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

Abstract

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.

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Acknowledgments

This research and development project was conducted by the Stress and Health Research Program at the San Francisco VA Medical Center and is made possible by a research grant that was awarded and administered by the US Army Medical Research and Materiel Command (USAMRMC) and the Telemedicine & Advanced Technology Research Center (TATRC), at Fort Detrick, MD (SI: W81XWH-05-2-0094). This study was also supported by the National Institute for Mental Health (TCN: 5R01MH073978-04, 5R34MH077667-03), the Veterans Health Research Institute, the Mental Illness Research and Education Clinical Center of the US Veterans Health Administration, and the Clinical Research Center of the National Center for Advancing Translational Sciences, National Institutes of Health, through UCSF-CTSI Grant Number UL1 RR024131. RLH was supported by a BLR&D Merit Review grant from the Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development, the VA Center of Excellence for Stress and Mental Health (CESAMH), and a NIH/NIMH (MH074697) RO1 grant.

The views, opinions, and/or findings contained in this research are those of the authors and do not necessarily reflect the views of the Department of Defense, Department of Veteran Affairs, or NIH and should not be construed as an official DoD/Army/VA/NIH position, policy, or decision unless so designated by official documentation. No official endorsement should be made. This material is the result of work supported with resources and the use of facilities at the Veterans Administration Medical Center, San Francisco, California. We acknowledge Alan Turken for his expert completion of the allopregnanolone immunoassays. We are grateful to Synthia Mellon, Ph.D. for her scientific input, Maryann Lenoci for her logistical and technical support, and Hollen Reischer for her editorial support on this manuscript.

Conflict of interest

Dr. Neylan reports receiving study medication from Actelion for a study funded by the Department of Defense and receiving study medication from Glaxo Smith Kline for a study funded by the Department of Veterans Affairs.

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Correspondence to Sabra S. Inslicht.

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Inslicht, S.S., Richards, A., Madden, E. et al. Sex differences in neurosteroid and hormonal responses to metyrapone in posttraumatic stress disorder. Psychopharmacology 231, 3581–3595 (2014). https://doi.org/10.1007/s00213-014-3621-3

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Keywords

  • Sex differences
  • Posttraumatic stress disorder
  • Progesterone
  • Allopregnanolone
  • ACTH
  • Metyrapone