[en] In several species, including the human fetus, insulin-like growth factors (IGF-I and IGF-II) have been reported to modulate adrenal steroidogenesis, thus contributing to adrenal cortical differentiation. In the present study, we examined the long term effects of IGF-I and -II on human adult adrenal fasciculata-reticularis cells cultured in a chemically defined medium and compared them to the effects of insulin, human GH, and ACTH. Treatment for 3 days with IGF-I or -II at nanomolar concentrations or with insulin at micromolar concentrations slightly increased the production of androstenedione, cortisol, and dehydroepiandrosterone about 1.5-fold over that by control cells. Moreover, the acute steroidogenic response to ACTH of cells pretreated with IGF-I, IGF-II, or insulin was 3- to 6-fold higher than that of control cells. For each hormone, these effects of IGF-I and -II were dose dependent between 0.1-26 nmol/L (1-200 ng/mL). The secretion of androstenedione was more potently stimulated than that of dehydroepiandrosterone and cortisol, and this effect was more clearly yielded by pretreatment with IGF-II than with IGF-I or insulin. Human GH had no effect on these cells. In cells treated with IGF-I or -II, the messenger ribonucleic acid (mRNA) levels of cytochrome P450 17 alpha-hydroxylase and of 3 beta-hydroxysteroid dehydrogenase were increased, and the abundance of ACTH receptor mRNA was also slightly enhanced, but the mRNA of cytochrome P450 cholesterol side-chain cleavage enzyme was unchanged. In conclusion, IGFs enhance the steroidogenesis and ACTH responsiveness of human adrenocortical cells in culture. We speculate, that by this mechanism, IGFs may contribute to clinical states with hyperandrogenemia.
Parker LN. 1989 Adrenal androgens in clinical medicine. San Diego: Academic Press; 98-133.
Pepe GJ, Albrecht ED. 1990 Regulation of the primate fetal adrenal cortex. Endocr Rev. 11:151-176.
Lebrethon MC, Jaillard C, Defayes G, Bégeot M, Saez JM. 1994 Human cultured adrenal fasciculata-reticularis cells are targets for angiotensin II: effects on cytochrome P450 cholesterol side-chain cleavage, cytochrome P450 17α-hydroxylase, and 3β-hydroxysteroid-dehydrogenase messenger ribonucleic acid and proteins and on steroidogenic responsiveness to corticotropin and angiotensin II. J Clin Endocrinol Metab. 78:1212-1219.
Penhoat A, Sanchez P, Jaillard C, Langlois D, Bégeot M, Saez JM. 1991 Human proopiomelanocortin-(79-96), a proposed cortical androgen-stimulating hormone, does not affect steroidogenesis in cultured human adult adrenal cells. J Clin Endocrinol Metab. 72:23-26.
Bornstein SR, Gonzalez-Hernandez JA, Ehrhart-Bornstein M, Adler G, Scherbaum WA. 1994 Intimate contact of chromaffin and cortical cells within the human adrenal gland forms the cellular basis for important intraadrenal interactions. J Clin Endocrinol Metab. 78:225-232.
Lebrethon MC, Jaillard C, Naville D, Begeot M, Saez JM. 1994 Effects of transforming growth factor β1 on human adrenocortical fasciculata-reticularis cell differentiated functions. J Clin Endocrinol Metab. 79:1033-1039.
Adashi EY, Resnick CE, D'Ercole JA, Svoboda ME, van Wyk JJ. 1985 Insulin-like growth factors as intraovarian regulators of granulosa cell growth and function. Endocr Rev. 6:400-420.
Saez JM. 1994 Leydig cells: endocrine, paracrine and autocrine regulation. Endocr Rev. 15:574-626.
Voutilainen R, Miller WL. 1987 Coordinate tropic hormone regulation of mRNAs for insulin-like growth factor II and the cholesterol side-chain cleavage enzyme, P450scc, in human steroidogenic tissues. Proc Natl Acad Sci USA. 84:1590-1599.
Mesiano S, Jaffé RB. 1993 Interaction of insulin-like growth factor II and estradiol directs steroidogenesis in the human fetal adrenal toward dehydroepiandrosterone sulfate production. J Clin Endocrinol Metab. 77:754-758.
Han VKM, D'Ercole AJ, Lund PK. 1987 Cellular localization of somatomedin (insulin like-growth factor) messenger RNA in the human fetus. Science. 236:193-197.
Mesiano S. Mellon SH, Jaffé RB. 1993 Mitogenic action, regulation, and localization of insulin-like growth factors in the human fetal adrenal gland. J Clin Endocrinol Metab. 76:968-976.
Ilvesmäki V, Blum WF, Voutilainen R. 1993 Insulin-like growth factor-II in human fetal adrenals: regulation by ACTH, protein kinase C and growth factors. J Endocrinol. 137:533-542.
Penhoat A, Rainey WE, Viard I, Saez JM. 1994 Regulation of adrenal cell-differentiated functions by growth factors. Horm Res. 42:39-43.
Pillion DJ, Arnold P, Yang M, Stockard CR, Grizzle WE. 1989 Receptors for insulin and insulin-like growth factor I in the human adrenal gland. Biochem Biophys Res Commun. 165:204-211.
Pham-Huu-Trung MT, Villette JM, Bogyo A, Duclos JM, Fiet J, Binoux M. 1991 Effects of insulin-like growth factor I (IGF-I) on enzymatic activity in human adrenocortical cells. Interactions with ACTH. J Steroid Biochem Mol Biol. 39:903-909.
Miller WL. 1989 Regulation of mRNAs for human steroidogenic enzymes. Endocr Res. 15:1-16.
l'Allemand D, Ardevol R, Penhoat A, Saez JM. 1994 Role of insulin-like growth factors on androgen formation in human adrenocortical cells in culture, secretion of IGF 1 and its binding proteins [Abstract 191]. Horm Res. 41:104.
Lebrethon MC, Naville D, Bégeot M, Saez J. 1994 Regulation of corticotrophin receptor number and mRNA in cultured human adrenocortical cells by corticotrophin and angiotensin II. J Clin Invest. 93:1828-1833.
Schöneshöfer M. 1977 Simultaneous determination of eight adrenal steroids in human serum by radioimmunoassay. J Steroid Biochem. 8:995-1009.
Luu The V, Lachance Y, Labrie C, et al. 1989 Full length cDNA structure and deduced amino acid sequence of human 3β-hydroxy-5-ene steroid dehydrogenase. Mol Endocrinol. 3:1310-1312.
Zuber MX, John ME, Okamura T, Simpson ER, Waterman MR. 1986 Bovine adrenocortical cytochrome P-450 17α: regulation of gene expression by ACTH and elucidation of primary sequence. J Biol Chem. 261:2475-2482.
John ME, John MC, Ashley P, Mac Donald RJ, Simpson ER, Waterman MR. 1984 Identification and characterization of cDNA clones specific for cholesterol side-chain cleavage cytochrome P-450. Proc Natl Acad Sci USA. 81:5628-5632.
Katagiri M, Kagawa N, Waterman M. 1995 The role of cytochrome b5 in the biosynthesis of androgens by human P450c17. Arch Biochem Biophys. 317:343-347.
Naseeruddin SA, Hornsby PJ. 1990 Regulation of 11β- and 17α-hydroxylase in cultured bovine adrenocortical cells: 3′,5′-cyclic adenosine monophosphate, insulin-like growth factor-I and activators of protein kinase C. Endocrinology. 127:1673-1681.
Weber MM, Simmler P, Engelhardt D. 1995 IGF-II more potently than IGF-I stimulates bovine adrenal steroidogenesis through interaction with the IGF-I receptor and IGF binding proteins. Endocrinology. 136:3714-3720.
Penhoat A, Ouali R, Viard I, Langlois D, Saez JM. 1996 Regulation of primary response and specific genes in adrenal cells by peptide hormones and growth factors. Steroids. 61:176-183.
Ilvesmäki V, Kahri AI, Miettinen PJ, Voutilainen R. 1993 Insulin-like growth factors (IGFs) and their receptors in adrenal tumours: high IGF-II expression in functional adrenocortical carcinomas. J Clin Endocrinol Metab. 77:852-858.
Nissley P, Kiess W, Sklar MM. 1991 The insulin-like growth factor II/mannose 6-phosphate receptor. In: LeRoith D, ed. Insulin-like growth factors: molecular and cellular aspects. Boca Raton: CRC Press; 111-150.
Ehrmann DA, Barnes RB, Rosenfield RL. 1995 Polycystic ovary syndrome as a form of functional ovarian hyperandrogenism due to dysregulation of androgen secretion. Endocr Rev. 16:322-353.
Han VKM, Lu F, Bassett N, Yang KP, Delhany PJD, Challis JRG. 1992 Insulin-like growth factor-II (IGF-II) messenger ribonucleic acid is expressed in steroidogenic cells of the developing ovine adrenal gland: evidence of an autocrine/paracrine role for IGF-II. Endocrinology. 131:3100-3109.
