title: Evidence for gonadotrophin secretory and steroidogenic abnormalities in brothers of women with polycystic ovary syndrome.
abstract: OBJECTIVE
  Are there abnormalities in gonadotrophin secretion, adrenal steroidogenesis and/or testicular steroidogenesis in brothers of women with polycystic ovary syndrome (PCOS)?
  
  
  CONCLUSIONS
  Brothers of women with PCOS have increased gonadotrophin responses to gonadotrophin releasing hormone (GnRH) agonist stimulation and alterations in adrenal and gonadal steroidogenesis.
  
  
  BACKGROUND
  PCOS is 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.
  
  
  METHODS
  This was a case-control study performed in 29 non-Hispanic white brothers of 22 women with PCOS and 18 control men.
  
  
  METHODS
  PCOS brothers and control men 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, Δ) across steroidogenic pathways in response to ACTH and GnRH agonist were examined.
  
  
  RESULTS
  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 Δ17-hydroxypregnenolone (17Preg)/Δ17-hydroxyprogesterone (17Prog) (7.8 ± 24.2 brothers versus 18.9 ± 21.3 controls, P = 0.04) and ΔDHEA/Δandrostenedione (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 Δ17Prog/ΔAD (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 ΔAD/ΔT (0.16 ± 0.14 brothers versus 0.08 ± 0.12 controls, P = 0.005) responses were increased in brothers compared with controls.
  
  
  CONCLUSIONS
  The modest sample size may have limited our ability to observe other possible differences in steroidogenesis between PCOS brothers and control men.
  
  
  CONCLUSIONS
  Decreased ACTH-stimulated Δ17Preg/Δ17Prog and ΔDHEA/ΔAD responses suggested increased adrenal 3β-hydroxysteroid dehydrogenase activity in the brothers. Decreased Δ17Prog/ΔAD and increased ΔAD/ΔT responses to GnRH agonist stimulation suggested increased gonadal 17,20-lyase and decreased gonadal 17β-hydroxysteroid dehydrogenase activity in the brothers. Increased LH and FSH responses to GnRH agonist 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.
  
  
  BACKGROUND
  This research was supported by P50 HD044405 (A.D.), K12 HD055884 (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.
authors.affiliation: Division of Endocrinology, Metabolism and Molecular Medicine, Northwestern University, Chicago, IL 60611, USA.
authors.forename: D M
authors.initials: DM
authors.lastname: Liu
authors.affiliation: Division of Endocrinology, Ann & Robert H Lurie Children's Hospital of Chicago, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
authors.forename: L C
authors.initials: LC
authors.lastname: Torchen
authors.affiliation: Division of Endocrinology, Ewha Womans University College of Medicine, Seoul, 158-710, Korea.
authors.forename: Y
authors.initials: Y
authors.lastname: Sung
authors.affiliation: Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USA.
authors.forename: R
authors.initials: R
authors.lastname: Paparodis
authors.affiliation: Department of Obstetrics and Gynecology, Pennsylvania State University College of Medicine, Hershey, PA 17033, USA.
authors.forename: R S
authors.initials: RS
authors.lastname: Legro
authors.affiliation: Department of Laboratory Medicine and Pathology and Department of Medicine, Mayo Clinic and Foundation, Rochester, MN 55905, USA.
authors.forename: S K
authors.initials: SK
authors.lastname: Grebe
authors.affiliation: Department of Laboratory Medicine and Pathology, Mayo Clinic and Foundation, Rochester, MN 55905, USA.
authors.forename: R J
authors.initials: RJ
authors.lastname: Singh
authors.affiliation: Department of Laboratory Medicine and Pathology, Mayo Clinic and Foundation, Rochester, MN 55905, USA.
authors.forename: R L
authors.initials: RL
authors.lastname: Taylor
authors.affiliation: Division of Endocrinology, Metabolism and Molecular Medicine, Northwestern University, Chicago, IL 60611, USA a-dunaif@northwestern.edu.
authors.forename: A
authors.initials: A
authors.lastname: Dunaif
mesh_terms: D006907:17-alpha-Hydroxypregnenolone / Q000097:blood; D019326:17-alpha-Hydroxyprogesterone / Q000097:blood; D000293:Adolescent; D000328:Adult; D000735:Androstenedione / Q000097:blood; D016022:Case-Control Studies; D003350:Cortodoxone / Q000097:blood; D019314:Dehydroepiandrosterone Sulfate / Q000097:blood; D005260:Female; D006062:Gonadotropins / Q000097:blood*; D006801:Humans; D008297:Male; D008875:Middle Aged; D011085:Polycystic Ovary Syndrome; D035781:Siblings; D013256:Steroids / Q000097:blood*
chemical_list: D006062:Gonadotropins; D013256:Steroids; D006907:17-alpha-Hydroxypregnenolone; D000735:Androstenedione; D019314:Dehydroepiandrosterone Sulfate; D019326:17-alpha-Hydroxyprogesterone; D003350:Cortodoxone
keywords: male phenotype; polycystic ovary syndrome; steroidogenesis; steroidogenic enzymes