Effect of Spironolactone and Cyproterone Acetate on Breast Growth in Transgender People: A Randomized Clinical Trial

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.