INSULIN-LOWERING THERAPEUTIC MODALITIES FOR POLYCYSTIC OVARY SYNDROME - 08/09/11
Riassunto |
In 1921 the French physicians Achard and Thiers provided the first description of the relationship between androgen excess in women and disturbances in carbohydrate metabolism which was dubbed “diabete des femmes á barbe” (diabetes of the bearded lady).2 It was not until 60 years later that hyperinsulinemia was demonstrated to be a characteristic finding in women with ovarian androgen excess, even in the absence of diabetes. In the ensuing decade, it became evident that insulin resistance was a cardinal feature of polycystic ovary syndrome (PCOS) that could serve as the pathogenetic link between hyperandrogenemia and hyperinsulinemia.13, 16, 19, 20
This article summarizes the relationship between insulin and androgen excess, with a focus on what is known regarding two related issues: (1) defects in insulin secretion in PCOS and their role in the development of glucose intolerance in this population, and (2) pharmacologic interventions designed to attenuate hyperinsulinemia and its sequelae in PCOS.
Because the majority of women with PCOS are obese, it seemed initially that their insulin resistance could be accounted for on this basis alone; however, the studies of Dunaif and colleagues13, 16, 19 firmly established that the magnitude of insulin resistance is greater in women with PCOS than in controls matched either for total or fat-free body mass. Several investigators subsequently corroborated this observation. The current consensus is that there is a distinctive form of insulin resistance, independent of obesity, that contributes to the extreme hyperinsulinemia in PCOS (see the article by Dunaif elsewhere in this issue).
Defects in insulin receptor number, receptor affinity, or both were initially considered as explanations for the insulin resistance but have effectively been excluded with careful binding assays.14, 44, 49 More recently, attention has been focused on possible defects in postreceptor signal transduction. Specifically, it has been shown that fibroblasts isolated from women with PCOS exhibit decreased insulin receptor autophosphorylation, both basally and in response to insulin stimulation.18 Phospho–amino acid analysis has revealed a decrease in insulin-dependent receptor tyrosine phosphorylation and increased insulin-dependent receptor serine phosphorylation.18 The relative increase in serine phosphorylation could account, at least in part, for the postreceptor defect in insulin action because it has been shown that insulin receptor serine phosphorylation decreases the tyrosine kinase activity of the receptor,35 which is critical in the transduction of the insulin signal. Although it has been proposed that the presence of such defects in ex vivo cell culture of fibroblasts supports a genetic rather than acquired basis for insulin resistance,17, 19 these defects have been more difficult to demonstrate in more traditional target tissues of insulin action (i.e., muscle and fat).
Given the previous findings, it is not surprising that women with PCOS are at substantial risk for the development of disorders of carbohydrate metabolism. Long-term follow-up of women with morphologic evidence of polycystic ovaries reveals an increased prevalence of type 2 diabetes mellitus when compared with appropriate controls (15% versus 2.3%; P<0.05).8 Although initial studies estimated the prevalence of diabetes to be approximately 20%,13 more recent data suggest that the prevalence of impaired glucose tolerance and type 2 diabetes mellitus among women with PCOS is even higher than initially suspected, with consistency across populations of varied ethnic and racial backgrounds.22, 36 Two recent large prospective studies estimate that the prevalence of impaired glucose tolerance ranges between 30% and 40% and that of type II diabetes from 5% to 10% (Figure 1).22, 36 These prevalences approach those in Pima Indian women between the ages of 20 and 39 years.54
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| Address reprint requests to David A. Ehrmann, MD, Department of Medicine, Section of Endocrinology, The University of Chicago Pritzker School of Medicine, 5841 South Maryland Avenue, MC 1027, Chicago, IL 60637 |
Vol 28 - N° 2
P. 423-438 - giugno 1999 Ritorno al numero
Articolo precedente
- ANTIANDROGEN TREATMENT OF POLYCYSTIC OVARY SYNDROME
- Roger S. Rittmaster
- CARDIOVASCULAR CONSEQUENCES OF POLYCYSTIC OVARY SYNDROME
- Lynn L. Amowitz, Burton E. Sobel
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