Transgender people with sex recorded male at birth desiring feminization commonly use cyproterone acetate or spironolactone as antiandrogens with estradiol, but the optimal antiandrogen is unclear.
We aimed to assess the effect of antiandrogens on breast development. We hypothesized this would be greater in those treated with cyproterone acetate than spironolactone due to more potent androgen receptor antagonism and suppression of serum total testosterone concentrations.
A randomized clinical trial was conducted between 2020-2022 at an outpatient endocrinology clinic. Transgender people aged 18+ years old commencing feminizing gender affirming hormone therapy were included. The intervention was standardized estradiol therapy plus either spironolactone 100 mg daily or cyproterone acetate 12.5 mg daily for 6 months. The primary outcome was breast development as measured by the breast–chest distance. Secondary outcomes included estimated breast volume, suppression of serum total testosterone concentration <2 nmol/L, and Gender Preoccupation and Stability Questionnaire (GPSQ).
Sixty-three people (median age 25 years) were enrolled, randomized, and included in intention to treat analysis (cyproterone acetate n = 32, spironolactone n = 31). At 6 months, there was no between-group difference in breast–chest distance (mean difference 0.27 cm, 95% CI −0.82 to 1.35, P = .6) or estimated breast volume (mean difference 17.26 mL, 95% CI −16.94 to 51.47, P = .3). Cyproterone acetate was more likely to suppress serum testosterone concentration to <2 nmol/L (odds ratio 9.01, 95% CI 1.83 to 4.44, P = .008). Changes in GPSQ were similar between groups.
Antiandrogen choice should be based on clinician and patient preference with consideration of side effects. Further research is needed to optimize breast development in transgender people.
People with a female or nonbinary gender whose sex was recorded male at birth commonly use antiandrogens with estradiol to induce physical changes such as breast development, body fat redistribution, and decreased facial and body hair. Antiandrogens decrease the effects and/or synthesis of testosterone through androgen receptor antagonism, inhibition of synthetic enzymes, and/or suppression of gonadotrophins. Common antiandrogens include spironolactone and cyproterone acetate, but use of nonsteroidal androgen receptor antagonists (eg, bicalutamide), gonadotrophin-releasing hormone analogues, progestogens, and 5-alpha-reductase inhibitors is well described.
Through potent progestogenic suppression of hypothalamic–pituitary–gonadal axis and moderate androgen receptor antagonism, cyproterone acetate is associated with greater suppression of serum testosterone than spironolactone but the effects on feminization remain unclear. A systematic review of antiandrogens in transgender people identified low-quality studies which suggested that cyproterone acetate, progestogens and gonadotrophin-releasing hormone analogues resulted in greater suppression of serum total testosterone concentrations than spironolactone or estradiol alone. Subsequently, a 12-week single-blinded randomized trial in transgender people on estradiol showed that those using cyproterone acetate resulted in lower median serum total testosterone concentrations than spironolactone (0.26 nmol/L vs 14.23 nmol/L, P < .001). These findings supported cross-sectional data but unfortunately did not include clinically relevant outcomes of feminization.
In the absence of robust evidence on comparative efficacy and safety of antiandrogens, prescribing practices vary significantly worldwide reflecting local differences in cost, availability, and experience. In this study of transgender people commencing feminizing hormone therapy, we aimed to assess the effects of cyproterone acetate and spironolactone on breast development, a commonly desired goal of feminization. We hypothesized that use of cyproterone acetate would result in greater breast development than spironolactone due to greater suppression of serum total testosterone due to its progestogenic effects and more potent antagonism of the androgen receptor.
Lachlan M Angus, Shalem Y Leemaqz, Anna K Kasielska-Trojan, Maksym Mikołajczyk, James C G Doery, Jeffrey D Zajac, Ada S Cheung, Effect of Spironolactone and Cyproterone Acetate on Breast Growth in Transgender People: A Randomized Clinical Trial, The Journal of Clinical Endocrinology & Metabolism, Volume 110, Issue 6, June 2025, Pages e1874–e1884, https://doi.org/10.1210/clinem/dgae650
― 17 Sep 2024