MENSTRUAL ABNORMALITIES IN WOMEN WITH CUSHINGS-DISEASE ARE CORRELATEDWITH HYPERCORTISOLEMIA RATHER THAN RAISED CIRCULATING ANDROGEN LEVELS

Menstrual irregularity is a common complaint at presentation in women with Gushing's syndrome, although the etiology has been little studied . We have assessed 45 female patients (median age, 32 yr; range, 16-41 yr) with newly diagnosed pituitary-dependent Cushing's syndrome. Pati ents were subdivided into 4 groups according to the duration of their menstrual cycle: normal cycles (NC; 26-30 days), oligomenorrhea (OL; 3 1-120 days), amenorrhea (AM; >120 days), and polymenorrhea (PM; <26 da ys). Blood was taken at 0900 h for measurement of LH, FSH, PRL, testos terone, androstenedione, dehydroepiandrosterone sulfate, estradiol (E- 2), sex hormone-binding globulin (SHBG), and ACTH; cortisol was sample d at 0900, 1800, and 2400 h. The LH and FSH responses to 100 mu g GnRH were analyzed in 23 patients. Statistical analysis was performed usin g the nonparametric Mann-Whitney U and Spearman tests. Only 9 patients had NC (20%), 14 had OL (31.1%), 15 had AM (33.3%), and 4 had PM (8.8 %), whereas 3 had Variable cycles (6.7%). By group, AM patients had lo wer serum E-2 levels (median, 110 pmol/L) than OL patients (225 pmol/L ; P < 0.05) or NC patients (279 pmol/L; P < 0.05), and higher serum co rtisol, levels at 0900 h (800 vs. 602 and 580 nmol/L, respectively; P < 0.05) and 1800 h (816 vs. 557 and 523 nnol/L, respectively; P < 0.05 ) and higher mean values from 6 samples obtained through the day (753 us. 491 and 459 nmol/L, respectively; P < 0.05). For the whole group o f patients there was a negative correlation between serum E-2 and cort isol at 0900 h (r = -0.50; P < 0.01) and 1800 h (r = -0.56; P < 0.01) and with mean cortisol (r = -0.46; P < 0.05). No significant correlati on was found between any serum androgen and E-2 or cortisol. The LH re sponse to GnRH was normal in 43.5% of the patients, exaggerated in 52. 1%, and decreased in 4.4%, but there were no significant differences a mong the menstrual groups. No differences were found in any other para meter. In summary, in our study 80% of patients with Gushing's syndrom e had menstrual irregularity, and this was most closely related to ser um cortisol rather than to circulating androgens. Patients with AM had higher levels of cortisol and lower levels of E-2, while the GnRH res ponse was either normal or exaggerated. Our data suggest that the mens trual irregularity in Gushing's disease appears to be the result of hy percortisolemic inhibition of gonadotropin release acting at a hypotha lamic level, rather than raised circulating androgen levels.