A Review of Selective Estrogen Receptor Modulators and their Potential for Transfeminine Hormone Therapy
By Lain | First published October 5, 2019 | Last modified October 6, 2020
As with my other posts this one was borne out of a personal need to understand. Like many transfeminine non-binary individuals my desired HRT outcome is a minimization of breast development with effective feminization elsewhere. From Aly’s excellent resource on non-binary hormone therapy came my knowledge of raloxifene and a desire to fully understand as precisely as possible its actions. I hope this post is illuminative to others undergoing similar experiences and that together we can build an even greater understanding in creating ourselves.
I encourage everyone that wishes a deeper understanding to read the sections below and for those that desire more knowledge to read the supplemental materials provided.
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.
The main SERM up for consideration for transgender HRT is raloxifene as of the two widely available, generic SERMs, it has the best safety profile and most relevant research.
Raloxifene acts largely anti-estrogenically 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.
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.
Lastly, this post 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.
That being said, they are an exciting frontier in the area of non-binary transfeminine hormone replacement therapy.
While many people that begin a path of MtF hormone replacement therapy 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, raloxifene, a selective estrogen receptor modulator (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 US) prevent osteoporosis. In this post I will review the estrogen receptor, the mechanism of action of SERMs and how they work in various relevant tissues as well as discuss a few tissue selective estrogen complexes (TSEC) that may be of interest.
For an extremely in-depth review of the estrogen receptors, how they form and the compounds that bind to them I recommend Structure-function relationship of estrogen receptor alpha and beta: impact on human health.
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.
The main types of estrogen receptors are estrogen receptor 𝛼 (ER𝛼) and ERβ as well as G-Protein coupled Estrogen Receptor (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.
This ER complex comes to exist due to the ER containing many binding domains and on these domains other proteins or molecules can bind that then cause the ER complex to be either activated, repressed, or destroyed.
In addition to the classic method of estrogen activation there exist 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 post will concern ourselves with classic ER activity.
Estradiol is the classic molecule that bind to the various estrogen receptors. Estradiol is an agonist of the estrogen receptors in that it activates them to action. In contrast, there exist full estrogen receptor antagonists such as ICI 182,780 a compound that completely blocks the estrogen receptors from activating. Selective estrogen receptor modulators 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 (anti-estrogenic) and in others it is an agonist (estrogenic) 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.
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.
Originally developed for the treatment of breast cancer the currently developed SERMs all display some similar properties. They act anti-estrogenically in breast tissue with many acting estrogenically on cholesterol and bones and thus have found use as a preventative measure for osteoporosis in post-menopausal women. The first SERM to become available was tamoxifen in 1978 with second generation SERM raloxifene becoming available in 1997 (in the US). More recently there have been a number of new third generation SERMs developed such as bazedoxifene, lasofoxifene and ospemifene, however, as these are still under patent they are expensive and therefore do not currently make good candidates for transgender HRT.
Tissue selective estrogen complexes (TSECs) are a combination of a SERM with an estrogen. The goal in their development was to create a unique mixture of estrogenic and anti-estrogenic effects that would combine the anti-estrogenic 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 post-menopausal women such as improved bone density, cardiovascular health and weight maintenance. The only currently approved TSEC is a combination of conjugated equine estrogen (CEE) with bazedoxifene. An abandoned TSEC estradiol/raloxifene will also be considered in this article - as its reasons for abandonment are largely irrelevant to transfeminine people undergoing HRT and has a number of advantages over CEE/BZE such as availability and lower risk of complications for transfeminine individuals.
The two generically available SERMs raloxifene and tamoxifen have both undergone long term, large scale studies specifically the ATLAS 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…).
Raloxifene similarly had the MORE and RUTH studies conducted and together they had the STAR study which shows that while it still has an increased risk of deep vein thrombosis, it is lower than tamoxifen and that it does not have the other negative side effects associated with tamoxifen.
Both tamoxifen and raloxifene have been shown to act anti-estrogenically 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. The exact mechanism of action of both raloxifene and tamoxifen in the breast is still not entirely known. While they induce ER changes there are also several pathways that are not via the ER they are involved with that may mediate their anti-breast cancer action and subsequently their anti-breast development activity
Changes in fat distribution and metabolism are a major aspect of HRT (see this article for an in depth look on changes in fat distribution and metabolism with HRT). 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. It also appears to act estrogenically directly in fat tissue (adipose tissue) again helping to increase subcutaneous fat around the thighs and buttocks that is a primary characteristic of gynoid fat distribution. In addition in post-menopausal 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 post-menopausal type-2 diabetes. It is unknown how exactly this may map to transfeminine individuals.
While muscle mass is strongly mediated via testosterone (see this review on muscle mass and testosterone) There also seems to be a correlation between estrogen and muscle mass. Post menopausal natal women undergo significant sarcopenia (age related muscle mass loss) that can be prevented or minimized via estrogen hormone replacement therapy. Similar to estrogens, raloxifene also helps increase muscle mass in post-menopausal women and prevent loss of muscle mass. Because the exact mechanism of action for 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.
In classic transfeminine hormone therapy the softening of skin is often one of the first noticeable effects. In addition in post-menopausal women a lack of estrogen can cause thinner skin and decreased elasticity, which is preventable via HRT. In studies tamoxifen appears to cause abnormal hair follicles, and skin atrophy and even possibly alopecia developing on the crown of the head, this and direct evidence suggests that tamoxifen is an antagonist of the estrogen receptor in hair follicles. However, there is some evidence to suggest that raloxifene has a positive estrogenic effects on collagen biosynthesis in human skin.
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. This highlights the importance of using an anti-androgen in conjunction with a SERM in transgender HRT.
The estrogen receptors have significant impact on brain function. Estradiol HRT has been associated with anti-depressant effects in post-menopausal 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-ER mediated pathways.
Tamoxifen in animal models has neuroprotective effects for a number of modes of neural dysfunction including traumatic injury, parkinson’s, alzheimer’s and mania. However, in some trials it is also associated with cognitive impairment, including visual memory, verbal memory, visuospatial ability and speed processing tasks.
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 and to reduce anxiety in ovariectomized rats and to decrease anxiety and depression in post-menopausal women. It may also regulate opiate and GABAergic activity by modulating endorphin levels as well and has been shown to positively impact schizophrenia.
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. However, it is still very far from understood all of its actions in the brain as estrogen receptors are found throughout.
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 conjugated equine estrogen and bazedoxifene CEE/BZA. Specifically the goal for TSECs was to gain many of the beneficial aspects of estrogen HRT in post-menopausal natal women while blocking the increased risks of breast cancer and endometrial thickening associated with it. In studies of ovariectomized rats BZA was found to maintain its anti-estrogenic activity in the endometrium without attenuating the estrogens positive effects in movement, fats or bone.
CEE/BZA while approved for post-menopausal 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 HRT. In the studies performed raloxifene + estradiol seemed to reduce many post-menopausal symptoms such as hot flashes, vaginal dryness, and overall treatment satisfaction compared to just raloxifene.
The primary driver of interest in using SERMs in transgender HRT is their anti-estrogenic 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.
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 a E2/RLX both in preventing breast growth and relative rate and degree of feminization otherwise vs. estradiol alone and raloxifene alone could potentially yield extremely interesting results for transfeminine individuals seeking HRT that includes minimal breast development.
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 post menopausal natal women, though there is some indication that tamoxifen has a low incidence of adverse effects in natal men. 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.
Beneficial effects of raloxifene and tamoxifen in the treatment of pubertal gynecomastia Lawrence, Sarah E. et al. The Journal of Pediatrics, Volume 145, Issue 1, 71 - 76
BMC Med. 2012 Aug 28;10:96. doi: 10.1186/1741-7015-10-96. Tamoxifen for the management of breast events induced by non-steroidal antiandrogens in patients with prostate cancer: a systematic review. Kunath F1, Keck B, Antes G, Wullich B, Meerpohl JJ.
Menopause. 2006 Jul-Aug;13(4):660-8. Serum leptin levels and body composition in postmenopausal women treated with tibolone and raloxifene. Tommaselli GA1, Di Carlo C, Di Spiezio Sardo A, Bifulco G, Cirillo D, Guida M, Capasso R, Nappi C.
Endocr Rev. 2013 Jun;34(3):309-38. doi: 10.1210/er.2012-1055. Epub 2013 Mar 4. The role of estrogens in control of energy balance and glucose homeostasis. Mauvais-Jarvis F1, Clegg DJ, Hevener AL.
J Endocrinol Invest. 2005 Jul-Aug;28(7):623-31. Effects of raloxifene on body fat distribution and lipid profile in healthy post-menopausal women. Francucci CM1, Daniele P, Iori N, Camilletti A, Massi F, Boscaro M.
Eur J Endocrinol. 2010 Feb;162(2):371-6. doi: 10.1530/EJE-09-0619. Epub 2009 Nov 2. Raloxifene and body composition and muscle strength in postmenopausal women: a randomized, double-blind, placebo-controlled trial. Jacobsen DE1, Samson MM, Emmelot-Vonk MH, Verhaar HJ.
Clin Interv Aging. 2007;2(3):283-97. Effect of estrogens on skin aging and the potential role of SERMs. Stevenson S1, Thornton J.
Int J Mol Med. 2003 Nov;12(5):803-9.Differential effects of estradiol and raloxifene on collagen biosynthesis in cultured human skin fibroblasts. Surazynski A1, Jarzabek K, Haczynski J, Laudanski P, Palka J, Wolczynski S.
Rev Urol. 2016;18(2):66-72. doi: 10.3909/riu0711. The Role of Estrogen Modulators in Male Hypogonadism and Infertility. Rambhatla A1, Mills JN1, Rajfer J1.
J Mol Endocrinol. 2011 Jan 19;46(1):R1-9. doi: 10.1677/JME-10-0122. Print 2011 Feb. Selective estrogen receptor modulators as brain therapeutic agents. Arevalo MA1, Santos-Galindo M, Lagunas N, Azcoitia I, Garcia-Segura LM.
Endocr Rev. 2004 Feb;25(1):45-71. Coregulator function: a key to understanding tissue specificity of selective receptor modulators. Smith CL1, O’Malley BW.
Menopause. 2018 Sep;25(9):1033-1045. doi: 10.1097/GME.0000000000001095. Tissue selective estrogen complex (TSEC): a review. Pickar JH1, Boucher M2, Morgenstern D3.
Andrology. 2016 Sep;4(5):776-88. doi: 10.1111/andr.12197. Epub 2016 May 6. Tamoxifen in men: a review of adverse events. Wibowo E1, Pollock PA1, Hollis N2, Wassersug RJ3.
Am J Cardiol. 2002 Dec 1;90(11):1204-10. Baseline characteristics of participants in the Raloxifene Use for The Heart (RUTH) trial. Wenger NK1, Barrett-Connor E, Collins P, Grady D, Kornitzer M, Mosca L, Sashegyi A, Baygani SK, Anderson PW, Moscarelli E.
JAMA. 2006 Jun 21;295(23):2727-41. Epub 2006 Jun 5. Effects of tamoxifen vs raloxifene on the risk of developing invasive breast cancer and other disease outcomes: the NSABP Study of Tamoxifen and Raloxifene (STAR) P-2 trial. Vogel VG1, Costantino JP, Wickerham DL, Cronin WM, Cecchini RS, Atkins JN, Bevers TB, Fehrenbacher L, Pajon ER Jr, Wade JL 3rd, Robidoux A, Margolese RG, James J, Lippman SM, Runowicz CD, Ganz PA, Reis SE, McCaskill-Stevens W, Ford LG, Jordan VC, Wolmark N; National Surgical Adjuvant Breast and Bowel Project (NSABP). JAMA. 1999 Aug 18;282(7):637-45.
Reduction of vertebral fracture risk in postmenopausal women with osteoporosis treated with raloxifene: results from a 3-year randomized clinical trial. Multiple Outcomes of Raloxifene Evaluation (MORE) Investigators. Ettinger B1, Black DM, Mitlak BH, Knickerbocker RK, Nickelsen T, Genant HK, Christiansen C, Delmas PD, Zanchetta JR, Stakkestad J, Glüer CC, Krueger K, Cohen FJ, Eckert S, Ensrud KE, Avioli LV, Lips P, Cummings SR.
Lancet. 2013 Mar 9;381(9869):805-16. Long-term effects of continuing adjuvant tamoxifen to 10 years versus stopping at 5 years after diagnosis of oestrogen receptor-positive breast cancer: ATLAS, a randomised trial. Davies C, Pan H, Godwin J, Gray R, Arriagada R, Raina V, Abraham M, Medeiros Alencar VH, Badran A, Bonfill X, Bradbury J, Clarke M, Collins R, Davis SR, Delmestri A, Forbes JF, Haddad P, Hou MF, Inbar M, Khaled H, Kielanowska J, Kwan WH, Mathew BS, Mittra I, Müller B, Nicolucci A, Peralta O, Pernas F, Petruzelka L, Pienkowski T, Radhika R, Rajan B, Rubach MT, Tort S, Urrútia G, Valentini M, Wang Y, Peto R; Adjuvant Tamoxifen: Longer Against Shorter (ATLAS) Collaborative Group.
Menopause. 2012 Jul;19(7):830-4. doi: 10.1097/gme.0b013e31824a74ce. Estrogens plus raloxifene on endometrial safety and menopausal symptoms—semisystematic review. Carneiro AL1, de Cassia de Maio Dardes R, Haidar MA.