Allopregnanolone in the brain: protecting pregnancy and birth outcomes

Abstract

A successful pregnancy requires multiple adaptations in the mother's brain that serve to optimise foetal growth and development, protect the foetus from adverse prenatal programming and prevent premature delivery of the young. Pregnancy hormones induce, organise and maintain many of these adaptations. Steroid hormones play a critical role and of particular importance is the progesterone metabolite and neurosteroid, allopregnanolone. Allopregnanolone is produced in increasing amounts during pregnancy both in the periphery and in the maternal and foetal brain. This review critically examines a role for allopregnanolone in both the maternal and foetal brain during pregnancy and development in protecting pregnancy and birth outcomes, with particular emphasis on its role in relation to stress exposure at this time. Late pregnancy is associated with suppressed stress responses. Thus, we begin by considering what is known about the central mechanisms in the maternal brain, induced by allopregnanolone, that protect the foetus(es) from exposure to harmful levels of maternal glucocorticoids as a result of stress during pregnancy. Next we discuss the central mechanisms that prevent premature secretion of oxytocin and consider a role for allopregnanolone in minimising the risk of preterm birth. Allopregnanolone also plays a key role in the foetal brain, where it promotes development and is neuroprotective. Hence we review the evidence about disruption to neurosteroid production in pregnancy, through prenatal stress or other insults, and the immediate and long-term adverse consequences for the offspring. Finally we address whether progesterone or allopregnanolone treatment can rescue some of these deficits in the offspring.

Keywords: 3α-hydroxysteroid dehydrogenase; 3αHSD; 5α-Reductase; ACTH; AVP; AgRP; CB1; CCK; CRH; CRH-R1; CRH-R2; CeA; DA; DAP; DHP; ER; Endogenous opioids; GABA; GABA(A) receptor; GR; Gestation; HPA; Hypothalamo-pituitary-adrenal axis; IL-1β; IUGR; MAP-2; MBP; MC-2; MCNs; MPOA; MR; NO; NPY; NTS; ORL1; OTR; PNS; POMC; PR; PRP; PVN; V1b; adrenocorticotropic hormone; agouti-related peptide; arginine vasopressin; cGMP; cannabinoid receptor type 1; central nucleus of the amygdala; cholecystokinin; corticotropin releasing hormone; corticotropin releasing hormone receptor type 1; corticotropin releasing hormone receptor type 2; cyclic guanosine monophosphate; depolarising after-potential; dihydroprogesterone; dopamine; eCB; endocannabinoids; estrogen receptor; gamma-aminobutyric acid; glucocorticoid receptor; hypothalamo-pituitary-adrenal; i.c.v.; interleukin-1β; intracerebroventricular; intrauterine growth restriction; magnocellular neurones; medial preoptic area; melanocortin-2; microtubular associated protein-2; mineralocorticoid receptor; myelin basic protein; nNOS; neuronal nitric oxide synthase; neuropeptide Y; nitric oxide; nucleus tractus solitarii; opioid receptor-like receptor; oxytocin receptor; pENK-A; pPVN; paraventricular nucleus; parvocellular subdivision of the paraventricular nucleus; prenatally stressed; pro-opiomelanocortin; proenkephalin-A; progesterone receptor; prolactin releasing peptide; vasopressin receptor type 1b.