KatCarney

PCOS: Current Understanding and Long-term Consequences

Zachary T. Bloomgarden, MD

Introduction
At the annual meeting of the American Association of Clinical Endocrinologists (AACE), Andrea Dunaif, MD,[1] Feinberg School of Medicine, Northwestern University, Chicago, Illinois, discussed polycystic ovary syndrome (PCOS) and its long-term health consequences.

The association between diabetes and hirsutism was first reported in 1921. PCOS is a syndrome of chronic anovulation and hyperandrogenism that affects 5% to 10% of premenopausal women and approximately 90% of women with irregular menses. It is the leading hormonally related cause of infertility. The recognition of its association with insulin resistance has led to increased attention to its importance.[2] The disorder combines a state of insulin resistance with abnormalities of hypothalamic and pituitary gonadotropin release and with hyperandrogenism. PCOS is frequently identified during the reproductive years, but may also be seen in utero with intrauterine growth retardation, prepubertally with exaggerated adrenarche, and later in life as the metabolic syndrome.

Long-term Health Consequences
The long-term health consequences of PCOS include cardiovascular disease (CVD), pregnancy-associated disorders, cancers, and seizure disorders. CVD is well recognized as part of the spectrum of the insulin resistance syndrome, leading to endothelial dysfunction, microalbuminuria, proatherosclerotic and inflammatory factors, diabetes, dyslipidemia, and a number of other abnormalities. Insulin resistance normally leads to beta-cell compensation, and persons at risk for diabetes are unable to compensate with increased insulin secretion. Such evidence of inadequate beta-cell compensation is seen frequently in women with PCOS,[3] leading to increased risk of diabetes.[4] Forty percent of women with PCOS have abnormal glucose tolerance, 10% already have type 2 diabetes, and the incidence of diabetes in adolescents with PCOS is comparable to that seen in adults.

"Women with PCOS," Dr. Dunaif commented, "have glucose intolerance rates as high as those in the highest risk ethnic groups in the world," such as the Pima Indians. Even correcting for obesity, PCOS is associated with elevated LDL cholesterol, while there is a synergistic effect of PCOS and obesity in causing hypertriglyceridemia.[5] Hypertension also is characteristically seen in women with both obesity and PCOS.[6] PCOS is associated with decreased fibrinolysis, increased C-reactive protein levels, and increased carotid intimal thickness.

There are no long-term studies of outcome. However, 77% of women with oligomenorrhea have evidence of PCOS and 33% have abnormal glucose tolerance. Using menstrual cycle length >/= 40 days as a surrogate marker, the Nurses' Health Study showed a 2.2-fold increase in the risk of type 2 diabetes development.[7] The study also showed that irregular menses was associated with a significant 53% increase in CVD events. Dr. Dunaif pointed out that one might expect the CVD risk to be even higher, suggesting protective factors such as the higher estrogen levels of women with PCOS.

Reproductive abnormality is a major clinical component of PCOS, with increased gestational diabetes in both obese and nonobese women, pregnancy-induced hypertension, and preeclampsia rates. There is also increased endometrial cancer risk, suggesting the need for cyclic progesterone administration.[8] The risk of ovarian cancer is increased 2.5-fold, particularly among women who had never used oral contraceptives.[9] Breast cancer risk is not clearly increased with PCOS. Women with seizure disorders have increased risk of PCOS.[10] One benefit of PCOS is that the syndrome appears to protect against osteoporosis.[11]

Evaluation of PCOS
Discussing the evaluation of women with PCOS, Dr. Dunaif suggested measuring total and biologically active testosterone, dehydroepiandrosterone sulfate, prolactin, and gonadotropin levels, as well as fasting lipids and oral glucose tolerance. She noted that only half of women with PCOS who have diabetes will be diagnosed with fasting glucose alone, which is particularly important because many of these women are candidates for insulin sensitizer treatment. Furthermore, it may be advisable to repeat the glucose tolerance test if relatively small increases (2-5 mg/dL) occur in fasting glucose. Tests for insulin resistance are not helpful in the office setting, with fasting insulin and insulin/glucose ratios and even glucose clamps showing a great deal of overlap with the normal population. Approximately half of siblings of women with PCOS also have the condition, even without clinical symptoms of androgen excess, suggesting that testing should be offered to this group.[12]

Therapy for PCOS
Lifestyle modification should be the first-line therapy. Seven percent to 10% weight loss is associated with regular ovulatory cycles in many cases. Calorie restriction is more important than dietary composition. Exercise improves insulin sensitivity, and both aerobic and resistance training are beneficial.

Insulin sensitizer treatment leads to improvement in glucose tolerance in women with PCOS[13] and decreases circulating androgen and estrogen levels.[14] Sex hormone binding globulin falls, causing a decrease in bioavailable testosterone; decreases are also seen in dehydroepiandrosterone and estrogen levels. These agents improve hirsutism in a dose-related fashion, although not as effectively as antiandrogens do. Luteinizing hormone levels decrease and resumption of ovulatory cycles is noted with these agents, so that "a very exciting application of these drugs is in infertility therapy."

Insulin sensitizers also improve the disposition index of insulin sensitivity vs secretion, suggesting that they may decrease the risk of development of diabetes. Levels of plasminogen activator inhibitor-1 (PAI-1) decrease, and endothelium-dependent vasodilation improves.[15] Metformin in doses of 1.5-2.55 g daily leads to ovulation in 1 to 3 months, may lead to preferential loss of visceral fat, and is associated with modest degrees of weight loss. There is controversy over its use during pregnancy, but Dr. Dunaif recommends stopping this agent when pregnancy begins, because it is designated "pregnancy category B." There are limited data for the thiazolidinediones, but these agents cause small-for-gestational age infants in animal models and are classified as "pregnancy category C," so they should be stopped when pregnancy begins. There is evidence that antiandrogens also may have benefit in treatment of insulin resistance in patients with PCOS.[16]

Dr. Dunaif concluded that PCOS is a condition associated with increased risk of type 2 diabetes and other insulin-resistance-related conditions, as well as with endometrial carcinoma, all potentially amenable to preventative treatment, either with lifestyle modification or with insulin sensitizers.

References
Dunaif A. Polycystic ovary syndrome and its long-term health consequences. Program of the American Association of Clinical Endocrinologists 12th Annual Meeting and Clinical Congress; May 14-18, 2003; San Diego, California.
Dunaif A, Graf M, Mandeli J, Laumas V, Dobrjansky A. Characterization of groups of hyperandrogenic women with acanthosis nigricans, impaired glucose tolerance, and/or hyperinsulinemia. J Clin Endocrinol Metab. 1987;65:499-507. Abstract
Dunaif A, Finegood DT. Beta-cell dysfunction independent of obesity and glucose intolerance in the polycystic ovary syndrome. J Clin Endocrinol Metab. 1996;81:942-947. Abstract
Legro RS, Kunselman AR, Dodson WC, Dunaif A. Prevalence and predictors of risk for type 2 diabetes mellitus and impaired glucose tolerance in polycystic ovary syndrome: a prospective, controlled study in 254 affected women. J Clin Endocrinol Metab. 1999;84:165-169. Abstract
Legro RS, Kunselman AR, Dunaif A. Prevalence and predictors of dyslipidemia in women with polycystic ovary syndrome. Am J Med. 2001;111:607-613. Abstract
Conway GS, Agrawal R, Betteridge DJ, Jacobs HS. Risk factors for coronary artery disease in lean and obese women with the polycystic ovary syndrome. Clin Endocrinol (Oxf). 1992;37:119-125. Abstract
Solomon CG, Hu FB, Dunaif A, et al. Menstrual cycle irregularity and risk for future cardiovascular disease. J Clin Endocrinol Metab. 2002;87:2013-2017. Abstract
Coulam CB, Annegers JF, Kranz JS. Chronic anovulation syndrome and associated neoplasia. Obstet Gynecol. 1983;61:403-407. Abstract
Schildkraut JM, Schwingl PJ, Bastos E, Evanoff A, Hughes C. Epithelial ovarian cancer risk among women with polycystic ovary syndrome. Obstet Gynecol. 1996;88:554-549. Abstract
Dunaif A, Thomas A. Current concepts in the polycystic ovary syndrome. Annu Rev Med. 2001;52:401-419. Abstract
Zborowski JV, Cauley JA, Talbott EO, Guzick DS, Winters SJ. Bone mineral density, androgens, and the polycystic ovary: the complex and controversial issue of androgenic influence in female bone. J Clin Endocrinol Metab. 2000;85:3496-3506. Abstract
Legro RS, Driscoll D, Strauss JF 3rd, Fox J, Dunaif A. Evidence for a genetic basis for hyperandrogenemia in polycystic ovary syndrome. Proc Natl Acad Sci U S A. 1998;95:14956-14960. Abstract
Ehrmann DA, Schneider DJ, Sobel BE, et al. Troglitazone improves defects in insulin action, insulin secretion, ovarian steroidogenesis, and fibrinolysis in women with polycystic ovary syndrome. J Clin Endocrinol Metab. 1997;82:2108-2116. Abstract
Dunaif A, Scott D, Finegood D, Quintana B, Whitcomb R. The insulin-sensitizing agent troglitazone improves metabolic and reproductive abnormalities in the polycystic ovary syndrome. J Clin Endocrinol Metab. 1996;81:3299-3306. Abstract
Paradisi G, Steinberg HO, Shepard MK, Hook G, Baron AD. Troglitazone therapy improves endothelial function to near normal levels in women with PCOS. J Clin Endocrinol Metab. 2003;88:576-580. Abstract
Moghetti P, Tosi F, Castello R, et al. The insulin resistance in women with hyperandrogenism is partially reversed by antiandrogen treatment: evidence that androgens impair insulin action in women. J Clin Endocrinol Metab. 1996;81:952-960. Abstract

source: http://www.medscape.com/viewarticle/458420

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