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Pregnanolone isomers (PIs) and their polar conjugates (PICs) modulate ionotropic receptors such as γ-aminobutyric acid or pregnane X receptors. Besides, brain synthesis, PI penetrates the blood–brain barrier. We evaluated the physiological importance of PI respecting the status of sex, menstrual cycle, and pregnancy. Accordingly, circulating levels of allopregnanolone (P3α 5α ), isopregnanolone (P3β 5α ), pregnanolone (P3α 5β ), epipregnanolone (P3β 5β ), their polar conjugates, and related steroids were measured in 15 men (M), 15 women in the follicular phase (F), 16 women in the luteal phase (L), and 30 women in the 36th week of gestation (P) using GC–MS. The steroid levels were similar in M and F, increased about thrice in L and escalated in P (38–410 times compared with F). The PICs were prevalent over the PIs (16–150 times). Higher ratios of 5α-PIC to 5α-PI found in P indicate the more intensive conjugation of 5α-PI during pregnancy. This mechanism probably provides for the elimination of neuroinhibitory P3α 5α in the maternal compartment. Additionally, our result points to a limited sulfation capacity for neuroinhibitory P3α 5β in P. In contrast to the situation in M, F, and L where the P3α 5β C is the most abundant PIC, and P3α 5β is present in minor quantities compared with the P3α 5α , P3α 5β may acquire physiological importance during pregnancy, contributing to the sustaining thereof. On the other hand, the declining formation of P3α 5β may participate in the initiation of parturition, given the relative abundance of the steroid, its potency to suppress the activity of oxytocin-producing cells and its effectiveness in uterine relaxation.

Relationships of circulating pregnanolone isomers and their polar conjugates to the status of sex, menstrual cycle, and pregnancy