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

Abstract

Allopregnanolone (ALLO) and pregnanolone (PREG), the 3alpha-reduced metabolites of progesterone (PROG), are potent modulators of gamma-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, 5alpha-dihydroprogesterone (5alpha-DHP), 5beta-dihydroprogesterone (5beta-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 5beta-DHP and PREGNEN which did not change significantly. PROG was the most abundant steroid throughout pregnancy, followed by 5alpha-DHP and ALLO. Metabolite to precursor ratios differed depending on the enzyme and substrate: the turnover of PROG to 5alpha-DHP (catalyzed by 5alpha-reductase) was stable while the conversion of PROG to 5beta-DHP (catalyzed by 5beta-reductase) decreased later in pregnancy. 3alpha-Hydroxysteroid oxidoreductase-mediated turnover of 5alpha- and 5beta-DHP to their metabolites ALLO and PREG, respectively, rose during pregnancy, but the turnover of 5alpha-DHP to ALLO dropped at the late prenatal visit. At 6 weeks postpartum all steroids were significantly reduced compared with late prenatal values, with 5alpha-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.

Circulating levels of pregnanolone isomers during the third trimester of human pregnancy

“…For instance, 5␤-PIs may take effect through a pregnane X receptor-mediated mechanism regulating uterine contractility [16]. It is likely that the decrease in activity of 5␤-reductase [34,36] and the increasing sulfation of PIs during the third trimester are associated with a reduced ability to sustain the pregnancy.…”

Steroid metabolome in fetal and maternal body fluids in human late pregnancy

“…Some studies including ours reported decreasing production of pregnancy sustaining 5␤-pregnane steroids that provide uterine quiescence via binding to nuclear pregnane X-receptors [13,26,[29][30][31].…”

“…Besides non-genomic effects, reduced progesterone metabolites, which are synthesized in large quantities in pregnancy [13,[21][22][23][24][25][26][27], may also bind on nuclear receptors such as progesterone receptors [28] providing uterine quiescence. Some studies including ours reported decreasing production of pregnancy sustaining 5␤-pregnane steroids that provide uterine quiescence via binding to nuclear pregnane X-receptors [13,26,[29][30][31].…”

Sex-dependent effect of a low neurosteroid environment and intrauterine growth restriction on fetal guinea pig brain development.

“…In order to minimise cross-reactivity, the concentration of progesterone was reduced by treating the samples with potassium permanganate to oxidise non-saturated steroids. Recovery was measured by the addition of tritium-labelled allopregnanolone (1000-1500 c.p.m., 5a- [9,11,12,3 H(N)]; PerkinElmer Life and Analytical Sciences, Boston, MA, USA) to each sample prior to extraction. Each sample was corrected for its extraction loss in the final calculation of allopregnanolone concentrations.…”