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An Exploration of Possibilities for Hormone Therapy in Non-Binary Transfeminine People

By Aly | First published June 13, 2019 | Last modified September 26, 2022

Notice: This page was originally posted as a thread on social media and has not been properly or fully revised since being moved to Transfeminine Science.

Abstract / TL;DR

Transfeminine people who are non-binary often desire different and more partial feminizing and demasculinizing changes compared to what occurs with conventional transfeminine hormone therapy. For example, non-binary transfeminine people may seek an intermediate physical and hormonal state between what is typical for males and females, may desire substantial or full feminization and demasculinization without breast development, may want to have a more sexually neutral or androgynous appearance, or may wish for feminization but concomitant preservation of more male-typical sexual desire and capacity. These partial goals for transfeminine hormone therapy are being increasingly encountered, but therapeutic methods for achieving them have not yet been studied or established in transgender medicine. Nonetheless, there are a variety of hormonal approaches by which such outcomes could theoretically be achieved. Demasculinization can be produced via partial to full testosterone suppression or blockade using varied doses of antiandrogens, progestogens, and/or gonadotropin-releasing hormone modulators. Feminization and other estrogenic effects with less or no breast development may be produced with selective estrogen receptor modulators or low doses of estradiol. Certain other hormonal agents can be used to achieve various specific effects, like 5α-reductase inhibitors to reduce body hair growth and scalp hair loss, topical androgens applied to the breasts to reduce breast development, and the androgen and anabolic steroid nandrolone decanoate as an alternative to testosterone with less effect in skin and hair follicles. Besides hormonal means, breast removal surgery can be sought to negate breast development. Health risks, particularly those related to androgen deprivation without adequate estrogenic replacement, are a concern with partial approaches to hormone therapy. One such risk, bone density loss, may be reduced with calcium and vitamin D supplementation, bisphosphonates, and weight-bearing exercise. There is increasing interest in partial approaches to hormone therapy in transgender health, so hopefully they will become better characterized and more available and utilized in transgender people in the future.

Introduction

“Non-binary” is a term that refers to transgender people who do not identify within the gender binary. Despite the fact that they do not identify as either male or female, many non-binary transmasculine and transfeminine people pursue hormone therapy just like transgender men and women. While some non-binary individuals opt for a full hormonal transition similarly to most binary-identified transgender people, many non-binary people would prefer only a partial hormonal transition. This could be to achieve an intermediate area between masculine and feminine characteristics, to achieve a more sexually neutral appearance, or to induce some but not all aspects of masculinization or feminization.

There are also individuals who seek hormonal feminization and/or demasculinization but do not actually identify as transgender. These cisgender-identified individuals often refer to themselves as “femboys”. Communities of these individuals exist on social media sites like Reddit (e.g., r/FemboyTransition). Feminization-inclined cisgender people who pursue hormonal transition often have similar preferences as transfeminine non-binary people—one of the most common of which is feminization without breast development. Sometimes these initially cisgender-identified hormonally transitioning individuals end up progressing to a transgender identity with time.

Partial approaches to hormonal transition and even widespread identification as non-binary are fairly recent developments. There is very little written on non-conventional approaches to hormone therapy of this sort in the published literature. Moreover, there are no available standards or guidelines for such therapy at this time. A number of recent reviews have started to discuss possibilities for non-binary hormone therapy however (Richards et al., 2016; Seal, 2017; Bass et al., 2018; Cocchetti et al., 2020). There is currently a discordance between the number of people who desire non-conventional hormonal transition and the clinical establishment of such therapy. Consequently, an exploration of the possibilities from a theoretical standpoint would be of value and is the aim of this review.

As a disclaimer, the ideas in this article are experimental and preliminary. No studies with the goal of partial hormonal transition in transgender people have been conducted as of present and there is no data or evidence in non-binary people to inform the use of such approaches. Instead, we can only extrapolate from theory and research in other groups of people at this time. Examples of these other groups in the case of transfeminine non-binary hormone therapy include cisgender men undergoing hormone therapy for prostate cancer, cisgender men going through treatment for gynecomastia (male breast development), and transgender women undergoing hormone therapy. For these reasons, the present discussion is exploratory and should not be taken as therapeutic recommendations.

Conventional Transfeminine Hormone Therapy

The goal of therapy in conventional hormone therapy for transgender women is to produce the maximum degrees of demasculinization and feminization—including breast development—that are possible. This is achieved by suppressing testosterone levels and increasing estradiol levels such that they are both within normal adult female ranges. Alternatively, the actions of testosterone can be blocked instead of full suppression of testosterone levels. The relevant hormonal changes are accomplished through the administration of hormonal medications including estrogens, progestogens, and/or antiandrogens. Estrogens produce feminization, including breast development, while testosterone suppression causes demasculinization—as well as disinhibits feminization. Estrogens, progestogens, and antiandrogens can all contribute to testosterone suppression.

The specific medications used in conventional transfeminine hormone therapy include estradiol and estradiol esters such as estradiol valerate; antiandrogens like spironolactone, bicalutamide, and gonadotropin-releasing hormone (GnRH) agonists and antagonists; and progestogens such as progesterone and cyproterone acetate (CPA). Androgen synthesis inhibitors such as the 5α-reductase inhibitors (5α-RIs) are also used. 5α-RIs inhibit the metabolism of testosterone into the more potent dihydrotestosterone (DHT), a conversion which only occurs in certain tissues. They have limited tissue-selective antiandrogenic effects, for instance in skin and hair follicles.

The therapeutic goals of a subset of non-binary transfeminine people are equivalent to those of transgender women and hence are compatible with the effects of conventional transfeminine hormone therapy. That is, the maximum possible feminization, including breast development, and demasculinization are the aims of therapy. Non-binary transfeminine people with these preferences can simply use conventional transfeminine hormone therapy for their hormonal transition as opposed to more experimental and non-conventional partial approaches.

For a comprehensive introduction to conventional transfeminine hormone therapy, see this article:

The above article is intended to provide everything one needs to know to achieve a basic understanding of the subject. If you are new to the topic of transgender hormone therapy, it is highly recommended reading prior to continuing in the current article. The introduction covers the sex hormones, their effects, specific hormonal medications used, routes, and dosages for this type of hormone therapy. Much of this information is also applicable to non-conventional transfeminine hormone therapy.

Partial Transfeminine Hormone Therapy

Some non-binary transfeminine people (as well as cisgender-identified individuals seeking hormonal feminization) desire only partial feminization and/or demasculinization. Depending on the specific aims, this can be more complicated and require more thought than conventional transfeminine hormone therapy. The following goals of partial transfeminine hormone therapy may be encountered:

  • An intermediate physical and hormonal state between male and female
  • A more sexually neutral or androgynous appearance that is not necessarily masculine or feminine
  • Substantial or maximal feminization and demasculinization with little or no breast development
  • Substantial or maximal feminization and demasculinization with minimal or no loss of sexual desire, sexual function (i.e., erectile and orgasmic capacity), and/or fertility

The first of these goals is fairly straightforward in that it can entail what is essentially conventional transfeminine hormone therapy using lower medication doses. This will result in partial testosterone suppression and a mixture of both androgens and estrogens as major active sex hormones. The second goal involves deprivation of both androgens and estrogens. While possible, this can have negative consequences as sex hormones are important for maintaining certain aspects of health and well-being. There are potential ways to avoid or mitigate such consequences however. The third and fourth goals are also technically possible but are more difficult to achieve and are likely to require more specialized and potentially complex hormonal approaches.

Suppression and Blockade of Testosterone

If the goal of non-binary transfeminine hormone therapy is simply to achieve an androgynous appearance with minimal or no feminization, this can be achieved via deprivation of testosterone without concomitant administration of an estrogen. There are multiple ways to achieve androgen deprivation or testosterone suppression in people assigned male at birth. These include high-dose progestogen therapy, medical and surgical castration with GnRH agonists/antagonists or gonadectomy, high-dose androgen receptor antagonist therapy, and a few other other possibilities. In this section, I’ll discuss androgen deprivation largely from the standpoint of efficacy. There are problems with androgen deprivation alone in terms of tolerability and safety due to the co-consequence of estrogen deficiency however, which I’ll discuss in the subsequent section.

Testosterone Suppression with High Doses of Progestogens

Androgen deprivation can be achieved with high doses of progestogens, which suppress testosterone levels by up to 50 to 70% (Aly, 2019). This is a substantial decrease in testosterone levels, but is not quite into the female range. Androgen receptor antagonists can additionally be included to block the remaining testosterone that is not suppressed if desired. For these purposes, low-dose cyproterone acetate (e.g., 5.0–12.5 mg/day) (Aly, 2019) plus bicalutamide (e.g., 12.5–50 mg/day) or spironolactone (e.g., 200–400 mg/day) is likely to be an effective regimen. As an alternative to cyproterone acetate, high doses of other progestogens, such as just about any other progestin, or alternatively rectal progesterone (Aly, 2018), can be used instead.

Testosterone Suppression with Medical or Surgical Castration

GnRH agonists and antagonists are another option for testosterone suppression. These medications suppress testosterone levels by about 95%, or into the normal female range or male castrate range (<50 ng/dL). However, GnRH agonists and antagonists are very expensive, although there may be some viable options for obtaining them more cheaply (e.g., certain online pharmacies) (Aly, 2019).

Gonadectomy, or surgical removal of the gonads, can be performed as a more permanent alternative to GnRH agonists and antagonists. However, this procedure is expensive (a few thousand dollars USD), requires minor surgery, and can be more difficult to obtain. Most surgeons require letters from gender therapists and real-life experience; informed-consent surgeons do exist however. Gonadectomy is also irreversible, notably resulting in permanent loss of testes and sterility. In any case, gonadectomy is far less expensive and more convenient than GnRH agonists and antagonists in the long run.

Testosterone Blockade with Antiandrogens

Androgen receptor antagonists like bicalutamide and spironolactone act by directly binding to the androgen receptor and displacing androgens like testosterone and DHT from the receptor, thereby preventing its activation by these androgens. This is in contrast to therapies that act by suppressing androgen production and levels.

High-dose bicalutamide monotherapy (e.g., 150–300 mg/day) is a possible approach for androgen deprivation therapy. However, bicalutamide monotherapy increases testosterone and hence estradiol levels. The testosterone will be blocked by bicalutamide and will not have effects, but estradiol is increased to a concentration range that allows for marked or full feminization, including breast development. In addition, bicalutamide alone, even at very high doses, might not be enough to completely block male-range testosterone. With these considerations, if the goal is full demasculinization with no feminization or breast development, bicalutamide monotherapy is not something that, at least alone, can achieve this.

High-dose bicalutamide is expensive and potentially cost-prohibitive. High-dose spironolactone monotherapy is not a good option for this route as it is a relatively weak antiandrogen and likely falls far short of being able to handle male-range levels of testosterone (at least 200 mg/day appears to be required to fully block female testosterone levels) (Aly, 2018; Wiki). Concomitant partial suppression of testosterone and estrogen levels via additional use of a progestogen (e.g., cyproterone acetate) may be a more feasible option than an androgen receptor antagonist alone.

Some potentially major advantages of high-dose bicalutamide monotherapy are that in contrast to marked or full suppression of testosterone levels, bicalutamide monotherapy largely preserves sexual desire and erectile function and likely does not result in infertility.

Other Options for Testosterone Suppression

Another option is only partial demasculinization, which can be achieved essentially by using lower dosages of the medications discussed above (e.g., cyproterone acetate, bicalutamide). If desired, 5α-reductase inhibitors can be added in this context to more substantially decrease scalp hair loss and body hair growth. Note that if testosterone is more fully suppressed or blocked however, there is likely to be little or no benefit with 5α-reductase inhibitors.

Yet another possibility could be to incorporate low-dose nandrolone decanoate, an androgen receptor agonist and anabolic–androgenic steroid (AAS) with much less masculinizing/androgenic effect in skin and hair follicles (Aly, 2020). This AAS will help to suppress and replace testosterone levels. Nandrolone decanoate might also have the benefit of helping to maintain sexual desire and function. However, nandrolone decanoate was recently discontinued in the United States. Oxandrolone is another, similar AAS, but has been associated with liver toxicity.

Estrogen Deficiency and Replacement

While androgen deprivation therapy is effective for achieving the desired changes—specifically demasculinization without feminization—it is not recommended by itself. This is because estradiol is produced from testosterone and hence androgen deprivation results in estrogen deficiency as well. Estrogens are essential for maintaining bone density in both men and women, and without them, a person will quickly lose bone mass, eventually develop osteoporosis, and be at a high risk for bone fractures. Skeletal and postural disfigurement may also eventually occur (Figure; Figure). In addition, the person is likely to experience other menopause-like symptoms, such as hot flashes, mood and sleep problems, sexual dysfunction (e.g., low sexual desire, erectile dysfunction), and accelerated aging of the skin (Wiki). An increased risk of weight gain, type 2 diabetes, cardiovascular disease, and dementia may be associated with sex hormone deficiency as well. As such, extended deprivation of both androgens and estrogens with no estrogenic supplementation is not advisable.

With that said, a couple of clarifications should be made. Due to preservation of estradiol levels, high-dose bicalutamide monotherapy has minimal to no risk of bone density loss or most other menopausal symptoms. In addition, the low-dose cyproterone acetate plus low-dose bicalutamide option may have less of a risk of menopausal symptoms and possibly osteoporosis as well. This is because high-dose progestogens (of which “low-dose” cyproterone acetate certainly qualifies) can help treat certain menopausal symptoms such as hot flashes and possibly bone density loss, and also because some estradiol will be preserved (since testosterone will only be suppressed by 70 to 80% rather than more fully). With that said however, in the latter case, it is probably best not to take any risks.

Selective Estrogen Receptor Modulators (SERMs)

Instead of only androgen and estrogen deprivation, the inclusion of selective estrogen receptor modulators (SERMs), so-called partial estrogens, can be employed. These medications are partial agonists of the estrogen receptor, and have mixed estrogenic and antiestrogenic effects depending on the tissue. For example, the SERM raloxifene has estrogenic effects in bone, fat tissue, and the liver, but antiestrogenic effects in the breasts. In general, SERMs reduce bone density loss and osteoporosis risk while not causing breast development (and actually blocking it). A full list of SERMs can be found here. However, practically speaking, only raloxifene (Evista), tamoxifen (Nolvadex), and toremifene (Fareston) are available, inexpensive, and commonly used. For an overview of the estrogenic and antiestrogenic effects of the different SERMs in different tissues, see here. In general, SERMs have a fairly similar pattern of effects. Although we have some idea of the differential tissue effects of SERMs, in many cases we do not know how they behave in specific tissues. For example, only a single clinical study has shown that a SERM, specifically raloxifene, has estrogenic effects in fat tissue (Francucci et al., 2014). In addition, it is less clear how SERMs behave in, for example, skin, or in most of the brain.

SERMs also have various side effects. For instance, SERMs commonly produce hot flashes as an adverse effect. However, the fairly recently introduced combination of bazedoxifene/conjugated estrogens (Duavee) has been found to reduce the incidence of hot flashes in postmenopausal women (Duavee label). It is still on-patent and hence is expensive however. In any case, SERMs are also likely to produce other menopause-like symptoms. Additionally, SERMs have estrogenic effects in the liver and therefore influence production of coagulation factors and decrease production of insulin-like growth factor-1 (IGF-1), among other potentially undesirable changes. Due to the increase in coagulation with SERMs, they have a notable risk of blood clots and cardiovascular complications like stroke (Aly, 2020). Some SERMs, like tamoxifen, also have unique off-target actions and risks, for instance rare liver toxicity. Raloxifene is a more selective and probably safer SERM than tamoxifen.

SERMs are effective for maintaining bone density. However, they are, unfortunately, only partially estrogenic in bone and hence are submaximally effective for such purposes—they are significantly more effective than no treatment at all but are not as effective as estrogens (Dane et al., 2007; Zirilli et al., 2009; Birzniece et al., 2012; Vestergaard, 2012). Indeed, SERMs have actually been found to significantly antagonize the effects of estradiol on bone, for instance on bone density in premenopausal women (Powles et al., 1996; Burshell et al., 1999) and on bone maturation and growth plate closure in cisgender girls with precocious puberty (Passone et al., 2015). One study in elderly men suggested that 60 mg/day raloxifene is maximally equivalent in terms of bone density effect to estradiol levels of about 26 pg/mL (Doran et al., 2001; Palacios et al., 2020). Below this estradiol level, raloxifene was estrogenic on bone density, whereas above this level, it was antiestrogenic on bone density (Doran et al., 2001; Palacios et al., 2020). As such, although SERMs increase bone density in the context of very low estradiol levels, they are not as effective as estrogens in terms of maintaining bone density and they may still allow for significantly decreased bone density when added to androgen deprivation in non-binary transfeminine people.

Low-Dose Estrogen Supplementation

An alternative to SERMs for avoiding estrogen deficiency is low-dose estrogen therapy. A dosage of oral estradiol of about 1 to 2 mg/day or estradiol levels of about 30 to 50 pg/mL (via another route, for instance transdermal patches) is all that is needed for complete or near-complete prevention of bone density loss (Barbieri, 1992; Roux, 1997; Hadji, Colli, & Regidor, 2019). Moreover, estradiol has a better tolerability and safety profile than SERMs, with a much lower risk of blood clots (Aly, 2020).

A problem with estrogen therapy however is that in the absence of androgens, estrogens even at low levels will induce substantial feminization and breast development. Estradiol levels in normal cisgender girls gradually increase from around 5 to 10 pg/mL at the start of puberty to 50 or 60 pg/mL by late puberty, and these low levels produce full developent of the female secondary sex characteristics (Aly, 2020). Similarly, cisgender females with complete androgen insensitivity syndrome (CAIS) have estradiol levels of only about 35 pg/mL on average yet have complete feminization and excellent breast development (Aly, 2020; Table). Hence, the addition of low-dose estradiol to androgen deprivation would likely be a full transition. Very low doses of estradiol, for instance 0.5 mg/day oral estradiol or a 14 μg/day estradiol patch, achieving estradiol levels of only maybe 20 pg/mL, may be feasible and may result in less feminization. But, while effective for improving bone density (Dane et al., 2007; Birzniece et al., 2012), such doses/levels would not fully protect against bone density loss and other menopause-like symptoms and would likely still produce at least partial feminization. It is notable that even GnRH agonists/antagonists and gonadectomy alone—which reduce estradiol levels to around 10 pg/mL—have a rate of mild gynecomastia of as high as 15% (Di Lorenzo et al., 2005).

Other Therapies for Bone Maintenance

In addition to SERMs and estrogens, other measures to maintain bone mineral density are effective and could be included for further benefit to bone health. Examples include calcium supplementation, vitamin D supplementation, and bisphosphonates like alendronic acid (Fosamax) and zoledronic acid (Zometa) (Chen, Ko, & Chen, 2019; Rizzoli, 2018). Bisphosphonates have adverse effects and risks however. Weight-bearing exercise is also beneficial for bone density (Rizzoli, 2018).

Interestingly, spironolactone was found at 100 mg/day to fully prevent GnRH agonist-induced bone density loss in women in a small randomized controlled trial (Moghetti et al., 1999). The authors hypothesized that this was due to its antimineralocorticoid activity, as aldosterone is negatively correlated with bone density (Moghetti et al., 1999). However, in another study, 100 mg/day spironolactone did not prevent bone density loss caused by high-dose progestogen therapy in the form of 5 mg/day lynestrenol in women (Preželj & Kocijančič, 1994; Preželj & Kocijančič, 1999). Hence, spironolactone should not be relied upon for preservation of bone density.

Onset and Reversibility of Bone Loss

Certain medications used in premenopausal women suppress gonadal sex hormone production and are associated with decreased bone density. These therapies can provide insight on the risk of bone density loss that may occur in non-binary transfeminine people deprived of sex hormones. Examples of such medications include progestogen-only birth control, which partially suppresses estradiol levels (to around 20–50 pg/mL) (Hadji, Colli, & Regidor, 2019), and GnRH agonists/antagonists, which partially to fully suppress estradiol levels depending on the medication and dose. Minimal or no bone density loss occurs with estradiol levels of 30 to 50 pg/mL, whereas significant bone density loss occurs with estradiol levels of 20 to 30 pg/mL (Hadji, Colli, & Regidor, 2019). Reassuringly however, bone density has been found to substantially or fully recover within a few years following discontinuation of progestogen-only birth control in young premenopausal women (Nelson, 2010). Along similar lines, therapy with the GnRH antagonist elagolix is considered to be acceptably safe in premenopausal women for up to 2 years at a dose that results in partial suppression of estradiol levels (to about 40 pg/mL) and for up to 6 months at a dose that results in maximal suppression of estradiol levels (to about 10 pg/mL) (Wiki). As such, a limited period of sex hormone deprivation—for instance as a trial of non-binary transfeminine hormone therapy—may be reasonably safe in terms of bone health. Long-term therapy should include adequate measures to avoid bone density loss however.

Prevention of Breast Development

Estrogen Blockade and Suppression

If the goal is to produce full demasculinization and some or full feminization with the sole exception of breast development, there are a number of ways to possibly achieve this. Androgen deprivation without estrogen supplementation will achieve demasculinization without any feminization or breast development (except for bicalutamide monotherapy of course). However, it is not recommended for reasons described above and would not provide feminization. SERMs are an option; in addition to their capacity to treat osteoporosis, they are used to treat gynecomastia in men, and are capable of fully blocking gynecomastia induced by estrogens when used at sufficient doses (Fentiman, 2018). However, SERMs may allow for only partial feminization rather than full. Aromatase inhibitors, in contrast to SERMs, have no apparent place in this form of hormone therapy, as they are, surprisingly, poorly effective for prevention of gynecomastia (Fagerlund et al., 2015; Bedognetti et al., 2010).

Selective Estrogen Receptor Modulators and Testosterone Elevation

SERMs can be used to prevent breast development, as previously described. A problem with the use of SERMs for this purpose however is that when they are used in people assigned male at birth in whom the gonads are intact and testosterone levels are not suppressed, they will induce substantial increases in gonadal testosterone production and circulating testosterone levels. In men with hypogonadism and consequent low testosterone levels, the SERMs clomifene (20–50 mg/day) and enclomifene (12.5–25 mg/day) increase testosterone levels from about 200–300 ng/dL to about 450–600 ng/dL on average (a change of about 2.0- to 2.5-fold, with an absolute increase of 250–400 ng/dL in this patient population) (Bach, Najari, & Kashanian, 2016; Trost & Khera, 2014). Because they are so effective at increasing testosterone levels, SERMs are used to treat male hypogonadism as an alternative to exogenous testosterone administration. Worse still, SERMs appear to cause even greater increases in testosterone levels in non-hypogonadal men. One study found that 50 mg/day clomifene increased testosterone levels by about 850 ng/dL in healthy younger men and by about 500 ng/dL in elderly men (Trost & Khera, 2014). Similarly, strong increases in testosterone levels have been observed with partial suppression of estradiol levels via aromatase inhibition in young and older men (T’Sjoen et al., 2005; Raven et al., 2006; de Ronde et al., 2009).

If testosterone levels are suppressed, increases in testosterone levels with SERMs will, depending on the degree of testosterone suppression, be less applicable (e.g., with high-dose progestogen therapy) or not applicable at all (e.g., with medical/surgical castration). However, if a SERM is combined with, say, bicalutamide alone, the situation may become even worse. This is because bicalutamide itself produces considerable increases in testosterone levels similarly to SERMs. In elderly men with prostate cancer, bicalutamide monotherapy induces a 1.5- to 2.0-fold rise in testosterone levels, increasing them from about 300–400 ng/dL to about 500–600 ng/dL (an absolute change of about 150–250 ng/dL) (Wiki). In healthy younger men, bicalutamide may increase testosterone levels into the upper end of the normal male range (potentially into the range of around 900–1,200 ng/dL) (Wiki).

As bicalutamide is a competitive antagonist of the androgen receptor, its efficacy is fundamentally both dose-dependent and dependent on testosterone levels. Consequently, in combination with a SERM, it is possible that testosterone levels will become too high for bicalutamide to block. Moreover, endogenous androgens and estrogens are together responsible for maintaining normal homeostatic negative feedback on the hypothalamic–pituitary–gonadal axis (HPG axis) in people assigned male at birth. It seems logical that with little to suppress the axis, gonadal production and hence circulating levels of testosterone and estradiol may simply continue to rise until they overwhelm bicalutamide and/or the SERM it is combined with and restore negative feedback on the HPG axis. For these reasons, it is possible that the combination of bicalutamide and a SERM alone might not be a practical option for non-conventional feminizing hormone therapy.

With all of that said however, the combination of bicalutamide and tamoxifen has been assessed in various studies in men with prostate cancer (PubMed), and increases in testosterone levels have, rather surprisingly, not been a problem in these studies. In terms of the findings, bicalutamide and tamoxifen together do, as expected, increase total testosterone levels. However, the rise in total testosterone levels is not much different from that which occurs with bicalutamide alone. Moreover, free testosterone levels are either increased to a certain degree or are not actually raised at all (Boccardo et al., 2005; Saltzstein et al., 2005; Fradet et al., 2007). This is thought to be due to the fact that SERMs have potent estrogenic effects in the liver and result in increased production of sex hormone-binding globulin (SHBG), consequently reducing the fraction of free and hence bioactive testosterone in the circulation. This serves to offset the biological influence of the increase in total testosterone levels. In accordance, and reassuringly, unfavorable changes in markers of androgen receptor signaling, like higher prostate-specific antigen (PSA) levels, have not been observed relative to bicalutamide alone in the studies.

It is not clear why studies of bicalutamide plus tamoxifen have observed increases in total testosterone levels that are not that different from those of bicalutamide alone. Whatever the reason, these studies suggest that the combination of bicalutamide and tamoxifen (or certain other SERMs) might actually be feasible still for non-conventional feminizing hormone therapy. With that said however, elderly men are a different patient population than non-binary transfeminine people. Older men have diminished increases in testosterone levels with bicalutamide and SERMs compared to healthy young men. In relation to this, the combination might not be as favorable for younger people assigned male at birth.

Tamoxifen very well may be exchangeable with raloxifene for use in combination with bicalutamide. However, it should be noted that in contrast to tamoxifen, raloxifene has never been studied in combination with bicalutamide. Or, at least, not in gonadally intact men; one study of bicalutamide with raloxifene in castrated men with prostate cancer does exist, but that does not provide much in the way of useful information (Ho et al., 2017). Nor has raloxifene actually been properly studied for prevention of gynecomastia. A single retrospective chart review reported that it was effective for pubertal gynecomastia in boys (Lawrence et al., 2004). But that is all the data we have. Conversely, there are many high-quality studies of tamoxifen for prevention of gynecomastia, including in combination with bicalutamide.

In any case, used by themselves in men, raloxifene has been found to result in lower increases in testosterone levels than tamoxifen or toremifene (Tsourdi et al., 2009). As such, bicalutamide and raloxifene together may indeed be similar in terms of testosterone levels relative to the combination of bicalutamide and tamoxifen. This might just be due to raloxifene having lower efficacy as a SERM than tamoxifen or toremifene at the relevant clinical doses however (Tsourdi et al., 2009).

Topical Androgens

Another possibility for prevention of breast development is topical application of a non-aromatizable androgen (i.e., an androgen that cannot be converted into an estrogen)—namely dihydrotestosterone (DHT; Andractim)—to the breasts. Androgens substantially oppose the actions of estrogens in the breasts, and both topical and systemic DHT have been reported to be effective in the treatment of gynecomastia similarly to SERMs in a number of small studies (Kuhn et al., 1982; Kuhn et al., 1983a; Kuhn et al., 1983b; Eberle & Keenan, 1985; Eberle, Sparrow, & Keenan, 1986; Caron et al., 1987; Keenan, Fagan, & Richards, 1989; De Corrado et al., 1998; Benveniste, Simon, & Herson, 2001). Other systemic androgens like nandrolone (Heresová et al., 1981; Heresová & Vrzanova, 2003) and danazol (Buckle, 1980; Ting, Chow, & Leung, 2000) have been reported to be effective as well.

Unfortunately, pharmaceutical topical DHT is only available today in France (Drugs.com). Some compounding pharmacies in certain countries might provide topical DHT preparations. However, DHT does not seem to be available from any compounding pharmacies in the United States. In contrast to DHT, testosterone readily converts into estradiol via aromatization and can actually induce some gynecomastia due to excessive estrogenic exposure. As such, unlike non-aromatizable androgens like DHT, use of testosterone for this purpose is likely inappropriate. There are few or no other options for topical androgens besides testosterone and DHT, so the practicality of this approach is limited.

In contrast to SERMs, topical androgens may not be fully effective for preventing breast development. Whereas SERMs can abolish breast development caused by estrogens, sufficient exposure to estrogens can still mediate significant breast development even in the context of strong androgenic exposure. In addition, topical application of androgens to the breasts is likely to cause local body hair growth and other local androgenic effects, like masculine skin changes, oily skin, and acne. For many transfeminine individuals, such changes would probably be unacceptable. Lastly, there is a risk of systemic distribution of the topically applied androgen (Kuhn et al., 1983a), and hence of elevated circulating androgen levels and androgenic effects elsewhere in the body. This risk would be lessened in combination with an androgen receptor antagonist like bicalutamide. However, androgen receptor antagonists also have the potential to block the local effects of the topical androgen.

Breast Removal Surgery and Breast Irradiation

Two non-medication-based alternatives for prevention of breast development are prophylactic surgical breast removal and prophylactic breast irradiation.

If there is no excess skin, mastectomy, or breast removal surgery, can remove the breasts without leaving obvious scars, as was the case in this young transgender man. Mastectomy is a highly effective means of preventing breast development. Of course, it requires surgery however.

Exposure of the breasts to radiation inhibits subsequent breast development (Photos). Irradiation of the breasts is an inexpensive, easy, and effective technique that is commonly used as prophylaxis against gynecomastia in men with prostate cancer treated with estrogens or high-dose bicalutamide monotherapy (Viani, da Silva, & Stefano, 2012). It is less effective than SERMs however and generally only reduces the severity of gynecomastia rather than fully prevents it (Viani, da Silva, & Stefano, 2012). More concerningly, there is a theoretical increased risk of breast cancer with exposure of the breasts to radiation (Aksnessæther et al., 2018). Research has found a 100-fold higher incidence of breast cancer in young women whose breasts were exposed to radiation during childhood as a consequence of radiotherapy for cancer when compared to other young women (Zacharin, 2010). On the other hand, limited available evidence so far suggests minimal if any increase in breast cancer incidence in elderly men on androgen deprivation and/or estrogen therapy treated with breast irradiation to prevent gynecomastia (Aksnessæther et al., 2018; Viani, da Silva, & Stefano, 2012). However, cancer radiotherapy and other forms of radiation exposure increase the risk of breast cancer in men, particularly those exposed at a young age (Niewoehner, 2008; Giordano, 2005). In addition to theoretical cancer risk, heart and lung issues have been associated with breast irradiation in elderly men with prostate cancer (Tunio et al., 2012; Viani, da Silva, & Stefano, 2012). Due to these health risks, breast irradiation for prevention of breast development is an inadvisable option.

An obvious drawback of breast development prevention with both surgical breast removal and prophylactic breast irradiation is that they are irreversible. If the person ever changes their mind about not wanting breasts or eventually decides to fully transition (a not uncommon occurrence), there is no going back on the choice to permanently negate breast development.

Degree, Onset, and Reversibility of Breast Development

For reasons that are not entirely clear, it is notable that transfeminine people tend to have poor or suboptimal breast development relative to cisgender women (Wierckx, Gooren, & T’Sjoen, 2014; de Blok et al., 2018; Reisman, Goldstein, & Safer, 2019). Likewise, in generally elderly men with prostate cancer, high-dose bicalutamide monotherapy and high-dose estrogen therapy both cause high rates of gynecomastia but produce only mild-to-moderate gynecomastia in 90% of cases (Wiki; Ockrim et al., 2003). (Whether their advanced age is a factor here or not is uncertain but could be involved however.) Hence, any person who was assigned male at birth should, generally speaking or on average, not necessarily expect a marked degree of breast development. Small breasts should generally be anticipated as the most likely outcome. There are always exceptions however, with a subset of transfeminine people experiencing substantial breast development. Hence, the degree of breast development one experiences is a matter of chance, and caution should be advised.

There are a few things to be aware of about breast development. One is that it happens slowly and is not something that becomes substantial overnight. Another is that will not continue to progress if hormones are withdrawn. And finally, it seems to be at least partially reversible if medications are discontinued within a certain amount of time (e.g., one year) (Mancino, Young, & Bland, 2018; Kanakis et al., 2019). However, a study found that bicalutamide monotherapy-induced gynecomastia outcome was worse if tamoxifen was introduced within a month of symptom onset rather than used from the start of therapy (Serretta et al. 2012). In any case, for the preceding reasons, a given individual could self-monitor their breast development, and, if it becomes too much for their liking, alter their medication regimen as desired in order to prevent further or reverse existing breast growth. Hence, breast development may not be something that should be feared excessively.

Updates

Update 1: Xu et al. (2021)

In June 2021, the following review on SERMs for non-binary transfeminine people was published:

  • Xu, J. Y., O’Connell, M. A., Notini, L., Cheung, A. S., Zwickl, S., & Pang, K. C. (2021). Selective Estrogen Receptor Modulators: A Potential Option For Non-Binary Gender-Affirming Hormonal Care? Frontiers in Endocrinology, 12, 701364. [DOI:10.3389/fendo.2021.701364]

The article is the first literature of its kind. In relation to the lack of evidence for the efficacy and safety of SERMs in non-binary transfeminine hormone therapy at present, it stated that SERMs should not be routinely recommended to non-binary transfeminine people. However, it was cautiously permissive of their use in non-binary transfeminine people who request them and provide informed consent. The review concluded that SERMs are a theoretically attractive potential option for non-binary transfeminine hormone therapy and called for clinical research on them for these purposes.

Ada S. Cheung of Trans Health Research in Australia is a co-author on the paper.

A handful of additional but more limited mentions as well as use instances of SERMs for non-binary transfeminine and transmasculine people have also occurred previously in the literature (Carswell & Roberts, 2017; Moser & Devereux, 2019; Pang et al., 2020; Naroji et al., 2021).

Update 2: van Dijken et al. (2022) and Cocchetti et al. (2022)

In March 2022, one of the first studies on tailored hormone therapy for non-binary people was published:

  • van Dijken, J. B., Steensma, T. D., Wensing-Kruger, S. A., Heijer, M. D., & Dreijerink, K. M. (2022). Tailored Gender-Affirming Hormone Treatment in Nonbinary Transgender Individuals: A Retrospective Study in a Referral Center Cohort. Transgender Health, 8(3), 220–225. [DOI:10.1089/trgh.2021.0032]

Moreover, a review of the work by the European Network for the Investigation of Gender Incongruence (ENIGI) described future plans for research by the ENIGI into hormone therapy for non-binary people:

  • Cocchetti, C., Romani, A., Collet, S., Greenman, Y., Schreiner, T., Wiepjes, C., den Heijer, M., T’Sjoen, G., & Fisher, A. D. (2022). The ENIGI (European Network for the Investigation of Gender Incongruence) Study: Overview of Acquired Endocrine Knowledge and Future Perspectives. Journal of Clinical Medicine, 11(7), 1784. [DOI:10.3390/jcm11071784]

Here are some excerpts from the review:

The main future perspectives [of the ENIGI] should include the evaluation of the efficacy and safety of non-standardized hormonal treatment in non-binary trans people.

Regarding GAHT protocols, all participants were treated in line with the World Professional Association for Transgender Health (WPATH) recommendations [2]. Originally, the binary conception of gender was also extended to the transgender experience, limiting hormonal treatment protocols to obtaining a full virilization or feminization/de-virilization. In line with that, trans AMAB (assigned male at birth) people received both anti-androgens and estrogens aimed at obtaining estradiol and testosterone levels within the adult cisgender women’s range.

Trans AFAB (assigned female at birth) people received—still in a binary perspective of gender—T treatment to obtain full virilization, following the same principles of hormone replacement treatment in hypogonadal cisgender men.

Despite growing evidence based on data from many participants, there are still many questions that need to be answered. First of all, to date the ENIGI collaboration has evaluated only the efficacy and safety profile of standardized GAHT in trans people requesting full de-/masculinization or de-/feminization. However, non-binary transgender people represent a growing body of those who refer to gender clinics, and requests for non-standardized GAHT are increasing [42,43]. In line with this, some authors hypothesized both pharmacological and non-pharmacological strategies to respond to the different requests of non-binary people [44,45]. Given the complete lack of data on the efficacy and safety of these treatments, the ENIGI collaboration should focus more on this issue in the near future, and given the large number of participants, individualized variations in hormone treatment are now welcomed.

Supplementary Material

An interesting anecdotal report of hormone therapy with bicalutamide 50 mg/day, cyproterone acetate 12.5 mg/day, and raloxifene 60 mg/day in a formerly self-identified femboy can be found here (PDF).

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