Sex differences in response 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. Among these, allopregnanolone is critical for fetal brain development, providing neuroprotective and trophic support by limiting excessive neuronal excitation and promoting oligodendrocyte development and myelination. Pregnancy complications, particularly preterm birth, can substantially reduce or eliminate this neurosteroid support, increasing vulnerability to hypoxic and excitotoxic injury. 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, often experience poorer outcomes following preterm birth and other perinatal insults. 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.