Inhibition of 5α‐Reductase Activity in Late Pregnancy Decreases Gestational Length and Fecundity and Impairs Object Memory and Central Progestogen Milieu of Juvenile Rat Offspring

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Psychological, physical and/or immune stressors during pregnancy are associated with negative birth outcomes, such as preterm birth and developmental abnormalities. In rodents, prenatal stressors can alter the expression of 5α-reductase enzymes in the brain and may influence cognitive function and anxiety-type behaviour in the offspring. Progesterone plays a critical role in maintaining gestation. In the present study, it was hypothesised that 5α-reduced progesterone metabolites influence birth outcomes and/or the cognitive and neuroendocrine function of the offspring. 5α-Reduced steroids were manipulated in pregnant Long-Evans rats via the administration of vehicle, the 5α-reduced, neuroactive metabolite of progesterone, 5α-pregnan-3α-ol-20-one (3α,5α-THP, allopregnanolone; 10 mg/kg/ml, s.c.), or the 5α-reductase inhibitor, finasteride (50 mg/kg/ml, s.c.), daily from gestational days 17-21. Compared to vehicle or 3α,5α-THP treatment, finasteride, significantly reduced the length of gestation and the number of pups per litter found in the dams' nests after parturition. The behaviour of the offspring in hippocampus-dependent tasks (i.e. object recognition, open field) was examined on post-natal days 28-30. Compared to vehicle-exposed controls, prenatal 3α,5α-THP treatment significantly increased motor behaviour in females compared to males, decreased progesterone content in the medial prefrontal cortex (mPFC) and diencephalon, increased 3α,5α-THP and 17β-oestradiol content in the hippocampus, mPFC and diencephalon, and significantly increased serum corticosterone concentrations in males and females. Prenatal finasteride treatment significantly reduced object recognition, decreased hippocampal 3α,5α-THP content, increased progesterone concentration in the mPFC and diencephalon, and increased serum corticosterone concentration in female (but not male) juvenile offspring, compared to vehicle-exposed controls. Thus, inhibiting the formation of 5α-reduced steroids during late gestation in rats reduces gestational length, the number of viable pups per litter, and impairs cognitive and neuroendocrine function in the juvenile offspring.