An Observational Study of Menstrual Function and Related Hormones Before and After Treatment of Cushing Syndrome

Context Although menstrual dysfunction occurs in Cushing syndrome (CS), drivers of its prevalence and prognosis are poorly documented. Objective Assess the prevalence of menstrual dysfunction, time to resolution after restoration of eucortisolism, and predictive factors for development and resolution. Design Retrospective evaluation. Setting Tertiary referral center. Patients 93 women treated for CS from 1987-2024. Interventions Surgery, medical therapy and/or irradiation to restore eucortisolism. Main Outcome Measures Prevalence of affected menses; rate and time to return to baseline pattern after remission. Patient, hormonal, tumor, and treatment factors predicting resolution. Results Sixty-eight percent (95%CI 57-77%) of women with CS had affected menses. Compared to unaffected women, those with irregular menses had higher total testosterone (TT) (91.0 vs 32.6 ng/dL, p=0.02), while amenorrheic women had lower estradiol (21.2 vs 41.9 pg/mL, p=0.01) and LH (1.0 vs 3.5 U/L, p=0.009). Gonadotropins correlated inversely with urine free cortisol (LH: r=-0.42, FSH: r= -0.30; both p<0.05). TT had no correlation. Menses returned to baseline in 84% (95%CI 66-94%) of 31 women without cyclic CS at median 6 months after achieving eucortisolism. Extensive pituitary exploration, pituitary irradiation, and mitotane reduced the likelihood of menses returning to baseline. A higher body mass index (42.4 vs 30.8 kg/m2, p<0.0001) predicted a delayed (>6 months) return to baseline. Conclusions Two-thirds of women with CS have menstrual dysfunction due to cortisol-induced suppression of gonadotropins. In most women with minimal pituitary damage, menses return to baseline after a median of 6 months of eucortisolism. Significant overweight can delay resolution.