Research Summary

Cyproterone Acetate vs Spironolactone: No Difference in Breast Development Among Transgender Individuals on Feminizing Hormone Therapy, Despite Superior Testosterone Suppression

Kate Young

Key Highlights:

  • No significant difference in breast development was observed between cyproterone acetate and spironolactone groups after 6 months of feminizing hormone therapy.
  • Cyproterone acetate was significantly more effective at suppressing serum total testosterone to < 2 nmol/L.
  • Estimated breast volume was positively associated with both age and serum estradiol concentration.
  • Both treatments were generally well tolerated with minimal clinically relevant adverse effects.

In a randomized clinical trial, the use of cyproterone acetate versus spironolactone in transgender individuals commencing feminizing hormone therapy yielded no significant difference in breast development after 6 months. Specifically, changes in breast-chest distance and estimated breast volume were similar between groups. However, cyproterone acetate was more effective in suppressing serum total testosterone levels to within the typical cisgender female range. Despite the modest breast growth overall, nearly 60% of participants reported satisfaction with their breast development.

Transgender individuals commonly use antiandrogens such as cyproterone acetate or spironolactone in combination with estradiol to achieve feminization. While both agents are widely prescribed, robust comparative data on their impact on feminizing outcomes—particularly breast development—have been lacking. Prior studies indicated that cyproterone acetate produces more potent testosterone suppression but did not assess clinically relevant feminization endpoints.

The study enrolled 63 transgender individuals (median age 25 years) who had not previously used antiandrogens and were newly initiating estradiol therapy. Participants were randomized to receive either cyproterone acetate (12.5 mg daily) or spironolactone (100 mg daily) for 6 months, in conjunction with standardized estradiol therapy. Primary outcome was change in breast–chest distance; secondary outcomes included estimated breast volume, serum total testosterone suppression (< 2 nmol/L), and changes in gender dysphoria using the Gender Preoccupation and Stability Questionnaire (GPSQ).

At 6 months, there was no statistically significant 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). Both groups had similar calculated cup sizes (AAA). Suppression of serum testosterone to < 2 nmol/L occurred in 68.8% of participants on cyproterone acetate compared with 45.2% on spironolactone (OR, 9.01; 95% CI 1.83–44.44; P = .008). Exploratory analyses showed greater breast volume change with higher serum estradiol concentrations (P = .003) and increasing age (P = .02). GPSQ scores declined significantly across both groups, indicating reduced gender-related distress, though no between-group difference was noted. Safety outcomes were largely comparable between groups, with elevated serum prolactin in the cyproterone group and slightly higher urea and creatinine in the spironolactone group, none of which were deemed clinically significant.

The study had several limitations, including the short 6-month duration, which may not capture longer-term breast development, use of breast-chest distance as a surrogate for breast tissue growth, and limited generalizability due to the homogeneous participant population (predominantly young, White, and healthy). Additionally, the trial may have been underpowered to detect differences in breast volume given the sample size calculation was based on testosterone suppression.

“Antiandrogen choice should be based on clinician and patient preference with consideration of side effects,” the study authors concluded. “Further research is needed to optimize breast development in transgender people.”

Reference
Angus LM, Leemaqz SY, Kasielska-Trojan AK, et al. Effect of Spironolactone and cyproterone acetate on breast growth in transgender people: a randomized clinical trial. J Clin Endocrinol Metab. 2025;110(6):e1874-e1884. doi:10.1210/clinem/dgae650