Insulin and the
Polycystic Ovary Syndrome

The very first RIA was an assay for insulin, developed exactly 40 years ago. A Nobel prize was awarded for this work.¹ Until quite recently, however, immunoassays for insulin have played a relatively minor role in the clinical laboratory, in spite of this hormone's association with diabetes. Yet all this may be changing due to a growing appreciation for the clinical implications of abnormal insulin levels in contexts which at first may seem far removed from issues of glucose regulation. One important example is the polycystic ovary syndrome (PCOS), a disorder adversely affecting the lives of upwards of 1 in 20 women of reproductive age, and defined by the presence of hyperandrogenism and chronic anovulation, once certain conditions have been excluded.²

Our understanding of the production of insulin and the effects of this hormone in various disease states has gradually evolved. Old models have given way to new, driven by incongruous findings. Thus, in a primitive model of diabetes (Figure 1), according to which underproduction of insulin by the pancreas is responsible for this disease, the discovery that some diabetics have elevated plasma insulin levels must have seemed paradoxical. But this was precisely what the first RIAs convincingly demonstrated.

For an enlarged view, click on the image.

The model required elaboration to take into account the hormone's target as well as its source (Figure 2). This entailed a distinction, broadly speaking, between one form of diabetes due essentially to deficient insulin production (problems at the source) and a second form characterized by insulin "resistance" (compromised action at the target--due perhaps to postreceptor abnormalities).³ In the latter, elevated circulating insulin levels reflect attempts by the pancreas to restore normal glucose regulation through increased production.

This model too is overly simplistic: we need to distinguish among the various targets involved (Figure 3). Resistance along some pathways may coexist with normal sensitivity along others.⁴ In particular, while insulin resistance vis-à-vis muscle and adipose tissue leads to compensatory hyperproduction of the hormone, the resulting hyperinsulinemia contributes towards the hyperandrogenism of PCOS, because insulin action at other targets, such as the ovaries and pituitary, is not correspondingly impaired.⁵

Profound insulin resistance--understood, as usual, in terms of peripheral glucose disposal--is typical of women with PCOS as a group and has been implicated in the development of characteristic features and sequelae of the disease. Indeed, among PCOS patients, insulin resistance is a common finding even in the absence of obesity--although obesity, when present (as it is in roughly half the cases), amplifies the problem. Given the role of insulin resistance and the compensatory hyperinsulinemia which it entails, it should be no surprise that, as a group, women with PCOS have a relatively high risk of developing type 2 diabetes and cardiovascular disease.^6,7 Nor should it be surprising that initial studies of drugs such as troglitazone and metformin have shown them to be, on balance, useful in the treatment of PCOS; for they help to reduce circulating insulin levels by acting, at least in part, to promote insulin sensitivity.^8-10

But PCOS is unlikely to be a single disease entity. Some evidence suggests a spectrum of variation ranging from cases where insulin resistance, aggravated by obesity, appears to be the driving force, to cases where excessive lutropin (LH) levels dominate the picture.^11-13

Accordingly, there is a need for simple measures of insulin resistance which can help to predict, for example, whether insulin-sensitizing agents are likely to be of value in the treatment of individual PCOS patients. But the classic methods for measuring the sensitivity of peripheral tissues to insulin-stimulated glucose uptake^14,15 are moderately invasive, labor-intensive, bedside procedures, requiring fairly sophisticated data analysis. In short, they are unsuited for routine clinical use. Approaches based on an oral glucose tolerance test (OGTT) supplemented with insulin determinations are still undesirably complex. At the other extreme, a fasting insulin level on its own is generally regarded as a less than satisfactory marker.

At the present time, the most promising candidates for a practical insulin resistance index are measures consisting of either the product^16-18 or the ratio of fasting insulin and glucose results. Thus, in two independent studies, one of them involving DPC's Coat-A-Count® Insulin assay, the ratio was shown to be reasonably predictive of hyperinsulinemic response during an OGTT,¹⁹ and highly correlated with one of the classic measures of insulin sensitivity.²⁰ Studies like these, some of them based on DPC assays, seem destined to promote more widespread use of insulin assays, especially as this hormone can now be measured on DPC's automated, random access IMMULITE® immunoassay analyzer.

References

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3. Mahler RJ, Adler ML. Type 2 diabetes mellitus; update on diagnosis, pathophysiology, and treatment. J Clin Endocrinol Metab 1999;84:1165-71.

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5. Nestler JE. Role of hyperinsulinemia in the pathogenesis of the polycystic ovary syndrome, and its clinical implications. Semin Reprod Endocr 1997;15:111-22.

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7. Ehrmann DA. Relation of functional ovarian hyperandrogenism to non-insulin dependent diabetes mellitus. Bailliere Clin Obstet Gyn 1997(June);11:335-47.

8. Dunaif A, et al. The insulin-sensitizing agent troglitazone improves metabolic and reproductive abnormalities in the polycystic ovary syndrome. J Clin Endocrinol Metab 1996;81:3299-306.

9. Davison RM. New approaches to insulin resistance in polycystic ovarian syndrome. Curr Opin Obstet Gynecol 1998;10:193-8.

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11. Anttila L, et al. Insulin hypersecretion together with high luteinizing hormone concentration augments androgen secretion in oral glucose tolerance test in women with polycystic ovarian disease. Hum Reprod 1993;8:1179-83.

12. Meirow D, et al. Insulin resistant and non-resistant polycystic ovary syndrome represent two clinical and endocrinological subgroups. Hum Reprod 1995;10:1951-6.

13. Fulghesu AM, et al. Changes in luteinizing hormone and insulin secretion in polycystic ovarian syndrome. Hum Reprod 1999;14:611-7.

14. American Diabetes Association. Consensus development conference on insulin resistance. Diabetes Care 1998;21:310-4.

15. Ferrannini E, Mari A. How to measure insulin sensitivity. J Hypertension 1998;16:895-906.

16. Duncan MH, et al. A simple measure of insulin resistance. Lancet 1995;346:120-1.

17. Cleland SJ, et al. FIRI; a fair insulin resistance index? Lancet 1996;347:770.

18. Nagasaka S, et al. Efficacy of troglitazone measured by insulin resistance index. Lancet 1997;350:184.

19. Parra A, et al. Fasting glucose/insulin ratio; an index to differentiate normo from hyperinsulinemic women with polycystic ovary syndrome. Rev Invest Clin 1994;46:363-8.

20. Legro RS, Finegood D, Dunaif A. A fasting glucose to insulin ratio is a useful measure of insulin sensitivity in women with polycystic ovary syndrome. J Clin Endocrinol Metab 1998;83:2694-8.