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

Although the effect of insulin-like growth factors (IGFs) in fetal adr enocortical cells has been investigated extensively, the role of the I GF system in the adult human adrenal gland remains unclear. In the pre sent study we investigated the effect of recombinant human IGF-I and I GF-II on cortisol, dehydroepiandrosterone sulfate (DHEA-S) and cAMP sy nthesis in adult human adrenocortical cells in primary culture. Both I GFs stimulate basal as well as adrenocorticotropin (ACTH)-induced ster oid secretion in a time- and dose-dependent fashion. While both IGFs ( 6.5 nM) induced only a moderate 2-fold increase in basal cortisol outp ut after 48 h, the effect on basal DHEA-S secretion was significantly stronger, with a 2.7- and 3.7-fold stimulation by IGF-I and IGF-II res pectively. Similarly, IGF-II enhanced ACTH-induced cortisol and DHEA-S secretion more potently than IGF-I. In dose-response experiments, the maximum stimulation of ACTH-induced DHEA-S secretion was induced by 1 .6 nM IGF-I (2-fold increase) or IGF-LI (29-fold increase), while the maximum response of cortisol secretion was elicited only at 13 nM IGF- I (2-fold increase) or IGF-II (2.5-fold increase). This resulted in a significant shift of the DHEA-S dose-response curves to the left, indi cating a relative selective stimulation of androgen biosynthesis by ph ysiologically low concentrations (0.4-3.2 nM) of IGF-II, and less pote ntly by IGF-I. At all doses tested, the steroidogenic effect of IGF-II was significantly stronger than the effect of IGF-I. Although both IG F receptors are present in adult human adrenocortical cells, the stero idogenic effect of IGF-II is mediated through the IGF-I receptor, sinc e [Arg(54,55)]IGF-II, which only binds to the IGF-I receptor, was equi potent with native IGF-II, whereas [Leu(27)]IGF-II, which preferential ly binds to the type II IGF receptor, did not show any effect. In addi tion, [des(1-3)]IGF-I, which exhibits only minimal binding to IGFBPs, was significantly more potent than native IGF-I in stimulating adrenal steroid biosynthesis, and elicited almost the same maximum stimulator y effect as IGF-II and [des(1-6)]IGF-II. By Western ligand blotting of conditioned medium it was shown that adult human adrenocortical cells secrete various IGF-binding proteins (IGFBPs), which are induced diff erentially by treatment with ACTH. In conclusion, these results demons trate that: (1) IGF-II stimulates basal as well as ACTH-induced DHEA-S and cortisol secretion from adult human adrenocortical cells more pot ently than IGF-I; (2) both IGFs predominantly stimulate androgen biosy nthesis; (3) the steroidogenic effect of IGF-I and IGF-II is mediated through interaction with the IGF-I receptor; (4) the different steroid ogenic potency of IGF-I and IGF-II might be explained by interaction o f these ligands with locally produced IGFBPs. These data indicate that the IGF system plays an important role in the regulation of the diffe rentiated function of adult human adrenocortical cells.