Neuroactive Ring A-Reduced Metabolites of Progesterone in Human Plasma during Pregnancy: Elevated Levels of 5α-Dihydroprogesterone in Depressed Patients during the Latter Half of Pregnancy

Abstract

Progesterone and its 5 reduced metabolite, 5-dihydropro-gesterone, 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 and 5 dihydroprogester-ones (DHP), and three tetrahydroprogesterones (THP)-3,5-THP, 3,5-THP, and 3,5-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 fol-licular level), 5-DHP (161-fold), 3,5-THP (56-fold), 3,5-THP (37-fold), pregnenolone (30-fold), 5-DHP (16-fold) and 3,5-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 3,5-tetrahydroprogesterone and 3,5-tetrahydroprogest-erone remained slightly elevated (P < 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-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. (J Clin Endocrinol Metab 86: 5981-5987, 2001) T HE TERM "neuroactive steroids" as used here refers to steroids that are active on neural tissue and that may be synthesized endogenously in the brain itself (neuro-steroids) or elsewhere in the body. Pregnenolone is the precursor of all mammalian steroid hormones, being produced by the adrenal cortex, the ovary, the testis, the placenta, and by the brain itself. These tissues produce a variety of corti-coids, progestins, androgens, and estrogens, and also the lesser known group of "anesthetic steroids" (neuroactive A-ring reduced steroids, NARS), whose physiological significance is still unknown. It has been recognized for more than 50 yr that, when injected as a bolus, many of the ring A-reduced metabolites of progesterone have potent direct (nongenomic) effects on the brains of mammals, and indeed are among the most powerful anesthetics known (1-4); however their blood levels are low, and their measurement is difficult. Interest in these compounds increased recently, when some of them, such as allopregnanolone (for structures and abbreviations of the steroids measured, see Table 1) were shown to bind stereoselectively and with high affinity to receptors for-aminobutyric acid (GABA), the major inhibitory neuro-transmitter in brain; they are thought to affect cognition, memory, and mood (for reviews, see Refs. 5 and 6). Others may be GABA receptor antagonists (7, 8). The pathways of steroid synthesis and metabolism are complex, so that changes in the availability of one steroid hormone may alter both the production and the route of metabolism of others through competition for enzymes and induction of enzymes. This means that lack of direct correlation between alterations of the principal steroid hormones and pathology does not preclude a major etiological role for steroids. Because progesterone rises more than 10-fold during pregnancy compared with the luteal phase of the menstrual cycle, it is pertinent to examine its neuroactive metabolites with respect to any physiological changes that may occur during and following pregnancy. The aim of this study was to document levels of preg-nenolone and progesterone and five of its neuroactive me-tabolites during pregnancy and the puerperium, using a method described recently (9). Pregnenolone, the precursor of progesterone, was also measured. In addition, patients with no previous history of mental problems who became depressed during pregnancy were also studied and showed Abbreviations: DHP, Dihydroprogesterone; GABA,-aminobutyric acid; Ham-D, Hamilton Depression Scale; NARS, neuroactive A-ring reduced steroids; THP, tetrahydroprogesterone.