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

Centre for Endocrinology, Diabetes, and Metabolism (D.A.V., B.A.H., J.W.T., W.A., P.M.S.), University of Birmingham, Edgbaston, Birmingham B15 2TT, United Kingdom; Oxford Centre for Diabetes, Endocrinology, and Metabolism (T.M.B., M.I.M., J.A.H.W.), University of Oxford, Oxford OX3 7LJ, United Kingdom; Institute of Reproductive and Developmental Biology (S.F.), Imperial College London, London W12 0NN, United Kingdom; and Wellcome Trust Clinical Research Facility (P.N.), University Hospital Birmingham, National Health Service Foundation Trust, Birmingham B15 2PR, United Kingdom

Address all correspondence and requests for reprints to: Paul M. Stewart, M.D., FRCP, FMedSci, Professor of Medicine, Centre for Endocrinology, Diabetes & Metabolism, School of Clinical and Experimental Medicine, University of Birmingham, Birmingham B15 2TT, United Kingdom. E-mail: p.m.stewart{at}bham.ac.uk.

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.