Sleep and hypothalamic pituitary adrenal axis responses to metyrapone in posttraumatic stress disorder

Psychoneuroendocrinology. 2018 Feb;88:136-143. doi: 10.1016/j.psyneuen.2017.12.002. Epub 2017 Dec 7.


Disturbed sleep is a core feature of posttraumatic stress disorder (PTSD), characterized in part by decreased delta power sleep that may result from stress-related alterations in corticotropin releasing factor (CRF), hypothalamic pituitary adrenal axis (HPA) regulation and glucocorticoid signaling. Overnight HPA axis response mediating sleep disturbances in men and women with PTSD was examined using a metyrapone challenge. Metyrapone blocks cortisol synthesis, removing negative feedback, and increases the release of hypothalamic CRF and pituitary adrenocorticotropic hormone (ACTH). Laboratory-based polysomnography was used to monitor the sleep of 66 medically healthy, medication-free men and pre-menopausal follicular phase women including 33 with chronic PTSD (16 women and 17 men) and 33 age- and sex-matched controls (14 women and 19 men) over 3 consecutive nights. Participants completed an overnight metyrapone challenge after an adaptation and baseline night of sleep and ACTH was obtained by repeated blood sampling. Metyrapone resulted in a greater increase in ACTH and greater decreases in cortisol and delta spectral power sleep in PTSD subjects compared to controls, and a greater increase in ACTH in women compared to men. There was no sex difference in metyrapone effects on delta power sleep, and no significant metyrapone by PTSD by sex interactions with either ACTH or delta power sleep. Regression analyses indicated that a greater increase in ACTH response was associated with a greater decrease in delta power sleep response in PTSD subjects, but no such relationship was found in controls. The PTSD group difference was similar in men and women. These results suggest that stress-related alterations of the HPA axis in PTSD may contribute to sleep difficulties. Therapeutics that target the HPA axis may offer promise as a potential future treatment for PTSD and related sleep difficulties.

Keywords: ACTH; Metyrapone; Posttraumatic stress disorder; Sex differences; Sleep.

Publication types

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

MeSH terms

  • Adrenocorticotropic Hormone / blood
  • Adrenocorticotropic Hormone / drug effects*
  • Adult
  • Corticotropin-Releasing Hormone / metabolism
  • Cross-Sectional Studies
  • Female
  • Humans
  • Hydrocortisone / blood
  • Hypothalamo-Hypophyseal System / drug effects
  • Hypothalamo-Hypophyseal System / metabolism
  • Male
  • Metyrapone / pharmacology*
  • Pituitary-Adrenal System / drug effects
  • Pituitary-Adrenal System / metabolism
  • Polysomnography / methods
  • Sleep / physiology*
  • Sleep Wake Disorders
  • Stress Disorders, Post-Traumatic / blood
  • Stress Disorders, Post-Traumatic / drug therapy


  • Adrenocorticotropic Hormone
  • Corticotropin-Releasing Hormone
  • Hydrocortisone
  • Metyrapone