Sex differences in responses to neurosteroid therapy after preterm birth

Progesterone production by the placenta leads to elevated levels of neurosteroids in both the maternal and fetal circulations during late gestation. Allopregnanolone levels are crucial because they provide both neuroprotective and trophic support in the fetal brain. These include protecting against excessive excitation and supporting oligodendrocyte development and myelination. Pregnancy compromises and particularly premature birth reduce or totally deprive the newborn brain of this neurosteroid mediated protection and support. The premature fall in allopregnanolone levels may increase susceptibility to damage from hypoxic episodes and excitotoxicity. Reduced neurosteroid support is also associated with alterations in oligodendrocyte maturation and myelination, which may contribute to subsequent neurodevelopmental and behavioural abnormalities. This in turn contributes to the onset of behavioural disorders including attention deficit hyperactivity disorder (ADHD). Importantly male offspring have been shown to do more poorly after preterm birth as well as after other compromises. Increasing allopregnanolone action using the synthetic analogue, zuranolone, markedly improved myelination after premature delivery in an animal model. Treatment with the mitochondrial translocator protein (TSPO) ligand etifoxine, which promotes endogenous allopregnanolone production, provided protective effects in primary cell cultures following oxygen-glucose deprivation in vitro. Prematurely delivered male offspring showed markedly increased hyperactive behaviour which was also reversed by zuranolone therapy. Female offspring exhibited reduced myelination following preterm birth, without evidence of oligodendrocyte maturational arrest, and this hypomyelination was restored by zuranolone therapy. In contrast, males showed oligodendrocyte maturational arrest and a hyperactive behavioural phenotype. Together, these findings suggest that the effects of preterm birth on white matter development may differ between males and females. These findings support further investigation of allopregnanolone replacement therapy after preterm birth, including pharmacokinetic, safety, toxicology and efficacy studies in neonatal populations.