Estrogen/hypothalamus-pituitary-adrenal axis interactions in the fetus: The interplay between placenta and fetal brain

OBJECTIVE: The hormonal interactions between the placenta and the fetal hypothalamus-pituitary-adrenal (HPA) axis are reviewed. METHODS: This review addresses data obtained from the chronically catheterized fetal sheep, drawing relevant comparisons to human fetuses. RESULTS: In the sheep, and perhaps in primate species, parturition is initiated by an increase in the activity of the HPA axis. The endogenous mechanisms underlying the increase in activity of the fetal HPA axis are incompletely understood but might involve an interplay between placenta and fetal hypothalamus and pituitary. Various hypotheses have been proposed, involving placental secretion of prostaglandins and various components of the fetal HPA axis. In the sheep, the influence of estradiol appears to be potent, and various experiments have suggested the possibility that, in late gestation, there exists a positive feedback relationship between placental estrogen secretion and pituitary adrenocorticotropin (ACTH) secretion. Estradiol circulates in concentrations known to stimulate fetal ACTH secretion. Additionally, estradiol circulates in the form of estradiol-3-sulfate, a molecular form that is taken up by the fetal brain and deconjugated by steroid sulfatase, which is expressed in the fetal brain. Recent evidence suggests that the interaction between estradiol and ACTH might involve production of paracrine or autocrine substances in the fetal brain. One candidate mediator is prostglandin E-2 (PGE(2)) highlighed by the action of estradiol on the expression of prostaglandin endoperoxide synthase-2 (PGHS-2 or COX-2) in brain regions known to be important for controlling HPA activity. CONCLUSION: Estradiol, secreted by the placenta in increasing amounts in late gestation, is a potent stimulator of fetal ACTH secretion. The interactions between estradiol and the fetal HPA axis might function as a positive feedback loop that increases the concentrations of both hormones before birth.