title: Sex differences in neurosteroid and hormonal responses to metyrapone in posttraumatic stress disorder.
abstract: BACKGROUND
  Mechanisms contributing to sex differences in the regulation of acute stress responsivity and their effect on the increased incidence of posttraumatic stress disorder (PTSD) in women are poorly understood. The reproductive hormone, progesterone, through conversion to allopregnanolone (ALLO), suppresses the hypothalamic pituitary adrenal (HPA) axis and has potent anxiolytic effects. The potential that progesterone and allopregnanolone reactivity modulate HPA axis responses and account for sex differences in PTSD has not been previously examined.
  
  
  OBJECTIVE
  The present study examined the effects of sex and PTSD on adrenocorticotropic hormone (ACTH), progesterone, and allopregnanolone responses to metyrapone and whether progesterone and allopregnanolone reactivity could affect the ACTH response in PTSD.
  
  
  METHODS
  Healthy medication-free male and premenopausal follicular phase female participants with chronic PTSD (n = 43; 49 % female) and controls (n = 42; 50 % female) completed an overnight metyrapone challenge and ACTH, progesterone, and allopregnanolone were obtained by repeated blood sampling.
  
  
  RESULTS
  The increase in ACTH response to metyrapone was higher in PTSD subjects compared to controls and in women compared to men. Contrary to our initial prediction of an inverse relationship, progesterone and allopregnanolone were positively associated with ACTH. Progesterone and allopregnanolone partially mediated the relationship between PTSD and ACTH.
  
  
  CONCLUSIONS
  Our findings of increased ACTH to metyrapone in PTSD and in women may reflect heightened hypothalamic CRF hypersecretion. Progesterone and allopregnanolone partially mediated the ACTH response in PTSD. Further characterizing sex differences in these processes will advance our understanding of the pathophysiology of PTSD, and may ultimately lead to better-targeted, more effective treatment.
authors: Stress and Health Research Program, San Francisco VA Medical Center, 4150 Clement St. (116P), San Francisco, CA, 94121, USA, sabra.inslicht@ucsf.edu.
authors: Sabra S
authors: SS
authors: Inslicht
authors: Anne
authors: A
authors: Richards
authors: Erin
authors: E
authors: Madden
authors: Madhu N
authors: MN
authors: Rao
authors: Aoife
authors: A
authors: O'Donovan
authors: Lisa S
authors: LS
authors: Talbot
authors: Evelyn
authors: E
authors: Rucker
authors: Thomas J
authors: TJ
authors: Metzler
authors: Richard L
authors: RL
authors: Hauger
authors: Thomas C
authors: TC
authors: Neylan
mesh_terms: D000324:Adrenocorticotropic Hormone / Q000097:blood; D000328:Adult; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D025461:Feedback, Physiological / Q000187:drug effects; D005260:Female; D006801:Humans; D006854:Hydrocortisone / Q000097:blood; D007030:Hypothalamo-Hypophyseal System / Q000187:drug effects; D008297:Male; D008797:Metyrapone / Q000627:therapeutic use*; D018377:Neurotransmitter Agents / Q000378:metabolism*; D010913:Pituitary-Adrenal System / Q000187:drug effects; D011280:Pregnanolone / Q000097:blood; D011374:Progesterone / Q000097:blood; D012727:Sex Characteristics; D013313:Stress Disorders, Post-Traumatic / Q000188:drug therapy* / Q000378:metabolism*; D055815:Young Adult
chemical_list: D004791:Enzyme Inhibitors; D018377:Neurotransmitter Agents; D011374:Progesterone; D000324:Adrenocorticotropic Hormone; D011280:Pregnanolone; D006854:Hydrocortisone; D008797:Metyrapone