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Published Literature on Bicalutamide as an Antiandrogen for Transfeminine People

By Aly W. | First published July 14, 2019 | Last modified December 30, 2020

2011

Gooren (2011)

Gooren, L. J. (2011). Care of transsexual persons. New England Journal of Medicine, 364(13), 1251–1257. [DOI:10.1056/NEJMcp1008161]:

Male-to-Female Transsexuals: Hormonal therapy is prescribed for male-to-female transsexuals to induce breast formation and a more female distribution of fat and to reduce male-pattern hair growth.19 To achieve these goals, the biologic action of androgens must be almost completely neutralized. Administration of estrogens suppresses gonadotropin output and therefore androgen production, but combining this treatment with a progestational agent, a gonadotropin-releasing-hormone (GnRH) analogue,20 or other medications that suppress androgen action (e.g., cyproterone acetate, flutamide, nilutamide, or bicalutamide) appears to be more effective.21

Supplemental Table 1. Cross-sex hormone administration to transsexuals: Male-to-female transsexuals: 1) Drugs suppressing testosterone levels and/or testosterone action: Non-steroidal pure antiandrogens: flutamide 250 mg twice daily, nilutamide 150 mg twice daily, or the more recent bicalutamide 50 mg once daily (fewer side effects).

Ho (2011)

Ho, C. K. (2011). Testosterone testing in adult males. The Malaysian Journal of Pathology, 33(2), 71–81. [PubMed] [URL]:

Anti-androgens such as flutamide, bicalutamide and cyproterone acetate are also used in patients with prostate cancer and sometimes in male-to-female transgender individuals; these anti-androgens bind to the androgen receptor and do not tend to markedly alter serum testosterone concentrations.

2014

Gooren & Asscheman (2014)

Gooren, L., & Asscheman, H. (2014). Sex Reassignment: Endocrinological Interventions in Adults with Gender Dysphoria. In Kreukels, B. P., Steensma, T. D., & de Vries, A. L. (Eds.). Gender Dysphoria and Disorders of Sex Development (pp. 277–297). Springer, Boston, MA. [Google Books] [DOI:10.1007/978-1-4614-7441-8]:

Male-to-Female Transsexual Subjects. […] Several agents are available to inhibit androgen action. In Europe, the most widely used drug is cyproterone acetate (50–100 mg/day), a progestational compound with antiandrogenic properties. If not available, medroxyprogesterone acetate (5–10 mg/day), probably somewhat less effective, is an alternative. Nonsteroidal antiandrogens, such as flutamide ([500–750] mg/day) and nilutamide (150 mg/day), are also used, but they increase gonadotropin output with a rise of testosterone and estradiol; the rise of estradiol is a desirable effect in this context. Spironolactone, a diuretic with antiandrogenic properties, widely used in the USA, has androgen receptor-blocking properties and also decreases testosterone production.

Wierckx, Gooren, & T’Sjoen (2014)

Wierckx, K., Gooren, L., & T’Sjoen, G. (2014). Clinical review: breast development in trans women receiving cross-sex hormones. The Journal of Sexual Medicine, 11(5), 1240–1247. [DOI:10.1111/jsm.12487]:

As there is no FDA approval of cyproterone acetate, many centers in the United States use spironolactone, a diuretic with mainly anti-androgen but also a weak estrogenic [10] and progestational activity [11]. Other agents with anti-androgenic properties used are nonsteroidal androgen receptor blockers, such as flutamide and bicalutamide or 5-alpha reductase inhibitors such as finasteride and dutasteride.

2016

Gooren (2016)

Gooren, L. J. (2016). The Endocrinology of Sexual Behavior and Gender Identity. In Jameson, J. L., & De Groot, L. J. Endocrinology: Adult and Pediatric, 7th Edition (pp. 2163–2176.e4). Elsevier Inc. [Google Books] [Google Books—6th/2010 Edition] [DOI:10.1016/B978-0-323-18907-1.00124-4]:

Male-to-Female Transsexual Treatment. […] For suppression of androgen secretion/action, several agents are available. In Europe, the most widely used drug is cyproterone acetate (usually 50 mg twice daily), a progestational compound with antiandrogenic properties. If not available, medroxyprogesterone acetate, 5 to 10 mg/day, is a less-effective alternative. Nonsteroidal anti-androgens, such as flutamide and nilutamide [and bicalutamide], are also used, but they increase gonadotropin secretion, causing increased secretion of testosterone and estradiol. The latter is desirable in this context, as it has feminizing effects. Spironolactone (up to 100 mg twice daily), a diuretic with antiandrogenic properties, has similar effects and is widely available.

Deutsch (2016)

Deutsch, M. B. (Ed.). (2016). Guidelines for the Primary and Gender-Affirming Care of Transgender and Gender Nonbinary People, 2nd Edition. UCSF Center of Excellence for Transgender Health, Department of Family & Community Medicine, University of California, San Francisco. [URL] [PDF]:

In many countries, cyproterone acetate, a synthetic progestagen with strong anti-androgen activity is commonly used. Cyproterone has been associated with uncommon episodes of fulminant hepatitis.[12] Bicalutamide, a direct anti-androgen used for the treatment of prostate cancer, also has a small but not fully quantified risk of liver function abnormalities (including several cases of fulminant hepatitis); while such risks are acceptable when considering the benefits of bicalutamide in the management of prostate cancer, such risks are less justified in the context of gender affirming treatment.[13] No evidence at present exists to inform such an analysis.

Bourgeois et al. (2016)

Bourgeois, A. L., Auriche, P., Palmaro, A., Montastruc, J. L., & Bagheri, H. (2016). Risk of hormonotherapy in transgender people: Literature review and data from the French Database of Pharmacovigilance. Annales d’Endocrinologie, 77(1), 14–21. [DOI:10.1016/j.ando.2015.12.001]:

Table 1: Drugs for cross-gender hormonal replacement therapy used in the male to female (MtoF) transsexual population: Drug: Non-steroidal anti-androgens: Bicalutamide, flutamide, nilutamide. Dosage and routes of administration: 750 mg/day (flutamide), per os. Mechanism of action: Androgen receptor blockers.

2017

Neyman, Fuqua, & Eugster (2017)

Neyman, A., Fuqua, J. S., & Eugster, E. A. (2017). P3-605. Bicalutamide as an Androgen Blocker with Secondary Effect of Promoting Feminization in Male to Female (MTF) Transgender Adolescents. 10th Individual Abstracts for International Meeting of Pediatric Endocrinology: Free Communication and Poster Sessions, Abstracts. Hormone Research in Paediatrics, 88(Suppl 1), 1–628 (477). [DOI:10.1159/000481424] [PDF]:

Objectives: GnRH analogs are first-line treatment for halting pubertal development in gender variant youth. However, this medication is often denied by third party payors. The pure androgen receptor blocker bicalutamide represents a potential alternative approach to blocking puberty in natal males. Here, we describe the use of bicalutamide in MTF transgender patients.

Methods: Medical records for patients with gender dysphoria (GD) followed in the pediatric endocrine clinic at Riley Hospital for Children were reviewed. All MTF transgender patients treated with bicalutamide were included. Variables evaluated comprised age, duration of follow up, timing of estrogen initiation, laboratory studies and physical exam findings including change in breast Tanner stage during treatment.

Results: Of 77 patients with GD identified, 29 were MTF, of whom 14 (48%) aged 15.8 ± 1.9 years (range 12–18.4 yr) were treated with bicalutamide 50 mg daily between 2013 and 2017. Of these, 3 were started on estrogen concurrently whereas 11 received bicalutamide alone, 7 of whom have returned for follow up thus far. After an average of 5.7 ± 1.5 months, 86% of the patients (n=6) had breast development consisting of Tanner stage III in 4, Tanner stage II in 1, and Tanner stage III/II of the right and left breast in 1. The 7th patient was noted to have Tanner Ill breasts at her 2nd follow-up clinic visit 12.5 months after starting bicalutamide. LFTs were obtained on 4 patients, estradiol on 3 patients and testosterone on 2 patients while exclusively taking bicalutamide. LFTs were unremarkable and concentrations of estradiol and testosterone were 26–61 pg/mL and 524–619 ng/dL, respectively.

Conclusions: Bicalutamide is used in rare forms of precocious puberty in males and has a known side effect of gynecomastia. Here, we report the novel use of bicalutamide as a puberty blocker in MTF patients with GD in whom it also results in feminization by causing breast development. Additional studies are needed to further evaluate the potential role of bicalutamide in the therapeutic armamentarium for the treatment of transgender MTF adolescents.

2018

Kinnear & Shumer (2018)

Kinnear, H. M., & Shumer, D. E. (2018). Duration of Pubertal Suppression and Initiation of Gender-Affirming Hormone Treatment in Youth. Finlayson, C. Pubertal Suppression in Transgender Youth, 73–85. [Google Books] [Google Scholar]:

As a class, the antiandrogens (bicalutamide, flutamide, and nilutamide) bind directly to the androgen receptor, thereby inhibiting its availability and increasing the receptors’ degradation.50 The primary indication is for metastatic prostate cancer, although it has been used in the transfeminine population.52 These three agents differ primarily by pharmacokinetics, bicalutamide having the longest duration of action. While on the medication, testosterone levels are expected to rise dramatically but do not have an effect. Gynecomastia is a recognized side effect and could be desired in the transfeminine population. There are cases of fulminant hepatitis described, and it is recommended that transaminase levels are checked prior to initiation and then at 4-month intervals.53 The use of antiandrogens has not been rigorously studied in the gender nonconforming population, but its use is recommended for consideration in some transgender-health related publications.54-56 (p. 98)

Spironolactone, a weak androgen receptor antagonist, can also be used in [adolescent transgender girls] if GnRH agonists are not used. The medication, prescribed at dosing ranging from 100 to 300 mg/day orally,7 blunts the effect of androgens and can be helpful at slowing development of unwanted facial and body hair, or other masculinizing effects of male puberty. Other medications that suppress androgen action, including cyproterone acetate, flutamide, nilutamide, and bicalutamide, have been reported for use in transgender women as well.38 (p. 81)

Vincent (2018)

Vincent, B. (2018). Gender Affirmation. Transgender Health: A Practitioner’s Guide to Binary and Non-Binary Trans Patient Care (pp. 147–172). Jessica Kingsley Publishers. [Google Books] [Google Scholar]:

Bicalutamide (Casodex®)

This antiandrogen is used by some clinicians in the United States, it is not used in the UK. Its primary use is in the treatment of prostate cancer, but may effectively block testosterone production at much lower doses than are given in that context. Bicalutamide is associated with some risk of liver function abnormalities (Kolvenbag and Blackledge 1996), which are deemed acceptable in the context of prostate cancer but less so in gender affirming medical intervention because of the range of other options available (Deutsch 2017). (pp. 158–159)

There has been specific publication of a case of prostate cancer in a transgender woman, 41 years after accessing HRT (Miksad et al. 2006). In this case, oral bicalutamide and dutasteride were prescribed, which were effective in their antiandrogenic functions while also being maintainable with the patient’s estrogen regimen. Indeed, bicalutamide may be an option as part of transfeminine HRT due to its antiandrogenic properties, such that synergy may be obtained in specific treatment circumstances. (p. 115–116)

Gao, Maurer, & Mirmirani (2018)

Gao, Y., Maurer, T., & Mirmirani, P. (2018). Understanding and addressing hair disorders in transgender individuals. American Journal of Clinical Dermatology, 19(4), 517–527. [DOI:10.1007/s40257-018-0343-z]:

Non-steroidal antiandrogens include flutamide, nilutamide, and bicalutamide, which do not lower androgen levels and may be favorable for individuals who want to preserve sex drive and fertility [9].

Randolph (2018)

Randolph, J. F. (2018). Gender-affirming hormone therapy for transgender females. Clinical Obstetrics and Gynecology, 61(4), 705–721. [DOI:10.1097/GRF.0000000000000396]:

ANDROGEN RECEPTOR BLOCKERS

Androgen receptor blockers bind directly to the androgen receptor and either competitively inhibit binding by testosterone or DHT, or irreversibly bind and induce variable antagonist/agonist effects. The prototype drug in this class is flutamide, a competitive inhibitor of the androgen receptor infrequently used clinically today due to complications including liver failure and death. Bicalutamide is a safer, longer acting alternative with a more favorable safety profile, although a small percentage of users will show elevated liver enzymes and rare cases of liver failure have been reported. Bicalutamide is approved for use in prostate cancer at an oral dose of 50 mg daily, but has been used in the treatment of hirsutism, polycystic ovary syndrome, precocious puberty, persistent erections, and in sex offenders. Studies in transwomen are quite limited, but bicalutamide appears to be effective and induces an actual increase in serum estradiol levels, a welcome adjunct effect in transwomen (Table 4).

TABLE 4. Available Antiandrogens/Androgen Suppressors and Routes of Administration: […] Bicalutamide Oral 50 mg daily

2019

Bretherton et al. (2019)

Bretherton, I., Thrower, E., Grossmann, M., Zajac, J. D., & Cheung, A. S. (2019). Cross‐sex hormone therapy in Australia: the prescription patterns of clinicians experienced in adult transgender healthcare. Internal Medicine Journal, 49(2), 182–188. [DOI:10.1111/imj.14035]:

Table 2. Preferred cross-sex hormone therapy medications: Anti-androgen medications used (more than one option could be selected): Bicalutamide: 1 (3.5%).

Neyman, Fuqua, & Eugster (2019)

Neyman, A., Fuqua, J. S., & Eugster, E. A. (2019). Bicalutamide as an androgen blocker with secondary effect of promoting feminization in male-to-female transgender adolescents. Journal of Adolescent Health, 64(4), 544–546. [DOI:10.1016/j.jadohealth.2018.10.296]:

This is a full paper and study of bicalutamide in adolescent transgender girls (the 2017 abstract above was a preliminary report on this study). It would be too much text to include the whole paper in this article, so here is the abstract instead:

Purpose: The purpose of the study was to describe the novel use of bicalutamide in transgender youth.

Methods: This is a retrospective review of patients with gender dysphoria followed in the pediatric endocrine clinic at Riley Hospital for Children.

Results: Of 104 patients with gender dysphoria, 23 male-to-female adolescents received bicalutamide 50 mg daily as a second-line puberty blocker after insurance company denial of a gonadotropin-releasing hormone analog. Six patients received estrogen concurrently. Of 13 patients treated exclusively with bicalutamide seen in follow-up, 84.6% had breast development within 6 months, the majority being ≥ Tanner stage III.

Conclusions: Bicalutamide may be an alternative to gonadotropin-releasing hormone analogs in transgender male-to-female youth who are also ready to undergo physical transition.

Keywords: Bicalutamide, Transgender care, Gender dysphoria, Puberty blocker

And some additional excerpts from the Introduction and Discussion sections of the paper:

The potent androgen receptor blocker bicalutamide represents a potential alternative approach to GnRHas in natal males. Other antiandrogens used in transgender females include spironolactone and cyproterone acetate. However, both are far less potent than bicalutamide and their use has primarily been limited to adults [1,3]. In contrast, bicalutamide has been used in the treatment of familial male precocious puberty and other forms of peripheral precocious puberty in young boys [4-6]. One of the most common side effects of bicalutamide is breast development due to an alteration in the ratio of androgens to estrogens. Our experience with the use of bicalutamide in precocious puberty formed the basis for the use of this medication in male-to-female (MTF) patients with GD as a strategy for blocking puberty when GnRHas are denied. Interestingly, the resulting “side effect” of breast development has been welcomed by these patients, all of whom are eager to receive cross-hormone treatment (in this case, estrogen) and to undergo feminizing changes. We are not aware of any previous reports of utilizing bicalutamide as a way to block puberty and promote feminization in the transgender MTF population.

We have found that bicalutamide appears to be effective in decreasing androgen exposure with the welcome side effect in these adolescents of promoting feminization. We suspect that the relatively rapid breast enlargement is because of the high potency and purely antagonistic action of bicalutamide on the androgen receptor, leading to increased testosterone levels that are subsequently aromatized to estrogen. In those tested, liver enzymes remained normal, and estradiol levels were above 20 pg/dl with only one exception. There were no apparent adverse effects of bicalutamide in our patients. However, our results must be considered extremely preliminary, and additional data are needed. How bicalutamide might compare to other androgen receptor blockers in terms of safety and efficacy in the adolescent age group is unknown, and the risk for liver toxicity needs to be investigated in larger sample sizes and over a longer duration of time.

The limitations of this study are its small size, minimal laboratory testing, and retrospective nature. Another limitation is that the efficacy of androgen suppression can only be monitored clinically, as testosterone levels actually increase. However, our results suggest that bicalutamide may be an option for transgender MTF adolescents who are denied GnRHas and are also ready for physical feminization. Bicalutamide is also significantly less costly than GnRHas, which costs thousands of dollars per dose. Larger, prospective studies with a more diverse patient population are needed to further evaluate the safety and potential role of bicalutamide in the therapeutic armamentarium for the treatment of transgender MTF youth.

Fishman et al. (2019)

Fishman, S. L., Paliou, M., Poretsky, L., & Hembree, W. C. (2019). Endocrine Care of Transgender Adults. In Poretsky, L. & Hembree, W. C. Transgender Medicine: A Multidisciplinary Approach (pp. 143–163). Humana Press, Cham. [DOI:10.1007/978-3-030-05683-4_8]:

Non-steroidal selective androgen receptor antagonists, developed as a treatment for androgen-sensitive prostate cancer, are occasionally used in transgender females who do not achieve their desired results or do not tolerate alternative drugs [52]. There are isolated reports of successful outcomes with flutamide (Eulexin), though reportedly not as effective as cyproterone acetate in reducing testosterone levels [12]. Both flutamide and bicalutamide (Casodex), in conjunction with oral contraceptive pills, have shown significant improvements in hirsutism in natal females with polycystic ovarian syndrome (PCOS) [53, 54, 55, 56, 57]. The use of these agents as antiandrogens in transgender patients has been limited by concerns of hepatotoxicity. However, at low doses, these agents have shown to be both well tolerated and effective when used for the treatment of hirsutism [57].

Table 8.2. Antiandrogens: […] Type: Bicalutamide. Route: Oral. Dose: 25–50 mg/day.

Note: The last/senior author, Wylie C. Hembree, is one of the authors of the Endocrine Society’s transgender clinical practice guidelines.

Libby, Lee, & Liu (2019)

Libby, V., Lee, M., & Liu, J. H. (2019). Transgender Health: Hormonal Management at 50 Years and Beyond. Maturitas, 126, 34–37. [DOI:10.1016/j.maturitas.2019.04.220]:

Spironolactone, an antiandrogen, has a risk of causing hyperkalemia and is contraindicated in patients with renal or hepatic disease, or cardiovascular disease susceptible to arrhythmias. […] Bicalutamide has been associated rarely with liver abnormalities. For these reasons, a complete metabolic profile is included in the pretreatment assessment and monitoring of antiandrogen therapy [15].

Table 2 Estradiol and Anti-Androgens Management for MTF [5,15,16]: […] Formulation: Bicalutamide. Route of Administration: Oral. Usual Effective Dose: 50 mg daily. Monitoring: Complete metabolic profile every 3 months in first year, then annually.

Hamidi & Davidge-Pitts (2019)

Hamidi, O., & Davidge-Pitts, C. J. (2019). Transfeminine Hormone Therapy. Endocrinology and Metabolism Clinics, 48(2), 341–355. [DOI:10.1016/j.ecl.2019.02.001]:

Antiandrogen Therapy (Spironolactone, Cyproterone Acetate, Finasteride, and Bicalutamide)

[…] Androgen receptor antagonists (eg, bicalutamide) do not reduce testosterone levels and are not recommended as a first-line therapy because of potentially serious hepatotoxic effects.17

Iwamoto et al. (2019)

Iwamoto, S. J., Defreyne, J., Rothman, M. S., Van Schuylenbergh, J., Van de Bruaene, L., Motmans, J., & T’Sjoen, G. (2019). Health Considerations for Transgender Women and Remaining Unknowns: A Narrative Review. Therapeutic Advances in Endocrinology and Metabolism, 10, 1–27. [DOI:10.1177/2042018819871166]:

Data on bicalutamide, an androgen receptor antagonist used in the treatment of prostate cancer, in [transgender women] are nonexistent, but Neyman and colleagues42 recently published on bicalutamide’s feminizing effects (particularly breast development) in AMAB trans adolescents. Another recent study in cisgender (cis) women, with polycystic ovary syndrome (PCOS) showed some improvement in hirsutism when bicalutamide was added to an oral contraceptive pill (OCP).43 It should be noted, however, that bicalutamide has been associated with an increase in liver enzymes.

Note: The last/senior author, Guy T’Sjoen, is one of the authors of the Endocrine Society’s transgender clinical practice guidelines.

TransLine (2019)

TransLine (2019). Gender Affirming Hormone Therapy Prescriber Guidelines. [URL] [PDF]:

Table: Trans Feminine: Medications to Supplement Estrogen. […] Less Frequently Used Anti-Androgens: Bicalutamide Oral (Casodex). Start/Usual Dose: 50mg (1x 50mg tablet). Typical Max Dose: 50mg (1x 50mg tablet). Frequency: Daily. Pros: - Non-steroidal androgen receptor antagonist. Cons: - Potential risk of rapid onset, severe, life-threatening liver toxicity; use extreme caution and monitor closely. Don’t use if +G6PD, or increased risk of methemoglobinemia (e.g. smokers); caution if other hepatotoxic drugs or alcohol. Notes: If utilized must check LFT at baseline, 1 mo, 2 mo, then every 6 mo for lifetime. Flutamide Oral (Eulexin): Start/Usual Dose: 250mg (2x 125mg tablets). Typical Max Dose: 250mg (2x 125mg tablets). Frequency: Daily. Pros: - Non-steroidal androgen receptor antagonist. Cons: See Flutamide Cons; however, Bicalutamide has less hepatotoxity, so if choosing between non-steroidal androgen antagonists, choose Bicalutamide over Flutamide. Notes: If utilized must check LFT at baseline, 1 mo, 2 mo, then every 6 mo for lifetime.

Everett (2019)

Erin Everett, NP-C. (2019 November 11). Episode 4: Fenway Recap on HRT Drugs for Transgender. Exclusively Inclusive. The Fenway Institute. [URL]:

I often get asked about Casodex, or Bicalutamide, which is the other one, the other name for it, sorry, the generic name. It’s prescribed in other countries. It’s more famously known for its work against prostate cancer. When I say that, I mean it’s usually prescribed for patients who’ve had prostate cancer to suppress the testosterone to prevent the prostate cancer from recurring. Of course, a lot of those medicines that block testosterone then have been experimented with blocking testosterone in gender diverse populations. However, it comes with this nasty side effect, which I have not prescribed this medication before for this very reason. One of the things that I set out on a mission for when I got to Fenway was to find out if I could start prescribing this or not. The answer is no, unfortunately, for my patients. The risk of liver toxicity, or as us in the field called hepatic toxicity, is just too large. There is just too much data supporting sudden liver failure and irreversible liver damage related to this drug.

Now people then say, “Well, how come people who’ve had prostate cancer can take it?” Well, it’s risk versus benefit. When it’s the risk of cancer coming back and consuming their body and metastasizing versus the risk of liver damage and liver failure, they take the risk of liver damage and liver failure in order to optimize their life and longevity. But when it comes to hormone replacement therapy and we have a safer option, albeit maybe more uncomfortable option because of side effects, but I can sleep well at night knowing that my patients aren’t going to have spontaneous liver failure or irreversible liver damage. We’re going to go with that one. Like, we’re going to continue to prescribe spironolactone. But what I also reassure my patients is even though spiro has this nasty side effects, you don’t have to stay on it forever.

Note: This is a podcast episode rather than a written published literature source.

2020

Lennie, Leareng, & Evered (2020)

Lennie, Y., Leareng, K., & Evered, L. (2020). Perioperative Considerations for Transgender Women Undergoing Routine Surgery: A Narrative Review. British Journal of Anaesthesia, 124(6), 702–711. [DOI:10.1016/j.bja.2020.01.024]:

Commonly utilised hormone therapies by transgender women are either oral or transdermal Oestradiol with or without an anti-androgen, such as cyproterone acetate, spironolactone, or bicalutamide.

Bicalutamide

Bicalutamide is a non-steroidal anti-androgen, without any other endocrine activity. Bicalutamide is extensively metabolised by the liver and is an inhibitor of CYP3A4. It has been shown to increase plasma concentrations of midazolam by up to 80% and has also been shown to displace warfarin from its protein binding sites, which can lead to an increased warfarin effect. Common side-effects also relevant to the anaesthetist include GI upset and vomiting, anaemia, and hepatic dysfunction. Uncommonly, interstitial lung disease has been reported.56

Kidd et al. (2020)

Kidd, K. M., Thornburgh, C., Casey, C. F., & Murray, P. J. (2020). Providing Care for Transgender and Gender Diverse Youth. Primary Care: Clinics in Office Practice, 47(2), 273–290. [DOI:10.1016/j.pop.2020.02.006]:

Spironolactone and bicalutamide are hormone blocking medications used in patients desiring feminization that selectively block androgen receptors, creating a relatively estrogenic hormonal milieu. They induce development of breast tissue and decrease androgen-dependent terminal hair, often on the face and trunk. Spironolactone is taken in divided doses twice daily when used to block the effects of testosterone and to stimulate breast development.48 Breast tissue resulting from this medication is unlikely to fully regress, making this intervention as well as a newer agent, bicalutamide, “partially reversible” interventions.

Bicalutamide has been described in a small sample as a possible alternative to GnRH agonists for patients desiring feminization.54 This medication, like leuprolide and histrelin, has been used for precocious puberty.54 There is notable breast tissue development with the drug and a theoretic risk of liver toxicity that was not found in the small (n = 13) sample studied.54

Cocchetti et al. (2020)

Cocchetti, C., Ristori, J., Romani, A., Maggi, M., & Fisher, A. D. (2020). Hormonal Treatment Strategies Tailored to Non-Binary Transgender Individuals. Journal of Clinical Medicine, 9(6), 1609. [DOI:10.3390/jcm9061609]:

Other options may include nonsteroidal antiandrogens, such as flutamide (50–75 mg/daily) and bicalutamide (25–50 mg/daily), which block the AR and, therefore, reduce androgens action. On the other hand, these compounds increase gonadotropin secretion, compromising the reduction of circulating testosterone levels observed with steroidal antiandrogens. The lack of data about their efficacy and safety in the transgender population, as well as the high risk of hepatotoxicity described in ciswomen, do not allow their use to be recommended [41].

Androgen lowering compounds can be included among hormonal treatment strategies in both non-binary AFAB and AMAB people (Figure 1). Indeed, in the case of AMAB agender persons—wishing only to attenuate masculine characteristics, without inducing any feminization—only nonsteroidal or steroidal anti-androgens can be considered. The choice between decreasing androgen production (with steroidal antiandrogens) or only androgen peripheral action (with nonsteroidal ones) may be based on individual phenotypical goals. As androgen-deprivation therapy results in a deleterious effect on bone mineral density [46], a lower dosage of estrogens can be discussed with clients. However, no data are available regarding long-term critical effects when estrogen levels during gender-affirming hormonal treatment do not reach the usual therapeutic goal for binary transgender individuals. Theoretically, nonsteroidal antiandrogens do not compromise estrogen synthesis, because testosterone levels are high and aromatase activity is still efficient.

Fortin & Moravek (2020)

Fortin, C. N., & Moravek, M. B. (2020). Medical Transition for Gender Diverse Patients. Current Obstetrics and Gynecology Reports. [DOI:10.1007/s13669-020-00297-7]:

Table 1: Overview of gender affirming hormone therapy regimens [1, 5••, 7••, 9–25]. […] Medication: Bicalutamide. Route: PO. Typical dose: 50 mg daily. Disadvantages: - Risk of hepatotoxicity. Relative cost: $$.

Another class of anti-androgen drugs, androgen receptor blockers, work by binding directly to the androgen receptor. Flutamide and bicalutamide are both competitive androgen receptor antagonists used primarily in the treatment of prostate cancer [19]. Data on the use of these agents in feminizing hormone therapy are scarce, but it is important to note that both bicalutamide and flutamide have been associated with hepatotoxicity, so are rarely used today [19, 21].

Angus et al. (2020)

Angus, L. M., Nolan, B. J., Zajac, J. D., & Cheung, A. S. (2020). A systematic review of anti‐androgens and feminisation in transgender women. Clinical Endocrinology. [DOI:10.1111/cen.14329]:

Non-steroid androgen receptor antagonists such as bicalutamide are highly potent and as monotherapy do not cause a reduction in gonadotrophins or testosterone levels in contrast to CPA. Aromatisation of testosterone to estradiol is hypothesised to contribute to increased feminisation which was observed in transgender girls treated with bicalutamide without estradiol. (16)

Serum total testosterone concentration is frequently used as a surrogate marker of feminising therapy and may be used for the titration of medication. However, there is a lack of data to support a clear relationship between suppression of serum total testosterone concentration and improved clinical feminisation, especially given some anti-androgens work predominantly via antagonism of the androgen receptor rather than by decreasing testosterone levels. Indeed, use of non-steroid androgen receptor antagonists (for example, bicalutamide) may cause feminisation with an increase in total testosterone concentrations due to potent androgen receptor antagonism without negative feedback of the hypothalamic pituitary gonadal axis. (16)

Given the perceived importance of increasing the estrogen to androgen ratio, it is plausible that an antiandrogen causing more potent antagonism of the androgen receptor, or more significantly lower testosterone levels may contribute to enhanced breast development in transgender women.

Recently, the addition of bicalutamide 50mg daily to the OCP did not significantly decrease the modified Ferriman–Gallwey score compared to placebo in women with PCOS but did significantly decrease the hair density assessed by videodermoscopy. (38)

While detailed discussion of the relative safety of anti-androgens is beyond the scope of this review, this will of course also influence anti-androgen prescribing practices. Severe and fatal hepatotoxicity has been reported in patients treated with flutamide, CPA, and rarely bicalutamide in the prostate cancer literature.

Table 1: Anti-androgen mechanisms of action [Image]

Anti-androgen drugsAR antagonistPR agonistER agonistSuppression
of HPG axis
SpironolactoneYes (weak)Yes (weak)#Yes (weak)#No*
Cyproterone acetateYes (moderate)Yes (strong)NoYes
Non-steroid anti-androgens
(e.g. bicalutamide)
Yes (strong)NoNoNo*
GnRH analogues
(e.g. leuprolide, triptorelin)
NoNoNoYes
5α-reductase inhibitors
(e.g. finasteride)
NoNoNoNo*

# Clinical significance uncertain

* When used as monotherapy, reduced stimulation of the androgen receptor would be expected to stimulate the HPG axis to increase testosterone production. When combined with estradiol at sufficient doses, suppression of the HPG axis may occur resulting in decreased testosterone levels

AR, androgen receptor, ER, estrogen receptor, HPG axis, hypothalamic pituitary gonadal axis, GnRH, gonadotrophin releasing hormone, > PR, progesterone receptor

von Vaupel-Klein & Walsh (2020)

von Vaupel‐Klein, A. M., & Walsh, R. J. Considerations in genetic counseling of transgender patients: Cultural competencies and altered disease risk profiles. Journal of Genetic Counseling, 00: 1–12. [DOI:10.1002/jgc4.1372]:

If testosterone is insufficiently suppressed by estradiol alone, antiandrogens are an option. Bicalutamide is sometimes used in the United States and may have side effects on liver function, although studies have so far focused on prostate cancer patients (Kolvenbag & Blackledge, 1996; Neyman et al., 2019), who take higher doses than transfeminine people (Hembree et al., 2017). More common options are cyproterone acetate and spironolactone, the latter also having some feminizing effect (see Hembree et al., 2017 for review). Cyproterone use is common in Europe but it is not available in the United States (Coleman et al., 2012).

Millington & Williams (2021)

Millington, K., & Williams, C. (2021). Transgender Care. In Stanley, T. & Misra, M. (Eds.). Endocrine Conditions in Pediatrics (pp. 357–363). Springer, Cham. [DOI:10.1007/978-3-030-52215-5_59]:

Table 59.1 Commonly used medications in gender-affirming care: Feminization: Bicalutamide. Route of administration: Oral. Dose range: 50 mg daily. Comments: (anti-androgen).

Green, Reisman, & Goldstein (2021)

Greene, D. N., Reisman, T., & Goldstein, Z. Transgender Endocrinology. In Winter, W. E., Holmquist, B., Sokoll, L. J., & Bertholf, R. L. Handbook of Diagnostic Endocrinology, 3rd Edition (pp. 639–661). Academic Press. [DOI:10.1016/B978-0-12-818277-2.00017-0]:

TABLE 17.4 Antiandrogens used in feminizing hormone therapy [5,6]. […] Generic name: Flutamide/bicalutamide. Trade name: No brand manufacturer/Casodex. Initial dose: 250 mg 3×/day / 50 mg/day. Max dose: 250 mg 3×/day / 50 mg/day. Comments: Direct androgen receptor antagonists; no effect on testosterone levels. Concerns about anemia and hepatotoxicity.

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