Significant advances in our understanding of the regulation of fetal adrenal growth, differentiation, and steroidogenesis have been made in the past several years. In vitro studies employing molecular biological techniques have demonstrated that the placenta and several fetal tissues synthesize growth factors and/or oncogene-related products, which have the capacity to modulate growth and maturation of the fetal adrenal. Moreover, there is evidence that the fetal adrenal itself produces IGF-I and IGF-II and that the mRNAs for these growth factors are responsive to ACTH and perhaps other peptides originating in the fetal pituitary and/or the placenta. Most fascinating are the studies demonstrating that growth factors may also regulate the pattern of steroidogenesis elicited by the fetal adrenal. For example, TGF beta modulates binding, internalization, and degradation of LDL-cholesterol in adult adrenals while IGF-I increases fetal adrenal steroidogenesis by mechanisms that do not involve induction of P-450scc or enhanced metabolism of LDL. These studies, coupled with the observation that activation of protein kinase C by EGF or bFGF can block ACTH and/or other cAMP-induced increases in the activity of P-450(17 alpha), provide new insight into the subcellular mechanisms that underlie the regulation of fetal adrenal function. However, in vivo investigations must be aggressively pursued because the latter provide a major and perhaps exclusive means to elucidate the complex and multiple mechanisms that are apparently operative in utero in the regulation of fetal adrenal development. Moreover, in vivo studies remain the only valid means to delineate whether the factors that have been shown to modulate fetal adrenal function in vitro are indeed operable in vivo. Thus, in vivo investigations have shown that a multifactorial regulation of the fetal adrenal exists in utero in which PRL and perhaps other peptides as well as ACTH selectively stimulate fetal adrenal androgen production. Moreover, in vivo studies have demonstrated that a feedback mechanism operates in utero whereby estrogen produced in the placenta from androgen precursors of fetal adrenal origin feeds back to modulate the responsivity of the fetal adrenal to tropic peptides perhaps by regulating peptide binding to cell membrane receptors and/or other mechanisms. Evidence has also been provided from in vivo studies to support the concept that the placenta via metabolism of maternal cortisol and cortisone regulates fetal pituitary production of ACTH by modulating the extent to which maternal cortisol arrives at the fetus.(ABSTRACT TRUNCATED AT 400 WORDS)