="https://doi.org/10.1016/j.fertnstert.2007.07.1298">Hemelaar et al., 2008</a>; <a href="https://doi.org/10.1055/s-0040-1714140">Doxufils, Morimont, &amp; Bouvy, 2020</a>). These estrogen-mediated changes in levels result in an overall procoagulatory effect, as assessed by <a href="https://en.wikipedia.org/wiki/Coagulation_activation_marker">markers of net coagulation activation</a> like <a href="https://en.wikipedia.org/wiki/Prothrombin_fragment_1+2">prothrombin fragment 1+2</a> (F1+2), <a href="https://en.wikipedia.org/wiki/D-Dimer">D-dimer</a>, and <a href="https://en.wikipedia.org/wiki/Thrombin–antithrombin_complex">thrombin–antithrombin complex</a> (TAT), as well as <a href="https://en.wikipedia.org/wiki/Global_coagulation_assay">global coagulation assays</a> like the <a href="https://en.wikipedia.org/wiki/Thrombin_generation_assay">endogenous thrombin potential</a>-based <a href="https://en.wikipedia.org/wiki/Activated_protein_C_resistance_test">activated protein C resistance test</a> (<a href="https://doi.org/10.1016/S0010-7824(99)00044-X">The Oral Contraceptive and Hemostasis Study Group, 1999</a>; <a href="https://doi.org/10.1002/cncr.21528">Kohli, 2006</a>; <a href="https://doi.org/10.1016/j.fertnstert.2007.07.1298">Hemelaar et al., 2008</a>; <a href="https://doi.org/10.1016/j.contraception.2020.08.015">Douxfils et al., 2020</a>; <a href="https://doi.org/10.1055/s-0040-1714140">Douxfils, Morimont, &amp; Bouvy, 2020</a>). The changes in levels of most coagulation factors caused by estrogens are relatively small and levels often remain within normal ranges. However, they combine and synergize to produce larger increases in global coagulation and clot risk (<a href="https://doi.org/10.1016/j.contraception.2020.08.015">Douxfils et al., 2020</a>; <a href="https://doi.org/10.1055/s-0040-1714140">Douxfils, Morimont, &amp; Bouvy, 2020</a>; <a href="https://doi.org/10.1055/a-1153-5824">Reda et al., 2020</a>).</p>
|
||
|
||
<p>Aside from coagulation factors, estrogens also modulate the <a href="https://en.wikipedia.org/wiki/Liver_protein_synthesis">synthesis of numerous other liver products</a> (<a href="https://files.transfemscience.org/pdfs/Kuhl%20(1999)%20-%20Hormonal%20Contraception%20%5BIn%20Estrogens%20and%20Antiestrogens%20II%20-%20Pharmacology%20and%20Clinical%20Application%20of%20Estrogens%20and%20Antiestrogens%20(Lauritzen%20et%20al.,%201999)%5D.pdf#page=3">Kuhl, 1999</a>; <a href="https://doi.org/10.1080/13697130500148875">Kuhl, 2005</a>; <a href="https://en.wikipedia.org/wiki/Template:Biochemical_parameters_affected_by_estrogen_therapy">Table</a>). Examples include <a href="https://en.wikipedia.org/wiki/Sex_hormone-binding_globulin">sex hormone-binding globulin</a> (SHBG), <a href="https://en.wikipedia.org/wiki/Transcortin">corticosteroid-binding globulin</a> (CBG), various other circulating <a href="https://en.wikipedia.org/wiki/Binding_protein">binding proteins</a>, <a href="https://en.wikipedia.org/wiki/Angiotensinogen">angiotensinogen</a>, <a href="https://en.wikipedia.org/wiki/Lipoprotein">lipoproteins</a>, and <a href="https://en.wikipedia.org/wiki/Triglyceride">triglycerides</a>, among others. In accordance with the mechanisms underlying increased coagulation and blood clot risk with estrogens, the differences in risk of blood clots with different types and routes of estrogens are mirrored in their influences on estrogen-sensitive liver products. Put another way, different estrogens have different relative <a href="https://en.wikipedia.org/wiki/Potency_(pharmacology)">potency</a> in the liver when compared to their estrogenic potency elsewhere in the body. Synthetic and non-bioidentical estrogens have greater impact on liver synthesis than estradiol, while oral administration of estradiol has greater influence on liver synthesis than non-oral routes like transdermal administration or intramuscular injection, and this is likely to explain the observed differences in coagulation and blood clot risk with these different estrogens. The table below shows the liver potency of different estrogenic exposures as measured by influence specifically on SHBG levels, one of the most sensitive and well-characterized estrogen-modulated liver products.</p>
|
||
|
||
<p><strong>Table 3:</strong> Relative increases in SHBG levels with different estrogenic exposures (see also <a href="/articles/shbg-unimportant/#effects-of-sex-hormones-on-shbg-production">Aly, 2020</a>):</p>
|
||
|
||
<table>
|
||
<thead>
|
||
<tr>
|
||
<th>Estrogen</th>
|
||
<th>SHBG increase</th>
|
||
<th>Source</th>
|
||
</tr>
|
||
</thead>
|
||
<tbody>
|
||
<tr>
|
||
<td>E2 patch 50 μg/day</td>
|
||
<td>1.1×</td>
|
||
<td><a href="https://doi.org/10.1080/13697130500148875">Kuhl (2005)</a></td>
|
||
</tr>
|
||
<tr>
|
||
<td>E2 patch 100 μg/day</td>
|
||
<td>1.2×</td>
|
||
<td><a href="https://doi.org/10.1210/jc.2007-2193">Shifren et al. (2008)</a></td>
|
||
</tr>
|
||
<tr>
|
||
<td>Oral E2 1 mg/day</td>
|
||
<td>1.6×</td>
|
||
<td><a href="https://files.transfemscience.org/pdfs/Kuhl%20(1998)%20-%20Adverse%20Effects%20of%20Estrogen%20Treatment_%20Natural%20versus%20Synthetic%20Estrogens.pdf">Kuhl (1998)</a></td>
|
||
</tr>
|
||
<tr>
|
||
<td>Oral E2 2 mg/day</td>
|
||
<td>2.2×</td>
|
||
<td><a href="https://files.transfemscience.org/pdfs/Kuhl%20(1998)%20-%20Adverse%20Effects%20of%20Estrogen%20Treatment_%20Natural%20versus%20Synthetic%20Estrogens.pdf">Kuhl (1998)</a></td>
|
||
</tr>
|
||
<tr>
|
||
<td>Oral E2 4 mg/day</td>
|
||
<td>1.9–3.2×</td>
|
||
<td><a href="https://doi.org/10.1530/acta.0.1010592">Fåhraeus &amp; Larsson-Cohn (1982)</a>; <a href="https://doi.org/10.1210/jc.2005-0173">Gibney<br />et al. (2005)</a>; <a href="https://doi.org/10.1210/jc.2005-0352">Ropponen et al. (2005)</a></td>
|
||
</tr>
|
||
<tr>
|
||
<td>Oral EV 6 mg/day (~4.5 mg/day E2)<sup>a</sup></td>
|
||
<td>2.5–3.0×</td>
|
||
<td><a href="http://doi.org/10.1055/s-2005-865900">Dittrich et al. (2005)</a>; <a href="https://doi.org/10.1530/eje.1.01943">Mueller et al. (2005)</a>;<br /><a href="https://doi.org/10.1055/s-2006-925198">Mueller et al. (2006)</a></td>
|
||
</tr>
|
||
<tr>
|
||
<td>Oral CEEs 0.625 mg/day</td>
|
||
<td>1.8×</td>
|
||
<td><a href="https://files.transfemscience.org/pdfs/Kuhl%20(1998)%20-%20Adverse%20Effects%20of%20Estrogen%20Treatment_%20Natural%20versus%20Synthetic%20Estrogens.pdf">Kuhl (1998)</a></td>
|
||
</tr>
|
||
<tr>
|
||
<td>Oral CEEs 1.25 mg/day</td>
|
||
<td>2.2×</td>
|
||
<td><a href="https://files.transfemscience.org/pdfs/Kuhl%20(1998)%20-%20Adverse%20Effects%20of%20Estrogen%20Treatment_%20Natural%20versus%20Synthetic%20Estrogens.pdf">Kuhl (1998)</a></td>
|
||
</tr>
|
||
<tr>
|
||
<td>Oral EE 5 μg/day</td>
|
||
<td>2.0×</td>
|
||
<td><a href="https://files.transfemscience.org/pdfs/Kuhl%20(1999)%20-%20Hormonal%20Contraception%20%5BIn%20Estrogens%20and%20Antiestrogens%20II%20-%20Pharmacology%20and%20Clinical%20Application%20of%20Estrogens%20and%20Antiestrogens%20(Lauritzen%20et%20al.,%201999)%5D.pdf#page=3">Kuhl (1999)</a></td>
|
||
</tr>
|
||
<tr>
|
||
<td>Oral EE 10 μg/day</td>
|
||
<td>3.0×</td>
|
||
<td><a href="https://files.transfemscience.org/pdfs/Kuhl%20(1998)%20-%20Adverse%20Effects%20of%20Estrogen%20Treatment_%20Natural%20versus%20Synthetic%20Estrogens.pdf">Kuhl (1998)</a></td>
|
||
</tr>
|
||
<tr>
|
||
<td>Oral EE 20 μg/day</td>
|
||
<td>3.4×</td>
|
||
<td><a href="https://files.transfemscience.org/pdfs/Kuhl%20(1998)%20-%20Adverse%20Effects%20of%20Estrogen%20Treatment_%20Natural%20versus%20Synthetic%20Estrogens.pdf">Kuhl (1998)</a></td>
|
||
</tr>
|
||
<tr>
|
||
<td>Oral EE 50 μg/day</td>
|
||
<td>4.0×</td>
|
||
<td><a href="https://doi.org/10.1007/PL00003042">Kuhl (1997)</a></td>
|
||
</tr>
|
||
<tr>
|
||
<td>Modern EE + P birth control<sup>b</sup></td>
|
||
<td>~3.0–4.0×</td>
|
||
<td><a href="https://www.tandfonline.com/doi/abs/10.1080/j.1600-0412.2002.810603.x">Odlind et al. (2002)</a></td>
|
||
</tr>
|
||
<tr>
|
||
<td>High-dose EE + P birth control<sup>b</sup></td>
|
||
<td>~5–10×</td>
|
||
<td><a href="https://doi.org/10.1007/978-3-319-53298-1_15">Hammond (2017)</a></td>
|
||
</tr>
|
||
<tr>
|
||
<td>E2 patches 200 μg/day</td>
|
||
<td>~1.5×</td>
|
||
<td><a href="https://doi.org/10.1016/j.clgc.2019.09.019">Smith et al. (2020)</a></td>
|
||
</tr>
|
||
<tr>
|
||
<td>E2 patches 300 μg/day</td>
|
||
<td>~1.7×</td>
|
||
<td><a href="https://doi.org/10.1016/j.clgc.2019.09.019">Smith et al. (2020)</a></td>
|
||
</tr>
|
||
<tr>
|
||
<td>E2 patches 600 μg/day</td>
|
||
<td>~2.3×</td>
|
||
<td><a href="https://doi.org/10.1002/cncr.20857">Bland et al. (2005)</a></td>
|
||
</tr>
|
||
<tr>
|
||
<td>High-dose E2 injections<sup>c</sup></td>
|
||
<td>1.7–3.2×</td>
|
||
<td><a href="https://doi.org/10.1097/00000421-198801102-00024">Stege et al. (1988)</a>; <a href="https://doi.org/10.1530/EJE-09-0265">Kronawitter et al.<br />(2009)</a> [<a href="https://archive.is/k2HTe">Table</a>]; <a href="https://doi.org/10.1055/s-0030-1255074">Mueller et al. (2011)</a>;<br /><a href="https://doi.org/10.1089/trgh.2016.0016">Nelson et al. (2016)</a></td>
|
||
</tr>
|
||
<tr>
|
||
<td>High-dose oral DES, EE, or EMP</td>
|
||
<td>~5–10×</td>
|
||
<td><a href="https://doi.org/10.1002/pros.2990140410">von Schoultz et al. (1989)</a></td>
|
||
</tr>
|
||
<tr>
|
||
<td>Pregnancy</td>
|
||
<td>~5–10×</td>
|
||
<td><a href="https://doi.org/10.1007/978-3-319-53298-1_15">Hammond (2017)</a></td>
|
||
</tr>
|
||
</tbody>
|
||
</table>
|
||
|
||
<p><small><strong>Footnotes:</strong> <sup>a</sup> Due to differences in molecular weight, estradiol valerate has about 75% of the amount of estradiol as regular estradiol. Hence, 6 mg/day estradiol valerate is approximately equivalent to 4.5 mg/day estradiol. <sup>b</sup> Modern EE + P birth control contains 20–35 μg/day EE, while high-dose EE + P birth control used in the 1960s and 1970s contained 50–150 μg/day EE. <sup>c</sup> In the form of 320 mg/month PEP (~700 pg/mL estradiol), 100 mg/month <a href="https://en.wikipedia.org/wiki/Estradiol_undecylate">estradiol undecylate</a> (~500–600 pg/mL estradiol), or 10 mg/10 days estradiol valerate (~500–1,200 pg/mL peak estradiol; <a href="https://web.archive.org/web/20220222214454/https://en.wikipedia.org/wiki/Template:Hormone_levels_with_estradiol_valerate_by_intramuscular_injection">Graphs</a>). <strong>Abbreviations:</strong> E2 = Estradiol; EV = Estradiol valerate; CEEs = Conjugated estrogens; EE = Ethinylestradiol; DES = Diethylstilbestrol; EMP = Estramustine phosphate; PEP = Polyestradiol phosphate; P = Progestogen.</small></p>
|
||
|
||
<p>The increase in SHBG levels with estrogen therapy correlates with increases in coagulation and blood clot risk and can serve as a reliable surrogate indicator of these effects (<a href="https://www.tandfonline.com/doi/abs/10.1080/j.1600-0412.2002.810603.x">Odlind et al., 2002</a>; <a href="https://doi.org/10.1016/S0002-9378(03)00950-5">van Rooijen et al., 2004</a>; <a href="https://doi.org/10.1093/humrep/deh612">van Vliet et al., 2005</a>; <a href="https://doi.org/10.1016/j.thromres.2010.01.045">Tchaikovski &amp; Rosing, 2010</a>; <a href="https://doi.org/10.1111/j.1538-7836.2012.04720.x">Raps et al., 2012</a>; <a href="https://doi.org/10.1111/jth.12054">Stegeman et al., 2013</a>; <a href="https://doi.org/10.1080/1354750X.2016.1204010">Hugon-Rodin et al., 2017</a>; <a href="https://doi.org/10.1097/MBC.0000000000000784">Eilertsen et al., 2019</a>). The increases in SHBG levels and blood clot risk even appear quite similar to each other with modern birth control pills (both ~4-fold), high-dose oral synthetic estrogen therapy (both ~5–10-fold), and late pregnancy (both ~5–10-fold). When data on blood clot risk with a given estrogen route or dose are limited or unavailable—for instance with high-dose oral estradiol or high-dose estradiol ester injections—changes in SHBG levels can be used as a rough proxy or surrogate instead to estimate overall liver impact, magnitude of change in coagulation systems, and blood clot risk. It should be noted however that progestogens may augment the blood clot risk with estrogens without necessarily affecting SHBG levels or even while decreasing SHBG levels via concomitant androgenic activity (<a href="https://doi.org/10.1080/13697130500148875">Kuhl, 2005</a>; <a href="https://doi.org/10.1136/bmj.k4810">Vinogradova, Coupland, &amp; Hippisley-Cox, 2019</a>).</p>
|
||
|
||
<p>Physiological levels of estradiol appear to have relatively minimal influence on liver synthesis (<a href="https://pubmed.ncbi.nlm.nih.gov/400323/">Eisenfeld &amp; Aten, 1979</a>; <a href="https://doi.org/10.1016/0022-4731(87)90198-1">Lax, 1987</a>; <a href="https://doi.org/10.1080/13697130500148875">Kuhl, 2005</a>). This is in accordance with the limited influence or non-influence of physiological estradiol levels in women on blood clot risk. It is thought that under normal physiological circumstances, estradiol is only supposed to considerably affect liver synthesis at very high levels—namely during pregnancy. The changes in synthesis of liver products during pregnancy presumably have important biological roles at this time (<a href="https://pubmed.ncbi.nlm.nih.gov/400323/">Eisenfeld &amp; Aten, 1979</a>). One of these is considered to be increased coagulation, as coagulation limits blood loss with childbirth and hence has survival benefits. Conversely, there is no obvious benefit to increased coagulation outside of pregnancy.</p>
|
||
|
||
<h3 id="estradiol-and-the-liver-first-pass-with-oral-administration">Estradiol and the Liver First Pass with Oral Administration</h3>
|
||
|
||
<p>The <a href="https://en.wikipedia.org/wiki/Oral_administration">oral</a> <a href="https://en.wikipedia.org/wiki/Route_of_administration">route of administration</a> is subject to a <a href="https://en.wikipedia.org/wiki/First_pass_effect">first pass</a> through the liver via the <a href="https://en.wikipedia.org/wiki/Hepatic_portal_vein">hepatic portal vein</a> which is not present with <a href="https://en.wikipedia.org/wiki/Non-oral_administration">non-oral</a> routes of administration (<a href="https://doi.org/10.2165/00003088-198409010-00001">Pond &amp; Tozer, 1984</a>; <a href="https://doi.org/10.1111/j.1365-2036.1987.tb00634.x">Back &amp; Rogers, 1987</a>). As such, oral estradiol is subject to a hepatic first pass while this does not occur with non-oral forms of estradiol such as transdermal estradiol and injectable estradiol (<a href="https://files.transfemscience.org/pdfs/Kuhl%20(1998)%20-%20Adverse%20Effects%20of%20Estrogen%20Treatment_%20Natural%20versus%20Synthetic%20Estrogens.pdf">Kuhl, 1998</a>; <a href="https://doi.org/10.1080/13697130500148875">Kuhl, 2005</a>). This first pass results in disproportionate exposure of the liver to estradiol as well as disproportionate estrogenic impact on liver protein synthesis (<a href="https://doi.org/10.1080/13697130500148875">Kuhl, 2005</a>). Oral estradiol likewise has disproportionate estrogenic impact on the hepatic synthesis of coagulation factors (<a href="https://files.transfemscience.org/pdfs/Kuhl%20(1998)%20-%20Adverse%20Effects%20of%20Estrogen%20Treatment_%20Natural%20versus%20Synthetic%20Estrogens.pdf">Kuhl, 1998</a>; <a href="https://doi.org/10.1080/13697130500148875">Kuhl, 2005</a>). Due to the first pass, it is estimated that there is a 4- or 5-fold greater estrogenic impact of oral estradiol in the liver relative to non-oral estradiol (<a href="https://doi.org/10.1080/13697130500148875">Kuhl, 2005</a>). Due to the absence of the hepatic first pass with most non-oral routes, there is strong biological plausibility for the lower risk of blood clots that has been found with transdermal estradiol in comparison to oral estradiol in observational studies (<a href="https://doi.org/10.3109/13697137.2015.1129166">Baber et al., 2016</a>).</p>
|
||
|
||
<table>
|
||
<thead>
|
||
<tr>
|
||
<th><img src="/assets/images/e-blood-clots-first-pass.png" alt="" /></th>
|
||
</tr>
|
||
</thead>
|
||
<tbody>
|
||
<tr>
|
||
<td><strong>Figure 1:</strong> Diagrammatic representation of increased coagulation via the liver first pass with oral estrogen therapy (<a href="https://doi.org/10.1136/heartjnl-2020-316907">Scarabin et al., 2020</a>). Abbreviations: E = estrogen; trans = transdermal; AT = <a href="https://en.wikipedia.org/wiki/Antithrombin">antithrombin</a>; PS = <a href="https://en.wikipedia.org/wiki/Protein_S">protein S</a>; TFPI = <a href="https://en.wikipedia.org/wiki/Tissue_factor_pathway_inhibitor">tissue factor protein inhibitor</a>; II = <a href="https://en.wikipedia.org/wiki/Prothrombin">prothrombin</a>; VII = <a href="https://en.wikipedia.org/wiki/Factor_VII">factor VII</a>; PC = <a href="https://en.wikipedia.org/wiki/Protein_C">protein C</a>; V = <a href="https://en.wikipedia.org/wiki/Factor_V">factor V</a>; VTE = venous thromboembolism; CHD = <a href="https://en.wikipedia.org/wiki/Coronary_heart_disease">coronary heart disease</a>. Other terms: <a href="https://en.wikipedia.org/wiki/Activated_protein_C_resistance">activated protein C resistance</a> (APCR).</td>
|
||
</tr>
|
||
</tbody>
|
||
</table>
|
||
|
||
<p>Although oral estradiol has a much higher relative potential for blood clots due to the liver first pass, sufficiently high levels of estradiol will diffuse into the liver from the blood to act on this tissue regardless of route of administration. Hence, high levels of estradiol via non-oral routes (or produced by the body itself) can increase coagulation and blood clot risk similarly to the oral route. This is clearly evidenced by hyperestrogenic situations like pregnancy and ovarian stimulation for <em>in-vitro</em> fertilization, when estradiol levels increase to very high concentrations and substantially influence liver protein synthesis.</p>
|
||
|
||
<h3 id="non-bioidentical-estrogens-and-resistance-to-liver-metabolism">Non-Bioidentical Estrogens and Resistance to Liver Metabolism</h3>
|
||
|
||
<p>Non-bioidentical estrogens such as EE, DES, and CEEs have greater impact on liver protein synthesis and risk of blood clots than either oral estradiol or non-oral estradiol (<a href="https://files.transfemscience.org/pdfs/Kuhl%20(1998)%20-%20Adverse%20Effects%20of%20Estrogen%20Treatment_%20Natural%20versus%20Synthetic%20Estrogens.pdf">Kuhl, 1998</a>; <a href="https://doi.org/10.1080/13697130500148875">Kuhl, 2005</a>; <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4052190/">Phillips et al., 2014</a>; <a href="https://doi.org/10.3109/21681805.2013.861508">Turo et al., 2014</a>; <a href="https://en.wikipedia.org/wiki/Template:Risk_of_venous_thromboembolism_with_hormone_therapy_and_birth_control_pills_(QResearch/CPRD)">Table</a>). This is because the liver strongly metabolizes and inactivates estradiol, whereas non-bioidentical estrogens have differences in their chemical structures relative to estradiol that result in them being much more resistant to liver metabolism (<a href="https://files.transfemscience.org/pdfs/Kuhl%20(1998)%20-%20Adverse%20Effects%20of%20Estrogen%20Treatment_%20Natural%20versus%20Synthetic%20Estrogens.pdf">Kuhl, 1998</a>; <a href="https://doi.org/10.1080/13697130500148875">Kuhl, 2005</a>; <a href="https://doi.org/10.1111/jth.14626">Connors &amp; Middeldorp, 2019</a>; <a href="https://doi.org/10.3389/fendo.2019.00685">Swee, Javaid, &amp; Quinton, 2019</a>).</p>
|
||
|
||
<p>EE can be considered as a case example. The oral <a href="https://en.wikipedia.org/wiki/Bioavailability">bioavailability</a> of EE is around 45%, while that of estradiol is only about 5% (<a href="https://doi.org/10.1080/13697130500148875">Kuhl, 2005</a>; <a href="https://doi.org/10.1016/j.contraception.2012.12.011">Stanczyk, Archer, &amp; Bhavnani, 2013</a>). In addition, the <a href="https://en.wikipedia.org/wiki/Elimination_half-life">blood half-life</a> of EE is in the range of 5 to 30 hours, compared to less than 1 hour in the case of estradiol (<a href="https://doi.org/10.1002/j.1875-9114.1998.tb03157.x">White et al., 1998</a>; <a href="https://doi.org/10.1080/13697130500148875">Kuhl, 2005</a>; <a href="https://doi.org/10.1016/j.contraception.2012.12.011">Stanczyk, Archer, &amp; Bhavnani, 2013</a>). As a result of these and other differences, EE is approximately 120 times as potent as estradiol by weight in terms of general estrogenic effect (<a href="https://doi.org/10.1080/13697130500148875">Kuhl, 2005</a>; <a href="https://en.wikipedia.org/wiki/Template:Relative_oral_potencies_of_estrogens">Table</a>). Hence, EE is used clinically in μg doses whereas oral estradiol is used at over 100-fold higher mg doses. The <a href="https://en.wikipedia.org/wiki/Pharmacokinetics">pharmacokinetic</a> differences between EE and estradiol reflect the strong resistance of EE to liver metabolism (<a href="https://doi.org/10.1080/13697130500148875">Kuhl, 2005</a>). EE, or 17α-ethynylestradiol, shows resistance to liver metabolism because of an <a href="https://en.wikipedia.org/wiki/Ethynyl_group">ethynyl group</a> at the C17α position which has been added to what is the otherwise unchanged structure of estradiol (<a href="https://doi.org/10.1080/13697130500148875">Kuhl, 2005</a>). This modification results in <a href="https://en.wikipedia.org/wiki/Steric_hindrance">steric hindrance</a> which blocks <a href="https://en.wikipedia.org/wiki/17β-Hydroxysteroid_dehydrogenase">17β-hydroxysteroid dehydrogenases</a> (17β-HSDs) as well as <a href="https://en.wikipedia.org/wiki/Conjugation_(biochemistry)">conjugating</a> enzymes like <a href="https://en.wikipedia.org/wiki/Sulfotransferase">sulfotransferases</a> and <a href="https://en.wikipedia.org/wiki/Glucuronosyltransferase">glucuronosyltransferases</a> from metabolizing EE at the C17β <a href="https://en.wikipedia.org/wiki/Hydroxy_group">hydroxyl group</a>. 17β-HSDs normally convert estradiol into the weakly active <a href="https://en.wikipedia.org/wiki/Estrone_(medication)">estrone</a> while the conjugating enzymes convert estradiol into inactive C17β <a href="https://en.wikipedia.org/wiki/Estrogen_conjugate">estrogen sulfate and glucuronide conjugates</a> like <a href="https://en.wikipedia.org/wiki/Estrone_sulfate">estrone sulfate</a> (<a href="https://doi.org/10.1080/13697130500148875">Kuhl, 2005</a>). An “ethinylestrone” metabolite is in fact a structural impossibility due to the requirement of a double bond for a C17 ketone group—the needed C17α position is already occupied in EE by its ethynyl group. As such, the metabolism of estradiol into weakly active or inactive metabolites like estrone and estrone sulfate in the liver is protective against activation of hepatic ERs and procoagulation, and the lack of this with EE is responsible for its greater blood clot risk (<a href="https://doi.org/10.1080/13697130500148875">Kuhl, 2005</a>; <a href="https://doi.org/10.1530/ERC-17-0153">Russell et al., 2017</a>).</p>
|
||
|
||
<table>
|
||
<thead>
|
||
<tr>
|
||
<th><img src="/assets/images/e2-e1-ee-des-structures.png" alt="" /></th>
|
||
</tr>
|
||
</thead>
|
||
<tbody>
|
||
<tr>
|
||
<td><strong>Figure 2:</strong> Chemical structures of selected estrogens. The C17 position in the case of the steroidal estrogens (E2, E1, and EE) is at the top right of the steroid nucleus.</td>
|
||
</tr>
|
||
</tbody>
|
||
</table>
|
||
|
||
<p>Due to the marked resistance of EE to hepatic metabolism and inactivation, it persists for a long time in the liver—often cycling through it many times before finally being broken down. Moreover, EE shows several-fold disproportionate impact on liver protein synthesis at otherwise equivalent doses relative to oral estradiol (<a href="https://doi.org/10.1080/13697130500148875">Kuhl, 2005</a>; <a href="https://en.wikipedia.org/wiki/Template:Relative_oral_potencies_of_estrogens">Table</a>). Consequently, whereas EE has around 120-fold the general potency of oral estradiol, the liver potency of EE is around 350 to 1,500 times greater than that of oral estradiol (<a href="https://doi.org/10.1002/pros.2990140410">von Schoultz et al., 1989</a>; <a href="https://doi.org/10.1080/13697130500148875">Kuhl, 2005</a>). A dose of EE of as little as 1 μg/day has been shown to impact liver metabolism (<a href="https://doi.org/10.1001/jama.1996.03540170041030">Speroff et al., 1996</a>; <a href="https://doi.org/10.1016/j.gyobfe.2011.10.009">Trémollieres, 2012</a>). In addition, the fact that EE shows similar hepatic impact and risk of blood clots regardless of whether it is administered orally, transdermally, or vaginally indicates that unlike oral estradiol, the first pass through the liver with oral administration is not necessary for blood clot risk with EE (<a href="https://doi.org/10.1016/j.beem.2012.11.002">Plu-Bureau et al., 2013</a>; <a href="https://doi.org/10.1016/j.fertnstert.2016.09.027">PCASRM, 2017</a>; <a href="https://doi.org/10.1016/B978-0-323-46202-0.00031-5">Konkle &amp; Sood, 2019</a>). EE is so resistant to metabolism that it does not seem to matter how it is administered—the liver impact is substantial regardless of route. The greatly increased liver potency of EE results in its influence on coagulation and blood clot risk being much higher than that of estradiol at equivalent doses.</p>
|
||
|
||
<p>CEEs show a few-fold disproportionate estrogenic impact on liver protein synthesis relative to oral estradiol but less than that of EE (<a href="https://doi.org/10.1080/13697130500148875">Kuhl, 2005</a>; <a href="https://en.wikipedia.org/wiki/Template:Relative_oral_potencies_of_estrogens">Table</a>). This can be attributed to the equine (horse) estrogens in CEEs, which humans are presumably not adapted to and which show resistance to liver metabolism in humans. DES, on the other hand, shows even greater estrogenic influence on the liver than EE (<a href="https://doi.org/10.1080/13697130500148875">Kuhl, 2005</a>; <a href="https://en.wikipedia.org/wiki/Template:Relative_oral_potencies_of_estrogens">Table</a>). The more disproportionate impact on liver synthesis of DES relative to EE or CEEs may be attributable to the fact that it is a <a href="https://en.wikipedia.org/wiki/Nonsteroidal_estrogen">nonsteroidal estrogen</a> and is far removed in structure from <a href="https://en.wikipedia.org/wiki/Steroid">steroidal</a> estrogens. This is relevant as steroidal estrogens are susceptible to varying extents to robust steroid-metabolizing enzymes in the liver (<a href="https://doi.org/10.1080/13697130500148875">Kuhl, 2005</a>). As with EE, 17β-HSDs have no affinity for DES and the hydroxyl groups of DES are not oxidized to form estrone-like ketone metabolites (<a href="https://doi.org/10.1016/j.physbeh.2009.08.013">Jensen et al., 2010</a>). Consequent to their resistance to liver metabolism relative to estradiol, CEEs and nonsteroidal estrogens like DES have greater impacts on coagulation and blood clot risk than equivalent doses of estradiol similarly to EE although to varying extents.</p>
|
||
|
||
<p>When compared to transdermal estradiol rather than oral estradiol, the disproportionate influence of oral non-bioidentical estrogens on estrogen-modulated liver protein synthesis becomes extreme. With a little math, it quickly becomes apparent why high doses of these estrogens have influences on liver proteins and blood clot risks that are comparable to those during pregnancy. The table below shows some roughly calculated estimates for comparative liver strength of the different estrogens.</p>
|
||
|
||
<p><strong>Table 4:</strong> Roughly calculated ratios of liver estrogenic potency to general/systemic estrogenic potency with estrogens based on a selection of liver products (e.g., SHBG, others) (<a href="https://doi.org/10.1080/13697130500148875">Kuhl, 2005</a>; <a href="https://en.wikipedia.org/wiki/Template:Relative_oral_potencies_of_estrogens">Table</a>):</p>
|
||
|
||
<htmlprotect>
|
||
<div style="max-width: 500px;">
|
||
<table>
|
||
<thead>
|
||
<tr>
|
||
<th rowspan="2"><b>Estrogen</b></th>
|
||
<th colspan="2"><b>Comparative liver potency</b></th>
|
||
</tr>
|
||
<tr>
|
||
<th><b>Relative to oral E2</b></th>
|
||
<th><b>Relative to transdermal E2</b></th>
|
||
</tr>
|
||
</thead>
|
||
<tbody>
|
||
<tr>
|
||
<td>Transdermal E2</td>
|
||
<td>~0.25×<sup>a</sup></td>
|
||
<td>1.0×<sup>a</sup></td>
|
||
</tr>
|
||
<tr>
|
||
<td>Oral E2</td>
|
||
<td>1.0×</td>
|
||
<td>~4.0×</td>
|
||
</tr>
|
||
<tr>
|
||
<td>Oral CEEs</td>
|
||
<td>1.3–4.5×</td>
|
||
<td>~5.2–18×</td>
|
||
</tr>
|
||
<tr>
|
||
<td>Oral EE</td>
|
||
<td>2.9–5.0×</td>
|
||
<td>~12–20×</td>
|
||
</tr>
|
||
<tr>
|
||
<td>Oral DES</td>
|
||
<td>5.7–7.5×</td>
|
||
<td>~23–30×</td>
|
||
</tr>
|
||
</tbody>
|
||
</table>
|
||
</div>
|
||
</htmlprotect>
|
||
|
||
<p><small><sup>a</sup> Based on a study that found oral estradiol to have 4-fold greater effect on SHBG levels than transdermal estradiol when used at doses that produced similar estradiol levels (<a href="https://doi.org/10.1097/00042192-200007040-00006">Nachtigall et al., 2000</a>).</small></p>
|
||
|
||
<p>Changes in liver protein synthesis induced by estrogens don’t scale linearly with dose or relative liver potency. There is progressive saturation in terms of changes in levels of SHBG and other liver products with estrogen dose—that is, higher doses have relatively diminished effect compared to lower doses (<a href="https://doi.org/10.1055/s-2008-1026392">Kuhl, 1990</a>; <a href="https://files.transfemscience.org/pdfs/Kuhl%20(1999)%20-%20Hormonal%20Contraception%20%5BIn%20Estrogens%20and%20Antiestrogens%20II%20-%20Pharmacology%20and%20Clinical%20Application%20of%20Estrogens%20and%20Antiestrogens%20(Lauritzen%20et%20al.,%201999)%5D.pdf#page=3">Kuhl, 1999</a>). As an example, oral EE shows the following dose-dependent increases in SHBG levels: 2.0-fold at 5 μg/day, 3.0-fold at 10 μg/day, 3.4-fold at 20 μg/day, and 4.0-fold at 50 μg/day (<a href="https://files.transfemscience.org/pdfs/Kuhl%20(1998)%20-%20Adverse%20Effects%20of%20Estrogen%20Treatment_%20Natural%20versus%20Synthetic%20Estrogens.pdf">Kuhl, 1998</a>; <a href="https://files.transfemscience.org/pdfs/Kuhl%20(1999)%20-%20Hormonal%20Contraception%20%5BIn%20Estrogens%20and%20Antiestrogens%20II%20-%20Pharmacology%20and%20Clinical%20Application%20of%20Estrogens%20and%20Antiestrogens%20(Lauritzen%20et%20al.,%201999)%5D.pdf#page=3">Kuhl, 1999</a>). These findings can be attributed to saturation of the competitive binding and/or activation of liver ERs by high estrogen concentrations (<a href="https://doi.org/10.1055/s-2008-1026392">Kuhl, 1990</a>). An implication of this dose-dependent saturation is that although for instance oral EE has much stronger potency in the liver than oral estradiol, oral estradiol can more quickly “catch up” to oral EE and other non-bioidentical estrogens in terms of liver impact than might be initially anticipated. Accordingly, oral estradiol has shown the following dose-dependent increases in SHBG levels: 1.6-fold at 1 mg/day, 2.2-fold at 2 mg/day, and 1.9- to 3.2-fold at 4 mg/day (<a href="https://doi.org/10.1530/acta.0.1010592">Fåhraeus &amp; Larsson-Cohn, 1982</a>; <a href="https://files.transfemscience.org/pdfs/Kuhl%20(1998)%20-%20Adverse%20Effects%20of%20Estrogen%20Treatment_%20Natural%20versus%20Synthetic%20Estrogens.pdf">Kuhl, 1998</a>; <a href="https://doi.org/10.1210/jc.2005-0173">Gibney et al., 2005</a>; <a href="https://doi.org/10.1210/jc.2005-0352">Ropponen et al., 2005</a>). Hence, although oral EE may have roughly 3- to 5-fold higher liver potency than oral estradiol, a dose of oral estradiol near-equivalent to that of oral EE in terms of general estrogenic effect can increase SHBG levels to an extent that is only somewhat lower in comparison.</p>
|
||
|
||
<h3 id="selective-estrogen-receptor-modulators-and-metabolism-resistance">Selective Estrogen Receptor Modulators and Metabolism Resistance</h3>
|
||
|
||
<p>SERMs like tamoxifen and raloxifene are essentially <a href="https://en.wikipedia.org/wiki/Partial_agonist">partial agonists</a> of the ER. This is in contrast to estrogens—like estradiol, CEEs, EE, and DES—which act as <a href="https://en.wikipedia.org/wiki/Full_agonist">full agonists</a> of the ER. Similarly to nonsteroidal estrogens like DES, the clinically used SERMs are all nonsteroidal in structure and are strongly resistant to hepatic metabolism. In fact, certain SERMs, like tamoxifen and <a href="https://en.wikipedia.org/wiki/Clomifene">clomifene</a>, are structurally related to and were derived from DES. SERMs show <a href="https://en.wikipedia.org/wiki/Tissue_selectivity">tissue differences</a> in their ER-mediated effects, with estrogenic effects in some tissues (e.g., bone) and <a href="https://en.wikipedia.org/wiki/Antiestrogen">antiestrogenic</a> effects in other tissues (e.g., breasts) (<a href="/articles/serms-transfem/">Lain, 2019</a>; <a href="https://en.wikipedia.org/wiki/Template:Tissue-specific_estrogenic_and_antiestrogenic_activity_of_SERMs">Table</a>). Although there is variation between SERMs in terms of their effects in certain tissues (e.g., uterus), they are uniformly estrogenic in the liver. Consequently, SERMs show similar increases in blood clot risk as estrogens (<a href="https://doi.org/10.1016/S1471-4914(02)02282-7">Park &amp; Jordan, 2002</a>; <a href="https://doi.org/10.1200/JCO.2005.11.005">Fabian &amp; Kimler, 2005</a>). As with non-bioidentical estrogens, the greater risk of blood clots with SERMs compared to oral estradiol can be attributed to their resistance to liver metabolism and hence to greater hepatic estrogenic potency. The SERMs that are used medically belong to diverse structural families (e.g., <a href="https://en.wikipedia.org/wiki/Triphenylethylene">triphenylethylenes</a> like tamoxifen and <a href="https://en.wikipedia.org/wiki/Benzothiophene">benzothiophenes</a> like raloxifene). The only way in which SERMs of different structural classes are known to be related is in their shared interactions with the ERs.</p>
|
||
|
||
<table>
|
||
<thead>
|
||
<tr>
|
||
<th><img src="/assets/images/tamox+ralox-structures.png" alt="" /></th>
|
||
</tr>
|
||
</thead>
|
||
<tbody>
|
||
<tr>
|
||
<td><strong>Figure 3:</strong> Chemical structures of selected SERMs. They are nonsteroidal in structure and include tamoxifen (a triphenylethylene) and raloxifene (a benzothiophene).</td>
|
||
</tr>
|
||
</tbody>
|
||
</table>
|
||
|
||
<h3 id="activation-of-the-estrogen-receptor-is-specifically-responsible-for-increased-coagulation-with-estrogens-and-serms">Activation of the Estrogen Receptor is Specifically Responsible for Increased Coagulation with Estrogens and SERMs</h3>
|
||
|
||
<p>Findings from preclinical and genetic research provide direct evidence for ER activation being responsible for the increased blood clot risk with estrogens. In an important animal study, EE was administered to mice and changes in procoagulant and anticoagulant biomarkers were measured (<a href="https://doi.org/10.1111/j.1538-7836.2010.03930.x">Cleuren et al., 2010</a>). EE caused changes in levels of a variety of coagulation factors (<a href="https://doi.org/10.1111/j.1538-7836.2010.03930.x">Cleuren et al., 2010</a>). The researchers also assessed estradiol and observed comparable changes (<a href="https://doi.org/10.1111/j.1538-7836.2010.03930.x">Cleuren et al., 2010</a>). Co-administration of the selective ER full antagonist <a href="https://en.wikipedia.org/wiki/Fulvestrant">fulvestrant</a> with EE neutralized all of the EE-induced coagulatory changes (<a href="https://doi.org/10.1111/j.1538-7836.2010.03930.x">Cleuren et al., 2010</a>). Additionally, EE showed no effect on coagulation factors in <a href="https://en.wikipedia.org/wiki/ERα">ERα</a> knockout mice (<a href="https://doi.org/10.1111/j.1538-7836.2010.03930.x">Cleuren et al., 2010</a>). These findings are consistent with human and mouse <a href="https://en.wikipedia.org/wiki/Genome-wide_association_study">genome-wide association studies</a> which have found <a href="https://en.wikipedia.org/wiki/Estrogen_response_element">estrogen response elements</a> (EREs)—DNA sequences that act as binding sites for genes regulated by the ER—embedded in a large number of genes involved in coagulatory pathways (<a href="https://doi.org/10.1111/j.1538-7836.2010.03930.x">Cleuren et al., 2010</a>; <a href="https://doi.org/10.1016/j.contraception.2016.07.007">Stanczyk, Mathews, &amp; Cortessis, 2017</a>).</p>
|
||
|
||
<p>The preceding findings are consistent with ER activation being responsible for increased coagulation and blood clot risk with estrogens and SERMs. This is in accordance with the fact that blood clot risk is a shared effect of selective ER agonists with highly diverse chemical structures, providing strong circumstantial support against a non-ER-mediated action of some sort being responsible (e.g., the weakly estrogenic metabolite estrone somehow mediating the blood clot risk with estradiol—<a href="https://doi.org/10.1111/j.1538-7836.2010.03953.x">Bagot et al., 2010</a>). Increased coagulation and blood clot risk can thus be regarded as class effects of estrogens and SERMs—provided sufficiently high liver exposure. Due to differences in susceptibility to liver metabolism however, different ER agonists show differences in their relative impact on coagulation. Owing to estradiol’s lack of resistance to metabolism and its robust inactivation in the liver, the dosage requirements for increased coagulation and blood clot risk with estradiol—particularly in the case of non-oral estradiol—are greater than with non-bioidentical estrogens. Hence, estradiol, especially when administered via non-oral routes, is a safer form of estrogen therapy than other estrogens.</p>
|
||
|
||
<h2 id="absolute-incidences-and-risk-factors">Absolute Incidences and Risk Factors</h2>
|
||
|
||
<p>States of estrogen and/or progestogen exposure, such as exogenous hormone administration and <a href="https://en.wikipedia.org/wiki/Pregnancy">pregnancy</a>, are of course established risk factors for blood clots in women. In healthy young individuals without relevant <a href="https://en.wikipedia.org/wiki/Risk_factor">risk factors</a> for blood clots however, the incidence of blood clots is rare even in situations of considerably increased risk due to hormones (<a href="https://pubmed.ncbi.nlm.nih.gov/16304352/">Rosendaal, 2005</a>). The absolute incidence of VTE in non-pregnant women is only 1 to 5 of every 10,000 women each year (i.e., 0.01–0.05% per year) (<a href="https://doi.org/10.1016/j.fertnstert.2016.09.027">PCASRM, 2017</a>; <a href="https://doi.org/10.1016/B978-0-323-46202-0.00031-5">Konkle &amp; Sood, 2019</a>). EE-containing birth control pills, which on average increase VTE risk by about 4-fold, are associated with an incidence of VTE of only 3 to 9 of every 10,000 women each year (i.e., 0.03–0.09% per year) (<a href="https://doi.org/10.1016/B978-0-323-46202-0.00031-5">Konkle &amp; Sood, 2019</a>). Likewise, the absolute risk of blood clots during pregnancy, when estradiol and progesterone levels increase to extremely high concentrations and VTE risk is increased up to 7-fold (<a href="https://doi.org/10.1136/bmjopen-2015-008864">Abdul Sultan et al., 2015</a>), is about 5 to 20 of every 10,000 women each year (i.e., 0.05–0.2% per year) (<a href="https://doi.org/10.1016/j.fertnstert.2016.09.027">PCASRM, 2017</a>; <a href="https://doi.org/10.1016/B978-0-323-46202-0.00031-5">Konkle &amp; Sood, 2019</a>).</p>
|
||
|
||
<p><strong>Table 5:</strong> Absolute incidences of VTE with different estrogenic exposures in premenopausal women (<a href="https://doi.org/10.1093/oxfordjournals.aje.a115799">Gerstman et al., 1991</a>; <a href="https://doi.org/10.1016/B978-0-323-46202-0.00031-5">Konkle &amp; Sood, 2019</a>; <a href="https://doi.org/10.1055/s-0040-1714140">Douxfils, Morimont, &amp; Bouvy, 2020</a>):</p>
|
||
|
||
<table>
|
||
<thead>
|
||
<tr>
|
||
<th>Group/therapy</th>
|
||
<th>Incidence (women per year)</th>
|
||
</tr>
|
||
</thead>
|
||
<tbody>
|
||
<tr>
|
||
<td>Non-pregnant women</td>
|
||
<td>1 to 5 in 10,000 (0.01–0.05%)<sup>a</sup></td>
|
||
</tr>
|
||
<tr>
|
||
<td>Modern birth control pills (&lt;50 μg/day EE)</td>
|
||
<td>3 to 12 in 10,000 (0.03–0.09%)</td>
|
||
</tr>
|
||
<tr>
|
||
<td>High-dose birth control pills (&gt;50 μg/day EE)</td>
|
||
<td>~10 in 10,000 (0.1%)</td>
|
||
</tr>
|
||
<tr>
|
||
<td>Pregnancy</td>
|
||
<td>5 to 20 in 10,000 (0.05–0.2%)</td>
|
||
</tr>
|
||
<tr>
|
||
<td>Postpartum period</td>
|
||
<td>40 to 65 in 10,000 (0.4–0.65%)</td>
|
||
</tr>
|
||
</tbody>
|
||
</table>
|
||
|
||
<p><small><sup>a</sup> 1–2/10,000 per year at &lt;19 years of age, 2–3/10,000 per year at 20–29 years of age, 3–4/10,000 per year at 30–39 years of age, 5–7/10,000 per year at 40–49 years of age; roughly 3–4/10,000 per year for age 15–49 years overall (<a href="https://www.kup.at/journals/summary/10169.html">Rabe et al., 2011</a>).</small></p>
|
||
|
||
<p>In any case, the risks of VTE and cardiovascular events with high estrogen exposure accumulate over time and add up on a population scale. It is estimated that 22,000 instances of VTE occur due to birth control pills in Europe each year (<a href="https://doi.org/10.1016/j.thromres.2020.08.006">Morimont, Dogné, &amp; Douxfils, 2020</a>) and that 300 to 400 healthy young women die due to blood clots caused by birth control pills in the United States every year (<a href="https://doi.org/10.1177/0024363918816683">Keenan, Kerr, &amp; Duane, 2019</a>). Notably, non-EE-containing birth control pills—which instead of EE contain estradiol or <a href="https://en.wikipedia.org/wiki/Estetrol_(medication)">estetrol</a>—appear to have considerably reduced procoagulatory effects and/or risk of blood clots in comparison, and if they become more established, will likely eliminate a substantial number of these cases (<a href="https://doi.org/10.1016/j.contraception.2012.12.011">Stanczyk, Archer, &amp; Bhavnani, 2013</a>; <a href="https://doi.org/10.1016/j.contraception.2016.06.010">Dinger, Minh, &amp; Heinemann, 2016</a>; <a href="https://doi.org/10.1080/13625187.2017.1372571">Grandi, Facchinetti, &amp; Bitzer, 2017</a>; <a href="https://doi.org/10.2147/OAJC.S179673">Fruzzetti &amp; Cagnacci, 2018</a>; <a href="https://doi.org/10.1080/17446651.2019.1604217">Grandi et al., 2019</a>; <a href="https://doi.org/10.1080/17512433.2020.1750365">Grandi et al., 2020</a>; <a href="https://doi.org/10.1055/s-0040-1714140">Douxfils, Morimont, &amp; Bouvy, 2020</a>; <a href="https://doi.org/10.1055/a-1153-5824">Reda et al., 2020</a>; <a href="https://doi.org/10.3389/fendo.2021.769187">Morimont et al., 2021</a>; <a href="https://doi.org/10.1080/13625187.2022.2029397">Grandi, Facchinetti, Bitzer, 2022</a>).</p>
|
||
|
||
<p>In addition to time and population considerations, there are, besides estrogen and progestogen exposure, a variety of other known risk factors for blood clots, and these risk factors can substantially augment blood clot risk (<a href="https://doi.org/10.1001/archinte.160.6.809">Heit et al., 2000</a>; <a href="https://pubmed.ncbi.nlm.nih.gov/16304352/">Rosendaal, 2005</a>). Age is among the strongest of the known risk factors (<a href="https://pubmed.ncbi.nlm.nih.gov/16304352/">Rosendaal, 2005</a>; <a href="https://doi.org/10.1007/s11239-009-0365-8">Montagnana et al., 2010</a>). Moreover, age is uniquely notable as a risk factor in that it is one that eventually becomes relevant to everyone. The risk of blood clots increases on the order of 100-fold going from ≤15 years of age (incidence &lt;0.005–0.01% per year) to ≥80 years of age (incidence ~0.5–1.0% per year) (<a href="https://pubmed.ncbi.nlm.nih.gov/16304352/">Rosendaal, 2005</a>; <a href="https://doi.org/10.1007/s11239-009-0365-8">Montagnana et al., 2010</a>; <a href="https://www.kup.at/journals/summary/10169.html">Rabe et al., 2011</a>). The figure below provides a graphical representation of the influence of age on risk of blood clots.</p>
|
||
|
||
<table>
|
||
<thead>
|
||
<tr>
|
||
<th><img src="/assets/images/age-blood-clot-risk-gender.png" alt="" /></th>
|
||
</tr>
|
||
</thead>
|
||
<tbody>
|
||
<tr>
|
||
<td><strong>Figure 4:</strong> Risk of first-incidence VTE (per 100,000 per year) by age group (in years) in men (black bars) and women (gray bars) (<a href="https://doi.org/10.1055/s-0037-1613887">Oger, 2000</a>; <a href="https://pubmed.ncbi.nlm.nih.gov/16304352/">Rosendaal, 2005</a>; <a href="https://doi.org/10.1186/s12959-016-0108-y">Rosendaal, 2016</a>).</td>
|
||
</tr>
|
||
</tbody>
|
||
</table>
|
||
|
||
<p>Other established risk factors for blood clots and associated cardiovascular problems include physical inactivity (due to, e.g., bed rest, long-distance travel, etc.), obesity, smoking, <a href="https://en.wikipedia.org/wiki/Thrombophilia">thrombophilic abnormalities</a>, cancer, surgery, and HIV, among many others (<a href="https://doi.org/10.1016/S0140-6736(97)10018-6">Baron et al., 1998</a>; <a href="https://doi.org/10.1001/archinte.160.6.809">Heit et al., 2000</a>; <a href="https://pubmed.ncbi.nlm.nih.gov/16304352/">Rosendaal, 2005</a>; <a href="https://doi.org/10.1111/j.1365-2141.2010.08206.x">Lijfering, Rosendaal, &amp; Cannegieter, 2010</a>; <a href="https://doi.org/10.1182/blood-2013-04-460121">Timp et al., 2013</a>). In addition to age, physical inactivity is one of the most important risk factors for blood clots and mediates the risk increases for many of the others (<a href="https://pubmed.ncbi.nlm.nih.gov/16304352/">Rosendaal, 2005</a>). Smoking on its own is not consistently associated with increased risk of VTE (<a href="https://doi.org/10.1111/j.1365-2141.2010.08206.x">Lijfering, Rosendaal, &amp; Cannegieter, 2010</a>), but in combination with EE-containing birth control pills has been associated with a synergistic increase in VTE risk (<a href="https://doi.org/10.1002/ajh.21059">Pomp, Rosendaal, &amp; Doggen, 2008</a>) as well as large increases in risk of heart attack—for instance 20-fold higher risk in heavy smokers (<a href="https://files.transfemscience.org/pdfs/Kuhl%20(1999)%20-%20Hormonal%20Contraception%20%5BIn%20Estrogens%20and%20Antiestrogens%20II%20-%20Pharmacology%20and%20Clinical%20Application%20of%20Estrogens%20and%20Antiestrogens%20(Lauritzen%20et%20al.,%201999)%5D.pdf#page=3">Kuhl, 1999</a>). The table below shows the influence of a selection of known risk factors for VTE:</p>
|
||
|
||
<p><strong>Table 6:</strong> Non-exogenous-hormone risk factors for VTE and relative VTE risk increases (<a href="https://doi.org/10.1016/S0140-6736(97)10018-6">Baron et al., 1998</a>; <a href="https://doi.org/10.1001/archinte.160.6.809">Heit et al., 2000</a>; <a href="https://pubmed.ncbi.nlm.nih.gov/16304352/">Rosendaal, 2005</a>; <a href="https://doi.org/10.1111/j.1365-2141.2010.08206.x">Lijfering, Rosendaal, &amp; Cannegieter, 2010</a>; <a href="https://doi.org/10.1182/blood-2013-04-460121">Timp et al., 2013</a>):</p>
|
||
|
||
<htmlprotect>
|
||
<div style="max-width: 400px;">
|
||
<table>
|
||
<tbody>
|
||
<tr>
|
||
<th><b>Risk factor</b></th>
|
||
<th><b>Relative risk</b></th>
|
||
</tr>
|
||
<tr>
|
||
<td>Age</td>
|
||
<td>1–∞×</td>
|
||
</tr>
|
||
<tr>
|
||
<td>Cancer</td>
|
||
<td>2–20×<sup>a</sup></td>
|
||
</tr>
|
||
<tr>
|
||
<td>HIV</td>
|
||
<td>3–10×</td>
|
||
</tr>
|
||
<tr>
|
||
<td>Overweightness/obesity</td>
|
||
<td>2–3×</td>
|
||
</tr>
|
||
<tr>
|
||
<td>Surgery, trauma, immobilization</td>
|
||
<td>5–50×</td>
|
||
</tr>
|
||
<tr>
|
||
<td>Bed rest at home</td>
|
||
<td>9×</td>
|
||
</tr>
|
||
<tr>
|
||
<td>Air travel</td>
|
||
<td>1.5–3×</td>
|
||
</tr>
|
||
<tr>
|
||
<td>Smoking</td>
|
||
<td>0.8–1.5×<sup>b</sup></td>
|
||
</tr>
|
||
<tr>
|
||
<td>Varicose veins</td>
|
||
<td>1–4×</td>
|
||
</tr>
|
||
<tr>
|
||
<td>Pregnancy</td>
|
||
<td>4×</td>
|
||
</tr>
|
||
<tr>
|
||
<td>Postpartum</td>
|
||
<td>15–20×</td>
|
||
</tr>
|
||
</tbody>
|
||
</table>
|
||
</div>
|
||
</htmlprotect>
|
||
|
||
<p><small><sup>a</sup> Varies by type and stage of cancer (<a href="https://doi.org/10.1016/S0140-6736(97)10018-6">Baron et al., 1998</a>; <a href="https://doi.org/10.1182/blood-2013-04-460121">Timp et al., 2013</a>). For breast and prostate cancer, one study found a 1.8-fold greater risk for breast cancer and 4.2-fold greater risk for prostate cancer relative to the general population (<a href="https://doi.org/10.1016/S0140-6736(97)10018-6">Baron et al., 1998</a>). <sup>b</sup> Smoking on its own is not consistently associated with VTE (<a href="https://doi.org/10.1111/j.1365-2141.2010.08206.x">Lijfering, Rosendaal, &amp; Cannegieter, 2010</a>; <a href="https://www.kup.at/journals/summary/10169.html">Rabe et al., 2011</a>).</small></p>
|
||
|
||
<p>Thrombophilias, heritable and acquired, exist in significant percentages of the population and can lead to large increases in blood clot risk (<a href="https://doi.org/10.1111/j.1365-2141.2010.08206.x">Lijfering, Rosendaal, &amp; Cannegieter, 2010</a>). Moreover, they are often if not usually unknown (<a href="https://doi.org/10.1016/j.thromres.2020.08.006">Morimont, Dogné, &amp; Douxfils, 2020</a>). This is due to the fact that screening for heritable thrombophilias is mainly based on family history, which has low sensitivity and poor predictive value for identifying people with these abnormalities (<a href="https://doi.org/10.1016/j.thromres.2020.08.006">Morimont, Dogné, &amp; Douxfils, 2020</a>). Hence, many people are at increased risk of blood clots without realizing it. The table below shows the prevalences of a variety of thrombophilic abnormalities and their impacts on blood clot risk.</p>
|
||
|
||
<p><strong>Table 7:</strong> Prevalences of thrombophilic abnormalities and relative risk of VTE (<a href="https://doi.org/10.1016/b978-0-7020-4087-0.00071-1">Martinelli, Passamonti, &amp; Bucciarelli, 2014</a>; <a href="https://doi.org/10.1160/TH15-02-0141">Mannucci &amp; Franchini, 2015</a>; see also <a href="https://doi.org/10.1002/9781444306286.ch24">Walker, 2009</a>; <a href="https://doi.org/10.1016/B978-0-323-46202-0.00031-5">Konkle &amp; Sood, 2019</a>).</p>
|
||
|
||
<htmlprotect>
|
||
<table>
|
||
<tbody>
|
||
<tr>
|
||
<th rowspan="2"><strong>Thrombophilia</strong></th>
|
||
<th colspan="2"><strong>Prevalence</strong></th>
|
||
<th colspan="2"><strong>Relative risk</strong></th>
|
||
</tr>
|
||
<tr>
|
||
<th><strong>General population</strong></th>
|
||
<th><strong>People with VTE</strong></th>
|
||
<th><strong>First VTE</strong></th>
|
||
<th><strong>Recurrent VTE</strong></th>
|
||
</tr>
|
||
<tr>
|
||
<td><a href="https://en.wikipedia.org/wiki/Antithrombin_deficiency">Antithrombin deficiency</a></td>
|
||
<td>0.02–0.2%</td>
|
||
<td>1%</td>
|
||
<td>50×</td>
|
||
<td>2.5×</td>
|
||
</tr>
|
||
<tr>
|
||
<td><a href="https://en.wikipedia.org/wiki/Protein_C_deficiency">Protein C deficiency</a></td>
|
||
<td>0.2–0.4%</td>
|
||
<td>3%</td>
|
||
<td>15×</td>
|
||
<td>2.5×</td>
|
||
</tr>
|
||
<tr>
|
||
<td><a href="https://en.wikipedia.org/wiki/Protein_S_deficiency">Protein S deficiency</a></td>
|
||
<td>0.03–0.1%</td>
|
||
<td>2%</td>
|
||
<td>10×</td>
|
||
<td>2.5×</td>
|
||
</tr>
|
||
<tr>
|
||
<td><a href="https://en.wikipedia.org/wiki/Factor_V_Leiden">Factor V Leiden</a> (het.)</td>
|
||
<td>5%</td>
|
||
<td>20%</td>
|
||
<td>7×</td>
|
||
<td>1.5×</td>
|
||
</tr>
|
||
<tr>
|
||
<td><a href="https://en.wikipedia.org/wiki/Factor_V_Leiden">Factor V Leiden</a> (homo.)</td>
|
||
<td>0.02%</td>
|
||
<td>1.5%</td>
|
||
<td>80×</td>
|
||
<td>–</td>
|
||
</tr>
|
||
<tr>
|
||
<td><a href="https://en.wikipedia.org/wiki/Prothrombin_G20210A">Prothrombin G20210A</a> (het.)</td>
|
||
<td>2%</td>
|
||
<td>6%</td>
|
||
<td>3–4×</td>
|
||
<td>1.5×</td>
|
||
</tr>
|
||
<tr>
|
||
<td><a href="https://en.wikipedia.org/wiki/Prothrombin_G20210A">Prothrombin G20210A</a> (homo.)</td>
|
||
<td>0.02%</td>
|
||
<td>&lt;1%</td>
|
||
<td>30×</td>
|
||
<td>–</td>
|
||
</tr>
|
||
<tr>
|
||
<td><a href="https://en.wikipedia.org/wiki/Blood_type">Non-O blood group</a></td>
|
||
<td>55–57%</td>
|
||
<td>75%</td>
|
||
<td>2×</td>
|
||
<td>2×</td>
|
||
</tr>
|
||
<tr>
|
||
<td><a href="https://en.wikipedia.org/wiki/Antiphospholipid_syndrome">Antiphospholipid antibodies</a></td>
|
||
<td>1–2%</td>
|
||
<td>5–15%</td>
|
||
<td>11×</td>
|
||
<td>?</td>
|
||
</tr>
|
||
<tr>
|
||
<td><a href="https://en.wikipedia.org/wiki/Hyperhomocysteinemia">Hyperhomocysteinemia</a></td>
|
||
<td>5%</td>
|
||
<td>10–15%</td>
|
||
<td>1.5×</td>
|
||
<td>?</td>
|
||
</tr>
|
||
</tbody>
|
||
</table>
|
||
</htmlprotect>
|
||
|
||
<p>Blood clots are considered to be a multicausal disease (<a href="https://pubmed.ncbi.nlm.nih.gov/16304352/">Rosendaal, 2005</a>). The risk of blood clots and associated cardiovascular complications with hormonal exposure is highest when multiple risk factors combine in a given individual. Under what are among the most extreme of circumstances in terms of risk—elderly people with cancer who are on high-dose oral synthetic estrogen therapy (e.g., DES)—blood clot incidence can be as high as 15 to 28% and overall incidence of cardiovascular complications as great as 35% (<a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4052190/">Phillips et al., 2014</a>; <a href="https://doi.org/10.1111/iju.12613">Sciarria et al., 2014</a>; <a href="https://doi.org/10.3109/21681805.2013.861508">Turo et al., 2014</a>). These adverse effects contribute to substantial morbidity and incidence of death in these populations. Most people are however at nowhere near as great of risk. Risk factors like age are why pregnant women can have massive levels of estradiol and progesterone with relatively little issue whereas elderly cancer patients on high-dose oral synthetic estrogen therapy have a considerable risk of death.</p>
|
||
|
||
<p>In the VUMC studies that found 20- to 45-fold increased incidence of blood clots with high-dose EE and CPA over 5 to 10 years in transfeminine people, the absolute incidence of blood clots was approximately 6.3% (142/10,000 people per year) in the 1989 report and 5.5% (58/10,000 people per year) in the 1997 follow up (<a href="https://doi.org/10.1016/0026-0495(89)90233-3">Asscheman, Gooren, &amp; Eklund, 1989</a>; <a href="https://doi.org/10.1046/j.1365-2265.1997.2601068.x">van Kesteren et al., 1997</a>; <a href="https://doi.org/10.1111/and.12150">Asscheman et al., 2014</a>; <a href="https://doi.org/10.2147/JBM.S166780">Goldstein et al., 2019</a>; <a href="https://doi.org/10.1007/978-3-030-18533-6_3">Min &amp; Hopkins, 2021</a>). In keeping with the known influence of age on blood clot risk, the absolute incidence was 2.1% in those under 40 years of age and 12% in those over 40 years of age in the 1989 study (<a href="https://doi.org/10.1016/0026-0495(89)90233-3">Asscheman, Gooren, &amp; Eklund, 1989</a>; <a href="https://doi.org/10.1111/and.12150">Asscheman et al., 2014</a>). In about 70% of cases, there were—aside from age—no known risk factors for blood clots (<a href="https://doi.org/10.1016/0026-0495(89)90233-3">Asscheman, Gooren, &amp; Eklund, 1989</a>; <a href="https://doi.org/10.1111/and.12150">Asscheman et al., 2014</a>). Following subsequent replacement of EE with low-to-moderate-dose transdermal estradiol in those over 40 years of age, the incidence of blood clots decreased substantially (with only one event occurring in the transdermal estradiol group) (<a href="https://doi.org/10.1046/j.1365-2265.1997.2601068.x">van Kesteren et al., 1997</a>; <a href="https://doi.org/10.1111/and.12150">Asscheman et al., 2014</a>; <a href="https://doi.org/10.1007/978-3-030-18533-6_3">Min &amp; Hopkins, 2021</a>). A later study in 2013 by the <a href="https://en.wikipedia.org/wiki/Ghent_University_Hospital">Ghent University Hospital</a> in Belgium observed a blood clot incidence of 5.1% in transfeminine people using mostly oral or transdermal estradiol with or without CPA over an average treatment period of 7.7 years (range 3 months to 35 years) (<a href="https://doi.org/10.1530/EJE-13-0493">Wierckx et al., 2013</a>; <a href="https://doi.org/10.1007/978-3-030-18533-6_3">Min &amp; Hopkins, 2021</a>). Those who had blood clots often had other risk factors such as older age, smoking, immoblization due to surgery, or hypercoagulability (<a href="https://doi.org/10.1530/EJE-13-0493">Wierckx et al., 2013</a>; <a href="https://doi.org/10.1007/978-3-030-18533-6_3">Min &amp; Hopkins, 2021</a>). In addition to cumulative exposure time, these studies further highlight the converging impact of multiple risk factors—with estrogen type, route, and dose, progestogen exposure, and age included among them—on the risk of blood clots.</p>
|
||
|
||
<h2 id="therapeutic-implications-for-transfeminine-people">Therapeutic Implications for Transfeminine People</h2>
|
||
|
||
<p>Due to their greater risk of blood clots and cardiovascular problems, non-bioidentical estrogens like EE and CEEs are mostly no longer used in transfeminine people. Instead, estradiol, both in oral and non-oral forms, is used. Transgender clinical guidelines generally recommend keeping estradiol levels within normal physiological ranges for non-pregnant females of around 100 to 200 pg/mL regardless of whether the route of administration of estradiol is oral or non-oral (<a href="/articles/transfem-intro/#normal-hormone-levels">Aly, 2018</a>). Higher estradiol levels are not currently known to have greater therapeutic benefit in terms of feminization or breast development (<a href="https://doi.org/10.1089/trgh.2020.0077">Nolan &amp; Cheung, 2020</a>). However, higher levels, in the range of 200 to 500 pg/mL, can provide additional therapeutic effect in the area of testosterone suppression—which can be indirectly beneficial to feminization if otherwise inadequate (<a href="/articles/transfem-intro/#gonadal-suppression">Aly, 2018</a>). Despite their recommendations for keeping estradiol levels in physiological ranges, transgender clinical guidelines notably recommend doses of estradiol ester injections that reach and even greatly exceed estradiol levels of 200 pg/mL (<a href="/articles/injectable-e2-meta-analysis/#insights-for-clinical-guidelines-and-dosing-recommendations">Aly, 2021</a>).</p>
|
||
|
||
<p>Based on the available research (e.g., the risk of blood clots with lower doses, comparative SHBG increases), it would not be surprising if high-dose oral estradiol (e.g., 8 mg/day) had similar risk of blood clots as the relatively lower amounts of EE in birth control pills. The risk is likely to be particularly great in combination with progestogens (e.g., CPA). Due to its greater and unnecessary risk of blood clots relative to non-oral estradiol, oral estradiol should ideally be avoided in transfeminine people—particularly in those with risk factors for blood clots such as older age (e.g., &gt;40 years) or concomitant progestogen use. However, the convenience of oral estradiol and its relative inexpensiveness (compared to e.g. transdermal forms) are significant advantages that will also be considered by transfeminine people and their clinicians. In contrast to oral estradiol, non-oral estradiol—with estradiol levels kept in physiological ranges of for instance 100 to 200 pg/mL—appears to have minimal to no risk of blood clots. Hence, non-oral estradiol at these levels can be used in transfeminine people with little concern.</p>
|
||
|
||
<p>In terms of higher estradiol levels delivered non-orally, the estimated 2-fold increase in risk of blood clots with estradiol levels of approximately 300 to 500 pg/mL (<a href="/articles/pep-cardiovascular-analysis/">Sam, 2020</a>) is notably lower than the average 4-fold increase in risk with widely used EE-containing birth control pills. Based on the usefulness of these levels for suppressing testosterone production and the widespread usage of EE-based birth control in cisgender women throughout the world, the degree of blood clot risk with high-dose non-oral estradiol, in reasonable amounts, could be considered therapeutically acceptable in transfeminine people (<a href="https://doi.org/10.1002/14651858.CD013138.pub2">Haupt et al., 2020</a>). This may be particularly true when high-dose non-oral estradiol monotherapy is compared to combination of estradiol with antiandrogens like <a href="https://en.wikipedia.org/wiki/Spironolactone">spironolactone</a>, CPA, or <a href="https://en.wikipedia.org/wiki/Bicalutamide">bicalutamide</a>, which all have their own unique risks and drawbacks. In any case, as with oral estradiol, high estradiol levels with non-oral estradiol should ideally be avoided due to the additional risk they pose, and this is especially true in those with relevant risk factors for blood clots (e.g., older age). In addition, very high doses of non-oral estradiol resulting in estradiol levels above those required for testosterone suppression are difficult to justify as they pose further unnecessary risk and offer no clear additional therapeutic benefit.</p>
|
||
|
||
<h2 id="prevention-of-blood-clots">Prevention of Blood Clots</h2>
|
||
|
||
<p>The best way to prevent blood clots from happening is to avoid risk altogether. Avoiding use of oral estradiol, excessively high doses of non-oral estradiol, and progestogens when feasible and opting for safer therapeutic choices is recommended in this regard. In addition, avoiding use of such therapies in those with risk factors like older age (&gt;40 years), known thrombophilic abnormalities, and sedentary lifestyle is advocated. Proactive behaviors like physical activity (e.g., <a href="https://en.wikipedia.org/wiki/Walking#Health_benefits">walking</a>, <a href="https://en.wikipedia.org/wiki/Exercise">exercise</a>), <a href="https://en.wikipedia.org/wiki/Smoking_cessation">quitting smoking</a>, and <a href="https://en.wikipedia.org/wiki/Weight_loss">weight loss</a> may help to reduce the risk of blood clots (<a href="https://books.google.com/books?id=hTKIxD4aJloC&amp;pg=PA351">Hibbs, 2008</a>).</p>
|
||
|
||
<p>Certain anticoagulant and <a href="https://en.wikipedia.org/wiki/Antiplatelet_drug">antiplatelet</a> medications are used to help prevent blood clots in high-risk individuals. Examples include low-dose <a href="https://en.wikipedia.org/wiki/Aspirin">aspirin</a> (<a href="https://doi.org/10.2147/TCRM.S92222">Mekaj, Daci, &amp; Mekaj, 2015</a>; <a href="https://doi.org/10.1001/jamainternmed.2019.6108">Matharu et al., 2020</a>), <a href="https://en.wikipedia.org/wiki/Direct_Xa_inhibitor">direct factor Xa inhibitors</a> like <a href="https://en.wikipedia.org/wiki/Rivaroxaban">rivaroxaban</a> (Xarelto) (<a href="https://ehaweb.org/assets/Uploads/Congresses/EHA25/Education-Book-Pre-release/HemaSphere-2020-0015.pdf">Blondon, 2020</a>), and <a href="https://en.wikipedia.org/wiki/Direct_thrombin_inhibitor">direct thrombin inhibitors</a> like <a href="https://en.wikipedia.org/wiki/Dabigatran">dabigatran</a> (Pradaxa), among others. Aspirin has been found to be effective in the prevention of blood clots (<a href="https://doi.org/10.2147/TCRM.S92222">Mekaj, Daci, &amp; Mekaj, 2015</a>; <a href="https://doi.org/10.1001/jamainternmed.2019.6108">Matharu et al., 2020</a>) and has been recommended for use specifically in transfeminine people on hormone therapy (<a href="https://web.archive.org/web/20210416001940/https://lgbtqpn.ca/wp-content/uploads/woocommerce_uploads/2014/08/Guidelines-primarycare.pdf">Feldman &amp; Goldberg, 2006</a>; <a href="https://transcare.ucsf.edu/sites/transcare.ucsf.edu/files/Transgender-PGACG-6-17-16.pdf#page=26">Deutsch, 2016</a>). However, evidence is limited and conflicting for prevention of blood clots related to hormone therapy (<a href="https://doi.org/10.7326/0003-4819-132-9-200005020-00002">Grady et al., 2000</a>; <a href="https://doi.org/10.1001/jama.292.13.1573">Cushman et al., 2004</a>) and use of aspirin in transfeminine people for such purposes has been recommended against by others (<a href="https://doi.org/10.1002/ajh.24593">Shatzel, Connelly, &amp; DeLoughery, 2017</a>). Rivaroxaban has been associated with more than completely offset risk of blood clots with oral menopausal hormonal therapy (<a href="https://ehaweb.org/assets/Uploads/Congresses/EHA25/Education-Book-Pre-release/HemaSphere-2020-0015.pdf">Blondon, 2020</a>). In any case, no anticoagulants are currently approved or well-supported for preventing risk of blood clots with hormone therapy. Accordingly, clinical guidelines state that there is insufficient evidence to guide decision-making in this area at this time (e.g., <a href="https://doi.org/10.1016/j.bpobgyn.2014.03.001">McLintock, 2014</a>). It should also be cautioned that anticoagulants have side effects and risks of their own and should be used carefully.</p>
|
||
|
||
<p><a href="https://en.wikipedia.org/wiki/Rutin">Rutin</a>, a naturally occurring <a href="https://en.wikipedia.org/wiki/Flavonoid">flavonoid</a> found in various plants and foods and available as a <a href="https://en.wikipedia.org/wiki/Herbal_supplement">herbal supplement</a>, has been suggested by some in the transfeminine community as a preventative against blood clots based on limited <a href="https://en.wikipedia.org/wiki/Preclinical_research">preclinical research</a> (<a href="https://doi.org/10.1172/JCI61228">Jasuja et al., 2012</a>; <a href="https://doi.org/10.1016/j.jbiosc.2014.12.012">Choi et al., 2015</a>). However, there is no clinical evidence to support its use or effectiveness at this time (e.g., <a href="https://doi.org/10.1002/14651858.CD003229.pub3">Martinez-Zapata et al., 2016</a>; <a href="https://doi.org/10.1002/14651858.CD005625.pub4">Morling et al., 2018</a>). <a href="https://en.wikipedia.org/wiki/Dose-ranging_study">Dose-finding studies</a> to determine appropriate doses for efficacy also have not been performed. Flavonoids like rutin are notably known to have unfavorable <a href="https://en.wikipedia.org/wiki/Pharmacokinetics">dispositions in the body</a> (e.g., very low bioavailability, high metabolism, short half-lives) and this has limited their usefulness by rendering them poorly active and therapeutically ineffective (<a href="https://doi.org/10.2174/1389200216666150206123719">Ma et al., 2014</a>; <a href="https://lpi.oregonstate.edu/mic/dietary-factors/phytochemicals/flavonoids">Higdon et al., 2016</a>; <a href="https://doi.org/10.3945/ajcn.116.136051">Cassidy &amp; Minihane, 2017</a>; <a href="https://doi.org/10.1016/j.ijpharm.2019.118642">Zhao, Yang, &amp; Xie, 2019</a>; <a href="https://doi.org/10.1039/d0fo03403g">Zhang et al., 2021</a>). Lastly, the tolerability and safety of rutin have not been evaluated. For these reasons, use of rutin to lower the risk of blood clots in transfeminine people cannot be recommended at this time.</p>
|
||
|
||
<p>Temporary discontinuation of estrogen therapy before surgery has traditionally been thought to help reduce the risk of blood clots during recovery based on theory and has been advised as well as mandated for transfeminine people undergoing surgical procedures (e.g., <a href="https://doi.org/10.1111/and.12150">Asscheman et al., 2014</a>). However, evidence is limited and inconclusive on this strategy at present and more research is needed to determine whether it is actually beneficial or not (<a href="https://doi.org/10.1001/jamasurg.2018.4598">Boskey, Taghinia, &amp; Ganor, 2019</a>; <a href="https://pubmed.ncbi.nlm.nih.gov/33005118/">Nolan &amp; Cheung, 2020</a>; <a href="https://doi.org/10.1097/SAP.0000000000002300">Haveles et al., 2021</a>; <a href="https://doi.org/10.1097/PRS.0000000000007786">Hontscharuk et al., 2021</a>; <a href="https://doi.org/10.1210/clinem/dgaa966">Kozato et al., 2021</a>; <a href="https://doi.org/10.1016/j.jsxm.2020.10.018">Nolan et al., 2021</a>; <a href="https://doi.org/10.1016/j.eprac.2021.03.010">Zucker, Reisman, &amp; Safer, 2021</a>). Recent studies have not found reduction in risk of blood clots with discontinuation of hormone therapy before surgery in transfeminine people but these studies have been underpowered and larger studies are needed (<a href="https://doi.org/10.1210/clinem/dgab243">Blasdel et al., 2021</a>). Temporarily stopping hormone therapy can be distressing for many transfeminine people and this should be weighed accordingly. A potential alternative to discontinuation of hormone therapy is temporary use of transdermal estradiol at physiological doses which has no known blood clot risk and is more likely to be safe.</p>
|
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|
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<h2 id="updates">Updates</h2>
|
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|
||
<h3 id="update-1-langley-et-al-2021-patch-study-results">Update 1: Langley et al. (2021) [PATCH Study Results]</h3>
|
||
|
||
<p>In February 2021, a report on long-term cardiovascular outcomes for the <a href="https://en.wikipedia.org/wiki/Prostate_Adenocarcinoma:_TransCutaneous_Hormones">Prostate Adenocarcinoma: TransCutaneous Hormones</a> (PATCH) trial was published (<a href="https://doi.org/10.1016/S0140-6736(21)00100-8">Langley et al., 2021</a>) [<a href="https://files.transfemscience.org/pdfs/Langley%20et%20al.%20(2021)%20-%20Transdermal%20Oestradiol%20for%20Androgen%20Suppression%20in%20Prostate%20Cancer.pdf">PDF</a>; <a href="https://files.transfemscience.org/pdfs/Langley%20et%20al.%20(2021)%20[Appendix]%20-%20Transdermal%20Oestradiol%20for%20Androgen%20Suppression%20in%20Prostate%20Cancer.pdf">Supplementary appendix</a>]. The PATCH trial is a large ongoing <a href="https://en.wikipedia.org/wiki/Phases_of_clinical_research#Phase_II">phase 2</a>/<a href="https://en.wikipedia.org/wiki/Phases_of_clinical_research#Phase_III">3</a> randomized controlled trial of high-dose transdermal estradiol patches versus GnRH agonists for the treatment of prostate cancer in men (<a href="https://doi.org/10.1016/S0140-6736(21)00100-8">Langley et al., 2021</a>). The estradiol patch dosage employed is specifically three to four 100 μg/day FemSeven or Progynova TS patches (<a href="https://doi.org/10.1016/S0140-6736(21)00100-8">Langley et al., 2021</a>). In the February 2021 report of the study, 1,694 men were enrolled and randomized, with 790 included in the analysis for the GnRH agonist group and 904 included in the analysis for the estradiol patch group (<a href="https://doi.org/10.1016/S0140-6736(21)00100-8">Langley et al., 2021</a>).</p>
|
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|
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<p>In those given estradiol, the median estradiol level was around 215 pg/mL (5%–95% range ~100–550 pg/mL) (<a href="https://doi.org/10.1016/S0140-6736(21)00100-8">Langley et al., 2021</a>). About 93% of the men in this group achieved suppression of testosterone levels into the castrate range (&lt;50 ng/dL), which was notably equal to the rate of suppression in the GnRH agonist group (~93%) (<a href="https://doi.org/10.1016/S0140-6736(21)00100-8">Langley et al., 2021</a>). However, actual testosterone levels—as opposed to rates of testosterone suppression—were not provided in this report and hence comparison between groups is unavailable for this metric (<a href="https://doi.org/10.1016/S0140-6736(21)00100-8">Langley et al., 2021</a>). After about 4 years median follow up, there were no significant differences on a variety of cardiovascular outcomes between the estradiol group and the GnRH agonist group (<a href="https://doi.org/10.1016/S0140-6736(21)00100-8">Langley et al., 2021</a>). Among these outcomes included VTE, <a href="https://en.wikipedia.org/wiki/Thromboembolic_stroke">thromboembolic stroke</a>, and other <a href="https://en.wikipedia.org/wiki/Arterial_embolism">arterial embolic events</a> (<a href="https://doi.org/10.1016/S0140-6736(21)00100-8">Langley et al., 2021</a>). These results are in contrast to previous large clinical trials of PEP in prostate cancer, which found increased cardiovascular morbidity and risk of VTE but notably involved higher estradiol levels than employed in the PATCH trial (<a href="https://doi.org/10.5173/ceju.2009.03.art1">Ockrim &amp; Abel, 2009</a>; <a href="/articles/pep-cardiovascular-analysis/">Sam, 2020</a>). Based on their promising safety findings, the PATCH researchers stated that transdermal estrogen should be reconsidered for the treatment of prostate cancer (<a href="https://doi.org/10.1016/S0140-6736(21)00100-8">Langley et al., 2021</a>).</p>
|
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|
||
<p>These findings are reassuring and suggest that limitedly high levels of estradiol (e.g., 200–300 pg/mL perhaps) may likewise be acceptably safe in terms of blood clot and cardiovascular risk in transfeminine people. It should be noted however that the <a href="https://en.wikipedia.org/wiki/Sample_size">sample size</a> of the trial, while large relative to previous clinical studies in this area, was underpowered for assessing risk of blood clots—which are relatively rare events that require very large samples to thoroughly quantify. Studies precisely assessing blood clot risk in peri- and postmenopausal women have included tens of thousands of individuals for instance. As such, while substantial increases in risk are not likely based on this trial, smaller increases in risk still cannot be ruled out at this time. It should additionally be noted that the robust testosterone suppression at the used doses in this study might not generalize to transfeminine people as a whole, as the men were mostly elderly and testosterone levels are known to decrease with age.</p>
|
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|
||
<h3 id="update-2-totaro-et-al-2021-and-kotamarti-et-al-2021">Update 2: Totaro et al. (2021) and Kotamarti et al. (2021)</h3>
|
||
|
||
<p>In November 2021, the following <a href="https://en.wikipedia.org/wiki/Systematic_review">systematic review</a> and <a href="https://en.wikipedia.org/wiki/Meta-analysis">meta-analysis</a> as well as <a href="https://en.wikipedia.org/wiki/Meta-regression">meta-regression</a> study of VTE risk with transfeminine hormone therapy was published:</p>
|
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|
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<ul>
|
||
<li>Totaro, M., Palazzi, S., Castellini, C., Parisi, A., D’Amato, F., Tienforti, D., Baroni, M. G., Francavilla, S., &amp; Barbonetti, A. (2021). Risk of Venous Thromboembolism in Transgender People Undergoing Hormone Feminizing Therapy: A Prevalence Meta-Analysis and Meta-Regression Study. <em>Frontiers in Endocrinology</em>, <em>12</em>, 741866. [DOI:<a href="https://doi.org/10.3389/fendo.2021.741866">10.3389/fendo.2021.741866</a>]</li>
|
||
</ul>
|
||
|
||
<p>This study is the largest of its kind that has been conducted to date. The meta-analysis included 18 studies totaling 11,542 transfeminine people on hormone therapy. The pooled prevalence of VTE was 2% with a 95% confidence interval of 1 to 3%. However, there was large variability between studies. In the meta-regression analysis, older age and longer length of estrogen therapy were significantly positively associated with VTE prevalence. When analysis was restricted to those greater than or equal to 37.5 years of age, the prevalence of VTE was 3% (95% CI: 0–5%). Conversely, in those less than 37.5 years of age, the prevalence of VTE was 0% (95% CI: 0–2%). VTE prevalence was 1% (95% CI: 0–3%) with greater than or equal to 4.4 years of estrogen therapy and was 0% (95% CI: 0–3%) with less than 4.4 years of estrogen therapy. With regard to the 0% estimates, it is not the case that there is truly no risk of VTE in these instances but rather it can be assumed that the risks are sufficiently low that the meta-analysis was not powered well enough to detect and quantify them.</p>
|
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|
||
<p>A limitation of the meta-analysis was that <a href="https://en.wikipedia.org/wiki/Subgroup_analysis">subgroup analyses</a> based on estrogen type (i.e., estradiol vs. CEEs vs. EE) and route (e.g., oral estrogens or oral estradiol vs. transdermal estradiol) were said to not be possible due to insufficient data and hence were not performed. However, another recent meta-analysis published in July 2021, which analyzed much of the same literature as <a href="https://doi.org/10.3389/fendo.2021.741866">Totaro et al. (2021)</a>, did perform subgroup analyses by estrogen type and route. This publication is as follows:</p>
|
||
|
||
<ul>
|
||
<li>Kotamarti, V. S., Greige, N., Heiman, A. J., Patel, A., &amp; Ricci, J. A. (2021). Risk for Venous Thromboembolism in Transgender Patients Undergoing Cross-Sex Hormone Treatment: A Systematic Review. <em>The Journal of Sexual Medicine</em>, <em>18</em>(7), 1280–1291. [DOI:<a href="https://doi.org/10.1016/j.jsxm.2021.04.006">10.1016/j.jsxm.2021.04.006</a>]</li>
|
||
</ul>
|
||
|
||
<p>And this is what they reported in terms of subgroup analyses for estrogen type and route:</p>
|
||
|
||
<blockquote>
|
||
<p>Because varying VTE rates have been reported with different estrogen regimens, analyses of VTE incidence were performed comparing oral or transdermal delivery, or the specific estrogen formulation. As many studies reported populations using mixed estrogen formulations or did not report the type of estrogen regimen, further statistical analysis could not be performed.</p>
|
||
</blockquote>
|
||
|
||
<blockquote>
|
||
<p>Route of estrogen administration appeared to play a role in the AMAB population. [Oral] estrogens (7 studies; 34.0 VTE per 10,000 person-years) vs transdermal estrogens (3 studies, 11.2 VTE per 10,000 person-years). Additionally, estrogen formulation also appeared to have a difference VTE incidence. Ethinyl estradiol was also associated with increased VTE incidence (3 studies, 293.1 VTE per 10,000 person-years) followed by conjugated equine estrogens (1 study, 49.0 VTE per 10,000 person-years) and estradiol valerate (4 studies, 31.5 VTE per 10,000 person-years).</p>
|
||
</blockquote>
|
||
|
||
<p>It is unclear how accurate these precise numbers are due to the quality limitations of the underlying data. Moreover, antiandrogens (e.g., CPA) were not controlled for and as discussed by this article are likely to additionally influence VTE risk. In any case, the reported numbers are interesting and are in accordance with different estrogen types and routes varying in terms of VTE risk.</p>
|
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|
||
<h2 id="references">References</h2>
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||
|
||
<ul>
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||
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<li>Wierckx, K., Elaut, E., Declercq, E., Heylens, G., De Cuypere, G., Taes, Y., Kaufman, J. M., &amp; T’Sjoen, G. (2013). Prevalence of cardiovascular disease and cancer during cross-sex hormone therapy in a large cohort of trans persons: a case–control study. <em>European Journal of Endocrinology</em>, <em>169</em>(4), 471–478. [DOI:<a href="https://doi.org/10.1530/eje-13-0493">10.1530/eje-13-0493</a>]</li>
|
||
<li>Writing Group for the Women’s Health Initiative Investigators. (2002). Risks and Benefits of Estrogen Plus Progestin in Healthy Postmenopausal Women: Principal Results From the Women’s Health Initiative Randomized Controlled Trial. <em>JAMA</em>, <em>288</em>(3), 321–333. [DOI:<a href="https://doi.org/10.1001/jama.288.3.321">10.1001/jama.288.3.321</a>]</li>
|
||
<li>Zhang, M., Zhu, S., Yang, W., Huang, Q., &amp; Ho, C. (2021). The biological fate and bioefficacy of citrus flavonoids: bioavailability, biotransformation, and delivery systems. <em>Food &amp; Function</em>, <em>12</em>(8), 3307–3323. [DOI:<a href="https://doi.org/10.1039/d0fo03403g">10.1039/d0fo03403g</a>]</li>
|
||
<li>Zhao, J., Yang, J., &amp; Xie, Y. (2019). Improvement strategies for the oral bioavailability of poorly water-soluble flavonoids: An overview. <em>International Journal of Pharmaceutics</em>, <em>570</em>, 118642. [DOI:<a href="https://doi.org/10.1016/j.ijpharm.2019.118642">10.1016/j.ijpharm.2019.118642</a>]</li>
|
||
<li>Zucker, R., Reisman, T., &amp; Safer, J. D. (2021). Minimizing Venous Thromboembolism in Feminizing Hormone Therapy: Applying Lessons From Cisgender Women and Previous Data. <em>Endocrine Practice</em>, <em>27</em>(6), 621–625. [DOI:<a href="https://doi.org/10.1016/j.eprac.2021.03.010">10.1016/j.eprac.2021.03.010</a>]</li>
|
||
</ul></content><author><name>{"first_name"=>"Aly", "last_name"=>"W.", "author-link"=>"/about/#aly", "articles-link"=>"/articles-by-author/aly/"}</name></author><category term="github" /><category term="workspace" /><summary type="html">Estrogens and Their Influences on Coagulation and Risk of Blood Clots By Aly | First published October 20, 2020 | Last modified March 28, 2023</summary></entry><entry><title type="html">The Interactions of Sex Hormones with Sex Hormone-Binding Globulin and Relevance for Transfeminine Hormone Therapy</title><link href="https://transfemscience.org/articles/shbg-unimportant/" rel="alternate" type="text/html" title="The Interactions of Sex Hormones with Sex Hormone-Binding Globulin and Relevance for Transfeminine Hormone Therapy" /><published>2020-07-10T15:45:23-07:00</published><updated>2023-03-25T00:00:00-07:00</updated><id>https://transfemscience.org/articles/shbg-unimportant</id><content type="html" xml:base="https://transfemscience.org/articles/shbg-unimportant/"><h1 id="the-interactions-of-sex-hormones-with-sex-hormone-binding-globulin-and-relevance-for-transfeminine-hormone-therapy">The Interactions of Sex Hormones with Sex Hormone-Binding Globulin and Relevance for Transfeminine Hormone Therapy</h1>
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<!-- Supports up to four authors per article currently (author, author2, author3, author4) -->
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<p>By
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<!-- First author --><a href="/about/#aly">Aly</a><!-- Second author --><!-- Third author --><!-- Fourth author --> | First published July 10, 2020
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| Last modified March 25, 2023</p>
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<h2 id="abstract--tldr">Abstract / TL;DR</h2>
|
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|
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<p>Sex hormones such as testosterone and estradiol bind to blood proteins like albumin and SHBG. This limits their biological activity by reducing their free fractions. Androgens decrease SHBG production while estrogens increase SHBG production. Hence, testosterone and estradiol can influence their own free fractions. Due to robust inactivation in the liver, testosterone and estradiol have relatively small influences on SHBG levels under normal physiological circumstances. At very high levels however, they can considerably influence SHBG levels. During pregnancy, when there are massive increases in estradiol levels (e.g., 100-fold), a maximal 5- to 10-fold elevation in SHBG levels occurs. Although large increases in SHBG levels can strongly limit the biological activity of testosterone, the situation with estradiol is different. In late pregnancy, the percentage of estradiol that is free appears to be decreased only to around 60% of that of non-pregnancy. Earlier in pregnancy, when estradiol levels are lower, the free fractions of estradiol are reduced to a lesser extent. At typical therapeutic levels of estradiol in transfeminine hormone therapy (&lt;200 pg/mL), the limiting influence of SHBG on free estradiol is minimal. Oral estradiol has a greater influence on SHBG production than non-oral estradiol and may be a different case however. In any case, consequent lesser activity of oral estradiol is only theoretical, and available clinical studies so far haven’t reported important therapeutic differences relative to non-oral estradiol. Although SHBG may reduce free estradiol fractions in some contexts, only relatively low estradiol levels (&lt;50 pg/mL) appear to be needed for maximal feminization and breast development in cisgender females and transfeminine people. In conclusion, the influence of SHBG on the effectiveness of estradiol isn’t something that should be a major source of concern in transfeminine hormone therapy.</p>
|
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|
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<h2 id="binding-of-sex-hormones-to-blood-proteins">Binding of Sex Hormones to Blood Proteins</h2>
|
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|
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<p><a href="http://en.wikipedia.org/wiki/Sex_hormone">Sex hormones</a> bind to proteins in the blood called <a href="http://en.wikipedia.org/wiki/Plasma_protein">plasma proteins</a>. This is a phenomenon known as <a href="https://en.wikipedia.org/wiki/Plasma_protein_binding">plasma protein binding</a>. In the case of androgens and estrogens, the plasma proteins they bind to are mainly <a href="https://en.wikipedia.org/wiki/Human_serum_albumin">albumin</a> and <a href="https://en.wikipedia.org/wiki/Sex_hormone-binding_globulin">sex hormone-binding globulin</a> (SHBG). Plasma protein binding serves to prevent sex hormones from interacting with their target cells and hence from binding to and activating their receptors (<a href="https://doi.org/10.1530/JOE-16-0070">Hammond, 2016</a>). This is because plasma proteins are too large and <a href="https://en.wikipedia.org/wiki/Lipophobicity">lipid-insoluble</a> to cross the lipid-rich <a href="http://en.wikipedia.org/wiki/Cell_membrane">cell membrane</a>. As a result, they’re unable to diffuse through <a href="https://en.wikipedia.org/wiki/Capillary">capillaries</a> to exit the circulation and enter into tissues or to be taken up into cells. When the sex hormone is bound to plasma protein, it can’t reach target cells either. Hence, plasma protein binding limits the biological activity of sex hormones (<a href="https://doi.org/10.1530/JOE-16-0070">Hammond, 2016</a>). Binding to plasma proteins also serves to extend the <a href="https://en.wikipedia.org/wiki/Biological_half-life">biological half-lives</a> of sex hormones. This is because protein-bound sex hormone is likewise unavailable for metabolism and elimination, processes that depend on cellular uptake.</p>
|
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|
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<p>There is only a single sex hormone binding site per molecule of SHBG (<a href="https://pubmed.ncbi.nlm.nih.gov/2469051/">Moore &amp; Bulbrook, 1988</a>), whereas albumin has six binding sites for different substrates (<a href="https://pubmed.ncbi.nlm.nih.gov/3072503/">Pardridge, 1988</a>). Androgens and estradiol have high affinity for SHBG (nM) and low affinity for albumin (μM) (<a href="https://pubmed.ncbi.nlm.nih.gov/2469051/">Moore &amp; Bulbrook, 1988</a>; <a href="https://doi.org/10.1530/JOE-16-0070">Hammond, 2016</a>). However, albumin levels are several orders of magnitude higher than SHBG levels (μM vs. nM), so this serves to balance out the fractions of sex hormone bound to each protein (<a href="https://doi.org/10.1530/JOE-16-0070">Hammond, 2016</a>). Androgens have higher affinities for SHBG than do estradiol or other estrogens. Estradiol has only about 10 to 20% of the affinity of dihydrotestosterone (DHT) and 33 to 50% of the affinity of testosterone for SHBG (<a href="https://doi.org/10.1111/j.1365-2265.1974.tb03298.x">Anderson, 1974</a>; <a href="https://aacrjournals.org/cancerres/article/38/11_Part_2/4186/482382/Unique-Steroid-Congeners-for-Receptor-Studies1">Ojasoo &amp; Raynaud, 1978</a>; <a href="https://doi.org/10.1210/jcem-53-1-69">Pugeat, Dunn, Nisula, 1981</a>). As such, testosterone and DHT bind more strongly to SHBG than does estradiol.</p>
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<p>The vast majority of sex hormone content in the blood is bound to plasma proteins; at any given time more than 97% of the testosterone, estradiol, and progesterone in the blood is plasma protein-bound (<a href="https://doi.org/10.1016/b978-0-323-47912-7.00004-4">Strauss &amp; FitzGerald, 2019</a>). The fraction of sex hormone that isn’t bound to plasma proteins is known as the <em>free</em> or <em>unbound</em> fraction. This is the fraction that is available for diffusion into cells and hence is considered to be biologically active (<a href="https://doi.org/10.1530/JOE-16-0070">Hammond, 2016</a>). <em>Total</em> levels refer to both free/unbound and bound hormone. <em>Bioavailable</em> levels include both albumin-bound and free hormone levels. Due to their relatively weak affinity for albumin, sex hormones bound to albumin may to some extent be biologically active—hence the “bioavailable” descriptor (<a href="https://www.jle.com/10.1684/abc.2008.0259">Nguyen et al., 2008</a>). However, more research is needed to fully elucidate the biological activity of albumin-bound sex hormone fractions.</p>
|
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|
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<p>The relative calculated free and bound percentages of estradiol, testosterone, and DHT to albumin, SHBG, and another plasma protein known as <a href="https://en.wikipedia.org/wiki/Corticosteroid-binding_globulin">corticosteroid-binding globulin</a> (CBG) (only binds small fractions of the androgens and has no binding to estradiol) are shown in the table below.</p>
|
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|
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<p><strong>Table 1:</strong> Calculated plasma protein binding of sex hormones (<a href="https://doi.org/10.1210/jcem-53-1-58">Dunn, Nisula, &amp; Rodbard, 1981</a>):</p>
|
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|
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<table>
|
||
<thead>
|
||
<tr>
|
||
<th>Hormone</th>
|
||
<th>Group</th>
|
||
<th>Albumin (%)</th>
|
||
<th>SHBG (%)</th>
|
||
<th>CBG (%)</th>
|
||
<th>Free (%)</th>
|
||
</tr>
|
||
</thead>
|
||
<tbody>
|
||
<tr>
|
||
<td>Estradiol</td>
|
||
<td>Women (follicular)</td>
|
||
<td>60.8</td>
|
||
<td>37.3</td>
|
||
<td>&lt;0.1</td>
|
||
<td>1.81</td>
|
||
</tr>
|
||
<tr>
|
||
<td> </td>
|
||
<td>Women (luteal)</td>
|
||
<td>61.1</td>
|
||
<td>37.0</td>
|
||
<td>&lt;0.1</td>
|
||
<td>1.82</td>
|
||
</tr>
|
||
<tr>
|
||
<td> </td>
|
||
<td>Women (pregnant)</td>
|
||
<td>11.7</td>
|
||
<td>87.8</td>
|
||
<td>&lt;0.1</td>
|
||
<td>0.49</td>
|
||
</tr>
|
||
<tr>
|
||
<td> </td>
|
||
<td>Men</td>
|
||
<td>78.0</td>
|
||
<td>19.6</td>
|
||
<td>&lt;0.1</td>
|
||
<td>2.32</td>
|
||
</tr>
|
||
<tr>
|
||
<td>Testosterone</td>
|
||
<td>Women (follicular)</td>
|
||
<td>30.4</td>
|
||
<td>66.0</td>
|
||
<td>2.26</td>
|
||
<td>1.36</td>
|
||
</tr>
|
||
<tr>
|
||
<td> </td>
|
||
<td>Women (luteal)</td>
|
||
<td>30.7</td>
|
||
<td>65.7</td>
|
||
<td>2.20</td>
|
||
<td>1.37</td>
|
||
</tr>
|
||
<tr>
|
||
<td> </td>
|
||
<td>Women (pregnant)</td>
|
||
<td>3.60</td>
|
||
<td>95.4</td>
|
||
<td>0.82</td>
|
||
<td>0.23</td>
|
||
</tr>
|
||
<tr>
|
||
<td> </td>
|
||
<td>Men</td>
|
||
<td>49.9</td>
|
||
<td>44.3</td>
|
||
<td>3.56</td>
|
||
<td>2.23</td>
|
||
</tr>
|
||
<tr>
|
||
<td>DHT</td>
|
||
<td>Women (follicular)</td>
|
||
<td>21.0</td>
|
||
<td>78.4</td>
|
||
<td>0.12</td>
|
||
<td>0.47</td>
|
||
</tr>
|
||
<tr>
|
||
<td> </td>
|
||
<td>Women (luteal)</td>
|
||
<td>21.3</td>
|
||
<td>78.1</td>
|
||
<td>0.12</td>
|
||
<td>0.48</td>
|
||
</tr>
|
||
<tr>
|
||
<td> </td>
|
||
<td>Women (pregnant)</td>
|
||
<td>2.15</td>
|
||
<td>97.8</td>
|
||
<td>0.04</td>
|
||
<td>0.07</td>
|
||
</tr>
|
||
<tr>
|
||
<td> </td>
|
||
<td>Men</td>
|
||
<td>39.2</td>
|
||
<td>59.7</td>
|
||
<td>0.22</td>
|
||
<td>0.88</td>
|
||
</tr>
|
||
</tbody>
|
||
</table>
|
||
|
||
<p>Free sex hormone levels and percentages are often calculated from levels of total sex hormone, albumin, SHBG, and CBG with validated mathematical models constructed from data of published studies. This is because free sex hormone levels are usually very low (pM range) and are difficult to measure with routine blood testing methods. While generally in the vicinity of the true values, calculated results may not always be fully accurate (<a href="https://doi.org/10.1016/j.steroids.2014.08.005">Rosner, 2015</a>; <a href="https://doi.org/10.1210/er.2017-00025">Goldman et al., 2017</a>; <a href="https://doi.org/10.1210/er.2017-00171">Handelsman, 2017</a>; <a href="https://doi.org/10.1016/j.jsbmb.2019.04.008">Keevil &amp; Adaway, 2019</a>). As such, measured levels, when feasible, are preferable.</p>
|
||
|
||
<h2 id="effects-of-sex-hormones-on-shbg-production">Effects of Sex Hormones on SHBG Production</h2>
|
||
|
||
<p>Plasma proteins like albumin and SHBG are synthesized in the liver and are then secreted into the blood. In addition to binding to SHBG, sex hormones modulate the liver production of SHBG and hence influence their own plasma protein binding. Androgens decrease SHBG production while estrogens increase SHBG production (<a href="https://doi.org/10.1111/j.1365-2265.1974.tb03298.x">Anderson, 1974</a>; <a href="https://pubmed.ncbi.nlm.nih.gov/2469051/">Moore &amp; Bulbrook, 1988</a>). Administration of the <a href="https://en.wikipedia.org/wiki/Anabolic_steroid">anabolic steroid</a> <a href="https://en.wikipedia.org/wiki/Stanozolol">stanozolol</a> (a synthetic DHT derivative) for just a few days suppresses SHBG levels by 63% (<a href="https://doi.org/10.1055/s-2004-817969">Krause et al., 2004</a>). Continuous therapy with extreme doses of testosterone and other anabolic steroids decrease SHBG levels by 90% (<a href="https://doi.org/10.1016/0022-4731(85)90257-2">Ruokonen et al., 1985</a>; <a href="https://pubmed.ncbi.nlm.nih.gov/2469051/">Moore &amp; Bulbrook, 1988</a>). Similarly, weakly androgenic progestins like <a href="https://en.wikipedia.org/wiki/Medroxyprogesterone_acetate">medroxyprogesterone acetate</a> (MPA), <a href="https://en.wikipedia.org/wiki/Norethisterone">norethisterone</a> (NET), and <a href="https://en.wikipedia.org/wiki/Levonorgestrel">levonorgestrel</a> (LNG) decrease SHBG production (<a href="https://doi.org/10.1080/13697130500148875">Kuhl, 2005</a>), and very high doses of medroxyprogesterone acetate and <a href="https://en.wikipedia.org/wiki/Megestrol_acetate">megestrol acetate</a> (MGA) have been reported to decrease SHBG levels by up to around 50 to 90% (<a href="https://doi.org/10.1016/0022-4731(87)91680-3">Heubner et al., 1987</a>; <a href="https://doi.org/10.1016/0022-4731(90)90118-C">Lundgren et al., 1990</a>; <a href="https://doi.org/10.1016/0022-4731(90)90119-D">Lundgren &amp; Lønning, 1990</a>). Conversely, <a href="https://en.wikipedia.org/wiki/Combined_birth_control_pill">combined birth control pills</a> containing the synthetic estrogen <a href="https://en.wikipedia.org/wiki/Ethinylestradiol">ethinylestradiol</a> (EE) (and a minimally androgenic or an antiandrogenic progestin) increase SHBG levels by about 4-fold (<a href="https://doi.org/10.1034/j.1600-0412.2002.810603.x">Odlind et al., 2002</a>). High doses of oral synthetic estrogens, like EE and <a href="https://en.wikipedia.org/wiki/Diethylstilbestrol">diethylstilbestrol</a> (DES), increase SHBG levels by up to 5- to 10-fold (<a href="https://doi.org/10.1002/pros.2990140410">von Schoultz et al., 1989</a>).</p>
|
||
|
||
<p>Testosterone, DHT, and estradiol are strongly inactivated by the liver and have relatively weak effects in this part of the body under normal circumstances. As a result, they have much less relative impact on SHBG production than do synthetic hormonal agents. Accordingly, SHBG levels change only slightly over the course of the menstrual cycle in women despite substantial fluctuations in estradiol levels (<a href="https://files.transfemscience.org/pdfs/Freymann%20et%20al.%20(1977)%20-%20Eine%20Spezifische,%20Radioimmunologisehe%20Bestimmung%20des%20Plasma%C3%B6stradiols%20ohne%20Chromatographie%20im%20Zyklus%20und%20in%20der%20Schwangersehaft%20und%20die%20Bestimmung%20des%20Freien,%20[...].pdf">Freymann et al., 1977b</a>; <a href="https://doi.org/10.1210/jcem-61-5-993">Plymate et al., 1985</a>; <a href="https://doi.org/10.1530/acta.0.1290130">Schijf et al., 1993</a>; <a href="https://doi.org/10.1111/j.1743-6109.2011.02380.x">Braunstein et al., 2011</a>; <a href="https://doi.org/10.1016/j.steroids.2010.10.010">Rothman et al., 2011</a>; <a href="https://doi.org/10.1210/jc.2013-1381">Fanelli et al., 2013</a>; <a href="https://doi.org/10.1080/00365513.2017.1286685">Rezaii et al., 2017</a>). In one study, SHBG levels increased by about 6 to 13% (+2.9–5.3 nmol/L) going from the follicular phase to the luteal phase of the cycle (<a href="https://doi.org/10.1111/j.1743-6109.2011.02380.x">Braunstein et al., 2011</a>). There is additionally only a small decrease in SHBG levels attributable to the sharp decline in estradiol with menopause (<a href="https://doi.org/10.1210/jcem.85.8.6740">Burger et al., 2000</a>; <a href="https://doi.org/10.1080/13697130400012163">Guthrie et al., 2004</a>). Nonetheless, estradiol therapy can more considerably influence the production of SHBG and other liver proteins as well under specific conditions (<a href="https://files.transfemscience.org/pdfs/Kuhl%20(1998)%20-%20Adverse%20Effects%20of%20Estrogen%20Treatment_%20Natural%20versus%20Synthetic%20Estrogens.pdf">Kuhl, 1998</a>). This is due to 1) use of oral estradiol, which because of the first pass through the liver has a greater impact on estrogen-sensitive liver synthesis than non-oral routes (<a href="https://doi.org/10.1080/13697130500148875">Kuhl, 2005</a>); and 2) use of high estradiol doses, for instance typical injectable doses. The table below shows SHBG increases from various studies with different estrogen routes, doses, and types.</p>
|
||
|
||
<p><strong>Table 2:</strong> Relative increases in SHBG levels with some different estrogenic exposures:</p>
|
||
|
||
<table>
|
||
<thead>
|
||
<tr>
|
||
<th>Estrogen</th>
|
||
<th>Typical E2 levels <sup>a</sup></th>
|
||
<th>SHBG increase</th>
|
||
<th>Source</th>
|
||
</tr>
|
||
</thead>
|
||
<tbody>
|
||
<tr>
|
||
<td>Oral E2 1 mg/day</td>
|
||
<td>~25 pg/mL</td>
|
||
<td>1.6×</td>
|
||
<td><a href="https://files.transfemscience.org/pdfs/Kuhl%20(1998)%20-%20Adverse%20Effects%20of%20Estrogen%20Treatment_%20Natural%20versus%20Synthetic%20Estrogens.pdf">Kuhl (1998)</a></td>
|
||
</tr>
|
||
<tr>
|
||
<td>Oral E2 2 mg/day</td>
|
||
<td>~50 pg/mL</td>
|
||
<td>2.2×</td>
|
||
<td><a href="https://files.transfemscience.org/pdfs/Kuhl%20(1998)%20-%20Adverse%20Effects%20of%20Estrogen%20Treatment_%20Natural%20versus%20Synthetic%20Estrogens.pdf">Kuhl (1998)</a></td>
|
||
</tr>
|
||
<tr>
|
||
<td>Oral E2 4 mg/day</td>
|
||
<td>~100 pg/mL</td>
|
||
<td>1.9–3.2×</td>
|
||
<td><a href="https://doi.org/10.1530/acta.0.1010592">Fåhraeus &amp; Larsson-Cohn (1982)</a>; <a href="https://doi.org/10.1210/jc.2005-0173">Gibney<br />et al. (2005)</a>; <a href="https://doi.org/10.1210/jc.2005-0352">Ropponen et al. (2005)</a></td>
|
||
</tr>
|
||
<tr>
|
||
<td>Oral EV 6 mg/day<sup>b</sup></td>
|
||
<td>~112.5 pg/mL</td>
|
||
<td>2.5–3.0×</td>
|
||
<td><a href="http://doi.org/10.1055/s-2005-865900">Dittrich et al. (2005)</a>; <a href="https://doi.org/10.1530/eje.1.01943">Mueller et al. (2005)</a>;<br /><a href="https://doi.org/10.1055/s-2006-925198">Mueller et al. (2006)</a></td>
|
||
</tr>
|
||
<tr>
|
||
<td>E2 patch 50 μg/day</td>
|
||
<td>~50 pg/mL</td>
|
||
<td>1.1×</td>
|
||
<td><a href="https://doi.org/10.1080/13697130500148875">Kuhl (2005)</a></td>
|
||
</tr>
|
||
<tr>
|
||
<td>E2 patch 100 μg/day</td>
|
||
<td>~100 pg/mL</td>
|
||
<td>1.2×</td>
|
||
<td><a href="https://doi.org/10.1210/jc.2007-2193">Shifren et al. (2008)</a></td>
|
||
</tr>
|
||
<tr>
|
||
<td>E2 patches 200 μg/day</td>
|
||
<td>~200 pg/mL</td>
|
||
<td>~1.5×</td>
|
||
<td><a href="https://doi.org/10.1016/j.clgc.2019.09.019">Smith et al. (2020)</a></td>
|
||
</tr>
|
||
<tr>
|
||
<td>E2 patches 300 μg/day</td>
|
||
<td>~300 pg/mL</td>
|
||
<td>~1.7×</td>
|
||
<td><a href="https://doi.org/10.1016/j.clgc.2019.09.019">Smith et al. (2020)</a></td>
|
||
</tr>
|
||
<tr>
|
||
<td>E2 patches 600 μg/day</td>
|
||
<td>~600 pg/mL</td>
|
||
<td>2.3×</td>
|
||
<td><a href="https://doi.org/10.1002/cncr.20857">Bland et al. (2005)</a></td>
|
||
</tr>
|
||
<tr>
|
||
<td>EU 100 mg/month</td>
|
||
<td>~550 pg/mL</td>
|
||
<td>2.0×</td>
|
||
<td><a href="https://www.worldcat.org/oclc/774239518">Derra (1981)</a></td>
|
||
</tr>
|
||
<tr>
|
||
<td>PEP 320 mg/month</td>
|
||
<td>~700 pg/mL</td>
|
||
<td>1.7×</td>
|
||
<td><a href="http://doi.org/10.1097/00000421-198801102-00024">Stege et al. (1988)</a></td>
|
||
</tr>
|
||
<tr>
|
||
<td>EV 10 mg/10 days</td>
|
||
<td>Variable (high)</td>
|
||
<td>3.2×</td>
|
||
<td><a href="http://doi.org/10.1055/s-0030-1255074">Mueller et al. (2011)</a> [<a href="https://archive.is/1X4Co">Table</a>]</td>
|
||
</tr>
|
||
<tr>
|
||
<td>EV 10 mg/14 days</td>
|
||
<td>Variable (high)</td>
|
||
<td>~3.2×</td>
|
||
<td><a href="https://doi.org/10.1530/EJE-09-0265">Kronawitter et al. (2009)</a> [<a href="https://archive.is/k2HTe">Table</a>]</td>
|
||
</tr>
|
||
<tr>
|
||
<td>Oral EE 10 μg/day</td>
|
||
<td>–</td>
|
||
<td>3.0×</td>
|
||
<td><a href="https://files.transfemscience.org/pdfs/Kuhl%20(1998)%20-%20Adverse%20Effects%20of%20Estrogen%20Treatment_%20Natural%20versus%20Synthetic%20Estrogens.pdf">Kuhl (1998)</a></td>
|
||
</tr>
|
||
<tr>
|
||
<td>Oral EE 50 μg/day</td>
|
||
<td>–</td>
|
||
<td>4.0×</td>
|
||
<td><a href="https://doi.org/10.1007/PL00003042">Kuhl (1997)</a></td>
|
||
</tr>
|
||
<tr>
|
||
<td>High-dose synthetic E</td>
|
||
<td>–</td>
|
||
<td>5–10×</td>
|
||
<td><a href="https://doi.org/10.1002/pros.2990140410">von Schoultz et al. (1989)</a></td>
|
||
</tr>
|
||
</tbody>
|
||
</table>
|
||
|
||
<p><small><sup>a</sup> Estimated typical estradiol levels from various sources (e.g., <a href="/articles/e2-equivalent-doses/">Aly, 2020</a>; <a href="https://en.wikipedia.org/wiki/Pharmacokinetics_of_estradiol">Wiki</a>). <sup>b</sup> Due to differences in molecular weight, EV has about 75% of the amount of estradiol as regular estradiol. Hence, 6 mg/day EV is approximately equivalent to 4.5 mg/day E2.</small></p>
|
||
|
||
<p>The influence of estradiol on SHBG levels is most relevant to pregnancy, when estradiol levels increase to far higher levels than usual. In late pregnancy, estradiol levels are generally around 15,000 to 25,000 pg/mL on average (<a href="https://en.wikipedia.org/wiki/Template:Hormone_levels_during_pregnancy_in_human_females">Graphs</a>; <a href="https://aacrjournals.org/cebp/article/12/5/452/167710/Correlation-of-Serum-Hormone-Concentrations-in">Troisi et al., 2003</a>; <a href="https://doi.org/10.33549/physiolres.934019">Adamcová et al., 2018</a>). These estradiol levels are on the order of 100-fold higher than normal menstrual cycle levels. In parallel with the massive increases in estradiol levels, SHBG levels increase by about 5- to 10-fold by late pregnancy (<a href="https://doi.org/10.1111/j.1365-2265.1974.tb03298.x">Anderson, 1974</a>; <a href="https://doi.org/10.1007/978-3-319-53298-1_15">Hammond, 2017</a>). The dose–response curve of estrogens on SHBG production shows saturation, with most of the increase in SHBG levels happening at lower estradiol levels as well as limits to how much SHBG levels can be increased (<a href="https://doi.org/10.1016/0009-8981(77)90276-5">Mean, Pellaton, &amp; Magrini, 1977</a>; <a href="https://doi.org/10.1093/clinchem/37.5.667">O’Leary et al., 1991</a>; <a href="https://doi.org/10.1111/j.1365-2265.1994.tb02478.x">Kerlan et al., 1994</a>; <a href="https://doi.org/10.1007/978-3-642-60107-1_18">Kuhl, 1999</a>). The graphs below show SHBG levels throughout pregnancy.</p>
|
||
|
||
<table>
|
||
<thead>
|
||
<tr>
|
||
<th><img src="/assets/images/2ibct7safz951.png" alt="" /></th>
|
||
</tr>
|
||
</thead>
|
||
<tbody>
|
||
<tr>
|
||
<td><strong>Figure 1:</strong> SHBG and total estradiol levels during pregnancy in women (<a href="https://doi.org/10.1093/clinchem/37.5.667">O’Leary et al., 1991</a>). The lines are the mean and/or 95th percentile levels while the points are individual measurements.</td>
|
||
</tr>
|
||
</tbody>
|
||
</table>
|
||
|
||
<table>
|
||
<thead>
|
||
<tr>
|
||
<th><img src="/assets/images/kf8a2oscfz951.png" alt="" /></th>
|
||
</tr>
|
||
</thead>
|
||
<tbody>
|
||
<tr>
|
||
<td><strong>Figure 2:</strong> Total sex hormone and SHBG levels during pregnancy in women (<a href="https://doi.org/10.1111/j.1365-2265.1994.tb02478.x">Kerlan et al., 1994</a>).</td>
|
||
</tr>
|
||
</tbody>
|
||
</table>
|
||
|
||
<h2 id="effects-of-shbg-increase-on-free-sex-hormone-levels">Effects of SHBG Increase on Free Sex Hormone Levels</h2>
|
||
|
||
<p>Changes in SHBG levels result in changes in SHBG-bound and free sex hormone levels. Aside from DHT, estradiol and testosterone are the hormones of the greatest interest in this regard.</p>
|
||
|
||
<h3 id="shbg-increase-and-free-testosterone">SHBG Increase and Free Testosterone</h3>
|
||
|
||
<p>EE-containing birth control pills, with their 4-fold increase in SHBG levels, substantially decrease the free percentage of testosterone (<a href="https://doi.org/10.1016/j.psyneuen.2006.12.011">Graham et al., 2007</a>; <a href="https://doi.org/10.1093/humupd/dmt038">Zimmerman et al., 2014</a>). In one study, an EE-containing birth control pill decreased the free testosterone fraction from 2.45% to 0.78% (a 3.2-fold decrease or to 32% of baseline) (<a href="https://doi.org/10.1016/j.psyneuen.2006.12.011">Graham et al., 2007</a>). Due to concomitant suppression of testosterone production and hence reduced total testosterone levels, free testosterone levels decreased from 0.89 pg/mL to 0.18 pg/mL (a 5-fold decrease, to 20% of baseline) (<a href="https://doi.org/10.1016/j.psyneuen.2006.12.011">Graham et al., 2007</a>). The influence of EE on SHBG levels contributes significantly to the antiandrogenic effects of EE-containing birth control pills, which are taken advantage of therapeutically to treat acne and hirsutism in women.</p>
|
||
|
||
<p>During pregnancy, testosterone levels increase to as much as 150 ng/dL (around 5-fold higher than non-pregnancy levels) (<a href="https://books.google.com/books?id=Ch-BsGAOtucC&amp;pg=PA108">McClamrock, 2007</a>). The increase in SHBG production during pregnancy serves an important function in that the higher SHBG levels neutralize the biological activity of the increased testosterone levels (<a href="https://doi.org/10.1007/978-3-319-53298-1_15">Hammond, 2017</a>). In one study, the free testosterone fraction was 6-fold lower in late pregnancy than in non-pregnant women (0.23% vs. 1.36%—or to 17% of non-pregnancy) (<a href="https://doi.org/10.1210/jcem-53-1-58">Dunn, Nisula, &amp; Rodbard, 1981</a>). Hence, despite substantial increases in total testosterone levels during pregnancy, free testosterone levels and by extension androgenic action in the body change minimally (<a href="https://doi.org/10.1093/clinchem/39.6.936">Barini, Liberale, &amp; Menini, 1993</a>; <a href="https://doi.org/10.1530/EC-19-0110">Schuijt et al., 2019</a>). A case report of marked hyperandrogenism due to severe SHBG deficiency in a pregnant woman evidences the role of SHBG in limiting the androgenic actions of testosterone during this time (<a href="https://doi.org/10.1172/JCI14060">Hogeveen et al., 2002</a>; <a href="https://doi.org/10.1007/978-3-319-53298-1_15">Hammond, 2017</a>).</p>
|
||
|
||
<h3 id="shbg-increase-and-free-estradiol">SHBG Increase and Free Estradiol</h3>
|
||
|
||
<h4 id="endogenous-and-non-oral-estradiol">Endogenous and Non-Oral Estradiol</h4>
|
||
|
||
<p>The research indicates that increases in SHBG levels and by extension decreases in the free estradiol fraction are minimal with physiological levels of estradiol (e.g., &lt;200 pg/mL). This is the case whether the estradiol is endogenous or exogenous in origin—so long as it is taken non-orally. Such conclusions are based on both calculated and measured studies of free estradiol (e.g., <a href="https://files.transfemscience.org/pdfs/Freymann%20et%20al.%20(1977)%20-%20Eine%20Spezifische,%20Radioimmunologisehe%20Bestimmung%20des%20Plasma%C3%B6stradiols%20ohne%20Chromatographie%20im%20Zyklus%20und%20in%20der%20Schwangersehaft%20und%20die%20Bestimmung%20des%20Freien,%20[...].pdf">Freymann et al., 1977b</a>).</p>
|
||
|
||
<p>Increases in SHBG levels and decreases in the free estradiol fraction become more significant with supraphysiological levels of estradiol however, for instance during pregnancy and with very-high-dose estradiol therapy. Studies on changes in free estradiol with high doses of estradiol are few. This is especially true in the case of measured as opposed to calculated free estradiol. In any case, one can look at pregnancy to gain insight on the question of free estradiol with high estradiol levels. Moreover, due to the very high estradiol levels in pregnancy, free estradiol is more amenable to measurement during this time. Accordingly, multiple studies of measured free estradiol in pregnancy are available.</p>
|
||
|
||
<p>Although free estradiol percentages during pregnancy certainly decrease, the increases in estradiol are far from neutralized by SHBG. Hence, the situation with free estradiol in pregnancy is very different from that of testosterone. This is illustrated in the following excerpt (<a href="https://doi.org/10.1016/B978-012532104-4/50086-X">Rubinow et al., 2002</a>):</p>
|
||
|
||
<blockquote>
|
||
<p>Pregnancy is accompanied by a slow but sustained rise in the plasma levels of many steroid and peptide hormones and is followed by a precipitous drop in their levels over the first few days after delivery. By the third trimester of pregnancy, plasma progesterone levels average approximately 150 ng/ml and estradiol levels range from 10 to 15 ng/ml. These amounts represent a 10- and 50-fold increase, respectively, of maximum menstrual cycle levels (Tulchinsky et al., 1972). Although only a small fraction of these steroids are unbound, the amount of “free” (and thus biologically active) progesterone and estrogen also undergo similarly large increases during pregnancy (Heidrich et al., 1994).</p>
|
||
</blockquote>
|
||
|
||
<p>In the study by Heidrich and colleagues cited in the excerpt, total estradiol levels at the time of delivery were 21,500 pg/mL and measured free estradiol levels were 232 pg/mL, with a resultant free estradiol fraction of 1.08% (<a href="https://doi.org/10.1016/0165-0327(94)90036-1">Heidrich et al., 1994</a>). For context, the free estradiol percentage in non-pregnant women ranges from 1.5 to 2.1% with RIA, while actual free estradiol levels are 0.30 to 4.1 pg/mL with RIA and 0.40 to 5.9 pg/mL with LC–MS/MS (<a href="https://doi.org/10.1016/B978-0-323-18907-1.00154-2">Nakamoto, 2016</a>). Hence, in this study free estradiol levels in late pregnancy were around 50-fold higher than maximal non-pregnancy levels.</p>
|
||
|
||
<p>Due to variable methodology, the findings of a single study may not be representative. As such, the table below provides measured free estradiol percentages in late pregnancy from several studies.</p>
|
||
|
||
<p><strong>Table 3:</strong> Measured free estradiol percentages in late pregnancy (mean ± SD) (<a href="http://doi.org/10.1055/s-2007-1011848">Perry et al., 1987</a>):</p>
|
||
|
||
<table>
|
||
<thead>
|
||
<tr>
|
||
<th>Study</th>
|
||
<th>Method</th>
|
||
<th>n</th>
|
||
<th>Free E2 (%)</th>
|
||
</tr>
|
||
</thead>
|
||
<tbody>
|
||
<tr>
|
||
<td><a href="http://doi.org/10.1055/s-2007-1011848">Perry et al. (1987)</a></td>
|
||
<td>Centrifugal ultrafiltration</td>
|
||
<td>25</td>
|
||
<td>1.27 ± 0.23</td>
|
||
</tr>
|
||
<tr>
|
||
<td><a href="https://doi.org/10.1016/s0021-9258(19)70742-x">Hammond et al. (1980)</a></td>
|
||
<td>Centrifugal ultrafiltration</td>
|
||
<td>5</td>
|
||
<td>0.96 ± 0.12</td>
|
||
</tr>
|
||
<tr>
|
||
<td><a href="https://doi.org/10.1016/0165-0327(94)90036-1">Heidrich et al. (1994)</a></td>
|
||
<td>Centrifugal ultrafiltration</td>
|
||
<td>26</td>
|
||
<td>1.08</td>
|
||
</tr>
|
||
<tr>
|
||
<td><a href="https://doi.org/10.1210/jcem-37-6-873">Tulchinsky et al. (1973)</a></td>
|
||
<td>Equilibrium dialysis</td>
|
||
<td>5</td>
|
||
<td>0.67 ± 0.18</td>
|
||
</tr>
|
||
<tr>
|
||
<td><a href="https://files.transfemscience.org/pdfs/Freymann%20et%20al.%20(1977)%20-%20Plasma%20Levels%20of%20Apparent%20Free%20Estradiol%20During%20Pregnancy.pdf">Freymann et al. (1977a)</a></td>
|
||
<td>Equilibrium dialysis</td>
|
||
<td>17</td>
|
||
<td>1.15</td>
|
||
</tr>
|
||
<tr>
|
||
<td><a href="https://doi.org/10.1677/joe.0.1040007">Anderson et al. (1985)</a></td>
|
||
<td>Steady-state gel filtration</td>
|
||
<td>12</td>
|
||
<td>1.48 ± 0.55</td>
|
||
</tr>
|
||
</tbody>
|
||
</table>
|
||
|
||
<p>As can be seen in the table, the free estradiol fraction in late pregnancy ranges from about 0.7 to 1.5%. Results for the free estradiol fraction from studies using calculated free estradiol levels in late pregnancy rather than measured levels are similar to measured findings, although sometimes a bit lower in comparison (e.g., 0.5%) (<a href="https://doi.org/10.1210/jcem-53-1-58">Dunn, Nisula, &amp; Rodbard, 1981</a>; <a href="https://doi.org/10.1093/humrep/16.12.2540">Campino et al., 2001</a>). The measured free estradiol percentage in late pregnancy can be cautiously compared to the fraction of 1.5 to 2.1% in non-pregnant women. Using middle values from these ranges, the free estradiol fraction in late pregnancy may be somewhere around 60% of that of non-pregnancy. This estimate is quite close to the actual findings of a study, which observed a decrease in the measured free estradiol percentage to 55% of that of non-pregnancy (<a href="https://files.transfemscience.org/pdfs/Freymann%20et%20al.%20(1977)%20-%20Plasma%20Levels%20of%20Apparent%20Free%20Estradiol%20During%20Pregnancy.pdf">Freymann et al., 1977a</a>; <a href="https://files.transfemscience.org/pdfs/Freymann%20et%20al.%20(1977)%20-%20Eine%20Spezifische,%20Radioimmunologisehe%20Bestimmung%20des%20Plasma%C3%B6stradiols%20ohne%20Chromatographie%20im%20Zyklus%20und%20in%20der%20Schwangersehaft%20und%20die%20Bestimmung%20des%20Freien,%20[...].pdf">Freymann et al., 1977b</a>).</p>
|
||
|
||
<p>In contrast to estradiol, the free percentages of estrone and estriol are not different in late pregnancy when compared to non-pregnancy (<a href="https://doi.org/10.1210/jcem-37-6-873">Tulchinsky &amp; Chopra, 1973</a>; <a href="https://doi.org/10.1016/S0002-9378(87)80260-0">Steingold et al., 1987</a>). This is attributable to the much lower affinities of estrone and estriol for SHBG relative to estradiol (<a href="https://doi.org/10.1080/13697130500148875">Kuhl, 2005</a>).</p>
|
||
|
||
<p>Studies have also assessed free estradiol fractions earlier in pregnancy, which might in theory differ from late pregnancy. The results of a study that measured free estradiol throughout pregnancy are shown in the table below (<a href="https://files.transfemscience.org/pdfs/Freymann%20et%20al.%20(1977)%20-%20Plasma%20Levels%20of%20Apparent%20Free%20Estradiol%20During%20Pregnancy.pdf">Freymann et al., 1977a</a>; <a href="https://files.transfemscience.org/pdfs/Freymann%20et%20al.%20(1977)%20-%20Eine%20Spezifische,%20Radioimmunologisehe%20Bestimmung%20des%20Plasma%C3%B6stradiols%20ohne%20Chromatographie%20im%20Zyklus%20und%20in%20der%20Schwangersehaft%20und%20die%20Bestimmung%20des%20Freien,%20[...].pdf">Freymann et al., 1977b</a>).</p>
|
||
|
||
<p><strong>Table 4:</strong> Total and free estradiol in pregnancy (mean ± SD) (<a href="https://files.transfemscience.org/pdfs/Freymann%20et%20al.%20(1977)%20-%20Plasma%20Levels%20of%20Apparent%20Free%20Estradiol%20During%20Pregnancy.pdf">Freymann et al., 1977a</a>; <a href="https://files.transfemscience.org/pdfs/Freymann%20et%20al.%20(1977)%20-%20Eine%20Spezifische,%20Radioimmunologisehe%20Bestimmung%20des%20Plasma%C3%B6stradiols%20ohne%20Chromatographie%20im%20Zyklus%20und%20in%20der%20Schwangersehaft%20und%20die%20Bestimmung%20des%20Freien,%20[...].pdf">Freymann et al., 1977b</a>):</p>
|
||
|
||
<table>
|
||
<thead>
|
||
<tr>
|
||
<th>Context</th>
|
||
<th>n</th>
|
||
<th>E2 (ng/mL)</th>
|
||
<th>Change</th>
|
||
<th>Free E2 (%)</th>
|
||
<th>Change</th>
|
||
<th>Free E2 (pg/mL)</th>
|
||
<th>Change</th>
|
||
</tr>
|
||
</thead>
|
||
<tbody>
|
||
<tr>
|
||
<td>Non-pregnant</td>
|
||
<td>35</td>
|
||
<td>0.16 ± 0.10</td>
|
||
<td>1.0×</td>
|
||
<td>2.2 ± 0.4</td>
|
||
<td>–0%</td>
|
||
<td>3.5 ± 2.0</td>
|
||
<td>1.0×</td>
|
||
</tr>
|
||
<tr>
|
||
<td>Pregnancy</td>
|
||
<td> </td>
|
||
<td> </td>
|
||
<td> </td>
|
||
<td> </td>
|
||
<td> </td>
|
||
<td> </td>
|
||
<td> </td>
|
||
</tr>
|
||
<tr>
|
||
<td>6–20 weeks</td>
|
||
<td>9</td>
|
||
<td>2.0 ± 1.1</td>
|
||
<td>13×</td>
|
||
<td>1.6 ± 0.4</td>
|
||
<td>–27%</td>
|
||
<td>32 ± 21</td>
|
||
<td>9.1×</td>
|
||
</tr>
|
||
<tr>
|
||
<td>12–20 weeks</td>
|
||
<td>10</td>
|
||
<td>5.5 ± 2.2</td>
|
||
<td>34×</td>
|
||
<td>1.3 ± 0.3</td>
|
||
<td>–41%</td>
|
||
<td>72 ± 39</td>
|
||
<td>21×</td>
|
||
</tr>
|
||
<tr>
|
||
<td>20–30 weeks</td>
|
||
<td>12</td>
|
||
<td>10.8 ± 4.6</td>
|
||
<td>68×</td>
|
||
<td>1.2 ± 0.3</td>
|
||
<td>–45%</td>
|
||
<td>130 ± 74</td>
|
||
<td>37×</td>
|
||
</tr>
|
||
<tr>
|
||
<td>30–38 weeks</td>
|
||
<td>17</td>
|
||
<td>16.0 ± 7.0</td>
|
||
<td>100×</td>
|
||
<td>1.2 ± 0.2</td>
|
||
<td>–45%</td>
|
||
<td>184 ± 103</td>
|
||
<td>53×</td>
|
||
</tr>
|
||
</tbody>
|
||
</table>
|
||
|
||
<p>In similar studies by another group of researchers, free estradiol fractions were measured in earlier pregnancy (weeks 7–16) and were found to be lower than those obtained by Freymann and colleagues (<a href="https://doi.org/10.1093/jnci/76.6.1035">Bernstein et al., 1986</a>; <a href="https://doi.org/10.1016/0002-9378(87)90126-8">Depue et al., 1987</a>; <a href="https://doi.org/10.1038/bjc.1988.223">Bernstein et al., 1988</a>). The free estradiol percentage was about 0.9 or 1.0% at 10 weeks and about 0.7% at 12 weeks (<a href="https://doi.org/10.1093/jnci/76.6.1035">Bernstein et al., 1986</a>; <a href="https://doi.org/10.1016/0002-9378(87)90126-8">Depue et al., 1987</a>; <a href="https://doi.org/10.1038/bjc.1988.223">Bernstein et al., 1988</a>). Hence, as with the results of Freymann and colleagues, the free estradiol fraction decreased as pregnancy progressed. The figure below provides a visualization of the findings.</p>
|
||
|
||
<table>
|
||
<thead>
|
||
<tr>
|
||
<th><img src="/assets/images/3qem22wgfz951.png" alt="" /></th>
|
||
</tr>
|
||
</thead>
|
||
<tbody>
|
||
<tr>
|
||
<td><strong>Figure 3:</strong> Changes in total and free estradiol levels (pg/mL), free estradiol fraction (%), and SHBG binding capacity (μg/dL) during weeks 7 to 16 of pregnancy in women (<a href="https://doi.org/10.1093/jnci/76.6.1035">Bernstein et al., 1986</a>).</td>
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</tr>
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</tbody>
|
||
</table>
|
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<p>Free estradiol during pregnancy can also be calculated using total estradiol levels and SHBG levels. I roughly calculated the free estradiol fraction during pregnancy using the data from <a href="https://doi.org/10.1093/clinchem/37.5.667">O’Leary et al. (1991)</a> and a published calculator spreadsheet by <a href="https://doi.org/10.1016/j.steroids.2009.01.008">Mazer (2009)</a> (<a href="/articles/shbg-unimportant-suppl/">Aly, 2020</a>). The results are shown below.</p>
|
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||
<table>
|
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<thead>
|
||
<tr>
|
||
<th><img src="/assets/images/f3utx64jfz951.png" alt="" /></th>
|
||
</tr>
|
||
</thead>
|
||
<tbody>
|
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<tr>
|
||
<td><strong>Figure 4:</strong> Average measured total estradiol and SHBG levels (<a href="https://doi.org/10.1093/clinchem/37.5.667">O’Leary et al., 1991</a>) and calculated free estradiol percentage (<a href="https://doi.org/10.1016/j.steroids.2009.01.008">Mazer, 2009</a>) throughout pregnancy in women. Another version of this graph scaled to only the first trimester of pregnancy (when estradiol levels are typically ≤2,000 pg/mL) is also provided (<a href="/assets/images/fdd36yplqia51.png">Graph</a>).</td>
|
||
</tr>
|
||
</tbody>
|
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</table>
|
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|
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<p>The free estradiol fractions in the figure are merely rough estimations and hence should be given conservative consideration. In any case, they are similar to the findings of the available studies on measured free estradiol in earlier pregnancy just discussed—for instance in magnitude (relative to Bernstein et al.) and pattern of change throughout pregnancy (relative to both Bernstein et al. and Freymann et al.). As such, these calculated values offer a plausible and interesting model.</p>
|
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|
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<p>To summarize, there are profound increases in total estradiol levels and proportionally lower but still substantial increases in SHBG levels during pregnancy. In accordance with the marked increase in SHBG levels, the free estradiol fraction progressively decreases over the course of pregnancy. Studies are conflicting on the exact degrees to which free estradiol percentages decrease. In any case, the possibilities for the free estradiol fraction by late pregnancy range from about 0.5 to 1.5%. These figures can be compared to non-pregnancy free estradiol percentages of 1.5 to 2.1%. This may correspond to a maximal decrease in the free estradiol fraction in late pregnancy to around 60% of non-pregnancy. At the greatest extreme, the decrease may be to around 25% of non-pregnancy. Conversely, in earlier pregnancy, when estradiol levels are lower, free estradiol percentages are higher.</p>
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<p>Despite the decreases in the free estradiol fraction during pregnancy, there are profound increases in free estradiol levels that parallel the massive increases in total estradiol. As such, the increase in estradiol levels during pregnancy markedly exceeds the limiting influences of the simultaneously elevated SHBG levels. For this reason, pregnancy is a profoundly hyperestrogenic state.</p>
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<p>SHBG doesn’t impact estradiol like it does testosterone during pregnancy because the proportional increases in estradiol levels relative to SHBG levels are far greater in comparison and because of the relatively lower affinity of estradiol for SHBG. In general, it’s not possible for SHBG to limit the activity of estradiol in the way that it can with testosterone due to the inherent requirement for substantially increased SHBG production of much more highly increased estradiol levels.</p>
|
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<h4 id="oral-estradiol">Oral Estradiol</h4>
|
||
|
||
<p>Oral estradiol may differ from non-oral estradiol when it comes to the issue of free estradiol. This is because oral estradiol undergoes a first pass that results in greater estradiol levels in the liver relative to the circulation. As a result, oral estradiol has disproportionate liver effects and increases SHBG levels to a proportionally greater extent than non-oral estradiol. Hence, the greater SHBG increases with oral estradiol may result in lower free estradiol fractions than with non-oral estradiol.</p>
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|
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<p>While this is probable, it is more difficult to determine the precise magnitudes of the differences between oral and non-oral estradiol in terms of free estradiol. Some data are available however. Clinical studies of low-dose oral estradiol in menopausal cisgender women have reported the limiting influence of the SHBG increase on calculated free estradiol to be modest (<a href="https://doi.org/10.1111/j.1471-0528.1984.tb03683.x">Nilsson, Holst, &amp; von Schoultz, 1984</a>; <a href="https://doi.org/10.1097/00042192-200007040-00006">Nachtigall et al., 2000</a>). Likewise, oral estradiol appears to have similar effectiveness for menopausal symptoms when compared to non-oral estradiol (<a href="https://en.wikipedia.org/wiki/Pharmacokinetics_of_estradiol#First-pass_effect_and_differences_from_other_routes">Wiki</a>; 2nd paragraph). Studies of higher doses of oral estradiol that provide data on SHBG or free estradiol levels are rare. In any case, a few studies by one group found that 6 mg/day oral estradiol valerate (a dose equivalent to approximately 4.5 mg/day oral estradiol) increased SHBG levels by about 2.5- to 3.0-fold in transgender women (<a href="http://doi.org/10.1055/s-2005-865900">Dittrich et al., 2005</a>; <a href="https://doi.org/10.1530/eje.1.01943">Mueller et al., 2005</a>; <a href="https://doi.org/10.1055/s-2006-925198">Mueller et al., 2006</a>). Using the numbers from one of the studies for total estradiol and SHBG levels, it can be roughly calculated (<a href="https://doi.org/10.1016/j.steroids.2009.01.008">Mazer, 2009</a>) that the free estradiol fraction may have decreased from around 2.1% to 1.2% (a 43% reduction). Analogously, a study using oral conjugated estrogens (CEEs; Premarin) at a dose that increased SHBG levels by 2.3-fold reported that the calculated free estradiol percentage was 40% lower relative to an equivalent dose of transdermal estradiol (in terms of total estradiol levels) (<a href="http://doi.org/10.1097/gme.0b013e31803867a">Shifren et al., 2007</a>). These findings suggest a non-trivial reduction in the free estradiol fraction with typical doses of oral estradiol in transfeminine people. Consequently, it’s possible that oral estradiol could be to a certain degree less potent at the same total estradiol levels relative to non-oral estradiol.</p>
|
||
|
||
<p>It’s important to be clear that it’s also not a certainty however. Levels of estrone are much higher with oral estradiol than with non-oral estradiol (~5-fold) (<a href="https://doi.org/10.1080/13697130500148875">Kuhl, 2005</a>), and estrone, although far less potent than estradiol, has significant intrinsic estrogenic activity similarly to estradiol (<a href="https://doi.org/10.1080/13697130500148875">Kuhl, 2005</a>). The degree to which estrone might add to the estrogenic activity of estradiol, if at all, is uncertain. In any case, it’s within the realm of possibility that estrone could contribute significantly to the estrogenic activity of oral estradiol (<a href="https://doi.org/10.1016/j.fct.2018.12.013">Pande et al., 2019</a>). This additional estrogenic exposure could potentially serve to offset the impact of the higher SHBG levels and reduced free estradiol fractions that occur with oral estradiol. Further research is needed to evaluate such a possibility however. As another consideration, the higher SHBG levels with oral estradiol can be expected to reduce the free testosterone fraction in addition to that of estradiol (and to an even greater extent in comparison). This is important as testosterone suppression is a key therapeutic effect of estradiol in transfeminine people and the main justified reason for use of higher estradiol levels. Due to possibilities like these and the fact that free levels of hormones only theoretically represent their biological activity, it shouldn’t necessarily be assumed that oral estradiol is less potent or efficacious than non-oral estradiol. Only further clinical studies comparing oral estradiol to non-oral estradiol will be able to clarify this question.</p>
|
||
|
||
<h2 id="relevance-for-transfeminine-hormone-therapy">Relevance for Transfeminine Hormone Therapy</h2>
|
||
|
||
<p>Some have concerns that SHBG may substantially limit the effectiveness of estradiol and thereby hinder feminization and/or breast development. Some have even claimed that high levels of estradiol may be less effective than lower levels as a result of SHBG increases at higher levels. Before even touching on SHBG however, such notions are likely to be misguided. This is because low estradiol levels (&lt;50 pg/mL) are known to be fully effective in terms of feminization and breast development. This is evidenced by normal and induced puberty in cisgender girls (<a href="/articles/hormone-levels-female-puberty/">Aly, 2020</a>), as well as by the excellent secondary sexual development of women with complete androgen insensitivity syndrome (CAIS) (<a href="/articles/progestogens-breast-dev/">Aly, 2020</a>; <a href="https://en.wikipedia.org/wiki/Complete_androgen_insensitivity_syndrome#Signs_and_symptoms">Wiki</a>). No evidence exists at this time to indicate that higher estradiol levels are necessary or beneficial in terms of feminization or breast development (<a href="https://doi.org/10.1089/trgh.2020.0077">Nolan &amp; Cheung, 2020</a>). Available studies in fact suggest no relationship between estradiol levels and breast development in transfeminine people at typical therapeutic levels of estradiol (e.g., 50–200 pg/mL) (<a href="https://doi.org/10.1210/jc.2017-01927">de Blok et al., 2017</a>; <a href="https://doi.org/10.1530/eje-19-0463">Meyer et al., 2020</a>; <a href="https://doi.org/10.1210/clinem/dgaa841">de Blok et al., 2020</a>). This is in accordance with the concept of the maximal effect of estradiol on feminization and breast development being established at lower estradiol levels. Hence, besides the use of higher estradiol levels for testosterone suppression in transfeminine people, concerns about incomplete feminizing efficacy of estradiol consequent to inadequate estrogenic exposure have little basis.</p>
|
||
|
||
<p>If SHBG is nonetheless explored however, the research indicates that the role of SHBG in restricting free estradiol, and hence presumably the biological activity of estradiol, is only so considerable. Within physiological non-pregnancy ranges for estradiol (e.g., &lt;200 pg/mL), changes in SHBG levels and free estradiol fractions due to endogenous or non-oral estradiol are minimal. Very high estradiol levels have greater influence on SHBG production than normal physiological levels however. During pregnancy, with the massive increases in estradiol and resultant 5- to 10-fold maximal elevation in SHBG levels, the free estradiol percentage may be decreased to around 60% of that of non-pregnancy. But actual free estradiol levels are nonetheless profoundly increased in pregnancy. Moreover, increases in SHBG levels and decreases in free estradiol fraction earlier in pregnancy are lower than in late pregnancy. Even with among the highest estradiol levels that would normally be encountered with non-oral estradiol therapy, the decreases in the free estradiol fraction due to SHBG are likely to be modest. The impact of such a reduction could easily be negated by a slightly greater estradiol dose.</p>
|
||
|
||
<p>While the preceding is applicable to non-oral estradiol, oral estradiol has a greater influence on SHBG production in comparison and hence the higher SHBG levels with oral estradiol could result in more significant limitation of free estradiol than with non-oral estradiol. The notion that this reduction in free estradiol corresponds to a decrease in the activity or potency of oral estradiol is only a theoretical possibility however. Therapeutically, oral estradiol has shown itself to be very effective. The decreases in free estradiol percentage with low-dose oral estradiol seem to be small. In addition, while no direct comparisons exist this time, higher doses of oral estradiol seem to show similar testosterone suppression as non-oral estradiol (<a href="https://en.wikipedia.org/wiki/Pharmacodynamics_of_estradiol#Effects_on_sex-hormone_levels">Wiki</a>; <a href="https://web.archive.org/web/20201112030301/https://en.wikipedia.org/wiki/Template:Antigonadotropic_effects_of_estradiol">Graphs</a>). Besides testosterone suppression, available studies have found no differences between oral and non-oral estradiol in terms of outcomes like breast development or feminization (<a href="/articles/oral-vs-transdermal-e2/">Sam, 2020</a>). As such, the differences between oral and non-oral estradiol in terms SHBG levels and free estradiol fraction may be of little therapeutic importance.</p>
|
||
|
||
<p>Aside from decreasing free estradiol fractions, increased SHBG levels also decrease free testosterone fractions to an even greater extent. This is advantageous in the case of transfeminine people.</p>
|
||
|
||
<p>Taken together, lower free estradiol due to increased SHBG levels, whether with non-oral or oral estradiol, isn’t something that should be a major source of concern in transfeminine hormone therapy.</p>
|
||
|
||
<h2 id="supplementary-material">Supplementary Material</h2>
|
||
|
||
<p>See <a href="/articles/shbg-unimportant-suppl/">here</a> for supplementary material for this article, including a spreadsheet and other calculators that can be used to estimate free hormone levels (e.g., <a href="https://doi.org/10.1016/j.steroids.2009.01.008">Mazer, 2009</a>).</p>
|
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||
<h2 id="references">References</h2>
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||
|
||
<ul>
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<li>Steingold, K. A., Pardridge, W. M., Judd, H. L., &amp; Chaudhuri, G. (1987). The effects of membrane permeability and binding by human serum proteins on steroid influx into the rabbit uterus. <em>American Journal of Obstetrics and Gynecology</em>, <em>157</em>(6), 1543–1549. [DOI:<a href="https://doi.org/10.1016/s0002-9378(87)80260-0">10.1016/s0002-9378(87)80260-0</a>]</li>
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<li>Strauss, J. F., &amp; FitzGerald, G. A. (2019). Steroid Hormones and Other Lipid Molecules Involved in Human Reproduction. In Strauss, J. F., &amp; Barbieri, R. L. (Eds.). <em>Yen and Jaffe’s Reproductive Endocrinology: Physiology, Pathophysiology, and Clinical Management, 8th Edition</em> (pp. 75–114.e7). Philadelphia: Elsevier. [<a href="https://books.google.com/books?id=67ZEDwAAQBAJ&amp;pg=PA97">Google Books</a>] [DOI:<a href="https://doi.org/10.1016/b978-0-323-47912-7.00004-4">10.1016/b978-0-323-47912-7.00004-4</a>]</li>
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<li>Troisi, R., Potischman, N., Roberts, J. M., Harger, G., Markovic, N., Cole, B., Lykins, D., Siiteri, P., &amp; Hoover, R. N. (2003). Correlation of serum hormone concentrations in maternal and umbilical cord samples. <em>Cancer Epidemiology, Biomarkers &amp; Prevention</em>, <em>12</em>(5), 452–456. [<a href="https://scholar.google.com/scholar?cluster=14676204285849360875">Google Scholar</a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/12750241/">PubMed</a>] [<a href="https://aacrjournals.org/cebp/article/12/5/452/167710/Correlation-of-Serum-Hormone-Concentrations-in">URL</a>]</li>
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<li>Tulchinsky, D., &amp; Chopra, I. J. (1973). Competitive Ligand-Binding Assay for Measurement of Sex Hormone-Binding Globulin (SHBG). <em>The Journal of Clinical Endocrinology &amp; Metabolism</em>, <em>37</em>(6), 873–881. [DOI:<a href="https://doi.org/10.1210/jcem-37-6-873">10.1210/jcem-37-6-873</a>]</li>
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<li>von Schoultz, B., Carlström, K., Collste, L., Eriksson, A., Henriksson, P., Pousette, Å., &amp; Stege, R. (1989). Estrogen therapy and liver function—metabolic effects of oral and parenteral administration. <em>The Prostate</em>, <em>14</em>(4), 389–395. [DOI:<a href="https://doi.org/10.1002/pros.2990140410">10.1002/pros.2990140410</a>]</li>
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<li>Zimmerman, Y., Eijkemans, M. J., Coelingh Bennink, H. J., Blankenstein, M. A., &amp; Fauser, B. C. (2013). The effect of combined oral contraception on testosterone levels in healthy women: a systematic review and meta-analysis. <em>Human Reproduction Update</em>, <em>20</em>(1), 76–105. [DOI:<a href="https://doi.org/10.1093/humupd/dmt038">10.1093/humupd/dmt038</a>]</li>
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</ul></content><author><name>{"first_name"=>"Aly", "last_name"=>"W.", "author-link"=>"/about/#aly", "articles-link"=>"/articles-by-author/aly/"}</name></author><category term="github" /><category term="workspace" /><summary type="html">The Interactions of Sex Hormones with Sex Hormone-Binding Globulin and Relevance for Transfeminine Hormone Therapy By Aly | First published July 10, 2020 | Last modified March 25, 2023</summary></entry><entry><title type="html">Supplement: The Interactions of Sex Hormones with Sex Hormone-Binding Globulin and Relevance for Transfeminine Hormone Therapy</title><link href="https://transfemscience.org/articles/shbg-unimportant-suppl/" rel="alternate" type="text/html" title="Supplement: The Interactions of Sex Hormones with Sex Hormone-Binding Globulin and Relevance for Transfeminine Hormone Therapy" /><published>2020-07-08T23:40:06-07:00</published><updated>2023-03-14T00:00:00-07:00</updated><id>https://transfemscience.org/articles/shbg-unimportant-suppl</id><content type="html" xml:base="https://transfemscience.org/articles/shbg-unimportant-suppl/"><h1 id="supplement-the-interactions-of-sex-hormones-with-sex-hormone-binding-globulin-and-relevance-for-transfeminine-hormone-therapy">Supplement: The Interactions of Sex Hormones with Sex Hormone-Binding Globulin and Relevance for Transfeminine Hormone Therapy</h1>
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<p>By
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<!-- First author --><a href="/about/#aly">Aly</a><!-- Second author --><!-- Third author --><!-- Fourth author --> | First published July 8, 2020
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| Last modified March 14, 2023</p>
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<h2 id="preface">Preface</h2>
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<p>This article is a supplement to the article <a href="/articles/shbg-unimportant/">here</a>. It was originally just for calculation of free sex hormone levels but I decided to add some other content to it as well.</p>
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<h2 id="calculation-of-free-hormone-levels">Calculation of Free Hormone Levels</h2>
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<h3 id="spreadsheet-calculator-mazer-2009">Spreadsheet Calculator (Mazer, 2009)</h3>
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<p>A researcher developed and published a “user-friendly” spreadsheet that can be used to calculate free and bioavailable levels of several steroid hormones (<a href="https://doi.org/10.1016/j.steroids.2009.01.008">Mazer, 2009</a>). This spreadsheet approach is analogous to how free hormone levels are calculated with actual conventional blood work. Total hormone levels and levels of plasma proteins like albumin and SHBG are taken as inputs by the spreadsheet, and free and bioavailable hormone levels are given as outputs.</p>
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<p>The spreadsheet is supplementary material for <a href="https://doi.org/10.1016/j.steroids.2009.01.008">Mazer (2009)</a> and is behind a paywall. Because of this, I’ve uploaded a copy of the original spreadsheet <a href="https://files.transfemscience.org/pdfs/misc/Mazer%20(2009)%20-%20Free%20Bioavailable%20Hormone%20Calculator.xls">here</a> (Microsoft Excel or XLS format).</p>
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<p>If you’re curious how SHBG may be influencing your free estradiol percentage, you can use the spreadsheet to get an estimate. If you don’t have albumin, CBG, or cortisol values, you can use the default input values in the spreadsheet. If you don’t have other input values (e.g., estrone or SHBG), you can input representative values that are sensible for your scenario. It should be noted that calculated free hormone levels are only estimates and hence can be inaccurate. In any case, they are generally fairly close to the values that would be obtained with actual measurement. Use of default input values as opposed to real measured numbers may further contribute to inaccuracy.</p>
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<h4 id="some-experimentation-with-the-calculator">Some Experimentation with the Calculator</h4>
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<p>Here are the results of some experimentation I did with the calculator:</p>
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<p><strong>Table:</strong> Relationships between SHBG levels and calculated free estradiol fraction at fixed estradiol levels:</p>
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<htmlprotect><table><thead><tr><th colspan="2"><b>SHBG</b></th><th colspan="2"><b>Estradiol fixed ≤1,000 pg/mL</b></th><th colspan="2"><b>Estradiol fixed 20,000 pg/mL</b></th></tr><tr><th><b>Level</b></th><th><b>Change <sup>a</sup></b></th><th><b>Free E2 fraction</b></th><th><b>Change <sup>a</sup></b></th><th><b>Free E2 fraction</b></th><th><b>Change <sup>a</sup></b></th></tr></thead><tbody><tr><td>0 nmol/L</td><td>0.0×</td><td>3.26%</td><td>+77.2%</td><td>3.26%</td><td>+37.0%</td></tr><tr><td>25 nmol/L</td><td>0.5×</td><td>2.36%</td><td>+28.3%</td><td>2.78%</td><td>+16.8%</td></tr><tr><td>50 nmol/L</td><td>1.0×</td><td>1.84%</td><td>0%</td><td>2.38%</td><td>0%</td></tr><tr><td>75 nmol/L</td><td>1.5×</td><td>1.50%</td><td>–18.5%</td><td>2.04%</td><td>–14.3%</td></tr><tr><td>100 nmol/L</td><td>2.0×</td><td>1.27%</td><td>–31.0%</td><td>1.77%</td><td>–25.6%</td></tr><tr><td>125 nmol/L</td><td>2.5×</td><td>1.10%</td><td>–40.2%</td><td>1.54%</td><td>–35.3%</td></tr><tr><td>150 nmol/L</td><td>3.0×</td><td>0.97%</td><td>–47.3%</td><td>1.36%</td><td>–42.9%</td></tr><tr><td>200 nmol/L</td><td>4.0×</td><td>0.79%</td><td>–57.1%</td><td>1.08%</td><td>–54.6%</td></tr><tr><td>250 nmol/L</td><td>5.0×</td><td>0.66%</td><td>–64.1%</td><td>0.89%</td><td>–62.6%</td></tr><tr><td>300 nmol/L</td><td>6.0×</td><td>0.57%</td><td>–69.0%</td><td>0.75%</td><td>–68.5%</td></tr><tr><td>350 nmol/L</td><td>7.0×</td><td>0.50%</td><td>–72.8%</td><td>0.65%</td><td>–72.7%</td></tr><tr><td>400 nmol/L</td><td>8.0×</td><td>0.44%</td><td>–76.1%</td><td>0.57%</td><td>–76.1%</td></tr></tbody></table></htmlprotect>
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<p><sup>a</sup> Change relative to a reasonable non-pregnancy physiological value (specifically 50 nmol/L for SHBG, 1.84% for free E2 at a fixed level of ≤1,000 pg/mL, 2.38% for free E2 at a fixed level of 20,000 pg/mL).</p>
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<p>Androgen levels were set to female levels, estrone levels were set to be the same as estradiol levels, and all other inputs besides SHBG and total estradiol levels were left as the defaults. There was very little variation in free estradiol fractions with different estradiol levels at and below 1,000 pg/mL for each given level of SHBG (hence why the table says “Estradiol fixed ≤1,000 pg/mL”).</p>
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<p>The estradiol levels fixed to ≤1,000 pg/mL are intended to represent typical therapeutic circumstances while the estradiol levels fixed to 20,000 pg/mL are supposed to represent late pregnancy.</p>
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<p>Note that since estradiol induces SHBG production, SHBG levels are strongly correlated with estradiol levels. Generally speaking, when estradiol is low, SHBG will also be low, and when estradiol is high, SHBG will also be high. Hence, having highly divergent SHBG and estradiol levels as in the table would be very unusual and is physiologically unrealistic. It is only explored here as a thought experiment.</p>
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<p>Note again that these free estradiol numbers are calculated and hence are only estimates.</p>
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<h3 id="other-papers-on-calculation-of-free-hormone-levels">Other Papers on Calculation of Free Hormone Levels</h3>
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<p>Aside from <a href="https://doi.org/10.1016/j.steroids.2009.01.008">Mazer (2009)</a>, other papers like <a href="https://doi.org/10.1210/jcem.84.10.6079">Vermeulen, Verdonck, &amp; Kaufman (1999)</a> and <a href="https://cebp.aacrjournals.org/content/11/10/1065.short">Rinaldi et al. (2002)</a> also discuss calculation of free sex hormone levels and the validity of this approach.</p>
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<h3 id="other-online-free-hormone-calculators">Other Online Free Hormone Calculators</h3>
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<p>Another tool for calculating free estradiol and testosterone can be found <a href="https://diyhrt.cafe/free-e2-estimator/">here</a>. Various other free testosterone calculators also exist on the web (<a href="https://www.google.com/search?q=free+testosterone+calculator">Google Search</a>).</p>
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<h2 id="additional-literature-on-shbg-and-free-estradiol">Additional Literature on SHBG and Free Estradiol</h2>
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<h3 id="additional-shbg-and-free-estradiol-clinical-studies">Additional SHBG and Free Estradiol Clinical Studies</h3>
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<p>Some more good studies on SHBG and free estradiol that weren’t discussed in the main article:</p>
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<ul>
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<li><a href="https://doi.org/10.1530/acta.0.1010248">Odlind et al. (1982)</a> – various forms of estrogen on SHBG in cis women</li>
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<li><a href="https://doi.org/10.1016/S0015-0282(16)49633-0">Ben-Rafael et al. (1986)</a> [<a href="https://archive.is/lXeD9">Table</a>] – gonadotropin stimulation in cis women</li>
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<li><a href="https://doi.org/10.1016/0378-5122(88)90066-7">Carlström, Pschera, &amp; Lunell (1986)</a> [<a href="https://archive.is/584c1">Excerpt</a>] – vaginal estradiol in cis women + review</li>
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<li><a href="https://doi.org/10.1016/0378-5122(88)90062-X">Jasonni et al. (1988)</a> [<a href="https://archive.is/DR81U">Excerpt</a>] – transdermal estradiol in cis women + review</li>
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<li><a href="https://doi.org/10.1530/EJE-07-0511">Elaut et al. (2008)</a> [<a href="https://archive.is/7gF49">Table</a>] – various estrogens in transfeminine people</li>
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<li><a href="https://doi.org/10.1016/j.bone.2008.09.001">Lapauw et al. (2008)</a> [<a href="https://archive.is/4pEEk">Table</a>] – various estrogens in transfeminine people</li>
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<li><a href="https://doi.org/10.1089/trgh.2016.0016">Nelson et al. (2016)</a> [<a href="https://archive.is/MlUU5">Table</a>] – mainly high-dose injectable estradiol in transfeminine people</li>
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</ul>
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<h3 id="miscellaneous">Miscellaneous</h3>
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<p>A case report of a young woman with <a href="https://en.wikipedia.org/wiki/Estrogen_insensitivity_syndrome">estrogen insensitivity syndrome</a> (EIS) (i.e., defective ERα) suggests that the <a href="https://en.wikipedia.org/wiki/Estrogen_receptor_alpha">ERα</a> is the specific <a href="https://en.wikipedia.org/wiki/Estrogen_receptor">estrogen receptor</a> that is responsible for increased SHBG production and levels with estrogens (<a href="http://doi.org/10.1056/NEJMoa1303611">Quaynor et al., 2013</a>). Due to her EIS and lack of negative feedback on the hypothalamus–pituitary–gonadal axis, the woman had estradiol levels of as high as 3,500 pg/mL. In spite of this however, her SHBG levels remained less than 50 nmol/L. During pregnancy, at the point in the second trimester at which estradiol levels reach 3,000 pg/mL, SHBG levels are normally around 300 nmol/L on average (a 6-fold increase from a pre-pregnancy baseline of about 50 nmol/L).</p>
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<h2 id="references">References</h2>
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<ul>
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<li>Ben-Rafael, Z., Mastroianni, L., Meloni, F., Strauss, J. F., &amp; Flickinger, G. L. (1986). Changes in serum sex hormone-binding globulin, free estradiol, and testosterone during gonadotropin treatment. <em>Fertility and Sterility</em>, <em>46</em>(4), 593–598. [DOI:<a href="https://doi.org/10.1016/s0015-0282(16)49633-0">10.1016/s0015-0282(16)49633-0</a>]</li>
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<li>Carlström, K., Pschera, H., &amp; Lunell, N. (1988). Serum levels of oestrogens, progesterone, follicle-stimulating hormone and sex-hormone-binding globulin during simultaneous vaginal administration of 17β-oestradiol and progesterone in the pre- and post-menopause. <em>Maturitas</em>, <em>10</em>(4), 307–316. [DOI:<a href="https://doi.org/10.1016/0378-5122(88)90066-7">10.1016/0378-5122(88)90066-7</a>]</li>
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<li>Elaut, E., De Cuypere, G., De Sutter, P., Gijs, L., Van Trotsenburg, M., Heylens, G., Kaufman, J., Rubens, R., &amp; T’Sjoen, G. (2008). Hypoactive sexual desire in transsexual women: prevalence and association with testosterone levels. <em>European Journal of Endocrinology</em>, <em>158</em>(3), 393–399. [DOI:<a href="https://doi.org/10.1530/eje-07-0511">10.1530/eje-07-0511</a>]</li>
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<li>Jasonni, V., Bulletti, C., Naldi, S., Ciotti, P., Di Cosmo, D., Lazzaretto, R., &amp; Flamigni, C. (1988). Biological and endocrine aspects of transdermal 17β-oestradiol administration in post-menopausal women. <em>Maturitas</em>, <em>10</em>(4), 263–270. [DOI:<a href="https://doi.org/10.1016/0378-5122(88)90062-x">10.1016/0378-5122(88)90062-x</a>]</li>
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<li>Lapauw, B., Taes, Y., Simoens, S., Van Caenegem, E., Weyers, S., Goemaere, S., Toye, K., Kaufman, J., &amp; T’Sjoen, G. G. (2008). Body composition, volumetric and areal bone parameters in male-to-female transsexual persons. <em>Bone</em>, <em>43</em>(6), 1016–1021. [DOI:<a href="https://doi.org/10.1016/j.bone.2008.09.001">10.1016/j.bone.2008.09.001</a>]</li>
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<li>Mazer, N. A. (2009). A novel spreadsheet method for calculating the free serum concentrations of testosterone, dihydrotestosterone, estradiol, estrone and cortisol: With illustrative examples from male and female populations. <em>Steroids</em>, <em>74</em>(6), 512–519. [DOI:<a href="https://doi.org/10.1016/j.steroids.2009.01.008">10.1016/j.steroids.2009.01.008</a>]</li>
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<li>Nelson, M. D., Szczepaniak, L. S., Wei, J., Szczepaniak, E., Sánchez, F. J., Vilain, E., Stern, J. H., Bergman, R. N., Bairey Merz, C. N., &amp; Clegg, D. J. (2016). Transwomen and the Metabolic Syndrome: Is Orchiectomy Protective? <em>Transgender Health</em>, <em>1</em>(1), 165–171. [DOI:<a href="https://doi.org/10.1089/trgh.2016.0016">10.1089/trgh.2016.0016</a>]</li>
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<li>Odlind, V., Elamsson, K., Englund, D. E., Victor, A., &amp; Johansson, E. D. (1982). Effects of oestradiol on sex hormone binding globulin. <em>Acta Endocrinologica</em>, <em>101</em>(2), 248–253. [DOI:<a href="https://doi.org/10.1530/acta.0.1010248">10.1530/acta.0.1010248</a>] [<a href="https://web.archive.org/web/20190219195439/https://pdfs.semanticscholar.org/1db8/6cdc77c182def190c67cf37822d8da34f52d.pdf">PDF</a>]</li>
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<li>Quaynor, S. D., Stradtman, E. W., Kim, H., Shen, Y., Chorich, L. P., Schreihofer, D. A., &amp; Layman, L. C. (2013). Delayed Puberty and Estrogen Resistance in a Woman with Estrogen Receptor α Variant. <em>New England Journal of Medicine</em>, <em>369</em>(2), 164–171. [DOI:<a href="https://doi.org/10.1056/nejmoa1303611">10.1056/nejmoa1303611</a>]</li>
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<li>Rinaldi, S., Geay, A., Déchaud, H., Biessy, C., Zeleniuch-Jacquotte, A., Akhmedkhanov, A., Shore, R. E., Riboli, E., Toniolo, P., &amp; Kaaks, R. (2002). Validity of free testosterone and free estradiol determinations in serum samples from postmenopausal women by theoretical calculations. <em>Cancer Epidemiology and Prevention Biomarkers</em>, <em>11</em>(10), 1065–1071. [<a href="https://scholar.google.com/scholar?cluster=18409886331928026045">Google Scholar</a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/12376508/">PubMed</a>] [<a href="https://aacrjournals.org/cebp/article/11/10/1065/166164/Validity-of-Free-Testosterone-and-Free-Estradiol">URL</a>]</li>
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<li>Vermeulen, A., Verdonck, L., &amp; Kaufman, J. M. (1999). A critical evaluation of simple methods for the estimation of free testosterone in serum. <em>The Journal of Clinical Endocrinology &amp; Metabolism</em>, <em>84</em>(10), 3666–3672. [DOI:<a href="https://doi.org/10.1210/jcem.84.10.6079">10.1210/jcem.84.10.6079</a>]</li>
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</ul></content><author><name>{"first_name"=>"Aly", "last_name"=>"W.", "author-link"=>"/about/#aly", "articles-link"=>"/articles-by-author/aly/"}</name></author><category term="github" /><category term="workspace" /><summary type="html">Supplement: The Interactions of Sex Hormones with Sex Hormone-Binding Globulin and Relevance for Transfeminine Hormone Therapy By Aly | First published July 8, 2020 | Last modified March 14, 2023</summary></entry><entry><title type="html">Bicalutamide and its Adoption by the Medical Community for Use in Transfeminine Hormone Therapy</title><link href="https://transfemscience.org/articles/bica-adoption/" rel="alternate" type="text/html" title="Bicalutamide and its Adoption by the Medical Community for Use in Transfeminine Hormone Therapy" /><published>2020-07-01T18:39:00-07:00</published><updated>2023-04-17T00:00:00-07:00</updated><id>https://transfemscience.org/articles/bica-adoption</id><content type="html" xml:base="https://transfemscience.org/articles/bica-adoption/"><h1 id="bicalutamide-and-its-adoption-by-the-medical-community-for-use-in-transfeminine-hormone-therapy">Bicalutamide and its Adoption by the Medical Community for Use in Transfeminine Hormone Therapy</h1>
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<p>By
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<!-- First author --><a href="/about/#aly">Aly</a><!-- Second author --><!-- Third author --><!-- Fourth author --> | First published July 1, 2020
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| Last modified April 17, 2023</p>
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<h2 id="abstract--tldr">Abstract / TL;DR</h2>
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<p>Bicalutamide is an antiandrogen which was introduced for the treatment of prostate cancer many years ago. Cost precluded its widespread use for other indications for many years. However, its cost has since come down and bicalutamide is now seeing significant adoption for use in transfeminine hormone therapy as well as for treatment of androgen-dependent conditions in other populations like cisgender women. Bicalutamide has risks of certain rare adverse effects like liver toxicity which have generated concerns about its safety and have limited its use in transfeminine people. However, while still significant, these risks are low with appropriate monitoring and clinical management. Prominent researchers in transgender medicine have recently shown openness to bicalutamide for potential use in transfeminine people and have written positively about it. Bicalutamide could eventually come to be regarded as acceptably safe for use in transfeminine hormone therapy, similarly to other antiandrogens with rare risks like spironolactone and cyproterone acetate. However, more studies and characterization of bicalutamide in transfeminine people will likely be needed before it could see wider adoption in transgender medicine.</p>
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<h2 id="history-of-bicalutamide-for-transfeminine-people">History of Bicalutamide for Transfeminine People</h2>
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<p><a href="https://en.wikipedia.org/wiki/Bicalutamide">Bicalutamide</a> (Casodex) is a <a href="https://en.wikipedia.org/wiki/Nonsteroidal_antiandrogen">nonsteroidal antiandrogen</a> and <a href="https://en.wikipedia.org/wiki/Binding_selectivity">selective</a> <a href="https://en.wikipedia.org/wiki/Receptor_antagonist">antagonist</a> of the <a href="https://en.wikipedia.org/wiki/Androgen_receptor">androgen receptor</a> which was originally introduced for the treatment of <a href="https://en.wikipedia.org/wiki/Prostate_cancer">prostate cancer</a> in cisgender men in 1995. Prostate cancer is an <a href="https://en.wikipedia.org/wiki/Androgen-dependent_condition">androgen-dependent disease</a>, so antiandrogens are effective in treating it. Bicalutamide has major advantages over other antiandrogens such as <a href="https://en.wikipedia.org/wiki/Spironolactone">spironolactone</a> (Aldactone) and <a href="https://en.wikipedia.org/wiki/Cyproterone_acetate">cyproterone acetate</a> (Androcur) in terms of <a href="https://en.wikipedia.org/wiki/Antiandrogen">antiandrogenic</a> <a href="https://en.wikipedia.org/wiki/Potency_(pharmacology)">potency</a>, <a href="https://en.wikipedia.org/wiki/Clinical_effectiveness">clinical effectiveness</a>, <a href="https://en.wikipedia.org/wiki/Binding_selectivity">pharmacological selectivity</a>, and <a href="https://en.wikipedia.org/wiki/Tolerability">tolerability</a>. It also has improved potency, <a href="https://en.wikipedia.org/wiki/Pharmacokinetics">pharmacokinetic</a> properties, and tolerability, as well as far better <a href="https://en.wikipedia.org/wiki/Drug_safety">safety</a>, compared to the older nonsteroidal antiandrogens <a href="https://en.wikipedia.org/wiki/Flutamide">flutamide</a> (Eulexin) and <a href="https://en.wikipedia.org/wiki/Nilutamide">nilutamide</a> (Anandron, Nilandron). However, use of bicalutamide as an antiandrogen in transfeminine hormone therapy is very recent. The employment of bicalutamide for transfeminine people was largely precluded for many years by the fact that bicalutamide had pharmaceutical patent protection and was very expensive. However, this changed with the availability of generic versions of bicalutamide starting in 2007 to 2009. In addition, newer and more effective antiandrogens like <a href="https://en.wikipedia.org/wiki/Abiraterone_acetate">abiraterone acetate</a> (Zytiga) in 2011 and <a href="https://en.wikipedia.org/wiki/Enzalutamide">enzalutamide</a> (Xtandi) in 2012 were introduced and superseded bicalutamide as the <a href="https://en.wikipedia.org/wiki/Standard_of_care#Medical_standard_of_care">standard-of-care</a> antiandrogen for the treatment of prostate cancer. These developments have greatly reduced the cost of bicalutamide and it has gradually become much more affordable in the last decade.</p>
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<p>Before 2015, there were only a few mentions in the literature of bicalutamide for transfeminine people and a handful of anecdotal reports online of transfeminine people using it. The earliest clear mention of bicalutamide in the literature in the context of transfeminine hormone therapy was by <a href="https://en.wikipedia.org/wiki/Louis_Gooren">Louis Gooren</a> in 2011 (<a href="http://doi.org/10.1056/NEJMcp1008161">Gooren, 2011</a>). Gooren is a major longtime researcher in the field of transgender medicine and is one of the coauthors of the <a href="https://en.wikipedia.org/wiki/Endocrine_Society">Endocrine Society</a>’s transgender hormone therapy guidelines (<a href="https://doi.org/10.1210/jc.2009-0345">Hembree et al., 2009</a>; <a href="https://doi.org/10.1210/jc.2017-01658">Hembree et al., 2017</a>). He and his colleagues at the <a href="https://en.wikipedia.org/wiki/Center_of_Expertise_on_Gender_Dysphoria">Center of Expertise on Gender Dysphoria</a> of the <a href="https://en.wikipedia.org/wiki/VU_University_Medical_Center">Vrije Universiteit Medical Center</a> (VUMC) in Amsterdam, Netherlands had conducted studies on <a href="https://en.wikipedia.org/wiki/Nilutamide">nilutamide</a> (Anandron, Nilandron) as an antiandrogen for transfeminine people in the late 1980s and early 1990s (<a href="https://kinseyinstitute.org/pdf/HBIGDA_S10_1987OCR.pdf#page=55">de Voogt et al., 1987a</a>; <a href="https://doi.org/10.1002/pros.2990110403">de Voogt et al., 1987b</a>; <a href="https://doi.org/10.1210/jcem-64-4-763">Gooren et al., 1987</a>; <a href="https://kinseyinstitute.org/pdf/HBIGDA_S10_1987OCR.pdf#page=35">Johannes et al., 1987</a>; <a href="https://doi.org/10.1016/0022-4731(88)90024-6">Rao et al., 1988</a>; <a href="https://doi.org/10.1111/j.1365-2230.1989.tb02585.x">Asscheman, Gooren, &amp; Peereboom-Wynia, 1989</a>; <a href="https://doi.org/10.1007/BF01543196">van Kemenade et al., 1989</a>; <a href="https://en.wikipedia.org/wiki/Nilutamide#Transgender_hormone_therapy">Wiki</a>). However, they seem to have abandoned it—probably due to its high incidence of lung toxicity and other <a href="https://en.wikipedia.org/wiki/Off-target_activity">off-target</a> side effects. Nonetheless, Gooren began including nonsteroidal antiandrogens like flutamide and nilutamide in his publications as potential treatment options for transfeminine hormone therapy starting in the 1990s (<a href="https://doi.org/10.1300/J056v05n04_03">Asscheman &amp; Gooren, 1992</a>; <a href="http://web.archive.org/web/20070430161048/http://www.symposion.com/ijt/ijt990301.htm">Gooren, 1999</a>). Subsequently, flutamide was included in transgender health guidelines and other publications, though not necessarily favorably (e.g., <a href="https://books.google.com/books?id=IlPX6E5glDEC&amp;pg=PA66">Israel &amp; Tarver, 1997</a>; <a href="https://doi.org/10.1046/j.1365-2265.2003.01821.x">Levy, Crown, &amp; Reid, 2003</a>; <a href="https://doi.org/10.1300/J485v09n03_06">Dahl et al., 2006a</a>; <a href="https://www.cpath.ca/wp-content/uploads/2009/12/guidelines-endocrine.pdf">Dahl et al., 2006b</a>; <a href="https://doi.org/10.1210/jc.2009-0345">Hembree et al., 2009</a>; <a href="https://doi.org/10.1016/j.endoen.2012.07.004">Moreno-Pérez et al., 2012</a>). As a researcher interested in nonsteroidal antiandrogens for transfeminine people, bicalutamide—with its far better safety profile than flutamide and nilutamide—may have been appealing to Gooren. However, Gooren and his colleagues didn’t conduct clinical studies on bicalutamide for transfeminine people and never went beyond brief mention of it for such uses in their publications. Nor did any other academics.</p>
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<p>Besides transfeminine people and men with prostate cancer, bicalutamide has been studied for use in the treatment of androgen-dependent conditions in other populations. For example, it has been used in the treatment of <a href="https://en.wikipedia.org/wiki/Hirsutism">hirsutism</a> (excessive facial/body hair growth) in cisgender women with and without <a href="https://en.wikipedia.org/wiki/Polycystic_ovary_syndrome">polycystic ovary syndrome</a> (PCOS) (<a href="https://doi.org/10.1093/humrep/14.Suppl_3.366-a">Müderris, Bayram, &amp; Güven, 1999</a>; <a href="https://doi.org/10.1080/gye.16.1.63.66">Müderris et al., 2002</a>; <a href="https://doi.org/10.1159/000081973">Bahceci et al., 2004</a>; <a href="https://www.turkiyeklinikleri.com/article/en-hirsutizm-tedavisinde-flutamid-ve-bikalutamid-kullanimi-55753.html">Müderris &amp; Öner, 2009</a>; <a href="https://endo.confex.com/endo/2016endo/webprogram/Paper26631.html">Moretti et al., 2016</a>; <a href="https://doi.org/10.1210/jc.2017-01186">Moretti et al., 2018</a>; <a href="https://en.wikipedia.org/wiki/Medical_uses_of_bicalutamide#Medical_uses_of_bicalutamide#Skin_and_hair_conditions">Wiki</a>). Bicalutamide has also been studied in combination with <a href="https://en.wikipedia.org/wiki/Anastrozole">anastrozole</a> (Arimidex), an <a href="https://en.wikipedia.org/wiki/Aromatase_inhibitor">aromatase inhibitor</a>, for the treatment of <a href="https://en.wikipedia.org/wiki/Familial_male-limited_precocious_puberty">gonadotropin-independent precocious puberty</a> in cisgender boys (<a href="https://doi.org/10.1016/j.jpeds.2006.04.027">Kreher et al., 2006</a>; <a href="https://doi.org/10.1159/000239668">Lewis et al., 2009</a>; <a href="https://doi.org/10.1515/JPEM.2009.22.12.1163">Mitre &amp; Lteif, 2009</a>; <a href="https://doi.org/10.1159/000239668">Stenger et al., 2009</a>; <a href="https://doi.org/10.1542/peds.2010-0596">Lenz et al., 2010</a>; <a href="https://doi.org/10.1515/jpem.2010.161">Reiter et al., 2010</a>; <a href="https://doi.org/10.1507/endocrj.ej11-0214">Tessaris et al., 2012</a>; <a href="https://doi.org/10.4274/jcrpe.2067">Özcabı et al., 2015</a>; <a href="https://doi.org/10.1007/s42000-018-0029-1">Kor, 2018</a>; <a href="https://doi.org/10.1515/jpem-2018-0419">Arya &amp; Davies, 2019</a>; <a href="https://doi.org/10.4158/ACCR-2018-0246">Nabhan &amp; Eugster, 2019</a>; <a href="https://doi.org/10.1097/DBP.0000000000000865">Finkle et al., 2020</a>; <a href="https://doi.org/10.4274/jcrpe.galenos.2020.2020.0067">Gurnurkar, DiLillo, &amp; Carakushansky, 2021</a>; <a href="https://en.wikipedia.org/wiki/Medical_uses_of_bicalutamide#Male_early_puberty">Wiki</a>). This is a rare form of <a href="https://en.wikipedia.org/wiki/Precocious_puberty">precocious puberty</a> in which <a href="https://en.wikipedia.org/wiki/Gonadotropin-releasing_hormone_modulator">gonadotropin-releasing hormone modulators</a> are not effective. A <a href="https://en.wikipedia.org/wiki/Phases_of_clinical_research#Phase_II">phase 2</a> clinical trial was completed and a <a href="https://en.wikipedia.org/wiki/New_Drug_Application">New Drug Application</a> (NDA) was submitted in the United States for treatment of the condition with bicalutamide and anastrozole, but the application was not approved due to inadequate evidence of effectiveness on the primary efficacy endpoint of limiting height (<a href="https://web.archive.org/web/20190730023433/https://www.fda.gov/media/75809/download">AstraZeneca, 2008</a>). However, bicalutamide is still used <a href="https://en.wikipedia.org/wiki/Off-label_use">off-label</a> for this indication, and information on bicalutamide for this use is provided in the the Casodex <a href="https://en.wikipedia.org/wiki/Food_and_Drug_Administration">Food and Drug Administration</a> (FDA) label (<a href="https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/020498s028lbl.pdf">FDA, 2017</a>).</p>
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<p>Although there was little discussion or use of bicalutamide in transfeminine people prior to 2015, this started to change in mid-2015. At that time, the <a href="https://en.wikipedia.org/wiki/Bicalutamide">Wikipedia content for bicalutamide</a> was greatly expanded, which made information about bicalutamide more accessible. In addition, certain transfeminine people, noting its advantages over existing options and its excellent potential for use in transfeminine hormone therapy, began advocating for use of bicalutamide in transfeminine people in online circles. A number of open-minded clinicians started adopting bicalutamide in transfeminine people around this time and thereafter as well. The first clinical study of bicalutamide in transfeminine people, which began in 2013, was published as an abstract in 2017 and as a full paper in 2019 (<a href="https://files.transfemscience.org/pdfs/Neyman,%20Fuqua,%20&amp;%20Eugster%20(2017)%20-%20Bicalutamide%20as%20an%20Androgen%20Blocker%20with%20Secondary%20Effect%20of%20Promoting%20Feminization%20in%20Male%20to%20Female%20(MTF)%20Transgender%20Adolescents.pdf#page=4">Neyman, Fuqua, &amp; Eugster, 2017</a>; <a href="https://doi.org/10.1016/j.jadohealth.2018.10.296">Neyman, Fuqua, &amp; Eugster, 2019</a>). It was a small retrospective chart review of bicalutamide alone as a second-line <a href="https://en.wikipedia.org/wiki/Puberty_blocker">puberty blocker</a> in adolescent transgender girls for whom <a href="https://en.wikipedia.org/wiki/Gonadotropin-releasing_hormone_analogue">gonadotropin-releasing hormone analogues</a> were denied by insurance. As of present, it remains the only published clinical data on bicalutamide in transfeminine people. It’s not exactly great data by any means, but it’s a study at least. The researchers who conducted the study had previously published on bicalutamide as a puberty blocker in boys with gonadotropin-independent precocious puberty (e.g., <a href="https://doi.org/10.1542/peds.2010-0596">Lenz et al., 2010</a>; <a href="https://doi.org/10.1007/978-1-4419-1795-9_71">Haddad &amp; Eugster, 2012</a>). While limited in its findings, <a href="https://doi.org/10.1016/j.jadohealth.2018.10.296">Neyman, Fuqua, and Eugster (2019)</a> helped to generate significant interest among clinicians and researchers in bicalutamide for use in transfeminine hormone therapy.</p>
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<p>In any case, due to the recent nature of bicalutamide as an option for use in transfeminine hormone therapy, as well as the lack of studies and characterization of bicalutamide in transfeminine people and concerns about its safety (see <a href="#concerns-about-bicalutamide-limiting-its-use">next section</a>), bicalutamide isn’t widely used in transfeminine people at this time. In fact, transgender hormone therapy guidelines largely don’t even mention it still. At present, the use of bicalutamide in transfeminine people is mostly limited to a number of more flexible clinicians and to people in the transgender <a href="https://en.wikipedia.org/wiki/Self-medication">do-it-yourself</a> (DIY) hormone therapy community.</p>
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<h2 id="concerns-about-bicalutamide-limiting-its-use">Concerns About Bicalutamide Limiting its Use</h2>
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<p>The transgender medical community has been reluctant to endorse the use of bicalutamide in transfeminine people to date. This is because of the lack of clinical studies and characterization of bicalutamide in transfeminine people, most importantly in terms of safety. There have been concerns about rare instances of <a href="https://en.wikipedia.org/wiki/Liver_failure">liver failure</a> that have occurred with bicalutamide in men with prostate cancer (<a href="https://en.wikipedia.org/wiki/Side_effects_of_bicalutamide#Liver_toxicity">Wiki</a>). The reported cases of liver toxicity with bicalutamide have generally been sudden-onset and severe. Rare liver toxicity is an acceptable risk in men with prostate cancer because the <a href="https://en.wikipedia.org/wiki/Risk%E2%80%93benefit_ratio">risk–benefit ratio</a> of bicalutamide therapy is very favorable, with the benefit of treating prostate cancer vastly outweighing the harm of the very rare instances of liver problems. But transfeminine people are typically young and healthy, and bicalutamide isn’t treating a terminal illness when it’s used in us. If a transfeminine person develops liver failure and dies because of bicalutamide, that’s unnecessary harm and a life needlessly lost. Accordingly, the <a href="https://en.wikipedia.org/wiki/University_of_California,_San_Francisco">University of California San Francisco</a> (UCSF) transgender care guidelines warn against use of bicalutamide in transfeminine people currently due to potential liver risks (<a href="https://transcare.ucsf.edu/guidelines">Deutsch, 2016</a>). Aside from risks, there is also a lack of data to guide appropriate dosing of bicalutamide in transfeminine people at this time. A typical bicalutamide dosage of 50 mg/day is being used and recommended, but this has been arbitrarily chosen with little basis to support it.</p>
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<p>To date, there are 10 published case reports of serious <a href="https://en.wikipedia.org/wiki/Hepatotoxicity">liver toxicity</a> in association with bicalutamide (<a href="https://en.wikipedia.org/wiki/Template:Published_case_reports_of_bicalutamide-associated_liver_injury">Table</a>). All of these cases were in men with prostate cancer and all occurred within 6 months of initiation of bicalutamide therapy, with two of the cases resulting in death. While this is not a lot of cases and may seem reassuring, it must be noted that quantity of published case reports tends to vastly underestimate the true incidence of rare adverse reactions. As an example, there are around 50 published case reports of meningioma with cyproterone acetate (<a href="https://en.wikipedia.org/wiki/Template:Published_case_reports_of_cyproterone_acetate-associated_meningioma">Table</a>), but a recent large study by the French government found that there were more than 500 <em>operated</em> instances of meningioma in association with high-dose cyproterone acetate over an 8-year period in France alone (<a href="/articles/cpa-meningioma/">Aly, 2020</a>). Accordingly, as of writing there are 40 reports of liver failure, including 25 consequent deaths, in association with bicalutamide in the U.S. FDA’s international <a href="https://www.fda.gov/drugs/questions-and-answers-fdas-adverse-event-reporting-system-faers/fda-adverse-event-reporting-system-faers-public-dashboard">MedWatch/FAERS database</a>. (As well as 240 cases of <a href="https://en.wikipedia.org/wiki/Interstitial_lung_disease">interstitial lung disease</a> associated with bicalutamide notably—relative to only 14 published case reports; <a href="https://en.wikipedia.org/wiki/Template:Published_case_reports_of_bicalutamide-associated_lung_toxicity">Table</a>.) Even with this database however, fewer than 10% of serious adverse reactions are estimated to be reported (<a href="https://doi.org/10.1002/0470853093.ch17">Graham, Ahmad, &amp; Piazza-Hepp, 2002</a>). Hence, the true numbers may be much greater. These instances are merely co-occurrences, and causality in terms of bicalutamide and liver toxicity has not been established. But they are concerning nonetheless. There is additionally an unpublished case anecdote of death in a young transfeminine person associated with bicalutamide that’s been making its rounds through the transgender medical community. Per certain very credible people in the field of transgender medicine (e.g., <a href="https://callen-lorde.org/providers/asa-radix/">Asa Radix</a> and <a href="https://callen-lorde.org/providers/zil-goldstein/">Zil Goldstein</a>), she is said to have been a 20-year-old transgender girl in Texas taking bicalutamide with rapid-onset liver failure and no warning signs. This case has given clinicians and researchers who are aware of it reservations about the use of bicalutamide in hormone therapy for transfeminine people. Another case of liver failure and death in a transgender person over 60 years of age who was treated with bicalutamide has also been informally reported (<a href="https://queerdoc.com/how-do-you-know-which-t-blocker-to-take-what-is-going-on-with-bica/">QueerDoc</a>).</p>
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<p>In any case, the reported cases of serious liver toxicity with bicalutamide in transgender people have not been published nor properly confirmed. In addition, the absolute incidence of liver toxicity with bicalutamide is likely to be very low. For instance, the incidence of abnormal <a href="https://en.wikipedia.org/wiki/Liver_function_tests">liver function tests</a> (i.e., <a href="https://en.wikipedia.org/wiki/Elevated_transaminases">elevated liver enzymes</a> on <a href="https://en.wikipedia.org/wiki/Blood_test">blood work</a>) was only 3.4% with high-dose (150 mg/day) bicalutamide monotherapy relative to 1.9% for placebo (a 1.5% difference attributable to bicalutamide) at 3.0 years of follow-up in the <a href="https://en.wikipedia.org/wiki/Early_Prostate_Cancer_(clinical_programme)">Early Prostate Cancer</a> (EPC) clinical programme, a series of three <a href="https://en.wikipedia.org/wiki/Phases_of_clinical_research#Phase_III">phase 3</a> <a href="https://en.wikipedia.org/wiki/Randomized_controlled_trial">randomized controlled trials</a> consisting of over 8,000 patients in which bicalutamide was evaluated for treatment of early prostate cancer (<a href="https://doi.org/10.1046/j.1464-410X.2003.04026.x">Anderson, 2003</a>; <a href="https://doi.org/10.1097/01.ju.0000139719.99825.54">Iversen et al., 2004</a>; <a href="https://en.wikipedia.org/wiki/Side_effects_of_bicalutamide#Liver_toxicity">Wiki</a>; <a href="https://en.wikipedia.org/wiki/Early_Prostate_Cancer_(clinical_programme)">Wiki</a>). Moreover, there were no cases of serious liver toxicity or liver failure with bicalutamide in the initial clinical development programme of bicalutamide for advanced prostate cancer, in which almost 4,000 men were treated with bicalutamide (<a href="https://doi.org/10.1159/000473847">Blackledge, 1996</a>; <a href="https://doi.org/10.1016/S0090-4295(96)80012-4">Kolvenbag &amp; Blackledge, 1996</a>; <a href="https://doi.org/10.1634/theoncologist.2-1-18">McLeod, 1997</a>; <a href="https://doi.org/10.1046/j.1464-410X.2003.04026.x">Anderson, 2003</a>; <a href="https://doi.org/10.1097/01.ju.0000139719.99825.54">Iversen et al., 2004</a>; <a href="https://en.wikipedia.org/wiki/Side_effects_of_bicalutamide#Liver_toxicity">Wiki</a>). However, it should be noted that this was with careful monitoring of liver function in patients and with prompt discontinuation of bicalutamide upon detection of clinically concerning hepatic abnormalities. About 0.5 to 1.5% of men taking 50 to 150 mg/day bicalutamide in the major clinical programmes of bicalutamide for prostate cancer developed liver changes sufficiently marked that they required discontinuation (<a href="https://doi.org/10.1159/000473847">Blackledge, 1996</a>; <a href="https://doi.org/10.1016/S0022-5347(05)64652-6">See et al., 2002</a>; <a href="https://en.wikipedia.org/wiki/Side_effects_of_bicalutamide#Liver_toxicity">Wiki</a>). Hence, regular liver monitoring is essential with bicalutamide to ensure that the possibility of severe liver toxicity is avoided.</p>
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<p>Bicalutamide has a much lower risk of liver toxicity than its analogue flutamide (<a href="https://doi.org/10.1016/S0090-4295(96)80012-4">Kolvenbag &amp; Blackledge, 1996</a>; <a href="https://doi.org/10.1016/s0090-4295(97)00279-3">Schellhammer et al., 1997</a>; <a href="https://doi.org/10.1159/000081585">Thole et al., 2004</a>; <a href="https://doi.org/10.1002/pds.1168">Manso et al., 2006</a>; <a href="https://en.wikipedia.org/wiki/Template:Side_effects_of_combined_androgen_blockade_with_nonsteroidal_antiandrogens">Table</a>). However, it retains a small risk of liver toxicity of its own—one with the potential for serious consequences. Hence, caution is warranted with its use, and careful liver monitoring is a necessity for anyone taking it.</p>
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<h2 id="recent-developments-and-the-future">Recent Developments and the Future</h2>
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<p>Bicalutamide is currently being adopted and characterized for use in the treatment androgen-dependent skin and hair conditions in cisgender women. For instance, a rigorous Italian phase 3 randomized controlled trial of bicalutamide for hirsutism was recently published (<a href="https://doi.org/10.1210/jc.2017-01186">Moretti et al., 2018</a>). Retrospective chart reviews of bicalutamide for scalp hair loss in cisgender women have also been published recently (<a href="https://doi.org/10.1111/dth.13096">Fernandez-Nieto et al., 2019</a>; <a href="https://doi.org/10.1016/j.jaad.2020.03.034">Ismail et al., 2020</a>; <a href="https://doi.org/10.1016/j.jaad.2020.04.054">Fernandez-Nieto et al., 2020</a>; <a href="https://doi.org/10.1016/j.jaad.2021.10.048">Moussa et al., 2021</a>). The hair loss studies have observed low though significant rates of liver changes with bicalutamide.</p>
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<p>Certain transgender medical researchers are showing interest in bicalutamide as well. Perhaps most notably, Wylie Hembree—the lead author of the Endocrine Society’s 2009 and 2017 transgender hormone therapy guidelines (<a href="https://doi.org/10.1210/jc.2009-0345">Hembree et al., 2009</a>; <a href="https://doi.org/10.1210/jc.2017-01658">Hembree et al., 2017</a>)—wrote positively about bicalutamide for transfeminine people in a recent review (<a href="https://doi.org/10.1007/978-3-030-05683-4_8">Fishman, Paliou, Poretsky, &amp; Hembree, 2019</a>). He and his colleagues cited the recent phase 3 trial of bicalutamide for hirsutism in cisgender women and the study of bicalutamide as a puberty blocker in transgender girls in support of potential use of bicalutamide for transfeminine people. <a href="https://nl.wikipedia.org/wiki/Guy_T'Sjoen">Guy T’Sjoen</a>—another major researcher in transgender medicine and co-author of the Endocrine Society guidelines (<a href="https://doi.org/10.1210/jc.2017-01658">Hembree et al., 2017</a>; <a href="https://doi.org/10.1016/S2213-8587(20)30192-3">Mitchell, 2020</a>)—seemed to show openness to bicalutamide with his colleagues in a recent review as well (<a href="https://doi.org/10.1177%2F2042018819871166">Iwamoto et al., 2019</a>). Researchers outside of the United States in particular may be more open to bicalutamide, owing to accumulating health concerns with cyproterone acetate—the most commonly used antiandrogen outside of the United States (<a href="/articles/cpa-meningioma/">Aly, 2020</a>). John Randolph, a researcher at the University of Michigan, has also written positively about bicalutamide (<a href="http://doi.org/10.1097/GRF.0000000000000396">Randolph, 2018</a>), though he may have since changed his mind on it (<a href="http://www.med.umich.edu/1libr/ComprehensiveGenderServicesProgram/MMapproachFemGenderAffirmingHormones.pdf">Michigan Medicine, 2020</a>). On the other hand, other authors have not been as welcoming of bicalutamide for transfeminine people (e.g., <a href="https://doi.org/10.1016/j.ecl.2019.02.001">Hamidi &amp; Davidge-Pitts, 2019</a>; <a href="https://doi.org/10.3390/jcm9061609">Cocchetti et al., 2020</a>).</p>
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<p>The small risks of bicalutamide with appropriate monitoring may prove to be acceptable to the transgender medical community. This would perhaps be analogous to the rare incidences of serious adverse effects with say spironolactone (e.g., hyperkalemia) or cyproterone acetate (e.g., benign brain tumors, blood clots, breast cancer, liver toxicity). It’s possible that bicalutamide may not ultimately be recommended as a first-line therapy due to its risks. However, it could still be allowed as a second-line option when other antiandrogens are less feasible or not possible due to being for instance inadequately effective, poorly tolerated, <a href="https://en.wikipedia.org/wiki/Contraindication">contraindicated</a>, or unavailable. The transgender medical community isn’t there at this time though. More developments—namely studies and characterization of bicalutamide in actual transfeminine people—are likely to be needed before bicalutamide could become more accepted for use in transfeminine people or recommended in transgender hormone therapy guidelines.</p>
|
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<h2 id="updates">Updates</h2>
|
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|
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<h3 id="update-1-thompson-et-al-2021-fenway-health-guidelines">Update 1: Thompson et al. (2021) [Fenway Health Guidelines]</h3>
|
||
|
||
<p>In March 2021, the <a href="https://en.wikipedia.org/wiki/Fenway_Health">Fenway Health</a> transgender health clinical practice guidelines were updated from the last version (October 2015) to the following latest edition (<a href="/articles/transfem-hormone-guidelines/">Aly, 2020</a>):</p>
|
||
|
||
<ul>
|
||
<li>Thompson, J., Hopwood, R. A., deNormand, S., &amp; Cavanaugh, T. (2021). <em>Medical Care of Trans and Gender Diverse Adults.</em> Boston: Fenway Health. [<a href="https://www.lgbtqiahealtheducation.org/publication/medical-care-of-trans-and-gender-diverse-adults-2021/">URL</a>] [<a href="https://www.lgbtqiahealtheducation.org/wp-content/uploads/2021/07/Medical-Care-of-Trans-and-Gender-Diverse-Adults-Spring-2021.pdf">PDF</a>]</li>
|
||
</ul>
|
||
|
||
<p>This update is notable as these guidelines included bicalutamide as an antiandrogen option for transfeminine people. While they did not recommend bicalutamide as a first-line agent due to its limited characterization in transfeminine people and its known small risk of liver toxicity, they were cautiously permissive of its use in transfeminine hormone therapy:</p>
|
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|
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<blockquote>
|
||
<p>Bicalutamide can be used for [gender-affirming hormone therapy], but there are very few studies examining its use and the relative risk/benefit for this purpose. Because of reported cases of fulminant hepatitis, consensus is that its use in gender affirming hormonal regimen should be carefully considered, used only after alternative options have been trialed or offered, and an in-depth discussion of these potential risks have been had.</p>
|
||
</blockquote>
|
||
|
||
<p>These are the first transgender care guidelines to allow the use of bicalutamide, and only the second guidelines to include bicalutamide. Previously, only the UCSF guidelines mentioned bicalutamide, but they were not permissive of its use in transfeminine people.</p>
|
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|
||
<h3 id="update-2-tomson-et-al-2021-sahcs-guidelines">Update 2: Tomson et al. (2021) [SAHCS Guidelines]</h3>
|
||
|
||
<p>In September 2021, the <a href="https://sahivsoc.org/">Southern African HIV Clinicians Society</a> (SAHCS) published clinical guidelines for transgender care for the first time:</p>
|
||
|
||
<ul>
|
||
<li>Tomson, A., McLachlan, C., Wattrus, C., Adams, K., Addinall, R., Bothma, R., Jankelowitz, L., Kotze, E., Luvuno, Z., Madlala, N., Matyila, S., Padavatan, A., Pillay, M., Rakumakoe, M. D., Tomson-Myburgh, M., Venter, W., &amp; de Vries, E. (2021). Southern African HIV Clinicians’ Society gender-affirming healthcare guideline for South Africa. <em>Southern African Journal of HIV Medicine</em>, <em>22</em>(1), a1299. [DOI:<a href="https://doi.org/10.4102/sajhivmed.v22i1.1299">10.4102/sajhivmed.v22i1.1299</a>] [<a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8517808/pdf/HIVMED-22-1299.pdf">PDF</a>]</li>
|
||
</ul>
|
||
|
||
<p>Surprisingly, these guidelines not only included bicalutamide but recommended it as the preferred antiandrogen over spironolactone and cyproterone acetate. The reason stated for this was “less risk of neurosteroid depletion (does not cross blood-brain-barrier readily).” However, this supposed effect isn’t a known concern with antiandrogens besides <a href="https://en.wikipedia.org/wiki/5%CE%B1-Reductase_inhibitor">5α-reductase inhibitors</a>, and bicalutamide actually does appear to be centrally permeable in humans (<a href="https://en.wikipedia.org/wiki/Pharmacology_of_bicalutamide#Distribution">Wiki</a>). Also surprisingly, no mention of liver toxicity or liver enzyme monitoring with bicalutamide was made in these guidelines. Considering these apparent oversights and others, these guidelines’s recommendations should probably be interpreted with caution.</p>
|
||
|
||
<h3 id="update-3-coleman-et-al-2022-wpath-soc8-guidelines">Update 3: Coleman et al. (2022) [WPATH SOC8 Guidelines]</h3>
|
||
|
||
<p>In September 2022, the <a href="https://en.wikipedia.org/wiki/World_Professional_Association_for_Transgender_Health">World Professional Association for Transgender Health</a> (WPATH) <a href="https://en.wikipedia.org/wiki/Standards_of_Care_for_the_Health_of_Transgender_and_Gender_Diverse_People">Standards of Care for the Health of Transgender and Gender Diverse People</a> Version 8 (SOC8) were published (<a href="https://doi.org/10.1080/26895269.2022.2100644">Coleman et al., 2022</a>). The WPATH SOC8 are among the most important if not the most important transgender care guidelines that exist and that are consulted by health care professionals. These guidelines briefly discussed bicalutamide including in the following two instances:</p>
|
||
|
||
<blockquote>
|
||
<p>Bicalutamide is an antiandrogen that has been used in the treatment of prostate cancer. It competitively binds to the androgen receptor to block the binding of androgens. Data on the use of bicalutamide in trans feminine populations is very sparse and safety data is lacking. One small study looked at the use of bicalutamide 50 mg daily as a puberty blocker in 23 trans feminine adolescents who could not obtain treatment with a GnRH analogue (Neyman et al., 2019). All adolescents experienced breast development which is also commonly seen in men with prostate cancer who are treated with bicalutamide. Although rare, fulminant hepatotoxicity resulting in death has been described with bicalutamide (O’Bryant et al., 2008). Given that bicalutamide has not been adequately studied in trans feminine populations, we do not recommend its routine use.</p>
|
||
</blockquote>
|
||
|
||
<blockquote>
|
||
<p>When selecting a medication, we advise using those which have been studied in multiple transgender populations (i.e., estrogen, cyproterone acetate, GnRH agonists) rather than medications with little to no peer-reviewed scientific studies (i.e., bicalutamide, rectal progesterone, etc.) (Angus et al., 2021; Butler et al., 2017; Efstathiou et al., 2019; Tosun et al., 2019).</p>
|
||
</blockquote>
|
||
|
||
<p>As can be seen, the WPATH SOC8 did not recommend the routine use of bicalutamide in transfeminine people owing to the lack of studies of it in this population and its potential risks. As touched on in the present article, it is likely that more studies of bicalutamide in transfeminine people will be needed before bicalutamide could become endorsed by major transgender care guidelines.</p>
|
||
|
||
<h3 id="update-4-jamie-reed-2023-bicalutamide-liver-toxicity-case">Update 4: Jamie Reed 2023 Bicalutamide Liver Toxicity Case</h3>
|
||
|
||
<p>In February 2023, Jamie Reed, a former case manager at the <a href="https://physicians.wustl.edu/specialties/lgbtq-health/washington-university-transgender-center/">The Washington University Transgender Center</a> at <a href="https://en.wikipedia.org/wiki/St._Louis_Children%27s_Hospital">St. Louis Children’s Hospital</a> in St. Louis, Missouri, published the op-ed <a href="https://www.thefp.com/p/i-thought-i-was-saving-trans-kids">“I Thought I Was Saving Trans Kids. Now I’m Blowing the Whistle.”</a> in a conservative online news outlet called <em><a href="https://en.wikipedia.org/wiki/The_Free_Press_(media_company)">The Free Press</a></em>. In this article, Reed expressed that she had become disillusioned with the medical care of transgender youth and layed out her grievances. In addition however, she briefly described an additional case of liver toxicity with bicalutamide in a transfeminine person that had allegedly occurred at her center. This individual was said to be 15 years of age and was given bicalutamide as a puberty blocker by <a href="https://profiles.wustl.edu/en/persons/christopher-lewis">Dr. Christopher Lewis</a>, one of the co-founders of the center. She was said to have subsequently developed liver toxicity and was taken off of bicalutamide. In an electronic message to the center, her mother said that they were “lucky her family was not the type to sue”. This instance, and Reed’s op-ed in general, were subsequently widely reported on in conservative news media, for instance on Fox News and in the <em>Daily Mail</em> (<a href="https://www.google.com/search?q=%22jamie+reed%22+bicalutamide+transgender+OR+trans+OR+gender-affirming&amp;tbs=cdr%3A1%2Ccd_min%3A2%2F9%2F2023%2Ccd_max%3A2%2F28%2F2023">Google</a>). In addition to her op-ed, Reed provided a sworn affidavit to the office of Republican Missouri attorney general <a href="https://en.wikipedia.org/wiki/Andrew_Bailey_(politician)">Andrew Bailey</a>, who proceeded to launch an investigation of the clinic (<a href="https://ago.mo.gov/home/news/2023/02/09/missouri-attorney-general-andrew-bailey-confirms-launch-of-multi-agency-investigation-into-st.-louis-transgender-center-for-harming-hundreds-of-children">Missouri Government, 2023a</a>). The following further information was released in the affidavit:</p>
|
||
|
||
<blockquote>
|
||
<p>One doctor at the Center, Dr. Chris Lewis, is giving patients a drug called Bicalutamide. The drug has a legitimate use for treating pancreatic cancer [<em>sic</em>], but it has a side effect of causing breasts to grow, and it can poison the liver. There are no clinical studies for using this drug for gender transitions, and there are no established standards of care for using this drug.</p>
|
||
|
||
<p>Because of these risks and the lack of scientific studies, other centers that do gender transitions will not use Bicalutamide. The adult center affiliated with Washington University will not use this medication for this reason. But the Center treating children does.</p>
|
||
|
||
<p>I know of at least one patient at the Center who was advised by the renal department to stop taking Bicalutamide because the child was experiencing liver damage. The child’s parent reported this to the Center through the patient’s online self-reporting medical chart (MyChart). The parent said they were not the type to sue, but “this could be a huge PR problem for you.”</p>
|
||
</blockquote>
|
||
|
||
<p>While unpublished and unverified like the earlier reports of liver toxicity with bicalutamide in transfeminine people, this case represents yet another report, and is notably by far the best-documented one. No other clinical details on the case were provided, and it is unclear whether it involved serious liver toxicity, merely asymptomatic liver function test abnormalities, or a clinical situation somewhere in-between these extremes. In any case, it does seem clear that this instance is not likely to have a positive influence on the further adoption of bicalutamide in transfeminine hormone therapy.</p>
|
||
|
||
<p>Subsequent to the investigation of the clinic being launched, in April 2023, Missouri greatly restricted gender-affirming care for transgender youth and adults, with some of the most severe limits that have been enacted in the United States (<a href="https://apnews.com/article/transgender-gender-affirming-care-restrictions-missouri-4def2189dac9979a00d298efb3baf12a">Associated Press, 2023</a>; <a href="https://ago.mo.gov/home/news/2023/04/13/missouri-attorney-general-andrew-bailey-promulgates-emergency-regulation-targeting-gender-transition-procedures-for-minors">Missouri Government, 2023b</a>). Bicalutamide and the liver toxicity instance were not further described with these developments.</p>
|
||
|
||
<h2 id="references">References</h2>
|
||
|
||
<ul>
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||
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||
<li>Arya, V. B., &amp; Davies, J. H. (2019). Idiopathic gonadotropin-independent precocious puberty - is regular surveillance required? <em>Journal of Pediatric Endocrinology &amp; Metabolism: JPEM</em>, <em>32</em>(4), 403–407. [DOI:<a href="https://doi.org/10.1515/jpem-2018-0419">10.1515/jpem-2018-0419</a>]</li>
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||
<li>Asscheman, H., Gooren, L. J., &amp; Peereboom-Wynia, J. D. (1989). Reduction in undesired sexual hair growth with anandron in male-to-female transsexuals—experiences with a novel androgen receptor blocker. <em>Clinical and Experimental Dermatology</em>, <em>14</em>(5), 361–363. [DOI:<a href="https://doi.org/10.1111/j.1365-2230.1989.tb02585.x">10.1111/j.1365-2230.1989.tb02585.x</a>]</li>
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||
<li>Asscheman, H., &amp; Gooren, L. J. (1992). Hormone Treatment in Transsexuals. In Bocking, W. O., Coleman, E. (Eds). <em>Gender Dysphoria: Interdisciplinary Approaches in Clinical Management</em> (pp. 39–54). Binghamton: Haworth Press. / <em>Journal of Psychology &amp; Human Sexuality</em>, <em>5</em>(4), 39–54. [<a href="https://scholar.google.com/scholar?cluster=3926911364428297742">Google Scholar</a>] [<a href="https://books.google.com/books?id=fny-DwAAQBAJ&amp;pg=PT38">Google Books</a>] [DOI:<a href="https://doi.org/10.1300/J056v05n04_03">10.1300/J056v05n04_03</a>]</li>
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||
<li>Bailey, A. (2023 February 9). <em>Missouri Attorney General Andrew Bailey Confirms Launch of Multi-Agency Investigation into St. Louis Transgender Center for Harming Hundreds of Children.</em> Attorney General Andrew Bailey, Missouri Government. [<a href="https://ago.mo.gov/home/news/2023/02/09/missouri-attorney-general-andrew-bailey-confirms-launch-of-multi-agency-investigation-into-st.-louis-transgender-center-for-harming-hundreds-of-children">URL</a>] [<a href="https://ago.mo.gov/docs/default-source/press-releases/2-07-2023-reed-affidavit---signed.pdf">Affadavit of Jamie Reed</a>]</li>
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||
<li>Bailey, A. (2023 April 13). <em>Missouri Attorney General Andrew Bailey Promulgates Emergency Regulation Targeting Gender Transition Procedures for Minors.</em> Attorney General Andrew Bailey, Missouri Government. [<a href="https://ago.mo.gov/home/news/2023/04/13/missouri-attorney-general-andrew-bailey-promulgates-emergency-regulation-targeting-gender-transition-procedures-for-minors">URL</a>] [<a href="https://ago.mo.gov/docs/default-source/press-releases/2023-04-13---emergency-reg.pdf">Emergency Regulation PDF</a>]</li>
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||
<li>Ballentine, S., &amp; Hollingsworth, H. (2023 April 13). Missouri to limit gender-affirming care for minors, adults. <em>Associated Press.</em> [<a href="https://apnews.com/article/transgender-gender-affirming-care-restrictions-missouri-4def2189dac9979a00d298efb3baf12a">URL</a>]</li>
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||
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||
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||
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||
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</ul></content><author><name>{"first_name"=>"Aly", "last_name"=>"W.", "author-link"=>"/about/#aly", "articles-link"=>"/articles-by-author/aly/"}</name></author><category term="github" /><category term="workspace" /><summary type="html">Bicalutamide and its Adoption by the Medical Community for Use in Transfeminine Hormone Therapy By Aly | First published July 1, 2020 | Last modified April 17, 2023</summary></entry></feed> |