Endogenous progesterone deficiency impairs neonatal brain development via microglial dysregulation under chronic...

Several studies have confirmed the important role of progesterone in fetal and neonatal brain development. Chronic hypoxia in the fetal period may mediate neurodevelopmental and cognitive impairment in offspring by interfering with placental steroid hormone synthesis, but the mechanism is unclear.

We systematically evaluated the effects of hypoxia on placental endocrine-fetal neuro-cognitive function by constructing a model of chronic hypoxia from fetal to early childhood, combined with progesterone supplementation, multi-omics of placenta and brain samples, microglial morphological analysis, and behavioral testing.

Chronic hypoxia significantly inhibited placental steroid synthase, leading to a concurrent decrease of progesterone levels in the fetal circulation and brain. Progesterone deficiency in the brain activates microglia, which in turn drives excessive inflammation under chronic hypoxic conditions, thereby interrupting oligodendrocyte differentiation and causing myelination deficits. Chronic hypoxia could also lead to impairment of spatial memory and learning ability shown by behavioral tests. During hypoxic pregnancy, administration of exogenous progesterone restored the progesterone gradient between the placenta and brain, inhibited abnormal activation of microglia, promoted myelination, and reversed cognitive deficits.

Chronic hypoxia downregulates placenta-derived progesterone through the "placenta-neural axis", which in turn leads to cognitive impairment through the microglia-myelin pathway. Progesterone supplementation during pregnancy can provide a theoretical basis for clinical intervention.