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Estrogen/Hypothalamus-Pituitary-Adrenal Axis Interactions in the Fetus: the Interplay Between Placenta and Fetal Brain

Department of Physiology and Functional Genomics, P.O. Box 100274, University of Florida College of Medicine, Gainesville, FL 32610-0274; cxvood{at}phys.med.ufl.edu

Objective: The hormonal interactions between the placenta and the fetal hypothalamus-pituitary adrenal (HPA) axis are reviewed.

Methods: This review addresses data obtainedfrom the chronically catheterized fetal sheep, drawing relevant comparisons to humanfetuses.

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 thefetal HPA axis are incompletely understood but might involve an interplay between placenta andfetal hypothalamus and pituitary. Various hypotheses have been proposed, involving placental secretion of prostaglandins and various components of thefetal 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 fornm of estradiol-3-su!fate, 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 A CTH might involve production of paracrine or autocrine substances in the fetal brain. One candidate mediator is prostaglandin E₂ (PGE2), highlighted by the action of estradiol on the expression ofprostaglandin 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 positivefeedback loop that increases the concentrations of both hormones before birth.

Key Words: Fetus • stress • adrenocorticotropin • cortisol • estradiol • parturition

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