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Metabolic Syndrome in Women With Polycystic Ovary Syndrome

Anita L. Nelson, MD

As a group, women with polycystic ovary syndrome (PCOS) are at risk for diabetes in greater numbers and at an earlier age than the general population. PCOS may also increase the risk associated with hypertension and dyslipidemia, especially among obese women. Linking these risks together in an assessment of metabolic syndrome provides a more complete approach to identify women with PCOS who may need therapies to reduce serious long-term health hazards.

Definitions of metabolic syndrome vary somewhat among organizations, but all current definitions include measures of central obesity, glucose intolerance, hypertension, and dyslipidemia (Table).1,2 These 4 common elements have been closely associated with the development of both coronary heart disease and peripheral vascular disease. According to the US census in 2000, about 47 million residents had metabolic syndrome at that time. The problem is growing; the data show that the age-adjusted prevalence of metabolic syndrome increased in women by 23% during the last decade of the 20th century.3 The risk of metabolic syndrome rises with age, but the incidence is also increasing among American teenagers. Ethnicity also influences the prevalence of metabolic syndrome, which is found more frequently in black and Mexican-American women.4

Although the discussion of metabolic syndrome began in the internal medicine literature, it is also relevant to ObGyns because of its relatively high prevalence in women with PCOS and in menopausal women. However, the ObGyn is faced with an array of inconsistent recommendations about testing women with PCOS for metabolic syndrome, and there is considerable controversy about the best treatments for women with both conditions.5,6

The need to test appropriate women with PCOS for metabolic syndrome has been underscored by recent studies showing that metabolic syndrome is twice as prevalent in PCOS women compared to controls matched for age and body mass index (BMI).7 Furthermore, the impact of metabolic syndrome may be more severe in some patients with PCOS; one study found that 33% of young, obese women with PCOS had evidence of coronary artery calcium deposits compared with 8% of age- and weight-matched controls.8 Generalized subclinical vascular risk has also been shown to be higher in young women with PCOS.9

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TABLE. Definitions of Metabolic Syndrome1,2

TESTING

Historically, care for women with PCOS has been fragmented, with gynecologists being consulted for PCOS-related problems with anovulatory bleeding, infertility, and endometrial cancer; dermatologists treating acne and hirsutism; and internists dealing with early-onset diabetes and cardiovascular disease. Today, the goal is to identify women with PCOS early and to integrate their care to prevent long-term sequelae.

Once the diagnosis of PCOS is established, what other tests should be performed?10 Blood pressure measurements are a routine part of every office visit, readily detecting hypertension. Because more than 60% of US women are overweight or obese, measurement of waist circumference is being recommended in addition to the customary “weigh-in.”11 For women of northern European descent, a circumference of more than 88 cm defines central obesity, but women of other ethnicities have different cutoffs.12 Although the procedure for obtaining a waist measurement would seem straightforward, this can pose significant technical challenges in women with central obesity (eFigure). Repeating the measurement at least once can help identify potential inaccuracies.

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eFIGURE. Placement of the measuring tape for obtaining waist (abdominal) circumference.

However, the diagnosis of metabolic syndrome does not automatically follow from the identification of PCOS or central obesity. Nearly 50% of the overweight population and 33% of the obese population are metabolically healthy.13 Targeted laboratory testing in women with PCOS is needed to better distinguish between those who have metabolic syndrome and those who do not. Accurate testing for insulin resistance not only is technically impractical in most clinical settings but also plays no role in the diagnosis or treatment of PCOS.10 Markers such as low sex-hormone–binding globulin levels or high testosterone values have been suggested to define high-risk subgroups; by contrast, elevated adiponectin levels have been associated with good metabolic health.14

The most direct approach for women with PCOS is to find those who have abnormal glucose tolerance and/or dyslipidemias.15 An oral glucose tolerance test (OGTT) is clearly indicated for PCOS women with a family history of diabetes, a personal history of gestational diabetes, or physical findings such as acanthosis nigricans; testing on the basis of obesity has a lower yield. On the other hand, the American Association of Clinical Endocrinologists recommends screening all women who have PCOS by age 30 with a 2-hour OGTT.16 Lipid profiles have also been recommended in the setting of PCOS and a BMI greater than 27.10

THERAPEUTIC LIFESTYLE CHANGES

Because lifestyle interventions improve all elements of the metabolic syndrome, they constitute first-line therapy and should be included in all treatment plans. The focus of these therapeutic lifestyle changes (TLC) is weight loss, with an emphasis on diet and physical activity. A 10% weight loss will often reduce insulin resistance, improve high-density lipoprotein cholesterol (HDL-C), lower low-density lipoprotein cholesterol (LDL-C) and triglycerides, and improve fibrinolysis. Ovulatory cycles can return with modest (10% to 15%) weight loss.

Weight Loss

The efficacy of proper diet is undisputable.17 The risk of cardiovascular disease (CVD) can be reduced by more than 50% by maintaining a healthy body weight while engaging in regular physical activity.18 In addition, reducing body weight by only 7% yields a 58% reduction in the risk of type 2 diabetes.18 However, PCOS women have unique challenges achieving and maintaining healthy weights. Because they consume less energy metabolizing their food, they often require a lower-calorie diet than other women do to lose weight. The current consensus is that obese women with PCOS should follow any hypocaloric diet (500 Kcal/d deficit) that reduces the glycemic load. Failing that, the patient should follow any calorie-restricted diet with which she can comply to achieve a 5% weight loss.19 Reducing alcohol consumption is another way to reduce caloric intake.20

Exercise

Exercise must be strongly recommended to help maintain long-term weight loss.18 The addition of exercise to calorie restriction improves body composition, but it confers no additional benefits for cardiometabolic outcomes.21 Patients with metabolic risk should be advised to engage in moderately intense physical activity for at least 30 minutes a day (preferably 45 to 60 minutes) for at least 5 days per week.

PHARMACOTHERAPY

Pharmacotherapy should be reserved for patients who are unable to implement TLC, who do not adequately respond to TLC within 6 months, who have an initial BMI exceeding 30 kg/m2, or who have an initial BMI greater than 27 kg/m2 and at least one other obesity-related disease. Use of orlistat or sibutramine has proved effective in helping women with PCOS who fail to lose enough weight with TLC alone.22-24

Dyslipidemia

The goals of therapy are to raise HDL-C and lower LDL-C and triglycerides. Niacin, glycemic control, and statins can be used to manage dyslipidemia. Statins can reduce vascular inflammation and may also increase adiponectin levels. However, niacin may increase insulin resistance.

Hypertension

Antihypertensive agents must be initiated to normalize blood pressure. New consensus statements recommend more stringent therapeutic targets for women with PCOS who are found to have prediabetes.25 Angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers are first-line treatments. Thiazides and beta-blockers, which can have an adverse impact on serum glucose levels, should be used with caution, especially in women with PCOS and prediabetes.

Diabetes

There are no studies demonstrating the safety of long-term metformin use in nondiabetic populations. As a result, most experts recommend against routinely using metformin to treat women with PCOS. In patients with PCOS who are trying to conceive, metformin should be reserved for those with glucose intolerance.19,26 There may be some benefits to using insulin-sensitizing agents for women with prediabetes diagnosed by either impaired fasting glucose levels or impaired glucose tolerance if diet and exercise are not effective.27 Metformin may be useful in delaying or preventing diabetes in prediabetic PCOS women with a history of gestational diabetes, but metformin does not reduce visceral fat and is not a weight-loss drug.28

CONCLUSION

Polycystic ovary syndrome is the most common endocrinopathy in reproductive-aged women. Many women with PCOS also have metabolic syndrome. Blood pressure and weight distribution can be easily gauged during an office visit. Glucose tolerance testing is generally indicated by some combination of family history of diabetes, personal history of gestational diabetes, elevated BMI, or suggestive physical findings. The need for lipid testing may be indicated by an elevated BMI, a strong family history of hyperlipidemia/CVD, or a diagnosis of metabolic syndrome based on other criteria. Diet and exercise remain the most effective long-term therapies. Pharmacologic agents should be reserved for high-risk women and those who fail lifestyle interventions. Importantly, women with PCOS and prediabetes have tight therapeutic targets for control of blood pressure and lipids—ie, the same as for women with overt diabetes.

Dr Nelson reports she is a member of the speakers bureau for Bayer HealthCare, Merck & Co, Schering-Plough, Teva Pharmaceutical Industries, and Wyeth; receives grant/research support from Bayer HealthCare, Teva Pharmaceutical Industries, and Wyeth; and is a consultant for Bayer HealthCare, Teva Pharmaceutical Industries, and Xanodyne Pharmaceuticals

Anita L. Nelson, MD, is Professor, Department of Obstetrics and Gynecology, Harbor-UCLA Medical Center, Torrance, CA.

References

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WHY DESIGNATE A METABOLIC SYNDROME?

As each element of the metabolic syndrome is itself a risk factor for cardiovascular disease (CVD), it would seem appropriate to simply treat the individual factors, such as hypertension or dyslipidemia. Furthermore, the metabolic syndrome does not include a number of important CVD risk factors—eg, smoking and family history. Support for this specific designation can be found in recent epidemiologic studies showing that the risk posed by the metabolic syndrome is greater than the sum of each of the individual risks associated with the defining elements. The parameters also have pathophysiologic interconnections; for example, visceral obesity is a risk factor for low levels of high-density lipoprotein cholesterol (HDL-C) and elevated triglyceride values. In the setting of visceral obesity, adipocytes release a variety of cytokines that create a state of chronic, systemic, low-grade inflammation conducive to the development of both atherosclerosis and type 2 diabetes. Central obesity is also associated with elevated levels of free fatty acids, which have been implicated in decreased glucose uptake (insulin resistance) and depressed insulin secretion. A third compelling argument for designating a separate syndrome is that lifestyle interventions, such as weight loss and exercise, have a favorable impact on all of its components.