Neuroactive ring A-reduced metabolites of progesterone in human plasma during pregnancy: elevated levels of 5 alpha-dihydroprogesterone in depressed patients during the latter half of pregnancy.

Progesterone and its 5 alpha reduced metabolite, 5 alpha-dihydroprogesterone, rise greatly in pregnancy. Both are known to have anesthetic properties, as do a number of other ring A-reduced progesterone metabolites. The possible significance of these steroids with respect to the mood changes that are common in pregnancy and in the puerperium has not been explored. In this study, pregnenolone, progesterone, and five neuroactive progesterone metabolites: the 5 alpha and 5 beta dihydroprogesterones (DHP), and three tetrahydroprogesterones (THP)-3 alpha,5 alpha-THP, 3 beta,5 beta-THP, and 3 beta,5 alpha-THP-were studied at various stages of pregnancy and in the early postpartum period. Levels of all of the steroids rose greatly during pregnancy (P < 0.001), being highest for progesterone (562-fold the follicular level), 5 alpha-DHP (161-fold), 3 beta,5 alpha-THP (56-fold), 3 alpha,5 alpha-THP (37-fold), pregnenolone (30-fold), 5 beta-DHP (16-fold) and 3 beta,5 beta-THP (16-fold) at 37 wk of gestation. During the period 2-7 d postpartum, the level of progesterone fell precipitously, whereas those of pregnenolone and the metabolites fell more slowly and mean levels were still elevated compared with follicular levels 2 wk after delivery. By 7 wk postpartum, only 3 alpha,5 alpha-tetrahydroprogesterone and 3 beta,5 beta-tetrahydroprogesterone remained slightly elevated (P < or = 0.012 and 0.007, respectively). Mean levels of the progesterone metabolites tended to be higher in depressed patients compared with controls, and this difference reached significance for 5 alpha-dihydroprogesterone both at 27 wk (P = 0.04) and at 37 wk (P = 0.02) of gestation (combined, P = 0.003). These results show that all five of these metabolites rise markedly during pregnancy and suggest that alterations in progesterone metabolites may be involved in the mood changes of pregnancy and the puerperium.