Insulin and hyperandrogenism in women with polycystic ovary syndrome

Abstract

Polycystic ovary syndrome (PCOS) is a very common endocrine disorder characterized by chronic anovulation, clinical and/or biochemical hyperandrogenism, and/or polycystic ovaries. But most experts consider that hyperandrogenism is the main characteristic of PCOS. Several theories propose different mechanisms to explain PCOS manifestations: (1) a primary enzymatic default in the ovarian and/or adrenal steroidogenesis; (2) an impairment in gonadotropin releasing hormone (GnRH) secretion that promotes luteal hormone (LH) secretion; or (3) alterations in insulin actions that lead to insulin resistance with compensatory hyperinsulinemia. However, in the past 20 years there has been growing evidence supporting that defects in insulin actions or in the insulin signalling pathways are central in the pathogenesis of the syndrome. Indeed, most women with PCOS are metabolically insulin resistant, in part due to genetic predisposition and in part secondary to obesity. But some women with typical PCOS do not display insulin resistance, which supports the hypothesis of a genetic predisposition specific to PCOS that would be revealed by the development of insulin resistance and compensatory hyperinsulinemia in most, but not all, women with PCOS. However, these hypotheses are not yet appropriately confirmed, and more research is still needed to unravel the true pathogenesis underlying this syndrome. The present review thus aims at discussing new concepts and findings regarding insulin actions in PCOS women and how it is related to hyperandrogenemia.

Fig. 1

Steroidogenesis occurring both in gonads and adrenal gland of human origin. As cholesterol is the precursor for all steroids, each zone of the adrenal gland or cell types of the ovary expresses specific enzymes necessary for appropriate steroid production. The ovaries, more particularly the thecal cells, possesses the P450c17 enzyme having both the 17α-hydroxylase/17,20-lyase activities needed for androgens secretions, DHEA/testosterone. Granulosa cells expresses the P450aromatase enzyme necessary for estrogens production. The adrenal gland has the capacity to secrete mineralocorticoid (aldosterone) due to the presence of the P450aldo synthase enzyme in the zona glomerulosa. The adrenal gland zona fasciculata, and to a much lesser extent the zona reticularis, produces glucocorticoid (such as cortisol in human) because they express the 17α-hydroxylase activity of the P450c17 enzyme. The zona reticularis expresses to a larger extent than the zona fasciculata both 17α-hydroxylase and 17,20-lyase activities of the P450c17 that are necessary to produce androgens, adapted from Ref. [13].

Fig. 2

Serum free testosterone, fasting insulin levels and insulin sensitivity (HOMA IS), in women with PCOS having normal insulin levels, before and after the administration of insulin-sensitizing drugs or placebo for 6 months. (a) Testosterone concentrations and (b) fasting insulin levels and HOMA IS are shown as data represented by mean and 95% confidence interval. *P < 0.05 for comparison with the group given placebo and ^†P < 0.05 for comparison with the group given rosiglitazone, using Tukey HSD tests after ANCOVA analysis, adapted from Baillargeon et al. [47], with permission.

Fig. 3

Proposed cellular mechanisms involved in insulin-stimulated androgen biosynthesis, PCOS-associated defects, free fatty acids-induced insulin resistance and increased androgen production, and PPARγ actions. Insulin binds to its receptor resulting in tyrosine phosphorylation of the receptor and insulin receptor substrates (IRSs) such as the IRS-1. IRS-1 activates phosphoinositide-3-kinase (PI-3K) and Akt, which mediate insulin-stimulated glucose metabolism. Serine phosphorylation of IRS-1 prevents its binding with PI-3K and inhibits insulin signalling. Furthermore, serine phosphorylation of P450c17 increases its 17,20-lyase activity and thus androgen biosynthesis. Interestingly, serine phosphorylation of IRS-1 is constitutively increased in PCOS women and increased by fatty acids (FAs) accumulation, and PPARγ agonists increase tyrosine phosphorylation of IRS-1. On the other hand, insulin-stimulated androgen production has been shown to be reduced by specific inhibition of PI-3K and increased by specific inhibition of MEK. MEK/ERK activity was found to be constitutively reduced in PCOS women, activated by PPARγ agonists and inhibited by FFAs. It was also suggested that P450c17 activity may be stimulated by other players of the MAPK pathway, such as MKK3/6-p38 and MKK4/7-JNK, which are at least normally functional in women with PCOS, adapted from Baillargeon [92].