Insulin-like growth factors I and/or II are expressed in adrenal cells, and modulate their proliferation and steroid hormone synthesis suggesting that they may function as paracrine/autocrine factors. In some species, at least ACTH induces insulin-like growth factor synthesis. Thus, these peptide growth factors mediate at least some of the effects of ACTH on adrenocortical cell proliferation and differentiation. Human fetal adrenals express insulin-like growth factor II gene abundantly and ACTH-dependently, while in adult adrenals, the expression is low and no ACTH dependent regulation has been demonstrated. Hormonally active adrenocortical carcinomas and virilizing adenomas express insulin-like growth factor II gene abundantly. This phenomenon is associated with reduced expression of two putative tumor suppressor genes (H19 and p57KIP2) locating on the same genomically imprinted locus on human chromosome 11p15.5. Tumor necrosis factor-alpha belongs to the cytokines which modulate hypothalamic-pituitary-adrenal axis. It is a potent inducer of ACTH secretion but, at the adrenal level, it seems to mainly inhibit ACTH-induced steroidogenesis and also insulin-like growth factor II expression. It is produced in adrenocortical steroidogenic cells in addition to macrophages, which suggests that tumor necrosis factor-alpha may have some autocrine/paracrine functions in the adrenal cortex.