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<!doctype html><html lang="en-US"><head><meta charset="UTF-8"><meta name="viewport" content="width=device-width, initial-scale=1, minimum-scale=1"><title>A Review of Selective Estrogen Receptor Modulators and their Potential for Transfeminine Hormone Therapy - Transfeminine Science</title><link rel="preload" href="../../assets/images/branding/logo.png" as="image" /><link rel="preload" href="../../assets/images/branding/logo-dark.png" as="image" /><link rel="stylesheet" href="../../assets/css/vendor/normalize.css"><link rel="stylesheet" href="../../assets/css/variables.css"><link rel="stylesheet" href="../../assets/css/site-layout.css"><link rel="stylesheet" href="../../assets/css/article-content.css"><link rel="stylesheet" href="../../assets/css/print.css"><meta name="robots" content="noarchive"><link rel="apple-touch-icon" sizes="180x180" href="../../apple-touch-icon.png"><link rel="icon" type="image/png" sizes="32x32" href="../../favicon-32x32.png"><link rel="icon" type="image/png" 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345 -1221 3 c-671 1 -1220 1 -1220 0z" /><path d="M1407 3493 c-1 -1 -1 -157 1 -347 l3 -346 344 0 345 0 0 340 c0 187 0 342 0 345 0 5 -689 13 -693 8z" /><path d="M2457 3493 c-1 -1 -1 -157 1 -347 l3 -346 1219 0 1220 0 0 340 c0 187 -1 342 -2 345 -3 4 -2437 13 -2441 8z" /><path d="M1409 2096 c-2 -2 -3 -160 -1 -350 l3 -346 344 0 344 0 3 346 c2 190 1 348 -1 350 -6 5 -686 5 -692 0z" /><path d="M2459 2096 c-2 -2 -3 -160 -1 -350 l3 -346 1219 0 1219 0 3 346 c2 190 1 348 -1 350 -6 5 -2436 5 -2442 0z" /></g></svg> </span> </button> <span id="sidebar-title">Contents</span></div><div id="sidebar-contents"><div class="toc-h1"><a id="heading-0" href="index.html#top" class="toc-link">Top of page</a><div><div class="toc-h2"><a id="heading-1" href="index.html#personal-statement" class="toc-link">Personal Statement</a></div><div class="toc-h2"><a id="heading-2" href="index.html#executive-summary" class="toc-link">Executive Summary</a></div><div class="toc-h2"><a id="heading-3" href="index.html#introduction" class="toc-link">Introduction</a></div><div class="toc-h2"><a id="heading-4" href="index.html#background" class="toc-link">Background</a></div><div class="toc-h2"><a id="heading-5" href="index.html#estrogen-receptors" class="toc-link">Estrogen Receptors</a></div><div class="toc-h2"><a id="heading-6" href="index.html#selective-estrogen-receptor-modulators-serms" class="toc-link">Selective Estrogen Receptor Modulators (SERMs)</a></div><div class="toc-h2"><a id="heading-7" href="index.html#tissue-selective-estrogen-complexes-tsecs" class="toc-link">Tissue-Selective Estrogen Complexes (TSECs)</a></div><div class="toc-h2"><a id="heading-8" href="index.html#safety-studies" class="toc-link">Safety Studies</a></div><div class="toc-h2"><a id="heading-9" href="index.html#tissue-specific-effects-of-serms" class="toc-link">Tissue-Specific Effects of SERMs</a><div><div class="toc-h3"><a id="heading-10" href="index.html#in-breasts" class="toc-link">In Breasts</a></div><div class="toc-h3"><a id="heading-11" href="index.html#in-fat" class="toc-link">In Fat</a></div><div class="toc-h3"><a id="heading-12" href="index.html#in-muscle" class="toc-link">In Muscle</a></div><div class="toc-h3"><a id="heading-13" href="index.html#in-skin" class="toc-link">In Skin</a></div><div class="toc-h3"><a id="heading-14" href="index.html#in-testes" class="toc-link">In Testes</a></div><div class="toc-h3"><a id="heading-15" href="index.html#in-the-brain" class="toc-link">In the Brain</a></div></div></div><div class="toc-h2"><a id="heading-16" href="index.html#tissue-specific-effects-of-tsecs" class="toc-link">Tissue-Specific Effects of TSECs</a></div><div class="toc-h2"><a id="heading-17" href="index.html#discussion" class="toc-link">Discussion</a></div><div class="toc-h2"><a id="heading-18" href="index.html#references" class="toc-link">References</a></div></div></div></div></div></div><div id="main-area"><div id="article"><h1 id="a-review-of-selective-estrogen-receptor-modulators-and-their-potential-for-transfeminine-hormone-therapy"> <a href="index.html#a-review-of-selective-estrogen-receptor-modulators-and-their-potential-for-transfeminine-hormone-therapy" aria-labelledby="a-review-of-selective-estrogen-receptor-modulators-and-their-potential-for-transfeminine-hormone-therapy" class="anchor-heading"><svg viewBox="0 0 16 16" aria-hidden="true"><use xlink:href="#svg-link"></use></svg></a> A Review of Selective Estrogen Receptor Modulators and their Potential for Transfeminine Hormone Therapy</h1><p>By <a href="../../about/index.html#lain">Lain</a> | First published October 5, 2019 | Last modified October 6, 2020</p><div class="notice">Notice: This page was <a href="../../about/index.html#history">originally posted as a thread on social media and has not been properly or fully revised</a> since being moved to Transfeminine Science.</div><h2 id="personal-statement"> <a href="index.html#personal-statement" aria-labelledby="personal-statement" class="anchor-heading"><svg viewBox="0 0 16 16" aria-hidden="true"><use xlink:href="#svg-link"></use></svg></a> Personal Statement</h2><p>As with my other articles, this one was borne out of a personal need to understand. Like many transfeminine non-binary individuals, my desired gender-affirming hormone therapy (GAHT) outcome is a minimization of breast development with effective feminization elsewhere. From <a href="../../about/index.html#aly">Aly’s</a> excellent resource on non-binary hormone therapy (<a href="../nonbinary-transfem-overview/index.html">Aly, 2019</a>) came my knowledge of raloxifene and a desire to fully understand as precisely as possible its actions. I hope this article is illuminative to others undergoing similar experiences and that together we can build an even greater understanding in creating ourselves.</p><h2 id="executive-summary"> <a href="index.html#executive-summary" aria-labelledby="executive-summary" class="anchor-heading"><svg viewBox="0 0 16 16" aria-hidden="true"><use xlink:href="#svg-link"></use></svg></a> Executive Summary</h2><p>I encourage everyone that wishes a deeper understanding to read the sections below and for those that desire more knowledge to read the <a href="../serms-transfem-suppl/index.html">supplement page</a> provided.</p><p>Selective estrogen receptor modulators (SERMs) work by blocking or activating different estrogen receptors at different levels. Since different tissues have different ratios of these estrogen receptors SERMs act like estrogens in some tissues and block estrogens in other tissues.</p><p>The main SERM up for consideration for transgender GAHT is raloxifene as of the two widely available, generic SERMs, it has the best safety profile and most relevant research.</p><p>Raloxifene acts largely antiestrogenically in breast tissue. It helps to prevent and treat breast cancer. It seems to act estrogenically in various tissues of interest to transgender individuals. It produces a gynoid (feminine) fat distribution, it causes estrogenic like actions on skin, and helps prevent osteoporosis by maintaining bone mineral density. Further it seems to have some estrogenic actions in the brain.</p><p>A TSEC of estradiol and raloxifene may warrant further study for transfeminine individuals. The reasons for discontinuation of research of combined estradiol and raloxifene were due to endometrial thickening and as transfeminine individuals (intersex individuals excepted) do not have an endometrium this is not a cause for concern.</p><p>Lastly, this article would be remiss if not to end with a major word of caution. There is to my knowledge, no published research on SERMs in transgender individuals. There is no long term research on raloxifene or tamoxifen on natal men. Finally, the mechanism of action of SERMs in general is that they partially suppress various types of estrogen receptor activity. They are far away from being fully characterized and it may be the case that the subtle ways in which they differ from estradiol may cause unforeseen long term consequences to transfeminine individuals.</p><p>That being said, they are an exciting frontier in the area of non-binary transfeminine gender-affirming hormone therapy (GAHT).</p><h2 id="introduction"> <a href="index.html#introduction" aria-labelledby="introduction" class="anchor-heading"><svg viewBox="0 0 16 16" aria-hidden="true"><use xlink:href="#svg-link"></use></svg></a> Introduction</h2><p>While many people that begin a path of transfeminine GAHT do so with the desire to fully develop breasts there exists a sizable number of people, many on the non-binary transfeminine spectrum who wish to medically feminize themselves with little breast development. Because of this, <a href="https://en.wikipedia.org/wiki/Raloxifene">raloxifene</a>, a <a href="https://en.wikipedia.org/wiki/Selective_estrogen_receptor_modulator">selective estrogen receptor modulator</a> (SERM), has become talked about as a potential way to achieve this. A second-generation SERM, it was developed to prevent and treat breast cancer and (in the U.S.) prevent osteoporosis. In this article, I will review the <a href="https://en.wikipedia.org/wiki/Estrogen_receptor">estrogen receptor</a>, the mechanism of action of SERMs and how they work in various relevant tissues, as well as discuss a few <a href="https://en.wikipedia.org/wiki/Tissue-selective_estrogen_complex">tissue-selective estrogen complexes</a> (TSEC) that may be of interest.</p><h2 id="background"> <a href="index.html#background" aria-labelledby="background" class="anchor-heading"><svg viewBox="0 0 16 16" aria-hidden="true"><use xlink:href="#svg-link"></use></svg></a> Background</h2><p>For an extremely in-depth review of the estrogen receptors, how they form, and the compounds that bind to them, I recommend <a href="https://doi.org/10.1016/j.mam.2006.07.001">Ascenzi, Bocedi, & Marino (2006)</a>.</p><h2 id="estrogen-receptors"> <a href="index.html#estrogen-receptors" aria-labelledby="estrogen-receptors" class="anchor-heading"><svg viewBox="0 0 16 16" aria-hidden="true"><use xlink:href="#svg-link"></use></svg></a> Estrogen Receptors</h2><p>Estrogens are compounds that cause changes in cells by binding to various estrogen receptors. These receptors are complexes consisting of proteins and other molecules. This binding causes a conformational change (change in shape) in the receptor that then results in some change in cell activity.</p><p>The main types of estrogen receptors are <a href="https://en.wikipedia.org/wiki/Estrogen_receptor_alpha">estrogen receptor alpha</a> (ERα) and <a href="https://en.wikipedia.org/wiki/Estrogen_receptor_beta">estrogen receptor beta</a> (ERβ) as well as <a href="https://en.wikipedia.org/wiki/G_protein-coupled_estrogen_receptor">G protein-coupled estrogen receptor</a> (GPER). The classical way in which estrogens were thought to have an impact is via ERα and ERβ. These are part of the nuclear receptor family. They exist on the nuclear membrane and once bound to an estrogen these receptors form a complicated biological machine that then causes a change in gene expression.</p><p>This estrogen receptor complex comes to exist due to the estrogen receptor containing many binding domains and on these domains other proteins or molecules can bind that then cause the estrogen receptor complex to be either activated, repressed, or destroyed.</p><p>In addition to the classic method of estrogen activation, there exists also GPER activity. G protein-coupled receptors are a huge super family of receptors that are membrane bound (they exist inside the cell membrane) and GPER receptors cause non genomic changes that can result in rapid actions within the cell as there is not a delay of having to generate RNA and then proteins. While there is some research into the role of SERMs with GPERs, much of the focus of research and this article will concern ourselves with classic estrogen receptor activity.</p><h2 id="selective-estrogen-receptor-modulators-serms"> <a href="index.html#selective-estrogen-receptor-modulators-serms" aria-labelledby="selective-estrogen-receptor-modulators-serms" class="anchor-heading"><svg viewBox="0 0 16 16" aria-hidden="true"><use xlink:href="#svg-link"></use></svg></a> Selective Estrogen Receptor Modulators (SERMs)</h2><p><a href="https://en.wikipedia.org/wiki/Estradiol_(medication)">Estradiol</a> is the classic molecule that binds to the various estrogen receptors. Estradiol is an agonist of the estrogen receptors in that it activates them to action. In contrast, there exist <a href="https://en.wikipedia.org/wiki/Antiestrogen">full estrogen receptor antagonists</a> such as <a href="https://en.wikipedia.org/wiki/Fulvestrant">fulvestrant</a> (ICI-182,780), a compound that completely blocks the estrogen receptors from activating. SERMs are molecules that bind to the various estrogen receptors in a way that is at least partially different from estradiol. This means that in some contexts it is an antagonist (<a href="https://en.wikipedia.org/wiki/Antiestrogen">antiestrogenic</a>) and in others it is an agonist (<a href="https://en.wikipedia.org/wiki/Estrogen_(medication)">estrogenic</a>) of the estrogen receptors. SERMs work by binding to ERα and ERβ and GPER at relatively different rates compared to estradiol and acting as either a full or partial antagonist at the receptor. Because different tissues have different ratios of expression of these receptors, the subsequent result is that SERMs act like estradiol in some tissues and act to suppress estradiol like actions in others.</p><p>At a molecular level, this occurs because a SERM is a different shape than estradiol and when it binds to the estrogen receptors its shape and the subsequent change in shape of the estrogen receptor may physically prevent (sterically inhibit) another compound or compounds that would need to bind to the estrogen receptor as well to activate its activity.</p><p>Originally developed for the treatment of breast cancer, the currently developed SERMs all display some similar properties. They act antiestrogenically in breast tissue, with many acting estrogenically on cholesterol and bones, and thus have found use as a preventative measure for osteoporosis in postmenopausal women. The first SERM to become available was <a href="https://en.wikipedia.org/wiki/Tamoxifen">tamoxifen</a> in 1978, with second-generation SERM <a href="https://en.wikipedia.org/wiki/Raloxifene">raloxifene</a> becoming available in 1997 (in the U.S.). More recently, there have been a number of new third-generation SERMs developed, such as <a href="https://en.wikipedia.org/wiki/Bazedoxifene">bazedoxifene</a>, <a href="https://en.wikipedia.org/wiki/Lasofoxifene">lasofoxifene</a>, and <a href="https://en.wikipedia.org/wiki/Ospemifene">ospemifene</a>. However, as these are still under patent they are expensive and therefore do not currently make good candidates for GAHT.</p><h2 id="tissue-selective-estrogen-complexes-tsecs"> <a href="index.html#tissue-selective-estrogen-complexes-tsecs" aria-labelledby="tissue-selective-estrogen-complexes-tsecs" class="anchor-heading"><svg viewBox="0 0 16 16" aria-hidden="true"><use xlink:href="#svg-link"></use></svg></a> Tissue-Selective Estrogen Complexes (TSECs)</h2><p><a href="https://en.wikipedia.org/wiki/Tissue-selective_estrogen_complex">Tissue-selective estrogen complexes</a> (TSECs) are a combination of a SERM with an estrogen. The goal in their development was to create a unique mixture of estrogenic and antiestrogenic effects that would combine the antiestrogenic effects of some SERMs in the breasts (to prevent breast cancer) and endometrium (to prevent endometrial cancer), while maintaining the positive effects of estrogens in postmenopausal women such as improved bone density, cardiovascular health and weight maintenance. The only currently approved TSEC is a combination of <a href="https://en.wikipedia.org/wiki/Conjugated_estrogens">conjugated equine estrogens</a> (CEE) with <a href="https://en.wikipedia.org/wiki/Bazedoxifene">bazedoxifene</a> (CEE/BZA). An abandoned TSEC, <a href="https://en.wikipedia.org/wiki/Estradiol/raloxifene">estradiol/raloxifene</a>, will also be considered in this article – as its reasons for abandonment are largely irrelevant to transfeminine people undergoing GAHT and has a number of advantages over CEE/BZA such as availability and lower risk of complications for transfeminine individuals.</p><h2 id="safety-studies"> <a href="index.html#safety-studies" aria-labelledby="safety-studies" class="anchor-heading"><svg viewBox="0 0 16 16" aria-hidden="true"><use xlink:href="#svg-link"></use></svg></a> Safety Studies</h2><p>The two generically available SERMs, raloxifene and tamoxifen, have both undergone long-term, large-scale studies, specifically the Adjuvant Tamoxifen: Longer Against Shorter (ATLAS) (<a href="https://doi.org/10.1016/s0140-6736(12)61963-1">Davis et al., 2013</a>) study for tamoxifen, showing that its largest risk is endometrial cancer. However, it has significant risk of other serious side effects such as reduced cognition, liver toxicity, and various negative cardiovascular issues (fatty liver disease, deep vein thrombosis, etc…).</p><p>Raloxifene similarly had the Multiple Outcomes of Raloxifene Evaluation (MORE) (<a href="https://doi.org/10.1001/jama.282.7.637">Ettinger, 1999</a>) and Raloxifene Use for The Heart (RUTH) (<a href="https://doi.org/10.1016/s0002-9149(02)02835-7">Wenger et al., 2002</a>) studies conducted and together they had the Study of Tamoxifen and Raloxifene (STAR) (<a href="https://doi.org/10.1001/jama.295.23.joc60074">Vogel et al., 2006</a>) study, which shows that while it still has an increased risk of deep vein thrombosis, it is lower than tamoxifen and it does not have the other negative side effects associated with tamoxifen.</p><h2 id="tissue-specific-effects-of-serms"> <a href="index.html#tissue-specific-effects-of-serms" aria-labelledby="tissue-specific-effects-of-serms" class="anchor-heading"><svg viewBox="0 0 16 16" aria-hidden="true"><use xlink:href="#svg-link"></use></svg></a> Tissue-Specific Effects of SERMs</h2><h3 id="in-breasts"> <a href="index.html#in-breasts" aria-labelledby="in-breasts" class="anchor-heading"><svg viewBox="0 0 16 16" aria-hidden="true"><use xlink:href="#svg-link"></use></svg></a> In Breasts</h3><p>Both tamoxifen and raloxifene have been shown to act antiestrogenically in the breast, and indeed this is the main reason for their development as drugs. They are both shown to decrease the risk of breast cancer in natal women and both have been shown to be effective in treating gynecomastia (male breast growth) (<a href="https://doi.org/10.1016/j.jpeds.2004.03.057">Lawrence et al., 2004</a>; <a href="https://doi.org/10.1186/1741-7015-10-96">Kunath et al., 2012</a>). The exact mechanism of action of both raloxifene and tamoxifen in the breast is still not entirely known. While they induce estrogen receptor changes, there are also several pathways that are not via the estrogen receptor they are involved with that may mediate their anti-breast cancer action and subsequently their anti-breast development activity.</p><h3 id="in-fat"> <a href="index.html#in-fat" aria-labelledby="in-fat" class="anchor-heading"><svg viewBox="0 0 16 16" aria-hidden="true"><use xlink:href="#svg-link"></use></svg></a> In Fat</h3><p>Changes in fat distribution and metabolism are a major aspect of GAHT (see <a href="../hormones-fat-metabolism/index.html">Lain (2019)</a> for an in-depth look on changes in fat distribution and metabolism with GAHT). Gynoid fat distribution occurs via both peripheral activity often by the leptin–ghrelin hormone system, and raloxifene seems to act estrogenically on the leptin-ghrelin hormone system helping to prevent abdominal adiposity (<a href="https://doi.org/10.1097/01.gme.0000227335.27996.d8">Tommaselli et al., 2006</a>; <a href="https://doi.org/10.1210/er.2012-1055">Mauvais-Jarvis, Clegg, & Hevener, 2013</a>). It also appears to act estrogenically directly in fat tissue (adipose tissue) (<a href="https://doi.org/10.1007/bf03347261">Francucci et al., 2005</a>), again helping to increase subcutaneous fat around the thighs and buttocks that is a primary characteristic of gynoid fat distribution. In addition in postmenopausal women, it is found to reduce total cholesterol and LDL cholesterol. However, it does not appear to impact glycemic index, meaning that it does not help prevent postmenopausal type 2 diabetes. It is unknown how exactly this may map to transfeminine individuals.</p><h3 id="in-muscle"> <a href="index.html#in-muscle" aria-labelledby="in-muscle" class="anchor-heading"><svg viewBox="0 0 16 16" aria-hidden="true"><use xlink:href="#svg-link"></use></svg></a> In Muscle</h3><p>While muscle mass is strongly mediated via testosterone (see <a href="../endo-system-muscle/index.html">Lain (2019)</a>, a review on muscle mass and testosterone), there also seems to be a correlation between estrogen and muscle mass. Postmenopausal natal women undergo significant sarcopenia (age-related muscle mass loss) that can be prevented or minimized via estrogen GAHT. Similar to estrogens, raloxifene also helps increase muscle mass in postmenopausal women and prevent loss of muscle mass (<a href="https://doi.org/10.1530/eje-09-0619">Jacobsen et al., 2010</a>). Because the exact mechanism of action by which the estrogen receptors mediates muscle strength is unknown, it is hard to understand how this translates to transfeminine individuals. However, it does point to estrogenic action in muscle tissue.</p><h3 id="in-skin"> <a href="index.html#in-skin" aria-labelledby="in-skin" class="anchor-heading"><svg viewBox="0 0 16 16" aria-hidden="true"><use xlink:href="#svg-link"></use></svg></a> In Skin</h3><p>In classic transfeminine hormone therapy, the softening of skin is often one of the first noticeable effects. In addition in postmenopausal women, a lack of estrogen can cause thinner skin and decreased elasticity, which is preventable via GAHT. In studies, tamoxifen appears to cause abnormal hair follicles, skin atrophy, and even possibly alopecia (hair loss) developing on the crown of the head; this and direct evidence suggests that tamoxifen is an antagonist of the estrogen receptor in hair follicles (<a href="https://doi.org/10.2147/cia.s798">Thornton, 2007</a>). However, there is some evidence to suggest that raloxifene has a positive estrogenic effect on collagen biosynthesis in human skin (<a href="https://doi.org/10.3892/ijmm.12.5.803">Surazynski et al., 2003</a>).</p><h3 id="in-testes"> <a href="index.html#in-testes" aria-labelledby="in-testes" class="anchor-heading"><svg viewBox="0 0 16 16" aria-hidden="true"><use xlink:href="#svg-link"></use></svg></a> In Testes</h3><p>SERMs such as raloxifene and tamoxifen have been found to cause an increase in serum gonadotropins (luteinizing hormone and follicle stimulating hormone) as well as a concurrent increase in testosterone (<a href="https://pubmed.ncbi.nlm.nih.gov/27601965/">Rambhatla, Mills, & Rajfer, 2016</a>). This highlights the importance of using an antiandrogen in conjunction with a SERM in GAHT.</p><h3 id="in-the-brain"> <a href="index.html#in-the-brain" aria-labelledby="in-the-brain" class="anchor-heading"><svg viewBox="0 0 16 16" aria-hidden="true"><use xlink:href="#svg-link"></use></svg></a> In the Brain</h3><p>The estrogen receptors have significant impact on brain function. Estradiol GAHT has been associated with antidepressant effects in postmenopausal women and estrogen receptors mediate significant changes in the hypothalamus related to maintaining body fat percentage and hunger. SERMs in general appear to act on the brain both via the estrogen receptor as well as via non-estrogen-receptor-mediated pathways.</p><p>Tamoxifen in animal models has neuroprotective effects for a number of modes of neural dysfunction including traumatic injury, Parkinson’s disease, Alzheimer’s disease, and mania. However, in some trials, it is also associated with cognitive impairment, including visual memory, verbal memory, visuospatial ability, and speed processing tasks (<a href="https://doi.org/10.1677/jme-10-0122">Arevalo et al., 2010</a>).</p><p>Raloxifene does not appear to have negative cognitive implications as tamoxifen does. However, it is shown to act at least partially estrogenically in the hypothalamus, to reduce anxiety in ovariectomized rats, and to decrease anxiety and depression in postmenopausal women. It may also regulate opioid and GABAergic activity by modulating endorphin levels and has been shown to positively impact schizophrenia (<a href="https://doi.org/10.1677/jme-10-0122">Arevalo et al., 2010</a>).</p><p>SERMs in general and raloxifene in particular seem to have some estrogenic like actions in the brain, though it does not seem to be especially significant (<a href="https://doi.org/10.1210/er.2003-0023">Smith & O’Malley, 2004</a>). However, it is still very far from understood all of its actions in the brain as estrogen receptors are found throughout.</p><h2 id="tissue-specific-effects-of-tsecs"> <a href="index.html#tissue-specific-effects-of-tsecs" aria-labelledby="tissue-specific-effects-of-tsecs" class="anchor-heading"><svg viewBox="0 0 16 16" aria-hidden="true"><use xlink:href="#svg-link"></use></svg></a> Tissue-Specific Effects of TSECs</h2><p>Up till now, we have only talked about individual compounds. However, TSECs came to be developed by the thinking that by combining an estrogen with a SERM you could get a different effect profile. The only currently medically approved TSEC is CEE/BZA. Specifically, the goal for TSECs was to gain many of the beneficial aspects of estrogen GAHT in postmenopausal natal women while blocking the increased risks of breast cancer and endometrial thickening associated with it. In studies of ovariectomized rats, bazedoxifene was found to maintain its antiestrogenic activity in the endometrium without attenuating the estrogen’s positive effects in movement, fat or bone (<a href="https://doi.org/10.1097/gme.0000000000001095">Pickar, Boucher, & Morgenstern, 2018</a>).</p><p>CEE/BZA while approved for postmenopausal women presents a potentially higher risk for transgender individuals due to its increased risk of deep vein thrombosis, and is less affordable being unavailable as a generic formulation. That being the case another TSEC – a combination of raloxifene and estradiol – has had a number of clinical studies performed on it. It was ultimately abandoned by the medical community due to causing endometrial thickening, again something not typically of concern to transfeminine individuals undergoing GAHT. In the studies performed, raloxifene plus estradiol seemed to reduce many postmenopausal symptoms, such as hot flashes, vaginal dryness, and overall treatment satisfaction, compared to just raloxifene (<a href="https://doi.org/10.1097/gme.0b013e31824a74ce">Carneiro, de Cassia de Maio Dardes, & Haidar, 2012</a>).</p><h2 id="discussion"> <a href="index.html#discussion" aria-labelledby="discussion" class="anchor-heading"><svg viewBox="0 0 16 16" aria-hidden="true"><use xlink:href="#svg-link"></use></svg></a> Discussion</h2><p>The primary driver of interest in using SERMs in GAHT is their antiestrogenic effects in the breasts with potential for feminization in other tissues. Of the two affordable and available SERMs, raloxifene by far seems to be the one that has the best safety profile, while also being most effective in the literal research we have on preventing breast growth.</p><p>That being said, TSECs seem to be a potentially untapped area of research. Raloxifene and estradiol, while potentially unsafe for those with uteruses, may be well-tolerated by those without. Research into the potential efficacy of raloxifene plus estradiol both in preventing breast growth and relative rate and degree of feminization otherwise versus estradiol alone and raloxifene alone could potentially yield extremely interesting results for transfeminine individuals seeking GAHT that includes minimal breast development.</p><p>Ultimately, SERMs, and how different they are from estradiol, is still far from being understood. While we have some knowledge that they are generally safe long-term, this information applies pretty much exclusively to postmenopausal natal women, though there is some indication that tamoxifen has a low incidence of adverse effects in natal men (<a href="https://doi.org/10.1111/andr.12197">Wibowo et al., 2016</a>). Because estrogen receptors and their actions in a wide variety of tissues are extremely complex and multifactorial, this means that each SERM and TSEC must be evaluated extremely carefully across these tissues to fully understand it.</p><h2 id="references"> <a href="index.html#references" aria-labelledby="references" class="anchor-heading"><svg viewBox="0 0 16 16" aria-hidden="true"><use xlink:href="#svg-link"></use></svg></a> References</h2><ul><li>Arevalo, M. A., Santos-Galindo, M., Lagunas, N., Azcoitia, I., & Garcia-Segura, L. M. (2010). Selective estrogen receptor modulators as brain therapeutic agents. <em>Journal of Molecular Endocrinology</em>, <em>46</em>(1), R1–R9. [DOI:<a href="https://doi.org/10.1677/jme-10-0122">10.1677/jme-10-0122</a>]</li><li>Ascenzi, P., Bocedi, A., & Marino, M. (2006). Structure–function relationship of estrogen receptor α and β: Impact on human health. <em>Molecular Aspects of Medicine</em>, <em>27</em>(4), 299–402. 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