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-Bicalutamide and its Adoption by the Medical Community for Use in Transfeminine Hormone Therapy - Transfeminine Science
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
Abstract / TL;DR
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.
History of Bicalutamide for Transfeminine People
Bicalutamide (Casodex) is a nonsteroidal antiandrogen and selectiveantagonist of the androgen receptor which was originally introduced for the treatment of prostate cancer in cisgender men in 1995. Prostate cancer is an androgen-dependent disease, so antiandrogens are effective in treating it. Bicalutamide has major advantages over other antiandrogens such as spironolactone (Aldactone) and cyproterone acetate (Androcur) in terms of antiandrogenicpotency, clinical effectiveness, pharmacological selectivity, and tolerability. It also has improved potency, pharmacokinetic properties, and tolerability, as well as far better safety, compared to the older nonsteroidal antiandrogens flutamide (Eulexin) and nilutamide (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 abiraterone acetate (Zytiga) in 2011 and enzalutamide (Xtandi) in 2012 were introduced and superseded bicalutamide as the standard-of-care 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.
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 Louis Gooren in 2011 (Gooren, 2011). Gooren is a major longtime researcher in the field of transgender medicine and is one of the coauthors of the Endocrine Society’s transgender hormone therapy guidelines (Hembree et al., 2009; Hembree et al., 2017). He and his colleagues at the Center of Expertise on Gender Dysphoria of the Vrije Universiteit Medical Center (VUMC) in Amsterdam, Netherlands had conducted studies on nilutamide (Anandron, Nilandron) as an antiandrogen for transfeminine people in the late 1980s and early 1990s (de Voogt et al., 1987a; de Voogt et al., 1987b; Gooren et al., 1987; Johannes et al., 1987; Rao et al., 1988; Asscheman, Gooren, & Peereboom-Wynia, 1989; van Kemenade et al., 1989; Wiki). However, they seem to have abandoned it—probably due to its high incidence of lung toxicity and other off-target 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 (Asscheman & Gooren, 1992; Gooren, 1999). Subsequently, flutamide was included in transgender health guidelines and other publications, though not necessarily favorably (e.g., Israel & Tarver, 1997; Levy, Crown, & Reid, 2003; Dahl et al., 2006a; Dahl et al., 2006b; Hembree et al., 2009; Moreno-Pérez et al., 2012). 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.
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 Wikipedia content for bicalutamide 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 (Neyman, Fuqua, & Eugster, 2017; Neyman, Fuqua, & Eugster, 2019). It was a small retrospective chart review of bicalutamide alone as a second-line puberty blocker in adolescent transgender girls for whom gonadotropin-releasing hormone analogues 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., Lenz et al., 2010; Haddad & Eugster, 2012). While limited in its findings, Neyman, Fuqua, and Eugster (2019) helped to generate significant interest among clinicians and researchers in bicalutamide for use in transfeminine hormone therapy.
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 next section), 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 do-it-yourself (DIY) hormone therapy community.
Concerns About Bicalutamide Limiting its Use
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 liver failure that have occurred with bicalutamide in men with prostate cancer (Wiki). 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 risk–benefit ratio 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 University of California San Francisco (UCSF) transgender care guidelines warn against use of bicalutamide in transfeminine people currently due to potential liver risks (Deutsch, 2016). 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.
To date, there are 10 published case reports of serious liver toxicity in association with bicalutamide (Table). 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 (Table), but a recent large study by the French government found that there were more than 500 operated instances of meningioma in association with high-dose cyproterone acetate over an 8-year period in France alone (Aly, 2020). 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 MedWatch/FAERS database. (As well as 240 cases of interstitial lung disease associated with bicalutamide notably—relative to only 14 published case reports; Table.) Even with this database however, fewer than 10% of serious adverse reactions are estimated to be reported (Graham, Ahmad, & Piazza-Hepp, 2002). 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., Asa Radix and Zil Goldstein), 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 (QueerDoc).
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 liver function tests (i.e., elevated liver enzymes on blood work) 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 Early Prostate Cancer (EPC) clinical programme, a series of three phase 3randomized controlled trials consisting of over 8,000 patients in which bicalutamide was evaluated for treatment of early prostate cancer (Anderson, 2003; Iversen et al., 2004; Wiki; Wiki). 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 (Blackledge, 1996; Kolvenbag & Blackledge, 1996; McLeod, 1997; Anderson, 2003; Iversen et al., 2004; Wiki). 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 (Blackledge, 1996; See et al., 2002; Wiki). Hence, regular liver monitoring is essential with bicalutamide to ensure that the possibility of severe liver toxicity is avoided.
Bicalutamide has a much lower risk of liver toxicity than its analogue flutamide (Kolvenbag & Blackledge, 1996; Schellhammer et al., 1997; Thole et al., 2004; Manso et al., 2006; Table). 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.
Recent Developments and the Future
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 (Moretti et al., 2018). Retrospective chart reviews of bicalutamide for scalp hair loss in cisgender women have also been published recently (Fernandez-Nieto et al., 2019; Ismail et al., 2020; Fernandez-Nieto et al., 2020; Moussa et al., 2021). The hair loss studies have observed low though significant rates of liver changes with bicalutamide.
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 (Hembree et al., 2009; Hembree et al., 2017)—wrote positively about bicalutamide for transfeminine people in a recent review (Fishman, Paliou, Poretsky, & Hembree, 2019). 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. Guy T’Sjoen—another major researcher in transgender medicine and co-author of the Endocrine Society guidelines (Hembree et al., 2017; Mitchell, 2020)—seemed to show openness to bicalutamide with his colleagues in a recent review as well (Iwamoto et al., 2019). 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 (Aly, 2020). John Randolph, a researcher at the University of Michigan, has also written positively about bicalutamide (Randolph, 2018), though he may have since changed his mind on it (Michigan Medicine, 2020). On the other hand, other authors have not been as welcoming of bicalutamide for transfeminine people (e.g., Hamidi & Davidge-Pitts, 2019; Cocchetti et al., 2020).
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, contraindicated, 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.
Updates
Update 1: Thompson et al. (2021) [Fenway Health Guidelines]
In March 2021, the Fenway Health transgender health clinical practice guidelines were updated from the last version (October 2015) to the following latest edition (Aly, 2020):
Thompson, J., Hopwood, R. A., deNormand, S., & Cavanaugh, T. (2021). Medical Care of Trans and Gender Diverse Adults. Boston: Fenway Health. [URL] [PDF]
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:
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.
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.
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., & de Vries, E. (2021). Southern African HIV Clinicians’ Society gender-affirming healthcare guideline for South Africa. Southern African Journal of HIV Medicine, 22(1), a1299. [DOI:10.4102/sajhivmed.v22i1.1299] [PDF]
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 5α-reductase inhibitors, and bicalutamide actually does appear to be centrally permeable in humans (Wiki). 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.
Update 3: Coleman et al. (2022) [WPATH SOC8 Guidelines]
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.
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).
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.
Update 4: Jamie Reed 2023 Bicalutamide Liver Toxicity Case
In February 2023, Jamie Reed, a former case manager at the The Washington University Transgender Center at St. Louis Children’s Hospital in St. Louis, Missouri, published the op-ed “I Thought I Was Saving Trans Kids. Now I’m Blowing the Whistle.” in a conservative online news outlet called The Free Press. 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 Dr. Christopher Lewis, 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 Daily Mail (Google). In addition to her op-ed, Reed provided a sworn affidavit to the office of Republican Missouri attorney general Andrew Bailey, who proceeded to launch an investigation of the clinic (Missouri Government, 2023a). The following further information was released in the affidavit:
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 [sic], 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.
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.
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.”
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.
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 (Associated Press, 2023; Missouri Government, 2023b). Bicalutamide and the liver toxicity instance were not further described with these developments.
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+Bicalutamide and its Adoption by the Medical Community for Use in Transfeminine Hormone Therapy - Transfeminine Science
Bicalutamide and its Adoption by the Medical Community for Use in Transfeminine Hormone Therapy
By Aly | First published July 1, 2020 | Last modified March 20, 2024
Abstract / TL;DR
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.
History of Bicalutamide for Transfeminine People
Bicalutamide (Casodex) is a nonsteroidal antiandrogen and selectiveantagonist of the androgen receptor which was originally introduced for the treatment of prostate cancer in cisgender men in 1995. Prostate cancer is an androgen-dependent disease, so antiandrogens are effective in treating it. Bicalutamide has major advantages over other antiandrogens such as spironolactone (Aldactone) and cyproterone acetate (Androcur) in terms of antiandrogenicpotency, clinical effectiveness, pharmacological selectivity, and tolerability. It also has improved potency, pharmacokinetic properties, and tolerability, as well as far better safety, compared to the older nonsteroidal antiandrogens flutamide (Eulexin) and nilutamide (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 abiraterone acetate (Zytiga) in 2011 and enzalutamide (Xtandi) in 2012 were introduced and superseded bicalutamide as the standard-of-care 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.
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 Louis Gooren in 2011 (Gooren, 2011). Gooren is a major longtime researcher in the field of transgender medicine and is one of the coauthors of the Endocrine Society’s transgender hormone therapy guidelines (Hembree et al., 2009; Hembree et al., 2017). He and his colleagues at the Center of Expertise on Gender Dysphoria of the Vrije Universiteit Medical Center (VUMC) in Amsterdam, Netherlands had conducted studies on nilutamide (Anandron, Nilandron) as an antiandrogen for transfeminine people in the late 1980s and early 1990s (de Voogt et al., 1987a; de Voogt et al., 1987b; Gooren et al., 1987; Johannes et al., 1987; Rao et al., 1988; Asscheman, Gooren, & Peereboom-Wynia, 1989; van Kemenade et al., 1989; Wiki). However, they seem to have abandoned it—probably due to its high incidence of lung toxicity and other off-target 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 (Asscheman & Gooren, 1992; Gooren, 1999). Subsequently, flutamide was included in transgender health guidelines and other publications, though not necessarily favorably (e.g., Israel & Tarver, 1997; Levy, Crown, & Reid, 2003; Dahl et al., 2006a; Dahl et al., 2006b; Hembree et al., 2009; Moreno-Pérez et al., 2012). 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.
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 Wikipedia content for bicalutamide 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 (Neyman, Fuqua, & Eugster, 2017; Neyman, Fuqua, & Eugster, 2019). It was a small retrospective chart review of bicalutamide alone as a second-line puberty blocker in adolescent transgender girls for whom gonadotropin-releasing hormone analogues 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., Lenz et al., 2010; Haddad & Eugster, 2012). While limited in its findings, Neyman, Fuqua, and Eugster (2019) helped to generate significant interest among clinicians and researchers in bicalutamide for use in transfeminine hormone therapy.
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 next section), 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 do-it-yourself (DIY) hormone therapy community.
Concerns About Bicalutamide Limiting its Use
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 liver failure that have occurred with bicalutamide in men with prostate cancer (Wiki). 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 risk–benefit ratio 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 University of California San Francisco (UCSF) transgender care guidelines warn against use of bicalutamide in transfeminine people currently due to potential liver risks (Deutsch, 2016). 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.
To date, there are 10 published case reports of serious liver toxicity in association with bicalutamide (Table). 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 (Table), but a recent large study by the French government found that there were more than 500 operated instances of meningioma in association with high-dose cyproterone acetate over an 8-year period in France alone (Aly, 2020). 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 MedWatch/FAERS database. (As well as 240 cases of interstitial lung disease associated with bicalutamide notably—relative to only 14 published case reports; Table.) Even with this database however, fewer than 10% of serious adverse reactions are estimated to be reported (Graham, Ahmad, & Piazza-Hepp, 2002). 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., Asa Radix and Zil Goldstein), 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 (QueerDoc).
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 liver function tests (i.e., elevated liver enzymes on blood work) 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 Early Prostate Cancer (EPC) clinical programme, a series of three phase 3randomized controlled trials consisting of over 8,000 patients in which bicalutamide was evaluated for treatment of early prostate cancer (Anderson, 2003; Iversen et al., 2004; Wiki; Wiki). 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 (Blackledge, 1996; Kolvenbag & Blackledge, 1996; McLeod, 1997; Anderson, 2003; Iversen et al., 2004; Wiki). 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 (Blackledge, 1996; See et al., 2002; Wiki). Hence, regular liver monitoring is essential with bicalutamide to ensure that the possibility of severe liver toxicity is avoided.
Bicalutamide has a much lower risk of liver toxicity than its analogue flutamide (Kolvenbag & Blackledge, 1996; Schellhammer et al., 1997; Thole et al., 2004; Manso et al., 2006; Table). 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.
Recent Developments and the Future
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 (Moretti et al., 2018). Retrospective chart reviews of bicalutamide for scalp hair loss in cisgender women have also been published recently (Fernandez-Nieto et al., 2019; Ismail et al., 2020; Fernandez-Nieto et al., 2020; Moussa et al., 2021). The hair loss studies have observed low though significant rates of liver changes with bicalutamide.
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 (Hembree et al., 2009; Hembree et al., 2017)—wrote positively about bicalutamide for transfeminine people in a recent review (Fishman, Paliou, Poretsky, & Hembree, 2019). 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. Guy T’Sjoen—another major researcher in transgender medicine and co-author of the Endocrine Society guidelines (Hembree et al., 2017; Mitchell, 2020)—seemed to show openness to bicalutamide with his colleagues in a recent review as well (Iwamoto et al., 2019). 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 (Aly, 2020). John Randolph, a researcher at the University of Michigan, has also written positively about bicalutamide (Randolph, 2018), though he may have since changed his mind on it (Michigan Medicine, 2020). On the other hand, other authors have not been as welcoming of bicalutamide for transfeminine people (e.g., Hamidi & Davidge-Pitts, 2019; Cocchetti et al., 2020).
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, contraindicated, 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.
Updates
Update 1: Thompson et al. (2021) [Fenway Health Guidelines]
In March 2021, the Fenway Health transgender health clinical practice guidelines were updated from the last version (October 2015) to the following latest edition (Aly, 2020):
Thompson, J., Hopwood, R. A., deNormand, S., & Cavanaugh, T. (2021). Medical Care of Trans and Gender Diverse Adults. Boston: Fenway Health. [URL] [PDF]
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:
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.
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.
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., & de Vries, E. (2021). Southern African HIV Clinicians’ Society gender-affirming healthcare guideline for South Africa. Southern African Journal of HIV Medicine, 22(1), a1299. [DOI:10.4102/sajhivmed.v22i1.1299] [PDF]
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 5α-reductase inhibitors, and bicalutamide actually does appear to be centrally permeable in humans (Wiki). 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.
Update 3: Coleman et al. (2022) [WPATH SOC8 Guidelines]
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.
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).
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.
Update 4: Jamie Reed 2023 Bicalutamide Liver Toxicity Case
In February 2023, Jamie Reed, a former case manager at the The Washington University Transgender Center at St. Louis Children’s Hospital in St. Louis, Missouri, published the op-ed “I Thought I Was Saving Trans Kids. Now I’m Blowing the Whistle.” in a conservative online news outlet called The Free Press. 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 Dr. Christopher Lewis, 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 Daily Mail (Google). In addition to her op-ed, Reed provided a sworn affidavit to the office of Republican Missouri attorney general Andrew Bailey, who proceeded to launch an investigation of the clinic (Missouri Government, 2023a). The following further information was released in the affidavit:
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 [sic], 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.
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.
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.”
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.
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 (Associated Press, 2023a; Missouri Government, 2023b). Bicalutamide and the liver toxicity instance were not further described with these developments. The new state law restricting gender-affirming care took effect August 28, 2023, and Washington University announced that it would stop prescribing puberty blockers and hormone therapy to transgender youth shortly thereafter (Associated Press, 2023b).
A New York Times article with additional information on the case was also subsequently published (Ghorayshi, 2023 [Excerpts]). It was noted that the adolescent had been on bicalutamide for 1 year and definitely experienced hepatotoxicity. However, she also had a complicated medical history, including being immunocompromised, having recently had COVID-19, and having taken another drug known to be associated with hepatotoxicity. As such, the hepatotoxicity cannot be definitively attributed to bicalutamide, but it simultaneously cannot be ruled out that bicalutamide was involved or causative.
Subsequent Burgener et al. (2023, 2024) Findings
Following the preceding case, Dr. Lewis and colleagues went on to publish a conference abstract and preprint of a study of bicalutamide in transfeminine youth and young adults in which they stated that it does not increase liver enzymes in this population (Burgener et al., 2023; Burgener et al., 2024). However, a closer look at their data show that bicalutamide did statistically significantly elevate certain liver parameters relative to other antiandrogens, namely rates of elevated aspartate aminotransferase (AST) (upper limit of normal 10.7% vs. 1.5%, P = 0.02) (Burgener et al., 2024). Likewise, rates of elevated alanine aminotransferase (ALT) appeared to trend in the direction of being increased, though this was not statistically significant (upper limit of normal 16.7% vs. 11.6%, P = 0.37) (Burgener et al., 2024). In any case, rates of clinically significant elevations in liver enzymes with bicalutamide, defined as greater than three times the upper limit of normal, were not significantly increased in the study.
On the basis of the relevant research in men with prostate cancer (Wiki), Dr. Lewis and colleagues’ study, with a bicalutamide-group sample size of only 84 transfeminine individuals, was clearly greatly underpowered for evaluating liver function changes. Per the Early Prostate Cancer trial of high-dose bicalutamide monotherapy in men with prostate cancer, elevated liver enzymes appear to occur with bicalutamide at a rate of only about 1.5% more than placebo, or roughly an additional 1 in every 66 people (Wiki). Based on power analysis, this would require a far larger sample size to have adequate statistical power and actually have a chance of achieving statistical significance.
As such, it seems to the present author premature to conclude that bicalutamide does not elevate liver enzymes in transfeminine people.
Dr. Lewis and colleagues didn’t mention in their study paper the transfeminine adolescent liver toxicity case reported by Jamie Reed that was said to have occurred at their clinic nor have they published a case report about this instance. Instead, only the following is stated:
One case report published in 2024 described a transgender female adolescent prescribed bicalutamide 50 mg daily who presented to a hospital with liver toxicity that resolved after stopping bicalutamide (Wilde et al., 2024). This appears to be the first documented case of bicalutamide-induced hepatoxicity in a transgender female.
While this case was, coincidentally, also a 17-year-old transfeminine adolescent (Wilde et al., 2024), this instance, per the medical histories and reporting authors/institutions, appears to be distinct from Dr. Lewis’s that was reported by Jamie Reed.
However, Dr. Lewis and colleagues did note the following in their paper, which plausibly might have been the Jamie Reed case:
There was one individual in whom bicalutamide was stopped after the follow-up period designated for the study. This individual developed ALT and AST >2x ULN after an episode of COVID and had a thorough hepatology evaluation. As ALT and AST were never > 3x ULN, it was not recommended that bicalutamide be stopped; however, ultimately a clinical decision was made to stop the medication and ALT and AST normalized.
Another concern with Dr. Lewis and colleagues’ paper pertains to the following statements:
Whereas bicalutamide doses for prostate cancer reach 150 mg daily, doses used in the care of AMAB transfeminine individuals are much lower (25-50 mg daily).
Bicalutamide doses used in prostate cancer are up to 150 mg daily. Due to these concerns of liver toxicity, bicalutamide has not been routinely used as an anti-androgen in AMAB transfeminine individuals, despite the much lower doses needed in this population (∼25-50 mg daily).
In actuality, bicalutamide is most widely used in prostate cancer, in the form of combined androgen blockade with surgical or medical castration, at a dosage of 50 mg/day, whereas the 150 mg/day dosage is used less commonly, in the form of monotherapy (Wiki). Among the published case reports of hepatotoxicity with bicalutamide in men with prostate cancer, half have been at a dose of 50 mg/day and the other half have been at a dose of 80 to 150 mg/day (Wiki). The two instances of death due to hepatotoxicity with bicalutamide were both at 50 mg/day. There is currently no evidence that the hepatotoxicity of bicalutamide is dose-dependent across its clinically used dosage range (Wiki), although employment of the lowest effective dose in transfeminine people nonetheless seems prudent just in case. Hence, in contrast to Dr. Lewis and colleague’s claims, a bicalutamide dosage of 50 mg/day is not less than that used in prostate cancer, and clearly retains substantial hepatotoxic potential.
Update 5: New 2022, 2023, and 2024 Bicalutamide Publications
2022
Angus, L., Nolan, B., Zajac, J., & Cheung, A. (November 2022). Use of bicalutamide as an androgen receptor antagonist in transgender women. ESA/SRB/APEG/NZSE ASM 2022, November 13-16, Christchurch, Abstracts and Programme, 127–127 (abstract no. 280). [URL] [PDF] [Full Abstract Book]
2023
Angus, L. M., Nolan, B. J., Zajac, J. D., & Cheung, A. S. (November 2023). Bicalutamide as an anti-androgen in trans people: a cross-sectional study. AusPATH 2023 Symposium. [URL] [PDF] [Slides] [Trans Health Research Blog Post]
Bambilla, A., Beal, C., & Vigil, P. (2023). Improving Access to Bicalutamide in Gender Affirming Medical Care. [Unpubished/pending publication] [QueerCME Blog Post]
Burgener, K., DeBosch, B., Lewis, C., Wallendorf, M., & Herrick, C. (May 2023). Assessment of Liver Function and Toxicity in Transgender Female Adolescents Prescribed Bicalutamide. Hormone Research in Paediatrics, 96(Suppl 3 [Abstracts of the 2023 Pediatric Endocrine Society (PES) Annual Meeting’ to Hormone Research in Paediatrics]): 377–378 (abstract no. 6232). [DOI:10.1159/000531602] [PDF]
Gómez-Aguilar, F., Martínez-Sánchez, L., Arias-Constantí, V., Muñoz-Santanach, D., & Sarquella-Brugada, G. (2023). QT prolongation and Torsade de Pointes in a 13-year-old transgender adolescent in treatment with bicalutamide and tacrolimus. Clinical Toxicology, 61(Suppl 1 [43rd International Congress of the European Association of Poisons Centres and Clinical Toxicologists (EAPCCT), 23–26 May 2023, Palma de Mallorca, Spain]), 81–82 (abstract no. 170). [DOI:10.1080/15563650.2023.2192024] [PDF] [Reactions Weekly]
Karakılıç Özturan, E., Öztürk, A. P., Baş, F., Erdoğdu, A. B., Kaptan, S., Kardelen Al, A. D., Poyrazoğlu, Ş., Yıldız, M., Direk, N., Yüksel, Ş., & Darendeliler, F. (2023). Endocrinological Approach to Adolescents with Gender Dysphoria: Experience of a Pediatric Endocrinology Department in a Tertiary Center in Turkey. Journal of Clinical Research in Pediatric Endocrinology, 15(3), 276–284. [DOI:10.4274/jcrpe.galenos.2023.2023-1-13]
Vierregger, K., Tetzlaff, M., Zimmerman, B., Dunn, N., Finney, N., Lewis, K., Slomoff, R., & Strutner, S. (May 2023). Bicalutamide Use as Antiandrogen in Trans Feminine Adults - A Safety Profile. National Transgender Health Summit (NTHS) 2023 Symposium. [Event Agenda PDF] [Symposium Session] [Symposium Abstracts/Program Book]
Vierregger, K. S. (November 2023). Bicalutamide Use as Antiandrogen in Trans Feminine Adults - A Safety Profile. USPATH 2023 Symposium. [Symposium Schedule]
Warus, J. (November 2023). Safety of Bicalutamide as Anti-Androgenic Therapy in Gender Affirming Care for Adolescents and Young Adults: A Retrospective Chart Review. USPATH 2023 Symposium. [Symposium Schedule]
Wilde, B., Diamond, J. B., Laborda, T. J., Frank, L., O’Gorman, M. A., & Kocolas, I. (2023). Bicalutamide-Induced Hepatotoxicity in a Transgender Male-to-Female Adolescent. Journal of Adolescent Health, 74(1), 202–204. [DOI:10.1016/j.jadohealth.2023.08.024]
2024
Burgener, K., DeBosch, B., Wang, J., Lewis, C., & Herrick, C. J. (2024). Bicalutamide does not raise transaminases in comparison to alternative anti-androgen regimens among transfeminine adolescents and young adults: a retrospective cohort study. medRxiv, preprint. [DOI:10.1101/2024.02.21.24302999v1] [PDF]
Fuqua, J. S., Shi, E., & Eugster, E. A. (2024). A retrospective review of the use of bicalutamide in transfeminine youth; a single center experience. International Journal of Transgender Health, advance online publication. [DOI:10.1080/26895269.2023.2294321]
Shumer, D., & Roberts, S. A. (2024). Placing a Report of Bicalutamide-Induced Hepatotoxicity in the Context of Current Standards of Care for Transgender Adolescents. Journal of Adolescent Health, 74(1), 5–6. [DOI:10.1016/j.jadohealth.2023.10.010]
Update 6: Original Bicalutamide Liver and Lung Toxicity Analysis by Sam
A few years ago back in 2021, Transfeminine Science author Sam conducted an original analysis of the incidence of liver and lung toxicity with bicalutamide in the published clinical trial literature. This project was never finished or made publicly available. However, with bicalutamide being increasingly studied and adopted for use in transfeminine people, it seems quite valuable and relevant today. As such, we have opted to now publish Sam’s analysis in this section.
Sam’s analysis can be found in the provided document here. In terms of methodology, she searched PubMed for all clinical trials of bicalutamide, collated all of the relevant results into a table, and then calculated the incidences of serious liver toxicity and lung toxicity from those data. In clinical trials, adverse events are rated in terms of grades of severity, with a Grade 3 adverse event defined as “severe”, Grade 4 as “life-threatening”, and Grade 5 as “death” (Wiki).
Of 229 results, 33 trials were found to be relevant and were included. Most of the trials were in men with prostate cancer, but a few were in women with cancer and boys with precocious puberty. Sam found that of a total of 7,703 evaluable participants, there were 2 instances of serious liver toxicity and 2 instances of serious lung toxicity with bicalutamide. This resulted in the same incidence rate of 0.026% (95% CI: 0.003% to 0.094%) or approximately 1 in 3,846 individuals for both liver toxicity and lung toxicity. Combining these toxicities resulted in a total incidence of serious liver or serious lung toxicity with bicalutamide of 0.052% (95% CI: 0.014% to 0.133%) or approximately 1 in 1,923 individuals. All of the observed toxicity events were rated as Grade 3 or 4. It should be noted that clinical trials of bicalutamide typically employ careful laboratory monitoring and assessment of clinical adverse events as well as prompt medication discontinuation upon unfavorable laboratory changes.
While the confidence intervals (CIs) in Sam’s analysis were wide and hence the estimates are very rough, they provide an idea of the potential real-world risk of serious toxicity with bicalutamide in transfeminine people based on high-quality clinical data. Notably, they do not suffer from the problem of under-reporting of adverse events that occurs with published case reports, pharmacovigilance databases, and certain types of observational studies. However, limitations of Sam’s analysis include (1) toxicity incidence rates for no-bicalutamide controls not being assessed and (2) most of the patients having cancer and being of older age, and hence the generalizability of the findings to healthy transfeminine people not being fully clear. In any case, I was surprised by how high the incidence rates were when I first saw her analysis, and I suspect that others may be as well.
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Angus, L. M., Nolan, B. J., Zajac, J. D., & Cheung, A. S. (2023). Bicalutamide as an anti-androgen in trans people: a cross-sectional study. AusPATH 2023 Symposium. [URL] [PDF] [Slides] [Trans Health Research Blog Post]
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-Low Doses of Cyproterone Acetate Are Maximally Effective for Testosterone Suppression in Transfeminine People - Transfeminine Science
Low Doses of Cyproterone Acetate Are Maximally Effective for Testosterone Suppression in Transfeminine People
By Aly | First published July 1, 2019 | Last modified March 31, 2023
Abstract / TL;DR
Cyproterone acetate (CPA) is a progestogen and antiandrogen which is widely used in transfeminine hormone therapy. It is far more potent as a progestogen than as an androgen receptor antagonist. CPA has typically been used at doses of 1 to 2 mg/day as a progestogen in cisgender women and at doses of 50 to 300 mg/day as an antiandrogen. At typical antiandrogen doses of CPA, there is profound progestogenic overdosage as well as associated side effects and risks. CPA has antigonadotropic effects due to its progestogenic activity and thereby suppresses testosterone levels. By itself, CPA can maximally suppress testosterone levels by 50 to 70%, and in combination with even small amounts of estrogen, it can fully suppress gonadal testosterone production and thereby reduce testosterone levels by about 95%—or well into the female range. Although doses of CPA of 50 to 100 mg/day have been used in transfeminine people historically, it is now clear that 5 to 10 mg/day CPA has maximal or near-maximal effectiveness in terms of suppression of testosterone levels. CPA alone is most commonly available as 50-mg tablets. These tablets can be split with a pill cutter and taken once every day to once every other day to achieve an overall CPA dosage of 6.25 to 12.5 mg/day. These lower doses of CPA are not only much more cost-effective than traditional doses but are also likely to have better tolerability and safety. Due to the retained effectiveness of lower CPA doses and the known dose-dependent risks of CPA, doses of CPA used clinically in transfeminine people have been in a rapid decline.
Introduction
This article is about the dosage of cyproterone acetate (CPA), a progestin and antiandrogen, for use in hormone therapy for transfeminine people. It argues for the use of lower doses of CPA and goes fairly in-depth to justify these doses. If you are only interested in recommended doses of CPA for transfeminine people, they can be found in the Recommended Dosages section below.
Potency, Conventional Dosages, and Health Risks
CPA is a potent progestogen, with an ovulation-inhibiting dosage of about 1 mg/day and endometrial transformation dosage of about 1 to 3 mg/day in cisgender women (Wiki; Table; Endrikat et al., 2011). These dosages of CPA are similar in strength of progestogenic effect to those of normal progesterone production and levels during the luteal phase of the menstrual cycle in premenopausal women (which are about 25 mg/day and 15 ng/mL, respectively). In relation to the preceding, when CPA is used as a progestogen in cisgender women, for instance in birth control pills and menopausal hormone therapy preparations, it is formulated at a dose of 1 or 2 mg per tablet (Wiki).
In contrast to its progestogenic activity, CPA is far less potent as an androgen receptor antagonist (Wiki). When used as an antiandrogen, it is generally given at a dosage of 50 to 300 mg/day, both in cisgender women and men. A dosage of 50 to 100 mg/day is typical for androgen-dependent skin and hair conditions like acne and hirsutism in women and a dosage of 100 to 300 mg/day is typically used for prostate cancer in men (specifically 100–200 mg/day for CPA combined with castration and 200–300 mg/day for CPA monotherapy) (Wiki). As such, CPA is generally formulated at a dose of 50 or 100 mg per tablet for use in androgen-dependent conditions (Wiki). As an antiandrogen, CPA has a dual mechanism of action of both suppressing testosterone levels via its progestogenic activity at low doses and additionally blocking the actions of testosterone directly at the androgen receptor at higher doses.
Because CPA is so much more potent as a progestogen than as an androgen receptor antagonist, there is profound overdosage of progestogenic effect when CPA is used as an antiandrogen at typical clinical dosages. This is described in the following three literature excerpts by Jürgen Hammerstein, one of the scientists who developed CPA (Hammerstein et al., 1975; Hammerstein, 1990; Hammerstein, 1979):
Like chlormadinone acetate, its parent compound, CPA is also a strong progestogen with the endometrial transformation dose of both drugs being between 20 and 30 mg. […] To take full therapeutic advantage of its antiandrogenicity, CPA must be administered in doses per month that are 30 times the physiological equivalent of progesterone production in the cycle. CPA, although the most useful compound available in this field at the moment, cannot be considered therefore an ideal antiandrogen, all the more as some of the side effects may be related to the progestational overdosage rather than to the administered antiandrogenic activity. […] Adverse reactions like tiredness, lassitude, and increase in body weight are possibly due to the enormous overdose of progestational activity in the formula which is necessary to take full advantage of the antiandrogenicity of CPA.
Fixson (1963) tested CPA in ovariectomized women after pre-treatment with oestrogens; with a transformation dose of 20–30 mg this proved a powerful progestogen. The potency of CPA in the menses delay test is not exactly known, but has been estimated to be below 1 mg/day (Miller and Jacobs 1986). In relation to this progestational potency, its antiandrogenicity must be considered rather weak. Thus, in order to take full advantage of the latter, 100 mg CPA must be given daily, i.e. three times the cyclic transformation dose per day (Hammerstein and Cupceancu 1969); notably, this parameter is equivalent to the total progesterone production of a corpus luteum throughout its entire cyclic life span.
CPA may be characterized endocrinologically as possessing strong progestational [and] moderate anti-androgenic […] potencies. […] Its progestational activity, in terms of the transformation dose in the oestrogen-primed human endometrium, is 20–30 mg [per month/cycle] which is comparable to that of chlormadinone acetate and other strong progestogens. To take full clinical advantage of its anti-androgenicity not less than 50–100 mg CPA must be taken orally per day, which totals 2 to 3 times the progestational activity the female organism is exposed to throughout a complete ovulatory menstrual cycle. Thus unless much lower and less efficacious doses of CPA are used, a tremendous progestational overdosage must be accepted. […] As already pointed out CPA is endocrinologically not a well-balanced compound because of the strong preponderance of the progestational over the anti-androgenic potency. A way to avoid the heavy progestogen overdosage inherent with the high-dose reverse sequential therapy would be to combine the low-dose contraceptive formulation just mentioned with a pure anti-androgen such as free cyproterone. […] It must be emphasized that CPA is far from being an ideal drug for the anti-androgenic treatment of hirsutism because its progestational potency is much too strong and it is not effective when administered topically. Therefore it is worthwhile looking for better-balanced anti-androgenic compounds for the future.
The massive overdosage of progestogenic effect that occurs at such doses of CPA is likely responsible for the known adverse effects and risks of higher doses of CPA (Wiki). Examples of these side effects include fatigue, depression, weight gain, high prolactin levels (Wiki), benign brain tumors (Aly, 2020; Wiki; Table; Table), blood clots (Wiki), and cardiovascular problems (Wiki). Such risks are dose-dependent and have not been associated with 1 or 2 mg/day CPA (with the exception of an expected increase in the risk of blood clots in combination with oral estrogens for birth control or menopausal hormone therapy). The risk of liver toxicity with CPA is also dose-dependent, with elevated liver enzymes occurring mostly only at a dosage of 20 mg/day and above and rare cases of liver failure occurring almost exclusively at dosages of 100 mg/day and above (Wiki; Table). As such, there is good rationale for using the lowest possible effective dosage of CPA, an approach that is likely to minimize risks.
In transfeminine people, CPA has historically been used at a dosage of 50 to 100 mg/day (e.g., Moore, Wisniewski, & Dobs, 2003). Some earlier papers have recommended even higher doses of CPA, for instance 100 to 150 mg/day (Asscheman & Gooren, 1993). In 2017, the Endocrine Society published the latest edition of their clinical practice guidelines on hormone therapy for transgender people and reduced their recommended dosage of CPA from 50–100 mg/day to 25–50 mg/day (Hembree et al., 2017; Hembree et al., 2009). This was motivated in part by increasing knowledge and awareness of the risks of higher doses of CPA and by findings that these lower doses of CPA were still effective. However, it is likely that even these new lower dosages are still far in excess of what is really needed.
Testosterone Suppression with Low and High Doses
Progestogens by themselves, including CPA, are able to considerably suppress testosterone levels in gonadally intact people assigned male at birth. Around a dozen small and low-quality but nonetheless notable studies of low-dose CPA from the 1970s and early 1980s found that 5 to 10 mg/day CPA suppressed testosterone levels by about 40 to 70% in healthy young men (Table 1). A couple of individual studies notably reported virtually identical suppression of testosterone levels with 5 mg/day versus 10 mg/day CPA (both ~50% suppression) (Wang & Yeung, 1980; Graph) and with 10 mg/day versus 20 mg/day CPA (both ~60–70% suppression) (Koch et al., 1976; Koch et al., 1975; Graph). This lack of additional testosterone suppression with a doubling of dosage within studies suggests that testosterone suppression with CPA might have actually been maximal at a dosage of only 5 or 10 mg/day. A more modern study, which used a newer and more reliable analytic method for quantification of blood testosterone, found that 10 mg/day CPA suppressed testosterone levels by 66%, from about 600 ± 150 ng/dL to about 185 ng/dL (Meriggiola et al., 2002a; Graph). Similarly, another more modern study found that 10 to 20 mg/day CPA suppressed testosterone levels by 65%, from about 431 ng/dL to about 149 ng/dL, with no reported differences between doses (Zitzmann et al., 2017; Graph).
Table 1: Levels of testosterone and other sex hormones with CPA at low doses (5–30 mg/day):
Treatment and subjects
Findings
Source(s)
30 mg/day CPA in 5 normal males
T decreased “remarkably”. Exact values not given, but has graphs of T levels in a few individuals. After 30 mg/day, 5 mg/day was tried in one case and was not as effective in suppressing sperm production or T. Also reported decreases in gonadotropin excretion.
10 or 20 mg/day CPA in 15 normal healthy fertile males (age 25–35 years) (7 in 10 mg/day group and 8 in 20 mg/day group)
“Androgens (mainly T)” decreased by 60% for both 10 and 20 mg/day. Inconsistent changes in LH and slight decrease in FSH. Exact values not given, except in graphs.
10 mg/day CPA in 10 young healthy fertile men (age mean 27.2 ± 3.2 (range 21–35) years)
T decreased by 70%, DHT by 50%, LH by 30%, and FSH by 40%, while PRL increased by 75%. T was 495 ± 66 ng/dL before, 154 ± 23 ng/dL after 4 weeks, and 187 ± 38 ng/dL after 12 weeks. Also has values and graphs for other hormones.
20 mg/day CPA in 10 healthy males (age 26–55 years)
T decreased by 73% (range 71–75%), from 482 ng/dL (range 410–560 ng/dL) to 130 ng/dL (110–162 ng/dL). DHT decreased by 51% (range 47–55%), LH by 39% (range 34–45%), FSH by 66% (range 47–78%), 17-OH-P4 by 59%, A4 by 30%, TS by 34%, and DHTS by 35%. Also has exact values and graphs for other hormones.
5 or 10 mg/day CPA in 7 males (4 in each group; 1 received both 5 and 10 mg/day CPA at different times)
T change was “−40%” or “–50%”. At 5 mg/day, T was 745 ng/dL before, 460 ng/dL with treatment (–38%), and 668 ng/dL after discontinuation. At 10 mg/day, T was 708 ng/dL before, 398 ng/dL with t (reatment–44%), and 670 ng/dL after discontinuation. Also reported LH and FSH levels.
0, 5, or 10 mg/day CPA in 25 normal healthy males (age 20–51 years); 7 in 5 mg group (mean 37 ± 10 years), 8 in 10 mg group (mean 32 ± 8 years), 10 in 0 mg group (mean 32 ± 10 years)
At 5 mg/day, T decreased from 663 ± 120 ng/dL to 320 ± 160 ng/dL (−52%), and at 10 mg/day, T decreased from 692 ± 180 ng/dL to 340 ± 160 ng/dL (−51%). E2 decreased in parallel to T. At 5 mg/day, LH decreased from 2.1 ± 0.7 IU/L to 1.4 ± 0.5 IU/L (−33%), and at 10 mg/day, LH decreased from 2.3 ± 1.0 IU/L to 1.2 ± 0.5 IU/L (−48%). At 5 mg/day, FSH decreased from 3.1 ± 1.9 IU/L to 1.8 ± 0.9 IU/L (−42%), and at 10 mg/day, FSH decreased from 2.7 ± 1.0 IU/L to 1.5 ± 0.7 IU/L (−44%).
10 or 25 mg/day CPA in 4 healthy men (age 29–37 years); 3 in 10 mg group, 1 in 25 mg group
T “slightly reduced”. E “more significantly lowered”. LH not significantly changed. FSH “reduced” in “more or less all cases”. Exact hormone levels not given, but graphs provided with the values.
10 mg/day CPA (also placebo and 2, 5, and 10 mg/day dienogest) in 5 healthy men in each group
With CPA, T decreased from ~600 ± 150 ng/dL to ~185 ng/dL (–66 ± 4%). Also reported LH, FSH, and SHBG, as well as hormonal changes with placebo and dienogest (2, 5, and 10 mg/day).
10 or 20 mg/day CPA in 14 healthy young men (7 in each group)
T decreased from ~431 ng/dL at baseline to ~149 ng/dL with CPA (–65%) for the 10 and 20 mg/day doses combined. Values for dose subgroups not given. No significant differences between LH/FSH suppression between groups (which is indirectly suggestive of no differences in T suppression as well). Also reported hormone levels with other progestins.
Studies with other progestogens, such as desogestrel, dienogest, and medroxyprogesterone acetate, have consistently found that maximal suppression of testosterone levels in men occurs at a dosage that is between 5 and 10 times that of the ovulation-inhibiting dosage in cisgender women (Wiki; Wiki; Wiki). Another study is likewise suggestive of this for norethisterone acetate and levonorgestrel (Zitzmann et al., 2017; Graph). Along similar lines, doses of progestogens investigated for use in male hormonal contraception, in which the goal is antigonadotropic effects and the lowest fully effective dose is targeted, have been noted as being between 5 and 12 times the doses used in cisgender women (Foegh, 1983). Based on an ovulation-inhibiting dosage of CPA of 1 mg/day, these findings would imply that suppression of testosterone levels with CPA would likely be maximal at a dose of between 5 and 10 mg/day. In accordance, this dose range matches up with the findings of the studies above.
Although progestogens can considerably suppress testosterone levels at maximally effective dosages, it has been found that a “recovery” or “escape phenomenon”, in which testosterone levels eventually increase back to higher levels, occurs when progestogen monotherapy is used on a long-term basis. This has most notably been observed with the related progestogen megestrol acetate (Wiki), but has also been seen with CPA (Goldenberg & Bruchovsky, 1991; Saborowski, 1987; Jacobi, Tunn, & Senge, 1982). In one of these studies, testosterone levels were initially suppressed by CPA by about 70%, but increased back to about 50% of baseline between 6 and 12 months of therapy, remaining stable thereafter up to 24 months. The testosterone escape phenomenon should be kept in mind in the context of progestogen monotherapy for testosterone suppression. In contrast to progestogen monotherapy, this phenomenon has not been associated with combined estrogen and progestogen therapy.
Testosterone Suppression in Combination with Estrogen
CPA is generally used in combination with an estrogen in transfeminine people. Estrogens suppress testosterone levels similarly to progestogens. The combination of an estrogen and a progestogen is synergistic in terms of testosterone suppression and results in suppression of testosterone levels with lower doses than with either an estrogen or progestogen alone (Fink, 1979; Geller & Albert, 1983; Bastianelli et al., 2018). Although estrogens can suppress testosterone levels to an equivalent extent as surgical or medical castration (i.e., orchiectomy or GnRH agonists/antagonists), this usually requires relatively high estrogen levels, for instance in the range of 200 to 500 pg/mL (Wiki; Graphs). Because of the high and supraphysiological estradiol levels required for maximal or near-maximal suppression of testosterone levels, lower doses of estradiol are frequently combined with antiandrogens and/or progestogens to block or suppress remaining testosterone levels instead.
CPA, as mentioned earlier, leads to an incomplete suppression of plasma testosterone levels, which decrease by about 70% and remain at about three times castration values. In a very systematic approach to the problem, Rennie et al. (59) investigated and compared 12 different procedures of androgen deprivation. These authors found that the combination of CPA with an extremely low dose (0.1 mg/d) of [diethylstilbestrol (DES)] led to a very effective withdrawal of androgens in terms of plasma testosterone and tissue dihydrotestosterone. The same group later showed that 200 mg of CPA, and even 100 mg/day, was sufficient to achieve a similar endocrine response, which was correlated to very favorable clinical responses in a Phase II situation (60,61). The approach has many potential advantages, and, from an endocrinological point of view, is very logical: this regimen combines the testosterone-reducing effects of two compounds, therefore, only small amounts of estrogen are required to bring down plasma testosterone to approximately castrate levels. Once castrate levels have been achieved, only low doses of CPA are necessary to counteract remaining androgens, mainly of adrenal origin. The regimen was shown to be associated with few side effects and a very low cost. The combination of low-dose CPA with low-dose DES was never studied in a Phase III situation in comparison to standard management. Considering the endocrine results and the observations in patients treated with this regimen (60), this combination treatment is very likely to be competitive with other standard forms of therapy.
A 2016 study of 50 mg/day CPA and 1 to 2 mg/day transdermal estradiol gel in transfeminine people showed that estradiol levels of about 45 pg/mL with CPA were insufficient to achieve female/castrate levels of testosterone, instead resulting in testosterone levels of about 120 to 190 ng/dL (Gava et al., 2016; Graph). Conversely, estradiol levels of about 85 pg/mL with CPA achieved complete suppression of gonadal testosterone production, with resulting testosterone levels of about 20 ng/dL. As such, a certain minimum level of estradiol with CPA appears to be required for complete testosterone suppression. A 2019 study of CPA and oral estradiol valerate in transfeminine people indicated that testosterone levels were still fully suppressed with median estradiol levels of 76 pg/mL and 25th percentile estradiol levels of 63 pg/mL (Angus et al., 2019; Graph).
Figures 5–7: Testosterone levels with CPA plus low doses/levels of estrogens in men and transfeminine people. Sources: Top-left: Goldenberg et al. (1988). Top-right: Gava et al. (2016). Bottom: Angus et al. (2019). See also on Wikipedia: Gallery. Note for the graph on the top right that the mean transdermal estradiol dosage increased between 6 and 12 months and this was likely responsible for the improvement in testosterone suppression.
Fung and colleagues showed that the combination of either 25 or 50 mg/day CPA with a moderate dosage of oral estradiol (~3.5 mg/day) or transdermal estradiol (~3.5 mg/day gel or ~100 μg/day patch) resulted in equivalent and complete suppression of gonadal testosterone production (~95% suppression of testosterone levels) in transfeminine people (Fung, Hellstern-Layefsky, & Lega, 2017). These dosages of estradiol would be expected to achieve estradiol levels of around 100 pg/mL on average (Aly, 2020; Wiki). This study was notably published 6 months before the 2017 second edition of the Endocrine Society guidelines were released (Hembree et al., 2017), and was probably responsible for the decrease in their recommended dosage of CPA from 50–100 mg/day to 25–50 mg/day.
Few studies to date have assessed testosterone suppression with low-dose CPA in combination with a low or moderate dosage of an estrogen. However, based on the fact that 5 to 10 mg/day CPA alone is probably maximal in terms of suppression of testosterone levels, it is likely that such dosages of CPA will be similarly effective as higher dosages. In accordance, studies of 5 to 12.5 mg/day CPA plus upper physiological replacement dosages of testosterone have demonstrated undetectable gonadotropin levels (<0.5 IU/L) and hence complete suppression of testicular function in healthy young men (Meriggiola et al., 1998; Meriggiola et al., 2002b). Estradiol is a more powerful antigonadotropin than testosterone (Wiki), so these findings probably apply to CPA in combination with physiological replacement levels of estradiol as well (e.g., mean estradiol levels of 100–200 pg/mL).
Accordingly, Meyer et al. (2020) assessed a dosage of CPA in combination with estradiol in 155 transfeminine people and found no difference in testosterone levels with 10, 25, or 50 mg/day CPA; testosterone levels were strongly suppressed with all three doses (to about 15–20 ng/dL on average, or into the lower end of the normal female range). The estradiol forms and doses used in this study were oral estradiol valerate (median 6 mg/day, range 3–10 mg/day), transdermal estradiol gel (median 2.25 mg/day, range 1.5–6 mg/day), and transdermal estradiol patches (100 μg/day in all cases). Estradiol levels were about 100 pg/mL on average, with an interquartile range (i.e., difference between 75th and 25th percentiles) of about 100 pg/mL. This study demonstrates that, provided estradiol levels are adequate, no more than 10 mg/day CPA is needed to fully suppress testosterone levels in transfeminine people. Another study likewise found no difference between <20 mg/day and >50 mg/day CPA in terms of testosterone suppression in transfeminine people (Even-Zohar et al., 2020).
Even doses of CPA lower than 5 mg/day (e.g., 2 mg/day) may be usefully effective for testosterone suppression if combined with sufficient levels of estradiol, although this has not been studied and remains to be validated. But there is certainly precedent for the notion when looking at studies with other progestogens. As an example, one study using 10 mg/day oral medroxyprogesterone acetate (which is roughly equivalent to 1 mg/day CPA in terms of ovulation inhibition in premenopausal women; Table) observed 63% lower testosterone levels (215 ng/dL vs. 79 ng/dL) when added to estradiol and spironolactone therapy in transfeminine people (Jain, Kwan, & Forcier, 2019). Analogous effects on testosterone levels would be anticipated for very-low-dose CPA. Moreover, such dosages of CPA would have the advantage of actually being physiological in terms of progestogenic exposure.
The androgen receptor antagonism of CPA is relatively weak in terms of potency; dosages of CPA of 50 to 300 mg/day seem to be necessary for meaningful or considerable androgen receptor antagonism. Unfortunately, such doses also result in extreme progestogenic overdosage and are associated with considerably greater risks and adverse effects. As a result, the use of such doses of CPA should no longer be considered advisable. Instead, CPA should be used at lower doses simply as a progestogen to suppress testosterone levels. As such, the highest effective dosage of CPA for testosterone suppression, which is probably about 10 mg/day or less (12.5 mg/day also being acceptable), should be around the maximal dosage of CPA that is used in transfeminine people.
It should be emphasized that since the combination of an estrogen and CPA can easily suppress testosterone levels well into the female/castrate range (typically to below average female levels), there isn’t necessarily a requirement for concomitant androgen receptor blockade. In any case, if androgen receptor antagonism to neutralize the remaining female/castrate levels of testosterone is still necessary or desired (e.g., to treat persisting acne or for some other purpose), a low dosage of a non-progestogenic androgen-receptor antagonist like spironolactone (e.g., 100–200 mg/day) or bicalutamide (e.g., 12.5–25 mg/day) can be added to CPA to more safely achieve this than use of higher CPA doses.
Recommended Dosages
Dosage for Testosterone Suppression
Estrogen Plus Cyproterone Acetate
The following recommended dosages of CPA in transfeminine people are for the combination of CPA with an estrogen and are specifically for achieving maximal suppression of testosterone levels:
Table 2: Recommended doses of CPA in combination with estrogen for maximal testosterone suppression in transfeminine people:
Form
Min. dosage
Max. dosage
Amount
10 mg tablets
5 mg/day
10 mg/day
1/2 of a tablet to 1 whole tablet per day
50 mg tablets
6.25 mg/day
12.5 mg/day
1/8th of a tablet to 1/4th of a tablet per day
Start with the minimum dosage of CPA for one month. After one month, have testosterone levels tested and confirm that they are in the normal female/castrate range (<50 ng/dL). Regardless of dosage, a concomitant minimum estradiol level of around 65 pg/mL needs to be attained in order to allow for complete suppression of testosterone levels with CPA. If testosterone levels aren’t sufficiently suppressed after a month and estradiol levels are adequate, increase to the maximum CPA dosage and re-check testosterone levels after another month. Alternatively, the dosage of estradiol can be increased instead; higher estradiol levels result in greater testosterone suppression as well.
Cyproterone Acetate Alone
The use of CPA alone (i.e., as a monotherapy for testosterone suppression) is not recommended due to the risk of decreased bone mineral density and other symptoms of sex-hormone deficiency (Wiki; Aly, 2019). In any case, the recommended dosages for CPA without an estrogen are essentially the same as those listed above of the combination of an estrogen with CPA for testosterone suppression. However, the higher CPA dose (10–12.5 mg/day) may be preferable for good measure in this scenario.
Dosage for Progestogenic Effects
The following recommended dosages of CPA in transfeminine people are for progestogenic effects similar to normal physiological exposure (equivalent of luteal-phase progesterone levels):
Table 3: Recommended doses of CPA for physiological progestogenic effects in transfeminine people:
Form
Dosage
Amount
10 mg tablets
2.5 mg/day
1/4th of a tablet per day
50 mg tablets
3.125 mg/day
1/16th of a tablet per day
Achieving Desired Dosages
CPA is available pharmaceutically most widely as 50-mg tablets. This can make achieving desired low doses of CPA more difficult. For splitting CPA tablets into small fractions, a pill cutter can be used. Additionally, CPA can be taken once every 2 or 3 days instead of once every day to help further divide doses. It is notable that CPA has a relatively long half-life in the body of about 1.5 to 2 days (but possibly up to 4 days) (Wiki; Graph). Hence, taking it once every other day instead of once per day, or even less frequently like once every 3 days, has sound basis and is likely to be entirely viable.
Updates
Update 1: GoLoCypro Study (In-Progress)
The GoLoCypro study (2019–2022) (more info) is being conducted by Dr. Judith Dean at the University of Queensland in Australia. It’s assessing the influence of estradiol plus CPA on testosterone levels at five different CPA dose levels (12.5 mg 2x/week, 12.5 mg/2 days, 12.5 mg/day, 25 mg/day, and 50 mg/day) in a total of 120 to 350 transfeminine people. CPA doses are being titrated to the minimum that maintain testosterone levels within the therapeutic goal range of 0.5 to 1.5 nmol/L (14–43 ng/dL). The study is among the first dose-ranging studies of CPA in transfeminine people to be conducted and is eagerly anticipated due to the valuable information that it should provide in terms of the minimum effective dosage of CPA for adequate testosterone suppression in transfeminine hormone therapy.
Update 2: Kuijpers et al. (2021) and Even Zohar et al. (2021)
Kuijpers, S. M., Wiepjes, C. M., Conemans, E. B., Fisher, A. D., T’Sjoen, G., & den Heijer, M. (2021). Toward a lowest effective dose of cyproterone acetate in trans women: Results from the ENIGI study. The Journal of Clinical Endocrinology & Metabolism, 106(10), e3936–e3945. [DOI:10.1210/clinem/dgab427]
The study employed estradiol (2–6 mg/day oral (as estradiol valerate), 50–150 μg/day patch, or gel) plus five different dose levels of CPA—0 mg/day (no CPA), 10 mg/day, 25 mg/day, 50 mg/day, and 100 mg/day. It found incompletely suppressed testosterone in the no CPA group but full and equivalent testosterone suppression with all doses of CPA. The results were as follows:
CPA dosage
0 mg/day
10 mg/day
25 mg/day
50 mg/day
100 mg/day
Initial subjects (n)
34
4
234
599
11
Dose increased (n)
16
1
11
2
0
Dose decreased (n)
0
0
4
40
7
T levels (nmol/L)
5.5
0.9
0.9
1.1
0.9
T levels (ng/dL)
~160
~26
~26
~32
~26
T <2 nmol/L [<~58 ng/dL] (%)
46.3
92.3
96.2
93.4
100.0
Abbreviations: T = testosterone.
The total numbers of subjects and blood tests after CPA dose increases/decreases were not provided. Hence, the exact total number of people and tests for the 10 mg/day group can’t be stated with certainty. The total number of tests for this group was at least 13 based on the testosterone suppression percentage provided however (92.3% or 12/13 but could potentially be 24/26, etc.). Regarding the small number of subjects/tests for the 10 mg/day group, the authors stated the following:
This study is part of the ENIGI initiative, a multicenter prospective cohort study. The main treatment protocol for trans women in this study was 50 mg of CPA daily combined with estrogens. In the first year of study inclusion, a few participants received a dose of 100 mg of CPA. Shortly thereafter, inhospital protocol changed to 50 mg of CPA. As more health concerns related to CPA use were raised over the years, the dose was further lowered from 50 mg to 25 mg and, finally, to 10 mg. However, due to the coronavirus (COVID-19) pandemic, limited results of participants with 10 mg of CPA were available for analysis.
Besides testosterone suppression, the study found that 10 mg/day CPA had less influence on prolactin and high-density lipoprotein (HDL) cholesterol levels than the higher doses of CPA. The study also assessed liver enzyme levels but found no differences between CPA doses.
The authors concluded with the following:
In conclusion, in this cohort of trans women, 10 mg of CPA was found to be effective in lowering testosterone concentrations to the range observed in cis women. A dose of 10 mg was equally effective as higher doses, was found to have less influence on prolactin concentrations and allows higher HDL-C concentrations to be maintained. While GnRH agonists are preferred over CPA due to the fewer associated long-term side effects, this study shows that CPA at a low dose is a viable option when GnRH agonists are contra-indicated, not available, or not reimbursed. Future research should focus on assessing the effectiveness of an even lower dose of CPA (e.g., 5 mg) and the potential long-term side effects.
Around the same that this study was published, Guy T’Sjoen (one of the authors of the study) and other colleagues in a review of optimal hormone therapy for transfeminine people recommended a dosage of no more than 10 or 12.5 mg/day CPA for no longer than 2 years (Glintborg et al., 2021). T’Sjoen is notable in being regarded as one of the foremost experts in transgender medicine and is a coauthor of the Endocrine Society transgender care guidelines (Hembree et al., 2017).
Shortly after the study of Kuijpers and colleagues and also in June 2021, Even Zohar and colleagues in Israel published the following study on low doses of CPA in transfeminine people:
Even Zohar, N., Sofer, Y., Yaish, I., Serebro, M., Tordjman, K., & Greenman, Y. (2021). Low-Dose Cyproterone Acetate Treatment for Transgender Women. The Journal of Sexual Medicine, 18(7), 1292–1298. [10.1016/j.jsxm.2021.04.008]
This study was initially reported as a conference abstract in May 2020 (Even-Zohar et al., 2020).
In the introduction section of the paper, the authors stated the following:
Treatment guidelines published by several organizations are available and assist clinicians in treating transgender women.4,7−9 A wide range of regimens for CPA administration have been proposed. By and large, the recommended doses have decreased over the years: doses of 50–100 mg/day were suggested in the 2009 Endocrine Society Guidelines,10 and amended to 25–50 mg/day in 2017.7 The proposed CPA doses were 12.5–25 mg/day in the 2019 guidelines of the Australian Professional Association for Transgender Health,4 and they were amended to 10–50 mg/day in the 2020 guidelines of the European Society for Sexual Medicine.8 There are no publications on data that compare different doses of CPA for efficacy or safety.
The researchers found that estradiol plus low-dose CPA (10–20 mg/day) suppressed testosterone levels to an equivalent extent as estradiol plus high-dose CPA (50–100 mg/day). Testosterone levels were suppressed into the female/castrate range or near so in both groups (generally ≤2 nmol/L or ≤58 pg/mL). Of the 38 transfeminine people on low-dose CPA, 32 (84%) were on 10 mg/day CPA and 6 (16%) were on 20 mg/day CPA (mean dose 11.6 ± 3.7 mg/day). Estradiol was given as transdermal estradiol patch (mean dose 83.7 ± 36.5 μg/day), transdermal estradiol gel (mean dose 3.8 ± 1.2 g/day), or oral estradiol (mean dose 4.1 ± 1.7 mg/day). Mean estradiol levels ranged from ~110 to 350 pmol/L (~30–95 pg/mL) in the low- and high-dose CPA groups over the follow-up period. Besides showing equivalent testosterone suppression, prolactin levels were significantly lower with low-dose CPA than with high-dose CPA (398 ± 69 mIU/mL vs. 804 ± 121 mIU/mL at 12 months of hormone therapy, respectively).
Based on their findings, the authors stated the following:
We suggest an adjustment of current clinical practice guidelines to recommend lower doses of CPA for the treatment of transgender women.
Both Kuijpers et al. (2021) and Even Zohar et al. (2021) claimed to be the first to demonstrate the efficacy of low-dose CPA in transfeminine people. However, that achievement actually appears to belong to Meyer et al. (2020), who in February 2020 found that estradiol plus 10, 25, or 50 mg/day CPA gave equivalent testosterone suppression across CPA doses in transfeminine people.
Although their study was not about CPA and testosterone suppression, Lim et al. (2020) reported in May/July 2020 that testosterone levels in transfeminine people were median (IQR) 0.6 (0.4–1.0) nmol/L for oral estradiol and 0.9 (0.7–1.6) nmol/L for transdermal estradiol in a mixed group of transfeminine people (n=26 total) on estradiol plus low-dose CPA (12.5 (12.5–18.8) mg/day) (n=14), estradiol alone post-gonadectomy (n=9), and estradiol plus spironolactone (n=3).
In December 2021, the following case report of fatal liver failure with low-dose CPA was published:
Kumar, P., Reddy, S., Kulkarni, A., Sharma, M., & Rao, P. N. (2021). Cyproterone acetate induced Acute liver failure: Case report and review of the literature. Journal of Clinical and Experimental Hepatology, 11(6), 739–741. [DOI:10.1016/j.jceh.2021.01.003]
The case report describes a 30-year-old cisgender woman who was on 25 mg/day CPA for treatment of hirsutism (excessive facial/body hair growth) for 6 months and developed acute liver failure. Four days following hospitalization, she died. This is the second published case report of liver toxicity with CPA at a dosage below 100 mg/day (the first and only other case was at 50 mg/day) (Wiki; Table). It is also the first report of liver failure in a cisgender woman taking CPA. The case indicates that CPA even at a relatively low dose of 25 mg/day is not fully safe in terms of liver toxicity. It further emphasizes the importance of using the lowest effective doses of CPA in transfeminine people (no more than 10–12.5 mg/day).
Update 4: Coleman et al. (2022) [WPATH SOC8 Guidelines]
In September 2022, the World Professional Association for Transgender Health (WPATH) Standards of Care for the Health of Transgender and Gender Diverse People Version 8 (SOC8) were published and made recommendations for transgender hormone therapy for the first time (Coleman et al., 2022). These guidelines recommended a dose of CPA of 10 mg/day in transfeminine people (Coleman et al., 2022). This dose is substantially lower than previous doses recommended by transgender care guidelines and is the first time that major guidelines have recommended a CPA dosage this low. The WPATH SOC8 cited Kuijpers et al. (2021) in support of this recommendation (though notably not Even Zohar et al. (2021) or Meyer et al. (2020)) and also discussed the dose-dependent risks of CPA such as meningiomas and high prolactin levels (Coleman et al., 2022). Considering the key position and importance of the WPATH SOC in transgender health, it is likely that lower CPA doses in transfeminine hormone therapy will now be widely adopted throughout the world. Continued use of higher CPA doses should be considered out of step with current accepted evidence-based practice.
Update 5: Collet et al. (2023)
In October 2022, a study more carefully assessing androgen suppression with estradiol plus CPA in transfeminine people was published:
Collet, S., Gieles, N., Wiepjes, C. M., Heijboer, A. C., Reyns, T., Fiers, T., Lapauw, B., den Heijer, M., & T’Sjoen, G. (2023). Changes in serum testosterone and adrenal androgen levels in transgender women with and without gonadectomy. The Journal of Clinical Endocrinology & Metabolism, 108(2), 331–338. [DOI:10.1210/clinem/dgac576]
In the study, 275 transfeminine people were treated with estradiol plus CPA, and levels of total testosterone, free testosterone, and the adrenal androgensdehydroepiandrosterone (DHEA), dehydroepiandrosterone sulfate (DHEA-S), and androstenedione (A4) were measured using liquid chromatography–mass spectrometry (LC–MS) at baseline and during follow-ups at 3 months, 12 months, 2 to 4 years, and after surgical gonadal removal (at which time CPA was discontinued). Estradiol was measured both with LC–MS (Amsterdam clinic) and with immunoassays (Ghent clinic). The forms and doses of estradiol used were most commonly oral estradiol valerate 4 mg/day or a transdermal estradiol patch 100 μg/day, while the dosage of CPA was usually 25 or 50 mg/day. About half of the transfeminine people eventually underwent surgical gonadal removal, usually after 2 years of hormone therapy.
Median estradiol levels ranged from 49 to 75 pg/mL (180–275 pmol/L) with LC–MS and from 63 to 69 pg/mL (232–255 pmol/L) with immunoassays at different follow-ups. After 3 months of hormone therapy, total testosterone decreased by 97.1%, from 536 ng/dL (18.6 nmol/L) to 12 ng/dL (0.40 nmol/L), and free testosterone decreased by 98.3%, from 109 pg/mL (378 pmol/L) to 2.0 pg/mL (7.1 pmol/L). Thereafter, total and free testosterone levels remained stable. Levels of DHEA, DHEA-S, and A4 decreased by 24.9 to 28.0%, 20.1 to 23.5%, and 36.5%, respectively, and likewise did not further change after the first 3 to 12 months of hormone therapy. No changes in androgen levels occurred upon surgical gonadal removal with discontinuation of CPA. The authors noted that testosterone levels in the transfeminine people on hormone therapy in the study were similar to or lower than those in cisgender women.
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+Low Doses of Cyproterone Acetate Are Maximally Effective for Testosterone Suppression in Transfeminine People - Transfeminine Science
Low Doses of Cyproterone Acetate Are Maximally Effective for Testosterone Suppression in Transfeminine People
By Aly | First published July 1, 2019 | Last modified March 18, 2024
Abstract / TL;DR
Cyproterone acetate (CPA) is a progestogen and antiandrogen which is widely used in transfeminine hormone therapy. It is far more potent as a progestogen than as an androgen receptor antagonist. CPA has typically been used at doses of 1 to 2 mg/day as a progestogen in cisgender women and at doses of 50 to 300 mg/day as an antiandrogen. At typical antiandrogen doses of CPA, there is profound progestogenic overdosage as well as associated side effects and risks. CPA has antigonadotropic effects due to its progestogenic activity and thereby suppresses testosterone levels. By itself, CPA can maximally suppress testosterone levels by 50 to 70%, and in combination with even small amounts of estrogen, it can fully suppress gonadal testosterone production and thereby reduce testosterone levels by about 95%—or well into the female range. Although doses of CPA of 50 to 100 mg/day have been used in transfeminine people historically, it is now clear that 5 to 10 mg/day CPA has maximal or near-maximal effectiveness in terms of suppression of testosterone levels. CPA alone is most commonly available as 50-mg tablets. These tablets can be split with a pill cutter and taken once every day to once every other day to achieve an overall CPA dosage of 6.25 to 12.5 mg/day. These lower doses of CPA are not only much more cost-effective than traditional doses but are also likely to have better tolerability and safety. Due to the retained effectiveness of lower CPA doses and the known dose-dependent risks of CPA, doses of CPA used clinically in transfeminine people have been in a rapid decline.
Introduction
This article is about the dosage of cyproterone acetate (CPA), a progestin and antiandrogen, for use in hormone therapy for transfeminine people. It argues for the use of lower doses of CPA and goes fairly in-depth to justify these doses. If you are only interested in recommended doses of CPA for transfeminine people, they can be found in the Recommended Dosages section below.
Potency, Conventional Dosages, and Health Risks
CPA is a potent progestogen, with an ovulation-inhibiting dosage of about 1 mg/day and endometrial transformation dosage of about 1 to 3 mg/day in cisgender women (Wiki; Table; Endrikat et al., 2011). These dosages of CPA are similar in strength of progestogenic effect to those of normal progesterone production and levels during the luteal phase of the menstrual cycle in premenopausal women (which are about 25 mg/day and 15 ng/mL, respectively). In relation to the preceding, when CPA is used as a progestogen in cisgender women, for instance in birth control pills and menopausal hormone therapy preparations, it is formulated at a dose of 1 or 2 mg per tablet (Wiki).
In contrast to its progestogenic activity, CPA is far less potent as an androgen receptor antagonist (Wiki). When used as an antiandrogen, it is generally given at a dosage of 50 to 300 mg/day, both in cisgender women and men. A dosage of 50 to 100 mg/day is typical for androgen-dependent skin and hair conditions like acne and hirsutism in women and a dosage of 100 to 300 mg/day is typically used for prostate cancer in men (specifically 100–200 mg/day for CPA combined with castration and 200–300 mg/day for CPA monotherapy) (Wiki). As such, CPA is generally formulated at a dose of 50 or 100 mg per tablet for use in androgen-dependent conditions (Wiki). As an antiandrogen, CPA has a dual mechanism of action of both suppressing testosterone levels via its progestogenic activity at low doses and additionally blocking the actions of testosterone directly at the androgen receptor at higher doses.
Because CPA is so much more potent as a progestogen than as an androgen receptor antagonist, there is profound overdosage of progestogenic effect when CPA is used as an antiandrogen at typical clinical dosages. This is described in the following three literature excerpts by Jürgen Hammerstein, one of the scientists who developed CPA (Hammerstein et al., 1975; Hammerstein, 1990; Hammerstein, 1979):
Like chlormadinone acetate, its parent compound, CPA is also a strong progestogen with the endometrial transformation dose of both drugs being between 20 and 30 mg. […] To take full therapeutic advantage of its antiandrogenicity, CPA must be administered in doses per month that are 30 times the physiological equivalent of progesterone production in the cycle. CPA, although the most useful compound available in this field at the moment, cannot be considered therefore an ideal antiandrogen, all the more as some of the side effects may be related to the progestational overdosage rather than to the administered antiandrogenic activity. […] Adverse reactions like tiredness, lassitude, and increase in body weight are possibly due to the enormous overdose of progestational activity in the formula which is necessary to take full advantage of the antiandrogenicity of CPA.
Fixson (1963) tested CPA in ovariectomized women after pre-treatment with oestrogens; with a transformation dose of 20–30 mg this proved a powerful progestogen. The potency of CPA in the menses delay test is not exactly known, but has been estimated to be below 1 mg/day (Miller and Jacobs 1986). In relation to this progestational potency, its antiandrogenicity must be considered rather weak. Thus, in order to take full advantage of the latter, 100 mg CPA must be given daily, i.e. three times the cyclic transformation dose per day (Hammerstein and Cupceancu 1969); notably, this parameter is equivalent to the total progesterone production of a corpus luteum throughout its entire cyclic life span.
CPA may be characterized endocrinologically as possessing strong progestational [and] moderate anti-androgenic […] potencies. […] Its progestational activity, in terms of the transformation dose in the oestrogen-primed human endometrium, is 20–30 mg [per month/cycle] which is comparable to that of chlormadinone acetate and other strong progestogens. To take full clinical advantage of its anti-androgenicity not less than 50–100 mg CPA must be taken orally per day, which totals 2 to 3 times the progestational activity the female organism is exposed to throughout a complete ovulatory menstrual cycle. Thus unless much lower and less efficacious doses of CPA are used, a tremendous progestational overdosage must be accepted. […] As already pointed out CPA is endocrinologically not a well-balanced compound because of the strong preponderance of the progestational over the anti-androgenic potency. A way to avoid the heavy progestogen overdosage inherent with the high-dose reverse sequential therapy would be to combine the low-dose contraceptive formulation just mentioned with a pure anti-androgen such as free cyproterone. […] It must be emphasized that CPA is far from being an ideal drug for the anti-androgenic treatment of hirsutism because its progestational potency is much too strong and it is not effective when administered topically. Therefore it is worthwhile looking for better-balanced anti-androgenic compounds for the future.
The massive overdosage of progestogenic effect that occurs at such doses of CPA is likely responsible for the known adverse effects and risks of higher doses of CPA (Wiki). Examples of these side effects include fatigue, depression, weight gain, high prolactin levels (Wiki), benign brain tumors (Aly, 2020; Wiki; Table; Table), blood clots (Wiki), and cardiovascular problems (Wiki). Such risks are dose-dependent and have not been associated with 1 or 2 mg/day CPA (with the exception of an expected increase in the risk of blood clots in combination with oral estrogens for birth control or menopausal hormone therapy). The risk of liver toxicity with CPA is also dose-dependent, with elevated liver enzymes occurring mostly only at a dosage of 20 mg/day and above and rare cases of liver failure occurring almost exclusively at dosages of 100 mg/day and above (Wiki; Table). As such, there is good rationale for using the lowest possible effective dosage of CPA, an approach that is likely to minimize risks.
In transfeminine people, CPA has historically been used at a dosage of 50 to 100 mg/day (e.g., Moore, Wisniewski, & Dobs, 2003). Some earlier papers have recommended even higher doses of CPA, for instance 100 to 150 mg/day (Asscheman & Gooren, 1993). In 2017, the Endocrine Society published the latest edition of their clinical practice guidelines on hormone therapy for transgender people and reduced their recommended dosage of CPA from 50–100 mg/day to 25–50 mg/day (Hembree et al., 2017; Hembree et al., 2009). This was motivated in part by increasing knowledge and awareness of the risks of higher doses of CPA and by findings that these lower doses of CPA were still effective. However, it is likely that even these new lower dosages are still far in excess of what is really needed.
Testosterone Suppression with Low and High Doses
Progestogens by themselves, including CPA, are able to considerably suppress testosterone levels in gonadally intact people assigned male at birth. Around a dozen small and low-quality but nonetheless notable studies of low-dose CPA from the 1970s and early 1980s found that 5 to 10 mg/day CPA suppressed testosterone levels by about 40 to 70% in healthy young men (Table 1). A couple of individual studies notably reported virtually identical suppression of testosterone levels with 5 mg/day versus 10 mg/day CPA (both ~50% suppression) (Wang & Yeung, 1980; Graph) and with 10 mg/day versus 20 mg/day CPA (both ~60–70% suppression) (Koch et al., 1976; Koch et al., 1975; Graph). This lack of additional testosterone suppression with a doubling of dosage within studies suggests that testosterone suppression with CPA might have actually been maximal at a dosage of only 5 or 10 mg/day. A more modern study, which used a newer and more reliable analytic method for quantification of blood testosterone, found that 10 mg/day CPA suppressed testosterone levels by 66%, from about 600 ± 150 ng/dL to about 185 ng/dL (Meriggiola et al., 2002a; Graph). Similarly, another more modern study found that 10 to 20 mg/day CPA suppressed testosterone levels by 65%, from about 431 ng/dL to about 149 ng/dL, with no reported differences between doses (Zitzmann et al., 2017; Graph).
Table 1: Levels of testosterone and other sex hormones with CPA at low doses (5–30 mg/day):
Treatment and subjects
Findings
Source(s)
30 mg/day CPA in 5 normal males
T decreased “remarkably”. Exact values not given, but has graphs of T levels in a few individuals. After 30 mg/day, 5 mg/day was tried in one case and was not as effective in suppressing sperm production or T. Also reported decreases in gonadotropin excretion.
10 or 20 mg/day CPA in 15 normal healthy fertile males (age 25–35 years) (7 in 10 mg/day group and 8 in 20 mg/day group)
“Androgens (mainly T)” decreased by 60% for both 10 and 20 mg/day. Inconsistent changes in LH and slight decrease in FSH. Exact values not given, except in graphs.
10 mg/day CPA in 10 young healthy fertile men (age mean 27.2 ± 3.2 (range 21–35) years)
T decreased by 70%, DHT by 50%, LH by 30%, and FSH by 40%, while PRL increased by 75%. T was 495 ± 66 ng/dL before, 154 ± 23 ng/dL after 4 weeks, and 187 ± 38 ng/dL after 12 weeks. Also has values and graphs for other hormones.
20 mg/day CPA in 10 healthy males (age 26–55 years)
T decreased by 73% (range 71–75%), from 482 ng/dL (range 410–560 ng/dL) to 130 ng/dL (110–162 ng/dL). DHT decreased by 51% (range 47–55%), LH by 39% (range 34–45%), FSH by 66% (range 47–78%), 17-OH-P4 by 59%, A4 by 30%, TS by 34%, and DHTS by 35%. Also has exact values and graphs for other hormones.
5 or 10 mg/day CPA in 7 males (4 in each group; 1 received both 5 and 10 mg/day CPA at different times)
T change was “−40%” or “–50%”. At 5 mg/day, T was 745 ng/dL before, 460 ng/dL with treatment (–38%), and 668 ng/dL after discontinuation. At 10 mg/day, T was 708 ng/dL before, 398 ng/dL with t (reatment–44%), and 670 ng/dL after discontinuation. Also reported LH and FSH levels.
0, 5, or 10 mg/day CPA in 25 normal healthy males (age 20–51 years); 7 in 5 mg group (mean 37 ± 10 years), 8 in 10 mg group (mean 32 ± 8 years), 10 in 0 mg group (mean 32 ± 10 years)
At 5 mg/day, T decreased from 663 ± 120 ng/dL to 320 ± 160 ng/dL (−52%), and at 10 mg/day, T decreased from 692 ± 180 ng/dL to 340 ± 160 ng/dL (−51%). E2 decreased in parallel to T. At 5 mg/day, LH decreased from 2.1 ± 0.7 IU/L to 1.4 ± 0.5 IU/L (−33%), and at 10 mg/day, LH decreased from 2.3 ± 1.0 IU/L to 1.2 ± 0.5 IU/L (−48%). At 5 mg/day, FSH decreased from 3.1 ± 1.9 IU/L to 1.8 ± 0.9 IU/L (−42%), and at 10 mg/day, FSH decreased from 2.7 ± 1.0 IU/L to 1.5 ± 0.7 IU/L (−44%).
10 or 25 mg/day CPA in 4 healthy men (age 29–37 years); 3 in 10 mg group, 1 in 25 mg group
T “slightly reduced”. E “more significantly lowered”. LH not significantly changed. FSH “reduced” in “more or less all cases”. Exact hormone levels not given, but graphs provided with the values.
10 mg/day CPA (also placebo and 2, 5, and 10 mg/day dienogest) in 5 healthy men in each group
With CPA, T decreased from ~600 ± 150 ng/dL to ~185 ng/dL (–66 ± 4%). Also reported LH, FSH, and SHBG, as well as hormonal changes with placebo and dienogest (2, 5, and 10 mg/day).
10 or 20 mg/day CPA in 14 healthy young men (7 in each group)
T decreased from ~431 ng/dL at baseline to ~149 ng/dL with CPA (–65%) for the 10 and 20 mg/day doses combined. Values for dose subgroups not given. No significant differences between LH/FSH suppression between groups (which is indirectly suggestive of no differences in T suppression as well). Also reported hormone levels with other progestins.
Studies with other progestogens, such as desogestrel, dienogest, and medroxyprogesterone acetate, have consistently found that maximal suppression of testosterone levels in men occurs at a dosage that is between 5 and 10 times that of the ovulation-inhibiting dosage in cisgender women (Wiki; Wiki; Wiki). Another study is likewise suggestive of this for norethisterone acetate and levonorgestrel (Zitzmann et al., 2017; Graph). Along similar lines, doses of progestogens investigated for use in male hormonal contraception, in which the goal is antigonadotropic effects and the lowest fully effective dose is targeted, have been noted as being between 5 and 12 times the doses used in cisgender women (Foegh, 1983). Based on an ovulation-inhibiting dosage of CPA of 1 mg/day, these findings would imply that suppression of testosterone levels with CPA would likely be maximal at a dose of between 5 and 10 mg/day. In accordance, this dose range matches up with the findings of the studies above.
Although progestogens can considerably suppress testosterone levels at maximally effective dosages, it has been found that a “recovery” or “escape phenomenon”, in which testosterone levels eventually increase back to higher levels, occurs when progestogen monotherapy is used on a long-term basis. This has most notably been observed with the related progestogen megestrol acetate (Wiki), but has also been seen with CPA (Goldenberg & Bruchovsky, 1991; Saborowski, 1987; Jacobi, Tunn, & Senge, 1982). In one of these studies, testosterone levels were initially suppressed by CPA by about 70%, but increased back to about 50% of baseline between 6 and 12 months of therapy, remaining stable thereafter up to 24 months. The testosterone escape phenomenon should be kept in mind in the context of progestogen monotherapy for testosterone suppression. In contrast to progestogen monotherapy, this phenomenon has not been associated with combined estrogen and progestogen therapy.
Testosterone Suppression in Combination with Estrogen
CPA is generally used in combination with an estrogen in transfeminine people. Estrogens suppress testosterone levels similarly to progestogens. The combination of an estrogen and a progestogen is synergistic in terms of testosterone suppression and results in suppression of testosterone levels with lower doses than with either an estrogen or progestogen alone (Fink, 1979; Geller & Albert, 1983; Bastianelli et al., 2018). Although estrogens can suppress testosterone levels to an equivalent extent as surgical or medical castration (i.e., orchiectomy or GnRH agonists/antagonists), this usually requires relatively high estrogen levels, for instance in the range of 200 to 500 pg/mL (Wiki; Graphs). Because of the high and supraphysiological estradiol levels required for maximal or near-maximal suppression of testosterone levels, lower doses of estradiol are frequently combined with antiandrogens and/or progestogens to block or suppress remaining testosterone levels instead.
CPA, as mentioned earlier, leads to an incomplete suppression of plasma testosterone levels, which decrease by about 70% and remain at about three times castration values. In a very systematic approach to the problem, Rennie et al. (59) investigated and compared 12 different procedures of androgen deprivation. These authors found that the combination of CPA with an extremely low dose (0.1 mg/d) of [diethylstilbestrol (DES)] led to a very effective withdrawal of androgens in terms of plasma testosterone and tissue dihydrotestosterone. The same group later showed that 200 mg of CPA, and even 100 mg/day, was sufficient to achieve a similar endocrine response, which was correlated to very favorable clinical responses in a Phase II situation (60,61). The approach has many potential advantages, and, from an endocrinological point of view, is very logical: this regimen combines the testosterone-reducing effects of two compounds, therefore, only small amounts of estrogen are required to bring down plasma testosterone to approximately castrate levels. Once castrate levels have been achieved, only low doses of CPA are necessary to counteract remaining androgens, mainly of adrenal origin. The regimen was shown to be associated with few side effects and a very low cost. The combination of low-dose CPA with low-dose DES was never studied in a Phase III situation in comparison to standard management. Considering the endocrine results and the observations in patients treated with this regimen (60), this combination treatment is very likely to be competitive with other standard forms of therapy.
A 2016 study of 50 mg/day CPA and 1 to 2 mg/day transdermal estradiol gel in transfeminine people showed that estradiol levels of about 45 pg/mL with CPA were insufficient to achieve female/castrate levels of testosterone, instead resulting in testosterone levels of about 120 to 190 ng/dL (Gava et al., 2016; Graph). Conversely, estradiol levels of about 85 pg/mL with CPA achieved complete suppression of gonadal testosterone production, with resulting testosterone levels of about 20 ng/dL. As such, a certain minimum level of estradiol with CPA appears to be required for complete testosterone suppression. A 2019 study of CPA and oral estradiol valerate in transfeminine people indicated that testosterone levels were still fully suppressed with median estradiol levels of 76 pg/mL and 25th percentile estradiol levels of 63 pg/mL (Angus et al., 2019; Graph).
Figures 5–7: Testosterone levels with CPA plus low doses/levels of estrogens in men and transfeminine people. Sources: Top-left: Goldenberg et al. (1988). Top-right: Gava et al. (2016). Bottom: Angus et al. (2019). See also on Wikipedia: Gallery. Note for the graph on the top right that the mean transdermal estradiol dosage increased between 6 and 12 months and this was likely responsible for the improvement in testosterone suppression.
Fung and colleagues showed that the combination of either 25 or 50 mg/day CPA with a moderate dosage of oral estradiol (~3.5 mg/day) or transdermal estradiol (~3.5 mg/day gel or ~100 μg/day patch) resulted in equivalent and complete suppression of gonadal testosterone production (~95% suppression of testosterone levels) in transfeminine people (Fung, Hellstern-Layefsky, & Lega, 2017). These dosages of estradiol would be expected to achieve estradiol levels of around 100 pg/mL on average (Aly, 2020; Wiki). This study was notably published 6 months before the 2017 second edition of the Endocrine Society guidelines were released (Hembree et al., 2017), and was probably responsible for the decrease in their recommended dosage of CPA from 50–100 mg/day to 25–50 mg/day.
Few studies to date have assessed testosterone suppression with low-dose CPA in combination with a low or moderate dosage of an estrogen. However, based on the fact that 5 to 10 mg/day CPA alone is probably maximal in terms of suppression of testosterone levels, it is likely that such dosages of CPA will be similarly effective as higher dosages. In accordance, studies of 5 to 12.5 mg/day CPA plus upper physiological replacement dosages of testosterone have demonstrated undetectable gonadotropin levels (<0.5 IU/L) and hence complete suppression of testicular function in healthy young men (Meriggiola et al., 1998; Meriggiola et al., 2002b). Estradiol is a more powerful antigonadotropin than testosterone (Wiki), so these findings probably apply to CPA in combination with physiological replacement levels of estradiol as well (e.g., mean estradiol levels of 100–200 pg/mL).
Accordingly, Meyer et al. (2020) assessed a dosage of CPA in combination with estradiol in 155 transfeminine people and found no difference in testosterone levels with 10, 25, or 50 mg/day CPA; testosterone levels were strongly suppressed with all three doses (to about 15–20 ng/dL on average, or into the lower end of the normal female range). The estradiol forms and doses used in this study were oral estradiol valerate (median 6 mg/day, range 3–10 mg/day), transdermal estradiol gel (median 2.25 mg/day, range 1.5–6 mg/day), and transdermal estradiol patches (100 μg/day in all cases). Estradiol levels were about 100 pg/mL on average, with an interquartile range (i.e., difference between 75th and 25th percentiles) of about 100 pg/mL. This study demonstrates that, provided estradiol levels are adequate, no more than 10 mg/day CPA is needed to fully suppress testosterone levels in transfeminine people. Another study likewise found no difference between <20 mg/day and >50 mg/day CPA in terms of testosterone suppression in transfeminine people (Even-Zohar et al., 2020).
Even doses of CPA lower than 5 mg/day (e.g., 2 mg/day) may be usefully effective for testosterone suppression if combined with sufficient levels of estradiol, although this has not been studied and remains to be validated. But there is certainly precedent for the notion when looking at studies with other progestogens. As an example, one study using 10 mg/day oral medroxyprogesterone acetate (which is roughly equivalent to 1 mg/day CPA in terms of ovulation inhibition in premenopausal women; Table) observed 63% lower testosterone levels (215 ng/dL vs. 79 ng/dL) when added to estradiol and spironolactone therapy in transfeminine people (Jain, Kwan, & Forcier, 2019). Analogous effects on testosterone levels would be anticipated for very-low-dose CPA. Moreover, such dosages of CPA would have the advantage of actually being physiological in terms of progestogenic exposure.
The androgen receptor antagonism of CPA is relatively weak in terms of potency; dosages of CPA of 50 to 300 mg/day seem to be necessary for meaningful or considerable androgen receptor antagonism. Unfortunately, such doses also result in extreme progestogenic overdosage and are associated with considerably greater risks and adverse effects. As a result, the use of such doses of CPA should no longer be considered advisable. Instead, CPA should be used at lower doses simply as a progestogen to suppress testosterone levels. As such, the highest effective dosage of CPA for testosterone suppression, which is probably about 10 mg/day or less (12.5 mg/day also being acceptable), should be around the maximal dosage of CPA that is used in transfeminine people.
It should be emphasized that since the combination of an estrogen and CPA can easily suppress testosterone levels well into the female/castrate range (typically to below average female levels), there isn’t necessarily a requirement for concomitant androgen receptor blockade. In any case, if androgen receptor antagonism to neutralize the remaining female/castrate levels of testosterone is still necessary or desired (e.g., to treat persisting acne or for some other purpose), a low dosage of a non-progestogenic androgen-receptor antagonist like spironolactone (e.g., 100–200 mg/day) or bicalutamide (e.g., 12.5–25 mg/day) can be added to CPA to more safely achieve this than use of higher CPA doses.
Recommended Dosages
Dosage for Testosterone Suppression
Estrogen Plus Cyproterone Acetate
The following recommended dosages of CPA in transfeminine people are for the combination of CPA with an estrogen and are specifically for achieving maximal suppression of testosterone levels:
Table 2: Recommended doses of CPA in combination with estrogen for maximal testosterone suppression in transfeminine people:
Form
Min. dosage
Max. dosage
Amount
10 mg tablets
5 mg/day
10 mg/day
1/2 of a tablet to 1 whole tablet per day
50 mg tablets
6.25 mg/day
12.5 mg/day
1/8th of a tablet to 1/4th of a tablet per day
Start with the minimum dosage of CPA for one month. After one month, have testosterone levels tested and confirm that they are in the normal female/castrate range (<50 ng/dL). Regardless of dosage, a concomitant minimum estradiol level of around 65 pg/mL needs to be attained in order to allow for complete suppression of testosterone levels with CPA. If testosterone levels aren’t sufficiently suppressed after a month and estradiol levels are adequate, increase to the maximum CPA dosage and re-check testosterone levels after another month. Alternatively, the dosage of estradiol can be increased instead; higher estradiol levels result in greater testosterone suppression as well.
Cyproterone Acetate Alone
The use of CPA alone (i.e., as a monotherapy for testosterone suppression) is not recommended due to the risk of decreased bone mineral density and other symptoms of sex-hormone deficiency (Wiki; Aly, 2019). In any case, the recommended dosages for CPA without an estrogen are essentially the same as those listed above of the combination of an estrogen with CPA for testosterone suppression. However, the higher CPA dose (10–12.5 mg/day) may be preferable for good measure in this scenario.
Dosage for Progestogenic Effects
The following recommended dosages of CPA in transfeminine people are for progestogenic effects similar to normal physiological exposure (equivalent of luteal-phase progesterone levels):
Table 3: Recommended doses of CPA for physiological progestogenic effects in transfeminine people:
Form
Dosage
Amount
10 mg tablets
2.5 mg/day
1/4th of a tablet per day
50 mg tablets
3.125 mg/day
1/16th of a tablet per day
Achieving Desired Dosages
CPA is available pharmaceutically most widely as 50-mg tablets. This can make achieving desired low doses of CPA more difficult. For splitting CPA tablets into small fractions, a pill cutter can be used. Additionally, CPA can be taken once every 2 or 3 days instead of once every day to help further divide doses. It is notable that CPA has a relatively long half-life in the body of about 1.5 to 2 days (but possibly up to 4 days) (Wiki; Graph). Hence, taking it once every other day instead of once per day, or even less frequently like once every 3 days, has sound basis and is likely to be entirely viable.
Updates
Update 1: GoLoCypro Study (In-Progress)
The GoLoCypro study (2019–2022) (more info) is being conducted by Dr. Judith Dean at the University of Queensland in Australia. It’s assessing the influence of estradiol plus CPA on testosterone levels at five different CPA dose levels (12.5 mg 2x/week, 12.5 mg/2 days, 12.5 mg/day, 25 mg/day, and 50 mg/day) in a total of 120 to 350 transfeminine people. CPA doses are being titrated to the minimum that maintain testosterone levels within the therapeutic goal range of 0.5 to 1.5 nmol/L (14–43 ng/dL). The study is among the first dose-ranging studies of CPA in transfeminine people to be conducted and is eagerly anticipated due to the valuable information that it should provide in terms of the minimum effective dosage of CPA for adequate testosterone suppression in transfeminine hormone therapy.
Update 2: Kuijpers et al. (2021) and Even Zohar et al. (2021)
Kuijpers, S. M., Wiepjes, C. M., Conemans, E. B., Fisher, A. D., T’Sjoen, G., & den Heijer, M. (2021). Toward a lowest effective dose of cyproterone acetate in trans women: Results from the ENIGI study. The Journal of Clinical Endocrinology & Metabolism, 106(10), e3936–e3945. [DOI:10.1210/clinem/dgab427]
The study employed estradiol (2–6 mg/day oral (as estradiol valerate), 50–150 μg/day patch, or gel) plus five different dose levels of CPA—0 mg/day (no CPA), 10 mg/day, 25 mg/day, 50 mg/day, and 100 mg/day. It found incompletely suppressed testosterone in the no CPA group but full and equivalent testosterone suppression with all doses of CPA. The results were as follows:
CPA dosage
0 mg/day
10 mg/day
25 mg/day
50 mg/day
100 mg/day
Initial subjects (n)
34
4
234
599
11
Dose increased (n)
16
1
11
2
0
Dose decreased (n)
0
0
4
40
7
T levels (nmol/L)
5.5
0.9
0.9
1.1
0.9
T levels (ng/dL)
~160
~26
~26
~32
~26
T <2 nmol/L [<~58 ng/dL] (%)
46.3
92.3
96.2
93.4
100.0
Abbreviations: T = testosterone.
The total numbers of subjects and blood tests after CPA dose increases/decreases were not provided. Hence, the exact total number of people and tests for the 10 mg/day group can’t be stated with certainty. The total number of tests for this group was at least 13 based on the testosterone suppression percentage provided however (92.3% or 12/13 but could potentially be 24/26, etc.). Regarding the small number of subjects/tests for the 10 mg/day group, the authors stated the following:
This study is part of the ENIGI initiative, a multicenter prospective cohort study. The main treatment protocol for trans women in this study was 50 mg of CPA daily combined with estrogens. In the first year of study inclusion, a few participants received a dose of 100 mg of CPA. Shortly thereafter, inhospital protocol changed to 50 mg of CPA. As more health concerns related to CPA use were raised over the years, the dose was further lowered from 50 mg to 25 mg and, finally, to 10 mg. However, due to the coronavirus (COVID-19) pandemic, limited results of participants with 10 mg of CPA were available for analysis.
Besides testosterone suppression, the study found that 10 mg/day CPA had less influence on prolactin and high-density lipoprotein (HDL) cholesterol levels than the higher doses of CPA. The study also assessed liver enzyme levels but found no differences between CPA doses.
The authors concluded with the following:
In conclusion, in this cohort of trans women, 10 mg of CPA was found to be effective in lowering testosterone concentrations to the range observed in cis women. A dose of 10 mg was equally effective as higher doses, was found to have less influence on prolactin concentrations and allows higher HDL-C concentrations to be maintained. While GnRH agonists are preferred over CPA due to the fewer associated long-term side effects, this study shows that CPA at a low dose is a viable option when GnRH agonists are contra-indicated, not available, or not reimbursed. Future research should focus on assessing the effectiveness of an even lower dose of CPA (e.g., 5 mg) and the potential long-term side effects.
Around the same that this study was published, Guy T’Sjoen (one of the authors of the study) and other colleagues in a review of optimal hormone therapy for transfeminine people recommended a dosage of no more than 10 or 12.5 mg/day CPA for no longer than 2 years (Glintborg et al., 2021). T’Sjoen is notable in being regarded as one of the foremost experts in transgender medicine and is a coauthor of the Endocrine Society transgender care guidelines (Hembree et al., 2017).
Shortly after the study of Kuijpers and colleagues and also in June 2021, Even Zohar and colleagues in Israel published the following study on low doses of CPA in transfeminine people:
Even Zohar, N., Sofer, Y., Yaish, I., Serebro, M., Tordjman, K., & Greenman, Y. (2021). Low-Dose Cyproterone Acetate Treatment for Transgender Women. The Journal of Sexual Medicine, 18(7), 1292–1298. [10.1016/j.jsxm.2021.04.008]
This study was initially reported as a conference abstract in May 2020 (Even-Zohar et al., 2020).
In the introduction section of the paper, the authors stated the following:
Treatment guidelines published by several organizations are available and assist clinicians in treating transgender women.4,7−9 A wide range of regimens for CPA administration have been proposed. By and large, the recommended doses have decreased over the years: doses of 50–100 mg/day were suggested in the 2009 Endocrine Society Guidelines,10 and amended to 25–50 mg/day in 2017.7 The proposed CPA doses were 12.5–25 mg/day in the 2019 guidelines of the Australian Professional Association for Transgender Health,4 and they were amended to 10–50 mg/day in the 2020 guidelines of the European Society for Sexual Medicine.8 There are no publications on data that compare different doses of CPA for efficacy or safety.
The researchers found that estradiol plus low-dose CPA (10–20 mg/day) suppressed testosterone levels to an equivalent extent as estradiol plus high-dose CPA (50–100 mg/day). Testosterone levels were suppressed into the female/castrate range or near so in both groups (generally ≤2 nmol/L or ≤58 pg/mL). Of the 38 transfeminine people on low-dose CPA, 32 (84%) were on 10 mg/day CPA and 6 (16%) were on 20 mg/day CPA (mean dose 11.6 ± 3.7 mg/day). Estradiol was given as transdermal estradiol patch (mean dose 83.7 ± 36.5 μg/day), transdermal estradiol gel (mean dose 3.8 ± 1.2 g/day), or oral estradiol (mean dose 4.1 ± 1.7 mg/day). Mean estradiol levels ranged from ~110 to 350 pmol/L (~30–95 pg/mL) in the low- and high-dose CPA groups over the follow-up period. Besides showing equivalent testosterone suppression, prolactin levels were significantly lower with low-dose CPA than with high-dose CPA (398 ± 69 mIU/mL vs. 804 ± 121 mIU/mL at 12 months of hormone therapy, respectively).
Based on their findings, the authors stated the following:
We suggest an adjustment of current clinical practice guidelines to recommend lower doses of CPA for the treatment of transgender women.
Both Kuijpers et al. (2021) and Even Zohar et al. (2021) claimed to be the first to demonstrate the efficacy of low-dose CPA in transfeminine people. However, that achievement actually appears to belong to Meyer et al. (2020), who in February 2020 found that estradiol plus 10, 25, or 50 mg/day CPA gave equivalent testosterone suppression across CPA doses in transfeminine people.
Although their study was not about CPA and testosterone suppression, Lim et al. (2020) reported in May/July 2020 that testosterone levels in transfeminine people were median (IQR) 0.6 (0.4–1.0) nmol/L for oral estradiol and 0.9 (0.7–1.6) nmol/L for transdermal estradiol in a mixed group of transfeminine people (n=26 total) on estradiol plus low-dose CPA (12.5 (12.5–18.8) mg/day) (n=14), estradiol alone post-gonadectomy (n=9), and estradiol plus spironolactone (n=3).
In December 2021, the following case report of fatal liver failure with low-dose CPA was published:
Kumar, P., Reddy, S., Kulkarni, A., Sharma, M., & Rao, P. N. (2021). Cyproterone acetate induced Acute liver failure: Case report and review of the literature. Journal of Clinical and Experimental Hepatology, 11(6), 739–741. [DOI:10.1016/j.jceh.2021.01.003]
The case report describes a 30-year-old cisgender woman who was on 25 mg/day CPA for treatment of hirsutism (excessive facial/body hair growth) for 6 months and developed acute liver failure. Four days following hospitalization, she died. This is the second published case report of liver toxicity with CPA at a dosage below 100 mg/day (the first and only other case was at 50 mg/day) (Wiki; Table). It is also the first report of liver failure in a cisgender woman taking CPA. The case indicates that CPA even at a relatively low dose of 25 mg/day is not fully safe in terms of liver toxicity. It further emphasizes the importance of using the lowest effective doses of CPA in transfeminine people (no more than 10–12.5 mg/day).
Update 4: Coleman et al. (2022) [WPATH SOC8 Guidelines]
In September 2022, the World Professional Association for Transgender Health (WPATH) Standards of Care for the Health of Transgender and Gender Diverse People Version 8 (SOC8) were published and made recommendations for transgender hormone therapy for the first time (Coleman et al., 2022). These guidelines recommended a dose of CPA of 10 mg/day in transfeminine people (Coleman et al., 2022). This dose is substantially lower than previous doses recommended by transgender care guidelines and is the first time that major guidelines have recommended a CPA dosage this low. The WPATH SOC8 cited Kuijpers et al. (2021) in support of this recommendation (though notably not Even Zohar et al. (2021) or Meyer et al. (2020)) and also discussed the dose-dependent risks of CPA such as meningiomas and high prolactin levels (Coleman et al., 2022). Considering the key position and importance of the WPATH SOC in transgender health, it is likely that lower CPA doses in transfeminine hormone therapy will now be widely adopted throughout the world. Continued use of higher CPA doses should be considered out of step with current accepted evidence-based practice.
Update 5: Collet et al. (2023)
In October 2022, a study more carefully assessing androgen suppression with estradiol plus CPA in transfeminine people was published:
Collet, S., Gieles, N., Wiepjes, C. M., Heijboer, A. C., Reyns, T., Fiers, T., Lapauw, B., den Heijer, M., & T’Sjoen, G. (2023). Changes in serum testosterone and adrenal androgen levels in transgender women with and without gonadectomy. The Journal of Clinical Endocrinology & Metabolism, 108(2), 331–338. [DOI:10.1210/clinem/dgac576]
In the study, 275 transfeminine people were treated with estradiol plus CPA, and levels of total testosterone, free testosterone, and the adrenal androgensdehydroepiandrosterone (DHEA), dehydroepiandrosterone sulfate (DHEA-S), and androstenedione (A4) were measured using liquid chromatography–mass spectrometry (LC–MS) at baseline and during follow-ups at 3 months, 12 months, 2 to 4 years, and after surgical gonadal removal (at which time CPA was discontinued). Estradiol was measured both with LC–MS (Amsterdam clinic) and with immunoassays (Ghent clinic). The forms and doses of estradiol used were most commonly oral estradiol valerate 4 mg/day or a transdermal estradiol patch 100 μg/day, while the dosage of CPA was usually 25 or 50 mg/day. About half of the transfeminine people eventually underwent surgical gonadal removal, usually after 2 years of hormone therapy.
Median estradiol levels ranged from 49 to 75 pg/mL (180–275 pmol/L) with LC–MS and from 63 to 69 pg/mL (232–255 pmol/L) with immunoassays at different follow-ups. After 3 months of hormone therapy, total testosterone decreased by 97.1%, from 536 ng/dL (18.6 nmol/L) to 12 ng/dL (0.40 nmol/L), and free testosterone decreased by 98.3%, from 109 pg/mL (378 pmol/L) to 2.0 pg/mL (7.1 pmol/L). Thereafter, total and free testosterone levels remained stable. Levels of DHEA, DHEA-S, and A4 decreased by 24.9 to 28.0%, 20.1 to 23.5%, and 36.5%, respectively, and likewise did not further change after the first 3 to 12 months of hormone therapy. No changes in androgen levels occurred upon surgical gonadal removal with discontinuation of CPA. The authors noted that testosterone levels in the transfeminine people on hormone therapy in the study were similar to or lower than those in cisgender women.
Update 6: Warzywoda et al. (2024) [GoLoCypro Study]
The GoLoCypro study, by Judith Dean and colleagues, was published online in February 2024:
Warzywoda, S., Fowler, J. A., Wood, P., Bisshop, F., Russell, D., Luu, H., Kelly, M., Featherstone, V., & Dean, J. A. (2024). How low can you go? Titrating the lowest effective dose of cyproterone acetate for transgender and gender diverse people who request feminizing hormones. International Journal of Transgender Health, advance online publication. [DOI:10.1080/26895269.2024.2317395]
The following are some noteworthy excerpts from the paper:
Of participants who completed the protocol, 74.0% (34/46) were able to achieve the target T-range (0.5–1.5 nmol/L) and 41.3% (19/46) were titrated to the lowest CPA level (12.5 mg cyproterone twice weekly).
Almost all participants who completed the protocol (91.3.0%, 42/46) recorded their CPA levels as level 3 (12.5 mg daily/25 [mg] alternate days) or lower, with 69.0% (29/42) of these being able to achieve the target T-range. Of those that completed, 41.3% (19/46) were able to achieve the lowest CPA level (12.5 mg cyproterone twice week) with 57.9% (11/19) being able to achieve the target T-range.
The study findings showed that for some patients, CPA doses as low as 12.5 mg on alternate days or less can successfully reduce testosterone to pre-menopausal ranges whilst ensuring testosterone was not over-suppressed.
Our study found that doses of CPA lower than the standard dose (12.5 mg CPA daily and/or 25 mg alternate days) were achievable for suppression of testosterone. Several studies have supported this finding that a lower dosage (10 mg CPA daily) is effective in testosterone reduction in individuals undergoing hormone feminization (Even Zohar et al., 2021; Kuijpers et al., 2021). While not all individuals within our study were able to titrate down CPA dosages, almost a quarter of participants who completed the protocol were achieving target T-ranges on 12.5 mg CPA twice weekly (equivalent to 3.5 mg/daily). To our knowledge ours is the first study to demonstrate that doses lower than 10 mg/daily as well as alternate days or twice weekly CPA are clinically effective in maintaining testosterone reduction within target ranges.
References
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-An Informal Meta-Analysis of Estradiol Curves with Injectable Estradiol Preparations - Transfeminine Science
An Informal Meta-Analysis of Estradiol Curves with Injectable Estradiol Preparations
By Aly | First published July 16, 2021 | Last modified June 23, 2023
Abstract / TL;DR
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.
Introduction
Estradiol is the main estrogen used in transfeminine hormone therapy and is available in a variety of different forms for use by different routes of administration. The most commonly employed forms are oral, sublingual, transdermal, and injectable 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 (Glintborg et al., 2021). However, they are still used by many transfeminine people particularly in the United States and in the do-it-yourself (DIY) community. The most commonly used forms include estradiol valerate, estradiol cypionate, and estradiol enanthate 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 testosterone suppression, less frequent administration, and theoretically reduced health risks relative to oral estradiol at equivalent doses due to the lack of the first pass with this route (Aly, 2020). The higher estradiol levels with injections are particularly useful for estradiol monotherapy, in which an antiandrogen is not used.
Clinically used injectable estradiol preparations are formulated not as estradiol but as estradiol esters. When injected into muscle or fat in oil solutions or crystalline aqueous suspensions, these estradiol esters form depots at the injection site from which they are slowly released. Subsequent to release, estradiol esters are rapidly metabolized into estradiol and hence act as prodrugs. When estradiol itself is given by intramuscular injection in an aqueous solution or oil solution, it is rapidly absorbed and has a very short duration. Due to having lipophilic esters, most clinically used injectable estradiol esters are more fat-soluble than estradiol (as measured by oil–water partition coefficient (P)) (Table). 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 fatty acid esters, the longer the chain length of the ester—as in e.g. estradiol valerate (5 carbons) vs. estradiol enanthate (7 carbons) vs. estradiol undecylate (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 (Edkins, 1959; Sinkula, 1978; Chien, 1981; Kuhl, 2005; Kalicharan, 2017; Vhora et al., 2019). The durations of both injectable oil solutions and aqueous suspensions depend on the ester and its particular physicochemical properties, but the characteristics of these preparations are different and they work in distinct ways to produce their depot effects (Enever et al., 1983; Aly, 2019). 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 crystal lattice as well as crystal sizes (Chien, 1981; Enever et al., 1983; Aly, 2019). The polymeric estradiol ester polyestradiol phosphate is more hydrophilic (water-soluble) than estradiol and works differently than other injectable estradiol preparations. Ιt is composed of many estradiol molecules linked together via phosphate esters (on average 13 molecules of estradiol per one molecule of polyestradiol phosphate) and has a prolonged duration due to slow cleavage 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 (Table).
In order to aid understanding of concentration–time profiles with injectable estradiol preparations, I’ve developed an interactive web-based injectable estradiol simulator for transfeminine people and their medical providers. During work on this simulator, it became apparent that there is substantial variability 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 estradiol benzoate, estradiol valerate, and estradiol cypionate in oil (Oriowo et al., 1980 [Graph]). 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 meta-analysis of estradiol curves with injectable estradiol formulations—was conducted for the simulator project.
Methods
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 Cmax estradiol levels (mean peak estradiol levels of individual subjects at time Tmax). Databases like PubMed, Google Scholar, and WorldCat 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 combined injectable contraceptives) were included. Studies were included regardless of the hypothalamic–pituitary–gonadal axis (HPG axis) status of the participants. The study selection criteria 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 WebPlotDigitizer.
Table 1: Major injectable estradiol formulations (ordered roughly from shortest- to longest-acting):
Following their collection, data were processed, aggregated, and modeled. Data were adjusted for endogenous estradiol production and were normalized by dose. Adjustment for endogenous estradiol production was generally done via subtraction of baseline estradiol levels. In a number of cases however, subtraction of trough estradiol levels or of estradiol levels from a control group was required instead. Data were also weighted by sample size. 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 fit via least squares regression to one-, two-, and three-compartmentpharmacokinetic models with first-order absorption and elimination that were obtained from the literature and other sources (e.g., Colburn, 1981; Wagner, 1993; Fisher & Shafer, 2007; Lixoft, 2008; Abuhelwa, Foster, & Upton, 2015; Certara, 2020). 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 Akaike information criterion (AIC) was used to help guide model selection for fitting of the preparations. Curve fitting was performed using the Python library Lmfit with the Levenberg–Marquardt algorithm. Cmax 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. Outlying data were also excluded from fitting in a number of instances and this allowed for improved curve fits with more uniform area-under-the-curve levels. 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).
A selection of pharmacokinetic parameters were calculated for each injectable estradiol preparation using the single-dose fit curves and compartmental pharmacokinetic analyses. These parameters included maximal or peak concentrations of estradiol after a single dose scaled to 5 mg (Cmax), time to maximal concentrations of estradiol after a single dose (Tmax), total area-under-the-curve concentrations of estradiol after a single dose (AUC0–∞), terminal elimination half-life after a single dose (t1/2), and the terminal 90% life after a single dose (t90%) (calculated as t1/2 × 3.322). In addition, selected pharmacokinetic parameters were calculated for simulated repeated administration of each injectable preparation at steady state 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 (Tmax), peak and trough concentrations of estradiol (Cmax and Cmin, respectively), peak–trough difference (PTD; Cmax – Cmin), peak–trough ratio (PTR; Cmax ÷ Cmin), and integratedmean concentrations of estradiol (Cavg). Simulation of repeated administration was performed by stacking estradiol levels for multiple injections. Cmax and Tmax 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 sanity check, were compared against those computed by PKSolver, a Microsoft Excel pharmacokinetics add-in program (Zhang et al., 2010).
Results
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. Cmax 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 (Desmos). As a result, and for consistency, this model was used in the fitting of all preparations.
Estradiol Benzoate
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 estrogen provocation test, 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).
Table 2: Studies of injectable estradiol benzoate (Spreadsheet; Plotly):
a Total number of injections, not total number of subjects.
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 (Akande, 1974; Weiss, Nachtigall, & Ganguly, 1976). Two studies were omitted due partly to being very old and using very early and inaccurate blood tests (Varangot & Cedard, 1957; Ittrich & Pots, 1965 [Graph]). The processed original data and fit of fits curve for estradiol benzoate are shown in Figure 1.
Figure 1: 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 (Spreadsheet; Plotly).
Estradiol Valerate
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).
Table 3: Studies of injectable estradiol valerate (Spreadsheet; Plotly):
Study
na
Subjects
Dose
Reference(s)
S7175
12
Premenopausal women with menstrual migraine (n=10) and amenorrheic/postmenopausal women with history of menstrual migraine (n=2)
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)
a Total number of injections, not total number of subjects.
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 Cmax data. One study was omitted as it only reported estrone levels rather than estradiol levels (Ibrahim, 1996). Another study was not included due to being in pregnant women with concomitant pregnancy termination (Garner & Armstrong, 1977). One last study was omitted due partly to being very old and using very early and inaccurate blood tests (Ittrich & Pots, 1965 [Graph]). The processed original data and fit curve for estradiol valerate are shown in Figure 2.
Figure 2: 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 (Spreadsheet; Plotly).
Estradiol Cypionate Oil
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).
Table 4: Studies of injectable estradiol cypionate in oil (Spreadsheet; Plotly):
a Total number of injections, not total number of subjects.
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.
Figure 3: 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 (Spreadsheet; Plotly).
Estradiol Cypionate Suspension
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).
Table 5: Studies of injectable estradiol cypionate suspension (Spreadsheet; Plotly):
a Total number of injections, not total number of subjects. b By subcutaneous injection rather than intramuscular injection.
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 (Sierra-Ramírez et al., 2011 [Graph]). Several Cmax 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 (Martins et al., 2019 [Graph]). The processed original data and fit of fit curves for estradiol cypionate suspension are shown in Figure 4.
Figure 4: 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 (Spreadsheet; Plotly).
Estradiol Enanthate
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).
Table 6: Studies of injectable estradiol enanthate (Spreadsheet; Plotly):
a Total number of injections, not total number of subjects.
Of the available data, 216 of the injections were from a single study and mainly included only Cmax levels. Wiemeyer et al. (1986) 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, Cmax studies were included in the fitting for this preparation. The processed original data and fit curve for estradiol enanthate are shown in Figure 5.
Figure 5: 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 (Spreadsheet; Plotly).
Estradiol Undecylate
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).
Table 7: Studies of injectable estradiol undecylate (Spreadsheet; Plotly):
a Total number of injections, not total number of subjects.
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 (Jacobi & Altwein, 1979 [Graph]; Jacobi et al., 1980 [Graph]; Derra, 1981 [Graph]). The processed original data and fit curve for estradiol undecylate are shown in Figure 6.
Figure 6: 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 (Spreadsheet; Plotly).
Polyestradiol Phosphate
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).
Table 8: Studies of injectable polyestradiol phosphate (Spreadsheet; Plotly):
a Total number of injections, not total number of subjects.
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.
Figure 7: 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 (Spreadsheet; Plotly).
Other Injectable Estradiol Preparations
A number of clinical studies with estradiol concentration–time data for other injectable estradiol preparations were also identified during literature search:
Estradiol (unesterified) in an “aqueous” preparation (type of aqueous preparation unspecified but probably a microcrystalline aqueous suspension) (Jones et al., 1978 [Graph])
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.
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 estradiol benzoate butyrate/dihydroxyprogesterone acetophenide in oil (Redimen, Soluna, Unijab) (another lesser-known combined injectable contraceptive).
All Injectable Estradiol Preparations Together
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 Discussion 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.
Figure 8: 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 (Graph).
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.
Figure 9: 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 (Graph).
For more simulated estradiol concentration–time curves with repeated injections of these injectable estradiol preparations, please see the accompanying interactive web simulator.
Selected Pharmacokinetic Parameters
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.
Table 9: Selected pharmacokinetic parameters for estradiol with injectable estradiol preparations following a single 5 mg dose by intramuscular injection:
Estradiol preparation
Tmax (d)
Cmax (pg/mL)
t1/2 (d)
t90% (d)
AUC0–∞ (pg•d/mL)
Estradiol benzoate in oil
0.65
971
1.2
3.9
2410
Estradiol valerate in oil
2.1
295
3.0
9.9
1886
Estradiol cypionate oil
4.3
155
6.7
22.3
2150
Estradiol cypionate suspension
1.2
241
5.1
16.9
2096
Estradiol enanthate in oil
6.5
160
4.6
15.1
2183
Polyestradiol phosphate a
18.0
34
28.4
94.2
2117
a Scaled instead to a single 32.5 mg injection (6.5 times higher dose than with the other esters).
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.
Table 10: Selected pharmacokinetic parameters for estradiol with injectable estradiol preparations with simulated repeated administration of 5 mg once every 7 days by intramuscular injection:
Estradiol preparation
Tmax (d)
Cmax (pg/mL)
Cmin (pg/mL)
Peak–trough diff. (pg/mL)
Peak–trough ratio
Cavg (pg/mL)
Estradiol benzoate in oil
0.64
990
29
962
35
344
Estradiol valerate in oil
1.9
384
142
242
2.7
269
Estradiol cypionate oil
3.1
339
262
77
1.3
307
Estradiol cypionate suspension
1.0
404
189
214
2.1
299
Estradiol enanthate in oil
4.0
329
288
41
1.1
312
Polyestradiol phosphate a
3.2
304
299
5
1.0
302
a Scaled instead to repeated injections of 32.5 mg every 7 days (6.5 times higher dose than with the other esters).
Terminal half-life (t1/2) is the time for the concentration of estradiol to decrease by 50% after pseudo-equilibrium of distribution has been reached—not the time required for half of an administered dose of the estradiol ester to be eliminated (Toutain & Bousquet-Mélou, 2004). It is calculated using only the terminal portion of a concentration–time curve, without the absorption or distribution phases influencing it (Toutain & Bousquet-Mélou, 2004). Due to flip–flop kinetics 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 (Toutain & Bousquet-Mélou, 2004; Yáñez et al., 2011).
Discussion
Data Quality, Limitations, and Variability Between Studies
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.
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 Cmax 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 luteinizing hormone levels after several days in gonadally intact women, and this may cause a delayed bump in estradiol levels (Wiki). One of the more overt instances of this can be seen in a study of estradiol benzoate in such women (Shaw, 1978 [Graph]). 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 Cmax data, these data when Cmax corresponds to the mean of individual peaks are a different type of data than the peak of the mean curve of all individuals. Cmax levels can differ in both magnitude and timing compared to the mean curve peak (e.g., Oriowo et al., 1980 [Graph]; Rahimy, Ryan, & Hopkins, 1999). 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, Cmax levels are in any case generally in the vicinity of the mean curve peak. While Cmax 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 Cmax 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 (Schiavon et al., 1988; Garza-Flores, 1994).
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 formulation (e.g., oil vehicle, other components and excipients, concentration, particle size), injection volume, site of injection (e.g., buttocks, thigh, upper arm), injection technique (e.g., force of injection—and resulting depot droplet dimensions), and syringe dead space. They additionally include various subject- and research-related variables like differing blood-testing methodology, differing sample characteristics (e.g., age, weight, gender, ethnicity, physical activity, HPG axis state), and sampling error (Sinkula, 1978; Chien, 1981; Minto et al., 1997; Larsen & Larsen, 2009; Larsen et al., 2009; Florence, 2010; Larsen, Thing, & Larsen, 2012; Kalicharan, 2017). 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 outliers 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.
It is in any case known from other studies that different oil vehicles are absorbed at different rates from the injection site (Svendsen & Aaes‐Jørgensen, 1979; Schultz et al., 1998; Larsen et al., 2001) and can result in different concentration–time curve shapes (Ballard, 1978 [Excerpt]; Knudsen, Hansen, & Larsen, 1985). This is thought to be due to differences in oil lipophilicity and depot release rates. Viscosity of oils has also been hypothesized to potentially influence rate of depot escape (Schug, Donath, & Blume, 2012). However, research so far has not supported this hypothesis (Larsen & Larsen, 2009; Larsen, Thing, & Larsen, 2012). Oil vehicles can vary with injectable estradiol preparations even for the same estradiol ester. For instance, pharmaceutical estradiol valerate is formulated in sesame oil, castor oil, or sunflower oil depending on the preparation (Table). It is notable however that these three oils have similar lipophilicities (Table). On the other hand, homebrewed injectable estradiol preparations used by DIY transfeminine people often employ medium-chain triglyceride (MCT) oil as the oil vehicle. This oil (in the proprietary form of Viscoleo) has notably been found to be much more rapidly absorbed than conventional oils like sesame oil and castor oil in animals (Svendsen & Aaes‐Jørgensen, 1979; Schultz et al., 1998; Larsen et al., 2001). In addition, although based on very limited data, MCT oil has been found to give spikier and shorter-lasting depot injectable curves in humans (Knudsen, Hansen, & Larsen, 1985). 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 benzyl alcohol, as well as factors like injection site and volume, have additionally been found to influence pharmacokinetic properties with depot injectables (Minto et al., 1997; Kalicharan, Schot, & Vromans, 2016). Excipients besides oil vehicle also vary by formulation (Table).
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.
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. Cmax 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).
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.
Durations and Curve Shapes
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.
Duration of Estradiol Valerate
The estradiol concentration–time curve for injectable estradiol valerate in the well-known Oriowo et al. (1980) [Graph] 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., Göretzlehner et al., 2002; Valle Alvarez, 2011; Schug, Donath, & Blume, 2012). It’s noteworthy that Oriowo et al. (1980) used a peanut oil-based formulation of estradiol valerate that differed from pharmaceutical injectable estradiol valerate preparations, which generally use sesame oil or castor oil as the carrier (as well as other excipients) (Table). This may have influenced the curve shape of estradiol valerate in Oriowo et al. (1980). The study also had a small sample size 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 Oriowo et al. (1980).
Duration of Estradiol Cypionate in Oil versus Estradiol Enanthate
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 Oriowo et al. (1980) and a review of the pharmacokinetics of combined injectable contraceptives (Garza-Flores, 1994 [Graph]), 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 Garza-Flores (1994) figure was based on Oriowo et al. (1980) [Graph], 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 Oriowo et al. (1980) used a formulation of estradiol cypionate that differs from conventional pharmaceutical estradiol cypionate in oil preparations—specifically, the study used a peanut oil-based formulation (with few other specifics) rather than the cottonseed oil-based preparation employed in marketed pharmaceutical formulations (Table). The study also had a somewhat small sample size (n=10) and may have had significant sampling error. Hence, single studies, perhaps particularly Oriowo et al. (1980), should be interpreted cautiously.
A small but interesting pharmacokinetic study which directly compared injectable testosterone cypionate (n=6) and testosterone enanthate (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 (Schulte-Beerbühl & Nieschlag, 1980 [Graph]). The findings of this study are consistent with the fact that the lipophilicities of testosterone cypionate and testosterone enanthate (as measured by predicted log P) are very similar when directly compared (e.g., 5.1 vs. 5.11 with ALOGPS, 6.29 vs. 6.11 with ChemAxon logP, and 6.4 vs. 6.3 with XLogP3, respectively (Table). This of course is of importance as lipophilicity is thought to be the key factor determining the release kinetics of oil-based depot injectables (Sinkula, 1978; Shah, 2007; Larsen & Larsen, 2009; Larsen, Thing, & Larsen, 2012; Shahiwala, Mehta, & Momin, 2018). 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) (Table). 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.
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 Oriowo et al. (1980). 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) (Depo-Estradiol Label). 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 Oriowo et al. (1980), and estradiol cypionate in oil and estradiol enanthate may have more similar curves than has been previously assumed.
Curve Shape of Estradiol Cypionate Suspension
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 (Aly, 2019). In line with this notion, injectable medroxyprogesterone acetate 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) (Graphs). Although aqueous suspensions generally last longer than oil solutions as injectables (Enever et al., 1983; Aly, 2019), this is not always the case, and estradiol cypionate suspension interestingly seems to be shorter-acting than estradiol cypionate in oil.
Estradiol Exposure and Potency
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) (Aly, 2019). After adjusting for the molecular weight 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% bioavailability (with this being less characterized but likely also the case for the other non-polymeric injectable estradiol esters) (Düsterberg & Nishino, 1982; Seibert & Günzel, 1994).
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%) (Table). The appearance of differences in area-under-the-curve levels of estradiol in the present meta-analysis is probably just due to statistical error, 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.
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 (Wiki; Estradurin Labels). 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 excreted before it can be cleaved into estradiol and thereby rendered partly inactive, in turn necessitating the use of higher doses to achieve the same estradiol levels and therapeutic effect.
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 potency (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 estrogen receptors for a given tissue should become saturated at a certain point due to the finite quantity of available receptors 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) (Aly, 2020). However, these possibilities are speculative and theoretical. Although some literature exists that is relevant to this issue (e.g., Parkes, 1937; Bradbury, Long, & Durham, 1953), 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.
Variability Between Individuals
There is substantial variation in total estradiol levels and curve shapes between people with the same injectable estradiol preparation. Indicators of interindividual variability such as standard deviation 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., Oriowo et al., 1980; Derra, 1981 [Graph]; Aedo et al., 1985 [Graphs]; Sang et al., 1987 [Graphs]; Rahimy & Ryan, 1999 [Graph]; Valle Alvarez, 2011 [Graph]; Schug, Donath, & Blume, 2012 [Graphs]). Highly variable estradiol levels are already well-established with oral and transdermal estradiol (Kuhl, 2005; Wiki). 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 (Aly, 2020)—nor underdosed—which may result in suboptimal testosterone suppression and therapeutic efficacy.
Insights for Clinical Guidelines and Dosing Recommendations
Clinical guidelines for transgender health (see also Aly (2020)) 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 <1 to 10 mg/week or <2 to 80 mg/2 weeks. For reference, the Endocrine Society guidelines and the University of California, San Francisco (UCSF) guidelines are the most major clinical guidelines for transgender hormone therapy at present (Aly, 2020). The Endocrine Society guidelines recommend 5 to 30 mg/2 weeks or 2 to 10 mg/week for either estradiol valerate or estradiol cypionate (Hembree et al., 2017). Conversely, the UCSF guidelines recommend <20 to 40 mg/2 weeks for estradiol valerate and <2 to 5 mg/2 weeks for estradiol cypionate (with the option to divide dose into weekly injections if cyclical side effects occur) (Deutsch, 2016a).
Table 11: Recommended doses and injection intervals of injectable estradiol preparations (specifically estradiol valerate and estradiol cypionate) in transgender medicine clinical guidelinesa:
a 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 (Aly, 2020).
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 supraphysiological, doses of injectable estradiol valerate or estradiol cypionate recommended by guidelines are as high as 15 to 20 mg 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) (Table). 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 “pseudopregnancy” 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 (Ulrich, Pfeifer, & Lauritzen, 1994). 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) (Aly, 2019). 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 (Aly, 2020). The very high doses of these preparations that are recommended by guidelines should raise considerable reservations about their safety.
Figure 10: 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 (Graph).
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 (Aly, 2020). 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 (Graph). 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 (Aly, 2019; Langley et al., 2021; Aly, 2020). In relation to this, doses of injectable estradiol need not be excessive.
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 (<20 to 40 mg/2 weeks for estradiol valerate and <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 (Garza-Flores, 1994; Newton, d’Arcangues, & Hall, 1994; Sang, 1994; Toppozada, 1994). 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.
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).
Figure 11: 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).
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 Christian Hamburger and Harry Benjamin in the late 1960s in the first medical textbook on transgender people (Hamburger & Benjamin, 1969). 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.
Among the surveyed guidelines for transgender hormone therapy, only the UCSF guidelines (Deutsch, 2016b) and the Sherbourne Health/Rainbow Health Ontario guidelines (Bourns, 2019) referenced pharmacokinetic literature in their discussion of injectable estradiol. The specific publications cited by these guidelines were Düsterberg & Nishino (1982), Sierra-Ramírez et al. (2011), and Thurman et al. (2013). 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. Düsterberg & Nishino (1982) 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 Düsterberg & Nishino (1982) 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, Bourns (2019) 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. Sierra-Ramírez et al. (2011) and Thurman et al. (2013), although better-quality studies than Düsterberg & Nishino (1982), 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.
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.
Interactive Web Simulator
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:
There are various possibilities for further work on this project in the future. For example, assessment of interindividual variability 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 hormonal preparations such as injectable testosterone preparations and other estradiol routes and forms like oral estradiol, sublingual estradiol, and estradiol pellets. 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.
Special Thanks
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 Tilia—an effort to empower trans people with tools to manage their hormonal transitions—and TransKit—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.
Updates
Update 1: WPATH SOC8 Guidelines
In September 2022, the World Professional Association for Transgender Health (WPATH) Standards of Care for the Health of Transgender and Gender Diverse People Version 8 (SOC8) were published and made recommendations on transgender hormone therapy for the first time (Coleman et al., 2022). 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 Endocrine Society’s 2017 guidelines on transgender hormone therapy (Hembree et al., 2017). 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.
Update 2: Literature Mentions
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:
Hughes et al. (2022)
Hughes, J. H., Woo, K. H., Keizer, R. J., & Goswami, S. (2022). Clinical Decision Support for Precision Dosing: Opportunities for Enhanced Equity and Inclusion in Health Care. Clinical Pharmacology & Therapeutics, 113(3), 565–574. [DOI:10.1002/cpt.2799]:
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.88 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.89 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.
89. Aly, W. An interactive web simulator for estradiol levels with injectable estradiol esters. Transfeminine Science <https://transfemscience.org/articles/injectable-e2-simulator-release/> (2021) Accessed November 1, 2022.
Jaafar et al. (2022)
Jaafar, S., Torres-Leguizamon, M., Duplessy, C., & 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.] Sante Publique, 34(HS2), 109–122. [Google Scholar] [PubMed] [DOI:10.3917/spub.hs2.0109] [Translated]:
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]. […]
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/.
Linet (2023)
Linet, T. (2023). Prise en charge endocrinologique d’une personne trans. [Endocrinological care of a trans person.] In Faucher, P., Hassoun, D., & Linet, T. (Eds.). Santé sexuelle et reproductive des personnes LGBT [Sexual and Reproductive Health of LGBT People] (pp. 109–124). Issy-les-Moulineaux, France: Elsevier Masson. [Google Books] [URL] [WorldCat] [Excerpt] [Translated]:
Choice of estrogen.
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.
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).
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.
Update 3: Herndon et al. (2023)
In March 2023, the following paper on injectable estradiol in transfeminine people was published online:
Herndon, J. S., Maheshwari, A. K., Nippoldt, T. B., Carlson, S. J., Davidge-Pitts, C. J., & Chang, A. Y. (2023). Comparison of Subcutaneous and Intramuscular Estradiol Regimens as part of Gender-Affirming Hormone Therapy. Endocrine Practice, 29(5), 356–361. [DOI:10.1016/j.eprac.2023.02.006] [URL]
The study was a retrospective analysis of individualized injectable estradiol in adult transfeminine people who received hormone therapy at the Mayo Clinic. 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.
Injectable estradiol doses were adjusted to achieve estradiol and testosterone levels within therapeutic ranges defined by the Endocrine Society 2017 guidelines (>100 pg/mL [367 pg/mL] for estradiol and <50 ng/dL [<1.7 nmol/L] for testosterone). Estradiol levels were measured exclusively using liquid chromatography–tandem mass spectrometry (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).
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 (interquartile range (IQR) 3–5.15 mg; range 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 (>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 (Graph). It can be seen that more individuals clustered into the higher range of doses with i.m. than with s.c. injections.
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.
On multiple regression analysis, injectable estradiol dose was significantly positively associated with estradiol levels (p < 0.001) following adjustment for several variables (injection route, body mass index (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.
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 (<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 spironolactone or finasteride. 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 (>100 pg/mL) and 88.2% achieved target testosterone levels (<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.
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 (Hembree et al., 2017) and UCSF 2016 guidelines (Deutsch, 2016a). 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 Oriowo et al. (1980) 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:
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 Deutsch, Bhakri, & Kubicek (2015) and Mueller et al. (2011) …]
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.
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.
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.
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 <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.
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+An Informal Meta-Analysis of Estradiol Curves with Injectable Estradiol Preparations - Transfeminine Science
An Informal Meta-Analysis of Estradiol Curves with Injectable Estradiol Preparations
By Aly | First published July 16, 2021 | Last modified March 18, 2024
Abstract / TL;DR
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.
Introduction
Estradiol is the main estrogen used in transfeminine hormone therapy and is available in a variety of different forms for use by different routes of administration. The most commonly employed forms are oral, sublingual, transdermal, and injectable 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 (Glintborg et al., 2021). However, they are still used by many transfeminine people particularly in the United States and in the do-it-yourself (DIY) community. The most commonly used forms include estradiol valerate, estradiol cypionate, and estradiol enanthate 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 testosterone suppression, less frequent administration, and theoretically reduced health risks relative to oral estradiol at equivalent doses due to the lack of the first pass with this route (Aly, 2020). The higher estradiol levels with injections are particularly useful for estradiol monotherapy, in which an antiandrogen is not used.
Clinically used injectable estradiol preparations are formulated not as estradiol but as estradiol esters. When injected into muscle or fat in oil solutions or crystalline aqueous suspensions, these estradiol esters form depots at the injection site from which they are slowly released. Subsequent to release, estradiol esters are rapidly metabolized into estradiol and hence act as prodrugs. When estradiol itself is given by intramuscular injection in an aqueous solution or oil solution, it is rapidly absorbed and has a very short duration. Due to having lipophilic esters, most clinically used injectable estradiol esters are more fat-soluble than estradiol (as measured by oil–water partition coefficient (P)) (Table). 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 fatty acid esters, the longer the chain length of the ester—as in e.g. estradiol valerate (5 carbons) vs. estradiol enanthate (7 carbons) vs. estradiol undecylate (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 (Edkins, 1959; Sinkula, 1978; Chien, 1981; Kuhl, 2005; Kalicharan, 2017; Vhora et al., 2019). The durations of both injectable oil solutions and aqueous suspensions depend on the ester and its particular physicochemical properties, but the characteristics of these preparations are different and they work in distinct ways to produce their depot effects (Enever et al., 1983; Aly, 2019). 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 crystal lattice as well as crystal sizes (Chien, 1981; Enever et al., 1983; Aly, 2019). The polymeric estradiol ester polyestradiol phosphate is more hydrophilic (water-soluble) than estradiol and works differently than other injectable estradiol preparations. Ιt is composed of many estradiol molecules linked together via phosphate esters (on average 13 molecules of estradiol per one molecule of polyestradiol phosphate) and has a prolonged duration due to slow cleavage 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 (Table).
In order to aid understanding of concentration–time profiles with injectable estradiol preparations, I’ve developed an interactive web-based injectable estradiol simulator for transfeminine people and their medical providers. During work on this simulator, it became apparent that there is substantial variability 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 estradiol benzoate, estradiol valerate, and estradiol cypionate in oil (Oriowo et al., 1980 [Graph]). 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 meta-analysis of estradiol curves with injectable estradiol formulations—was conducted for the simulator project.
Methods
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 Cmax estradiol levels (mean peak estradiol levels of individual subjects at time Tmax). Databases like PubMed, Google Scholar, and WorldCat 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 combined injectable contraceptives) were included. Studies were included regardless of the hypothalamic–pituitary–gonadal axis (HPG axis) status of the participants. The study selection criteria 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 WebPlotDigitizer.
Table 1: Major injectable estradiol formulations (ordered roughly from shortest- to longest-acting):
Following their collection, data were processed, aggregated, and modeled. Data were adjusted for endogenous estradiol production and were normalized by dose. Adjustment for endogenous estradiol production was generally done via subtraction of baseline estradiol levels. In a number of cases however, subtraction of trough estradiol levels or of estradiol levels from a control group was required instead. Data were also weighted by sample size. 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 fit via least squares regression to one-, two-, and three-compartmentpharmacokinetic models with first-order absorption and elimination that were obtained from the literature and other sources (e.g., Colburn, 1981; Wagner, 1993; Fisher & Shafer, 2007; Lixoft, 2008; Abuhelwa, Foster, & Upton, 2015; Certara, 2020). 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 Akaike information criterion (AIC) was used to help guide model selection for fitting of the preparations. Curve fitting was performed using the Python library Lmfit with the Levenberg–Marquardt algorithm. Cmax 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. Outlying data were also excluded from fitting in a number of instances and this allowed for improved curve fits with more uniform area-under-the-curve levels. 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).
A selection of pharmacokinetic parameters were calculated for each injectable estradiol preparation using the single-dose fit curves and compartmental pharmacokinetic analyses. These parameters included maximal or peak concentrations of estradiol after a single dose scaled to 5 mg (Cmax), time to maximal concentrations of estradiol after a single dose (Tmax), total area-under-the-curve concentrations of estradiol after a single dose (AUC0–∞), terminal elimination half-life after a single dose (t1/2), and the terminal 90% life after a single dose (t90%) (calculated as t1/2 × 3.322). In addition, selected pharmacokinetic parameters were calculated for simulated repeated administration of each injectable preparation at steady state 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 (Tmax), peak and trough concentrations of estradiol (Cmax and Cmin, respectively), peak–trough difference (PTD; Cmax – Cmin), peak–trough ratio (PTR; Cmax ÷ Cmin), and integratedmean concentrations of estradiol (Cavg). Simulation of repeated administration was performed by stacking estradiol levels for multiple injections. Cmax and Tmax 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 sanity check, were compared against those computed by PKSolver, a Microsoft Excel pharmacokinetics add-in program (Zhang et al., 2010).
Results
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. Cmax 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 (Desmos). As a result, and for consistency, this model was used in the fitting of all preparations.
Estradiol Benzoate
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 estrogen provocation test, 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).
Table 2: Studies of injectable estradiol benzoate (Spreadsheet; Plotly):
a Total number of injections, not total number of subjects.
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 (Akande, 1974; Weiss, Nachtigall, & Ganguly, 1976). Two studies were omitted due partly to being very old and using very early and inaccurate blood tests (Varangot & Cedard, 1957; Ittrich & Pots, 1965 [Graph]). The processed original data and fit of fits curve for estradiol benzoate are shown in Figure 1.
Figure 1: 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 (Spreadsheet; Plotly).
Estradiol Valerate
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).
Table 3: Studies of injectable estradiol valerate (Spreadsheet; Plotly):
Study
na
Subjects
Dose
Reference(s)
S7175
12
Premenopausal women with menstrual migraine (n=10) and amenorrheic/postmenopausal women with history of menstrual migraine (n=2)
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)
a Total number of injections, not total number of subjects.
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 Cmax data. One study was omitted as it only reported estrone levels rather than estradiol levels (Ibrahim, 1996). Another study was not included due to being in pregnant women with concomitant pregnancy termination (Garner & Armstrong, 1977). One last study was omitted due partly to being very old and using very early and inaccurate blood tests (Ittrich & Pots, 1965 [Graph]). The processed original data and fit curve for estradiol valerate are shown in Figure 2.
Figure 2: 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 (Spreadsheet; Plotly).
Estradiol Cypionate Oil
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).
Table 4: Studies of injectable estradiol cypionate in oil (Spreadsheet; Plotly):
a Total number of injections, not total number of subjects.
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.
Figure 3: 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 (Spreadsheet; Plotly).
Estradiol Cypionate Suspension
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).
Table 5: Studies of injectable estradiol cypionate suspension (Spreadsheet; Plotly):
a Total number of injections, not total number of subjects. b By subcutaneous injection rather than intramuscular injection.
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 (Sierra-Ramírez et al., 2011 [Graph]). Several Cmax 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 (Martins et al., 2019 [Graph]). The processed original data and fit of fit curves for estradiol cypionate suspension are shown in Figure 4.
Figure 4: 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 (Spreadsheet; Plotly).
Estradiol Enanthate
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).
Table 6: Studies of injectable estradiol enanthate (Spreadsheet; Plotly):
a Total number of injections, not total number of subjects.
Of the available data, 216 of the injections were from a single study and mainly included only Cmax levels. Wiemeyer et al. (1986) 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, Cmax studies were included in the fitting for this preparation. The processed original data and fit curve for estradiol enanthate are shown in Figure 5.
Figure 5: 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 (Spreadsheet; Plotly).
Estradiol Undecylate
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).
Table 7: Studies of injectable estradiol undecylate (Spreadsheet; Plotly):
a Total number of injections, not total number of subjects.
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 (Jacobi & Altwein, 1979 [Graph]; Jacobi et al., 1980 [Graph]; Derra, 1981 [Graph]). The processed original data and fit curve for estradiol undecylate are shown in Figure 6.
Figure 6: 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 (Spreadsheet; Plotly).
Polyestradiol Phosphate
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).
Table 8: Studies of injectable polyestradiol phosphate (Spreadsheet; Plotly):
a Total number of injections, not total number of subjects.
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.
Figure 7: 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 (Spreadsheet; Plotly).
Other Injectable Estradiol Preparations
A number of clinical studies with estradiol concentration–time data for other injectable estradiol preparations were also identified during literature search:
Estradiol (unesterified) in an “aqueous” preparation (type of aqueous preparation unspecified but probably a microcrystalline aqueous suspension) (Jones et al., 1978 [Graph])
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.
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 estradiol benzoate butyrate/dihydroxyprogesterone acetophenide in oil (Redimen, Soluna, Unijab) (another lesser-known combined injectable contraceptive).
All Injectable Estradiol Preparations Together
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 Discussion 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.
Figure 8: 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 (Graph).
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.
Figure 9: 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 (Graph).
For more simulated estradiol concentration–time curves with repeated injections of these injectable estradiol preparations, please see the accompanying interactive web simulator.
Selected Pharmacokinetic Parameters
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.
Table 9: Selected pharmacokinetic parameters for estradiol with injectable estradiol preparations following a single 5 mg dose by intramuscular injection:
Estradiol preparation
Tmax (d)
Cmax (pg/mL)
t1/2 (d)
t90% (d)
AUC0–∞ (pg•d/mL)
Estradiol benzoate in oil
0.65
971
1.2
3.9
2410
Estradiol valerate in oil
2.1
295
3.0
9.9
1886
Estradiol cypionate oil
4.3
155
6.7
22.3
2150
Estradiol cypionate suspension
1.2
241
5.1
16.9
2096
Estradiol enanthate in oil
6.5
160
4.6
15.1
2183
Polyestradiol phosphate a
18.0
34
28.4
94.2
2117
a Scaled instead to a single 32.5 mg injection (6.5 times higher dose than with the other esters).
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.
Table 10: Selected pharmacokinetic parameters for estradiol with injectable estradiol preparations with simulated repeated administration of 5 mg once every 7 days by intramuscular injection:
Estradiol preparation
Tmax (d)
Cmax (pg/mL)
Cmin (pg/mL)
Peak–trough diff. (pg/mL)
Peak–trough ratio
Cavg (pg/mL)
Estradiol benzoate in oil
0.64
990
29
962
35
344
Estradiol valerate in oil
1.9
384
142
242
2.7
269
Estradiol cypionate oil
3.1
339
262
77
1.3
307
Estradiol cypionate suspension
1.0
404
189
214
2.1
299
Estradiol enanthate in oil
4.0
329
288
41
1.1
312
Polyestradiol phosphate a
3.2
304
299
5
1.0
302
a Scaled instead to repeated injections of 32.5 mg every 7 days (6.5 times higher dose than with the other esters).
Terminal half-life (t1/2) is the time for the concentration of estradiol to decrease by 50% after pseudo-equilibrium of distribution has been reached—not the time required for half of an administered dose of the estradiol ester to be eliminated (Toutain & Bousquet-Mélou, 2004). It is calculated using only the terminal portion of a concentration–time curve, without the absorption or distribution phases influencing it (Toutain & Bousquet-Mélou, 2004). Due to flip–flop kinetics 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 (Toutain & Bousquet-Mélou, 2004; Yáñez et al., 2011).
Discussion
Data Quality, Limitations, and Variability Between Studies
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.
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 Cmax 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 luteinizing hormone levels after several days in gonadally intact women, and this may cause a delayed bump in estradiol levels (Wiki). One of the more overt instances of this can be seen in a study of estradiol benzoate in such women (Shaw, 1978 [Graph]). 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 Cmax data, these data when Cmax corresponds to the mean of individual peaks are a different type of data than the peak of the mean curve of all individuals. Cmax levels can differ in both magnitude and timing compared to the mean curve peak (e.g., Oriowo et al., 1980 [Graph]; Rahimy, Ryan, & Hopkins, 1999). 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, Cmax levels are in any case generally in the vicinity of the mean curve peak. While Cmax 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 Cmax 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 (Schiavon et al., 1988; Garza-Flores, 1994).
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 formulation (e.g., oil vehicle, other components and excipients, concentration, particle size), injection volume, site of injection (e.g., buttocks, thigh, upper arm), injection technique (e.g., force of injection—and resulting depot droplet dimensions), and syringe dead space. They additionally include various subject- and research-related variables like differing blood-testing methodology, differing sample characteristics (e.g., age, weight, gender, ethnicity, physical activity, HPG axis state), and sampling error (Sinkula, 1978; Chien, 1981; Minto et al., 1997; Larsen & Larsen, 2009; Larsen et al., 2009; Florence, 2010; Larsen, Thing, & Larsen, 2012; Kalicharan, 2017). 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 outliers 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.
It is in any case known from other studies that different oil vehicles are absorbed at different rates from the injection site (Svendsen & Aaes‐Jørgensen, 1979; Schultz et al., 1998; Larsen et al., 2001) and can result in different concentration–time curve shapes (Ballard, 1978 [Excerpt]; Knudsen, Hansen, & Larsen, 1985). This is thought to be due to differences in oil lipophilicity and depot release rates. Viscosity of oils has also been hypothesized to potentially influence rate of depot escape (Schug, Donath, & Blume, 2012). However, research so far has not supported this hypothesis (Larsen & Larsen, 2009; Larsen, Thing, & Larsen, 2012). Oil vehicles can vary with injectable estradiol preparations even for the same estradiol ester. For instance, pharmaceutical estradiol valerate is formulated in sesame oil, castor oil, or sunflower oil depending on the preparation (Table). It is notable however that these three oils have similar lipophilicities (Table). On the other hand, homebrewed injectable estradiol preparations used by DIY transfeminine people often employ medium-chain triglyceride (MCT) oil as the oil vehicle. This oil (in the proprietary form of Viscoleo) has notably been found to be much more rapidly absorbed than conventional oils like sesame oil and castor oil in animals (Svendsen & Aaes‐Jørgensen, 1979; Schultz et al., 1998; Larsen et al., 2001). In addition, although based on very limited data, MCT oil has been found to give spikier and shorter-lasting depot injectable curves in humans (Knudsen, Hansen, & Larsen, 1985). 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 benzyl alcohol, as well as factors like injection site and volume, have additionally been found to influence pharmacokinetic properties with depot injectables (Minto et al., 1997; Kalicharan, Schot, & Vromans, 2016). Excipients besides oil vehicle also vary by formulation (Table).
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.
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. Cmax 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).
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.
Durations and Curve Shapes
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.
Duration of Estradiol Valerate
The estradiol concentration–time curve for injectable estradiol valerate in the well-known Oriowo et al. (1980) [Graph] 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., Göretzlehner et al., 2002; Valle Alvarez, 2011; Schug, Donath, & Blume, 2012). It’s noteworthy that Oriowo et al. (1980) used a peanut oil-based formulation of estradiol valerate that differed from pharmaceutical injectable estradiol valerate preparations, which generally use sesame oil or castor oil as the carrier (as well as other excipients) (Table). This may have influenced the curve shape of estradiol valerate in Oriowo et al. (1980). The study also had a small sample size 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 Oriowo et al. (1980).
Duration of Estradiol Cypionate in Oil versus Estradiol Enanthate
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 Oriowo et al. (1980) and a review of the pharmacokinetics of combined injectable contraceptives (Garza-Flores, 1994 [Graph]), 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 Garza-Flores (1994) figure was based on Oriowo et al. (1980) [Graph], 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 Oriowo et al. (1980) used a formulation of estradiol cypionate that differs from conventional pharmaceutical estradiol cypionate in oil preparations—specifically, the study used a peanut oil-based formulation (with few other specifics) rather than the cottonseed oil-based preparation employed in marketed pharmaceutical formulations (Table). The study also had a somewhat small sample size (n=10) and may have had significant sampling error. Hence, single studies, perhaps particularly Oriowo et al. (1980), should be interpreted cautiously.
A small but interesting pharmacokinetic study which directly compared injectable testosterone cypionate (n=6) and testosterone enanthate (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 (Schulte-Beerbühl & Nieschlag, 1980 [Graph]). The findings of this study are consistent with the fact that the lipophilicities of testosterone cypionate and testosterone enanthate (as measured by predicted log P) are very similar when directly compared (e.g., 5.1 vs. 5.11 with ALOGPS, 6.29 vs. 6.11 with ChemAxon logP, and 6.4 vs. 6.3 with XLogP3, respectively (Table). This of course is of importance as lipophilicity is thought to be the key factor determining the release kinetics of oil-based depot injectables (Sinkula, 1978; Shah, 2007; Larsen & Larsen, 2009; Larsen, Thing, & Larsen, 2012; Shahiwala, Mehta, & Momin, 2018). 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) (Table). 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.
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 Oriowo et al. (1980). 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) (Depo-Estradiol Label). 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 Oriowo et al. (1980), and estradiol cypionate in oil and estradiol enanthate may have more similar curves than has been previously assumed.
Curve Shape of Estradiol Cypionate Suspension
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 (Aly, 2019). In line with this notion, injectable medroxyprogesterone acetate 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) (Graphs). Although aqueous suspensions generally last longer than oil solutions as injectables (Enever et al., 1983; Aly, 2019), this is not always the case, and estradiol cypionate suspension interestingly seems to be shorter-acting than estradiol cypionate in oil.
Estradiol Exposure and Potency
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) (Aly, 2019). After adjusting for the molecular weight 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% bioavailability (with this being less characterized but likely also the case for the other non-polymeric injectable estradiol esters) (Düsterberg & Nishino, 1982; Seibert & Günzel, 1994).
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%) (Table). The appearance of differences in area-under-the-curve levels of estradiol in the present meta-analysis is probably just due to statistical error, 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.
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 (Wiki; Estradurin Labels). 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 excreted before it can be cleaved into estradiol and thereby rendered partly inactive, in turn necessitating the use of higher doses to achieve the same estradiol levels and therapeutic effect.
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 potency (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 estrogen receptors for a given tissue should become saturated at a certain point due to the finite quantity of available receptors 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) (Aly, 2020). However, these possibilities are speculative and theoretical. Although some literature exists that is relevant to this issue (e.g., Parkes, 1937; Bradbury, Long, & Durham, 1953), 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.
Variability Between Individuals
There is substantial variation in total estradiol levels and curve shapes between people with the same injectable estradiol preparation. Indicators of interindividual variability such as standard deviation 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., Oriowo et al., 1980; Derra, 1981 [Graph]; Aedo et al., 1985 [Graphs]; Sang et al., 1987 [Graphs]; Rahimy & Ryan, 1999 [Graph]; Valle Alvarez, 2011 [Graph]; Schug, Donath, & Blume, 2012 [Graphs]). Highly variable estradiol levels are already well-established with oral and transdermal estradiol (Kuhl, 2005; Wiki). 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 (Aly, 2020)—nor underdosed—which may result in suboptimal testosterone suppression and therapeutic efficacy.
Insights for Clinical Guidelines and Dosing Recommendations
Clinical guidelines for transgender health (see also Aly (2020)) 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 <1 to 10 mg/week or <2 to 80 mg/2 weeks. For reference, the Endocrine Society guidelines and the University of California, San Francisco (UCSF) guidelines are the most major clinical guidelines for transgender hormone therapy at present (Aly, 2020). The Endocrine Society guidelines recommend 5 to 30 mg/2 weeks or 2 to 10 mg/week for either estradiol valerate or estradiol cypionate (Hembree et al., 2017). Conversely, the UCSF guidelines recommend <20 to 40 mg/2 weeks for estradiol valerate and <2 to 5 mg/2 weeks for estradiol cypionate (with the option to divide dose into weekly injections if cyclical side effects occur) (Deutsch, 2016a).
Table 11: Recommended doses and injection intervals of injectable estradiol preparations (specifically estradiol valerate and estradiol cypionate) in transgender medicine clinical guidelinesa:
a 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 (Aly, 2020).
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 supraphysiological, doses of injectable estradiol valerate or estradiol cypionate recommended by guidelines are as high as 15 to 20 mg 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) (Table). 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 “pseudopregnancy” 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 (Ulrich, Pfeifer, & Lauritzen, 1994). 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) (Aly, 2019). 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 (Aly, 2020). The very high doses of these preparations that are recommended by guidelines should raise considerable reservations about their safety.
Figure 10: 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 (Graph).
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 (Aly, 2020). 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 (Graph). 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 (Aly, 2019; Langley et al., 2021; Aly, 2020). In relation to this, doses of injectable estradiol need not be excessive.
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 (<20 to 40 mg/2 weeks for estradiol valerate and <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 (Garza-Flores, 1994; Newton, d’Arcangues, & Hall, 1994; Sang, 1994; Toppozada, 1994). 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.
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).
Figure 11: 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).
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 Christian Hamburger and Harry Benjamin in the late 1960s in the first medical textbook on transgender people (Hamburger & Benjamin, 1969). 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.
Among the surveyed guidelines for transgender hormone therapy, only the UCSF guidelines (Deutsch, 2016b) and the Sherbourne Health/Rainbow Health Ontario guidelines (Bourns, 2019) referenced pharmacokinetic literature in their discussion of injectable estradiol. The specific publications cited by these guidelines were Düsterberg & Nishino (1982), Sierra-Ramírez et al. (2011), and Thurman et al. (2013). 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. Düsterberg & Nishino (1982) 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 Düsterberg & Nishino (1982) 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, Bourns (2019) 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. Sierra-Ramírez et al. (2011) and Thurman et al. (2013), although better-quality studies than Düsterberg & Nishino (1982), 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.
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.
Interactive Web Simulator
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:
There are various possibilities for further work on this project in the future. For example, assessment of interindividual variability 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 hormonal preparations such as injectable testosterone preparations and other estradiol routes and forms like oral estradiol, sublingual estradiol, and estradiol pellets. 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.
Special Thanks
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 Tilia—an effort to empower trans people with tools to manage their hormonal transitions—and TransKit—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.
Updates
Update 1: WPATH SOC8 Guidelines
In September 2022, the World Professional Association for Transgender Health (WPATH) Standards of Care for the Health of Transgender and Gender Diverse People Version 8 (SOC8) were published and made recommendations on transgender hormone therapy for the first time (Coleman et al., 2022). 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 Endocrine Society’s 2017 guidelines on transgender hormone therapy (Hembree et al., 2017). 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.
Update 2: Literature Mentions
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:
Hughes et al. (2022)
Hughes, J. H., Woo, K. H., Keizer, R. J., & Goswami, S. (2022). Clinical Decision Support for Precision Dosing: Opportunities for Enhanced Equity and Inclusion in Health Care. Clinical Pharmacology & Therapeutics, 113(3), 565–574. [DOI:10.1002/cpt.2799]:
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.88 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.89 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.
89. Aly, W. An interactive web simulator for estradiol levels with injectable estradiol esters. Transfeminine Science <https://transfemscience.org/articles/injectable-e2-simulator-release/> (2021) Accessed November 1, 2022.
Jaafar et al. (2022)
Jaafar, S., Torres-Leguizamon, M., Duplessy, C., & 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.] Sante Publique, 34(HS2), 109–122. [Google Scholar] [PubMed] [DOI:10.3917/spub.hs2.0109] [Translated]:
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]. […]
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/.
Linet (2023)
Linet, T. (2023). Prise en charge endocrinologique d’une personne trans. [Endocrinological care of a trans person.] In Faucher, P., Hassoun, D., & Linet, T. (Eds.). Santé sexuelle et reproductive des personnes LGBT [Sexual and Reproductive Health of LGBT People] (pp. 109–124). Issy-les-Moulineaux, France: Elsevier Masson. [Google Books] [URL] [WorldCat] [Excerpt] [Translated]:
Choice of estrogen.
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.
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).
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.
Update 3: Herndon et al. (2023)
In March 2023, the following study on injectable estradiol in transfeminine people was published online:
Herndon, J. S., Maheshwari, A. K., Nippoldt, T. B., Carlson, S. J., Davidge-Pitts, C. J., & Chang, A. Y. (2023). Comparison of Subcutaneous and Intramuscular Estradiol Regimens as part of Gender-Affirming Hormone Therapy. Endocrine Practice, 29(5), 356–361. [DOI:10.1016/j.eprac.2023.02.006] [URL]
The study was a retrospective analysis of individualized injectable estradiol in adult transfeminine people who received hormone therapy at the Mayo Clinic. 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.
Injectable estradiol doses were adjusted to achieve estradiol and testosterone levels within therapeutic ranges defined by the Endocrine Society 2017 guidelines (>100 pg/mL [367 pg/mL] for estradiol and <50 ng/dL [<1.7 nmol/L] for testosterone). Estradiol levels were measured exclusively using liquid chromatography–tandem mass spectrometry (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).
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 (interquartile range (IQR) 3–5.15 mg; range 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 (>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 (Graph). It can be seen that more individuals clustered into the higher range of doses with i.m. than with s.c. injections.
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.
On multiple regression analysis, injectable estradiol dose was significantly positively associated with estradiol levels (p < 0.001) following adjustment for several variables (injection route, body mass index (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.
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 (<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 spironolactone or finasteride. 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 (>100 pg/mL) and 88.2% achieved target testosterone levels (<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.
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 (Hembree et al., 2017) and UCSF 2016 guidelines (Deutsch, 2016a). 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 Oriowo et al. (1980) 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:
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 Deutsch, Bhakri, & Kubicek (2015) and Mueller et al. (2011) …]
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.
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.
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.
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 <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.
Update 4: Rothman et al. (2024)
In February 2024, the following review on injectable estradiol in transfeminine people was published online:
Rothman, M. S., Hamnvik, O. P. R., Davidge-Pitts, C., Safer, J. D., Ariel, D., Tangpricha, V., Abramowitz, J., Soe, K., Sarvaideo, J., Kelley, C., Irwig, M. S., & Iwamoto, S. J. (2024). Revisiting Injectable Estrogen Dosing Recommendations for Gender-Affirming Hormone Therapy. Transgender Health, ahead of print. [DOI:10.1089/trgh.2023.0209]
Here is the abstract of the paper:
Injectable estrogens are options for gender-affirming hormone therapy per guidelines, which suggest intramuscular dosages of 5–30 mg every 2 weeks or 2–10 mg weekly with estradiol cypionate or valerate interchangeably. Data among transgender and gender-diverse patients are limited due to local unavailability and concerns around laboratory assay variability and estradiol (E2) level fluctuation. We note a concerning trend where patients are prescribed high-dose injections based on the guidelines leading to serum E2 levels well above the range recommended in the same guidelines. Our review indicates that 5 mg weekly or lower should be prescribed when initiating injectable estrogens to avoid supraphysiologic E2 levels.
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-Analysis of Estradiol and Testosterone Levels with Oral Estradiol in Transfeminine People Based on Leinung et al. (2018) - Transfeminine Science
Analysis of Estradiol and Testosterone Levels with Oral Estradiol in Transfeminine People Based on Leinung et al. (2018)
By Aly | First published March 27, 2019 | Last modified February 17, 2023
Abstract / TL;DR
Analysis has been performed and information is provided on estradiol and testosterone levels with different doses of oral estradiol alone or in combination with antiandrogens including spironolactone (200 mg/day) and finasteride (5 mg/day) in transfeminine people based on published data from Leinung et al. (2018). With oral estradiol alone, mean estradiol levels ranged from 39 to 159 pg/mL across a dose range of 1 to 8 mg/day and mean testosterone levels ranged from 160 ng/dL at estradiol levels of <50 pg/mL to 44–61 ng/dL at estradiol levels of >100 pg/mL. Finasteride was associated with higher testosterone levels at all estradiol dose levels while spironolactone was associated with lower estradiol levels but only at an oral estradiol dose of 8 mg/day and not at other doses (2–6 mg/day). Mean testosterone levels in post-gonadectomy transfeminine people were 22 ng/dL. These findings suggest that oral estradiol dose-dependently suppresses testosterone levels and that estradiol and testosterone levels with oral estradiol may be modified by antiandrogens in transfeminine people.
Introduction
A retrospective chart study which quantified estradiol levels and suppression of testosterone levels with oral estradiol alone and in combination with an antiandrogen in a large sample of transfeminine people in the United States was published in May 2018 by Leinung and colleagues. The sample size for the study was 166 transfeminine people and estradiol and testosterone levels were determined with chemiluminescent immunoassay (CLIA). Here is the citation for the study:
Leinung, M. C., Feustel, P. J., & Joseph, J. (2018). Hormonal Treatment of Transgender Women with Oral Estradiol. Transgender Health, 3(1), 74–81. [DOI:10.1089/trgh.2017.0035]
This is a very useful study because it has data in transfeminine people that can provide precise estimates for answers to several open questions about transfeminine hormone therapy. These include what estradiol levels will be achieved with different doses of oral estradiol, how much testosterone levels will be suppressed with different doses/levels of estradiol, and the influence of certain antiandrogens—specifically spironolactone and finasteride—on estradiol and testosterone levels with oral estradiol.
I’ve digitized and recreated the two main graphs of interest from the paper. These new graphs are of higher image quality than the originals and I feel have an improved appearance. They aren’t perfect replicas of the originals (overlapping data points in the original graphs prevented this from being possible), but they should be quite close (e.g., ± 4 data points). In addition to the remade graphs, I’ve created two new graphs using data from the figures in the paper. These new graphs are variations of the originals that I think may be more understandable and useful. The four graphs are shown below (Figures 1–4). A supplementary spreadsheet containing the extracted data used to create these graphs can be found here. Some of the raw data in the spreadsheet is also included below in the Data Tables section.
As this study was not a randomized controlled trial (RCT) and was instead a retrospective chart review, there are limitations with these data that must be noted. For example, estradiol levels with different doses of oral estradiol may be inaccurate to a degree because transfeminine people in the study had their doses adjusted based on hormone levels (e.g., low/unsatisfactory estradiol levels or testosterone suppression resulting in increased doses and high/excessive estradiol levels resulting in dose decreases). In any case, estradiol levels with oral estradiol in this study were fairly similar to those that have been reported in other studies (e.g., Lobo & Cassidenti, 1992; Kuhl, 2005; Wiki; Graphs). It should also be noted that hormone levels vary by study and blood-testing methodology used.
Graphs
Recreated Graphs
Figure 1: Estradiol levels (pg/mL) with different doses (mg/day) of oral estradiol (E2) in transfeminine people. Estradiol levels are represented by blue circles (●) with oral estradiol alone, by red squares (■) with oral estradiol plus finasteride, and by green diamonds (◆) with oral estradiol plus spironolactone. The lines of colors corresponding to those of the points represent linear trendlines for the data points. This figure has also been uploaded to and can be found on Wikipedia (Wiki).
Figure 2: Testosterone levels (ng/dL) at different levels of estradiol (pg/mL) with oral estradiol (E2) in transfeminine people. Testosterone levels are represented by blue circles (●) with oral estradiol alone, by red squares (■) with oral estradiol plus finasteride, and by green diamonds (◆) with oral estradiol plus spironolactone. The dashed horizontal grey line is the mean testosterone level in a comparison group of post-gonadectomy transfeminine people (21.7 ± 12.4 ng/dL, with 13 determinations below 10 ng/dL, the lower limit of detection for the assay). This figure has also been uploaded to and can be found on Wikipedia (Wiki).
New Graphs
Figure 3: Estradiol levels (pg/mL) with 1 to 8 mg/day oral estradiol (E2) alone (blue line) or in combination with 200 mg/day oral spironolactone (green line) in transfeminine people. The oral estradiol alone group is actually a combination of oral estradiol alone and oral estradiol taken together with finasteride (5 mg/day); these two groups showed no significant differences in estradiol levels in the original data so they were combined for this graph. Estradiol levels with estradiol alone versus estradiol plus spironolactone seemed to be different only at the highest oral estradiol dose level (8 mg/day). The error bars represent standard deviations from the mean. This figure has also been uploaded to and can be found on Wikipedia (Wiki).
Figure 4: Testosterone levels (ng/dL) at different ranges of estradiol levels (pg/mL) with oral estradiol (E2) alone (blue line) or in combination with 5 mg/day finasteride (red line) or 200 mg/day oral spironolactone (green line) in transfeminine people. The typical oral estradiol doses (mg/day) for each range of estradiol levels are also provided. The dashed horizontal purple line is the upper limit for the normal female or castrate range (~50 ng/dL), while the dashed horizontal grey line is the mean testosterone level in a comparison group of post-gonadectomy transfeminine people (21.7 ± 12.4 ng/dL, with 13 determinations below 10 ng/dL, the lower limit of detection for the assay). The error bars represent standard deviations from the mean. This figure has also been uploaded to and can be found on Wikipedia (Wiki).
Data Tables
Estradiol Levels with Oral Estradiol
Table 1: Estradiol levels with different doses of oral estradiol alonea in transfeminine people:
Dosage
n
Estradiol level (mean ± SD)
1 mg/day
5
39 ± 25 pg/mL
2 mg/day
24
62 ± 23 pg/mL
4 mg/day
34
102 ± 59 pg/mL
6 mg/day
80
125 ± 62 pg/mL
8 mg/day
24
159 + 76 pg/mL
a Actually pooled data for oral estradiol alone and oral estradiol combined with finasteride (5 mg/day); these two groups showed no significant differences in estradiol levels in the original data so they were pooled together for this table.
Testosterone Levels with Oral Estradiol
Table 2: Testosterone levels at different estradiol levels with oral estradiol alonea in transfeminine people:
Estradiol level range
n
Estradiol level (mean ± SD)
Testosterone level (mean ± SD)
<50 pg/mL
11
33 ± 8.4 pg/mL
160 ± 139 ng/dL
50–100 pg/mL
24
76 ± 15 pg/mL
83 ± 106 ng/dL
100–150 pg/mL
21
125 ± 14 pg/mL
50 ± 37 ng/dL
150–200 pg/mL
8
170 ± 15 pg/mL
61 ± 57 ng/dL
200–250 pg/mL
4
227 ± 14 pg/mL
44 ± 33 ng/dL
a Only oral estradiol alone; oral estradiol combined with finasteride or spironolactone not included.
Update: Jain, Kwan, & Forcier (2019)
Shortly following the publication of Leinung et al. (2018), Jain and colleagues published a similar study of sublingual estradiol in combination with spironolactone and with or without medroxyprogesterone acetate in transfeminine people (Jain, Kwan, & Forcier, 2019).
Jain, J., Kwan, D., & Forcier, M. (2019). Medroxyprogesterone acetate in Gender-Affirming therapy for Transwomen: results from a retrospective study. The Journal of Clinical Endocrinology & Metabolism, 104(11), 5148–5156. [DOI:10.1210/jc.2018-02253]
Kuhl, H. (2005). Pharmacology of estrogens and progestogens: influence of different routes of administration. Climacteric, 8(Suppl 1), 3–63. [DOI:10.1080/13697130500148875] [PDF]
Leinung, M. C., Feustel, P. J., & Joseph, J. (2018). Hormonal Treatment of Transgender Women with Oral Estradiol. Transgender Health, 3(1), 74–81. [DOI:10.1089/trgh.2017.0035]
Lobo, R. A., & Cassidenti, D. L. (1992). Pharmacokinetics of Oral 17 β-Estradiol. The Journal of Reproductive Medicine, 37(1), 77–84. [Google Scholar] [PubMed] [PDF]
\ No newline at end of file
+Analysis of Estradiol and Testosterone Levels with Oral Estradiol in Transfeminine People Based on Leinung et al. (2018) - Transfeminine Science
Analysis of Estradiol and Testosterone Levels with Oral Estradiol in Transfeminine People Based on Leinung et al. (2018)
By Aly | First published March 27, 2019 | Last modified February 17, 2023
Abstract / TL;DR
Analysis has been performed and information is provided on estradiol and testosterone levels with different doses of oral estradiol alone or in combination with antiandrogens including spironolactone (200 mg/day) and finasteride (5 mg/day) in transfeminine people based on published data from Leinung et al. (2018). With oral estradiol alone, mean estradiol levels ranged from 39 to 159 pg/mL across a dose range of 1 to 8 mg/day and mean testosterone levels ranged from 160 ng/dL at estradiol levels of <50 pg/mL to 44–61 ng/dL at estradiol levels of >100 pg/mL. Finasteride was associated with higher testosterone levels at all estradiol dose levels while spironolactone was associated with lower estradiol levels but only at an oral estradiol dose of 8 mg/day and not at other doses (2–6 mg/day). Mean testosterone levels in post-gonadectomy transfeminine people were 22 ng/dL. These findings suggest that oral estradiol dose-dependently suppresses testosterone levels and that estradiol and testosterone levels with oral estradiol may be modified by antiandrogens in transfeminine people.
Introduction
A retrospective chart study which quantified estradiol levels and suppression of testosterone levels with oral estradiol alone and in combination with an antiandrogen in a large sample of transfeminine people in the United States was published in May 2018 by Leinung and colleagues. The sample size for the study was 166 transfeminine people and estradiol and testosterone levels were determined with chemiluminescent immunoassay (CLIA). Here is the citation for the study:
Leinung, M. C., Feustel, P. J., & Joseph, J. (2018). Hormonal Treatment of Transgender Women with Oral Estradiol. Transgender Health, 3(1), 74–81. [DOI:10.1089/trgh.2017.0035]
This is a very useful study because it has data in transfeminine people that can provide precise estimates for answers to several open questions about transfeminine hormone therapy. These include what estradiol levels will be achieved with different doses of oral estradiol, how much testosterone levels will be suppressed with different doses/levels of estradiol, and the influence of certain antiandrogens—specifically spironolactone and finasteride—on estradiol and testosterone levels with oral estradiol.
I’ve digitized and recreated the two main graphs of interest from the paper. These new graphs are of higher image quality than the originals and I feel have an improved appearance. They aren’t perfect replicas of the originals (overlapping data points in the original graphs prevented this from being possible), but they should be quite close (e.g., ± 4 data points). In addition to the remade graphs, I’ve created two new graphs using data from the figures in the paper. These new graphs are variations of the originals that I think may be more understandable and useful. The four graphs are shown below (Figures 1–4). A supplementary spreadsheet containing the extracted data used to create these graphs can be found here. Some of the raw data in the spreadsheet is also included below in the Data Tables section.
As this study was not a randomized controlled trial (RCT) and was instead a retrospective chart review, there are limitations with these data that must be noted. For example, estradiol levels with different doses of oral estradiol may be inaccurate to a degree because transfeminine people in the study had their doses adjusted based on hormone levels (e.g., low/unsatisfactory estradiol levels or testosterone suppression resulting in increased doses and high/excessive estradiol levels resulting in dose decreases). In any case, estradiol levels with oral estradiol in this study were fairly similar to those that have been reported in other studies (e.g., Lobo & Cassidenti, 1992; Kuhl, 2005; Wiki; Graphs). It should also be noted that hormone levels vary by study and blood-testing methodology used.
Graphs
Recreated Graphs
Figure 1: Estradiol levels (pg/mL) with different doses (mg/day) of oral estradiol (E2) in transfeminine people. Estradiol levels are represented by blue circles (●) with oral estradiol alone, by red squares (■) with oral estradiol plus finasteride, and by green diamonds (◆) with oral estradiol plus spironolactone. The lines of colors corresponding to those of the points represent linear trendlines for the data points. This figure has also been uploaded to and can be found on Wikipedia (Wiki).
Figure 2: Testosterone levels (ng/dL) at different levels of estradiol (pg/mL) with oral estradiol (E2) in transfeminine people. Testosterone levels are represented by blue circles (●) with oral estradiol alone, by red squares (■) with oral estradiol plus finasteride, and by green diamonds (◆) with oral estradiol plus spironolactone. The dashed horizontal grey line is the mean testosterone level in a comparison group of post-gonadectomy transfeminine people (21.7 ± 12.4 ng/dL, with 13 determinations below 10 ng/dL, the lower limit of detection for the assay). This figure has also been uploaded to and can be found on Wikipedia (Wiki).
New Graphs
Figure 3: Estradiol levels (pg/mL) with 1 to 8 mg/day oral estradiol (E2) alone (blue line) or in combination with 200 mg/day oral spironolactone (green line) in transfeminine people. The oral estradiol alone group is actually a combination of oral estradiol alone and oral estradiol taken together with finasteride (5 mg/day); these two groups showed no significant differences in estradiol levels in the original data so they were combined for this graph. Estradiol levels with estradiol alone versus estradiol plus spironolactone seemed to be different only at the highest oral estradiol dose level (8 mg/day). The error bars represent standard deviations from the mean. This figure has also been uploaded to and can be found on Wikipedia (Wiki).
Figure 4: Testosterone levels (ng/dL) at different ranges of estradiol levels (pg/mL) with oral estradiol (E2) alone (blue line) or in combination with 5 mg/day finasteride (red line) or 200 mg/day oral spironolactone (green line) in transfeminine people. The typical oral estradiol doses (mg/day) for each range of estradiol levels are also provided. The dashed horizontal purple line is the upper limit for the normal female or castrate range (~50 ng/dL), while the dashed horizontal grey line is the mean testosterone level in a comparison group of post-gonadectomy transfeminine people (21.7 ± 12.4 ng/dL, with 13 determinations below 10 ng/dL, the lower limit of detection for the assay). The error bars represent standard deviations from the mean. This figure has also been uploaded to and can be found on Wikipedia (Wiki).
Data Tables
Estradiol Levels with Oral Estradiol
Table 1: Estradiol levels with different doses of oral estradiol alonea in transfeminine people:
Dosage
n
Estradiol level (mean ± SD)
1 mg/day
5
39 ± 25 pg/mL
2 mg/day
24
62 ± 23 pg/mL
4 mg/day
34
102 ± 59 pg/mL
6 mg/day
80
125 ± 62 pg/mL
8 mg/day
24
159 ± 76 pg/mL
a Actually pooled data for oral estradiol alone and oral estradiol combined with finasteride (5 mg/day); these two groups showed no significant differences in estradiol levels in the original data so they were pooled together for this table.
Testosterone Levels with Oral Estradiol
Table 2: Testosterone levels at different estradiol levels with oral estradiol alonea in transfeminine people:
Estradiol level range
n
Estradiol level (mean ± SD)
Testosterone level (mean ± SD)
<50 pg/mL
11
33 ± 8.4 pg/mL
160 ± 139 ng/dL
50–100 pg/mL
24
76 ± 15 pg/mL
83 ± 106 ng/dL
100–150 pg/mL
21
125 ± 14 pg/mL
50 ± 37 ng/dL
150–200 pg/mL
8
170 ± 15 pg/mL
61 ± 57 ng/dL
200–250 pg/mL
4
227 ± 14 pg/mL
44 ± 33 ng/dL
a Only oral estradiol alone; oral estradiol combined with finasteride or spironolactone not included.
Update: Jain, Kwan, & Forcier (2019)
Shortly following the publication of Leinung et al. (2018), Jain and colleagues published a similar study of sublingual estradiol in combination with spironolactone and with or without medroxyprogesterone acetate in transfeminine people (Jain, Kwan, & Forcier, 2019).
Jain, J., Kwan, D., & Forcier, M. (2019). Medroxyprogesterone acetate in Gender-Affirming therapy for Transwomen: results from a retrospective study. The Journal of Clinical Endocrinology & Metabolism, 104(11), 5148–5156. [DOI:10.1210/jc.2018-02253]
Kuhl, H. (2005). Pharmacology of estrogens and progestogens: influence of different routes of administration. Climacteric, 8(Suppl 1), 3–63. [DOI:10.1080/13697130500148875] [PDF]
Leinung, M. C., Feustel, P. J., & Joseph, J. (2018). Hormonal Treatment of Transgender Women with Oral Estradiol. Transgender Health, 3(1), 74–81. [DOI:10.1089/trgh.2017.0035]
Lobo, R. A., & Cassidenti, D. L. (1992). Pharmacokinetics of Oral 17 β-Estradiol. The Journal of Reproductive Medicine, 37(1), 77–84. [Google Scholar] [PubMed] [PDF]
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index 39e8f71b..3e842ae1 100644
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-Considerations in Understanding the Possible Role and Influence of Progestogens in Terms of Breast Development - Transfeminine Science
Meyer et al. (1986) assessed the effects of progestogens added to estrogen therapy on breast development and other clinical parameters in transfeminine people. Of the 60 transfeminine people in the study, 15 (25%) received an oral progestogen, usually MPA at a dosage of 10 mg/day, for “at least for a short time” (with only 8 (13.3%) receiving progestogen therapy for the full treatment period). In an earlier report of the study, it was noted that in 90% of observation periods the dose was 10 mg/day and for the remainder it was 20 mg/day (Meyer et al., 1981). A dosage of 10 mg/day MPA is roughly comparable to luteal-phase progesterone exposure in terms of progestogenic potency (Wiki). Breast development was measured in the study via breast hemicircumference (Diagram). Progestogen therapy was reported to not modify estrogen-induced changes, including laboratory measurements, hormone levels, and physical parameters like weight and breast growth. The lack of apparent changes in hormone levels is unexpected, as MPA in higher-quality studies has shown clear testosterone suppression (e.g., Jain, Kwan, & Forcier, 2019; Wiki). Meyer and colleagues concluded that adding progestogens to estrogen does not seem to enhance breast development in transfeminine people. However, they noted that the number of individuals who received progestogens was small and further studies were needed.
Prior et al. (1986) and Prior, Vigna, & Watson (1989) studied estrogen, high-dose spironolactone (100–600 mg/day), and MPA (10–20 mg/day cylically or continuously) in transfeminine people who were either pre-hormone therapy or had previously been on higher doses of estrogens (and/or progestogens) without spironolactone prior to the study. The researchers reported that following 12 months of treatment with the study’s hormone therapy regimen, there was increased breast size and increased nipple development. Most individuals reached an A cup size, or approximately 8 to 14 cm in diameter of breast tissue, by the end of the study. Breast development was measured in part with photographic documentation. Although breast development reportedly improved, the researchers themselves noted that it was difficult to determine whether the enhanced breast development could be attributed to spironolactone or to MPA. Moreover, testosterone suppression was inadequate before the study and improved with the study’s hormone therapy regimen, which may have helped to improve breast development regardless of any potential direct progestogenic action of MPA on the breasts. Finally, it is possible that breast development with estrogen may not yet have been complete, and that the improved breast development may have simply been continued progression due to estrogen alone. In other publications, Jerilynn Prior, the lead study author, has claimed that progesterone enhances breast development, and has cited the preceding studies by her in support of this claim (Prior, 2011; Prior, 2019a; Prior, 2019b; Prior, 2020). However, her claim is not well-supported due to the study limitations discussed here and elsewhere (Aly, 2019).
Dittrich et al. (2005) reported that the combination of oral estradiol valerate and a gonadotropin-releasing hormone (GnRH) agonist for 2 years resulted in self-reported breast cup sizes of C cup or greater in 5%, B cup in 30%, A cup in 35%, and less than A cup in 30% in transfeminine people. They noted however that 70% were unsatisfied with their breast development and wished to undergo breast augmentation. The researchers claimed that the regimen had similar effectiveness in terms of feminization, including increases in breast size, compared to prior reported treatment regimens of ethinylestradiol and CPA. No other details or specifics were given. The claim about similar breast development to regimens containing CPA is relevant as CPA is a very strong progestogen at the doses used historically in transfeminine people. It should be cautioned however that this study did not actually employ or study progestogens itself. In addition, self-reported breast cup size is a subjective and low-quality means of measuring breast development and size. As such, the findings of this study are of questionable value in terms of understanding progestogens and breast development.
Estrogen is primarily involved in ductal development of the breasts, whereas progesterone is mainly involved in lobuloalveolar development. Kanhai et al. (2000) compared histological breast tissue changes with estrogen and CPA 100 mg/day (i.e. very-high-dose progestogen) therapy in 14 transfeminine people versus nonsteroidal antiandrogen monotherapy with flutamide or bicalutamide in 2 cisgender men with prostate cancer. Both types of treatments block androgens, increase estrogen levels, and are known to induce breast development or gynecomastia at similarly high rates. However, nonsteroidal antiandrogen monotherapy differs from combined estrogen and progestogen therapy in that it lacks any progestogenic effects. In the transfeminine people, full lobuloalveolar formation was apparent in the biopsied breast tissue, whereas in the men with prostate cancer, only “moderate” and incomplete lobuloalveolar maturation was found. It was also noted that lobuloalveolar formation tended to regress upon discontinuation of CPA following gonadectomy in transfeminine people. The researchers concluded that progestogenic exposure is needed for the breasts to fully develop on a histological level and for the breast tissue of transfeminine people to completely mimic the histology of the mature female breast. While the findings of this study are interesting, they only concern tissue characteristics and do not actually provide any information about breast development in terms of physical form or appearance. With regard to this, tissue-level differences may or may not translate to relevant differences in for instance breast size or shape. As such, the study is of limited value in understanding whether progestogens improve breast development in transfeminine people in the ways that are actually valued.
Jain, Kwan, & Forcier (2019) studied sublingual estradiol and spironolactone with and without MPA in 92 transfeminine people. MPA was given at a dose of 5 to 10 mg/day sublingually or at a dose of 150 mg once every 3 months by intramuscular injection. Of 39 transfeminine people who received MPA, 26 (67%) self-reported improved breast development. No further details were provided, but measurement of breast development was presumably subjective and anecdotal. Igo & Visram (2021) studied addition of progesterone to hormone therapy in transfeminine people. Progesterone was provided as 100 mg micronized progesterone (probably oral) and was prescribed when progesterone was specifically requested by the patient or when the patient expressed dissatisfaction with feminization and/or breast development. Of 190 individuals, 51 (26.8%) received progesterone therapy. Treatment with progesterone on average began after 12.7 months of estradiol therapy, and the mean total follow-up time was 14.3 months of hormone therapy. Of those who received progesterone, only 6 (11.8%) reported benefit to breast development. No further details were provided, but as with other studies, breast development was likely quantified anecdotally via self-report. As breast development does not appear to have been objectively measured or compared to a control group in either Jain, Kwan, & Forcier (2019) or Igo & Visram (2021), the findings of these studies are limitedly informative.
Nolan and colleagues assessed the short-term effects of low-dose oral micronized progesterone on breast development in transfeminine people on stable hormone therapy in a prospective controlled study (Nolan et al., 2022a; Nolan et al., 2022b). Progesterone was given at a dose of 100 mg/day for 3 months to 23 transfeminine people and findings were compared to those of a control group of 19 transfeminine people. Breast development was measured using self-reported Tanner stage, with participants provided photographs of different Tanner stages to self-select from. At the end of the 3 months, Tanner stage was not significantly different between groups (mean 3.5, 95% CI 3.2–3.7 for progesterone vs. mean 3.6, 95% CI 3.3–3.9 for controls; p = 0.42). A limitation of this study is that oral progesterone has very low bioavailability and 100 mg/day oral progesterone achieves very low progesterone levels that are well below normal luteal-phase progesterone levels (Aly, 2018). As such, progestogenic exposure in this study, and notably also in Igo & Visram (2021), is likely to have been inadequate. Besides the issue of progestogenic strength, the very short duration of the study (3 months) and the reliance on self-reported subjective Tanner stages (as opposed to more objective physical breast measurements) are also major methodological limitations. In any case, this study is of noticeably higher quality than previous studies, and is notably likely to continue and report further follow-up at later points in the future.
Aside from the above studies, a variety of other studies have also reported breast development with estrogen and CPA in transfeminine people, often with objective physical measurements (e.g., breast volume, breast–chest difference, breast cup size, breast hemicircumference), but have lacked comparison groups and so have not been discussed in the present section. These studies are instead briefly discussed elsewhere (see the section below). In any case, to briefly summarize the findings, breast development in transfeminine people has unfortunately usually been poor in these studies.
The findings from the preceding studies in transfeminine people are of very low-quality due to methodological limitations, including lack of control groups, lack of randomization, reliance on poor measures of breast development (e.g., subjective and self-report), short treatment durations, and small sample sizes, among others. This is likely to explain the conflicting results of the studies. More research is still needed to assess the influence of progestogens on breast development in transfeminine people. A 2014 review on hormone therapy in transfeminine people summarize the state of research on progestogens and breast development in transfeminine people (Wierckx, Gooren, & T’Sjoen, 2014):
Our knowledge concerning the natural history and effects of different cross-sex hormone therapies on breast development in trans women is extremely sparse and based on low quality of evidence. Current evidence does not provide evidence that progestogens enhance breast development in trans women. Neither do they prove the absence of such an effect. This prevents us from drawing any firm conclusion at this moment and demonstrates the need for further research to clarify these important clinical questions.
Progesterone and its Role in Breast Development During Normal Female Puberty
The role of progesterone in breast development and its possible usefulness for helping with breast development in transfeminine hormone therapy can be informed by the normal biological circumstances of puberty in cisgender females. Puberty in cisgender girls takes an average of 3 to 4 years, though with a possible range of about 2 to 6 years in most cases. Progesterone essentially doesn’t appear during puberty until ovulatorymenstrual cycles begin. Menarche, the onset of menstruation and hence menstrual cycling, occurs on average at Tanner breast stage 4, although it occurs at Tanner breast stage 3 or Tanner breast stage 5 (complete breast development) in significant subsets of girls (Marshall & Tanner, 1969; Marshall, 1978; Hillard, 2007). Hence, a significant portion of girls reach Tanner breast stage 5 (complete breast development) before experiencing menarche or any progesterone production. This indicates that progesterone is not essential to reach Tanner breast stage 5, at least for a subset of girls. Tanner breast stage 4 is on average about 2.5 years into breast development, while breast development as a whole takes on average about 3.5 years. As such, the appearance of progesterone in normal female puberty is a relatively late event (Marshall, 1978; Begley, Firth, & Hoult, 1980; Drife, 1986).
Taken together, production of progesterone is a late event in normal female puberty, and even once it does begin, exposure to progesterone is low and sporadic until well after puberty has completed. Moreover, a subset of girls complete breast development before progesterone production starts. These facts call into some question the role of progesterone in breast development in female puberty.
Progesterone and Mammary Development in Animals
Pubertal Mammary Development
Knockout of the progesterone receptor in female rice results in complete infertility and severely compromised ovarian, uterine, and reproductive–behavioral functions (Lydon et al., 1995; Ismail et al., 2003). Conversely however, pubertal ductal mammary development in progesterone receptor knockout mice is normal and in fact morphologically indistinguishable from that of regular mice (Ismail et al., 2003). This is in contrast to the case of estrogen receptor alpha knockout mice, in which pubertal mammary development is abolished (Ismail et al., 2003; Wiki; Wiki). However, subsequent studies revealed that mammary ductal development during puberty is in fact delayed though eventually normal in female mice that have loss of progesterone production, loss of the progesterone receptor, or progesterone receptor antagonism (Shi, Lydon, & Zhang, 2004). In other words, progesterone stimulates and accelerates ductal development during puberty and hence appears to have a significant physiological role in early mammary development during puberty. The stimulation of ductal development by progesterone appears to be mediated by induction of the expression of amphiregulin in mammary ducts and terminal end buds (Kariagina et al., 2010; Aupperlee et al., 2013). This growth factor is an agonist of the epidermal growth factor receptor (EGFR), and is also notably the major growth factor that estrogen induces the expression of to mediate mammary gland development during puberty (Ciarloni, Mallepell, & Brisken, 2007; LaMarca & Rosen, 2007; McBryan et al., 2008). However, as mammary ductal development during puberty without progesterone is delayed but eventually completely normal, it has been stated that progesterone is dispensable for pubertal mammary gland development in mice (Ismail et al., 2003).
Breast Composition and Lobuloalveolar Content
Progestogens are involved primarily in lobuloalveolar development of the breasts. This type of breast development is necessary for lactation and breastfeeding and occurs mainly during pregnancy. The breasts are made up of two main types of tissue: (1) epithelial tissue (the actual internal mammary glandular tissue, including ducts and alveoli or lobules); and (2) stromal tissue (a mixture of connective tissue and adipose (fat) tissue). Lobuloalveolar development refers to growth and maturation of the alveoli and lobules and hence is a form of epithelial or glandular development. In women who are not pregnant or lactating, only about 5 to 20% of the volume of the breasts on average is composed of epithelial tissue, while the remaining 80 to 95% is composed of stromal tissue (Hutson, Cowen, & Bird, 1985; Drife, 1986; Bryant et al., 1998; Gertig et al., 1999; Howard & Gusterson, 2000; Cline & Wood, 2006; Lorincz & Sukumar, 2006; Wilson et al., 2006; Xu et al., 2010; Pandya & Moore, 2011; Hagisawa, Shimura, & Arisaka, 2012; Sandhu et al., 2016; Rosenfield, Cooke, & Radovick, 2021). More specifically, one study found that about 10 to 20% is epithelial tissue, about 10 to 35% is fat tissue, and about 60 to 80% is connective tissue in reproductive-age women (Hutson, Cowen, & Bird, 1985; Wilson et al., 2006). Similarly, in women with macromastia (breast hypertrophy), only a small proportion of the breasts is glandular tissue (e.g., 1–7%) (Bames, 1948; Cruz-Korchin et al., 2001). During pregnancy and lactation however, the breasts undergo dramatic changes, and epithelial tissue comes to make up a much greater proportion of the breasts (Ramsay et al., 2005; Bland, Copeland, & Klimberg, 2018). In fact, sources state that glandular tissue comprises a majority of the breast during pregnancy and lactation, with one study of lactating women finding that the breasts were composed 63% (range 46–83%) of glandular tissue (Ramsay et al., 2005). In any case, under more normal physiological circumstances and progesterone exposure, the contribution of lobuloalveolar tissue to the size of the breasts is quite small. In relation to this, the significance of progestogen-mediated breast lobuloalveolar growth in terms of breast size is unclear but seemingly questionable (Wierkcx, Gooren, & T’Sjoen, 2014).
Complete Androgen Insensitivity Syndrome, Progesterone, and Breast Development
It has been claimed that progesterone helps to move transfeminine people and cisgender females from Tanner stage 4 to 5 breast development and that it helps to round out the breasts at this time (e.g., Prior, 2011; Prior, 2019a; Prior, 2020). It has also been claimed in the online transgender community that cisgender women with complete androgen insensitivity syndrome (CAIS), an experiment of nature of women who lack progesterone, are stuck at Tanner stage 4 breast development and have “cone-shaped” breasts due to their absence of progesterone. In actuality however, there is no good evidence at this time that progesterone is required for normal pubertal breast development, that it is needed to reach Tanner stage 5, or that it helps to round out the breasts. Moreover, such claims are contradicted by significant available literature and evidence, including notably on CAIS women themselves.
Women with CAIS are individuals who have a 46,XY karyotype (i.e. are genetically “male”), testes, and who would otherwise have physically developed as males, but did not because they have a mutation in the gene encoding the androgen receptor which makes them completely insensitive to the effects of androgens. CAIS women have a male-typical hormonal profile, generated by their testes, including high male-range levels of testosterone, low female-range but nonetheless significant estradiol levels, and no significant progesterone production with very low progesterone levels. Instead of developing physically as males however, CAIS women are perfectly phenotypically female, with a normal female body, vagina, and breasts (Wiki; Photo). Their testosterone has been unable to masculinize them, while their estradiol, unopposed by androgens, is able to feminize them. The internal reproductive system in CAIS women is essentially that of an underdeveloped male, with testes instead of ovaries, and no uterus or fallopian tubes. The vagina is often short and is blind-ending with no cervix, which is related to the lack of a uterus.
Women with CAIS have breast development that is described throughout the literature as “good”, “excellent”, “normal”, “full”, “complete”, “well-developed”, “generous”, “typically above-average”, “large”, and even “voluptuous” (Morris, 1953; Hertz et al., 1966; Valentine, 1969; Adams et al., 1970; Polani, 1970; Weisberg, Malkasian, & Pratt, 1970; Dewhurst, 1971; Perez-Palacios & Jaffe, 1972; Glenn, 1976; Dewhurst & Spence, 1977; Rutgers & Scully, 1991; Patterson, McPhaul, & Hughes, 1994; Quigley et al., 1995; McPhaul, 2002; Galani et al., 2008; Oakes et al., 2008; Tiefenbacher & Daxenbichler, 2008; Barbieri, 2017). The gynecologist, John McLean Morris, who reviewed and summarized all of the existing scientific literature on CAIS women in 1953 (including 82 cases) and gave their condition the since-abandoned name “testicular feminization”, described their breasts as “unusually large” and “jumbo-sized” (Morris, 1953; Quigley et al., 1995). He additionally said in his famous 1953 review that they had “normal female breasts, often with a tendency to be overdeveloped” (Morris, 1953). In actuality however, some CAIS women have large breasts, while some have small breasts (Wisniewski et al., 2000), and we have no clear data that their breasts are actually larger on average. The variation in breast growth in CAIS women parallels the same large variation in breast size between individuals that is seen in natal women in general. Here is a collection of photos of CAIS women and their breast development from published case reports and reviews throughout the literature. As can be seen from these photos, breast development in CAIS women is normal and excellent, although subject to considerable variation between individuals in terms of breast size and shape as in women in general.
CAIS women have never been described as having “cone-shaped”, “pointy”, or otherwise abnormal breasts. The only exception is that they are often said to have “juvenile”—or relatively “small” and “pale”—areolas/nipples (e.g., Photo) (e.g., Morris, 1953; Morris & Mahesh, 1963; Khoo & Mackay, 1972; Perez-Palacios & Jaffe, 1972; Dewhurst & Spence, 1977; many others). This is probably because estradiol levels in CAIS women are only about 35 pg/mL on average (Table). This is relevant as estrogens dose-dependently induce nipple and areolar enlargement and pigmentation (Davis et al., 1945; Kennedy & Nathanson, 1953). Hence, higher estrogen levels may be necessary for full adult-like nipple and areolar maturation.
Individuals with complete [androgen insensitivity syndrome (AIS)] have excellent feminization at puberty, with normal or augmented breast development, and clear, smooth, acne-free complexions. Feminization of the breasts and body contours occurs in response to estrogen (produced mainly by testicular and, to a lesser extent, peripheral aromatization of androgens) that is unopposed by the effects of androgens. […] Breast development, ranging from mild gynecomastia to abundant Tanner stage V female breasts, can occur with all grades of AIS, tending to be more pronounced with the more severe grades.
By “more severe grades”, they mean CAIS, the complete form of the syndrome, as opposed to the incomplete forms of androgen insensitivity syndrome (AIS), including the partial and mild presentations (Quigley, 1988). The condition is a spectrum, and those with CAIS, the most “severe” grade, are the only ones who are completely insensitive to the androgen receptor-mediated actions of androgens and who have a fully feminized body. Even individuals with partial androgen insensitivity syndrome (PAIS) likewise have substantial breast development however (e.g., Saito et al., 2014; Lee et al., 2015).
As already touched on, CAIS women are notable because they have very low and negligible levels of progesterone (<2 ng/mL) due to their testes and lack of progesterone production (Table; Barbieri, 2017). CAIS women, perhaps more convincingly than any other evidence available at this time, suggest that progesterone is not needed for normal and complete breast development (Barbieri, 2017):
A genetic experiment of nature, androgen insensitivity syndrome, provides a clinical example of the important interplay between estrogens and androgens in the regulation of breast growth.38 In androgen insensitivity due to mutations in the androgen receptor (AR), genetic males (46,XY) do not have a fully functional AR. Testosterone is produced by the testis, but target tissues are not capable of responding to the high levels of circulating androgens. In this syndrome, circulating estradiol concentration is in the range of 50 pg/mL, comparable to early follicular-phase levels observed in women. Breast volume in individuals with androgen insensitivity is typically above average. This suggests that, in the complete absence of androgen inhibition, modest levels of estradiol are capable of stimulating significant breast growth. Progesterone levels are low in individuals with loss of the AR. This suggests that breast volume is not absolutely dependent on progesterone stimulation.
Despite their often large breasts, CAIS women are said to have relatively little breast glandular tissue (as opposed to fat and connective tissue) and minimal lobuloalveolar development (Morris, 1953; Morris & Mahesh, 1963; Simmer, Pion, & Dignam, 1965; McMillan, 1966; Perez-Palacios & Jaffe, 1972; Dewhurst & Spence, 1977; Shapiro, 1982). This is potentially in accordance with their lack of progesterone, as progesterone is involved in lobuloalveolar maturation. It is notable that in women in general, the breasts are mostly composed of stromal fat and connective tissue (~80–90%), rather than glandular tissue (10–20%) (Wiki). Additionally, when lobuloalveolar development occurs, for instance during pregnancy, it replaces stromal tissue (Alex, Bhandary, & McGuire, 2020). Hence, greater glandular or lobuloalveolar formation in the breasts may not necessarily translate to greater breast size, as seems apparent in CAIS women. Also in spite of their well-developed breasts, breast cancer has never been reported in CAIS women (Aly, 2020a; Aly, 2020b). This may be related to factors like their lack of progesterone and lobuloalveolar maturation and/or their absence of a second X chromosome (Aly, 2020a; Aly, 2020b).
Early Progestogen Exposure and the Possibility of Suboptimal Breast Development
However, species differences in mammary gland development and hormonal responses exist, and no hard data or evidence has been published to substantiate the claims of the clinical publications. As such, it is unknown whether suboptimal breast development could occur with early progestogen exposure in humans. Moreover, if it does occur in humans, it is unknown what level of progestogen exposure would be required to produce it. In any case, a few other areas of research interest are also relevant to the issue of progestogens possibly resulting in worse breast development, including the antiestrogenic effects of progestogens in the breasts, clinical studies of breast development with estrogen and CPA (a very strong progestogen) in transfeminine people, case reports of progestogens for treatment of macromastia in cisgender females, and theoretical suggestions of poor breast development in cisgender girls with 17α-hydroxylase/17,20-lyase deficiency being related to high progesterone exposure. These topics will be discussed in the subsequent sections.
Antiestrogenic Effects of Progestogens in the Breasts
Breast Development with Cyproterone Acetate in Transfeminine People
The possibility of suboptimal breast development with progestogens is of particular relevance to CPA. This is because CPA is a potent progestogen in addition to antiandrogen and is used in transfeminine people at doses that result in very strong progestogenic exposure (Aly, 2019). Studies using estrogen plus CPA in transfeminine people have generally reported poor breast development (Kanhai et al., 1999; Sosa et al., 2003; Sosa et al., 2004; Wierckx et al., 2014; Fisher et al., 2016; Tack et al., 2017; de Blok et al., 2018; Reisman, Goldstein, & Safer, 2019; de Blok et al., 2020; Meyer et al., 2020). However, transfeminine people could simply have poor breast development in general without this necessarily being related to CPA or progestogen exposure. Indeed, a study in transfeminine people who underwent pubertal suppression in adolescence presumably with GnRH agonists and then hormone therapy showed similarly poor breast development as in adults (Boogers et al., 2022). A randomized controlled trial of estradiol plus spironolactone versus estradiol plus CPA assessing breast development in transfeminine people is underway in Australia and may provide more insight on this issue (ANZCTR).
Progestogens in the Treatment of Breast Hypertrophy
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+Considerations in Understanding the Possible Role and Influence of Progestogens in Terms of Breast Development - Transfeminine Science
Meyer et al. (1986) assessed the effects of progestogens added to estrogen therapy on breast development and other clinical parameters in transfeminine people. Of the 60 transfeminine people in the study, 15 (25%) received an oral progestogen, usually MPA at a dosage of 10 mg/day, for “at least for a short time” (with only 8 (13.3%) receiving progestogen therapy for the full treatment period). In an earlier report of the study, it was noted that in 90% of observation periods the dose was 10 mg/day and for the remainder it was 20 mg/day (Meyer et al., 1981). A dosage of 10 mg/day MPA is roughly comparable to luteal-phase progesterone exposure in terms of progestogenic potency (Wiki). Breast development was measured in the study via breast hemicircumference (Diagram). Progestogen therapy was reported to not modify estrogen-induced changes, including laboratory measurements, hormone levels, and physical parameters like weight and breast growth. The lack of apparent changes in hormone levels is unexpected, as MPA in higher-quality studies has shown clear testosterone suppression (e.g., Jain, Kwan, & Forcier, 2019; Wiki). Meyer and colleagues concluded that adding progestogens to estrogen does not seem to enhance breast development in transfeminine people. However, they noted that the number of individuals who received progestogens was small and further studies were needed.
Prior et al. (1986) and Prior, Vigna, & Watson (1989) studied estrogen, high-dose spironolactone (100–600 mg/day), and MPA (10–20 mg/day cylically or continuously) in transfeminine people who were either pre-hormone therapy or had previously been on higher doses of estrogens (and/or progestogens) without spironolactone prior to the study. The researchers reported that following 12 months of treatment with the study’s hormone therapy regimen, there was increased breast size and increased nipple development. Most individuals reached an A cup size, or approximately 8 to 14 cm in diameter of breast tissue, by the end of the study. Breast development was measured in part with photographic documentation. Although breast development reportedly improved, the researchers themselves noted that it was difficult to determine whether the enhanced breast development could be attributed to spironolactone or to MPA. Moreover, testosterone suppression was inadequate before the study and improved with the study’s hormone therapy regimen, which may have helped to improve breast development regardless of any potential direct progestogenic action of MPA on the breasts. Finally, it is possible that breast development with estrogen may not yet have been complete, and that the improved breast development may have simply been continued progression due to estrogen alone. In other publications, Jerilynn Prior, the lead study author, has claimed that progesterone enhances breast development, and has cited the preceding studies by her in support of this claim (Prior, 2011; Prior, 2019a; Prior, 2019b; Prior, 2020). However, her claim is not well-supported due to the study limitations discussed here and elsewhere (Aly, 2019).
Dittrich et al. (2005) reported that the combination of oral estradiol valerate and a gonadotropin-releasing hormone (GnRH) agonist for 2 years resulted in self-reported breast cup sizes of C cup or greater in 5%, B cup in 30%, A cup in 35%, and less than A cup in 30% in transfeminine people. They noted however that 70% were unsatisfied with their breast development and wished to undergo breast augmentation. The researchers claimed that the regimen had similar effectiveness in terms of feminization, including increases in breast size, compared to prior reported treatment regimens of ethinylestradiol and CPA. No other details or specifics were given. The claim about similar breast development to regimens containing CPA is relevant as CPA is a very strong progestogen at the doses used historically in transfeminine people. It should be cautioned however that this study did not actually employ or study progestogens itself. In addition, self-reported breast cup size is a subjective and low-quality means of measuring breast development and size. As such, the findings of this study are of questionable value in terms of understanding progestogens and breast development.
Estrogen is primarily involved in ductal development of the breasts, whereas progesterone is mainly involved in lobuloalveolar development. Kanhai et al. (2000) compared histological breast tissue changes with estrogen and CPA 100 mg/day (i.e. very-high-dose progestogen) therapy in 14 transfeminine people versus nonsteroidal antiandrogen monotherapy with flutamide or bicalutamide in 2 cisgender men with prostate cancer. Both types of treatments block androgens, increase estrogen levels, and are known to induce breast development or gynecomastia at similarly high rates. However, nonsteroidal antiandrogen monotherapy differs from combined estrogen and progestogen therapy in that it lacks any progestogenic effects. In the transfeminine people, full lobuloalveolar formation was apparent in the biopsied breast tissue, whereas in the men with prostate cancer, only “moderate” and incomplete lobuloalveolar maturation was found. It was also noted that lobuloalveolar formation tended to regress upon discontinuation of CPA following gonadectomy in transfeminine people. The researchers concluded that progestogenic exposure is needed for the breasts to fully develop on a histological level and for the breast tissue of transfeminine people to completely mimic the histology of the mature female breast. While the findings of this study are interesting, they only concern tissue characteristics and do not actually provide any information about breast development in terms of physical form or appearance. With regard to this, tissue-level differences may or may not translate to relevant differences in for instance breast size or shape. As such, the study is of limited value in understanding whether progestogens improve breast development in transfeminine people in the ways that are actually valued.
Jain, Kwan, & Forcier (2019) studied sublingual estradiol and spironolactone with and without MPA in 92 transfeminine people. MPA was given at a dose of 5 to 10 mg/day sublingually or at a dose of 150 mg once every 3 months by intramuscular injection. Of 39 transfeminine people who received MPA, 26 (67%) self-reported improved breast development. No further details were provided, but measurement of breast development was presumably subjective and anecdotal. Igo & Visram (2021) studied addition of progesterone to hormone therapy in transfeminine people. Progesterone was provided as 100 mg micronized progesterone (probably oral) and was prescribed when progesterone was specifically requested by the patient or when the patient expressed dissatisfaction with feminization and/or breast development. Of 190 individuals, 51 (26.8%) received progesterone therapy. Treatment with progesterone on average began after 12.7 months of estradiol therapy, and the mean total follow-up time was 14.3 months of hormone therapy. Of those who received progesterone, only 6 (11.8%) reported benefit to breast development. No further details were provided, but as with other studies, breast development was likely quantified anecdotally via self-report. As breast development does not appear to have been objectively measured or compared to a control group in either Jain, Kwan, & Forcier (2019) or Igo & Visram (2021), the findings of these studies are limitedly informative.
Nolan and colleagues assessed the short-term effects of low-dose oral micronized progesterone on breast development in transfeminine people on stable hormone therapy in a prospective controlled study (Nolan et al., 2022a; Nolan et al., 2022b). Progesterone was given at a dose of 100 mg/day for 3 months to 23 transfeminine people and findings were compared to those of a control group of 19 transfeminine people. Breast development was measured using self-reported Tanner stage, with participants provided photographs of different Tanner stages to self-select from. At the end of the 3 months, Tanner stage was not significantly different between groups (mean 3.5, 95% CI 3.2–3.7 for progesterone vs. mean 3.6, 95% CI 3.3–3.9 for controls; p = 0.42). A limitation of this study is that oral progesterone has very low bioavailability and 100 mg/day oral progesterone achieves very low progesterone levels that are well below normal luteal-phase progesterone levels (Aly, 2018). As such, progestogenic exposure in this study, and notably also in Igo & Visram (2021), is likely to have been inadequate. Besides the issue of progestogenic strength, the very short duration of the study (3 months) and the reliance on self-reported subjective Tanner stages (as opposed to more objective physical breast measurements) are also major methodological limitations. In any case, this study is of noticeably higher quality than previous studies, and is notably likely to continue and report further follow-up at later points in the future.
Aside from the above studies, a variety of other studies have also reported breast development with estrogen and CPA in transfeminine people, often with objective physical measurements (e.g., breast volume, breast–chest difference, breast cup size, breast hemicircumference), but have lacked comparison groups and so have not been discussed in the present section. These studies are instead briefly discussed elsewhere (see the section below). In any case, to briefly summarize the findings, breast development in transfeminine people has unfortunately usually been poor in these studies.
The findings from the preceding studies in transfeminine people are of very low-quality due to methodological limitations, including lack of control groups, lack of randomization, reliance on poor measures of breast development (e.g., subjective and self-report), short treatment durations, and small sample sizes, among others. This is likely to explain the conflicting results of the studies. More research is still needed to assess the influence of progestogens on breast development in transfeminine people. A 2014 review on hormone therapy in transfeminine people summarizes the state of research on progestogens and breast development in transfeminine people (Wierckx, Gooren, & T’Sjoen, 2014):
Our knowledge concerning the natural history and effects of different cross-sex hormone therapies on breast development in trans women is extremely sparse and based on low quality of evidence. Current evidence does not provide evidence that progestogens enhance breast development in trans women. Neither do they prove the absence of such an effect. This prevents us from drawing any firm conclusion at this moment and demonstrates the need for further research to clarify these important clinical questions.
Progesterone and its Role in Breast Development During Normal Female Puberty
The role of progesterone in breast development and its possible usefulness for helping with breast development in transfeminine hormone therapy can be informed by the normal biological circumstances of puberty in cisgender females. Puberty in cisgender girls takes an average of 3 to 4 years, though with a possible range of about 2 to 6 years in most cases. Progesterone essentially doesn’t appear during puberty until ovulatorymenstrual cycles begin. Menarche, the onset of menstruation and hence menstrual cycling, occurs on average at Tanner breast stage 4, although it occurs at Tanner breast stage 3 or Tanner breast stage 5 (complete breast development) in significant subsets of girls (Marshall & Tanner, 1969; Marshall, 1978; Hillard, 2007). Hence, a significant portion of girls reach Tanner breast stage 5 (complete breast development) before experiencing menarche or any progesterone production. This indicates that progesterone is not essential to reach Tanner breast stage 5, at least for a subset of girls. Tanner breast stage 4 is on average about 2.5 years into breast development, while breast development as a whole takes on average about 3.5 years. As such, the appearance of progesterone in normal female puberty is a relatively late event (Marshall, 1978; Begley, Firth, & Hoult, 1980; Drife, 1986).
Taken together, production of progesterone is a late event in normal female puberty, and even once it does begin, exposure to progesterone is low and sporadic until well after puberty has completed. Moreover, a subset of girls complete breast development before progesterone production starts. These facts call into some question the role of progesterone in breast development in female puberty.
Progesterone and Mammary Development in Animals
Pubertal Mammary Development
Knockout of the progesterone receptor in female rice results in complete infertility and severely compromised ovarian, uterine, and reproductive–behavioral functions (Lydon et al., 1995; Ismail et al., 2003). Conversely however, pubertal ductal mammary development in progesterone receptor knockout mice is normal and in fact morphologically indistinguishable from that of regular mice (Ismail et al., 2003). This is in contrast to the case of estrogen receptor alpha knockout mice, in which pubertal mammary development is abolished (Ismail et al., 2003; Wiki; Wiki). However, subsequent studies revealed that mammary ductal development during puberty is in fact delayed though eventually normal in female mice that have loss of progesterone production, loss of the progesterone receptor, or progesterone receptor antagonism (Shi, Lydon, & Zhang, 2004). In other words, progesterone stimulates and accelerates ductal development during puberty and hence appears to have a significant physiological role in early mammary development during puberty. The stimulation of ductal development by progesterone appears to be mediated by induction of the expression of amphiregulin in mammary ducts and terminal end buds (Kariagina et al., 2010; Aupperlee et al., 2013). This growth factor is an agonist of the epidermal growth factor receptor (EGFR), and is also notably the major growth factor that estrogen induces the expression of to mediate mammary gland development during puberty (Ciarloni, Mallepell, & Brisken, 2007; LaMarca & Rosen, 2007; McBryan et al., 2008). However, as mammary ductal development during puberty without progesterone is delayed but eventually completely normal, it has been stated that progesterone is dispensable for pubertal mammary gland development in mice (Ismail et al., 2003).
Breast Composition and Lobuloalveolar Content
Progestogens are involved primarily in lobuloalveolar development of the breasts. This type of breast development is necessary for lactation and breastfeeding and occurs mainly during pregnancy. The breasts are made up of two main types of tissue: (1) epithelial tissue (the actual internal mammary glandular tissue, including ducts and alveoli or lobules); and (2) stromal tissue (a mixture of connective tissue and adipose (fat) tissue). Lobuloalveolar development refers to growth and maturation of the alveoli and lobules and hence is a form of epithelial or glandular development. In women who are not pregnant or lactating, only about 5 to 20% of the volume of the breasts on average is composed of epithelial tissue, while the remaining 80 to 95% is composed of stromal tissue (Hutson, Cowen, & Bird, 1985; Drife, 1986; Bryant et al., 1998; Gertig et al., 1999; Howard & Gusterson, 2000; Cline & Wood, 2006; Lorincz & Sukumar, 2006; Wilson et al., 2006; Xu et al., 2010; Pandya & Moore, 2011; Hagisawa, Shimura, & Arisaka, 2012; Sandhu et al., 2016; Rosenfield, Cooke, & Radovick, 2021). More specifically, one study found that about 10 to 20% is epithelial tissue, about 10 to 35% is fat tissue, and about 60 to 80% is connective tissue in reproductive-age women (Hutson, Cowen, & Bird, 1985; Wilson et al., 2006). Similarly, in women with macromastia (breast hypertrophy), only a small proportion of the breasts is glandular tissue (e.g., 1–7%) (Bames, 1948; Cruz-Korchin et al., 2001). During pregnancy and lactation however, the breasts undergo dramatic changes, and epithelial tissue comes to make up a much greater proportion of the breasts (Ramsay et al., 2005; Bland, Copeland, & Klimberg, 2018). In fact, sources state that glandular tissue comprises a majority of the breast during pregnancy and lactation, with one study of lactating women finding that the breasts were composed 63% (range 46–83%) of glandular tissue (Ramsay et al., 2005). In any case, under more normal physiological circumstances and progesterone exposure, the contribution of lobuloalveolar tissue to the size of the breasts is quite small. In relation to this, the significance of progestogen-mediated breast lobuloalveolar growth in terms of breast size is unclear but seemingly questionable (Wierkcx, Gooren, & T’Sjoen, 2014).
Complete Androgen Insensitivity Syndrome, Progesterone, and Breast Development
It has been claimed that progesterone helps to move transfeminine people and cisgender females from Tanner stage 4 to 5 breast development and that it helps to round out the breasts at this time (e.g., Prior, 2011; Prior, 2019a; Prior, 2020). It has also been claimed in the online transgender community that cisgender women with complete androgen insensitivity syndrome (CAIS), an experiment of nature of women who lack progesterone, are stuck at Tanner stage 4 breast development and have “cone-shaped” breasts due to their absence of progesterone. In actuality however, there is no good evidence at this time that progesterone is required for normal pubertal breast development, that it is needed to reach Tanner stage 5, or that it helps to round out the breasts. Moreover, such claims are contradicted by significant available literature and evidence, including notably on CAIS women themselves.
Women with CAIS are individuals who have a 46,XY karyotype (i.e. are genetically “male”), testes, and who would otherwise have physically developed as males, but did not because they have a mutation in the gene encoding the androgen receptor which makes them completely insensitive to the effects of androgens. CAIS women have a male-typical hormonal profile, generated by their testes, including high male-range levels of testosterone, low female-range but nonetheless significant estradiol levels, and no significant progesterone production with very low progesterone levels. Instead of developing physically as males however, CAIS women are perfectly phenotypically female, with a normal female body, vagina, and breasts (Wiki; Photo). Their testosterone has been unable to masculinize them, while their estradiol, unopposed by androgens, is able to feminize them. The internal reproductive system in CAIS women is essentially that of an underdeveloped male, with testes instead of ovaries, and no uterus or fallopian tubes. The vagina is often short and is blind-ending with no cervix, which is related to the lack of a uterus.
Women with CAIS have breast development that is described throughout the literature as “good”, “excellent”, “normal”, “full”, “complete”, “well-developed”, “generous”, “typically above-average”, “large”, and even “voluptuous” (Morris, 1953; Hertz et al., 1966; Valentine, 1969; Adams et al., 1970; Polani, 1970; Weisberg, Malkasian, & Pratt, 1970; Dewhurst, 1971; Perez-Palacios & Jaffe, 1972; Glenn, 1976; Dewhurst & Spence, 1977; Rutgers & Scully, 1991; Patterson, McPhaul, & Hughes, 1994; Quigley et al., 1995; McPhaul, 2002; Galani et al., 2008; Oakes et al., 2008; Tiefenbacher & Daxenbichler, 2008; Barbieri, 2017). The gynecologist, John McLean Morris, who reviewed and summarized all of the existing scientific literature on CAIS women in 1953 (including 82 cases) and gave their condition the since-abandoned name “testicular feminization”, described their breasts as “unusually large” and “jumbo-sized” (Morris, 1953; Quigley et al., 1995). He additionally said in his famous 1953 review that they had “normal female breasts, often with a tendency to be overdeveloped” (Morris, 1953). In actuality however, some CAIS women have large breasts, while some have small breasts (Wisniewski et al., 2000), and we have no clear data that their breasts are actually larger on average. The variation in breast growth in CAIS women parallels the same large variation in breast size between individuals that is seen in natal women in general. Here is a collection of photos of CAIS women and their breast development from published case reports and reviews throughout the literature. As can be seen from these photos, breast development in CAIS women is normal and excellent, although subject to considerable variation between individuals in terms of breast size and shape as in women in general.
CAIS women have never been described as having “cone-shaped”, “pointy”, or otherwise abnormal breasts. The only exception is that they are often said to have “juvenile”—or relatively “small” and “pale”—areolas/nipples (e.g., Photo) (e.g., Morris, 1953; Morris & Mahesh, 1963; Khoo & Mackay, 1972; Perez-Palacios & Jaffe, 1972; Dewhurst & Spence, 1977; many others). This is probably because estradiol levels in CAIS women are only about 35 pg/mL on average (Table). This is relevant as estrogens dose-dependently induce nipple and areolar enlargement and pigmentation (Davis et al., 1945; Kennedy & Nathanson, 1953). Hence, higher estrogen levels may be necessary for full adult-like nipple and areolar maturation.
Individuals with complete [androgen insensitivity syndrome (AIS)] have excellent feminization at puberty, with normal or augmented breast development, and clear, smooth, acne-free complexions. Feminization of the breasts and body contours occurs in response to estrogen (produced mainly by testicular and, to a lesser extent, peripheral aromatization of androgens) that is unopposed by the effects of androgens. […] Breast development, ranging from mild gynecomastia to abundant Tanner stage V female breasts, can occur with all grades of AIS, tending to be more pronounced with the more severe grades.
By “more severe grades”, they mean CAIS, the complete form of the syndrome, as opposed to the incomplete forms of androgen insensitivity syndrome (AIS), including the partial and mild presentations (Quigley, 1988). The condition is a spectrum, and those with CAIS, the most “severe” grade, are the only ones who are completely insensitive to the androgen receptor-mediated actions of androgens and who have a fully feminized body. Even individuals with partial androgen insensitivity syndrome (PAIS) likewise have substantial breast development however (e.g., Saito et al., 2014; Lee et al., 2015).
As already touched on, CAIS women are notable because they have very low and negligible levels of progesterone (<2 ng/mL) due to their testes and lack of progesterone production (Table; Barbieri, 2017). CAIS women, perhaps more convincingly than any other evidence available at this time, suggest that progesterone is not needed for normal and complete breast development (Barbieri, 2017):
A genetic experiment of nature, androgen insensitivity syndrome, provides a clinical example of the important interplay between estrogens and androgens in the regulation of breast growth.38 In androgen insensitivity due to mutations in the androgen receptor (AR), genetic males (46,XY) do not have a fully functional AR. Testosterone is produced by the testis, but target tissues are not capable of responding to the high levels of circulating androgens. In this syndrome, circulating estradiol concentration is in the range of 50 pg/mL, comparable to early follicular-phase levels observed in women. Breast volume in individuals with androgen insensitivity is typically above average. This suggests that, in the complete absence of androgen inhibition, modest levels of estradiol are capable of stimulating significant breast growth. Progesterone levels are low in individuals with loss of the AR. This suggests that breast volume is not absolutely dependent on progesterone stimulation.
Despite their often large breasts, CAIS women are said to have relatively little breast glandular tissue (as opposed to fat and connective tissue) and minimal lobuloalveolar development (Morris, 1953; Morris & Mahesh, 1963; Simmer, Pion, & Dignam, 1965; McMillan, 1966; Perez-Palacios & Jaffe, 1972; Dewhurst & Spence, 1977; Shapiro, 1982). This is potentially in accordance with their lack of progesterone, as progesterone is involved in lobuloalveolar maturation. It is notable that in women in general, the breasts are mostly composed of stromal fat and connective tissue (~80–90%), rather than glandular tissue (10–20%) (Wiki). Additionally, when lobuloalveolar development occurs, for instance during pregnancy, it replaces stromal tissue (Alex, Bhandary, & McGuire, 2020). Hence, greater glandular or lobuloalveolar formation in the breasts may not necessarily translate to greater breast size, as seems apparent in CAIS women. Also in spite of their well-developed breasts, breast cancer has never been reported in CAIS women (Aly, 2020a; Aly, 2020b). This may be related to factors like their lack of progesterone and lobuloalveolar maturation and/or their absence of a second X chromosome (Aly, 2020a; Aly, 2020b).
Early Progestogen Exposure and the Possibility of Suboptimal Breast Development
However, species differences in mammary gland development and hormonal responses exist, and no hard data or evidence has been published to substantiate the claims of the clinical publications. As such, it is unknown whether suboptimal breast development could occur with early progestogen exposure in humans. Moreover, if it does occur in humans, it is unknown what level of progestogen exposure would be required to produce it. In any case, a few other areas of research interest are also relevant to the issue of progestogens possibly resulting in worse breast development, including the antiestrogenic effects of progestogens in the breasts, clinical studies of breast development with estrogen and CPA (a very strong progestogen) in transfeminine people, case reports of progestogens for treatment of macromastia in cisgender females, and theoretical suggestions of poor breast development in cisgender girls with 17α-hydroxylase/17,20-lyase deficiency being related to high progesterone exposure. These topics will be discussed in the subsequent sections.
Antiestrogenic Effects of Progestogens in the Breasts
Breast Development with Cyproterone Acetate in Transfeminine People
The possibility of suboptimal breast development with progestogens is of particular relevance to CPA. This is because CPA is a potent progestogen in addition to antiandrogen and is used in transfeminine people at doses that result in very strong progestogenic exposure (Aly, 2019). Studies using estrogen plus CPA in transfeminine people have generally reported poor breast development (Kanhai et al., 1999; Sosa et al., 2003; Sosa et al., 2004; Wierckx et al., 2014; Fisher et al., 2016; Tack et al., 2017; de Blok et al., 2018; Reisman, Goldstein, & Safer, 2019; de Blok et al., 2020; Meyer et al., 2020). However, transfeminine people could simply have poor breast development in general without this necessarily being related to CPA or progestogen exposure. Indeed, a study in transfeminine people who underwent pubertal suppression in adolescence presumably with GnRH agonists and then hormone therapy showed similarly poor breast development as in adults (Boogers et al., 2022). A randomized controlled trial of estradiol plus spironolactone versus estradiol plus CPA assessing breast development in transfeminine people is underway in Australia and may provide more insight on this issue (ANZCTR).
Progestogens in the Treatment of Breast Hypertrophy
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-Clinical Guidelines with Information on Transfeminine Hormone Therapy - Transfeminine Science
Clinical Guidelines with Information on Transfeminine Hormone Therapy
By Aly | First published November 20, 2020 | Last modified May 23, 2023
Abstract / TL;DR
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.
Introduction
Clinicians use clinical practice guidelines (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. Literature reviews can serve a similar function. However, clinical practice guidelines are generally more substantial and are more founded in evidence-based medicine. 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.
There are many clinical practice guidelines for transgender medicine (for review, Deutsch, Radix, & Reisner, 2016; Radix, 2019; Radix, 2019; UpToDate; Bewley et al., 2021; Dahlen et al., 2021; Ziegler, Carroll, & Charnish, 2021). 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.
Fisher et al. / Italian Society of Gender, Identity and Health (SIGIS) / Italian Society of Andrology and Sexual Medicine (SIAMS) / Italian Society of Endocrinology (SIE)
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]
Vacharathit et al. / Center of Excellence in Transgender Health / Chulalongkorn University [Thailand]
2021
Online document
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Oliphant, J., Veale, J., Macdonald, J., Carroll, R., Johnson, R., Harte, M., Stephenson, C. & Bullock, J. (2018). Guidelines for Gender Affirming Healthcare for Gender Diverse and Transgender Children, Young People and Adults in Aotearoa New Zealand. Waikato: Transgender Health Research Lab/University of Waikato. [URL] [PDF]
Pan American Health Organization, John Snow, Inc., World Professional Association for Transgender Health, et al. (2014). Blueprint for the Provision of Comprehensive Care for Trans Persons andTheir Communities in the Caribbean and Other Anglophone Countries. Arlington: John Snow, Inc. [Alt] [PDF]
Radix, A. (2019). Hormone Therapy for Transgender Adults. The Urologic Clinics of North America, 46(4), 467–473. [DOI:10.1016/j.ucl.2019.07.001]
Radix, A. (2019). Primary Care of Transgender Adults. In Poretsky, L., & Hembree, W. C. (Eds.). Transgender Medicine: A Multidisciplinary Approach(Contemporary Endocrinology) (pp. 51–67). Cham: Humana Press. [DOI:10.1007/978-3-030-05683-4_4]
Sappho for Equality. (2019). A Good Practice Guide to Gender-Affirmative Care. Kolkata: Sappho for Equality. [PDF]
Seal, L. J. (2016). Information About Hormonal Treatment for Trans Women. London: West London Mental Health NHS Trust/West London NHS Trust. [PDF]
Seal, L., & Barrett, J. (2017). Shared Care Prescribing Guidance for Treatment of Gender Dysphoria in Transwomen (Male to Female Transsexuals). London: West London Mental Health NHS Trust/West London NHS Trust. [PDF]
Sullivan, C., & Dean, J. (2015). Prescribing Guideline. Pharmacological Treatment of Gender Dysphoria. Devon: Devon Partnership NHS Trust. [PDF]
Tangpricha, V., & Safer, J. D. (2020). Transgender Women: Evaluation and Management. UpToDate. [URL] [PDF]
Telfer, M. M., Tollit, M. A., Pace, C. C., & Pang, K. C. (2020). Australian Standards of Care and Treatment Guidelines for Trans and Gender Diverse Children and Adolescents Version 1.2. Melbourne: The Royal Children’s Hospital. [PDF]
Thomas, C. (2015). Guidelines for the Use of Feminising Hormone Therapy. Information for Primary Care. Sunderland: City Hospitals Sunderland NHS Trust. [PDF]
Thompson, J., Hopwood, R. A., deNormand, S., & Cavanaugh, T. (2021). Medical Care of Trans and Gender Diverse Adults. Boston: Fenway Health. [URL] [PDF]
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., & de Vries, E. (2021). Southern African HIV Clinicians’ Society gender-affirming healthcare guideline for South Africa. Southern African Journal of HIV Medicine, 22(1), a1299. [DOI:10.4102/sajhivmed.v22i1.1299] [PDF]
Trans Care BC. (2021). Gender-affirming Care for Trans, Two-Spirit, and Gender Diverse Patients in BC: A Primary Care Toolkit. Vancouver: Provincial Health Services Authority/Trans Care BC. [URL] [PDF]
T’Sjoen, G., Arcelus, J., De Vries, A. L., Fisher, A. D., Nieder, T. O., Özer, M., & 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”. The Journal of Sexual Medicine, 17(4), 570–584. [DOI:10.1016/j.jsxm.2020.01.012]
UpToDate. (2021). Society Guideline Links: Transgender Health. UpToDate. [URL]
Vacharathit, V., Ratanalert, W., & Samitpol, K. (2021). The Thai Handbook of Transgender Healthcare Services. Thailand: Center of Excellence in Transgender Health/Chulalongkorn University. [URL] [PDF]
Wilczynski, C., & Emanuele, M. A. (2014). Treating a transgender patient: overview of the guidelines. Postgraduate Medicine, 126(7), 121–128. [DOI:10.3810/pgm.2014.11.2840]
Wylie, K., Barrett, J., Besser, M., Bouman, W. P., Bridgman, M., Clayton, A., Green, R., Hamilton, M., Hines, M., Ivbijaro, G., Khoosal, D., Lawrence, A., Lenihan, P., Loewenthal, D., Ralph, D., Reed, T., Stevens, J., Terry, T., Thom, B., Thornton, J., Walsh, D., & Ward, D. (2014). Good Practice Guidelines for the Assessment and Treatment of Adults with Gender Dysphoria. Sexual and Relationship Therapy, 29(2), 154–214. [DOI:10.1080/14681994.2014.883353]
Ziegler, E., Carroll, B., & Charnish, E. (2021). Review and Analysis of International Transgender Adult Primary Care Guidelines. Transgender Health, 6(3), 139–147. [DOI:10.1089/trgh.2020.0043]
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+Clinical Guidelines with Information on Transfeminine Hormone Therapy - Transfeminine Science
Clinical Guidelines with Information on Transfeminine Hormone Therapy
By Aly | First published November 20, 2020 | Last modified March 21, 2024
Abstract / TL;DR
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.
Introduction
Clinicians use clinical practice guidelines (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. Literature reviews can serve a similar function. However, clinical practice guidelines are generally more substantial and are more founded in evidence-based medicine. 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.
There are many clinical practice guidelines for transgender medicine (for review, Deutsch, Radix, & Reisner, 2016; Radix, 2019; Radix, 2019; UpToDate; Bewley et al., 2021; Dahlen et al., 2021; Ziegler, Carroll, & Charnish, 2021). 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.
Fisher et al. / Italian Society of Gender, Identity and Health (SIGIS) / Italian Society of Andrology and Sexual Medicine (SIAMS) / Italian Society of Endocrinology (SIE)
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]
Vacharathit et al. / Center of Excellence in Transgender Health / Chulalongkorn University [Thailand]
2021
Online document
References
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Deutsch, M. B., Radix, A., & Reisner, S. (2016). What’s in a Guideline? Developing Collaborative and Sound Research Designs that Substantiate Best Practice Recommendations for Transgender Health Care. AMA Journal of Ethics, 18(11), 1098–1106. [DOI:10.1001/journalofethics.2016.18.11.stas1-1611]
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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., & Lombardo, F. (2021). SIGIS–SIAMS–SIE position statement of gender affirming hormonal treatment in transgender and non-binary people. Journal of Endocrinological Investigation, 45(3), 657–673. [DOI:10.1007/s40618-021-01694-2]
Godano, A., Maggi, M., Jannini, E., Meriggiola, M. C., Ghigo, E., Todarello, O., Lenzi, A., & Manieri, C. (2009). SIAMS-ONIG Consensus on Hormonal Treatment in Gender Identity Disorders. Journal of Endocrinological Investigation, 32(10), 857–864. [DOI:10.1007/BF03345758]
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Hembree, W. C., Cohen-Kettenis, P. T., Gooren, L., Hannema, S. E., Meyer, W. J., Murad, M. H., Rosenthal, S. M., Safer, J. D., Tangpricha, V., & T’Sjoen, G. G. (2017). Endocrine Treatment of Gender-Dysphoric/Gender-Incongruent Persons: An Endocrine Society Clinical Practice Guideline. The Journal of Clinical Endocrinology and Metabolism, 102(11), 3869–3903. [DOI:10.1210/jc.2017-01658] [PDF]
International Planned Parenthood Federation (IPPF). (2015). IMAP Statement on Hormone Therapy for Transgender People. International Medical Advisory Panel/International Planned Parenthood Federation. [URL] [PDF]
Latkin, S., & Coakley, G. (2017). [Transgender Women] Prescribing Guidelines. Doncaster/Bassetlaw: Doncaster and Bassetlaw Teaching Hospitals NHS Foundation Trust. [PDF]
Majumder, A., Chatterjee, S., Maji, D., Roychaudhuri, S., Ghosh, S., Selvan, C., George, B., Kalra, P., Maisnam, I., & Sanyal, D. (2020). IDEA Group Consensus Statement on Medical Management of Adult Gender Incongruent Individuals Seeking Gender Reaffirmation as Female. Indian Journal of Endocrinology and Metabolism, 24(2), 128–135. [DOI:10.4103/ijem.IJEM_593_19]
Oliphant, J., Veale, J., Macdonald, J., Carroll, R., Johnson, R., Harte, M., Stephenson, C. & Bullock, J. (2018). Guidelines for Gender Affirming Healthcare for Gender Diverse and Transgender Children, Young People and Adults in Aotearoa New Zealand. Waikato: Transgender Health Research Lab/University of Waikato. [URL] [PDF]
Pan American Health Organization, John Snow, Inc., World Professional Association for Transgender Health, et al. (2014). Blueprint for the Provision of Comprehensive Care for Trans Persons andTheir Communities in the Caribbean and Other Anglophone Countries. Arlington: John Snow, Inc. [Alt] [PDF]
Radix, A. (2019). Hormone Therapy for Transgender Adults. The Urologic Clinics of North America, 46(4), 467–473. [DOI:10.1016/j.ucl.2019.07.001]
Radix, A. (2019). Primary Care of Transgender Adults. In Poretsky, L., & Hembree, W. C. (Eds.). Transgender Medicine: A Multidisciplinary Approach(Contemporary Endocrinology) (pp. 51–67). Cham: Humana Press. [DOI:10.1007/978-3-030-05683-4_4]
Sappho for Equality. (2019). A Good Practice Guide to Gender-Affirmative Care. Kolkata: Sappho for Equality. [PDF]
Seal, L. J. (2016). Information About Hormonal Treatment for Trans Women. London: West London Mental Health NHS Trust/West London NHS Trust. [PDF]
Seal, L., & Barrett, J. (2017). Shared Care Prescribing Guidance for Treatment of Gender Dysphoria in Transwomen (Male to Female Transsexuals). London: West London Mental Health NHS Trust/West London NHS Trust. [PDF]
Sullivan, C., & Dean, J. (2015). Prescribing Guideline. Pharmacological Treatment of Gender Dysphoria. Devon: Devon Partnership NHS Trust. [PDF]
Tangpricha, V., & Safer, J. D. (2020). Transgender Women: Evaluation and Management. UpToDate. [URL] [PDF]
Telfer, M. M., Tollit, M. A., Pace, C. C., & Pang, K. C. (2020). Australian Standards of Care and Treatment Guidelines for Trans and Gender Diverse Children and Adolescents Version 1.2. Melbourne: The Royal Children’s Hospital. [PDF]
Thomas, C. (2015). Guidelines for the Use of Feminising Hormone Therapy. Information for Primary Care. Sunderland: City Hospitals Sunderland NHS Trust. [PDF]
Thompson, J., Hopwood, R. A., deNormand, S., & Cavanaugh, T. (2021). Medical Care of Trans and Gender Diverse Adults. Boston: Fenway Health. [URL] [PDF]
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., & de Vries, E. (2021). Southern African HIV Clinicians’ Society gender-affirming healthcare guideline for South Africa. Southern African Journal of HIV Medicine, 22(1), a1299. [DOI:10.4102/sajhivmed.v22i1.1299] [PDF]
Trans Care BC. (2021). Gender-affirming Care for Trans, Two-Spirit, and Gender Diverse Patients in BC: A Primary Care Toolkit. Vancouver: Provincial Health Services Authority/Trans Care BC. [URL] [PDF]
T’Sjoen, G., Arcelus, J., De Vries, A. L., Fisher, A. D., Nieder, T. O., Özer, M., & 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”. The Journal of Sexual Medicine, 17(4), 570–584. [DOI:10.1016/j.jsxm.2020.01.012]
UpToDate. (2021). Society Guideline Links: Transgender Health. UpToDate. [URL]
Vacharathit, V., Ratanalert, W., & Samitpol, K. (2021). The Thai Handbook of Transgender Healthcare Services. Thailand: Center of Excellence in Transgender Health/Chulalongkorn University. [URL] [PDF]
Wilczynski, C., & Emanuele, M. A. (2014). Treating a transgender patient: overview of the guidelines. Postgraduate Medicine, 126(7), 121–128. [DOI:10.3810/pgm.2014.11.2840]
Wylie, K., Barrett, J., Besser, M., Bouman, W. P., Bridgman, M., Clayton, A., Green, R., Hamilton, M., Hines, M., Ivbijaro, G., Khoosal, D., Lawrence, A., Lenihan, P., Loewenthal, D., Ralph, D., Reed, T., Stevens, J., Terry, T., Thom, B., Thornton, J., Walsh, D., & Ward, D. (2014). Good Practice Guidelines for the Assessment and Treatment of Adults with Gender Dysphoria. Sexual and Relationship Therapy, 29(2), 154–214. [DOI:10.1080/14681994.2014.883353]
Ziegler, E., Carroll, B., & Charnish, E. (2021). Review and Analysis of International Transgender Adult Primary Care Guidelines. Transgender Health, 6(3), 139–147. [DOI:10.1089/trgh.2020.0043]
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-Published Case Reports of Lactation and/or Breastfeeding in Transfeminine People - Transfeminine Science
Published Case Reports of Lactation and/or Breastfeeding in Transfeminine People
By Aly | First published March 26, 2019 | Last modified April 7, 2023
Abstract / TL;DR
A number of case reports of hormonally induced lactation and breastfeeding in transfeminine people have been published. The earliest report of lactation in a transfeminine person was in the 1950s and the earliest report of breastfeeding was in the 1980s. Starting in 2019, more case reports have been published in the modern scientific literature. Unpublished cases also exist (e.g., that of Dr. Christine McGinn), and lactation has been induced or occurred in cisgender men as well. Lactation may be induced in transfeminine people with the use estrogens, progestogens, and/or prolactin releasers. Reviews discussing lactation induction in transfeminine people have recently been published.
Introduction
Last year, a case report of lactation and breastfeeding in a transgender woman was published:
Reisman, T., & Goldstein, Z. (2018). Case report: Induced lactation in a transgender woman. Transgender Health, 3(1), 24–26. [DOI:10.1089/trgh.2017.0044]
In the paper, the authors state the following:
We believe that this is the first formal report in the medical literature of induced lactation in a transgender woman.
However, this actually wasn’t the first case report of lactation and/or breastfeeding in a transfeminine person in the literature. There are various previous published cases dating back as far as the 1950s. These instances are provided below in the format of sources and excerpts.
Published Case Reports
Foss (1956)
Foss, G. L. (1956). Abnormalities of form and function of the human breast. Journal of Endocrinology, 14(4 Suppl) [Proceedings of the Society for Endocrinology: Fifty-Fourth Meeting. Symposium on Selected Aspects of the Practice of Hormone Administration in Animals and Man], vi–vii. [Google Scholar] [Google Books] [URL] [PDF]:
Based on the theories of lactogenesis and stimulated by the success of Lyons, Li, Johnson & Cole [1955], who succeeded in producing lactation in male rats, an attempt was made to initiate lactogenesis in a male transvestist. Six years ago this patient had been given oestrogens. Both testes and penis were then removed and an artificial vagina was constructed by plastic surgery. The patient was implanted with 500 mg oestradiol in September 1954, and 600 mg in July 1955. The breasts were then developed more intensively with daily injections of oestradiol dipropionate and progesterone for 6 weeks. Immediately following withdrawal of this treatment, prolactin 22·9 mg was injected daily for 3 days without effect. After a second month on oestradiol and progesterone daily, combined injections of prolactin and somatotrophin were given for 4 days and suction was applied by a breast pump—four times daily. On the 4th and 5th days a few drops of colostrum were expressed from the right nipple.
Tindal & McNaught (1958)
Tindal, J. S., & McNaught, M. L. (1958). Hormonal Factors in Breast Development and Milk Secretion. In Gardiner-Hill, H. (Ed.). Modern Trends in Endocrinology, Volume 1 (pp. 188–211) (Modern Trends). London: Butterworth. [Google Scholar] [Google Books] [OpenLibrary] [WorldCat] [Archive.org]:
Recently, an attempt has been made by Foss (1956) to initiate lactation in a castrated male transvestist. He was given an implant of 500 milligrams of oestradiol, and 10 months later, a further 600 milligrams of oestradiol, followed by daily injections of oestradiol dipropionate and progesterone for 6 weeks. Immediately after withdrawal of this treatment, 22·9 milligrams of prolactin were injected daily for 3 days but without effect. After a second month of treatment with oestradiol and progesterone daily, he was given combined injections of prolactin and somatotrophin for 4 days, suction with a breast-pump being employed 4 times daily. On the fourth and fifth days a few drops of colostrum were expressed from the right nipple. There is a possible application here of modern hormone knowledge to man, and further trials would be of interest.
Experimentally I have been able to induce lactogenesis in a male transvestite whose testes had been removed some years before and whose breasts had been well developed over a long period with stilbestrol and ethisterone.9 In July, 1955, 600 mg. of estradiol was implanted subcutaneously and weekly injections of 50 mg. of progesterone were given for four months. For the next month daily injections of 10 mg. estradiol dipropionate and 50 mg. progesterone were given. These injections were continued for another month, increasing progesterone to 100 mg. daily. Both hormones were then withdrawn, and daily injections of increasing doses of prolactin and somatotropin were given for four days; at the same time, the patient used a breast pump four times daily for 5 minutes on both sides. During this time the mammary veins were visibly enlarged and on the sixth and seventh days 1 to 2 cc. of milky fluid was collected.
Flückiger, Del Pozo, & von Werder (1982)
Flückiger, E., Del Pozo, E., & von Werder, K. (1982). Prolactin: Synthesis, Fate and Actions. In Flückiger, E. W., Del Pozo, E., & von Werder, K. (Eds.). Prolactin: Physiology, Pharmacology, and Clinical Findings (Monographs on Endocrinology, Volume 23) (pp. 1–23). Berlin/Heidelberg: Springer-Verlag. [Google Scholar] [Google Books] [DOI:10.1007/978-3-642-81721-2_1]:
An observation (Wyss and Del Pozo unpublished) in a male transsexual showed that induction of lactation can be similarly achieved in the human male.
Flückiger, E., Del Pozo, E., & von Werder, K. (1982). Nontumoral hyperprolactinemia. In Flückiger, E. W., Del Pozo, E., & von Werder, K. (Eds.). Prolactin: Physiology, Pharmacology, and Clinical Findings (Monographs on Endocrinology, Volume 23) (pp. 102–152). Berlin/Heidelberg: Springer-Verlag. [Google Scholar] [Google Books] [DOI:10.1007/978-3-642-81721-2_4]:
4.3.2 Effect of Hyperprolactinemia in Male Subjects
Although PRL circulates in male blood in appreciable concentrations its physiologic role has not been clarified. The lack of lactational requirements does not preclude that under adequate priming the male mammary gland will respond to a PRL challenge with milk production. Thus, Wyss and del Pozo (unpublished data) found that PRL stimulation with TRH was able to induce milk secretion in a male individual pretreated with estrogens. Certainly, the chronic ingestion of dopamine antagonists or estrogens may lead to sustained hyperprolactinemia, and the same effect can be expected in male subjects on chronic estrogen therapy of prostatic cancer or transsexualism (Frantz 1973; del Pozo, to be published).
Certainly, the prolonged intake of estrogens, in male subjects also, as observed in the treatment of prostatic carcinoma and in transsexuals, can lead to hyperprolactinemia (Frantz 1972b; del Pozo, to be published).
Kozlov, Mel’nichenko, & Golubeva (1985)
Kozlov, G. I., Mel’nichenko, G. A., & Golubeva, I. V. (1985). Случай лактореи у больного мужского пола с транссексуализмом. [Sluchai laktorei u bol’nogo muzhskogo pola s transseksualizmom. / Case of galactorrhea in a transsexual male patient.] Проблемы Эндокринологии [Problemy Èndokrinologii (Moskva) / Problems of Endocrinology (Moscow)], 31(1), 37–38. [ISSN:0375-9660] [Google Scholar 1] [Google Scholar 2] [PubMed] [DOI:10.14341/probl198531137-38] [PDF] [Translation] [Translated]:
The appearance of galactorrhea in men is most often a symptom of pituitary prolactinoma. Combined with gynecomastia and atrophy of the testicles, galactorrhea caused by adenomas of the pituitary gland in men is known as O’Connell syndrome (1).
In recent years, however, cases of galactorrhea have been described in men without radiological or clinical signs of pituitary adenoma (12). Of course, in these cases, the presence of undetected microadenomas of the pituitary gland cannot be excluded, especially since the level of prolactin in these patients is significantly increased (1, 2).
Some medications, especially antipsychotics and estrogen-containing oral contraceptives (7, 10), increase serum levels of prolactin and can lead to the development of galactorrhea.
There is information about the influence of psycho-emotional factors on the lactation process: the possibility of the development (induction) of psychogenic lactation during false pregnancy (3) is known, and, conversely, the possibility of the termination of lactation in nursing mothers after mental stress.
Accumulated clinical observations on the frequent development of depressive states in persistent galactorrhea–amenorrhea syndrome (4), cases of galactorrhea in the mentally ill, even in the absence of neuroleptics (7), as well as experimental observations on the effect of hyperprolactinemia on the behavioral responses of animals (5), require careful study of the relationship of hyperprolactinemia and psycho-emotional factors. In connection with this, we present the following observation.
The patient (P), was born a normal, full-term boy. He remembers well from 6 years. Early development was unremarkable, he did not differ from peers, but loved to play more with girls. He played with dolls and cars. At 10 years of age, there was a desire to wear women’s clothes. From the age of 12 he swam with girls in a shirt and shorts, as he was embarrassed by the lack of breasts. From the age of 14 he changed clothes in his mother’s dress, and only in such clothes “felt like a person”. From the same age in a woman’s dress he went to get acquainted with young men and got pleasure from it. At the age of 15, he came to the firm conviction that he was a girl, began to urinate like a girl, squatting, use lipstick, and put on powdered makeup. He suffered greatly from the presence of “deformities” – male genital organs. At the age of 17, while working as a “nurse” in a hospital, he began to self-inject himself with folliculin (estrogen) and progesterone, which caused the development of the breasts. With pleasure, he did women’s housework, and loved to tinker with children. Having received a passport, he redid it as female, thus resulting in a female civilian gender.
Twice he tried to commit suicide (he took sleeping pills), since he could not bear the duality of his existence. Twice he was treated in psychiatric hospitals about transsexualism, unsuccessfully.
During the examination in IEE and HCG at the age of 20 years, no abnormalities in somatic status were revealed: complex as a man, male genitals, shaved from 17 years of age daily. Erotic dreams were frequent, wherein he played the role of a woman, and denied emissions. The ejaculate was studied (obtained by vibratory massage): volume – 1.4 mL, pH 8.8 (norm 7.6–8.2), sperm count 31 million per 1 mL, mobility 57%, and morphologically normal 69%. Sex chromatin is negative.
At age 22, a course of treatment with cyproterone acetate was conducted at the Institute of Psychiatry of the Ministry of Health of the USSR. Muscle weakness, reduction of sexual hairiness, and appearance of colostrum excretion was noted.
When examined in IEE and HCG at 23 years, the breasts corresponded to the age of 15–16 years (on his own initiative he periodically took estrogens), and colostrum was secreted from the nipples (abundant drops when pressed – galactorrhea (++)). He insisted on castration and amputation of the penis, since, being a “woman”, he was ashamed of not having the appropriate genitals for his sex, which he called “deformities”.
On X-ray of the skull, the shape and size of the sella turcica were normal, but signs of increased intracranial pressure were revealed. On EEG against the background of the general phenomena of irritation, the focus of pathology was recorded in the left parietal lead. Indicators of the functional state of the thyroid gland were in the normal range. In the study of the radioimmunoassay method using standard kits from the Sorin company, some increase in prolactin level of 24 ng/mL was detected in the serum (normal for men is 4–15 ng/mL).
In connection with the repeated suicidal attempts, failure of psychiatric treatment, and in consideration of the fact that the patient has a female civilian sex and performs a female social role, castration and feminizing plastic surgery of the external genitalia were performed for the purpose of social rehabilitation.
Some time after the operation, the patient developed a renewed interest in life. After the surgical and hormonal correction, the patient irresistibly developed maternal instincts. Unmarried, the patient obtained permission for the adoption of a child, simulated pregnancy, and was discharged from the maternity hospital with a son. From the first days after the “birth”, galactorrhea sharply increased, and spontaneous outflow of milk appeared, with galactorrhea (+++). The baby was breastfed up to 6 months of age.
Thus, it can be thought that several factors played a role in the genesis of galactorrhea in this patient:
Increased prolactin levels with estrogen and cyproterone acetate. The hyperprolactic properties of estrogens have long been known; the ability of cyproterone acetate to increase serum prolactin levels was shown by K. Schmidt–Golewizer et al (9).
Increased intracranial pressure, the role of this factor and the genesis of neuroendocrine disorders and, in particular, in the development of galactorrhea was shown by R. Peterson (8).
Our message is the second in the world literature describing galactorrhea in a male patient with transsexualism. The first description of this kind was made in 1983 by R. Flüskiger et al. (6).
This observation demonstrates the independence of the mechanism of lactation development from one’s genetic sex and is alarming with regard to the possibility of drug-induced galactorrhea development in men.
Barber et al. (2004)
Barber, T., Basu, A., Rizvi, K., & Chapman, J. (2004). Normoprolactinaemic galactorrhoea in a male-to-female transsexual. Endocrine Abstracts, 7 [23rd Joint Meeting of the British Endocrine Societies with the European Federation of Endocrine Societies], 271–271. [Google Scholar] [URL]:
Hormonal therapies in the form of oestrogens, anti-androgens and progestogens are often used in the treatment of male-to-female transsexuals. We present the case of a 36 year old phenotypic male with karyotype 46XY who presented with normoprolactinaemic galactorrhoea likely to be related to prior oestrogen administration. He had been self-administering oestrogen and progesterone preparations continuously for 7 years (aged 26 - 33 years) in an attempt to develop female phenotypic characteristics in spite of a heterosexual desire. During this time he developed gynaecomastia with galactorrhoea, increased energy and libido, voice change and an attraction towards both men and women. However due to lack of financial resources to secure a complete gender change, he stopped self-medication with these preparations 3 years ago. Instead he embarked on a regime involving self-administered testosterone in an attempt to reverse the biological changes. After discontinuation of oestrogen the gynaecomastia regressed somewhat, although galactorrhoea continued and worsened with testosterone. Prior to referral he had been treated with dopamine agonists with little improvement in galactorrhoea and gynaecomastia.
Routine biochemistry and haematology are within their reference ranges. Baseline endocrinology is normal: Prolactin 197 milliUnits per litre, LH 2.9 Units per litre, FSH 7.9 Units per litre, free Testosterone 20 nanoMoles per litre, 17 beta-oestradiol less than 110 picoMoles per litre, TSH 0.96 milliUnits per litre and free T4 16.5 picoMoles per litre.
This case illustrates fascinating effects of exogenous oestrogen in the male. The effects of oestrogenic products of aromatised endogenous and briefly also exogenous testosterone acting on oestrogen-primed breast tissue may account for, at least in part, his continuing symptom of normoprolactinaemic galactorrhoea. However two other features do not have any direct explanations: the development of osteopenia during this period, and complete disappearance of vascular migraine, a condition worsened with oestrogens in the female. He is now on Tamoxifen although an opportunity to use the aromatase inhibitor, Anastrozole still remains.
Subsequent Case Reports
Moravek & Pasque (2019)
Moravek, M. B., & Pasque, K. B. (2019). Lactation Can Be Successfully Induced in Transgender Women While Maintaining Gender-Congruent Serum Hormone Levels. Reproductive Sciences, 26(Suppl 1), 136A–136A (abstract no. T-055). [Google Scholar] [DOI:10.1177/1933719119834079]:
Introduction: Transgender women may be interested in breastfeeding their children, but there are no established protocols for lactation induction in this population. The only case report of a lactation induction protocol in a transgender woman significantly lowered her estradiol dose, which would likely result in decreased serum estradiol and increased testosterone levels, with resultant increase in gender dysphoria. Our objective was to induce lactation in a transgender woman without interrupting her gendercongruent hormone profile.
Methods: A 34-year-old transgender woman with a 15-year history of gender-affirming hormone therapy with estradiol and spironolactone presented for lactation induction once her cisgender wife conceived. A modification of the Newman-Goldfarb method for adoptive mothers was used to induce lactation, and serum hormone levels followed.
Results: Baseline labs were obtained (time point 1), then medroxyprogesterone 1.25mg daily was added to her existing hormone regimen of estradiol 6mg daily and spironolactone 100mg twice daily (time point 2). Domperidone 10mg four times daily was initiated 1 month later. Approximately 5 weeks prior to the due date, the patient stopped medroxyprogesterone, decreased estradiol to 2mg daily, and began breast pumping (time point 3). Just prior to the infant’s birth, the patient was pumping 2-3 ounces of breastmilk every 3 hours (time point 4). Spironolactone was decreased to 50mg twice daily. Her son was born at term, via uncomplicated vaginal delivery. The infant was able to breastfeed from both mothers without difficulty, with both mothers pumping when they weren’t actively breastfeeding to maintain supply (time point 5). When the infant was approximately 2 months old, the patient noticed an increase in facial hair growth. Estradiol was increased to 3mg daily and spironolactone increased to 100mg twice daily, with resolution of hair growth and no decrease in milk supply (time point 6). The patient continued to breastfeed on this regimen for >6 months following her son’s birth. Serum hormone levels on the hormone regimens referenced at each time point throughout the patient’s course are displayed in table 1.
Conclusion: Lactation can be successfully induced in transgender women, without a significant decrease in estradiol supplementation. This regimen allows transgender women to breastfeed without developing male secondary sex characteristics incongruent with their gender identity
Table 1 Hormone profile at different time points.
Time Point
Estradiol (pg/mL)
Progesterone (ng/mL)
Testosterone (ng/mL)
Prolactin (ng/mL)
1
114
1.1
0.36
2
130
1.1
0.05
9
3
30
1.3
0.06
152
4
39
5
29
1.4
0.89
184
6
51
0.16
59
Unnithan, Elson, & Shenker (2020)
Unnithan, R., Elson, D. F., & Shenker, Y. (2020). Galactorrhea and Hyperprolactinemia in a Transgender Female. Journal of the Endocrine Society, 4(Suppl 1), A899–A899 (abstract no. SUN-043). [Google Scholar] [PubMed Central] [DOI:10.1210/jendso/bvaa046.1781] [PDF]:
Background: Galactorrhea is a rare manifestation of hyper-prolactinemia in males and post-menopausal females, however the hormonal milieu of the transgender female may increase its incidence
Clinical Case: A 43 year old transgender female presented with three years of bilateral breast discharge. She had chronic, stable headaches and fatigue, but no vision changes or other symptoms. Notably, she had breast augmentation surgery with saline breast implants placed shortly before the galactorrhea commenced. She was on a stable dose of estradiol tablets 1 mg twice daily for six years. On physical exam she had pronounced bilateral breast discharge of a milky quality with nipple compression. Prolactin levels were checked several times and were 40-50 ng/mL, TSH was 2.36 uIU/mL. An MRI showed a left inferior pituitary lesion measuring 6 mm x 3 mm x 5 mm with no mass effect on adjacent structures. Her breast discharge was not bothersome to her, and her pituitary lesion was small. It was unclear whether there was a relationship between her prolactin levels and the lesion seen on MRI, as we expected more pronounced prolactin elevation with a prolactinoma. Instead, given the timing of her symptoms in relation to her breast augmentation surgery, her galactorrhea and hyper-prolactinemia were thought to be the result of nipple irritation related to her breast implants combined with a hyper-estrogenemic state.
Clinical Lessons: In the setting of a prolactin secreting micro-adenoma, galactorrhea in a male is highly unusual. This case highlights the importance of recognizing that the unique medical and surgical characteristics of male to female transgender patients can lead to hyper-prolactinemia and galactorrhea.
Reference: Reisman T, Goldstein Z. Case report: induced lactation in a transgender woman. Transgender Health. 2018;3(1):24-26.
Wamboldt, Shuster, & Sidhu (2021)
Wamboldt, R., Shuster, S., & Sidhu, B. S. (2021). Lactation Induction in a Transgender Woman Wanting to Breastfeed: Case Report. The Journal of Clinical Endocrinology & Metabolism, 106(5), e2047–e2052. [DOI:10.1210/clinem/dgaa976]:
Context: Breastfeeding is known to have many health and wellness benefits to the mother and infant; however, breastfeeding in trans women has been greatly under-researched.
Objective: To review potential methods of lactation induction in trans women wishing to breastfeed and to review the embryological basis for breastfeeding in trans women.
Design: This article summarizes a case of successful lactation in a trans woman, in which milk production was achieved in just over 1 month.
Setting: This patient was followed in an outpatient endocrinology clinic.
Participant: A single trans woman was followed in our endocrinology clinic for a period of 9 months while she took hormone therapy to help with lactation.
Interventions: Readily available lactation induction protocols for nonpuerpural mothers were reviewed and used to guide hormone therapy selection. Daily dose of progesterone was increased from 100 mg to 200 mg daily. The galactogogue domperidone was started at 10 mg 3 times daily and titrated up to effect. She was encouraged to use an electric pump and to increase her frequency of pumping.
Main outcome measure: Lactation induction.
Results: At one month, she had noticed a significant increase in her breast size and fullness. Her milk supply had increased rapidly, and she was producing up to 3 to 5 ounces of milk per day with manual expression alone.
Conclusions: We report the second case in the medical literature to demonstrate successful breastfeeding in a trans woman through use of hormonal augmentation.
Dr. Christine McGinn
Dr. Christine McGinn is a transgender woman and well-known surgeon in Pennsylvania who performs gender-affirming surgeries for transgender people. When she had children with her cisgender female partner, McGinn induced a hormonal pseudopregnancy in herself and her and her partner breastfed their twins together. This was described in the media, including in books and television. McGinn’s case was never formally published as a case report in the scientific literature however.
The Oprah Winfrey Show (2010)
Terry, J. C. (Director), & Winfrey, O. G. (Presenter). (2010 September 29). The Mom Who “Fathered” Her Own Children, Plus the Cast of Modern Family [Television series episode]. The Oprah Winfrey Show (Season 25, Episode 13). Chicago: Harpo Studios. [URL 1] [URL 2] [URL 3]
Trans (2012)
Arnold, C. (Director), Schoen, M. (Producer), RoseWorks (Firm), & Sex Smart Films (Firm). (2012). Trans [DVD] (1:21:32–1:21:55). [WorldCat] [IMDB] [Amazon Prime Video]
Boylan (2014)
Boylan, J. F. (2014). Dr. Christine McGinn. In Boylan, J. F. Stuck in the Middle with You: A Memoir of Parenting in Three Genders (pp. 223–233). New York: Broadway Books. [Google Scholar] [Google Books 1] [Google Books 2] [WorldCat] [PDF]:
Dr. Christine McGinn is a surgeon, a mother of two, a backup flight surgeon for the space shuttle progarm, and a transgender woman. As a man, she saved her sperm before transition; ten years later she used that sperm to have children with her partner Lisa. The two of them are both biological mothers of their son and daughter, and each mother was able to breast-feed the twins. I sat down with Christine at her office in New Hope, Pennsylvania, on a hot summer day in 2011.
CM: […] Then there’s the scientist in me that knows that there is a difference, there is not a binary, but a gender spectrum. There are chemicals that are different in men and women. And when a transgender woman transitions, we are somewhere in the middle. Especialy having gone through a simulated pregnancy, in order to breast-feed, I felt the changes of those hormones. I felt my milk let down when not only my baby would cry, but a baby on TV would cry, and even, ridiculously, when a door would close and make a squeak.
JFB: You had to induce a false pregnancy in order to breast-feed? Tell me how you did that.
CM: As a doctor, I knew it was possible. I followed the protocol that involves simulating pregnancy with hormones. It’s estrogen and progesterone. My simulation pregnancy was over a month before Lisa delivered—with twins, we were expecting them to be born earlier. That entire month I was just pumping nonstop, every two hours. We had a whole freezer full of milk. And you know, the first couple of weeks it was no good, because it had all of the hormones in it. So we only saved, like, the last week or so. But still, it was a freezer full of milk.
Lisa had no idea about the way breast-feeding takes over your life, because this was her first. It was kind of funny that I went through that on my own, first, weeks before she did. And then it took her a couple of days to actually—for her milk to let down.
The children were so small when they were born. They were only five pounds. At first we had to feed them with a syringe. They were breast-feeding as well, but they weren’t latching that great on either of us.
JFB: What was it like when they finally muckled on to you?
CM: Oh, I can’t even put it in words. I really cannot put it in words. It was—I was just—oh.
JFB: Were you amazed? Were you afraid?
CM: It was heaven. I was afraid. I don’t know, it was uncharted territory. Like, I knew the milk was good. Lisa was a little concerned that it would be like skimmed milk, or something, you know. [Laughs] Like—she’s like, “Is it the same stuff?”
JFB: Is it the same milk?
CM: And she was a little dubious about, like, is this really all right? I think that’s totally natural for a mother, to be concerned.
I will just say that there are things snobody thinks about when two women are both breast-feeding. Like, technical stuff that you don’t think about. When you have a mother and a father, the mother decides when the kids get fed. Right? The father doesn’t, really. Right?
But you know, when you have two women who are filled with pregnancy hormones and have that, like, mother-bear attitude about how things should be done… It was really crazy.
JFB: So did that cause serious conflict between you and Lisa?
CM: Totally not serious conflict, because the most important thing are the babies.
Eden finally latched—I breast-fed her more than Luke. Luke was never really good. Lisa hated breast-feeding. Eventually we decided to stop.
I’m putting on my science hat again—when you decide to stop, there are hormonal issues. The strongest emotion a person can feel in their life comes frm oxytocin, which is the love drug.
JFB: Oxytocin?
CM: That’s what’s responsible for babies’ bonding during breastfeeding. So the baby latches on, breast-feeds, your brain just [makes oozing sounds], just like, oozes this gooey love substance, oxytocin. Fathers are proven to have higher oxytocin before the delivery, and just stroking your child’s head. You know, when the baby—when you smell a newborn’s head, it really—that smell, it’s like—
JFB: I just saw a friend’s newborn on Friday, and I was like, [makes sniffing sound]—
CM: My niece said it best. She came in and smell them, and she was five years old at the time, and she’s like, “They smell like cupcakes.” [Laughs] And it’s universal. When you ask me what that’s like, I can’t describe it, you know, and I’m a huge fan of food and cupcakes and chocolate, and so that’s the closest I can come to it—it’s like chocolate. [Laughs]
JFB: So when you stopped breast-feeding, was it a kind of a mourning, a loss?
CM: Yes. Lisa wanted to stop before I did. The problem is, once a baby gets a nipple, a plastic nipple, it gives more milk. And so they don’t have to work as hard.
It’s a unique situation that two breast-feeders in a relationship would experience, but a mother and father would not.
JFB: So did one of you stop breast-feeding before the other?
CM: Yes, Lisa did.
JFB: Lisa stopped. And how much longer did you keep it up?
CM: Not long, because they got the nipple.
They were both so small. We weren’t all that successful at it. We were so worried about their birth weight, and making sure they got enough with the syringes. There were definitely times where, you know, we both would breast-feed and, man, I will never forget that. Like, three ‘clock in the morning, four o’clock in the morning, in the little cocoon, nursing.
The heat of their body, their naked body on your chest. The amazing thing is, it really does kind of hurt when they really get going, you know. And you just… I don’t know how else to describe it. You feel like the life force is just coming out through you. It’s so powerful. It relieves that pain that you have in your breast. It releases that oxytocin, and it’s just—it’s even.
JFB: Did you ever do that thing where you would fall asleep with the children in the bed, and wake up with the children in the bed beside you?
CM: Yeah.
JFB: I loved that. It’s one of my stnogest memories of being a father. Having gotten up in the middle of the night. And they are so small, but such an incredibly powerful feeling, the two of you together surrounding the child. With us, we also had a dog at the bottom of the bed. [Laughs]
CM: And we have two, and that was also very important to me, too. We have miniature pinschers.
JFB: So how many months along did you stop breast-feeding?
CM: Three months. It was really emotionally painful, and I cried a lot. I was really sad.
I was pretty sure we were not going to have any more kids. So I’m like, “This is it.” It was very sad.
JFB: Is there a moment frm the last year and two months where you think, This is what it’s like to be a mother, this is it?
CM: Yes, immediately. It was hot as Hades outside. It was, like, a million degrees. We had just had the kids. It was like, May or June, and my mom was over, and it was, like, we had all this help, initially, because Lisa and I were just not getting any sleep and it was, like, round-the-clock feedings and the kids were small, and Lucas had an apnea monitor that he had to wear all the time, and it was just really hard. And there was a big thunderstorm, and the power went out.
And so, at this point, they weren’t really latching very well, so we both had to pump, and then feed them with the syringes. So Lisa and I are totally, like, engorged with milk. And the power’s out, and the pumps are electric. Right?
JFB: Right.
CM: So there’s no electricity, it’s hot as hell, we’re worried for the kids. Lisa and I are in pain. We’re both leaking. And it was the weirdest, funniest situation. And my mom’s there. She runs out to the store to get batteries, and you know, she’s just beng a mom. She’s getting everything, running around like an angel. And Lisa and I are in pain we’re miserable. When she finally came back, the batteries wouldn’t work on the pumps—something else was wrong. Lisa and I are dying.
And so, here’s the guy part of me… I get the pump that has the backup battery power and the backup car charger. Like, I got all tech on it. [Laughs] I’m out int he car trying to get the car charger to work on the pump in the pouring rain. And it’s ninety-five degrees out. It’s all wet inside, like, the humidity on the windows.
And I’m just trying to get some kind of relief.
And this stupid pump didn’t work that way, either. We come back in and my mom has candles lit.
And then the electricity comes back on. And we all just laugh and pump and breast-feed. And every one of us is in heaven.
Pfeffer (2017)
Pfeffer, C. A. (2017). Trans Partnerships and Families: Historical Traces and Contemporary Representations. In Pfeffer, C. A. Queering Families: The Postmodern Partnerships of Cisgender Women and Transgender Men (pp. 1–34). New York: Oxford University Press. [Google Scholar] [Google Books] [WorldCat] [DOI:10.1093/acprof:oso/9780199908059.003.0001]:
Just 2 years later, Winfrey would feature another interview that elicited many of the same audience reactions. In this 2010 episode, lesbian partners Dr. Christine McGinn and Lisa Bortz beamed with joy as they held their infant twins. Again, audience members’ jaws dropped when it was revealed that beautiful Christine was a male-to-female transsexual who used to be a handsome military officer Chris, and that Lisa had given birth to the couple’s biological children using sperm Chris banked prior to gender confirmation surgeries.10 And it was Winfrey’s chin that nearly hit the floor as she watched video of Christine breastfeeding the couples’ children (the episode is referred to online as “The Mom Who Fathered Her Own Children”).
Other Instances
Published
Estrogen plus cyproterone acetate has been reported to produce pregnancy-like breast changes—specifically, lobuloalveolar development of the breasts—in transfeminine people (Kanhai et al., 2000). Accordingly, galactorrhea (spontaneous or excessive lactation) has been reported as a low-incidence side effect (7–14%) of hormone therapy regimens containing estrogen plus cyproterone acetate in transfeminine people (Gooren, Harmsen-Louman, & van Kessel, 1985; Schlatterer et al., 1998; Bazarra-Castro, 2009). It has also been reported at low incidence (6%) for other hormone therapy regimens (Futterweit, 1980). Sudden cessation of hormone therapy regimens including cyproterone acetate has been reported to result in the onset of lactation as well (Levy, Crown, & Reid, 2003).
Unpublished
Many unpublished reports of lactation and breastfeeding in transfeminine people have been described on the web including at the following pages:
Richards, A. (2003). Lactation and the Transsexual Woman. Second Type Woman. [Updated August 2018] [URL] [PDF]
MacDonald, T. (2013). Trans Women and Breastfeeding: A Personal Interview. Milk Junkies. [URL]
MacDonald, T. (2013). Trans Women and Breastfeeding: The Health Care Provider. Milk Junkies. [URL]
MacDonald, T. (2017). Jenna’s Breastfeeding Journey: Trans Motherhood. Milk Junkies. [URL]
Burns, K. (2018). Yes, Trans Women Can Breastfeed — Here’s How. them. [URL]
Cisgender Men
Induction of lactation has been reported in cisgender men and is noteworthy:
Geschickter (1945)
Geschickter, C. F. (1945). Endocrine Physiology of the Breast. In Geschickter, C. F. Diseases of the Breast: Diagnosis, Pathology, Treatment, 2nd Edition (pp. 42–81). Philadelphia: J.B. Lippincott. [Google Scholar] [Google Books] [OpenLibrary] [WorldCat] [PDF]:
The results obtained indicate that a lactogenic substance in anterior pituitary extracts may cause mammary secretion in nonpregnant women when they have been previously stimulated with estrogenic hormone but true lactation does not occur. Secretion was also obtained in two adult men with gynecomastia after injections of lactogenic hormone.
Huggins (1949)
Huggins, C. (1949). Endocrine substances in the treatment of cancers. Journal of the American Medical Association, 141(11), 750–754. [DOI:10.1001/jama.1949.02910110002002]:
The administration of estrogen in effective amounts causes testicular atrophy and mammary hypertrophy. Growth of the breasts can be so extensive that lactation may be induced, as illustrated in the following case.
W. N., aged 64, had carcinoma of the prostate with osseous metastases, for which he was treated by a permanent suprapubic cystotomy in 1941. Diethylstilbestrol, 20 mg. daily, was given orally for two years beginning September 1942. In September 1944, 25 mg. (500 international units) of prolactin14 was injected daily for five days, and at the end of this time creamy milk could be expressed from both breasts. Orchiectomy and removal of the cystostomy tube were carried out September 6, when administration of estrogen was discontinued; both incisions healed promptly. Since then the patient has been clinically well but has continued to lactate, a large drop of milk being easily expressed from each breast at frequent intervals.
Huggins & Dao (1954)
Huggins, C., & Dao, T. L. (1954). Lactation induced by luteotrophin in women with mammary cancer. Growth of the breast of the human male following estrogenic treatment. Cancer Research, 14(4), 303–306. [Google Scholar] [PubMed] [URL]:
In the observations to be presented luteotrophin [prolactin] was employed as a stimulus for mammary secretion in patients with cancer of the breast, and the results throw new light on the physiology of women bearing this neoplasm. We shall also describe conditions which resulted in the induction of physiologic maturity in the human male, since knowledge of the action of hormones on the human breast is vague.
The effects of luteotrophin on the breast of women post partum has been extensively investigated, but otherwise few observations have been made in the human. Werner (14) administered a crude pituitary extract containing luteotrophin to eight castrate women 21–35 years of age; lactation was not observed, although in one woman “a few drops of colostrum-like fluid” could be expressed from the breasts. Goldzieher (4) treated menstrual disorders in women with luteotrophin, but mammary secretion was not described by him.
PROCEDURE
Luteotrophin,1 dissolved in physiological saline made slight ly alkaline (pH 9) with sodium hydroxide, was injected subcutaneously in daily amounts of 500 International Units; the solutions were freshly prepared, and the injections were continued for 7 days only.
This series comprised 21 female patients who had dis seminated mammary cancer, and all had been subjected to unilateral mastectomy. There were also three men with advanced prostatic carcinoma who had been treated for thera peutic purposes with oral diethylstilbestrol for 20 months, 2, and 6 years, respectively. There were eight persons without mammary or prostatic cancers who served as controls.
In each case of mammary cancer a biopsy of the breast was obtained for histological purposes, the material being stained with Sudan III.3
OBSERVATIONS
Lactation, when it occurred, was never profuse; it varied from a tiny drop to ca. 0.5 cc. from each breast. Clear colostrum was not observed, and the mammary secretion was always milk, as defined above.
Mammary growth in the human male.—Estrogenic substances had been administered to three men in the treatment of disseminated prostate cancer for many months; after luteotrophin injection two lactated and one did not lactate.
W. N. (reported in brief earlier [5]), age 64, had taken diethylstilbestrol, 20 mg/day, orally for 2 years, after which interval sub-areolar button-like masses of mammary tissue could be palpated bilaterally; luteotrophin was then injected for 5 days, and milk was expressed from the breast on the 6th day. Orchiectomy was then performed, and both luteotrophin and estrogenic substances were discontinued. This man continued to lactate for 7 years when the formation of milk gradually ceased.
In the case of A. W., age 62, diethylstilbestrol (5–15 mg/day) had been ingested for 20 months after bilateral orchiectomy; the breasts became slightly enlarged. Luteotrophin was injected, and lactation occurred on the 7th day. A biopsy of the breast showed moderately well developed mammary ducts and alveoli containing milk. In the case of E. G., age 59, diethylstilbestrol (5 mg/day) was ingested almost continuously for 6 years; this resulted in the development of large pendulous breasts, but no lactation occurred after injections of luteotrophin.
Lactation in humans without cancer.—Luteotrophin was administered to two normal males, age 51 and 59, and to four normal females, age 84–59, and none lactated.
DISCUSSION
It must be emphasized that lactation was not copious in any of the humans when it had been induced by luteotrophin; merely small amounts of milk were obtained. It was apparent, however, from the histological studies of the mammary tissue obtained by biopsy that the secretion of milk in any quantity was a criterion of maturity of mammary epithelium.
In the goat and guinea pig it is known that estrogenic substances can induce mammary ma turity without the intervention of exogenous synergistic steroids. In the experiments of Lewis and Turner (9) diethylstilbestrol was implanted in two castrate male goats; one of these animals failed to lactate, while the other produced a small quantity of milk without luteotrophin injections. They obtained small amounts of milk from a male kid similarly treated. Nelson (10) found that estrone induced mammary growth with, later, lactation in the male guinea pig. Our observations demonstrate that diethylstilbestrol ingested for prolonged periods of time can induce maturity of the breast in certain elderly human males. However, the human male differs from the animals just described in that spontaneous lactation was not observed; the injection of luteotrophin was necessary for milk formation.
The duration of lactation induced by luteo trophin was impressive, since milk commonly persisted for many months—and in one male for 7 years. The mechanism whereby this type of lactation is maintained for such long periods of time is at present unknown; we know that milk continues to be secreted both in the presence of the adrenal glands and in the absence of these structures and the gonads as well. Observations (8) have been made on experimental animals which are analogous to the clinical findings; most dogs with spontaneous mammary cancer possess lactation, and this characteristic persists for many months, at least, despite the removal of the adrenal glands and the ovaries.
SUMMARY
The breast of the human male can be induced to grow to a functionally mature state by the administration of estrogenic substances without additional exogenous steroid synergists. Spontaneous lactation was not observed in these men, but it was induced by luteotrophin.
The formation of milk in any amount by the breast is a criterion of functional maturity of the mammary epithelium. Luteotrophin induced the secretion of small amounts of milk in a group of women with mammary cancer and in a number of healthy women as well, and, in addition, in two human males to whom estrogenic substances had been administered for therapeutic purposes. Lactation did not occur in two normal males.
When lactation was induced in human beings, the secretion often persisted for many months; it lasted for 7 years in one man.
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Brodribb, W., & Academy of Breastfeeding Medicine. (2018). ABM Clinical Protocol #9: Use of galactogogues in initiating or augmenting maternal milk production, second revision 2018. Breastfeeding Medicine, 13(5), 307–314. [DOI:10.1089/bfm.2018.29092.wjb]
MacDonald, T. K. (2019). Lactation care for transgender and non-binary patients: Empowering clients and avoiding aversives. Journal of Human Lactation, 35(2), 223–226. [DOI:10.1177/0890334419830989]
Paynter, M. J. (2019). Medication and Facilitation of Transgender Women’s Lactation. Journal of Human Lactation, 35(2), 239–243. [DOI:10.1177/0890334419829729]
Cazorla-Ortiz, G., Obregón-Guitérrez, N., Rozas-Garcia, M. R., & Goberna-Tricas, J. (2020). Methods and Success Factors of Induced Lactation: A Scoping Review. Journal of Human Lactation, 36(4), 739–749. [DOI:10.1177/0890334420950321]
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+Published Case Reports of Lactation and/or Breastfeeding in Transfeminine People - Transfeminine Science
Published Case Reports of Lactation and/or Breastfeeding in Transfeminine People
By Aly | First published March 26, 2019 | Last modified March 20, 2024
Abstract / TL;DR
A number of case reports of hormonally induced lactation and breastfeeding in transfeminine people have been published. The earliest report of lactation in a transfeminine person was in the 1950s and the earliest report of breastfeeding was in the 1980s. Starting in 2019, more case reports have been published in the modern scientific literature. Unpublished cases also exist (e.g., that of Dr. Christine McGinn), and lactation has been induced or occurred in cisgender men as well. Lactation may be induced in transfeminine people with the use estrogens, progestogens, and/or prolactin releasers. Reviews discussing lactation induction in transfeminine people have recently been published.
Introduction
Last year, a case report of lactation and breastfeeding in a transgender woman was published:
Reisman, T., & Goldstein, Z. (2018). Case report: Induced lactation in a transgender woman. Transgender Health, 3(1), 24–26. [DOI:10.1089/trgh.2017.0044]
In the paper, the authors state the following:
We believe that this is the first formal report in the medical literature of induced lactation in a transgender woman.
However, this actually wasn’t the first case report of lactation and/or breastfeeding in a transfeminine person in the literature. There are various previous published cases dating back as far as the 1950s. These instances are provided below in the format of sources and excerpts.
Published Case Reports
Foss (1956)
Foss, G. L. (1956). Abnormalities of form and function of the human breast. Journal of Endocrinology, 14(4 Suppl) [Proceedings of the Society for Endocrinology: Fifty-Fourth Meeting. Symposium on Selected Aspects of the Practice of Hormone Administration in Animals and Man], vi–vii. [Google Scholar] [Google Books] [URL] [PDF]:
Based on the theories of lactogenesis and stimulated by the success of Lyons, Li, Johnson & Cole [1955], who succeeded in producing lactation in male rats, an attempt was made to initiate lactogenesis in a male transvestist. Six years ago this patient had been given oestrogens. Both testes and penis were then removed and an artificial vagina was constructed by plastic surgery. The patient was implanted with 500 mg oestradiol in September 1954, and 600 mg in July 1955. The breasts were then developed more intensively with daily injections of oestradiol dipropionate and progesterone for 6 weeks. Immediately following withdrawal of this treatment, prolactin 22·9 mg was injected daily for 3 days without effect. After a second month on oestradiol and progesterone daily, combined injections of prolactin and somatotrophin were given for 4 days and suction was applied by a breast pump—four times daily. On the 4th and 5th days a few drops of colostrum were expressed from the right nipple.
Tindal & McNaught (1958)
Tindal, J. S., & McNaught, M. L. (1958). Hormonal Factors in Breast Development and Milk Secretion. In Gardiner-Hill, H. (Ed.). Modern Trends in Endocrinology, Volume 1 (pp. 188–211) (Modern Trends). London: Butterworth. [Google Scholar] [Google Books] [OpenLibrary] [WorldCat] [Archive.org]:
Recently, an attempt has been made by Foss (1956) to initiate lactation in a castrated male transvestist. He was given an implant of 500 milligrams of oestradiol, and 10 months later, a further 600 milligrams of oestradiol, followed by daily injections of oestradiol dipropionate and progesterone for 6 weeks. Immediately after withdrawal of this treatment, 22·9 milligrams of prolactin were injected daily for 3 days but without effect. After a second month of treatment with oestradiol and progesterone daily, he was given combined injections of prolactin and somatotrophin for 4 days, suction with a breast-pump being employed 4 times daily. On the fourth and fifth days a few drops of colostrum were expressed from the right nipple. There is a possible application here of modern hormone knowledge to man, and further trials would be of interest.
Experimentally I have been able to induce lactogenesis in a male transvestite whose testes had been removed some years before and whose breasts had been well developed over a long period with stilbestrol and ethisterone.9 In July, 1955, 600 mg. of estradiol was implanted subcutaneously and weekly injections of 50 mg. of progesterone were given for four months. For the next month daily injections of 10 mg. estradiol dipropionate and 50 mg. progesterone were given. These injections were continued for another month, increasing progesterone to 100 mg. daily. Both hormones were then withdrawn, and daily injections of increasing doses of prolactin and somatotropin were given for four days; at the same time, the patient used a breast pump four times daily for 5 minutes on both sides. During this time the mammary veins were visibly enlarged and on the sixth and seventh days 1 to 2 cc. of milky fluid was collected.
Flückiger, Del Pozo, & von Werder (1982)
Flückiger, E., Del Pozo, E., & von Werder, K. (1982). Prolactin: Synthesis, Fate and Actions. In Flückiger, E. W., Del Pozo, E., & von Werder, K. (Eds.). Prolactin: Physiology, Pharmacology, and Clinical Findings (Monographs on Endocrinology, Volume 23) (pp. 1–23). Berlin/Heidelberg: Springer-Verlag. [Google Scholar] [Google Books] [DOI:10.1007/978-3-642-81721-2_1]:
An observation (Wyss and Del Pozo unpublished) in a male transsexual showed that induction of lactation can be similarly achieved in the human male.
Flückiger, E., Del Pozo, E., & von Werder, K. (1982). Nontumoral hyperprolactinemia. In Flückiger, E. W., Del Pozo, E., & von Werder, K. (Eds.). Prolactin: Physiology, Pharmacology, and Clinical Findings (Monographs on Endocrinology, Volume 23) (pp. 102–152). Berlin/Heidelberg: Springer-Verlag. [Google Scholar] [Google Books] [DOI:10.1007/978-3-642-81721-2_4]:
4.3.2 Effect of Hyperprolactinemia in Male Subjects
Although PRL circulates in male blood in appreciable concentrations its physiologic role has not been clarified. The lack of lactational requirements does not preclude that under adequate priming the male mammary gland will respond to a PRL challenge with milk production. Thus, Wyss and del Pozo (unpublished data) found that PRL stimulation with TRH was able to induce milk secretion in a male individual pretreated with estrogens. Certainly, the chronic ingestion of dopamine antagonists or estrogens may lead to sustained hyperprolactinemia, and the same effect can be expected in male subjects on chronic estrogen therapy of prostatic cancer or transsexualism (Frantz 1973; del Pozo, to be published).
Certainly, the prolonged intake of estrogens, in male subjects also, as observed in the treatment of prostatic carcinoma and in transsexuals, can lead to hyperprolactinemia (Frantz 1972b; del Pozo, to be published).
Kozlov, Mel’nichenko, & Golubeva (1985)
Kozlov, G. I., Mel’nichenko, G. A., & Golubeva, I. V. (1985). Случай лактореи у больного мужского пола с транссексуализмом. [Sluchai laktorei u bol’nogo muzhskogo pola s transseksualizmom. / Case of galactorrhea in a transsexual male patient.] Проблемы Эндокринологии [Problemy Èndokrinologii (Moskva) / Problems of Endocrinology (Moscow)], 31(1), 37–38. [ISSN:0375-9660] [Google Scholar 1] [Google Scholar 2] [PubMed] [DOI:10.14341/probl198531137-38] [PDF] [Translation] [Translated]:
The appearance of galactorrhea in men is most often a symptom of pituitary prolactinoma. Combined with gynecomastia and atrophy of the testicles, galactorrhea caused by adenomas of the pituitary gland in men is known as O’Connell syndrome (1).
In recent years, however, cases of galactorrhea have been described in men without radiological or clinical signs of pituitary adenoma (12). Of course, in these cases, the presence of undetected microadenomas of the pituitary gland cannot be excluded, especially since the level of prolactin in these patients is significantly increased (1, 2).
Some medications, especially antipsychotics and estrogen-containing oral contraceptives (7, 10), increase serum levels of prolactin and can lead to the development of galactorrhea.
There is information about the influence of psycho-emotional factors on the lactation process: the possibility of the development (induction) of psychogenic lactation during false pregnancy (3) is known, and, conversely, the possibility of the termination of lactation in nursing mothers after mental stress.
Accumulated clinical observations on the frequent development of depressive states in persistent galactorrhea–amenorrhea syndrome (4), cases of galactorrhea in the mentally ill, even in the absence of neuroleptics (7), as well as experimental observations on the effect of hyperprolactinemia on the behavioral responses of animals (5), require careful study of the relationship of hyperprolactinemia and psycho-emotional factors. In connection with this, we present the following observation.
The patient (P), was born a normal, full-term boy. He remembers well from 6 years. Early development was unremarkable, he did not differ from peers, but loved to play more with girls. He played with dolls and cars. At 10 years of age, there was a desire to wear women’s clothes. From the age of 12 he swam with girls in a shirt and shorts, as he was embarrassed by the lack of breasts. From the age of 14 he changed clothes in his mother’s dress, and only in such clothes “felt like a person”. From the same age in a woman’s dress he went to get acquainted with young men and got pleasure from it. At the age of 15, he came to the firm conviction that he was a girl, began to urinate like a girl, squatting, use lipstick, and put on powdered makeup. He suffered greatly from the presence of “deformities” – male genital organs. At the age of 17, while working as a “nurse” in a hospital, he began to self-inject himself with folliculin (estrogen) and progesterone, which caused the development of the breasts. With pleasure, he did women’s housework, and loved to tinker with children. Having received a passport, he redid it as female, thus resulting in a female civilian gender.
Twice he tried to commit suicide (he took sleeping pills), since he could not bear the duality of his existence. Twice he was treated in psychiatric hospitals about transsexualism, unsuccessfully.
During the examination in IEE and HCG at the age of 20 years, no abnormalities in somatic status were revealed: complex as a man, male genitals, shaved from 17 years of age daily. Erotic dreams were frequent, wherein he played the role of a woman, and denied emissions. The ejaculate was studied (obtained by vibratory massage): volume – 1.4 mL, pH 8.8 (norm 7.6–8.2), sperm count 31 million per 1 mL, mobility 57%, and morphologically normal 69%. Sex chromatin is negative.
At age 22, a course of treatment with cyproterone acetate was conducted at the Institute of Psychiatry of the Ministry of Health of the USSR. Muscle weakness, reduction of sexual hairiness, and appearance of colostrum excretion was noted.
When examined in IEE and HCG at 23 years, the breasts corresponded to the age of 15–16 years (on his own initiative he periodically took estrogens), and colostrum was secreted from the nipples (abundant drops when pressed – galactorrhea (++)). He insisted on castration and amputation of the penis, since, being a “woman”, he was ashamed of not having the appropriate genitals for his sex, which he called “deformities”.
On X-ray of the skull, the shape and size of the sella turcica were normal, but signs of increased intracranial pressure were revealed. On EEG against the background of the general phenomena of irritation, the focus of pathology was recorded in the left parietal lead. Indicators of the functional state of the thyroid gland were in the normal range. In the study of the radioimmunoassay method using standard kits from the Sorin company, some increase in prolactin level of 24 ng/mL was detected in the serum (normal for men is 4–15 ng/mL).
In connection with the repeated suicidal attempts, failure of psychiatric treatment, and in consideration of the fact that the patient has a female civilian sex and performs a female social role, castration and feminizing plastic surgery of the external genitalia were performed for the purpose of social rehabilitation.
Some time after the operation, the patient developed a renewed interest in life. After the surgical and hormonal correction, the patient irresistibly developed maternal instincts. Unmarried, the patient obtained permission for the adoption of a child, simulated pregnancy, and was discharged from the maternity hospital with a son. From the first days after the “birth”, galactorrhea sharply increased, and spontaneous outflow of milk appeared, with galactorrhea (+++). The baby was breastfed up to 6 months of age.
Thus, it can be thought that several factors played a role in the genesis of galactorrhea in this patient:
Increased prolactin levels with estrogen and cyproterone acetate. The hyperprolactic properties of estrogens have long been known; the ability of cyproterone acetate to increase serum prolactin levels was shown by K. Schmidt–Golewizer et al (9).
Increased intracranial pressure, the role of this factor and the genesis of neuroendocrine disorders and, in particular, in the development of galactorrhea was shown by R. Peterson (8).
Our message is the second in the world literature describing galactorrhea in a male patient with transsexualism. The first description of this kind was made in 1983 by R. Flüskiger et al. (6).
This observation demonstrates the independence of the mechanism of lactation development from one’s genetic sex and is alarming with regard to the possibility of drug-induced galactorrhea development in men.
Barber et al. (2004)
Barber, T., Basu, A., Rizvi, K., & Chapman, J. (2004). Normoprolactinaemic galactorrhoea in a male-to-female transsexual. Endocrine Abstracts, 7 [23rd Joint Meeting of the British Endocrine Societies with the European Federation of Endocrine Societies], 271–271. [Google Scholar] [URL]:
Hormonal therapies in the form of oestrogens, anti-androgens and progestogens are often used in the treatment of male-to-female transsexuals. We present the case of a 36 year old phenotypic male with karyotype 46XY who presented with normoprolactinaemic galactorrhoea likely to be related to prior oestrogen administration. He had been self-administering oestrogen and progesterone preparations continuously for 7 years (aged 26 - 33 years) in an attempt to develop female phenotypic characteristics in spite of a heterosexual desire. During this time he developed gynaecomastia with galactorrhoea, increased energy and libido, voice change and an attraction towards both men and women. However due to lack of financial resources to secure a complete gender change, he stopped self-medication with these preparations 3 years ago. Instead he embarked on a regime involving self-administered testosterone in an attempt to reverse the biological changes. After discontinuation of oestrogen the gynaecomastia regressed somewhat, although galactorrhoea continued and worsened with testosterone. Prior to referral he had been treated with dopamine agonists with little improvement in galactorrhoea and gynaecomastia.
Routine biochemistry and haematology are within their reference ranges. Baseline endocrinology is normal: Prolactin 197 milliUnits per litre, LH 2.9 Units per litre, FSH 7.9 Units per litre, free Testosterone 20 nanoMoles per litre, 17 beta-oestradiol less than 110 picoMoles per litre, TSH 0.96 milliUnits per litre and free T4 16.5 picoMoles per litre.
This case illustrates fascinating effects of exogenous oestrogen in the male. The effects of oestrogenic products of aromatised endogenous and briefly also exogenous testosterone acting on oestrogen-primed breast tissue may account for, at least in part, his continuing symptom of normoprolactinaemic galactorrhoea. However two other features do not have any direct explanations: the development of osteopenia during this period, and complete disappearance of vascular migraine, a condition worsened with oestrogens in the female. He is now on Tamoxifen although an opportunity to use the aromatase inhibitor, Anastrozole still remains.
Subsequent Case Reports
Moravek & Pasque (2019)
Moravek, M. B., & Pasque, K. B. (2019). Lactation Can Be Successfully Induced in Transgender Women While Maintaining Gender-Congruent Serum Hormone Levels. Reproductive Sciences, 26(Suppl 1), 136A–136A (abstract no. T-055). [Google Scholar] [DOI:10.1177/1933719119834079]:
Introduction: Transgender women may be interested in breastfeeding their children, but there are no established protocols for lactation induction in this population. The only case report of a lactation induction protocol in a transgender woman significantly lowered her estradiol dose, which would likely result in decreased serum estradiol and increased testosterone levels, with resultant increase in gender dysphoria. Our objective was to induce lactation in a transgender woman without interrupting her gendercongruent hormone profile.
Methods: A 34-year-old transgender woman with a 15-year history of gender-affirming hormone therapy with estradiol and spironolactone presented for lactation induction once her cisgender wife conceived. A modification of the Newman-Goldfarb method for adoptive mothers was used to induce lactation, and serum hormone levels followed.
Results: Baseline labs were obtained (time point 1), then medroxyprogesterone 1.25mg daily was added to her existing hormone regimen of estradiol 6mg daily and spironolactone 100mg twice daily (time point 2). Domperidone 10mg four times daily was initiated 1 month later. Approximately 5 weeks prior to the due date, the patient stopped medroxyprogesterone, decreased estradiol to 2mg daily, and began breast pumping (time point 3). Just prior to the infant’s birth, the patient was pumping 2-3 ounces of breastmilk every 3 hours (time point 4). Spironolactone was decreased to 50mg twice daily. Her son was born at term, via uncomplicated vaginal delivery. The infant was able to breastfeed from both mothers without difficulty, with both mothers pumping when they weren’t actively breastfeeding to maintain supply (time point 5). When the infant was approximately 2 months old, the patient noticed an increase in facial hair growth. Estradiol was increased to 3mg daily and spironolactone increased to 100mg twice daily, with resolution of hair growth and no decrease in milk supply (time point 6). The patient continued to breastfeed on this regimen for >6 months following her son’s birth. Serum hormone levels on the hormone regimens referenced at each time point throughout the patient’s course are displayed in table 1.
Conclusion: Lactation can be successfully induced in transgender women, without a significant decrease in estradiol supplementation. This regimen allows transgender women to breastfeed without developing male secondary sex characteristics incongruent with their gender identity
Table 1 Hormone profile at different time points.
Time Point
Estradiol (pg/mL)
Progesterone (ng/mL)
Testosterone (ng/mL)
Prolactin (ng/mL)
1
114
1.1
0.36
2
130
1.1
0.05
9
3
30
1.3
0.06
152
4
39
5
29
1.4
0.89
184
6
51
0.16
59
Unnithan, Elson, & Shenker (2020)
Unnithan, R., Elson, D. F., & Shenker, Y. (2020). Galactorrhea and Hyperprolactinemia in a Transgender Female. Journal of the Endocrine Society, 4(Suppl 1), A899–A899 (abstract no. SUN-043). [Google Scholar] [PubMed Central] [DOI:10.1210/jendso/bvaa046.1781] [PDF]:
Background: Galactorrhea is a rare manifestation of hyper-prolactinemia in males and post-menopausal females, however the hormonal milieu of the transgender female may increase its incidence
Clinical Case: A 43 year old transgender female presented with three years of bilateral breast discharge. She had chronic, stable headaches and fatigue, but no vision changes or other symptoms. Notably, she had breast augmentation surgery with saline breast implants placed shortly before the galactorrhea commenced. She was on a stable dose of estradiol tablets 1 mg twice daily for six years. On physical exam she had pronounced bilateral breast discharge of a milky quality with nipple compression. Prolactin levels were checked several times and were 40-50 ng/mL, TSH was 2.36 uIU/mL. An MRI showed a left inferior pituitary lesion measuring 6 mm x 3 mm x 5 mm with no mass effect on adjacent structures. Her breast discharge was not bothersome to her, and her pituitary lesion was small. It was unclear whether there was a relationship between her prolactin levels and the lesion seen on MRI, as we expected more pronounced prolactin elevation with a prolactinoma. Instead, given the timing of her symptoms in relation to her breast augmentation surgery, her galactorrhea and hyper-prolactinemia were thought to be the result of nipple irritation related to her breast implants combined with a hyper-estrogenemic state.
Clinical Lessons: In the setting of a prolactin secreting micro-adenoma, galactorrhea in a male is highly unusual. This case highlights the importance of recognizing that the unique medical and surgical characteristics of male to female transgender patients can lead to hyper-prolactinemia and galactorrhea.
Reference: Reisman T, Goldstein Z. Case report: induced lactation in a transgender woman. Transgender Health. 2018;3(1):24-26.
Wamboldt, Shuster, & Sidhu (2021)
Wamboldt, R., Shuster, S., & Sidhu, B. S. (2021). Lactation Induction in a Transgender Woman Wanting to Breastfeed: Case Report. The Journal of Clinical Endocrinology & Metabolism, 106(5), e2047–e2052. [DOI:10.1210/clinem/dgaa976]:
Context: Breastfeeding is known to have many health and wellness benefits to the mother and infant; however, breastfeeding in trans women has been greatly under-researched.
Objective: To review potential methods of lactation induction in trans women wishing to breastfeed and to review the embryological basis for breastfeeding in trans women.
Design: This article summarizes a case of successful lactation in a trans woman, in which milk production was achieved in just over 1 month.
Setting: This patient was followed in an outpatient endocrinology clinic.
Participant: A single trans woman was followed in our endocrinology clinic for a period of 9 months while she took hormone therapy to help with lactation.
Interventions: Readily available lactation induction protocols for nonpuerpural mothers were reviewed and used to guide hormone therapy selection. Daily dose of progesterone was increased from 100 mg to 200 mg daily. The galactogogue domperidone was started at 10 mg 3 times daily and titrated up to effect. She was encouraged to use an electric pump and to increase her frequency of pumping.
Main outcome measure: Lactation induction.
Results: At one month, she had noticed a significant increase in her breast size and fullness. Her milk supply had increased rapidly, and she was producing up to 3 to 5 ounces of milk per day with manual expression alone.
Conclusions: We report the second case in the medical literature to demonstrate successful breastfeeding in a trans woman through use of hormonal augmentation.
Further Case Reports
Delgado, D., Stellwagen, L., McCune, S., Sejane, K., & Bode, L. (2023). Experience of Induced Lactation in a Transgender Woman: Analysis of Human Milk and a Suggested Protocol. Breastfeeding Medicine, 18(11), 888–893. [DOI:10.1089/bfm.2023.0197]
Weimer, A. K. (2023). Lactation induction in a transgender woman: macronutrient analysis and patient perspectives. Journal of Human Lactation, 39(3), 488–494. [DOI:10.1177/08903344231170559]
van Amesfoort, J. E., Van Mello, N. M., & van Genugten, R. (2024). Lactation induction in a transgender woman: case report and recommendations for clinical practice. International Breastfeeding Journal, 19(1), 18. [DOI:10.1186/s13006-024-00624-1]
Dr. Christine McGinn
Dr. Christine McGinn is a transgender woman and well-known surgeon in Pennsylvania who performs gender-affirming surgeries for transgender people. When she had children with her cisgender female partner, McGinn induced a hormonal pseudopregnancy in herself and her and her partner breastfed their twins together. This was described in the media, including in books and television. McGinn’s case was never formally published as a case report in the scientific literature however.
The Oprah Winfrey Show (2010)
Terry, J. C. (Director), & Winfrey, O. G. (Presenter). (2010 September 29). The Mom Who “Fathered” Her Own Children, Plus the Cast of Modern Family [Television series episode]. The Oprah Winfrey Show (Season 25, Episode 13). Chicago: Harpo Studios. [URL 1] [URL 2] [URL 3]
Trans (2012)
Arnold, C. (Director), Schoen, M. (Producer), RoseWorks (Firm), & Sex Smart Films (Firm). (2012). Trans [DVD] (1:21:32–1:21:55). [WorldCat] [IMDB] [Amazon Prime Video]
Boylan (2014)
Boylan, J. F. (2014). Dr. Christine McGinn. In Boylan, J. F. Stuck in the Middle with You: A Memoir of Parenting in Three Genders (pp. 223–233). New York: Broadway Books. [Google Scholar] [Google Books 1] [Google Books 2] [WorldCat] [PDF]:
Dr. Christine McGinn is a surgeon, a mother of two, a backup flight surgeon for the space shuttle progarm, and a transgender woman. As a man, she saved her sperm before transition; ten years later she used that sperm to have children with her partner Lisa. The two of them are both biological mothers of their son and daughter, and each mother was able to breast-feed the twins. I sat down with Christine at her office in New Hope, Pennsylvania, on a hot summer day in 2011.
CM: […] Then there’s the scientist in me that knows that there is a difference, there is not a binary, but a gender spectrum. There are chemicals that are different in men and women. And when a transgender woman transitions, we are somewhere in the middle. Especialy having gone through a simulated pregnancy, in order to breast-feed, I felt the changes of those hormones. I felt my milk let down when not only my baby would cry, but a baby on TV would cry, and even, ridiculously, when a door would close and make a squeak.
JFB: You had to induce a false pregnancy in order to breast-feed? Tell me how you did that.
CM: As a doctor, I knew it was possible. I followed the protocol that involves simulating pregnancy with hormones. It’s estrogen and progesterone. My simulation pregnancy was over a month before Lisa delivered—with twins, we were expecting them to be born earlier. That entire month I was just pumping nonstop, every two hours. We had a whole freezer full of milk. And you know, the first couple of weeks it was no good, because it had all of the hormones in it. So we only saved, like, the last week or so. But still, it was a freezer full of milk.
Lisa had no idea about the way breast-feeding takes over your life, because this was her first. It was kind of funny that I went through that on my own, first, weeks before she did. And then it took her a couple of days to actually—for her milk to let down.
The children were so small when they were born. They were only five pounds. At first we had to feed them with a syringe. They were breast-feeding as well, but they weren’t latching that great on either of us.
JFB: What was it like when they finally muckled on to you?
CM: Oh, I can’t even put it in words. I really cannot put it in words. It was—I was just—oh.
JFB: Were you amazed? Were you afraid?
CM: It was heaven. I was afraid. I don’t know, it was uncharted territory. Like, I knew the milk was good. Lisa was a little concerned that it would be like skimmed milk, or something, you know. [Laughs] Like—she’s like, “Is it the same stuff?”
JFB: Is it the same milk?
CM: And she was a little dubious about, like, is this really all right? I think that’s totally natural for a mother, to be concerned.
I will just say that there are things snobody thinks about when two women are both breast-feeding. Like, technical stuff that you don’t think about. When you have a mother and a father, the mother decides when the kids get fed. Right? The father doesn’t, really. Right?
But you know, when you have two women who are filled with pregnancy hormones and have that, like, mother-bear attitude about how things should be done… It was really crazy.
JFB: So did that cause serious conflict between you and Lisa?
CM: Totally not serious conflict, because the most important thing are the babies.
Eden finally latched—I breast-fed her more than Luke. Luke was never really good. Lisa hated breast-feeding. Eventually we decided to stop.
I’m putting on my science hat again—when you decide to stop, there are hormonal issues. The strongest emotion a person can feel in their life comes frm oxytocin, which is the love drug.
JFB: Oxytocin?
CM: That’s what’s responsible for babies’ bonding during breastfeeding. So the baby latches on, breast-feeds, your brain just [makes oozing sounds], just like, oozes this gooey love substance, oxytocin. Fathers are proven to have higher oxytocin before the delivery, and just stroking your child’s head. You know, when the baby—when you smell a newborn’s head, it really—that smell, it’s like—
JFB: I just saw a friend’s newborn on Friday, and I was like, [makes sniffing sound]—
CM: My niece said it best. She came in and smell them, and she was five years old at the time, and she’s like, “They smell like cupcakes.” [Laughs] And it’s universal. When you ask me what that’s like, I can’t describe it, you know, and I’m a huge fan of food and cupcakes and chocolate, and so that’s the closest I can come to it—it’s like chocolate. [Laughs]
JFB: So when you stopped breast-feeding, was it a kind of a mourning, a loss?
CM: Yes. Lisa wanted to stop before I did. The problem is, once a baby gets a nipple, a plastic nipple, it gives more milk. And so they don’t have to work as hard.
It’s a unique situation that two breast-feeders in a relationship would experience, but a mother and father would not.
JFB: So did one of you stop breast-feeding before the other?
CM: Yes, Lisa did.
JFB: Lisa stopped. And how much longer did you keep it up?
CM: Not long, because they got the nipple.
They were both so small. We weren’t all that successful at it. We were so worried about their birth weight, and making sure they got enough with the syringes. There were definitely times where, you know, we both would breast-feed and, man, I will never forget that. Like, three ‘clock in the morning, four o’clock in the morning, in the little cocoon, nursing.
The heat of their body, their naked body on your chest. The amazing thing is, it really does kind of hurt when they really get going, you know. And you just… I don’t know how else to describe it. You feel like the life force is just coming out through you. It’s so powerful. It relieves that pain that you have in your breast. It releases that oxytocin, and it’s just—it’s even.
JFB: Did you ever do that thing where you would fall asleep with the children in the bed, and wake up with the children in the bed beside you?
CM: Yeah.
JFB: I loved that. It’s one of my stnogest memories of being a father. Having gotten up in the middle of the night. And they are so small, but such an incredibly powerful feeling, the two of you together surrounding the child. With us, we also had a dog at the bottom of the bed. [Laughs]
CM: And we have two, and that was also very important to me, too. We have miniature pinschers.
JFB: So how many months along did you stop breast-feeding?
CM: Three months. It was really emotionally painful, and I cried a lot. I was really sad.
I was pretty sure we were not going to have any more kids. So I’m like, “This is it.” It was very sad.
JFB: Is there a moment frm the last year and two months where you think, This is what it’s like to be a mother, this is it?
CM: Yes, immediately. It was hot as Hades outside. It was, like, a million degrees. We had just had the kids. It was like, May or June, and my mom was over, and it was, like, we had all this help, initially, because Lisa and I were just not getting any sleep and it was, like, round-the-clock feedings and the kids were small, and Lucas had an apnea monitor that he had to wear all the time, and it was just really hard. And there was a big thunderstorm, and the power went out.
And so, at this point, they weren’t really latching very well, so we both had to pump, and then feed them with the syringes. So Lisa and I are totally, like, engorged with milk. And the power’s out, and the pumps are electric. Right?
JFB: Right.
CM: So there’s no electricity, it’s hot as hell, we’re worried for the kids. Lisa and I are in pain. We’re both leaking. And it was the weirdest, funniest situation. And my mom’s there. She runs out to the store to get batteries, and you know, she’s just beng a mom. She’s getting everything, running around like an angel. And Lisa and I are in pain we’re miserable. When she finally came back, the batteries wouldn’t work on the pumps—something else was wrong. Lisa and I are dying.
And so, here’s the guy part of me… I get the pump that has the backup battery power and the backup car charger. Like, I got all tech on it. [Laughs] I’m out int he car trying to get the car charger to work on the pump in the pouring rain. And it’s ninety-five degrees out. It’s all wet inside, like, the humidity on the windows.
And I’m just trying to get some kind of relief.
And this stupid pump didn’t work that way, either. We come back in and my mom has candles lit.
And then the electricity comes back on. And we all just laugh and pump and breast-feed. And every one of us is in heaven.
Pfeffer (2017)
Pfeffer, C. A. (2017). Trans Partnerships and Families: Historical Traces and Contemporary Representations. In Pfeffer, C. A. Queering Families: The Postmodern Partnerships of Cisgender Women and Transgender Men (pp. 1–34). New York: Oxford University Press. [Google Scholar] [Google Books] [WorldCat] [DOI:10.1093/acprof:oso/9780199908059.003.0001]:
Just 2 years later, Winfrey would feature another interview that elicited many of the same audience reactions. In this 2010 episode, lesbian partners Dr. Christine McGinn and Lisa Bortz beamed with joy as they held their infant twins. Again, audience members’ jaws dropped when it was revealed that beautiful Christine was a male-to-female transsexual who used to be a handsome military officer Chris, and that Lisa had given birth to the couple’s biological children using sperm Chris banked prior to gender confirmation surgeries.10 And it was Winfrey’s chin that nearly hit the floor as she watched video of Christine breastfeeding the couples’ children (the episode is referred to online as “The Mom Who Fathered Her Own Children”).
Other Instances
Published
Estrogen plus cyproterone acetate has been reported to produce pregnancy-like breast changes—specifically, lobuloalveolar development of the breasts—in transfeminine people (Kanhai et al., 2000). Accordingly, galactorrhea (spontaneous or excessive lactation) has been reported as a low-incidence side effect (7–14%) of hormone therapy regimens containing estrogen plus cyproterone acetate in transfeminine people (Gooren, Harmsen-Louman, & van Kessel, 1985; Schlatterer et al., 1998; Bazarra-Castro, 2009). It has also been reported at low incidence (6%) for other hormone therapy regimens (Futterweit, 1980). Sudden cessation of hormone therapy regimens including cyproterone acetate has been reported to result in the onset of lactation as well (Levy, Crown, & Reid, 2003).
Unpublished
Many unpublished reports of lactation and breastfeeding in transfeminine people have been described on the web including at the following pages:
Richards, A. (2003). Lactation and the Transsexual Woman. Second Type Woman. [Updated August 2018] [URL] [PDF]
MacDonald, T. (2013). Trans Women and Breastfeeding: A Personal Interview. Milk Junkies. [URL]
MacDonald, T. (2013). Trans Women and Breastfeeding: The Health Care Provider. Milk Junkies. [URL]
MacDonald, T. (2017). Jenna’s Breastfeeding Journey: Trans Motherhood. Milk Junkies. [URL]
Burns, K. (2018). Yes, Trans Women Can Breastfeed — Here’s How. them. [URL]
Cisgender Men
Induction of lactation has been reported in cisgender men and is noteworthy:
Geschickter (1945)
Geschickter, C. F. (1945). Endocrine Physiology of the Breast. In Geschickter, C. F. Diseases of the Breast: Diagnosis, Pathology, Treatment, 2nd Edition (pp. 42–81). Philadelphia: J.B. Lippincott. [Google Scholar] [Google Books] [OpenLibrary] [WorldCat] [PDF]:
The results obtained indicate that a lactogenic substance in anterior pituitary extracts may cause mammary secretion in nonpregnant women when they have been previously stimulated with estrogenic hormone but true lactation does not occur. Secretion was also obtained in two adult men with gynecomastia after injections of lactogenic hormone.
Huggins (1949)
Huggins, C. (1949). Endocrine substances in the treatment of cancers. Journal of the American Medical Association, 141(11), 750–754. [DOI:10.1001/jama.1949.02910110002002]:
The administration of estrogen in effective amounts causes testicular atrophy and mammary hypertrophy. Growth of the breasts can be so extensive that lactation may be induced, as illustrated in the following case.
W. N., aged 64, had carcinoma of the prostate with osseous metastases, for which he was treated by a permanent suprapubic cystotomy in 1941. Diethylstilbestrol, 20 mg. daily, was given orally for two years beginning September 1942. In September 1944, 25 mg. (500 international units) of prolactin14 was injected daily for five days, and at the end of this time creamy milk could be expressed from both breasts. Orchiectomy and removal of the cystostomy tube were carried out September 6, when administration of estrogen was discontinued; both incisions healed promptly. Since then the patient has been clinically well but has continued to lactate, a large drop of milk being easily expressed from each breast at frequent intervals.
Huggins & Dao (1954)
Huggins, C., & Dao, T. L. (1954). Lactation induced by luteotrophin in women with mammary cancer. Growth of the breast of the human male following estrogenic treatment. Cancer Research, 14(4), 303–306. [Google Scholar] [PubMed] [URL]:
In the observations to be presented luteotrophin [prolactin] was employed as a stimulus for mammary secretion in patients with cancer of the breast, and the results throw new light on the physiology of women bearing this neoplasm. We shall also describe conditions which resulted in the induction of physiologic maturity in the human male, since knowledge of the action of hormones on the human breast is vague.
The effects of luteotrophin on the breast of women post partum has been extensively investigated, but otherwise few observations have been made in the human. Werner (14) administered a crude pituitary extract containing luteotrophin to eight castrate women 21–35 years of age; lactation was not observed, although in one woman “a few drops of colostrum-like fluid” could be expressed from the breasts. Goldzieher (4) treated menstrual disorders in women with luteotrophin, but mammary secretion was not described by him.
PROCEDURE
Luteotrophin,1 dissolved in physiological saline made slight ly alkaline (pH 9) with sodium hydroxide, was injected subcutaneously in daily amounts of 500 International Units; the solutions were freshly prepared, and the injections were continued for 7 days only.
This series comprised 21 female patients who had dis seminated mammary cancer, and all had been subjected to unilateral mastectomy. There were also three men with advanced prostatic carcinoma who had been treated for thera peutic purposes with oral diethylstilbestrol for 20 months, 2, and 6 years, respectively. There were eight persons without mammary or prostatic cancers who served as controls.
In each case of mammary cancer a biopsy of the breast was obtained for histological purposes, the material being stained with Sudan III.3
OBSERVATIONS
Lactation, when it occurred, was never profuse; it varied from a tiny drop to ca. 0.5 cc. from each breast. Clear colostrum was not observed, and the mammary secretion was always milk, as defined above.
Mammary growth in the human male.—Estrogenic substances had been administered to three men in the treatment of disseminated prostate cancer for many months; after luteotrophin injection two lactated and one did not lactate.
W. N. (reported in brief earlier [5]), age 64, had taken diethylstilbestrol, 20 mg/day, orally for 2 years, after which interval sub-areolar button-like masses of mammary tissue could be palpated bilaterally; luteotrophin was then injected for 5 days, and milk was expressed from the breast on the 6th day. Orchiectomy was then performed, and both luteotrophin and estrogenic substances were discontinued. This man continued to lactate for 7 years when the formation of milk gradually ceased.
In the case of A. W., age 62, diethylstilbestrol (5–15 mg/day) had been ingested for 20 months after bilateral orchiectomy; the breasts became slightly enlarged. Luteotrophin was injected, and lactation occurred on the 7th day. A biopsy of the breast showed moderately well developed mammary ducts and alveoli containing milk. In the case of E. G., age 59, diethylstilbestrol (5 mg/day) was ingested almost continuously for 6 years; this resulted in the development of large pendulous breasts, but no lactation occurred after injections of luteotrophin.
Lactation in humans without cancer.—Luteotrophin was administered to two normal males, age 51 and 59, and to four normal females, age 84–59, and none lactated.
DISCUSSION
It must be emphasized that lactation was not copious in any of the humans when it had been induced by luteotrophin; merely small amounts of milk were obtained. It was apparent, however, from the histological studies of the mammary tissue obtained by biopsy that the secretion of milk in any quantity was a criterion of maturity of mammary epithelium.
In the goat and guinea pig it is known that estrogenic substances can induce mammary ma turity without the intervention of exogenous synergistic steroids. In the experiments of Lewis and Turner (9) diethylstilbestrol was implanted in two castrate male goats; one of these animals failed to lactate, while the other produced a small quantity of milk without luteotrophin injections. They obtained small amounts of milk from a male kid similarly treated. Nelson (10) found that estrone induced mammary growth with, later, lactation in the male guinea pig. Our observations demonstrate that diethylstilbestrol ingested for prolonged periods of time can induce maturity of the breast in certain elderly human males. However, the human male differs from the animals just described in that spontaneous lactation was not observed; the injection of luteotrophin was necessary for milk formation.
The duration of lactation induced by luteo trophin was impressive, since milk commonly persisted for many months—and in one male for 7 years. The mechanism whereby this type of lactation is maintained for such long periods of time is at present unknown; we know that milk continues to be secreted both in the presence of the adrenal glands and in the absence of these structures and the gonads as well. Observations (8) have been made on experimental animals which are analogous to the clinical findings; most dogs with spontaneous mammary cancer possess lactation, and this characteristic persists for many months, at least, despite the removal of the adrenal glands and the ovaries.
SUMMARY
The breast of the human male can be induced to grow to a functionally mature state by the administration of estrogenic substances without additional exogenous steroid synergists. Spontaneous lactation was not observed in these men, but it was induced by luteotrophin.
The formation of milk in any amount by the breast is a criterion of functional maturity of the mammary epithelium. Luteotrophin induced the secretion of small amounts of milk in a group of women with mammary cancer and in a number of healthy women as well, and, in addition, in two human males to whom estrogenic substances had been administered for therapeutic purposes. Lactation did not occur in two normal males.
When lactation was induced in human beings, the secretion often persisted for many months; it lasted for 7 years in one man.
HUGGINS,C. Endocrine Substances in the Treatment of Cancers. J.A.M.A., 141:750–54, 1949.
Brodribb, W., & Academy of Breastfeeding Medicine. (2018). ABM Clinical Protocol #9: Use of galactogogues in initiating or augmenting maternal milk production, second revision 2018. Breastfeeding Medicine, 13(5), 307–314. [DOI:10.1089/bfm.2018.29092.wjb]
MacDonald, T. K. (2019). Lactation care for transgender and non-binary patients: Empowering clients and avoiding aversives. Journal of Human Lactation, 35(2), 223–226. [DOI:10.1177/0890334419830989]
Paynter, M. J. (2019). Medication and Facilitation of Transgender Women’s Lactation. Journal of Human Lactation, 35(2), 239–243. [DOI:10.1177/0890334419829729]
Cazorla-Ortiz, G., Obregón-Guitérrez, N., Rozas-Garcia, M. R., & Goberna-Tricas, J. (2020). Methods and Success Factors of Induced Lactation: A Scoping Review. Journal of Human Lactation, 36(4), 739–749. [DOI:10.1177/0890334420950321]
Ferri, R. L., Rosen-Carole, C. B., Jackson, J., Carreno-Rijo, E., Greenberg, K. B., & Academy of Breastfeeding Medicine. (2020). ABM Clinical Protocol #33: Lactation Care for Lesbian, Gay, Bisexual, Transgender, Queer, Questioning, Plus Patients. Breastfeeding Medicine, 15(5), 284–293. [DOI:10.1089/bfm.2020.29152.rlf]
García-Acosta, J. M., Juan-Valdivia, S., María, R., Fernández-Martínez, A. D., Lorenzo-Rocha, N. D., & Castro-Peraza, M. E. (2020). Trans* Pregnancy and Lactation: A Literature Review from a Nursing Perspective. International Journal of Environmental Research and Public Health, 17(1), 44. [DOI:10.3390/ijerph17010044]
LeCain, M., Fraterrigo, G., & Drake, W. M. (2020). Induced Lactation in a Mother Through Surrogacy With Complete Androgen Insensitivity Syndrome (CAIS). Journal of Human Lactation, 36(4), 791–794. [DOI:10.1177/0890334419888752]
Trautner, E., McCool-Myers, M., & Joyner, A. B. (2020). Knowledge and practice of induction of lactation in trans women among professionals working in trans health. International Breastfeeding Journal, 15(1), 63. [DOI:10.1186/s13006-020-00308-6]
References (Inline Citations)
Bazarra-Castro, M. A. (2009). Etiological aspects, therapy regimes, side effects and treatment satisfaction of transsexual patients. (Doctoral dissertation, Ludwig Maximilian University of Munich.) [DOI:10.5282/edoc.9984] [URN:urn:nbn:de:bvb:19-99840] [PDF]
Delgado, D., Stellwagen, L., McCune, S., Sejane, K., & Bode, L. (2023). Experience of Induced Lactation in a Transgender Woman: Analysis of Human Milk and a Suggested Protocol. Breastfeeding Medicine, 18(11), 888–893. [DOI:10.1089/bfm.2023.0197]
Futterweit, W. (1980). Endocrine management of transsexual. Hormonal profiles of serum prolactin, testosterone, and estradiol. New York State Journal of Medicine, 80(8), 1260–1264. [Google Scholar] [PubMed] [Archive.org] [PDF]
Gooren, L. J., Harmsen-Louman, W., & Kessel, H. (1985). Follow-up of prolactin levels in long-term oestrogen-treated male-to-female transsexuals with regard to prolactinoma induction. Clinical Endocrinology, 22(2), 201–207. [DOI:10.1111/j.1365-2265.1985.tb01081.x]
Greenblatt, R. B. (1972). Inappropriate lactation in men and women. Medical Aspects of Human Sexuality, 6(6), 25–33. [Google Scholar] [Google Books]
Greenblatt, R. B., & Leng, J. J. (1972). Lactation anormale chez l’homme. [Abnormal lactation in males.] Bordeaux Medical, 5(3), 241–243. [Google Scholar] [PubMed]
Kanhai, R. C., Hage, J. J., van Diest, P. J., Bloemena, E., & Mulder, J. W. (2000). Short-Term and Long-Term Histologic Effects of Castration and Estrogen Treatment on Breast Tissue of 14 Male-to-Female Transsexuals in Comparison With Two Chemically Castrated Men. The American Journal of Surgical Pathology, 24(1), 74–80. [DOI:10.1097/00000478-200001000-00009]
Levy, A., Crown, A., & Reid, R. (2003). Endocrine intervention for transsexuals. Clinical Endocrinology, 59(4), 409–418. [DOI:10.1046/j.1365-2265.2003.01821.x]
Schlatterer, K., Yassouridis, A., Werder, K. V., Poland, D., Kemper, J., & Stalla, G. K. (1998). Archives of Sexual Behavior, 27(5), 475–492. [DOI:10.1023/a:1018704630036]
van Amesfoort, J. E., Van Mello, N. M., & van Genugten, R. (2024). Lactation induction in a transgender woman: case report and recommendations for clinical practice. International Breastfeeding Journal, 19(1), 18.[DOI:10.1186/s13006-024-00624-1]
Weimer, A. K. (2023). Lactation induction in a transgender woman: macronutrient analysis and patient perspectives. Journal of Human Lactation, 39(3), 488–494. [DOI:10.1177/08903344231170559]
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-Jekyll2024-02-18T00:39:56-08:00https://transfemscience.org/feed.xmlTransfeminine Science | ArticlesTransfeminine Science is a site for information on hormone therapy for transfeminine people.Transfeminine SciencePuberty Blockers: A Review of GnRH Analogues in Transgender Youth2022-01-30T15:04:00-08:002022-01-31T00:00:00-08:00https://transfemscience.org/articles/puberty-blockersPuberty Blockers: A Review of GnRH Analogues in Transgender Youth
+Jekyll2024-03-21T19:23:45-07:00https://transfemscience.org/feed.xmlTransfeminine Science | ArticlesTransfeminine Science is a site for information on hormone therapy for transfeminine people.Transfeminine SciencePuberty Blockers: A Review of GnRH Analogues in Transgender Youth2022-01-30T15:04:00-08:002022-01-31T00:00:00-08:00https://transfemscience.org/articles/puberty-blockersPuberty Blockers: A Review of GnRH Analogues in Transgender Youth
@@ -467,13 +467,13 @@ Using the term desistence in this way does not imply anything about the identity
Behre, H. M., Abshagen, K., Oettel, M., Hubler, D., & Nieschlag, E. (1999). Intramuscular injection of testosterone undecanoate for the treatment of male hypogonadism: phase I studies. European Journal of Endocrinology, 140(5), 414–419. [DOI:10.1530/eje.0.1400414]
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]]>{"first_name"=>"Aly", "last_name"=>"W.", "author-link"=>"/about/#aly", "articles-link"=>"/articles-by-author/aly/"}An Informal Meta-Analysis of Estradiol Curves with Injectable Estradiol Preparations2021-07-16T12:00:00-07:002023-06-23T00:00:00-07:00https://transfemscience.org/articles/injectable-e2-meta-analysisAn Informal Meta-Analysis of Estradiol Curves with Injectable Estradiol Preparations
+]]>{"first_name"=>"Aly", "last_name"=>"W.", "author-link"=>"/about/#aly", "articles-link"=>"/articles-by-author/aly/"}An Informal Meta-Analysis of Estradiol Curves with Injectable Estradiol Preparations2021-07-16T12:00:00-07:002024-03-18T00:00:00-07:00https://transfemscience.org/articles/injectable-e2-meta-analysisAn Informal Meta-Analysis of Estradiol Curves with Injectable Estradiol Preparations
By
Aly | First published July 16, 2021
- | Last modified June 23, 2023
+ | Last modified March 18, 2024
Abstract / TL;DR
@@ -1944,7 +1944,7 @@ Using the term desistence in this way does not imply anything about the identity
Update 3: Herndon et al. (2023)
-
In March 2023, the following paper on injectable estradiol in transfeminine people was published online:
+
In March 2023, the following study on injectable estradiol in transfeminine people was published online:
Herndon, J. S., Maheshwari, A. K., Nippoldt, T. B., Carlson, S. J., Davidge-Pitts, C. J., & Chang, A. Y. (2023). Comparison of Subcutaneous and Intramuscular Estradiol Regimens as part of Gender-Affirming Hormone Therapy. Endocrine Practice, 29(5), 356–361. [DOI:10.1016/j.eprac.2023.02.006] [URL]
@@ -1980,6 +1980,20 @@ Using the term desistence in this way does not imply anything about the identity
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 <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.
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Update 4: Rothman et al. (2024)
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In February 2024, the following review on injectable estradiol in transfeminine people was published online:
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Rothman, M. S., Hamnvik, O. P. R., Davidge-Pitts, C., Safer, J. D., Ariel, D., Tangpricha, V., Abramowitz, J., Soe, K., Sarvaideo, J., Kelley, C., Irwig, M. S., & Iwamoto, S. J. (2024). Revisiting Injectable Estrogen Dosing Recommendations for Gender-Affirming Hormone Therapy. Transgender Health, ahead of print. [DOI:10.1089/trgh.2023.0209]
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Here is the abstract of the paper:
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Injectable estrogens are options for gender-affirming hormone therapy per guidelines, which suggest intramuscular dosages of 5–30 mg every 2 weeks or 2–10 mg weekly with estradiol cypionate or valerate interchangeably. Data among transgender and gender-diverse patients are limited due to local unavailability and concerns around laboratory assay variability and estradiol (E2) level fluctuation. We note a concerning trend where patients are prescribed high-dose injections based on the guidelines leading to serum E2 levels well above the range recommended in the same guidelines. Our review indicates that 5 mg weekly or lower should be prescribed when initiating injectable estrogens to avoid supraphysiologic E2 levels.
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Supplementary Material
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Reimann, I. W., Britzelmeier, C., Haber, P., Wollmann, H., Antonin, K. H., & Bieck, P. R. (1987). Influence of Oestradiol on Alpha2-Adrenoceptor Binding Sites on Intact Platelets of Young Male Volunteers. European Journal of Clinical Pharmacology, 33(2), 147–150. [DOI:10.1007/BF00544558]
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Rosenfield, R. L., & Fang, V. S. (1974). The effects of prolonged physiologic estradiol therapy on the maturation of hypogonadal teen-agers. The Journal of Pediatrics, 85(6), 830–837. [DOI:10.1016/S0022-3476(74)80355-0]
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Rothman, M. S., Hamnvik, O. P. R., Davidge-Pitts, C., Safer, J. D., Ariel, D., Tangpricha, V., Abramowitz, J., Soe, K., Sarvaideo, J., Kelley, C., Irwig, M. S., & Iwamoto, S. J. (2024). Revisiting Injectable Estrogen Dosing Recommendations for Gender-Affirming Hormone Therapy. Transgender Health, ahead of print. [DOI:10.1089/trgh.2023.0209]
Sang, G. W., Ge, J. L., Liu, X. H., Shao, Q. X., Zhao, X. J., & Mao, S. M. (1987). 不同剂量庚炔诺酮单独或配伍戊酸雌二醇后的药代动力学及药效学. [Pharmacokinetics and pharmacodynamics of different doses of norethisterone enanthate alone and in combination with estradiol valerate.] 中国 临 床药理 学杂志 / Chinese Journal of Clinical Pharmacology, 3(1), 7–18. [Google Scholar] [CNKI] [DOI:10.13699/j.cnki.1001-6821.1987.01.002] [PDF]
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Schiavon, R., Benavides, S., Oropeza, G., Garza-Flores, J., Recio, R., Díaz-Sanchez, V., & Pérez-Palacios, G. (1988). Serum estrogens and ovulation return in chronic users of a once-a-month injectable contraceptive. Contraception, 37(6), 591–598. [DOI:10.1016/0010-7824(88)90005-4]
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Yáñez, J. A., Remsberg, C. M., Sayre, C. L., Forrest, M. L., & Davies, N. M. (2011). Flip-flop pharmacokinetics–delivering a reversal of disposition: challenges and opportunities during drug development. Therapeutic Delivery, 2(5), 643–672. [DOI:10.4155/tde.11.19]
Zhang, Y., Huo, M., Zhou, J., & Xie, S. (2010). PKSolver: An add-in program for pharmacokinetic and pharmacodynamic data analysis in Microsoft Excel. Computer Methods and Programs in Biomedicine, 99(3), 306–314. [DOI:10.1016/j.cmpb.2010.01.007]
Zhou, X. F., Shao, Q. X., Han, X. J., Weng, L. J., & Sang, G. W. (1998). Pharmacokinetics of medroxyprogesterone acetate after single and multiple injection of Cyclofem® in Chinese women. Contraception, 57(6), 405–411. [DOI:10.1016/S0010-7824(98)00048-1]
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{"first_name"=>"Aly", "last_name"=>"W.", "author-link"=>"/about/#aly", "articles-link"=>"/articles-by-author/aly/"}An Exploration of Sublingual Estradiol as an Alternative to Oral Estradiol in Transfeminine People2021-06-11T20:26:25-07:002021-09-06T00:00:00-07:00https://transfemscience.org/articles/sublingual-e2-transfemAn Exploration of Sublingual Estradiol as an Alternative to Oral Estradiol in Transfeminine People
+]]>{"first_name"=>"Aly", "last_name"=>"W.", "author-link"=>"/about/#aly", "articles-link"=>"/articles-by-author/aly/"}An Exploration of Sublingual Estradiol as an Alternative to Oral Estradiol in Transfeminine People2021-06-11T20:26:25-07:002021-09-06T00:00:00-07:00https://transfemscience.org/articles/sublingual-e2-transfemAn Exploration of Sublingual Estradiol as an Alternative to Oral Estradiol in Transfeminine People
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Wiegratz, I., Fink, T., Rohr, U. D., Lang, E., Leukel, P., & Kuhl, H. (2001). Überkreuz-Vergleich der Pharmakokinetik von Estradiol unter der Hormonsubstitution mit Estradiolvalerat oder mikronisiertem Estradiol. [Cross-over comparison of the pharmacokinetics of estradiol during hormone replacement therapy with estradiol valerate or micronized estradiol.] Zentralblatt für Gynäkologie, 123(9), 505–512. [PubMed] [DOI:10.1055/s-2001-18223]
Wisner, K. L., Sit, D. K., Moses-Kolko, E. L., Driscoll, K. E., Prairie, B. A., Stika, C. S., Eng, H. F., Dills, J. L., Luther, J. F., & Wisniewski, S. R. (2015). Transdermal estradiol treatment for postpartum depression: a pilot randomized trial. Journal of Clinical Psychopharmacology, 35(4), 389–395. [DOI:10.1097/JCP.0000000000000351]
Wren, B. G., Day, R. O., McLachlan, A. J., & Williams, K. M. (2003). Pharmacokinetics of estradiol, progesterone, testosterone and dehydroepiandrosterone after transbuccal administration to postmenopausal women. Climacteric, 6(2), 104–111. [DOI:10.1080/cmt.6.2.104.111]
-]]>{"first_name"=>"Sam", "last_name"=>"S.", "author-link"=>"/about/#sam", "articles-link"=>"/articles-by-author/sam/"}Clinical Guidelines with Information on Transfeminine Hormone Therapy2020-11-20T10:00:00-08:002023-05-23T00:00:00-07:00https://transfemscience.org/articles/transfem-hormone-guidelinesClinical Guidelines with Information on Transfeminine Hormone Therapy
+]]>{"first_name"=>"Sam", "last_name"=>"S.", "author-link"=>"/about/#sam", "articles-link"=>"/articles-by-author/sam/"}Clinical Guidelines with Information on Transfeminine Hormone Therapy2020-11-20T10:00:00-08:002024-03-21T00:00:00-07:00https://transfemscience.org/articles/transfem-hormone-guidelinesClinical Guidelines with Information on Transfeminine Hormone Therapy
By
Aly | First published November 20, 2020
- | Last modified May 23, 2023
+ | Last modified March 21, 2024
Abstract / TL;DR
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Deutsch / Center of Excellence for Transgender Health, University of California, San Francisco (UCSF) [San Francisco, California]
2016
Online document
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AusPATH. (2022). Australian Informed Consent Standards of Care for Gender Affirming Hormone Therapy. Australia: Australian Professional Association for Trans Health. [URL] [PDF]
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Belzer, M. E., Burnett, J., Deutsch, M., Franicevich, J., Gorton, R. N., Hastings, J., Karasic, D., Kohler, L., Vanderleest, J., Van Maasdam, J., Olson, J., Green, J., & DeVries, C. (April 2011). Primary Care Protocol for Transgender Patient Care, 1st Edition. Center of Excellence for Transgender Health, University of California, San Francisco, Department of Family and Community Medicine. [URL] [PDF]
Bewley, S., Dahlen, S., Connolly, D., Arif, I., Junejo, M., & Catherine, M. (2021). International Clinical Practice Guidelines for Gender Minority/Trans People: Systematic Review & Quality Assessment. How Does the Endocrine Society Fare? Journal of the Endocrine Society, 5(Suppl 1), A791–A791. [DOI:10.1210/jendso/bvab048.1609]
Bourns, A. (2019). Guidelines for Gender-Affirming Primary Care with Trans and Non-Binary Patients, 4th Edition. Toronto: Rainbow Health Ontario/Sherbourne Health. [URL] [PDF]
Callen-Lorde Community Health Center. (2018). Protocols for the Provision of Hormone Therapy. New York City: Callen-Lorde Community Health Center. [URL] [PDF]
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Wilczynski, C., & Emanuele, M. A. (2014). Treating a transgender patient: overview of the guidelines. Postgraduate Medicine, 126(7), 121–128. [DOI:10.3810/pgm.2014.11.2840]
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Ziegler, E., Carroll, B., & Charnish, E. (2021). Review and Analysis of International Transgender Adult Primary Care Guidelines. Transgender Health, 6(3), 139–147. [DOI:10.1089/trgh.2020.0043]
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]]>{"first_name"=>"Aly", "last_name"=>"W.", "author-link"=>"/about/#aly", "articles-link"=>"/articles-by-author/aly/"}Spironolactone and Claims About Increased Visceral Fat in Transfeminine People2020-10-25T09:56:15-07:002022-10-02T00:00:00-07:00https://transfemscience.org/articles/spiro-visceral-fatSpironolactone and Claims About Increased Visceral Fat in Transfeminine People
+]]>{"first_name"=>"Aly", "last_name"=>"W.", "author-link"=>"/about/#aly", "articles-link"=>"/articles-by-author/aly/"}Spironolactone and Claims About Increased Visceral Fat in Transfeminine People2020-10-25T09:56:15-07:002022-10-02T00:00:00-07:00https://transfemscience.org/articles/spiro-visceral-fatSpironolactone and Claims About Increased Visceral Fat in Transfeminine People
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Quaynor, S. D., Stradtman, E. W., Kim, H., Shen, Y., Chorich, L. P., Schreihofer, D. A., & Layman, L. C. (2013). Delayed Puberty and Estrogen Resistance in a Woman with Estrogen Receptor α Variant. New England Journal of Medicine, 369(2), 164–171. [DOI:10.1056/nejmoa1303611]
Rinaldi, S., Geay, A., Déchaud, H., Biessy, C., Zeleniuch-Jacquotte, A., Akhmedkhanov, A., Shore, R. E., Riboli, E., Toniolo, P., & Kaaks, R. (2002). Validity of free testosterone and free estradiol determinations in serum samples from postmenopausal women by theoretical calculations. Cancer Epidemiology and Prevention Biomarkers, 11(10), 1065–1071. [Google Scholar] [PubMed] [URL]
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-]]>{"first_name"=>"Aly", "last_name"=>"W.", "author-link"=>"/about/#aly", "articles-link"=>"/articles-by-author/aly/"}Bicalutamide and its Adoption by the Medical Community for Use in Transfeminine Hormone Therapy2020-07-01T18:39:00-07:002023-04-17T00:00:00-07:00https://transfemscience.org/articles/bica-adoptionBicalutamide and its Adoption by the Medical Community for Use in Transfeminine Hormone Therapy
+]]>{"first_name"=>"Aly", "last_name"=>"W.", "author-link"=>"/about/#aly", "articles-link"=>"/articles-by-author/aly/"}Bicalutamide and its Adoption by the Medical Community for Use in Transfeminine Hormone Therapy2020-07-01T18:39:00-07:002024-03-20T00:00:00-07:00https://transfemscience.org/articles/bica-adoptionBicalutamide 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
+ | Last modified March 20, 2024
Abstract / TL;DR
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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.
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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 (Associated Press, 2023; Missouri Government, 2023b). Bicalutamide and the liver toxicity instance were not further described with these developments.
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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 (Associated Press, 2023a; Missouri Government, 2023b). Bicalutamide and the liver toxicity instance were not further described with these developments. The new state law restricting gender-affirming care took effect August 28, 2023, and Washington University announced that it would stop prescribing puberty blockers and hormone therapy to transgender youth shortly thereafter (Associated Press, 2023b).
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A New York Times article with additional information on the case was also subsequently published (Ghorayshi, 2023 [Excerpts]). It was noted that the adolescent had been on bicalutamide for 1 year and definitely experienced hepatotoxicity. However, she also had a complicated medical history, including being immunocompromised, having recently had COVID-19, and having taken another drug known to be associated with hepatotoxicity. As such, the hepatotoxicity cannot be definitively attributed to bicalutamide, but it simultaneously cannot be ruled out that bicalutamide was involved or causative.
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Subsequent Burgener et al. (2023, 2024) Findings
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Following the preceding case, Dr. Lewis and colleagues went on to publish a conference abstract and preprint of a study of bicalutamide in transfeminine youth and young adults in which they stated that it does not increase liver enzymes in this population (Burgener et al., 2023; Burgener et al., 2024). However, a closer look at their data show that bicalutamide did statistically significantly elevate certain liver parameters relative to other antiandrogens, namely rates of elevated aspartate aminotransferase (AST) (upper limit of normal 10.7% vs. 1.5%, P = 0.02) (Burgener et al., 2024). Likewise, rates of elevated alanine aminotransferase (ALT) appeared to trend in the direction of being increased, though this was not statistically significant (upper limit of normal 16.7% vs. 11.6%, P = 0.37) (Burgener et al., 2024). In any case, rates of clinically significant elevations in liver enzymes with bicalutamide, defined as greater than three times the upper limit of normal, were not significantly increased in the study.
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On the basis of the relevant research in men with prostate cancer (Wiki), Dr. Lewis and colleagues’ study, with a bicalutamide-group sample size of only 84 transfeminine individuals, was clearly greatly underpowered for evaluating liver function changes. Per the Early Prostate Cancer trial of high-dose bicalutamide monotherapy in men with prostate cancer, elevated liver enzymes appear to occur with bicalutamide at a rate of only about 1.5% more than placebo, or roughly an additional 1 in every 66 people (Wiki). Based on power analysis, this would require a far larger sample size to have adequate statistical power and actually have a chance of achieving statistical significance.
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As such, it seems to the present author premature to conclude that bicalutamide does not elevate liver enzymes in transfeminine people.
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Dr. Lewis and colleagues didn’t mention in their study paper the transfeminine adolescent liver toxicity case reported by Jamie Reed that was said to have occurred at their clinic nor have they published a case report about this instance. Instead, only the following is stated:
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One case report published in 2024 described a transgender female adolescent prescribed bicalutamide 50 mg daily who presented to a hospital with liver toxicity that resolved after stopping bicalutamide (Wilde et al., 2024). This appears to be the first documented case of bicalutamide-induced hepatoxicity in a transgender female.
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While this case was, coincidentally, also a 17-year-old transfeminine adolescent (Wilde et al., 2024), this instance, per the medical histories and reporting authors/institutions, appears to be distinct from Dr. Lewis’s that was reported by Jamie Reed.
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However, Dr. Lewis and colleagues did note the following in their paper, which plausibly might have been the Jamie Reed case:
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There was one individual in whom bicalutamide was stopped after the follow-up period designated for the study. This individual developed ALT and AST >2x ULN after an episode of COVID and had a thorough hepatology evaluation. As ALT and AST were never > 3x ULN, it was not recommended that bicalutamide be stopped; however, ultimately a clinical decision was made to stop the medication and ALT and AST normalized.
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Another concern with Dr. Lewis and colleagues’ paper pertains to the following statements:
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Whereas bicalutamide doses for prostate cancer reach 150 mg daily, doses used in the care of AMAB transfeminine individuals are much lower (25-50 mg daily).
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Bicalutamide doses used in prostate cancer are up to 150 mg daily. Due to these concerns of liver toxicity, bicalutamide has not been routinely used as an anti-androgen in AMAB transfeminine individuals, despite the much lower doses needed in this population (∼25-50 mg daily).
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In actuality, bicalutamide is most widely used in prostate cancer, in the form of combined androgen blockade with surgical or medical castration, at a dosage of 50 mg/day, whereas the 150 mg/day dosage is used less commonly, in the form of monotherapy (Wiki). Among the published case reports of hepatotoxicity with bicalutamide in men with prostate cancer, half have been at a dose of 50 mg/day and the other half have been at a dose of 80 to 150 mg/day (Wiki). The two instances of death due to hepatotoxicity with bicalutamide were both at 50 mg/day. There is currently no evidence that the hepatotoxicity of bicalutamide is dose-dependent across its clinically used dosage range (Wiki), although employment of the lowest effective dose in transfeminine people nonetheless seems prudent just in case. Hence, in contrast to Dr. Lewis and colleague’s claims, a bicalutamide dosage of 50 mg/day is not less than that used in prostate cancer, and clearly retains substantial hepatotoxic potential.
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Update 5: New 2022, 2023, and 2024 Bicalutamide Publications
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2022
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Angus, L., Nolan, B., Zajac, J., & Cheung, A. (November 2022). Use of bicalutamide as an androgen receptor antagonist in transgender women. ESA/SRB/APEG/NZSE ASM 2022, November 13-16, Christchurch, Abstracts and Programme, 127–127 (abstract no. 280). [URL] [PDF] [Full Abstract Book]
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2023
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Angus, L. M., Nolan, B. J., Zajac, J. D., & Cheung, A. S. (November 2023). Bicalutamide as an anti-androgen in trans people: a cross-sectional study. AusPATH 2023 Symposium. [URL] [PDF] [Slides] [Trans Health Research Blog Post]
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Bambilla, A., Beal, C., & Vigil, P. (2023). Improving Access to Bicalutamide in Gender Affirming Medical Care. [Unpubished/pending publication] [QueerCME Blog Post]
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Burgener, K., DeBosch, B., Lewis, C., Wallendorf, M., & Herrick, C. (May 2023). Assessment of Liver Function and Toxicity in Transgender Female Adolescents Prescribed Bicalutamide. Hormone Research in Paediatrics, 96(Suppl 3 [Abstracts of the 2023 Pediatric Endocrine Society (PES) Annual Meeting’ to Hormone Research in Paediatrics]): 377–378 (abstract no. 6232). [DOI:10.1159/000531602] [PDF]
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Gómez-Aguilar, F., Martínez-Sánchez, L., Arias-Constantí, V., Muñoz-Santanach, D., & Sarquella-Brugada, G. (2023). QT prolongation and Torsade de Pointes in a 13-year-old transgender adolescent in treatment with bicalutamide and tacrolimus. Clinical Toxicology, 61(Suppl 1 [43rd International Congress of the European Association of Poisons Centres and Clinical Toxicologists (EAPCCT), 23–26 May 2023, Palma de Mallorca, Spain]), 81–82 (abstract no. 170). [DOI:10.1080/15563650.2023.2192024] [PDF] [Reactions Weekly]
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Karakılıç Özturan, E., Öztürk, A. P., Baş, F., Erdoğdu, A. B., Kaptan, S., Kardelen Al, A. D., Poyrazoğlu, Ş., Yıldız, M., Direk, N., Yüksel, Ş., & Darendeliler, F. (2023). Endocrinological Approach to Adolescents with Gender Dysphoria: Experience of a Pediatric Endocrinology Department in a Tertiary Center in Turkey. Journal of Clinical Research in Pediatric Endocrinology, 15(3), 276–284. [DOI:10.4274/jcrpe.galenos.2023.2023-1-13]
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Vierregger, K., Tetzlaff, M., Zimmerman, B., Dunn, N., Finney, N., Lewis, K., Slomoff, R., & Strutner, S. (May 2023). Bicalutamide Use as Antiandrogen in Trans Feminine Adults - A Safety Profile. National Transgender Health Summit (NTHS) 2023 Symposium. [Event Agenda PDF] [Symposium Session] [Symposium Abstracts/Program Book]
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Vierregger, K. S. (November 2023). Bicalutamide Use as Antiandrogen in Trans Feminine Adults - A Safety Profile. USPATH 2023 Symposium. [Symposium Schedule]
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Warus, J. (November 2023). Safety of Bicalutamide as Anti-Androgenic Therapy in Gender Affirming Care for Adolescents and Young Adults: A Retrospective Chart Review. USPATH 2023 Symposium. [Symposium Schedule]
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Wilde, B., Diamond, J. B., Laborda, T. J., Frank, L., O’Gorman, M. A., & Kocolas, I. (2023). Bicalutamide-Induced Hepatotoxicity in a Transgender Male-to-Female Adolescent. Journal of Adolescent Health, 74(1), 202–204. [DOI:10.1016/j.jadohealth.2023.08.024]
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2024
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Burgener, K., DeBosch, B., Wang, J., Lewis, C., & Herrick, C. J. (2024). Bicalutamide does not raise transaminases in comparison to alternative anti-androgen regimens among transfeminine adolescents and young adults: a retrospective cohort study. medRxiv, preprint. [DOI:10.1101/2024.02.21.24302999v1] [PDF]
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Fuqua, J. S., Shi, E., & Eugster, E. A. (2024). A retrospective review of the use of bicalutamide in transfeminine youth; a single center experience. International Journal of Transgender Health, advance online publication. [DOI:10.1080/26895269.2023.2294321]
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Shumer, D., & Roberts, S. A. (2024). Placing a Report of Bicalutamide-Induced Hepatotoxicity in the Context of Current Standards of Care for Transgender Adolescents. Journal of Adolescent Health, 74(1), 5–6. [DOI:10.1016/j.jadohealth.2023.10.010]
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Update 6: Original Bicalutamide Liver and Lung Toxicity Analysis by Sam
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A few years ago back in 2021, Transfeminine Science author Sam conducted an original analysis of the incidence of liver and lung toxicity with bicalutamide in the published clinical trial literature. This project was never finished or made publicly available. However, with bicalutamide being increasingly studied and adopted for use in transfeminine people, it seems quite valuable and relevant today. As such, we have opted to now publish Sam’s analysis in this section.
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Sam’s analysis can be found in the provided document here. In terms of methodology, she searched PubMed for all clinical trials of bicalutamide, collated all of the relevant results into a table, and then calculated the incidences of serious liver toxicity and lung toxicity from those data. In clinical trials, adverse events are rated in terms of grades of severity, with a Grade 3 adverse event defined as “severe”, Grade 4 as “life-threatening”, and Grade 5 as “death” (Wiki).
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Of 229 results, 33 trials were found to be relevant and were included. Most of the trials were in men with prostate cancer, but a few were in women with cancer and boys with precocious puberty. Sam found that of a total of 7,703 evaluable participants, there were 2 instances of serious liver toxicity and 2 instances of serious lung toxicity with bicalutamide. This resulted in the same incidence rate of 0.026% (95% CI: 0.003% to 0.094%) or approximately 1 in 3,846 individuals for both liver toxicity and lung toxicity. Combining these toxicities resulted in a total incidence of serious liver or serious lung toxicity with bicalutamide of 0.052% (95% CI: 0.014% to 0.133%) or approximately 1 in 1,923 individuals. All of the observed toxicity events were rated as Grade 3 or 4. It should be noted that clinical trials of bicalutamide typically employ careful laboratory monitoring and assessment of clinical adverse events as well as prompt medication discontinuation upon unfavorable laboratory changes.
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While the confidence intervals (CIs) in Sam’s analysis were wide and hence the estimates are very rough, they provide an idea of the potential real-world risk of serious toxicity with bicalutamide in transfeminine people based on high-quality clinical data. Notably, they do not suffer from the problem of under-reporting of adverse events that occurs with published case reports, pharmacovigilance databases, and certain types of observational studies. However, limitations of Sam’s analysis include (1) toxicity incidence rates for no-bicalutamide controls not being assessed and (2) most of the patients having cancer and being of older age, and hence the generalizability of the findings to healthy transfeminine people not being fully clear. In any case, I was surprised by how high the incidence rates were when I first saw her analysis, and I suspect that others may be as well.
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Vierregger, K., Tetzlaff, M., Zimmerman, B., Dunn, N., Finney, N., Lewis, K., Slomoff, R., & Strutner, S. (2023). Bicalutamide Use as Antiandrogen in Trans Feminine Adults - A Safety Profile. National Transgender Health Summit (NTHS) 2023 Symposium. [Event Agenda PDF] [Symposium Session] [Symposium Abstracts/Program Book]
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Vierregger, K. S. (2023). Bicalutamide Use as Antiandrogen in Trans Feminine Adults - A Safety Profile. USPATH 2023 Symposium. [Symposium Schedule]
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Warus, J. (2023). Safety of Bicalutamide as Anti-Androgenic Therapy in Gender Affirming Care for Adolescents and Young Adults: A Retrospective Chart Review. USPATH 2023 Symposium. [Symposium Schedule]
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Wilde, B., Diamond, J. B., Laborda, T. J., Frank, L., O’Gorman, M. A., & Kocolas, I. (2023). Bicalutamide-Induced Hepatotoxicity in a Transgender Male-to-Female Adolescent. Journal of Adolescent Health, 74(1), 202–204. [DOI:10.1016/j.jadohealth.2023.08.024]
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-WPATH Symposia Materials - Transfeminine Science
Note: WPATH was renamed from the Harry Benjamin International Gender Dysphoria Association (HBIGDA) to the World Professional Association for Transgender Health (WPATH) in 2007.
Note: WPATH was renamed from the Harry Benjamin International Gender Dysphoria Association (HBIGDA) to the World Professional Association for Transgender Health (WPATH) in 2007.
