Effect of spironolactone and cyproterone acetate on breast growth in transgender people: a randomized clinical trial

Context: Transgender people with sex recorded male at birth desiring feminization commonly use cyproterone acetate or spironolactone as anti-androgens with estradiol, but the optimal anti-androgen is unclear.

Objective: To assess the effect of anti-androgens 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.

Design: Randomised clinical trial 2020-2022.

Setting: Outpatient endocrinology clinic.

Participants: Transgender people aged 18+ years old commencing feminizing gender affirming hormone therapy.

Interventions: Standardized estradiol therapy plus either spironolactone 100mg daily or cyproterone acetate 12.5mg daily for six months.

Main outcome measures: Primary outcome was breast development as measured by the breast chest distance. Secondary outcomes included estimated breast volume, suppression of serum total testosterone concentration <2nmol/L and Gender Preoccupation and Stability Questionnaire (GPSQ).

Results: 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 six months, there was no between-group difference in breast chest distance (mean difference 0.27 cm, 95% CI -0.82 to 1.35, p=0.6) or estimated breast volume (mean difference 17.26 mL, 95% CI -16.94 to 51.47, p=0.3). 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=0.008). Changes in GPSQ were similar between groups.

Conclusion: Anti-androgen 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.