title: Elevated androgens during puberty in female rhesus monkeys lead to increased neuronal drive to the reproductive axis: a possible component of polycystic ovary syndrome.
abstract: BACKGROUND
  Hyperandrogenemia is associated with several clinical disorders in which both reproductive dysfunction and metabolic changes may coexist [i.e. polycystic ovary syndrome (PCOS), obesity and congenital adrenal hyperplasia]. Moreover, there is growing evidence that the elevated levels of circulating androgens in obese girls may lead to an increased neuroendocrine drive to the reproductive axis, similar to that associated with PCOS.
  
  
  METHODS
  To test whether androgen exposure in the childhood and adolescent period could lead to pubertal alterations in LH secretory patterns, female rhesus monkeys received subcutaneous testosterone implants prepubertally beginning at 1 year of age, maintaining a 3.7-fold increase (P = 0.001) in circulating testosterone levels over cholesterol-implant controls (n = 6/group) into the post-pubertal period. In early adulthood, pulsatile secretion of LH was measured over 12 h during the early follicular phase of a menstrual cycle, and responsiveness of the pituitary to gonadotrophin-releasing hormone was determined. In addition, ultrasounds were performed to assess ovarian morphology and glucose tolerance testing was performed to assess insulin sensitivity.
  
  
  RESULTS
  The timing of menarche was similar between groups. Testosterone-treated animals had a significantly greater LH pulse frequency during the early follicular phase compared with controls (P = 0.039) when measured at 5 years of age. There was a larger LH response to GnRH when testosterone-treated animals were 4 years of age (P = 0.042), but not when the animals were 5 years old (P = 0.57). No differences were seen in insulin sensitivity or ovarian morphology, and the groups showed similar rates of ovulation in early adulthood.
  
  
  CONCLUSIONS
  Exposure to increased levels of androgens over the course of pubertal development appears to trigger physiological changes in the neural drive to the reproductive axis that resemble those of obese hyperandrogenemic girls in early adulthood and are characteristic of PCOS.
authors: Division of Reproductive Sciences, Oregon National Primate Research Center, Beaverton, OR 97006, USA. mcgeew@ohsu.edu
authors: W K
authors: WK
authors: McGee
authors: C V
authors: CV
authors: Bishop
authors: A
authors: A
authors: Bahar
authors: C R
authors: CR
authors: Pohl
authors: R J
authors: RJ
authors: Chang
authors: J C
authors: JC
authors: Marshall
authors: F K
authors: FK
authors: Pau
authors: R L
authors: RL
authors: Stouffer
authors: J L
authors: JL
authors: Cameron
mesh_terms: D000728:Androgens / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood; D000818:Animals; D004195:Disease Models, Animal; D004702:Endocrine Glands / Q000187:drug effects / Q000254:growth & development / Q000294:innervation*; D005260:Female; D005836:Genitalia, Female / Q000187:drug effects / Q000254:growth & development / Q000294:innervation*; D007987:Gonadotropin-Releasing Hormone / Q000378:metabolism; D017588:Hyperandrogenism / Q000503:physiopathology*; D007333:Insulin Resistance; D007986:Luteinizing Hormone / Q000097:blood / Q000378:metabolism; D008253:Macaca mulatta; D008572:Menarche / Q000187:drug effects; D008597:Menstrual Cycle / Q000097:blood; D009490:Neurosecretory Systems / Q000187:drug effects / Q000254:growth & development; D009765:Obesity / Q000503:physiopathology; D010053:Ovary / Q000000981:diagnostic imaging / Q000254:growth & development; D010060:Ovulation / Q000187:drug effects; D010902:Pituitary Gland / Q000254:growth & development / Q000378:metabolism; D011085:Polycystic Ovary Syndrome / Q000097:blood / Q000209:etiology* / Q000378:metabolism; D012741:Sexual Maturation / Q000187:drug effects; D013739:Testosterone / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood; D014463:Ultrasonography
chemical_list: D000728:Androgens; D007987:Gonadotropin-Releasing Hormone; D013739:Testosterone; D007986:Luteinizing Hormone