Inhibition of 5alpha-reductase activity in late pregnancy decreases gestational length and fecundity and impairs object memory and central progestogen milieu of juvenile rat offspring

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 5alpha-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. Here it was hypothesised that 5alpha-reduced progesterone metabolites influence birth outcomes and/or the cognitive and neuroendocrine function of the offspring. 5alpha-reduced steroids were manipulated in pregnant Long-Evans rats via administration of vehicle, the 5alpha-reduced, neuroactive metabolite of progesterone, 5alpha-pregnan-3alpha-ol-20-one (3alpha,5alpha-THP, allopregnanolone; 10 mg/kg/ml, SC), or the 5alpha-reductase inhibitor, finasteride (50 mg/kg/ml, SC), daily from gestational days 17-21. Compared to vehicle or 3alpha,5alpha-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 (object recognition, open field) was examined on post-natal days 28-30. Compared to vehicle-exposed controls, prenatal 3alpha,5alpha-THP treatment significantly increased motor behaviour in females compared to males, decreased progesterone content in the medial prefrontal cortex (mPFC) and diencephalon, increased 3alpha,5alpha-THP and 17beta-estradiol 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 3alpha,5alpha-THP content, increased progesterone concentration in the mPFC and diencephalon, and increased serum corticosterone concentration in female (but not male) juvenile offspring, compared with vehicle-exposed controls. Thus, inhibiting formation of 5alpha-reduced steroids during late gestation in rats reduces gestational length, the number of viable pups/litter, and impairs cognitive and neuroendocrine function in the juvenile offspring.