Learning Objectives:After participating in this continuing professional development activity, the provider should be better able to:
1. Define the criteria for diagnosis of polycystic ovary syndrome (PCOS).
2. Describe components of metabolic syndrome.
3. Explain the association between PCOS and metabolic syndrome and review screening recommendations in this population.
Definitions and Epidemiology
Polycystic Ovary Syndrome
Polycystic ovary syndrome (PCOS) is a complex endocrine disorder characterized by irregular menses, chronic anovulation, hyperandrogenism, and metabolic aberrations. Although there is significant variability in clinical presentation among women, PCOS is considered the most common endocrine disorder in women of reproductive age, with prevalence ranging between 6% and 18% depending on the diagnostic criteria used.1,2 In addition, PCOS is the most common cause of female infertility due to anovulation.1
Different sets of criteria have been proposed for diagnosis (Table 1). In 1990, the National Institutes of Health (NIH) developed the first formal set of criteria that included simply combined presence of clinical and/or biochemical hyperandrogenism along with oligo-/amenorrhea. In 2003, the Rotterdam Criteria were proposed, which added ultrasound evidence of polycystic ovarian morphology to the NIH criteria. In an attempt to broaden the phenotypic variability captured by a diagnosis, the ESHRE/ASRM Rotterdam Consensus Workshop in 2004 specified that the diagnosis of PCOS required the presence of at least any 2 of 3 of the following criteria: oligo- and/or anovulation; laboratory and/or clinical evidence of hyperandrogenism; and ultrasound evidence of polycystic ovarian morphology.3 The caveat of the Rotterdam criteria is that, although it captures the heterogeneity of patients with ovarian dysfunction, a diagnosis may be made in the absence of signs of androgen excess. Consequently, the Androgen Excess Society determined that androgen excess was the principal component of PCOS pathogenesis and should be a required criterion for diagnosis accompanied by oligomenorrhea and/or polycystic ovarian morphology.4 All criteria require that other causes of androgen excess be excluded before establishing a diagnosis of PCOS.
Metabolic Syndrome
Substantial evidence indicates that patients with PCOS are at increased risk of metabolic syndrome, a syndrome characterized by a constellation of related risk factors for cardiovascular disease (Table 2).5 Although multiple organizations including the National Cholesterol Education Program Adult Treatment Panel guidelines (NCEP-ATP III), World Health Organization, American Heart Association/National Heart Lung Blood Institute, International Diabetes Federation, and Rotterdam ESHRE/ASRM-Sponsored PCOS Consensus Workshop have proposed different criteria for diagnosis, overall the syndrome is defined by the presence of 3 or more of the following abnormalities: abdominal obesity (waist circumference at least 88 cm or 35 inches in women); high blood pressure (>=130 mm Hg systolic and/or >=85 mm Hg diastolic); high serum triglycerides (>=150 mg); high fasting blood glucose (>=100 mg/dL); and low serum high-density lipoprotein cholesterol (HDL-C) (<50 mg/dL in women).6
A diagnosis of metabolic syndrome is associated with a significantly increased risk of type 2 diabetes mellitus,7 cardiovascular disease,8 and mortality due to cardiovascular causes.9 A study using data from the National Health and Nutrition Examination Survey (1988-1994 and 1999-2004) to evaluate the prevalence of metabolic syndrome among women of reproductive age in the United States demonstrated that approximately 50% of the study population either already had metabolic syndrome or were at increased risk of developing it.10
Many women with PCOS have features consistent with metabolic syndrome, including insulin resistance, dyslipidemia, and/or hypertension. Each component of the metabolic syndrome contributes to increasing one's risk of atherosclerosis and cardiovascular morbidity and mortality in addition to increasing the risk of developing type 2 diabetes.11 Understanding the relationship between women with PCOS and their health risks related to metabolic syndrome is essential for primary prevention and health maintenance. The earlier a diagnosis of PCOS is made and metabolic syndrome is recognized, the sooner one's health risks can be mitigated, having a greater impact on long-term health. Metabolic syndrome is particularly prevalent among women with PCOS; thus, the purpose of the current review is to describe for providers of women's health care the important relationship between PCOS and the metabolic syndrome.
Association of PCOS With Metabolic Syndrome
Insulin Resistance and Type 2 Diabetes Mellitus
The association between PCOS, insulin resistance, and type 2 diabetes mellitus has been clearly described in the literature. As early as 1987, impaired glucose tolerance (IGT) during an oral glucose tolerance test (OGTT) was identified as more prevalent in obese women with PCOS, with 20% afflicted when compared with 5.3% in age- and weight-matched controls.12 The prevalence of insulin resistance in women with PCOS ranges between 44% and 85%, depending on ethnicity and PCOS phenotype.13 A recent large-scale meta-analysis aimed at investigating the prevalence of IGT (defined as 2-hour 75-g OGTT of 140-199 mg/dL) and type 2 diabetes mellitus (defined as 2-hour OGTT values >200 mg/dL) among women with PCOS supported these findings. In this study, the investigators found that women with PCOS had a 3.26-fold increased risk of IGT and a 2.87-fold increased risk of type 2 diabetes mellitus when compared with women without PCOS. These associations differed by ethnicity, with risk of IGT increased by 5.2-fold in Asian women, 4-fold in North/South American women, and 3-fold in European women for IGT when compared with their ethnicity-matched counterparts. Similar findings were shown for type 2 diabetes mellitus, with a 4.4-fold increase in Asian women and a 4.7-fold increase in North/South American women.14
Some portion of insulin resistance, identified by the euglycemic hyperinsulinemic clamp test, seems to be independent of obesity. The euglycemic hyperinsulinemic clamp test uses an insulin infusion to achieve hyperinsulinemia, whereas the rate of glucose infusion necessary to achieve euglycemia is calculated. The glucose infusion rate is equal to glucose uptake and utilization and is a measure of insulin sensitivity. One euglycemic hyperinsulinemic clamp study in 12 nonobese women with PCOS demonstrated significantly elevated serum insulin levels (32.33 +/- 4.98 vs 19.56 +/- 2.21 [mu]U/mL) and decreased insulin sensitivity when compared with age- and weight- matched controls.13
Similarly, a more recent euglycemic hyperinsulinemic clamp study demonstrated that women with PCOS have more profound insulin resistance than their body mass index (BMI)-matched controls.13 Even so, obesity exacerbates insulin resistance in women with PCOS, such that women with both PCOS and obesity have significantly higher rates of insulin resistance compared with nonobese women with PCOS.15 The CARDIA (Coronary Artery Risk Development in Young Adults) Women's study, a large prospective cohort study, demonstrated that women with PCOS have a higher risk of developing type 2 diabetes by age 38 to 50 years (23% vs 13%). Further, normal-weight women with PCOS had a 3-fold increased risk of developing type 2 diabetes compared with women without PCOS, thus supporting the concept that PCOS is associated with an increased incidence of diabetes, independent of BMI.16
Although not part of any PCOS diagnostic criteria, insulin resistance and hyperinsulinemia are central to the PCOS phenotype. The pathogenesis of this relationship is complex and not completely understood. Several studies have demonstrated that, in the setting of insulin resistance and excess, insulin acts directly on the ovarian thecal cells to increase androgen production, thus exacerbating the hyperandrogenism that is present in PCOS.13 Hyperandrogenism is further exacerbated by hyperinsulinemia due to effects of insulin on tissues other than the ovary; excess circulating insulin decreases hepatic production of sex hormone-binding globulin, functionally increasing free testosterone levels.17 These mechanistic associations are confirmed by improvement of PCOS symptoms when insulin sensitivity is improved, either through weight loss or pharmaceutical therapy.
Dyslipidemia
Women with PCOS have other metabolic dysfunctions, namely dyslipidemias, which contribute to the long-term adverse cardiovascular consequences of metabolic syndrome.5 Because atherosclerotic plaque buildup begins during reproductive years, identifying and managing disturbances in lipid profiles early on may reduce long-term cardiovascular risk. Early literature investigating the relationship between PCOS and dyslipidemia focused on decreasing triglycerides and increasing HDL-C to improve cardiovascular risk.18 Additional studies have since been performed to better characterize all lipid parameters, including low-density lipoprotein cholesterol (LDL-C), and their relationship with PCOS.5,18
Current literature is conflicting as to the clinical significance of disturbances in lipid panels of women with PCOS. Many studies have shown that lipid profiles of women with PCOS are similar to those with classic atherogenic dyslipidemia, specifically elevated triglycerides, decreased HDL-C, and elevated LDL-C.5,18 This suggests that the atherogenic lipoprotein phenotype associated with PCOS is similar to that found in type 2 diabetes mellitus, underscoring the effect of excess insulin on lipid metabolism.5 Additionally, there is evidence that obesity and hyperandrogenism are each independently associated with a more atherogenic lipid profile in women with PCOS.19 Thus, severity of lipid disturbances may be directly correlated to severity of PCOS. In a large recent meta-analysis of 30 studies, triglyceride levels were on average 26 mg/dL higher and HDL-C levels 6 mg/dL lower in women with PCOS when compared with BMI-matched controls.5 Similarly, LDL-C and non-HDL-C levels were higher, on average 9 and 16 mg/dL higher, respectively, in women with PCOS compared with BMI-matched controls. However, although these associations were found to be statistically significant, the absolute levels of these metabolites often were within the normal physiologic range.5 Thus, disturbances in lipid levels in women with PCOS may not always be clinically significant.
Hypertension
Evidence showing a direct correlation of PCOS with elevated blood pressure has been lacking, with few studies assessing hypertension as a primary outcome. A large cohort study of Australian women revealed a higher prevalence of hypertension in women with PCOS than in healthy controls (5.5% vs 2.0%), an association that was independent of BMI within the PCOS group.20 These findings are consistent with prior smaller studies in which women with PCOS were found to have higher mean ambulatory blood pressures and daytime systolic blood pressures even after controlling for BMI, adiposity, and insulin resistance.21 Conversely, multiple studies have shown no association in 24-hour ambulatory blood pressure between women with PCOS and healthy controls, despite increased arterial stiffness and endothelial dysfunction within the PCOS group.22
Hyperandrogenism and hyperinsulinemia have been linked to elevated blood pressure, providing a possible mechanism for elevated blood pressures within this population. Elevated levels of testosterone in women with PCOS increased the risk of elevated blood pressures, independent of age, insulin resistance, obesity, or dyslipidemia.23 Similarly, aldosterone levels were found to be significantly higher in women with PCOS compared with age- and BMI-matched controls, associated with vascular dysfunction via the renin-angiotensin-aldosterone system. Hyperinsulinemia may influence blood pressures through disturbance in the autonomic nervous system, increased renal sodium resorption, and decreased nitric oxide production.24 With conflicting evidence regarding this relationship, there is no consensus regarding the interplay between PCOS and hypertension.
Nonalcoholic Fatty Liver Disease
Although not part of the diagnostic criteria, nonalcoholic fatty liver disease (NAFLD) is the hepatic manifestation of metabolic syndrome, in which excess fat accumulates in the liver in those with minimal alcohol consumption.25 The disease exists on a spectrum ranging from simple hepatic steatosis to nonalcoholic steatosis hepatitis (NASH) worsening to irreversible hepatic fibrosis and cirrhosis, all of which carry an increased risk of hepatocellular carcinoma.25 The predominant risk factors for NAFLD are obesity and diabetes mellitus. As prevalence of these diseases has risen, so has NAFLD, such that an estimated 25% of the world's population is currently affected with NAFLD.26 PCOS and NAFLD share key characteristics of metabolic syndrome including obesity, hypertension, dyslipidemia, and insulin resistance.26 A systematic review of 7 cohort studies reported a 4-fold increased risk of NAFLD among women with PCOS compared with controls.27 Similarly, a more recent meta-analysis of 17 studies demonstrated that women with PCOS had a 2-fold higher chance of developing NAFLD, independent of BMI and geographic region worldwide.28 Interestingly, the prevalence of more advanced NAFLD with progression to NASH is higher in women with PCOS, even in adolescent girls with PCOS.26
Women with PCOS have an increased rate of NAFLD above that conferred by obesity or insulin resistance alone, likely due to excess of androgen hormones.29,30 A large longitudinal cohort study of over 63,000 women with PCOS demonstrated an increased risk of NAFLD in women with PCOS than in age-, BMI-, and location-matched controls, and found that androgen excess, anovulation, and hyperglycemia each independently increased the risk of developing NAFLD.30 Jones et al29 found that liver fat was significantly higher in hyperandrogenic women with PCOS compared with women with PCOS with normal androgens (3.7% vs 2.1%), even when controlling for insulin resistance and internal and visceral adipose tissue. In short, NAFLD is more frequently seen in women with PCOS, with an even stronger association if characteristics of metabolic syndrome are present, especially insulin resistance and obesity.
Sleep Apnea
Obstructive sleep apnea (OSA) is a chronic sleep disorder caused by recurrent collapse of the upper airway during sleep leading to intermittent hypoxia. The disorder is clinically characterized by the number of apneic (no airflow for 10 seconds) and hypopneic (decreased airflow for 10 seconds) events associated with a desaturation or arousal from sleep.31 The diagnosis is made by measuring the apnea-hypopnea index (AHI) on polysomnography, where OSA is defined at an AHI 15 or more without symptoms or an AHI of 5 or more with symptoms including daytime sleepiness, witnessed apneic events, or loud snoring.31 Although OSA affects 2% to 5% of adult women, a recent meta-analysis of 8 studies showed a prevalence of OSA of 32% (95% confidence interval, 13%-55%) among women with PCOS.32 Similarly, women with PCOS have been shown to have an increased AHI, despite not meeting diagnosis for OSA.32 Even in the absence of OSA, PCOS has been associated with excessive daytime sleepiness, affecting 80% of women with PCOS as compared with 27% in controls.33 Of those women with PCOS reporting daytime sleepiness, only 17% met criteria for OSA.33
Metabolic mechanisms linking PCOS and OSA are not entirely clear. Obesity is the most common risk factor and exacerbating factor in OSA, as increased body weight plays an important role in anatomical changes of the upper airway and thoracic region predisposing to OSA.31 However, conflicting evidence exists whether obesity is a confounding factor in the relationship between PCOS and OSA. Studies have shown an association independent of obesity, with one study showing a significantly increased number of AHI in nonobese women with PCOS than in age- and BMI-matched controls (higher mean AHI: 0.79 vs 0.29, P = 0.041).32 Similarly, a study of obese women with PCOS showed no relationship between increased BMI and severity of OSA.31 Conversely, in a smaller study of 44 women with PCOS and 34 control women, the risk for OSA among women with PCOS was not increased when the populations were stratified into obese and nonobese women.31 Overall, OSA affects a disproportionate number of women with PCOS, although it is unclear whether obesity plays an intervening role.
Screening Guidelines for Women With PCOS
Metabolic syndrome is highly prevalent among women with PCOS. It is important for the general obstetrician/gynecologist to recognize that this population is at higher risk for cardiovascular disease and type 2 diabetes; therefore, women should be screened for comorbid conditions. We review the recommendations for screening, which are based on both the Endocrine Society-appointed task force guideline for assessment and management of PCOS and recommendations set by the American College of Obstetricians and Gynecologists (Table 3).34-35
Screening in women with PCOS is centered around determining the patient's global cardiovascular disease risk, identifying modifiable risk factors, and intervening when possible to change the course of disease. A detailed history should be taken to assess for cardiovascular risk factors. This includes a family history of early-onset cardiovascular disease, obesity, cigarette smoking, dyslipidemia, hypertension, IGT, and lack of physical activity. Women with these risk factors should be considered at increased risk for cardiovascular disease.
As discussed, women with PCOS are at significantly increased risk for IGT and type 2 diabetes. Therefore, glycemic status of all women with PCOS should be assessed at baseline and every 3 to 5 years throughout their life course or more frequently if indicated. Rescreening is important as conversion to IGT approaches 20% per year.36
Women with PCOS should be screened for dyslipidemia with a fasting lipid profile at baseline as recommended by both the Endocrine Society and the American College of Obstetricians and Gynecologists. Frequency of lipid measurement should be based on the detection of hyperlipidemia and the patient's overall cardiovascular disease risk stratification.
Although the Endocrine Society Task Force recommends that physicians recognize the increased prevalence of NAFLD in patients with PCOS, there is insufficient evidence to recommend screening for this condition. However, if patients demonstrate dyslipidemia and liver dysfunction, liver ultrasound with subsequent biopsy if needed may be considered.3,37
Screening for OSA may be performed if the patient reports snoring, daytime sleepiness, or excessive fatigue after waking from sleep. However, research thus far has not found any metabolic benefit in treating OSA in patients with PCOS.
Abdominal obesity is associated with hyperandrogenism and increased metabolic and cardiovascular risk. Women with PCOS should be screened for obesity with BMI calculation and waist circumference measurement to assess for abdominal adiposity. Patients should be counseled on the importance of lifestyle changes, including modification of diet and adequate exercise for weight loss.
Conclusion
The strong relationship between PCOS and metabolic syndrome calls for close evaluation in women with PCOS to mitigate their lifetime risk of associated conditions such as cardiovascular disease and type 2 diabetes. It is also important for women with PCOS to be educated on their long-term health risks. The role of the general obstetrician/gynecologist is to keep these conditions in mind when caring for women with PCOS. Early recognition, lifestyle modifications, and aggressive management to attenuate insulin resistance and its downstream consequences are key in these populations.
REFERENCES