Relationships between cerebrospinal fluid GABAergic neurosteroid levels and symptom severity in men with PTSD

Psychoneuroendocrinology. 2019 Apr:102:95-104. doi: 10.1016/j.psyneuen.2018.11.027. Epub 2018 Nov 22.

Abstract

Allopregnanolone and pregnanolone (together termed allo + pregnan) are neurosteroid metabolites of progesterone that equipotently facilitate the action of gamma-amino-butyric acid (GABA) at GABAA receptors. The adrenal steroid dehydroepiandrosterone (DHEA) allosterically antagonizes GABAA receptors and facilitates N-methyl-D-aspartate (NMDA) receptor function. In prior research, premenopausal women with posttraumatic stress disorder (PTSD) displayed low cerebrospinal fluid (CSF) levels of allo + pregnan [undifferentiated by the gas chromatography-mass spectrometry (GC-MS) method used] that correlated strongly and negatively with PTSD reexperiencing and negative mood symptoms. A PTSD-related decrease in the ratio of allo + pregnan to 5α-dihydroprogesterone (5α-DHP: immediate precursor for allopregnanolone) suggested a block in synthesis of these neurosteroids at 3α-hydroxysteroid dehydrogenase (3α-HSD). In the current study, CSF was collected from unmedicated, tobacco-free men with PTSD (n = 13) and trauma-exposed healthy controls (n = 17) after an overnight fast. Individual CSF steroids were quantified separately by GC-MS. In the men with PTSD, allo + pregnan correlated negatively with Clinician-Administered PTSD Scale (CAPS-IV) total (ρ=-0.74, p = 0.006) and CAPS-IV derived Simms dysphoria cluster (ρ=-0.71, p = 0.01) scores. The allo+pregnan to DHEA ratio also was negatively correlated with total CAPS (ρ=-0.74, p = 0.006) and dysphoria cluster (ρ=-0.79, p = 0.002) scores. A PTSD-related decrease in the 5α-DHP to progesterone ratio indicated a block in allopregnanolone synthesis at 5α-reductase. This study suggests that CSF allo + pregnan levels correlate negatively with PTSD and negative mood symptoms in both men and women, but that the enzyme blocks in synthesis of these neurosteroids may be sex-specific. Consideration of sex, PTSD severity, and function of 5α-reductase and 3α-HSD thus may enable better targeting of neurosteroid-based PTSD treatments.

Keywords: Allopregnanolone; Cerebrospinal fluid; Dehydroepiandrosterone; Depression; GABA; Gas chromatography-mass spectrometry; Neurosteroids; PTSD.

Publication types

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

MeSH terms

  • 5-alpha-Dihydroprogesterone / analysis
  • 5-alpha-Dihydroprogesterone / cerebrospinal fluid
  • Adult
  • Cholestenone 5 alpha-Reductase
  • Dehydroepiandrosterone / analysis
  • Dehydroepiandrosterone / cerebrospinal fluid
  • Dehydroepiandrosterone Sulfate / analysis
  • Dehydroepiandrosterone Sulfate / cerebrospinal fluid
  • Depressive Disorder, Major / metabolism
  • GABAergic Neurons / pathology*
  • Gas Chromatography-Mass Spectrometry / methods
  • Humans
  • Hydroxysteroid Dehydrogenases
  • Male
  • Middle Aged
  • Neurosteroids / cerebrospinal fluid*
  • Pregnanolone / analysis
  • Pregnanolone / cerebrospinal fluid
  • Progesterone / analysis
  • Progesterone / cerebrospinal fluid
  • Severity of Illness Index
  • Stress Disorders, Post-Traumatic / metabolism*
  • Stress Disorders, Post-Traumatic / physiopathology

Substances

  • Neurosteroids
  • Dehydroepiandrosterone
  • Progesterone
  • Dehydroepiandrosterone Sulfate
  • 5-alpha-Dihydroprogesterone
  • Pregnanolone
  • Hydroxysteroid Dehydrogenases
  • Cholestenone 5 alpha-Reductase