5α-reduced neurosteroids sex-dependently reverse central prenatal programming of neuroendocrine stress responses in rats

Maternal social stress during late pregnancy programmes hypothalamo-pituitary-adrenal (HPA) axis hyper-responsiveness to stressors, such that adult prenatally stressed (PNS) offspring display exaggerated HPA axis responses to a physical stressor (systemic interleukin-1β, IL-1β) in adulthood, compared with controls. IL-1β acts via a noradrenergic relay from the nucleus tractus solitarii (NTS) to corticotropin releasing hormone (CRH) neurons in the paraventricular nucleus (PVN). Neurosteroids can reduce HPA axis responses, so allopregnanolone and androstanediol (3β-diol) (5α-reduced metabolites of progesterone and testosterone, respectively) were given sub-acutely (over 24h) to PNS rats to seek reversal of the ‘programmed’ hyper-responsive HPA phenotype. Allopregnanolone attenuated ACTH responses to IL-1β (500 ng/kg, i.v.) in PNS females, but not in PNS males. However, 3β-diol normalized HPA axis responses to IL-1β in PNS males. Impaired testosterone and progesterone metabolism or increased secretion in PNS rats was indicated by greater plasma testosterone and progesterone concentrations in male and female PNS rats, respectively. Deficits in central neurosteroid production were indicated by reduced 5α-reductase mRNA levels in both male and female PNS offspring in the NTS, and in the PVN in males. In PNS females, adenovirus-mediated gene transfer was used to up-regulate expression of 5α-reductase and 3α-hydroxysteroid dehydrogenase (3αHSD) mRNAs in the NTS, and this normalized hyperactive HPA axis responses to IL-1β. Thus, down-regulation of neurosteroid production in the brain may underlie HPA axis hyper-responsiveness in prenatally programmed offspring, and administration of 5α-reduced steroids acutely to PNS rats over-rides programming of hyperactive HPA axis responses to immune challenge in a sex-dependent manner.