The Role of Insulin on Adrenal Steroidogenesis
Insulin is able to regulate gonadal steroidogenesis in both males and females. In women with PCOS, insulin excess amplifies ovarian androgen production rates, independent of changes in gonadotropin secretion and activity. Although earlier studies produced conflicting results,[46,47] a study performed in PCOS women and healthy controls, where LH responses to varying doses of gonadotropin releasing hormone (GnRH) during a fixed rate of insulin infusion and LH responses to a fixed dose of GnRH during varying doses of insulin infusion were investigated, showed that in the latter both basal LH and LH responses to GnRH were unaltered by insulin infusion, whereas these measures were reduced during insulin infusion in women with PCOS, and that this effect was negatively dependent on body weight. The role of insulin and other factors, particularly IGFs 1 and 2, in the regulation of ovarian theca and granulosa cells has been repeatedly demonstrated by in vitro studies performed in animal models and human tissues. These studies provided the basis for the role of insulin excess in determining increased androgen production and enhanced follicular cyst development in the PCOS. The key enzyme system representing the target of insulin action in the ovaries is cytochrome P450c17α, as shown by the increased activity of 17α-hydroxylase and, to a lesser extent, of 17,20-lyase, resulting in excessive ovarian androgen production. A more recent study further supported that sustained hyperinsulinemia is capable of potentiating gonadotropin-stimulated ovarian androgen steroidogenesis in women with PCOS.
Whether insulin regulates adrenal steroidogenesis, in particular androgen production rates, is still a matter of debate. The theoretical basis for investigating this issue was that insulin may act on both ovarian and adrenal tissue by regulating the same enzyme system, therefore explaining the combination of androgen excess of both ovarian and adrenal source in the same individual with PCOS. Preliminary in vitro studies performed in fresh adrenal tissue minced from normal human adrenals incubated with insulin showed that the hormone stimulated DHEAS and suppressed DHEA production, whereas it had no consistent effect on cortisol, suggesting a potential role of insulin in increasing adrenocortical sulfotransferase activity. Further in vitro studies supported and expanded these preliminary data, providing some evidence that insulin excess in women with PCOS may also be a candidate cause of increased adrenal steroidogenesis, since cytochrome P450c17a is present in the adrenals other than in the ovaries.[52,53] More recent studies provided in vivo data demonstrating that, in women with PCOS, a steady state of insulin excess produced proof of the concept that hyperinsulinemia is associated with an amplification of the 17α-hydroxycorticosteroid intermediate response to ACTH stimulation, without alterations in serum cortisol or androgen response to stimulation. This was demonstrated by evaluating the adrenal steroid response to ACTH (1–24) or saline infusion during a 3-h hyperinsulinemic (80 mU/m2 × min) euglycemic clamp in a group of 21 hyperandrogenic women with PCOS. It was found that no significant difference in the cortisol, progesterone or androstenedione response to ACTH was present between the ACTH and the saline infusion. By contrast, ACTH-stimulated serum 17-hydroxypregnenolone (p < 0.005) and 17-hydroxyprogestrone (p < 0.01) were significantly higher during insulin than during saline infusion, with a modest but significant increase in serum DHEA during hyperinsulinemia. In addition, ACTH-stimulated 17-hydroxypregnenolone/DHEA (p < 0.001) and 17b-hydroxyprogestrone/androstenedione (p < 0.005) molar ratios, indexes of apparent 17,20-lyase activity, were significantly higher during the clamp studies than during saline infusion. These in vivo data therefore support the hypothesis that insulin potentiates ACTH-stimulated steroidogenesis, and that this effect of insulin is probably to be associated with a relative impairment of 17,20-lyase activity. In a more recent study, the same research group provided further evidence for the presence of an insulin-mediated dysregulation of adrenal steroidogenesis. A small homogeneous group of hyperandrogenic PCOS women was submitted on two separate days to an 8 h hyperinsulinemic (80 mU/m2 × min) euglycemic clamp, and to an 8 h saline infusion; in the second half of both the protocols, a 4 h ACTH (1–24) infusion (62.5 µg/h) was carried out. During insulin infusion, ACTH-stimulated 17-hydroxypregnenolone and 17-hydroxyprogestrone were significantly higher than during saline infusion; however, no significant differences in cortisol and androgen response to ACTH were found between the protocols. Nevertheless, urinary excretion of ACTH-stimulated C19 and C21 steroid metabolites was significantly higher during hyperinsulinemia than at basal insulin levels, and these changes are consistent with a potential stimulation by insulin of 5α-reductase activity. These in vivo data therefore support the hypothesis that insulin acutely enhances ACTH effects on both androgen and glucocorticoid pathways.
Few studies on the efficacy in the treatment with insulin sensitizers in women with PCOS may add further information on the ability of insulin to regulate adrenal steroidogenesis. In fact, the use of pioglitazone for a few months has been found to decrease insulin blood levels without any changes in ACTH and cortisol response to hCRF, but a significant decrease of the response of androstenedione and 17b-hydroxyprogesterone in one study, or with a significant decrease in the daily blood values of allotetrahydrocortisol/tetrahydrocortisol and the androsterone/etiocholanolone ratios in another study. These findings demonstrate that the decrease of circulating insulin may improve adrenal steroidogenesis, possibly through a regulation of peripheral cortisol metabolism, rather than affecting cortisol production rate from the adrenals. By contrast, studies with metformin have produced disparate results, showing changes in the circulating hormones compatible with a significant decrease in the activity of 3b-hydroxysteroid dehydrogenase in C steroids and in 17b-hydroxysteroid dehydrogenase after ACTH stimulation in one study, or unaltered 17b-hydroxyprogesterone and androstenedione responses to ACTH (1–24) stimulation in another study suggesting no direct relationship between insulin resistance and adrenal P450c17a enzyme dysregulation.
Expert Rev Endocrinol Metab. 2012;7(5):555-566. © 2012 Expert Reviews Ltd.