Sex differences in neurosteroid and hormonal responses to metyrapone in posttraumatic stress disorder

Psychopharmacology (Berl). 2014 Sep;231(17):3581-95. doi: 10.1007/s00213-014-3621-3. Epub 2014 Jun 21.


Rationale: 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Adrenocorticotropic Hormone / blood
  • Adult
  • Enzyme Inhibitors / therapeutic use*
  • Feedback, Physiological / drug effects
  • Female
  • Humans
  • Hydrocortisone / blood
  • Hypothalamo-Hypophyseal System / drug effects
  • Male
  • Metyrapone / therapeutic use*
  • Neurotransmitter Agents / metabolism*
  • Pituitary-Adrenal System / drug effects
  • Pregnanolone / blood
  • Progesterone / blood
  • Sex Characteristics
  • Stress Disorders, Post-Traumatic / drug therapy*
  • Stress Disorders, Post-Traumatic / metabolism*
  • Young Adult


  • Enzyme Inhibitors
  • Neurotransmitter Agents
  • Progesterone
  • Adrenocorticotropic Hormone
  • Pregnanolone
  • Hydrocortisone
  • Metyrapone