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

Summary

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.

Introduction

Neuroactive steroids are endogenous neuromodulators, synthesized de novo in brain as well as in the adrenals and gonads. They have potent effects on neurotransmission mediated by GABA_A receptors (Paul and Purdy, 1992). The 3α,5α- and 3α,5β-reduced metabolites of progesterone, deoxycorticosterone, and dehydroepiandrosterone (DHEA) (Biggio and Purdy, 2001, Frye et al., 1996, Majewska et al., 1986) induce potent GABAergic actions, including anxiolytic, anticonvulsant, sedative/hypnotic and anti-nociceptive effects (Biggio and Purdy, 2001, Frye et al., 1996, Frye et al., 2004, Kavaliers and Wiebe, 1987, Morrow, 2007) – actions, consistent with an integrated and adaptive response to stress (Purdy et al., 1991). In addition to these adaptive behavioral effects of neuroactive steroids, animal models provide strong and consistent evidence that these steroid metabolites also act as endogenous suppressors of the hypothalamic-pituitary-adrenal (HPA)-axis following stress (Barbaccia et al., 1997, Purdy et al., 1991, Strous et al., 2006). Although concentrations of neuroactive steroids in brain are somewhat higher than in plasma, plasma concentrations are likely to reflect brain concentrations because these neuroactive steroids can readily cross the blood–brain barrier (Paul and Purdy, 1992, Purdy et al., 1991) and are likely to play important physiological roles.

For example, there is robust evidence from both animal and human studies that the 3α-reduced neuroactive steroid metabolites of progesterone, (3α,5α)-3-hydroxypregnan-20-one (3α,5α-THP or allopregnanolone) and (3α,5β)-3-hydroxypregnan-20-one (3α,5β-THP) are decreased in depression (Eser et al., 2006, Nappi et al., 2001, Romeo et al., 1998, Strohle et al., 1999, Strohle et al., 2000, Uzunova et al., 1998, Uzunova et al., 2006). When compared with non-depressed controls, depressed patients have lower plasma and CSF concentrations of 3α,5α-THP (Eser et al., 2006, Nappi et al., 2001, Romeo et al., 1998, Strohle et al., 1999, Strohle et al., 2000, Uzunova et al., 1998, Uzunova et al., 2006), but higher concentrations of the 3α,5α-metabolite of deoxycorticosterone (3α,5α)-3,21-dihydroxypregnan-20-one (3α,5α-THDOC) (Strohle et al., 1999, Strohle et al., 2000), which may reflect differential alteration in the biosynthesis of deoxycorticosterone or its metabolites in depression (Strohle et al., 1999, Strohle et al., 2000). Our prior research also suggested there may be a differential regulation of metabolic pathways involved in the conversion of progesterone to 3α,5α-THP in women with a menstrually related depressive disorder (premenstrual dysphoric disorder: PMDD), since those patients showed significantly elevated 3α,5α-THP/progesterone ratios relative to non-affected controls (Girdler et al., 2001, Klatzkin et al., 2006a). Our prior studies were limited, however, by the absence of measurement of other neuroactive steroids, thereby preventing us from examining the relationship of 3α,5β-THP to other neurosteroids. Indeed, it is likely that the GABAergic metabolites of progesterone, deoxycorticosterone, and DHEA are both singularly and coordinately significant physiological regulators of central nervous system excitability (Morrow, 2007).

Regardless of mechanism, the pathophysiological relevance of altered neurosteroid concentrations in humans comes from studies showing inverse relationships between 3α,5α-THP concentrations and severity of the depressive illness (Nappi et al., 2001, Uzunova et al., 1998) and from other studies showing that clinically efficacious treatment with antidepressants is associated with increases in 3α,5β-THP (Romeo et al., 1998, Strohle et al., 1999, Strohle et al., 2000, Uzunova et al., 1998) and decreases in 3α,5α-THDOC (Strohle et al., 1999, Strohle et al., 2000).

With our recent validation of a method using gas chromatography–mass spectrometry (GC–MS) to simultaneously identify serum levels of 3α,5α- and 3α,5β-reduced derivatives of progesterone, deoxycorticosterone, DHEA and testosterone in both human and rat serum (Porcu et al., 2009), we report here a secondary analysis of the serum samples collected from women enrolled in a prior study that was designed to examine the metabolism of oral micronized progesterone to 3α,5α-THP in women with PMDD and in non-PMDD controls (Klatzkin et al., 2006a). That initial study assessed only 3α,5α-THP, using radioimmunoassay techniques, but found that women with a history of depression (both PMDD and non-PMDD women) had lower 3α,5α-THP levels following oral micronized progesterone than never depressed women (Klatzkin et al., 2006a).

In the present report, we sought to extend the previous literature on neuroactive steroid levels in depression, which has focused almost exclusively on the 3α,5α- and 3α,5β-reduced derivatives of progesterone (Uzunova et al., 2006), by assessing a broader array of GABAergic neuroactive steroids in women with a history of depression compared with never depressed women (all non-PMDD women). Specifically, using GC–MS methods, we examined serum levels of four progesterone-derived GABAergic neuroactive steroids:3α,5α-THP, 3α,5β-THP, 3α,5α-THDOC and (3α,5β)-3,21-dihydroxypregnan-20-one (3α,5β-THDOC), as well as the precursor pregnenolone. We also examined the androstenedione-derived neuroactive steroids (3α,5α)-3-hydroxyandrostan-17-one (3α,5α-A) and (3α,5β)-3-hydroxyandrostan-17-one (3α,5β-A), and the precursor DHEA (see Fig. 1 for the biosynthetic pathway). Finally, we examined whether histories of depression would be associated with evidence for differential regulation of the metabolic pathways involved in the conversion of progesterone to its 3α,5α- or 3α,5β-neuroactive steroids following a controlled dose of oral micronized progesterone.