Hirsutism in Cushing’s syndrome: prospective evidence from the PROMPT study and available literature

Objective By inhibiting 11β-hydroxylase, metyrapone may increase androgen precursors; however, systematic prospective data on potential correlation with treatment-emergent hirsutism are limited. We evaluated longitudinal changes in hirsutism severity, and their association with testosterone and baseline CS severity, in women with Cushing’s syndrome (CS) treated with metyrapone for 36 weeks in the PROMPT study, and reviewed the published literature. Methods Of 34 women enrolled in PROMPT, a prospective, single-arm, open-label study, 32 with an evaluable baseline modified Ferriman-Gallwey (mFG) score were analyzed. CS severity was classified from baseline mean 24-hour urinary free cortisol (mUFC) as mild (>1.5–2-fold), moderate (>2–5-fold) or severe (>5-fold the upper limit of normal). Overall and body area-specific mFG scores were assessed at baseline and weeks 12, 24 and 36, and serum testosterone at baseline and weeks 12 and 36. Group-level changes were analyzed with linear mixed-effects models, and individual trajectories were classified using an operational ≥2-point threshold. Spearman correlation and exploratory ROC analyses examined testosterone changes in relation to mFG changes. A targeted PubMed search was done to identify the reporting of hirsutism in previous studies. Results At baseline, 21 women (65.6%) had hirsutism (mFG ≥8), predominantly mild. Model-estimated mean mFG did not change significantly (9.41 [95% CI: 7.17–11.65] at baseline; 9.63 [7.36–11.91] at week 36), including among women with baseline hirsutism (all Holm-adjusted p≥0.696). Worsening occurred in 4/32 women (12.5%), de novo in one of them. Testosterone increased during treatment, but its changes were not significantly correlated with mFG changes at week 12 or week 36, and its ability to predict worsening could not be reliably determined. Baseline CS severity (defined by mUFC) was not associated with hirsutism severity. Across 12 published studies (384 women), relatively few cases of hirsutism were reported, although ascertainment was heterogeneous, and only three discontinuations were attributed to it. Conclusions Hirsutism was frequently observed among women with CS; however, group-level mFG scores did not significantly increase during 36 weeks of metyrapone therapy. No clear association between testosterone levels and changes in hirsutism was demonstrated in this cohort. These preliminary findings are consistent with the published literature.