Increased 5-Reductase Activity and Adrenocortical Drive in Women with Polycystic Ovary Syndrome

CONTEXT: Polycystic ovary syndrome (PCOS) is characterized by hyperandrogenism, anovulation, and susceptibility to the metabolic syndrome. Altered peripheral cortisol metabolism has been reported in PCOS, but also in simple obesity. OBJECTIVE: The aim of the study was to describe cortisol metabolism and metabolic characteristics of a large PCOS cohort and to delineate the effect of obesity by comparison to body mass index (BMI)-matched controls. DESIGN AND SETTING: We conducted an observational, cross-sectional study at outpatient clinics of two secondary/tertiary care centers. Patients or Other Participants: A total of 178 PCOS patients fulfilling Rotterdam criteria and 100 BMI-matched controls participated in the study. INTERVENTION: The study included 24-h urine collection for steroid metabolite excretion and fasting blood samples, followed by an oral glucose tolerance test. MAIN OUTCOME MEASURES: We measured urinary steroid metabolites including glucocorticoids and androgens and the ratios reflecting enzymatic activities involved in peripheral cortisol and androgen metabolism, 5-reductase, and 11β-hydroxysteroid dehydrogenase types 1 and 2. We also measured circulating levels of glucose, insulin, dehydroepiandrosterone, dehydroepiandrosterone sulfate, and testosterone and calculated homeostasis model assessment. RESULTS: Total androgen metabolites were higher in PCOS patients compared to BMI-matched controls (4,105 ± 2,047 vs. 2,532 ± 1,610 µg/24 h for the nonobese; 5,547 ± 2,911 vs. 2,468 ± 1,794 µg/24 h for the obese; both P < 0.001). Total glucocorticoid metabolites were higher in obese PCOS vs. controls (10,786 ± 3,852 vs. 8,834 ± 4,487 µg/24 h; P = 0.001). 5-Reductase activity correlated with BMI, insulin levels, and homeostasis model assessment. Both obese and nonobese PCOS patients had higher 5-reductase activity than controls (all P < 0.05). 11β-Hydroxysteroid dehydrogenase activities did not differ between PCOS and controls. CONCLUSIONS: PCOS is associated with enhanced androgen and cortisol metabolite excretion and increased 5-reductase activity that cannot be explained by obesity alone. Increased adrenal corticosteroid production represents an important pathogenic pathway in PCOS.