COMMENTARY: Polycystic Ovary Syndrome: A Syndrome of Ovarian Hypersensitivity to Insulin?

Polycystic ovary syndrome (PCOS) affects 6–10% of women of child-bearing age (1). It is defined by hyperandrogenism, chronic anovulation, and/or polycystic ovaries (two of three criteria); after exclusion of secondary causes (2). However, it has become apparent that insulin resistance and hyperinsulinemia play a critical role in the syndrome’s pathogenesis (1). Despite advances over the past decade, many questions remain regarding both the nature of insulin resistance in PCOS and the mechanism by which insulin resistance or insulin produces hyperandrogenemia.

Ovarian Androgen Production and in Vitro Insulin Action

During the past 15 yr, several studies demonstrated that insulin stimulates ovarian steroidogenesis in vitro. At physiological concentrations, insulin increases androgen production by cultured ovarian cells from women with PCOS (3), an increase significantly greater than that after stimulation of cells from normal women. Moreover, combined stimulation with LH and insulin at physiological concentrations have been shown to synergistically increase androgen biosynthesis by ovarian tissues from normal and PCOS women (4).

LH enhances theca cell steroidogenesis mostly through the cAMP-protein kinase A pathway. The molecular mechanism by which insulin regulates steroidogenesis is less well understood, but it has clearly been shown that insulin acts through its own receptor (3). In classical insulin-responsive tissues, insulin’s actions are mediated via three major pathways: the phosphatidyl-inositol 3-kinase (PI-3K) pathway, implicated in the metabolic effects of insulin; the MAPK pathway, responsible for the mitogenic effects of insulin; and the protein kinase C (PKC) pathway, which can also be activated via G protein activation of phospholipase C.

Because LH and insulin act physiologically via distinct intracellular signaling mechanisms, their synergistic enhancement of theca cell steroidogenesis likely entails important interactions between pathways of these two respective hormone. Indeed, it has been shown that insulin significantly increases LH-driven cAMP accumulation in theca cells (5). This insulin-stimulated increase in cAMP could be induced through PI-3K and/or PKC (6, 7) but probably not via the MAPK pathway (7). These observations provide a molecular basis to the hypothesis of significant cross talk between the LH and insulin signaling pathways and support the possibility of a defect in women with PCOS affecting both insulin and LH-stimulated ovarian androgen production as well as synergistic responses.

Hyperandrogenemia in PCOS and in Vivo Insulin Action

Increased ovarian androgen production in women with PCOS, compared with normal women, has also been demonstrated in vivo (8). Both chronic stimulation by LH and insulin have been implicated in this ovarian androgen hyperresponsiveness because most women with PCOS have increased LH and/or insulin levels.

To control for chronic stimulation by LH, normal and PCOS women were challenged with human chorionic gonadotropin before and 4 wk after LH suppression with a long-acting analog of GnRH (8). Suppression of LH did not alter the typical exaggerated plasma 17α-hydroxyprogester-one response to human chorionic gonadotropin. Conversely, serum total and non-SHBG-bound testosterone levels decreased significantly after direct suppression of pancreatic insulin release for 10 d with diazoxide in PCOS women (9). Moreover, reduction of insulinemia with acarbose, which slows down intestinal absorption of carbohydrates, also reduced serum testosterone levels in PCOS (10). These studies all underscore the importance of insulin in the pathogenesis of PCOS.

Numerous studies have demonstrated that any treatment aimed at improving insulin resistance in women with PCOS results in lower androgen levels and improves ovulatory function (1). The exaggerated steroidogenic response to LH stimulation tests also improved (11, 12), suggesting normalization of ovarian androgen hyperresponsiveness.

Finally, we conducted a study using insulin-sensitizing drugs [namely metformin, a biguanine, and rosiglitazone, a peroxisomal proliferator-activated receptor (PPAR)-γ agonist] in nonobese women with PCOS and normal insulin levels (13). The results demonstrated a normalization of serum testosterone levels and ovulation in actively treated groups, compared with placebo. Even if the women were normoinsulinemic at baseline, metformin significantly reduced their insulin levels, but rosiglitazone did not. These findings suggest that some women with PCOS have an increased ovarian sensitivity to insulin without global insulin resistance or hyperinsulinemia. In this case, any reduction in insulin levels (as with metformin) or any direct effect on the ovarian hyperresponsiveness (which may be the case with rosiglitazone) would be beneficial. Rosiglitazone might reduce ovarian androgen hyperresponsiveness through insulin-dependent or insulin-independent mechanisms.

Selective Defects of Insulin Sensitivity

Clinical examples of selective defects in the metabolic pathway of insulin action have been reported in pseudoacromegaly (14) and diabetic patients with a strong family history of type 2 diabetes (15). Resistance to insulin action on carbohydrate metabolism with preserved insulin stimulation of mitogenesis has been demonstrated in cultured skin fibroblasts from such patients (15). Book and Dunaif (16) also demonstrated that there is a selective defect in insulin action in PCOS fibroblasts that affects metabolic, but not mitogenic, signaling pathways.

A recent study (17) also highlighted a selective defect in insulin activity in granulosa cells from women with PCOS, i.e. resistance in the metabolic pathway associated with an increase in mitogenic activity. Moreover, the study demonstrated that troglitazone, a PPARγ agonist, can correct this insulin hypersensitivity of the mitogenic pathway along with a significant improvement of the insulin-resistant metabolic pathway. Therefore, these results support the hypothesis that PPARγ may directly improve the ovarian androgen hyper-responsiveness typically observed in PCOS.

Another group of investigators demonstrated that inhibition of the metabolic branch of insulin signaling, by blocking PI-3K, led to an enhanced mitogenic action of insulin in endothelial cells, suggesting significant cross talk between the various pathways of insulin signaling (18). Furthermore, the studies of King and Wakasaki (19) led to the hypothesis that cardiovascular complications of diabetes, for example, result from a decrease in PI-3K pathway activity, which in turn causes a decrease in the antiatherogenic effects of insulin, along with PKC-induced up-regulation of the MAPK pathway, hence resulting in an increase in the atherogenic effects of insulin.

The observation that insulin-signaling pathways may express differential, and even divergent, activity levels under various circumstances supports the possibility of a selective defect of the insulin androgenic pathway in women with PCOS. It is also possible that this defect is associated with or the cause of insulin resistance at its metabolic pathway level, considering the interactions previously noted.

Hypersensitivity of the Androgen Insulin Signaling Pathway: the Cause of PCOS?

It is not excluded that insulin resistance with compensatory hyperinsulinemia could chronically increase the sensitivity of the LH steroidogenic pathway, without actual implication of the androgenic insulin signaling pathway. However, ovarian hypersensitivity to insulin could explain why women with PCOS exhibit substantial reductions in serum testosterone when treated with insulin-sensitizing drugs, even when changes in insulin sensitivity or circulating insulin are modest. Moreover, not every woman with insulin resistance and hyperinsulinemia develops PCOS, and there is evidence that a subgroup of women with typical PCOS is neither insulin resistant nor hyperinsulinemic (13, 20). Absence of ovarian hypersensitivity to insulin in the former group and more extreme ovarian hypersensitivity in the latter group could explain these phenomena. Finally, we recently sought to determine whether a reduction in insulin levels with diazoxide, an agent devoid of any influence on insulin signaling pathways, can improve ovarian androgen production in non obese, normoinsulinemic women with PCOS and normal sensitivity to insulin (20). The six women studied to date exhibited normalization of their serum free and total testosterone levels after treatment with diazoxide, which were statistically significant and more pronounced than after LH suppression with a long-acting agonist of GnRH. These results further support the notion that insulin contributes to hyperandrogenemia, even in women with PCOS and normal sensitivity to insulin.

In light of these clinical and physiological data, we hypothesize that women develop PCOS in part because of a selective and tissue-specific increase in insulin sensitivity in the ovarian androgenic pathway (i.e. ovarian hypersensitivity to insulin). We propose that this defect is intrinsic and not secondary to chronic stimulation by LH. In a minority of women, this defect is sufficiently severe to cause typical PCOS without insulin resistance. However, it is important to recognize that in most women with PCOS, the severity of the ovarian hypersensitivity is such that the concomitant development of insulin resistance and hyperinsulinemia is necessary for phenotypic expression of the syndrome. The ovarian androgen hypersensitivity to insulin could result from up-regulation of the androgenic insulin signaling pathway, up-regulation of IGF-I receptors, decreased ovarian IGF binding protein-1 or SHBG, or other defects that need to be elucidated.

Conclusion

Insulin can stimulate ovarian androgen production in normal women and women with PCOS. However, ovarian cells of women with PCOS display a higher responsiveness for insulin-stimulated androgen synthesis in vitro. We demonstrated in vivo that nonobese and normoinsulinemic women with PCOS significantly improve their serum testosterone levels after serum insulin levels are reduced. It is therefore probable that women develop PCOS because of a hypersensitivity of their intraovarian insulin androgen signaling pathway. The characterization of this potential defect could have important implications in the development of specific and more efficient treatments of PCOS.

Abbreviations

PCOS

Polycystic ovary syndrome

PI-3K

phosphatidyl-inositol 3-kinase

PKC

protein kinase C

PPAR

peroxisomal proliferator-activated receptor