Toward a Lowest Effective Dose of Cyproterone Acetate in Trans Women: Results From the ENIGI Study

Abstract

Context Cyproterone acetate (CPA) is a competitive inhibitor of the androgen receptor and exerts negative hypothalamic feedback. It is often used in combination with estrogens in trans women to achieve feminization. However, CPA has been associated with side effects such as changes in liver enzyme concentrations and increases in prolactin concentrations. The question is whether testosterone lowering, as well as these side effects, are dose-dependent. Objective To assess the lowest effective dose of CPA in trans women to prevent side effects. Design This longitudinal study is part of the European Network for the Investigation of Gender Incongruence (ENIGI), a multicenter prospective cohort study. Setting Gender identity centers in Amsterdam, Ghent, and Florence Participants Trans women (n = 882) using estrogens only or in combination with 10mg, 25mg, 50mg, or 100mg CPA daily. Intervention Different doses of CPA. Main Outcome measure The concentration of testosterone at 3 and/or 12 months of hormone therapy. Results Using estrogens only (without CPA) led to testosterone concentrations of 5.5nmol/L (SEM 0.3). All doses of CPA resulted in testosterone concentrations below the pre-defined threshold of suppression of 2nmol/L (10mg: 0.9nmol/L, SEM 0.7; 25mg: 0.9nmol/L, SEM 0.1; 50mg: 1.1nmol/L, SEM 0.1; 100mg: 0.9nmol/L, SEM 0.7). Higher prolactin and lower high-density lipoprotein concentrations were observed with increasing doses of CPA. No differences in liver enzyme concentrations were found between the doses. Conclusions Compared to higher doses of CPA, a daily dose of 10mg is equally effective in lowering testosterone concentrations in trans women, while showing fewer side effects.

The ENIGI (European Network for the Investigation of Gender Incongruence) Study: Overview of Acquired Endocrine Knowledge and Future Perspectives

“…Cyproterone acetate (CPA) is the most commonly used anti-androgen. Initially, CPA was administered at a dosage of 50 mg/daily, which has recently been reduced to 25 mg/daily, and often to 10 mg/daily (range 10–50 mg) in consideration of the similar anti-androgenic effectiveness against a lower risk of side effects [ 3 , 4 , 5 ]. Among anti-androgenic compounds, alternatives are represented by spironolactone (100–300 mg/daily) and gonadotropin releasing hormone analogues (i.e., triptorelin 3.75 mg per 4 weeks or pamorelin 11.25 mg per 12 weeks).…”

Rodent Model of Gender-Affirming Hormone Therapies as Specific Tool for Identifying Susceptibility and Vulnerability of Transgender People and Future Applications for Risk Assessment

“…It also influences sexual desire and spermatogenesis and showed anti-gonadotropic effect causing a decrease in luteinizing hormone (LH) and follicle-stimulating hormone (FSH) secretion. As CPA is a progestogen, it also has progestogen-like effects, such as changes in lipid metabolism [ 23 ]. The T-lowering agent most commonly used in the United States is spironolactone.…”

“…T concentrations usually do not decline up to cisgender ranges and only the use of spironolactone in combination with high doses of E2 (i.e., median dose of 6 mg/day) causes T decline in the cisgender range. However, no data are available on the adverse effects caused by E2 high doses in combination with spironolactone; nevertheless, differently from CPA, spironolactone has not been associated with increases in prolactin levels [ 23 ].…”

“…However, over time, the overstimulation of the hypothalamic–pituitary–gonadal axis produces a decrease in LH and FSH levels and, subsequently, reduces T concentrations. Different from CPA and spironolactone, GnRH-a is administered by im or sc injection and the data on long-term safety are limited [ 23 ]. While oestrogens are considered a lifelong therapy, anti-androgens are generally discontinued after genital surgery (orchiectomy) or if oestrogen-only treatment has proven to be sufficient [ 22 ].…”

Bone health in transgender people: a narrative review

“…The antiandrogen effects of CA are the result of its antigonadotropic effect that leads to suppression of gonadal T production and of its competitive blocking of androgen action at the androgen receptor. 18 …”