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The fetal zone is a unique adrenal cortical compartment that exists only during fetal life in humans and higher primates and produces large amounts of the adrenal androgen dehydroepiandrosterone sulfate (DHEA-S). Growth of the fetal zone is primarily regulated by ACTH, the actions of which are mediated in part by locally produced autocrine/paracrine growth factors. We previously demonstrated that one of these growth factors, insulin-like growth factor II (IGF-II), is mitogenic for cultured fetal zone cells and is produced in high abundance by these cells in response to ACTH. In the present study, we determined whether IGF-II also modulates the differentiated function of fetal zone cells. We examined the effects of recombinant human IGF-II and the closely related peptide, IGF-I, on 1) basal and agonist-stimulated [ACTH-(1-24), forskolin, or 8-bromo-cAMP] cortisol and DHEA-S production, 2) basal and ACTH-stimulated steady state abundance of messenger ribonucleic acids (mRNAs) encoding the steroidogenic enzymes cytochrome P450 side-chain cleavage (P450scc) and cytochrome P450 17alpha-hydroxylase/17,20-lyase (P450c17), and 3) basal and ACTH-stimulated steady state abundance of mRNA encoding the ACTH receptor. Basal cortisol (23.93 +/- 1.20 pmol/10(5) cells x 24 h) and DHEA-S (548.87 +/- 43.17 pmol/10(5) cells x 24 h) productions were significantly (P &lt; 0.05) increased by IGF-I (2.3- and 1.8-fold, respectively) and IGF-II (2.8- and 1.8-fold, respectively). As expected, ACTH, forskolin, and cAMP markedly increased the production of cortisol by 26-, 10-, and 13-fold, respectively, and that of DHEA-S by 5.4-, 4.6-, and 5.5-fold, respectively, compared with basal levels. IGF-II (100 ng/mL) significantly (P &lt; 0.001) increased ACTH-, forskolin-, and cAMP-stimulated production of cortisol by 2.4-, 4.3-, and 3.2-fold, respectively, and that of DHEA-S by 1.4, 1.6-, and 1.4-fold, respectively. IGF-I (100 ng/mL) had similar effects as IGF-II and significantly (P &lt; 0.001) increased ACTH-, forskolin-, and cAMP-stimulated production of cortisol by 2.8-, 3.9-, and 3.1-fold, respectively, and that of DHEA-S by 1.3-, 1.6-, and 1.4-fold, respectively. The similar potencies of IGF-I and IGF-II suggest that the actions of these factors were mediated via a common receptor, most likely the type I IGF receptor. The effects of IGF-II on ACTH-stimulated steroid production were dose-dependent (EC50, 0.5-1.0 nmol/L), and IGF-II markedly increased the steroidogenic responsiveness of fetal zone cells to ACTH. With respect to cortisol production, IGF-II shifted the ACTH dose-response curve to the left by 1 log10 order of magnitude. IGF-II also increased ACTH-stimulated abundance of mRNA encoding P450scc (1.9-fold) and P450c17 (2.2-fold). Basal expression of P450scc was not affected by IGF-II. In contrast, basal expression of P450c17 was increased 2.2-fold by IGF-II and IGF-I in a dose-responsive fashion. Neither IGF-I nor IGF-II affected basal or ACTH-stimulated abundance of mRNA encoding the ACTH receptor, suggesting that the increase in ACTH responsiveness was not mediated by an increase in ACTH-binding capacity. Taken together, these data indicate that activation of the type I IGF receptor increases ACTH responsiveness in fetal zone cells by modulating ACTH signal transduction at some point distal to ACTH receptor activation. These data also indicate that locally produced IGF-II modulates fetal adrenal cortical cell function by increasing responsiveness to ACTH and possibly (based on its direct stimulation of P450c17 expression) augmenting the potential for adrenal androgen synthesis. Thus, activation of the type I IGF receptor on adrenal cortical cells may play a pivotal role in adrenal androgen production, both physiologically in utero and at adrenarche, and in pathophysiological conditions ofhyperandrogenemia, such as the polycystic ovary syndrome.

the journal of clinical endocrinology and metabolism/journal of clinical endocrinology and metabolism

Insulin-Like Growth Factors Augment Steroid Production and Expression of Steroidogenic Enzymes in Human Fetal Adrenal Cortical Cells: Implications for Adrenal Androgen Regulation<sup>1</sup>

Insulin-Like Growth Factors Augment Steroid Production and Expression of Steroidogenic Enzymes in Human Fetal Adrenal Cortical Cells: Implications for Adrenal Androgen Regulation1

Insulin-Like Growth Factors Augment Steroid Production and Expression of Steroidogenic Enzymes in Human Fetal Adrenal Cortical Cells: Implications for Adrenal Androgen Regulation¹