A history of depression in women is associated with an altered GABAergic neuroactive steroid profile

Abstract

The 3α,5α- and 3α,5β-reduced metabolites of progesterone, deoxycorticosterone, and dehydroepiandrosterone (DHEA) have potent effects on neurotransmission mediated by GABA(A) receptors, and dysregulation of these receptors has been implicated in depression. Using gas chromatography-mass spectrometry, we compared neuroactive steroid concentrations in women with a history of depressive disorders, but who were in full remission at the time of testing (n=11) to never depressed women (n=17) both before and after a challenge with oral micronized progesterone (300 mg). Serum concentrations of the following were obtained: four progesterone-derived GABAergic neuroactive steroids, the precursor pregnenolone, androstenedione-derived neuroactive steroids, and the precursor DHEA. As an index of conversion of progesterone to neuroactive steroids, we also examined ratios of neuroactive steroids to progesterone following the oral progesterone challenge. Results indicated that both before and after oral progesterone, women with histories of depression showed lower concentrations of all GABAergic neuroactive steroids than never depressed women. Those with a history of depression also had lower cortisol concentrations. Because serum neuroactive steroids are mainly synthesized in the adrenals, we hypothesize that histories of depression may be associated with persistent adrenal suppression. Following the progesterone challenge, ratios of the progesterone-derived neuroactive steroids to plasma progesterone concentrations were elevated in women with depression histories, suggesting there may be an adaptive shift in the metabolism of progesterone that compensates for lower circulating neuroactive steroid concentrations.

Figure 1

Biosynthetic pathway for the GABAergic neuroactive steroids measured herein (indicated in bold capitalized letters). Abbreviations – 3α,5α-THP: (3α,5α)-3-hydroxypregnan-20-one; 3α,5β-THP: (3α,5β)-3-hydroxypregnan-20-one; 3α,5α-THDOC: (3α,5α)-3,21-dihydroxypregnan-20-one; 3α,5β-THDOC: (3α,5β)-3,21-dihydroxypregnan-20-one; 3α,5α-A: (3α,5α)-3-hydroxyandrostan-17-one; 3α,5β-A: (3α,5β)-3-hydroxyandrostan-17-one; 5α-DHP: 5α-dihydroprogesterone; 5β-DHP: 5β-dihydroprogesterone; 5α-DHDOC: 5α-dihydrodeoxycorticosterone; 5β-DHDOC: 5β-dihydrodeoxycorticosterone; 5α-DHT: 5α-dihydrotestosterone; 5β-DHT: 5β-dihydrotestosterone; DHEA: dehydroepiandrosterone; HSD: hydroxysteroid dehydrogenase.

Figure 2

Ratio of (3α,5α)-3-hydroxypregnan-20-one (3A,5B-THP), (3α,5β)-3-hydroxypregnan-20-one (3A,5B-THP), (3α,5α)-3,21-dihydroxypregnan-20-one (3A,5B-THDOC), and (3α,5β)-3,21-dihydroxypregnan-20-one (3A,5B-THDOC) to progesterone in women as a function of depression histories.