3α-reduced neuroactive steroids and their precursors during pregnancy and the postpartum period

Abstract

Allopregnanolone (ALLO) and pregnanolone (PREG), the 3α-reduced metabolites of progesterone (PROG), are potent modulators of γ-aminobutyric acid type A receptors that may function as endogenous anxiolytics. They are purported to be involved in the etiology or expression of clinical depression. In the present study we quantified ALLO and PREG, as well as PROG, 5α-dihydroprogesterone (5α-DHP), 5β-dihydroprogesterone (5β-DHP), epiallopregnanolone and pregnenolone (PREGNEN), in plasma from healthy women at five time points during pregnancy and the postpartum period. Analysis was by gas chromatography/electron capture – negative chemical ionization – mass spectrometry. Neuroactive steroids increased significantly from 10 to 36 weeks of pregnancy, except for 5β-DHP and PREGNEN which did not change significantly. PROG was the most abundant steroid throughout pregnancy, followed by 5α-DHP and ALLO. Metabolite to precursor ratios differed depending on the enzyme and substrate: the turnover of PROG to 5α-DHP (catalyzed by 5α-reductase) was stable while the conversion of PROG to 5β-DHP (catalyzed by 5β-reductase) decreased later in pregnancy. 3α-Hydroxysteroid oxidoreductase-mediated turnover of 5α- and 5β-DHP to their metabolites ALLO and PREG, respectively, rose during pregnancy, but the turnover of 5α-DHP to ALLO dropped at the late prenatal visit. At 6 weeks postpartum all steroids were significantly reduced compared with late prenatal values, with 5α-DHP being the most abundant postpartum steroid. These results provide the basis for further study of neuroactive steroids in psychiatric conditions of pregnancy and the postpartum period.

Keywords:

• Allopregnanolone
• depression
• gas chromatography/mass spectrometry
• neuroactive steroids
• postpartum
• pregnancy
• progesterone