MITOGENIC ACTION, REGULATION, AND LOCALIZATION OF INSULIN-LIKE GROWTH-FACTORS IN THE HUMAN FETAL ADRENAL-GLAND

Polypeptide growth factors may play an important role in the regulation of human fetal adrenal cortical growth by mediating the tropic actions of ACTH. The abundance of mRNA encoding insulin-like growth factor-II (IGF-II) is high in the human fetal adrenal gland and is stimulated by ACTH in cultured fetal adrenal cortical cells. Therefore, we studied the mitogenic action, regulation, and localization of IGF-II and a closely related peptide, IGF-I, in primary cultures of human fetal adrenal cortical cells and whole human fetal adrenal glands. Recombinant human IGF-I and IGF-II stimulated proliferation of fetal adrenal cortical cells in a dose-dependent fashion (1-1000 ng/mL; 0.133-133 nm). At 1000 ng/mL (133 nm), both peptides increased cell number 1.8- to 2-fold. Combinations of IGF-I or -II (100 ng/mL; 13.3 nm) with basic fibroblast growth factor (bFGF; 0.1 ng/mL; 6 pm) or epidermal growth factor (EGF; 1.0 ng/mL; 0.17 nm) had a greater effect on proliferation than bFGF, EGF, or either of the IGFs alone, suggesting an additive interaction. IGF-II mRNA was detected in cultured adrenal cortical cells by in situ hybridization analysis, and its abundance was stimulated by ACTH. In contrast, IGF-I mRNA was not detected in cultured fetal zone cells and was not regulated by ACTH. In whole human fetal adrenal glands, IGF-II mRNA was detected in the definitive and fetal zones and in the capsule, whereas IGF-I mRNA was detected only in the capsule and not in the two cortical zones. Using Northern blot analysis, we found that mRNA encoding IGF-II was present in high abundance in fetal adrenal glands (16-22 weeks) and barely detectable in adult adrenals, whereas mRNA encoding IGF-I was present in very low abundance in the fetal adrenal, but was high in adult human adrenals. As IGF-II expression is high in the human fetal adrenal cortex and is regulated by ACTH, we propose that it is the dominant of the two IGFs regulating human fetal adrenal growth. The cooperative mitogenic effect of IGF-II with bFGF and EGF and the regulation of its expression by ACTH support the hypothesis that IGF-II may act as a mediator, in concert with bFGF and possibly EGF, of the tropic action of ACTH in regulating the rapid growth of the human fetal adrenal cortex during midgestation.