Estrogen elicits cortical zone-specific effects on development of the primate fetal adrenal gland

In the present study, we determined whether endogenous estrogen, the levels of which increase with advancing pregnancy, regulates growth and development of the baboon fetal adrenal cortex. Fetal adrenal glands were obtained at mid- (d 100) and late (d 165, term is 184 d) gestation from untreated baboons and on d 165 from animals in which endogenous estrogen production was suppressed by administration of aromatase inhibitor CGS 20267 between d 100 and 165. Volumes of the respective cortical zones were determined by zone-specific immunocytochemical staining of steroidogenic enzymes and image analysis. Fetal adrenal weight and volume increased (P < 0.01) 3-fold between mid- and late gestation and an additional 70% (P < 0.01) by administration of CGS 20267, which decreased (P < 0.001) fetal serum estradiol levels by more than 95%. Mean +/- se volume (x10(-10) mum(3)) of the fetal cortical zone increased from 3.45 +/- 0.28 at midgestation to 6.64 +/- 0.69 at late gestation in untreated baboons and to 12.55 +/- 0.99 (P < 0.01) in baboons in which estrogen production was suppressed by CGS 20267 administration. The levels of umbilical artery serum dehydroepiandrosterone sulfate, which is secreted primarily by the fetal zone, were increased almost 3-fold (P < 0.01) by administration of CGS 20267. Concomitant administration of CGS 20267 and estradiol returned fetal cortical zone volume and serum dehydroepiandrosterone sulfate levels to normal. In contrast to the effect of estrogen deprivation on the fetal zone, the volumes of the definitive and transitional zones in untreated baboons late in gestation (3.18 +/- 0.63 and 2.62 +/- 0.43, respectively) and levels of fetal serum cortisol, a steroid secreted from the transitional zone, were not altered by estrogen suppression. The changes in fetal zone growth were not associated with alterations in fetal pituitary proopiomelanocortin mRNA levels. We propose that estrogen acts directly on the fetal adrenal cortex to selectively repress the morphological and functional development of the fetal zone, potentially as a feedback system to maintain physiological secretion of estrogen precursors and thus placental estrogen production to promote normal primate fetal and placental development.