title: Placental estrogen suppresses cyclin D1 expression in the nonhuman primate fetal adrenal cortex.
abstract: We have previously shown that estrogen selectively suppresses growth of the fetal zone of the baboon fetal adrenal cortex, which produces the C19-steroid precursors, eg, dehydroepiandrosterone sulfate, which are aromatized to estrogen within the placenta. In the present study, we determined whether fetal adrenal expression of cell cycle regulators are altered by estrogen and thus provide a mechanism by which estrogen regulates fetal adrenocortical development. Cyclin D1 mRNA levels in the whole fetal adrenal were increased 50% (P < .05), and the number of cells in the fetal adrenal definitive zone expressing cyclin D1 protein was increased 2.5-fold (P < .05), whereas the total number of cells in the fetal zone and fetal serum dehydroepiandrosterone sulfate levels were elevated 2-fold (P < .05) near term in baboons in which fetal serum estradiol levels were decreased by 95% (P < .05) after maternal administration of the aromatase inhibitor letrozole and restored to normal by concomitant administration of letrozole plus estradiol throughout second half of gestation. However, fetal adrenocortical expression of cyclin D2, the cyclin-dependent kinase (Cdk)-2, Cdk4, and Cdk6, and Cdk regulatory proteins p27(Kip1) and p57(Kip2) were not changed by letrozole or letrozole plus estradiol administration. We suggest that estrogen controls the growth of the fetal zone of the fetal adrenal by down-regulating cyclin D1 expression and thus proliferation of progenitor cells within the definitive zone that migrate to the fetal zone. We propose that estrogen restrains growth and function of the fetal zone via cyclin D1 to maintain estrogen levels in a physiological range during primate pregnancy.
authors.affiliation: Department of Obstetrics, Gynecology, and Reproductive Sciences (G.W.A., E.D.A.), Center for Studies in Reproduction, University of Maryland School of Medicine, Baltimore, Maryland 21201; and Departments of Obstetrics and Gynecology and Physiological Sciences (A.D., G.J.P.), Eastern Virginia Medical School, Norfolk, Virginia 23507.
authors.forename: Adina
authors.initials: A
authors.lastname: Dumitrescu
authors.forename: Graham W
authors.initials: GW
authors.lastname: Aberdeen
authors.forename: Gerald J
authors.initials: GJ
authors.lastname: Pepe
authors.forename: Eugene D
authors.initials: ED
authors.lastname: Albrecht
mesh_terms: D000302:Adrenal Cortex / Q000196:embryology* / Q000378:metabolism; D000818:Animals; D047072:Aromatase Inhibitors; D002352:Carrier Proteins / Q000097:blood; D019938:Cyclin D1 / Q000378:metabolism*; D018844:Cyclin-Dependent Kinases / Q000378:metabolism*; D019314:Dehydroepiandrosterone Sulfate / Q000097:blood; D004958:Estradiol / Q000097:blood; D004967:Estrogens / Q000502:physiology*; D005260:Female; D047109:Fetal Development; D020567:Fetal Weight; D006854:Hydrocortisone / Q000097:blood; D019394:Ki-67 Antigen / Q000378:metabolism; D000077289:Letrozole; D008297:Male; D009570:Nitriles; D048530:Papio anubis; D010920:Placenta / Q000378:metabolism; D011247:Pregnancy; D014230:Triazoles
chemical_list: D047072:Aromatase Inhibitors; D002352:Carrier Proteins; D004967:Estrogens; D019394:Ki-67 Antigen; D009570:Nitriles; D014230:Triazoles; C027091:cortisol binding globulin; D019938:Cyclin D1; D004958:Estradiol; D019314:Dehydroepiandrosterone Sulfate; D000077289:Letrozole; D018844:Cyclin-Dependent Kinases; D006854:Hydrocortisone