Regulation of the Primate Fetal Adrenal Cortex*

Abstract

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)

Regulation of steroidogenesis by insulin-like growth factors (IGFs) in adult human adrenocortical cells: IGF-I and, more potently, IGF-II preferentially enhance androgen biosynthesis through interaction with the IGF-I receptor and IGF-binding proteins

“…The steroidogenic effect of IGF-I in adult human adrenocortical cells reported in this study is consistent with previous reports of an IGF-I-stimulated steroidogenic response in bovine, ovine and human adrenocortical cells (Penhoat et al 1989, Reed & James 1989, Pepe & Albrecht 1990, Pham-Huu-Trung et al 1991, Weber et al 1995, L Allemand et al 1996. However, little information is available on the effect of IGF-II in the adult human adrenal gland.…”

“…Although circulating ACTH is the major regulator of corticosteroid and androgen synthesis in the adrenal gland, it has become apparent that the control of adrenocortical cell function is also modulated at a local level by a variety of growth factors (Penhoat et al 1989, Reed & James 1989, Pepe & Albrecht 1990, Parker 1991. In the present studies, we have shown that, in adult human adrenocortical cells, IGF-I and IGF-II direct steroid biosynthesis toward androgen biosynthesis.…”

“…In bovine adrenocortical cells, IGF-I upregulates ACTH receptors, while ACTH increases the abundance of IGF-I receptors and the secretion of IGFs (Penhoat et al 1989, Reed & James 1989, Pepe & Albrecht 1990, Pham-Huu-Trung et al 1991. In human adrenocortical cells, IGF-I induces synthesis of the mRNA of key steroidogenic enzymes and slightly increases ACTH receptor mRNA (L'Allemand et al 1996, Kristiansen et al 1997.…”

MYCN-regulated microRNAs repress estrogen receptor-α ( ESR1 ) expression and neuronal differentiation in human neuroblastoma

“…During human fetal life, the androgenic precursors dehydroepiandrosterone sulfate and 16α-hydroxyde-dehydroepiandrosterone sulfate of fetal and maternal adrenal origin are hydrolyzed in the placenta with the subsequent formation of estrogens (39,40). Like other steroid hormones, estrogens easily pass through the placental barrier and enter the fetal adrenomedullary circulation (41). As a result, immature sympathetic cell groups that are in sufficient contact with the circulation may undergo differentiation in response to estrogen, given that they express estrogen receptors.…”

Developmental expression of and effect of betamethasone on the messenger ribonucleic acid levels for peptide growth factors in the baboon fetal adrenal gland

“…The primate fetal adrenal gland exhibits remarkable growth, and morphologic and functional differentiation in utero (for reviews see Jaffe et al 1981, Pepe & Albrecht 1990, Mesiano & Jaffe 1997, processes essential to the production of cortisol required for fetal organ systems maturation (Ballard & Ballard 1972) and C 19 -steroids such as dehydroepiandrosterone (DHA) utilized for placental estrogen biosynthesis (Albrecht & Pepe 1990). Our understanding of the mechanisms regulating fetal adrenocortical maturation, however, remains incomplete.…”