초록/요약

STUDY QUESTION: Are there abnormalities in gonadotrophin secretion, adrenal steroidogenesis and/or testicular steroidogenesis in brothers of women with polycystic ovary syndrome (PCOS)? SUMMARY ANSWER: Brothers of women with PCOS have increased gonadotrophin responses to gonadotrophin releasing hormone (GnRH) agonist stimulation and alterations in adrenal and gonadal steroidogenesis. WHAT IS KNOWN ALREADY: PCOSis a complex genetic disease. Male as well as female first-degree relatives have reproductive features of the syndrome. We previously reported that brothers of affected women have elevated circulating dehydroepiandrosterone sulfate levels. STUDY DESIGN, SIZE, DURATION: This was a case-control study performed in 29 non-Hispanic white brothers of 22 women with PCOS and 18 control men. PARTICIPANTS/MATERIALS, SETTING, METHODS: PCOS brothers and controlmen were of comparable age, weight and ethnicity. Adrenocorticotrophic hormone (ACTH) and GnRH agonist stimulation tests were performed. Gonadotrophin responses to GnRH agonist as well as changes in precursor-product steroid pairs (delta, Delta) across steroidogenic pathways in response to ACTH and GnRH agonistwere examined. MAIN RESULTS AND THE ROLE OF CHANCE: Basal total (T) levels did not differ, but dehydroepiandrosterone (DHEA) levels (0.13 +/- 0.08 brothers versus 0.22 +/- 0.09 controls, nmol/l, P = 0.03) were lower in brothers compared with control men. ACTH-stimulated Delta 17-hydroxypregnenolone (17Preg)/Delta 17-hydroxyprogesterone (17Prog) (7.8 +/- 24.2 brothers versus 18.9 +/- 21.3 controls, P = 0.04) and Delta DHEA/Delta androstenedione (AD) (0.10 +/- 0.05 brothers versus 0.14 +/- 0.08 controls, P = 0.04) were lower in brothers than in the controls. GnRH agonist-stimulated Delta 17Prog/Delta AD (0.28 +/- 8.47 brothers versus 4.79 +/- 10.28 controls, P = 0.003) was decreased and luteinizing hormone (38.6 +/- 20.6 brothers versus 26.0 +/- 9.8 controls, IU/l, P = 0.02), follicle-stimulating hormone (10.2 +/- 7.5 brothers versus 4.8 +/- 4.1 controls, IU/l P = 0.002), AD (1.7 +/- 1.4 brothers versus 0.9 +/- 1.5 controls, nmol/l, P = 0.02) and Delta AD/Delta T (0.16 +/- 0.14 brothers versus 0.08 +/- 0.12 controls, P = 0.005) responses were increased in brothers compared with controls. LIMITATIONS, REASONS FOR CAUTION: The modest sample size may have limited our ability to observe other possible differences in steroidogenesis between PCOS brothers and control men. WIDER IMPLICATIONS OF THE FINDINGS: Decreased ACTH-stimulated Delta 17Preg/Delta 17Prog and Delta DHEA/Delta AD responses suggested increased adrenal 3 beta-hydroxysteroid dehydrogenase activity in the brothers. Decreased Delta 17Prog/Delta AD and increased Delta AD/Delta T responses to GnRH agonist stimulation suggested increased gonadal 17,20-lyase and decreased gonadal 17 beta-hydroxysteroid dehydrogenase activity in the brothers. Increased LH and FSH responses to GnRHagonist stimulation suggested neuroendocrine alterations in the regulation of gonadotrophin secretion similar to those in their proband sisters. These changes in PCOS brothers may reflect the impact of PCOS susceptibility genes and/or programming effects of the intrauterine environment. STUDY FUNDING/COMPETING INTEREST(S): This research was supported by P50 HD044405 (A.D.), K12HD055884 (L.C.T.), U54 HD034449 (A.D.,R.S.L.) from the National Institute of Child Health and Development. Some hormone assays were performed at the University of Virginia Center for Research in Reproduction Ligand Assay and Analysis Core that is supported by U54 HD28934 from the Eunice Kennedy Shriver National Institute of Child Health and Human Development. Partial support for some of the clinical studies was provided by UL1 RR025741 and UL1 TR000150 (Northwestern University Clinical and Translational Sciences Institute) from the National Center for Research Resources, National Institutes of Health, which is now the National Center for Advancing Translational Sciences. The authors have no conflict of interest to declare.