By Aly W. | First published July 14, 2019 | Last modified March 14, 2022
Bicalutamide (brand name Casodex) is a nonsteroidal antiandrogen which is sometimes used in transfeminine hormone therapy. It is used to a much lesser extent than other antiandrogens in this context and there is relatively little published literature on it in transfeminine people. This page is a collection of all known literature on bicalutamide in transfeminine hormone therapy to date.
Several agents are available to inhibit androgen action. In Europe the most widely used drug is cyproterone acetate, a progestational compound with antiandrogenic properties. The usual starting dose is 100 mg per day. Later when testosterone levels are effectively suppressed the dose may be reduced to 50 mg per day. If not available medroxyprogesterone acetate, 5–10 mg per day, probably somewhat less effective, is an alternative. Nonsteroidal antiandrogens such as flutamide and nilutamide are also used but they increase gonadotropin output with a rise of testosterone and estradiol; the latter is a desirable effect in this context. Spironolactone, a diuretic with antiandrogenic properties, has similar effects. Also [luteinizing hormone-releasing hormone (LHRH)] (ant)agonists as monthly injections can be considered but these compounds are rarely used.
Gooren, L. (2005). Hormone treatment of the adult transsexual patient. Hormone Research in Paediatrics, 64(Suppl 2), 31–36. [DOI:10.1159/000087751]:
Suppression of Androgen Secretion. Several agents are available for suppression of androgen secretion or action. In Europe, the most widely used drug is cyproterone acetate (usually 50 mg twice daily), a progestational compound with antiandrogenic properties. If it is unavailable, medroxyprogesterone acetate (5–10 mg/day) is an alternative although less effective. Non-steroidal antiandrogens, such as flutamide and nilutamide, are also used, but they increase gonadotropin secretion, causing increased secretion of testosterone and oestradiol; the latter is a desirable effect in this context and has feminizing effects. Spironolactone (100 mg twice daily), a diuretic with antiandrogenic properties, has similar effects. Long-acting gonadotropin releasing hormone agonists, taken as monthly injections, also inhibit gonadotropin secretion.
Gooren, L. J. G. (2006). Treatment of Gender Dysphoria. In Schill, W. B., Comhaire, F., & Hargreave, T. B. (Eds.). Andrology for the Clinician (pp. 524–528). Berlin/Heidelberg: Springer. [DOI:10.1007/3-540-33713-X_89]:
Suppression of Androgen Secretion or Action. Several agents are available to inhibit androgen secretion or action. In Europe, the most widely used drug is cyproterone acetate (usually 50 mg twice daily), a progestational compound with antiandrogenic properties. If it is not available, medroxyprogesterone acetate, 5–10 mg/day, is an alternative, although less effective. Nonsteroidal antiandrogens, such as flutamide and nilutamide, are also used, but they increase gonadotrophin secretion, causing increased secretion of testosterone and oestradiol; the latter is a desirable effect in this context. Spironolactone (100 mg twice daily), a diuretic with antiandrogenic properties, has similar effects. Long-acting gonadotrophin-releasing hormone (GnRH) agonists, used as monthly injections, also inhibit gonadotrophin secretion.
T’Sjoen, G. G. R. (2006). Gender Dysphoria. In Schill, W. B., Comhaire, F., & Hargreave, T. B. (Eds.). Andrology for the Clinician (pp. 19–23). Berlin/Heidelberg: Springer. [DOI:10.1007/3-540-33713-X_7]:
Antiandrogens. Several agents are available to inhibit androgen secretion or action. In Europe, the most widely used drug is cyproterone acetate (usually 50 mg daily), a progestational compound with antiandrogenic properties. If it is not available, medroxyprogesterone acetate, 5–10 mg/day, is an alternative, although less effective. Nonsteroidal antiandrogens, such as flutamide and nilutamide, are also used, but they increase gonadotrophin secretion, causing increased secretion of testosterone and oestradiol; the latter is a desirable effect in this context. Spironolactone (100 mg twice daily), a diuretic with antiandrogenic properties, has similar effects. Long-acting gonadotrophin-releasing hormone (GnRH) agonists, used as monthly injections, also inhibit gonadotrophin secretion.
Anti-androgens. Several agents are available to inhibit androgen secretion or action. Anti-androgens are theorised to lower serum levels of testosterone by suppression of gonadotropins or to block testosterone binding to the androgen receptor, thereby decreasing masculine secondary characteristics. In Europe the most widely used drug is cyproterone acetate (usually 50 to 100 mg daily), a progestational compound with anti-androgenic properties. If this is not available, medroxyprogesterone acetate, 5 to 10 mg per day is an alternative although less effective. Non-steroidal anti-androgens, such as flutamide, are also used, but they increase gonadotropin secretion causing increased secretion of testosterone and oestradiol; the latter is a desirable effect in this context. Spironolactone (100 mg twice daily), a diuretic with anti-androgenic properties, has been said to have similar effects (Prior et al., 1989). Long-acting [gonadotropin-releasing hormone (GnRH)] agonists, used as monthly injections, also inhibit gonadotropin secretion and have been considered by some to increase oestrogen effects when risk factors limit the dose of oestrogen.
Gooren, L. J., & Delemarre-van de Waal, H. A. (2007). Hormone Treatment of Adult and Juvenile Transsexual Patients. In Ettner, R., Monstrey, S., & Coleman, E. (Eds.). Principles of Transgender Medicine and Surgery, 1st Edition (pp. 73–88). [Google Scholar] [Google Books] [DOI:10.4324/9780203822579-12]:
For suppression of androgen secretion or 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 it is not available, then medroxyprogesterone acetate, 5 to 10 mg per day, is a less effective alternative. Nonsteroidal antiandrogens, such as flutamide and nilutamide, 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, if tolerated), a diuretic with antiandrogenic properties, has similar effects, and is widely available. Long-acting [gonadotropin-releasing hormone (GnRH)] agonists, injected monthly, also inhibit gonadotropin secretion.
Gooren, L. J. (2010). The Endocrinology of Sexual Behavior and Gender Identity. In Jameson, J. L., & De Groot, L. J. (Eds.). Endocrinology: Adult and Pediatric, 6th Edition, Volume 2 (pp. 2274–2287). Philadelphia: Saunders/Elsevier. [Google Books] [DOI:10.1016/B978-1-4160-5583-9.00124-6]:
For suppression of androgen secretion or 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.116,117 If not available, medroxyprogesterone acetate, 5 to 10 mg/day, is a less effective alternative.118,119 Nonsteroidal antiandrogens (e.g., flutamide and nilutamide) are also used, but they increase gonadotropin secretion, causing increased secretion of testosterone and estradiol.119 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.118,119 Long-acting gonadotropin-releasing hormone (GnRH) agonists, injected monthly, also inhibit gonadotropin secretion.120
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).
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.
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). Boston: Springer. [Google Books] [DOI:10.1007/978-1-4614-7441-8_14]:
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 (50–75 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. Also luteinizing hormone-releasing hormone (LHRH) agonists, blocking LHRH receptors on the pituitary and decreasing LH production and therewith testosterone production, can be used as monthly injections.
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 [Food and Drug Administration (FDA)] approval of cyproterone acetate, many centers in the United States use spironolactone, a diuretic with mainly anti-androgen but also a weak estrogenic  and progestational activity . 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. Several centers use gonadotropin-releasing hormone (GnRH) analogs to suppress androgen production [12,13], but the use of GnRH analogs is limited mainly because of its high costs .
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. [abridged]
Drug for reversible hormonal replacement therapy
Dosage and routes of administration
Mechanism of action
Anti-gonadotropic, saturates pituitary LHRH binding sites, resulting in reduced gonadotropins and therefore testosterone
Cyproterone acetate (e.g. Androcur®)
50–100 mg/day, per os
Anti-gonadotropic, anti-androgenic (peripheral)
10 mg/day, per os
Androgen receptor blockers
100–200 mg/day, per os
Bicalutamide, flutamide, nilutamide
750 mg/day (flutamide), per os
Androgen receptor blockers
5 alpha-reductase inhibitor, prevent the conversion of testosterone into dihydroxytestosterone
Deutsch, M. B. (2016). Overview of feminizing hormone therapy. In Deutsch, M. B. (Ed.). Guidelines for the Primary and Gender-Affirming Care of Transgender and Gender Nonbinary People, 2nd Edition (pp. 26–48). San Francisco: University of California, San Francisco/UCSF Transgender Care. [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. 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. No evidence at present exists to inform such an analysis.
Note: This is a chapter of the University of California, San Francisco (UCSF) transgender health clinical practice guidelines (Aly W., 2020).
Gooren, L. J. (2016). The Endocrinology of Sexual Behavior and Gender Identity. In Jameson, J. L., & De Groot, L. J. (Eds.). Endocrinology: Adult and Pediatric, 7th Edition, Volume 2 (pp. 2163–2176.e4). Philadelphia: Saunders/Elsevier. [Google Books] [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, 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. Long-acting [gonadotropin-releasing hormone (GnRH)] agonists, injected monthly, also inhibit gonadotropin secretion.
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: [Gonadotropin-releasing hormone (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.
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 .
Kinnear, H. M., & Shumer, D. E. (2018). Duration of Pubertal Suppression and Initiation of Gender-Affirming Hormone Treatment in Youth. In Finlayson, C. (Ed.). Pubertal Suppression in Transgender Youth (pp. 73–85). St. Louis: Elsevier. [Google Scholar] [Google Books]:
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 [gonadotropin-releasing hormone (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)
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
Vincent, B. (2018). Gender Affirmation. In Vincent, B. Transgender Health: A Practitioner’s Guide to Binary and Non-Binary Trans Patient Care (pp. 147–172). London/Philadelphia: Jessica Kingsley Publishers. [Google Scholar] [Google Books]:
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)
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%).
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 by Fenway Health, not a formally published source.
Fishman, S. L., Paliou, M., Poretsky, L., & Hembree, W. C. (2019). Endocrine Care of Transgender Adults. In Poretsky, L., & Hembree, W. C. (Eds.). Transgender Medicine: A Multidisciplinary Approach (pp. 143–163). Cham: Humana Press. [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 . There are isolated reports of successful outcomes with flutamide (Eulexin), though reportedly not as effective as cyproterone acetate in reducing testosterone levels . 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 .
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 hormone therapy guidelines.
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, 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 [assigned male at birth] 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.
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 .
Table 2 Estradiol and Anti-Androgens Management for [Male-to-Female] [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.
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 [Gonadotropin-releasing hormone analogs (GnRHa)] 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.
T’Sjoen, G., Arcelus, J., Gooren, L., Klink, D. T., & Tangpricha, V. (2019). Endocrinology of Transgender Medicine. Endocrine Reviews, 40(1), 97–117. [DOI:10.1210/er.2018-00011]
Androgen-lowering therapies. Transgender women will often require the addition of a medication to lower testosterone levels into the female range (59). In most European countries, the most commonly prescribed androgen-lowering medication is oral [cyproterone acetat3e (CPA)] 50 mg daily (44, 52, 60). […] in the United Kingdom, transgender women are now prescribed [gonadotropin-releasing hormone (GnRH)] agonists to lower testosterone concentrations (65). In contrast to the rest of Europe and the United States, GnRH agonists are provided free of charge to transgender women by the National Health Service in the United Kingdom (56). […] Spironolactone is the most commonly prescribed testosterone-lowering medication in the United States (57, 58). […] Peripheral androgen receptor blockers such as flutamide or dutasteride have not been recommended for use in transgender women because these agents do not lower serum testosterone levels and there are limited published studies in this population (40).
Gorton, N., Jaffe, J. M., Thompson, J., Menkin, D., Nesteby, A., Dunn, D., Baker, K. K., Harbatkin, D., Do, T., Radix, A., Meacher, P., Goldstein, Z., Carpenter, W., Caine, M., Henn, S., Murayama, R., Feldmann, J., & Zayas, S. (2019). TransLine Gender Affirming Hormone Therapy Prescriber Guidelines. San Francisco: Lyon-Martin Health Services/TransLine. [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.
Cirrincione, L. R., Senneker, T., Scarsi, K., & Tseng, A. (2020). Drug Interactions with Gender-Affirming Hormone Therapy: Focus on Antiretrovirals and Direct Acting Antivirals. Expert Opinion on Drug Metabolism & Toxicology, 16(7), 565–581. [DOI:10.1080/17425255.2020.1777278]:
For many trans women, [gender-affirming hormone therapy (GAHT)] is an important part of gender-affirming care. GAHT supports the development of secondary sex characteristics, including breast development, decreased muscle mass, body fat redistribution, and softening of the skin. Estrogen (as 17β-estradiol) is the mainstay of GAHT. It is available as oral, transdermal, or injectable (intramuscular, subcutaneous) preparations. Adjunctive agents may include an oral antiandrogen: spironolactone, cyproterone acetate, 5α-reductase inhibitors (dutasteride or finasteride), progestogens (medroxyprogesterone or micronized progesterone) or bicalutamide. Gonadotropin releasing hormone analogues (GnRH, leuprolide or goserelin) are also available.
Bicalutamide, a racemic mixture, is predominantly metabolized by conjugation. Its active R-bicalutamide isomer inhibits and it may increase the concentration of CYP3A4 substrates, although this may only be clinically relevant for drugs with a narrow therapeutic range.
We identified no pharmacokinetic studies evaluating drugdrug interactions between adjunctive antiandrogens (spironolactone, cyproterone, 5α-reductase inhibitors, GnRH analogues, or bicalutamide), or testosterone and either [antiretroviral therapy] or [direct acting antivirals].
Table 1. Metabolic pathways and major drug transport of estrogens, anti-androgens, progestogens, and testosterone. […] Antiandrogens. Drug (Route): Bicalutamide (PO). Metabolizing Enzymes: Inhibition: CYP3A4 (weak). Drug Transporters: None. References: . […]
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 [androgen receptor] 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 .
Androgen lowering compounds can be included among hormonal treatment strategies in both non-binary [assigned female at birth] and [assigned male at birth] people (Figure 1). Indeed, in the case of [assigned male at birth] 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 , 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.
Deutsch, M. (July 2020). Information on Estrogen Therapy. San Francisco: UCSF Transgender Care. [URL]:
Bicalutamide is an anti-androgen that some transgender and non-binary people ask about. This medication is typically used in the treatment of prostate cancer. This medication blocks the action of testosterone in cells, but does not block the production of testosterone. Because of this, testosterone levels in the body remain high, and measuring blood testosterone level is not useful for tailoring treatment. This makes it difficult to monitor whether this medication is being optimally dosed. Because bicalutamide has a risk of liver injury and because spironolactone and [gonadotropin-releasing hormone (GnRH)] analogs like leuprolide are so safe and effective, bicalutamide is not recommended for use as part of a feminizing hormone regimen.
Note: This is an informational page on hormone therapy for transgender people by Madeline Deutsch, not a formally published source. Deutsch is the editor of the University of California, San Francisco (UCSF) transgender health clinical practice guidelines (Aly W., 2020).
Everett, R. G., Luck, K. M., Toburen, B. A., & Sandlow, J. I. (2020). MP66-17 Clinical Effectiveness of Bilateral Orchiectomy in Reducing Anti-Androgens in Transgender Females. The Journal of Urology, 203(Suppl 4), e990–e990. [DOI:10.1097/JU.0000000000000941.017]:
Androgen reducing medications are often given to suppress testosterone levels and reduce the dosage of exogenous estrogens in transwomen with gender dysphoria [GD]. […] The objective of this study was to assess the impact of [bilateral orchiectomy] on the hormone regimen of patients with [gender dysphoria].
Retrospective chart review was used to identify patients with GD who underwent BO for GD at our institution between 2008-2018. […] Nineteen patients underwent BO. Sixteen had pre-operative medication regimen information available. […] Pre-operative and post-operative medication regimens were available for twelve patients. Of these, eleven (91.7%) were treated pre-operatively with spironolactone and one with bicalutamide (8.3%). […] Post-operatively, ten patients (90.9%) were noted to have cessation of spironolactone and the one patient (100%) had discontinued bicalutamide.
[Table:] Changes in Hormone Medication Regimens Before and After Bilateral Orchiectomy. […] Patient # 12: Bicalutamide 12.5 mg PO. Post-Op [antiandrogen therapy]: –. Pre-op Estrogen: Estradiol valerate 5 mg IM weekly. Post-op Estrogen: Estradiol valerate 5 mg IM weekly.
Fortin, C. N., & Moravek, M. B. (2020). Medical Transition for Gender Diverse Patients. Current Obstetrics and Gynecology Reports, 9, 166–177. [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 . 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].
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 [gonadotropin-releasing hormone (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
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 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
Bicalutamide is an anti-testosterone blocker that was developed as a medication to treat prostate cancer. We try to avoid using bicalutamide because there is a concern that it may lead to severe liver failure that may be life-threatening. Other side effects include swelling of the legs, pain, and constipation. While such risks are acceptable when considering the benefits of bicalutamide in the management of prostate cancer, they are less justified in gender-affirming treatment, especially since other therapies for blocking testosterone are available for gender-affirming care.
Note: This is an informational PDF handout on hormone therapy for transgender people by Michigan Medicine of the University of Michigan, not a formally published source.
Nolan, B. J., Brownhill, A., Bretherton, I., Wong, P., Fox, S., Locke, P., Russell, N., Grossmann, M., Zajac, J. D., & Cheung, A. S. (2020). Relationships between body mass index with oral estradiol dose and serum estradiol concentration in transgender adults undergoing feminising hormone therapy. Therapeutic Advances in Endocrinology and Metabolism, 11, 1–7. [DOI:10.1177/2042018820924543]:
A retrospective cross-sectional analysis was undertaken of consultations for gender-affirming hormone therapy (GAHT) at Equinox Gender Diverse Clinic, a primary care clinic specialising in transgender health, and an Endocrine Specialist Centre, a secondary care clinic, in Melbourne, Australia. […] In all, 73 individuals were treated with oral estradiol valerate without anti-androgen, 95 with spironolactone, 87 with cyproterone acetate, 2 with both cyproterone acetate and spironolactone, and 2 with bicalutamide.
von Vaupel‐Klein, A. M., & Walsh, R. J. (2020). Considerations in genetic counseling of transgender patients: Cultural competencies and altered disease risk profiles. Journal of Genetic Counseling, 30(1), 98–109. [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).
Angus, L. M., Nolan, B. J., Zajac, J. D., & Cheung, A. S. (2021). A systematic review of antiandrogens and feminization in transgender women. Clinical Endocrinology, 94(5), 743–752. [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 [cyproterone acetate (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 [oral contraceptive pill (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 drugs AR antagonist PR agonist ER agonist Suppression
of HPG axis
Spironolactone Yes (weak) Yes (weak)# Yes (weak)# No* Cyproterone acetate Yes (moderate) Yes (strong) No Yes Non-steroid anti-androgens
Yes (strong) No No No* GnRH analogues
(e.g. leuprolide, triptorelin)
No No No Yes 5α-reductase inhibitors
No No No No*
# 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
Bretherton, I., Thrower, E., Zwickl, S., Wong, A., Chetcuti, D., Grossmann, M., Zajac, J. D., & Cheung, A. S. (2021). The Health and Well-Being of Transgender Australians: A National Community Survey LGBT Health, 8(1), 42–49. [DOI:10.1089/lgbt.2020.0178]:
This anonymous, cross-sectional online survey utilized nonprobability snowball sampling of Australian adults (18 years and over) who self-identified as trans between September 2017 and January 2018. […] Table 2. Access to Health Care and Health Burden […] Feminizing hormone treatments in birth-assigned males […] Number of responses received: 402 […] Spironolactone: Frequency, n (%): 130 (32). Cyproterone acetate: 106 (26). Bicalutamide: Frequency, n (%): 1 (<1). [Gonadotropin-releasing hormone (GnRH)] analogs: 2 (<1).
Cirrincione, L. R., & Huang, K. J. (2021). Sex and gender differences in clinical pharmacology: Implications for transgender medicine. Clinical Pharmacology & Therapeutics. [DOI:10.1002/cpt.2234]:
Bicalutamide, a nonsteroidal androgen receptor antagonist, is available in certain settings, although limited data from clinics in Sweden and Norway suggest it is used less frequently than other antiandrogens.45
Cirrincione, L. R., & Narla, R. R. (2021). Gender-Affirming Hormone Therapy and Bone Health: Do Different Regimens Influence Outcomes in Transgender Adults? A Narrative Review and Call for Future Studies. The Journal of Applied Laboratory Medicine, 6(1), 219–235. [DOI:10.1093/jalm/jfaa213]:
Bicalutamide, a nonsteroidal antiandrogen, is an emerging [gender-affirming hormone therapy] agent (22, 23), but supportive safety and efficacy data are lacking for adult trans women.
Greene, D. N., Reisman, T., & Goldstein, Z. (2021). Transgender Endocrinology. In Winter, W. E., Holmquist, B., Sokoll, L. J., & Bertholf, R. L. (Eds.). Handbook of Diagnostic Endocrinology, 3rd Edition (pp. 639–661). Cambridge/London/Oxford/San Diego: AACC Press/Academic Press/Elsevier. [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.
Hojbjerg, J. A., Saini, S. L., Hvas, A. M., & Hojgaard, A. D. (2021). Current Treatment Regimens for Transfeminine Individuals in the Nordic Countries. The Journal of Sexual Medicine, 18(3), 656–663. [DOI:10.1016/j.jsxm.2020.12.018]:
Table 3. Target ranges of plasma testosterone and plasma free testosterone with matching reference intervals for premenopausal cisgender women at the local laboratory and anti—androgenic drugs used at the specialized clinics (%): […] Bicalutamide: Denmark: Copenhagen: 0, Odense: 0, Aalborg: 0. Norway: Oslo: 0, Grimstad: <10. Sweden: Linköping: <10, Sahlgrenska: 0, Blekinge: 0, Uppsala: <10. Finland: Helsinki: 0, Tampere: 0.
Maheshwari, A., Nippoldt, T., & Davidge-Pitts, C. (2021). An Approach to Non-Suppressed Testosterone in Transgender Women Receiving Gender Affirming Feminizing Hormonal Therapy. Journal of the Endocrine Society, 5(9), bvab068. [10.1210/jendso/bvab068]:
Anti-Androgens and androgen lowering therapies vary in their mechanism to achieve desired feminization. Several classes of therapies are available – spironolactone, gonadotropin-releasing hormone analogs (GnRH), non-steroidal anti androgens, cyproterone acetate, and 5 alpha reductase inhibitors (Table 1). Choice of adjunctive therapy may reflect region-specific regulatory approval, price, availability, adverse effect profile, and prescriber preference . […] Non-steroidal anti-androgens also act as antagonists at the androgen receptor, though more potent [than spironolactone].
Table 1: Estradiols and Adjunctive Agents Used in Feminizing Hormonal Treatment [abridged]
Anti-Androgens Typical Doses Non-Steroidal Anti-Androgens Bicalutamide 25 – 50 mg/day
Millington, K., & Williams, C. (2021). Transgender Care. In Stanley, T., & Misra, M. (Eds.). Endocrine Conditions in Pediatrics (pp. 357–363). Cham: Springer. [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).
Rosenthal, S. M. (2021). Challenges in the care of transgender and gender-diverse youth: an endocrinologist’s view. Nature Reviews Endocrinology. [DOI:10.1038/s41574-021-00535-9]:
Although [gonadotropin-releasing hormone (GnRH)] agonists are the preferred option for pubertal suppression, these medications are costly and often inaccessible. Additional options for pubertal suppression include depot and oral progestins25. Bicalutamide, a non-steroidal antiandrogen, has also been used as an option for pubertal suppression in individuals designated as male at birth who had gender dysphoria (and whose insurance company denied provision of GnRH agonists)86. However, this medication has not been widely used in patients with gender dysphoria in view of concern about potential hepatotoxicity in other clinical contexts87.
Screening/Baseline Laboratory Testing
Consider liver function tests if patient will be using a [gonadotropin-releasing hormone (GnRH)] agonist or bicalutamide as an androgen blocker
Anti-Androgen Therapy - Oral
Medication name bicalutamide Frequency By mouth once daily Additional comments • A nonsteroidal androgen blocker that works by competitively blocking the androgen receptor. Bicalutamide does not suppress testosterone itself, but blocks its ability to bind to the receptor, and therefore its effects on the body
• Bicalutamide can have indirect estrogenic effects, such as increased breast growth, due to increased serum testosterone levels resulting in aromatization to estrogen, which would be a desired effect when used for gender affirming care27
• Bicalutamide has a rare, but severe potential side effect of fulminant hepatitis. There are only several documented cases worldwide. Though uncommon, fulminant hepatitis can result in death28
• Bicalutamide can be used for [gender-affirming hormone therapy (GAHT)], but there are very few studies examining its use and the relative risk/benefit for this purpose. Because of reported cases of fulminant hepatitis, consensus is that its use in gender affirming hormonal regimen should be carefully considered, used only after alternative options have been trialed or offered, and an in-depth discussion of these potential risks have been had.
Dosing for Androgen-Blocking Medications
Medication Name Dose Frequency Low Dose Common Dose Max Dose Non-steroidal androgen receptor antagonist bicalutamide Daily 25mg n/a 50mg
Laboratory Monitoring by Visit Timelines
Estrogen and/or Anti-Androgen Use
Labs Baseline 3mo 6mo 12mo Yearly PRN Additional Comments Transaminases X X X X X X only necessary if taking a GnRH agonist or bicalutamide
APPENDIX 3 Hormone Options: Anti-Androgen Therapy - Oral
Medication name bicalutamide Frequency By mouth once daily Additional comments A nonsteroidal androgen blocker that works by blocking the androgen receptor. Bicalutamide does not suppress testosterone itself, but blocks its ability to bind to the receptor. Bicalutamide can also have indirect estrogenic effects, such as increased breast growth. This occurs when testosterone levels increase as a result of blocked receptors, and the body then converts this excess testosterone to estrogen.
Bicalutamide has a rare, but severe potential side effect of liver toxicity (fulminant hepatitis). There are only several documented cases worldwide. Though uncommon, fulminant hepatitis can result in death.
Bicalutamide can be used for GAHT, but there are very few studies examining its use and the relative risk/benefit for this purpose. Because of reported cases of fulminant hepatitis, consensus is that its use in gender affirming hormonal regimen should be carefully considered, used only after alternative options have been trialed or offered, and an in-depth discussion of these potential risks have been had.
Tomson, A., McLachlan, C., Wattrus, C., Adams, K., Addinall, R., Bothma, R., Jankelowitz, L., Kotze, E., Luvuno, Z., Madlala, N., Matyila, S., Padavatan, A., Pillay, M., Rakumakoe, M. D., Tomson-Myburgh, M., Venter, W., & de Vries, E. (2021). Southern African HIV Clinicians’ Society gender-affirming healthcare guideline for South Africa. Southern African Journal of HIV Medicine, 22(1), a1299. [DOI:10.4102/sajhivmed.v22i1.1299] [PDF]:
TABLE 4: Feminising hormone therapy and antiandrogens.
Medication Dose Notes Bicalutamide110,121,122,123,124,125 (oral) • Starting dose: 25 mg twice weekly
• Increase by 25 mg twice weekly, or on alternating days
• Usual maintenance dose: 25 mg – 50 mg daily
• Maximum dose: 50 mg daily
• Preferred antiandrogen as less risk of neurosteroid depletion (does not cross blood-brain-barrier readily).
• Possible side effects: constipation, back pain and fatigue.
Feminising HT is prescribed for assigned-male-at-birth clients who wish to feminise. The backbone of feminising HT is oestrogen therapy. Anti-androgens (spironolactone, cyproterone acetate or bicalutamide) are sometimes used, although many clients can achieve testosterone suppression using oestrogen therapy alone.
Yanes Cardozo, L. L., & Romero, D. G. (2021). Management of cardiometabolic complications in polycystic ovary syndrome: Unmet needs. The FASEB Journal, 35(11), e21945. [DOI:10.1096/fj.202002526RR]:
The most recent International Evidence-Based Guideline for the Assessment and Management of PCOS recommend that antiandrogens are added to COCsto ameliorate the skin manifestations of the syndrome, not the cardiometabolic risks.34 The two drugs most frequently used to block the androgen receptor are cyproterone acetate and spironolactone. Cyproterone is not available for use in the US. A recent study showed that high doses (>25 mg/day) of cyproterone for more than a year had been linked to an increased risk of meningioma.35 The European Medicine Agency has recommended that daily doses of 10 mg or more of cyproterone should only be used once other treatment options, including treatment with lower doses, have failed. Spironolactone is the antiandrogen used in the US; it is not a pure antiandrogen because it also blocks the mineralocorticoid receptor with the potential side effect of hyperkalemia and hypotension. Bicalutamide and flutamide are nonsteroidal, relatively pure antiandrogens. Bicalutamide and flutamide bind competitively to the ligand-binding pocket of the androgen receptor leading to the assembly of a transcriptionally inactive complex due to the inability of the ligand-bound androgen receptor to recruit coactivators.36 Clinical experiences with flutamide are limited due to its severe liver toxicity.37 Bicalutamide has a longer half-life than flutamide and has been used to treat familial male precocious puberty and other forms of peripheral precocious puberty in young boys.38 In a retrospective small clinical trial, bicalutamide has been shown to promote feminization in male-to-female transgender adolescents.39 Unfortunately, bicalutamide use has also been associated with liver toxicity.40
O’Connell, M. A., Nguyen, T. P., Ahler, A., Skinner, S. R., & Pang, K. C. (2022). Approach to the Patient: Pharmacological Management of Trans and Gender-Diverse Adolescents. The Journal of Clinical Endocrinology & Metabolism, 107(1), 241–257. [DOI:10.1210/clinem/dgab634]:
Antiandrogens with reported use in [transgender (TGD)] populations include cyproterone acetate (CPA), spironolactone, medroxyprogesterone acetate, and bicalutamide (26). Of these, spironolactone and CPA are most commonly used (27, 28), although outcome data specific to TGD adolescents are limited. Spironolactone has well documented antiandrogenic effects (29, 30). CPA has been found to effectively reduce facial and body hair in a majority of late pubertal transgirls, with fewer spontaneous erections also reported by some (31). Choice of agent may be influenced by availability (CPA is not available in the United States because of safety concerns), clinician experience, cost, patient preference, and tolerability. Some antiandrogens contribute to breast development (26, 31, 32). This may arise because of lower testosterone levels (hence altered circulating estrogen:testosterone ratio), as a progestogenic effect or a combination of mechanisms; however, the relative roles of different hormones or agents in promoting breast growth are not well established in TGD populations (33). Optimal dosing strategies are unknown but much lower doses of agents such as CPA (eg,12.5 mg daily or alternate daily) than were initially studied (up to 100 mg daily) are currently used.
Table 5 – Gender affirming pharmacological interventions – examples of agents used, mechanism of action, effects and suggested monitoring.
Indication Examples of agents and dosing* Mode & frequency of administration* Mechanism(s) of action Effects considered reversible# Potentially irreversible effects# Monitoring§ Modulation of androgen effect Cyproterone acetate (CPA) 50-100mg**
Spironolactone (S) 50-100mg
Bicalutamide (B) 50mg
PO; daily (or alt daily**)
PO; daily or bd
AR antagonist: B, CPA, S
PR agonist: CPA, S
HPG suppression: CPA
Inhibition of steroidogenic pathway (T production): S
Reduction of body and facial hair;
Decreased oiliness of skin;
If it arises, breast development (B, S) may not fully revert
HPG – hypothalamic-pituitary-gonadal; BMD – bone mineral density; PBM -peak bone mass; IM – intramuscular; SC: subcutaneous; PO.: by mouth; IUD: intra-uterine device; CPA – cyproterone acetate; S – spironolactone; B – bicalutamide; AR – androgen receptor; PR – progestogen receptor; b.d. - twice daily
* Relates to reports in the literature in [transgender (TGD)] populations; note - use in this context may be off-label and not all agents have reported data in adolescent TGD populations
** Optimal dosing of anti-androgenic agents is unknown; studies of smaller and less frequent doses of agents such as CPA are underway
# Either gender-affirming or potentially unwanted effects
§ Ongoing monitoring of potential unwanted / adverse effects (e.g. drug reaction, mood effects, fatigue / altered energy, fluid retention, headaches)
32. Neyman A, Fuqua JS, Eugster EA. Bicalutamide as an Androgen Blocker With Secondary Effect of Promoting Feminization in Male-to-Female Transgender Adolescents. J Adolesc Health. 2019;64(4):544-6.
Rothman, M. S., & Iwamoto, S. J. (2022). Feminizing Gender-Affirming Hormone Therapy: Special Considerations for Older Adults. In Davis, T. F. (Ed.). A Case-Based Guide to Clinical Endocrinology (pp. 513–523). Cham: Springer. [DOI:10.1007/978-3-030-84367-0_58]:
The most common antiandrogen medication in the United States is spironolactone, which was identifed as such when it was associated with gynecomastia in cisgender men. It is a potassium-sparing diuretic antihypertensive which must be monitored accordingly. In Europe, cyproterone acetate (a progestin) is more common but is associated with hyperprolactinemia and possibly increased VTE risk. Hepatotoxicity and meningiomas are also reported with cyproterone acetate.
Although more expensive, gonadotropin-releasing hormone agonists (GnRHa) are extremely effective at lowering testosterone. In youth and adolescents, GnRHa can also be used to block pubertal changes prior to the initiation of GAHT.
Other agents of interest to patients include 5-alpha reductase inhibitors (which block testosterone conversion to dihydrotestosterone and are often used for hair loss), bicalutamide (which acts at the level of the androgen receptor to block action but many oppose its use due to concerns of hepatotoxicity), and progestins other than cyproterone acetate (specifcally discussed below under breast development).
Harris, M. S., Goodrum, B. A., & Krempasky, C. N. (2022). An introduction to gender-affirming hormone therapy for transgender and gender-nonbinary patients. The Nurse Practitioner, 47(3), 18–28. [DOI:10.1097/01.NPR.0000819612.24729.c7]:
In the US, spironolactone is the most commonly used antiandrogen for GAHT due to its efficacy, availability, and low risk for severe adverse reactions. […] The next most commonly used antiandrogens, 5-alpha reductase inhibitors (such as, finasteride, dutasteride), block the conversion of testosterone to dihydrotestosterone (DHT). […] In the US, less commonly used antiandrogens include cyproterone acetate, bicalutamide, and gonadotropin releasing hormone (GnRH) analogues. Cyproterone acetate is not available in the US. Bicalutamide is associated with a small risk for hepatotoxicity.41 Determining if this risk is justified is a matter of clinician judgment, however, the authors conclude that the risks associated with bicalutamide outweigh the benefi ts when used for GAHT, when safer alternatives are available. GnRH analogues, more often used for pubertal suppression within the context of TGNB health, are also effective antiandrogens.42 Use of GnRH analogues is limited by high cost and challenges in obtaining insurance authorization.
Krebs, D., Harris, R. M., Steinbaum, A., Pilcher, S., Guss, C., Kremen, J., Roberts, S. A., Baskaran, C., Carswell, J., & Millington, K. (2022). The Care of Transgender Young People. Hormone Research in Paediatrics, advance online publication. [DOI:10.1159/000524030]
Medications with anti-androgen properties have been used either alone or in combination with estrogen to achieve feminization in transfeminine individuals especially when GnRHa are unavailable or cost prohibitive. In the United States, spironolactone, an aldosterone antagonist, is commonly used to reduce the appearance of unwanted facial hair and acne via its inhibition of testosterone synthesis and action. Although it is associated with hyperkalemia when used in as diuretic in patients with heart failure, TGD young people taking spironolactone have very low rates of hyperkalemia and frequent monitoring may not be necessary. Bicalutamide, an androgen receptor blocker, has been associated with fulminant liver failure when used in the treatment of prostate cancer, but this has not been reported in transfeminine individuals. Data on bicalutamide use in TGD young people is very limited and longer term follow-up studies are needed.[26,27]