Clinical Review

Polycystic ovary syndrome: 3 key challenges

OBG Manag. 2003 June;15(6):62-72

Newer findings have broadened options for medical management of insulin resistance, anovulation, and hyperandrogenism.

References

1. Zawadzki JK, Dunaif A. Diagnostic criteria for polycystic ovary syndrome: toward a rational approach. In: Dunaif A, Givens JR, Haseline F, Merriam GR, eds. Polycystic Ovary Syndrome. Boston: Blackwell Scientific; 1990;377-384.

2. Kauffman RP, Baker VM, DiMarino P, et al. Polycystic ovarian syndrome and insulin resistance in white and Mexican American women: a comparison of two distinct populations. Am J Obstet Gynecol. 2002;187:1362-1369.

3. Chang RJ, Nakamura RM, Judd HL, Kaplan SA. Insulin resistance in nonobese patients with polycystic ovarian disease. J Clin Endocrinol Metab. 1983;57:356-359.

4. 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;83:2694-2698.

5. Goke B. Type II diabetes: Are current treatment options sufficient? Exp Clin Endocrinol Diabetes. 2000;108:S243-S249.

6. Stumvoll M, Nurjhan N, Perriello G, Dailey G, Gerich JE. Metabolic effects of metformin in non-insulin-dependent diabetes mellitus. N Engl J Med. 1995;333:550-554.

7. Velazquez EM, Mendoza S, Hamer T, Sosa F, Glueck CJ. Metformin therapy in polycystic ovary syndrome reduces hyperinsulinemia, insulin resistance, hyperan-drogenemia, and systolic blood pressure, while facilitating normal menses and pregnancy. Metabolism. 1994;43:647-654.

8. Velazquez EM, Acosta A, Mendoza SG. Menstrual cyclicity after metformin therapy in polycystic ovary syndrome. Obstet Gynecol. 1997;90:392-395.

9. Morin-Papunen LC, Koivunen RM, Ruokonen A, Martikainen HK. Metformin therapy improves the menstrual pattern with minimal endocrine and metabolic effects in women with polycystic ovary syndrome. Fertil Steril. 1998;69:691-696.

10. Glueck CJ, Wang P, Fontaine R, Tracy T, Sieve-Smith L. Metformin-induced resumption of normal menses in 39 of 43 (91%) previously amenorrheic women with the polycystic ovary syndrome. Metabolism. 1999;48:511-519.

11. Sarlis NJ, Weil SJ, Nelson LM. Administration of metformin to a diabetic woman with extreme hyperandrogenemia of nontumoral origin: management of infertility and prevention of inadvertent masculinization of a female fetus. J Clin Endocrinol Metab. 1999;84:1510-1512.

12. Ibanez L, Valls C, Potau N, Marcos MV, de Zegher F. Sensitization to insulin in adolescent girls to normalize hirsutism, hyperandrogenism, oligomenorrhea, dys-lipidemia, and hyperinsulinism after precocious puberty. J Clin Endocrinol Metab. 2000;85:3526-3530.

13. Kolodziejczyk B, Duleba AJ, Spaczynski RZ, Pawelczyk L. Metformin therapy decreases hyperandrogenism and hyperinsulinemia in women with polycystic ovary syndrome. Fertil Steril. 2000;73:1149-1154.

14. Moghetti P, Castello R, Negri C, et al. Metformin effects on clinical features, endocrine and metabolic profiles, and insulin sensitivity in polycystic ovary syndrome: a randomized, double-blinded, placebo-controlled 6-month trial, followed by open, long-term clinical evaluation. J Clin Endocrinol Metab. 2000;85:139-146.

15. Pasquali R, Gambineri A, Biscotti D, et al. Effect of long-term treatment of met-formin added to hypocaloric diet on body composition, fat distribution, and androgen and insulin levels in abdominally obese women with and without the polycystic ovary syndrome. J Clin Endocrinol Metab. 2000;85:2767-2774.

16. Seale FG, Robinson RD, Neal GS. Association of metformin and pregnancy in the polycystic ovary syndrome. A report of three cases. J Reprod Med. 2000;45:507-510

17. Crave JC, Fimbel S, Lejeune H, Cugnardey N, Dechaud H, Pugeat M. Effects of diet and metformin administration on sex hormone-binding globulin, androgens, and insulin in hirsute and obese women. J Clin Endocrinol Metab. 1995;80:2057-2062.

18. Acbay O, Gundogdu S. Can metformin reduce insulin resistance in polycystic ovary syndrome? Fertil Steril. 1996;65:946-949.

19. Ehrmann DA, Cavaghan MK, Imperial J, Sturis J, Rosenfield RL, Polonsky KS. Effects of metformin on insulin secretion, insulin action, and ovarian steroidogen-esis in women with polycystic ovary syndrome. J Clin Endocrinol Metab. 1997;82:524-530.

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KEY POINTS

Women with PCOS and insulin resistance are at increased risk for impaired glucose tolerance or diabetes. Hypoglycemic agents can reduce circulating androgen levels, increase sex hormone binding globulin, facilitate weight loss, and induce ovulation.
Take steps to enhance or induce ovulation. Even women who do not desire fertility stand to gain, because chronic anovulation increases the risk of endometrial cancer.
Address hirsutism and other hyperandrogenic effects. Treatment of hirsutism is best approached with a combination of medical and mechanical means. Counsel patients that response is likely to be slow and subtle.

An expanded array of pharmacologic combinations and regimens has increased our options for treating women with polycystic ovary syndrome (PCOS).

Managing PCOS has always been a complex process, due to the wide range of troubles experienced by patients with this disorder. An effective treatment strategy should address the 3 clinical challenges typical of the syndrome:

insulin resistance,
menstrual irregularities associated with anovulation, and
hyperandrogenic symptoms such as hirsutism.

Here, I review recent findings—including new data on the use of insulinsensitizing agents for hyperinsulinemia—and offer a practical guide, complete with algorithm (FIGURE), for managing women with PCOS.

PCOS: A diagnosis of exclusion

PCOS clearly is a common cause of hirsutism and anovulation and is associated with intrinsic insulin resistance in many women. This disorder affects up to 6% of reproductiveage women and tends to develop shortly after menarche.

Although there is considerable disagreement about diagnostic criteria, most clinicians rely on the 1990 National Institutes of Health (NIH) Consensus Conference guidelines.¹ These include clinical or biochemical evidence of hyperandrogenism and ovulatory dysfunction, and the absence of other causes. Thus, at present, PCOS is a diagnosis of exclusion.

Surprisingly, ultrasound visualization of “polycystic” ovaries is not one of the diagnostic criteria for PCOS. That is because women who have polycystic ovaries are not necessarily anovulatory. Conversely, the ovaries of women who meet the NIH criteria for PCOS may not appear to be polycystic.

1. Treat insulin resistance

Insulin exerts its primary effects in the liver, signaling the organ to reduce glycogenolysis and gluconeogenesis. Insulin also affects muscle, adipose tissue, and other organs, where it increases glucose uptake.

Insulin resistance—a reduction in the tissue response to insulin—affects one third to one half of all women with PCOS and leads to compensatory hyperinsulinemia.² Although the obesity associated with PCOS may exacerbate insulin resistance, even lean PCOS patients can be affected.³

Insulin augments the stimulating effect of luteinizing hormone on the growth and androgen secretion of ovarian theca cells and inhibits the production of sex hormone binding globulin. For this reason, women with PCOS and insulin resistance are at increased risk for betacell dysfunction and subsequent impaired glucose tolerance or diabetes. Thus, it is not surprising that oral hypoglycemic agents have been used to treat these patients. In fact, numerous studies have demonstrated that oral hypoglycemic agents can reduce circulating androgen levels, increase sex hormone binding globulin, facilitate weight loss, and induce ovulation in these women.

Measure tissue response. The “gold standard” for assessing insulin sensitivity is the hyperinsulinemic-euglycemic clamp. Unfortunately, because it requires a constant intravenous infusion of insulin, this technique is not clinically practical.

Fortunately, many other methods are available to assess insulin sensitivity, including the insulin tolerance, oral glucose tolerance, and fasting insulin tests. One method that has gained popularity is the fasting glucose:insulin ratio.⁴ However, there are clear ethnic and racial differences in the normal values for this test. Since these values are not available for all subpopulations, the usefulness of this study is limited.²

Nevertheless, assessing a woman’s fasting plasma glucose helps determine whether she has impaired glucose tolerance. The National Diabetes Association defines diabetes as a fasting plasma glucose level of 126 mg or more per deciliter on 2 separate occasions; impaired glucose tolerance is defined as a fasting plasma glucose level between 110 mg and 126 mg per deciliter. Since impaired glucose tolerance is a risk factor for the development of diabetes, this test is useful in populations at risk.

Metformin’s efficacy in improving insulin resistance and enhancing ovulation is overwhelming in nonmorbidly obese and lean women with PCOS.

I use fasting plasma glucose to assess glucose tolerance and screen for diabetes mellitus. However, as neither serum insulin levels nor impaired glucose tolerance are predictive of response to insulinsensitizing agents, I do not use the results to determine who should receive these drugs.

Choose the appropriate agent. Oral hypoglycemic agents are classified by type, each of which affects a different area in the glucose metabolism scheme.

Sulfonylureas, which have been available since the 1950s, reduce glucose levels by stimulating the release of insulin.⁵ Sulfonylureas may cause hypoglycemia and have not been studied in women with PCOS.
α-glucosidase inhibitors slow or block the breakdown of starches and sugars in the gastrointestinal tract, thereby reducing the absorption of glucose.
Insulin-sensitizing agents work through various mechanisms (TABLE 1). Like the α-glucosidase inhibitors, they rarely cause hypoglycemia. Since insulin resistance is likely to lead to impaired glucose tolerance and subsequent type 2 diabetes, insulin-sensitizing agents make good clinical sense.