title: Neuroactive steroids in pregnancy: key regulatory and protective roles in the foetal brain.
abstract: Neuroactive steroid concentrations are remarkably high in the foetal brain during late gestation. These concentrations are maintained by placental progesterone synthesis and the interaction of enzymes in the placenta and foetal brain. 5α-Pregnane-3α-ol-20-one (allopregnanolone) is a key neuroactive steroid during foetal life, although other 3α-hydroxy-pregnanes may make an additional contribution to neuroactive steroid action. Allopregnanolone modulates GABAergic inhibition to maintain a suppressive action on the foetal brain during late gestation. This action suppresses foetal behaviour and maintains the appropriate balance of foetal sleep-like behaviours, which in turn are important to normal neurodevelopment. Neuroactive steroid-induced suppression of excitability has a key role in protecting the foetal brain from acute hypoxia/ischaemia insults. Hypoxia-induced brain injury is markedly increased if neuroactive steroid levels are suppressed and there is increased seizure activity. There is also a rapid increase in allopregnanolone synthesis and hence levels in response to acute stress that acts as an endogenous protective mechanism. Allopregnanolone has a trophic role in regulating development, maintaining normal levels of apoptosis and increasing myelination during late gestation in the brain. In contrast, chronic foetal stressors, including intrauterine growth restriction, do not increase neuroactive steroid levels in the brain and exposure to repeated synthetic corticosteroids reduce neuroactive steroid levels. The reduced availability of neuroactive steroids may contribute to the adverse effects of chronic stressors on the foetal and newborn brain. Preterm birth also deprives the foetus of neuroactive steroid mediated protection and may increase vulnerability to brain injury and suboptimal development. These finding suggest replacement therapies should be explored. This article is part of a Special Issue entitled 'Pregnancy and steroids'.
authors.affiliation: School of Biomedical Sciences and Pharmacy, University of Newcastle, Callaghan, NSW 2308, Australia. Electronic address: Jon.Hirst@newcastle.edu.au.
authors.forename: Jonathan J
authors.initials: JJ
authors.lastname: Hirst
authors.forename: Meredith A
authors.initials: MA
authors.lastname: Kelleher
authors.forename: David W
authors.initials: DW
authors.lastname: Walker
authors.forename: Hannah K
authors.initials: HK
authors.lastname: Palliser
mesh_terms: D013741:3-Oxo-5-alpha-Steroid 4-Dehydrogenase / Q000502:physiology; D000818:Animals; D001921:Brain / Q000166:cytology / Q000196:embryology / Q000378:metabolism*; D005260:Female; D005333:Fetus / Q000378:metabolism*; D059330:GABAergic Neurons / Q000378:metabolism; D006801:Humans; D007231:Infant, Newborn; D009414:Nerve Growth Factors / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology; D010920:Placenta / Q000201:enzymology; D011247:Pregnancy; D011280:Pregnanolone / Q000494:pharmacology / Q000502:physiology*; D047928:Premature Birth / Q000378:metabolism; D011374:Progesterone / Q000502:physiology; D013312:Stress, Physiological
chemical_list: D009414:Nerve Growth Factors; D018696:Neuroprotective Agents; D011374:Progesterone; D011280:Pregnanolone; D013741:3-Oxo-5-alpha-Steroid 4-Dehydrogenase
keywords: Allopregnanolone; Foetus; Neonatal seizures; Neonate; Neuroprotection; Placenta; Pregnancy compromise; Stressors in pregnancy