ROLE OF GROWTH-FACTORS IN THE DEVELOPMENTAL REGULATION OF THE HUMAN FETAL ADRENAL-CORTEX

Development of the human fetal adrenals is characterized by rapid grow th and high levels of steroidogenic activity during the latter two-thi rds of pregnancy. By midgestation, the human fetal adrenals are compos ed of two distinct cortical zones: the predominant fetal zone, which o ccupies 80-90% of the cortical volume and produces large amounts of th e Delta(5)-steroid dehydroepiandrosterone sulfate, and the narrow defi nitive zone, which surrounds the fetal zone. Late in gestation, the pe ripheral portion of the fetal zone develops into a third, functionally distinct compartment, the transitional zone, which is the likely site of cortisol synthesis. Soon after birth, the adrenal cortex is remode led and the fetal zone disappears. The adult cortical zones are though t to arise from the definitive zone, which persists postnatally. Devel opment of he human fetal adrenals is regulated primarily by corticortr opin (ACTH) secreted from the fetal pituitary. However, as ACTH is not a mitogen per se, its proliferative actions on human fetal adrenal co rtical cells are thought to be mediated by autocrine/paracrine growth factors produced by adrenal cortical cells in response to ACTH. In add ition, these growth factors appear in modulate the functional response of fetal adrenal cortical cells to ACTH. The roles of several growth factors, including the insulin like growth factors I and II (IGF-I and IGF-II), epidermal growth factor (EGF), basic fibroblast growth facto r (bFGF), activin, inhibin, and the transforming growth factors alpha and beta (TGF-alpha and TGF-beta) have been examined. In cultured huma n fetal adrenal cortical cells, EGF, bFGF, and IGF-I and -II are mitog enic, whereas activin and TGF-beta inhibit proliferation. IGF-II, acti n, and TGF-beta also modulate ACTH-stimulated steroidogenesis. Human f etal adrenal cortical cells express IGF-II, bFGF, and the activin/inhi bin subunits, and the abundance of mRNAs for each of these factors is up-regulated by ACTH, suggesting that these growth factors are autocri ne/paracrine mediators of ACTH action. Thus, although human adrenal de velopment is primarily regulated by ACTH, its actions appear to be med iated/modulated by a cohort of locally expressed growth factors, the n et effect of which results in the unique growth growth and steroidogen ic activity of the human fetal adrenal cortex. (C) 1997 by Elsevier Sc ience Inc.