title: Hyperandrogenism induces a proinflammatory TNFα response to glucose ingestion in a receptor-dependent fashion.
abstract: BACKGROUND
  Hyperandrogenism and inflammation are related in polycystic ovary syndrome (PCOS). Hyperandrogenemia can induce inflammation in reproductive-age women, but the mechanism for this phenomenon is unclear.
  
  
  OBJECTIVE
  We examined the in vivo and in vitro effects of hyperandrogenism on mononuclear cell (MNC)-derived androgen receptor (AR) status and TNFα release.
  
  
  METHODS
  This study combined a randomized, controlled, double-blind protocol with laboratory-based cell culture experiments.
  
  
  METHODS
  This work was performed in an academic medical center.
  
  
  METHODS
  Lean, healthy, reproductive-age women were treated with 130 mg of dehydroepiandrosterone (DHEA) or placebo (n = 8 subjects each) for 5 days and also provided untreated fasting blood samples (n = 12 subjects) for cell culture experiments.
  
  
  METHODS
  AR mRNA content and TNFα release were measured before and after DHEA administration in the fasting state and 2 hours after glucose ingestion. TNFα release in the fasting state was also measured in cultured MNCs exposed to androgens with or without flutamide preincubation.
  
  
  RESULTS
  At baseline, subjects receiving DHEA or placebo exhibited no significant difference in androgens and TNFα release from MNCs before and after glucose ingestion. Compared with placebo, DHEA administration raised levels of T, androstenedione, and DHEA sulfate, and increased MNC-derived AR mRNA content and TNFα release in the fasting state and in response to glucose ingestion. Compared with MNC exposure to baseline concentrations of DHEA (175 ng/dL) or T (50 ng/dL), the absolute change in TNFα release increased after exposure to T concentrations of 125 and 250 ng/dL and a DHEA concentration of 1750 ng/dL. Preincubation with flutamide reduced the TNFα response by ≥ 60% across all T concentrations.
  
  
  CONCLUSIONS
  Androgen excess in vivo and in vitro comparable to what is present in PCOS increases TNFα release from MNCs of lean healthy reproductive-age women in a receptor-dependent fashion. Hyperandrogenemia activates and sensitizes MNCs to glucose in this population.
authors: Department of Obstetrics and Gynecology (F.G., C.L.S.), Indiana University School of Medicine, Indianapolis, Indiana 46202; and Department of Laboratory Medicine and Pathology (D.M.B., H.E.B.), College of Medicine, Mayo Clinic, Rochester, Minnesota 55905.
authors: Frank
authors: F
authors: González
authors: Chang Ling
authors: CL
authors: Sia
authors: Dawn M
authors: DM
authors: Bearson
authors: Hilary E
authors: HE
authors: Blair
mesh_terms: D000328:Adult; D000735:Androstenedione / Q000097:blood; D003687:Dehydroepiandrosterone; D019314:Dehydroepiandrosterone Sulfate / Q000097:blood; D004311:Double-Blind Method; D005260:Female; D005947:Glucose / Q000008:administration & dosage*; D006801:Humans; D017588:Hyperandrogenism / Q000139:chemically induced / Q000378:metabolism*; D007249:Inflammation / Q000378:metabolism*; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000378:metabolism; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism*; D013739:Testosterone / Q000097:blood; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
chemical_list: D011944:Receptors, Androgen; D014409:Tumor Necrosis Factor-alpha; D013739:Testosterone; D000735:Androstenedione; D003687:Dehydroepiandrosterone; D019314:Dehydroepiandrosterone Sulfate; D005947:Glucose