Polycystic ovarian syndrome is a common disorder affecting many reproductive age women. The disease presents with many symptoms including hyperandrogenism and chronic anovulation. It is important to realize that many patients with PCOS also have many of the features of metabolic syndrome. Metabolic syndrome is associated with increased risk for developing many serious diseases such as diabetes mellitus and cardiovascular disease. It is important to recognize and treat the metabolic syndrome that presents in PCOS patients. The principal underlying PCOC may be insulin resistance. Insulin resistance results in hyperinsulinemia, which appears to be a major determinant of the metabolic syndrome. It is important for health care providers to be aware that PCOS patients may develop metabolic syndrome. There are measures that can be taken to prevent and eliminate metabolic syndrome that presents in these patients, and drugs that can be taken to help decrease risk factors of the metabolic syndrome. Lifestyle modifications and insulin sensitizing agents can be useful in the treatment and management of these patients.
Polycystic ovarian syndrome is a common disorder affecting 4-12% of
reproductive age women (12). Two hallmarks with which the disease presents are hyperandrogenism and chronic anovulation. Polycystic ovarian syndrome (PCOS) patients will present with symptoms that are troublesome to them, yet these symptoms are not life threatening. These troublesome symptoms include hirsutism, acne, oligomenorrhea, amenorrhea, dysfunctional uterine bleeding, and/or infertility. These symptoms may be devastating but they are not life threatening.
Unfortunately there is more to PCOS then troublesome symptoms. Metabolic syndrome has also been linked to patients with polycystic ovarian syndrome. This has a considerable amount of significance because metabolic syndrome is associated with increased risk for developing diabetes mellitus and cardiovascular disease. Therefore, it is important to take measures to prevent or to recognize and treat the already existing metabolic syndrome that presents in PCOS patients.
Due to PCOS being so diverse and heterogeneous in nature, a uniform definition does not exist. In April 1990, a conference sponsored by the National Institutes of Health was held on the disorder (2). A clear consensus was never reached, but there was a general agreement that hyperandrogenism and chronic anovulation are the principle facets of the syndrome, and once other disorders are ruled out, the diagnosis may be presumed.
There is still much debate on the diagnosis of PCOS and diagnostic criteria used vary among providers because a uniform definition has not yet been established. The lack of well-defined diagnostic criteria makes identification of this common disease confusing to many clinicians (12). Clinical features of polycystic ovarian syndrome include menstrual disturbance secondary to chronic anovulation or oligoovulation, and hirsutism and/or acne due to hyperandrogenaemia. All clinical features need not be present in order to diagnose a patient with PCOS. Some women never develop signs of androgen excess because of genetic differences in target tissue number and/or sensitivity to androgens (3).
In order to confirm the diagnosis of PCOS in patients who present with some or all of the clinical features mentioned, a provider may perform an ultrasound where the appearance of enlarged ovaries and an increased echo dense stroma surrounded by multiple, small, peripherally situated follicles may confirm the diagnosis in these symptomatic patients. It is important to realize that the presence of this characteristic ovarian morphology may be present in patients who are asymptomatic. Patients who are asymptomatic and have polycystic ovaries do not necessarily have the syndrome. Polycystic ovaries are not specific for PCOS, 20% of normal women have this morphological ovarian finding (12). Therefore, those who rely on ultrasound alone may misdiagnose the syndrome.
In order to diagnose PCOS in asymptomatic patients who have polycystic ovaries a provider may perform biochemical examinations (elevated serum testosterone, elevated LH concentrations, fasting glucose:insulin <4.5m, elevated free androgen index or elevated testosterone) (16). These biochemical examinations may also be performed to confirm the diagnosis of PCOS in symptomatic patients who do not display polycystic ovaries upon ultrasound.
Elevated free testosterone activity, defined by the free androgen index, represents the most sensitive biochemical marker supporting the diagnosis (16). A raised LH concentration, although a useful marker of the syndrome, is now less favored as a diagnostic tool (16).
Exclusion of other possible etiologies that may present in a similar fashion is also important in the diagnosis of PCOS. Possible etiologies include late onset congenital adrenal hyperplasia, thyroid disease, hyperprolactinemia, and androgen secreting tumors.
Table 1. Diagnostic Criteria of Polycystic Ovarian Syndrome
Elevated luteinizing hormone concentration with normal follicle stimulating hormone concentration
Increased testosterone activity (often expresses as raised free androgen index)
Insulin Resistance with compensatory hyperinsulinaemia
The cause of PCOS is unknown, but the principal underlying the disorder may be insulin resistance. This insight into the pathophysiology of PCOS is what has brought the long-term issues of type 2 diabetes mellitus and its resultant increased risk of coronary artery disease to the forefront. Insulin resistance results in hyperinsulinemia, which stimulates excess ovarian androgen production. Insulin resistance is associated with dyslipidemia and a predisposition to non-insulin dependent diabetes and cardiovascular disease later in life. This is the reason that polycystic ovarian syndrome seems to have many of the hallmarks of the metabolic syndrome. The exact mechanism for insulin resistance in PCOS is uncertain, but a post-receptor defect in adipose tissue has been identified (16). Cell surface insulin receptors are at normal levels, but there is a post receptor defect in signal transduction, causing a decrease in glucose transport (9). It has recently been suggested that the post receptor binding defect is an increase in insulin receptor mediated serine phosphorylation with a concomitant decrease in protein kinase activity and necessary tyrosine kinase activity, thereby interfering with transduction of the insulin signal and causing it to be defective (9).
Though the cause of PCOS is uncertain, there is some evidence of autosomal transmission related to strong familial clustering (16). Potentially, a gene or series of genes makes the ovaries susceptible to insulin stimulation of androgen secretion while blocking follicular maturation. Although there is insulin resistance in adipose and skeletal muscle, the ovary remains relatively sensitive to insulin, and both insulin and insulin-like growth factor 1 have stimulatory effects on thecal androgen production. Excess insulin along with the ovarian sensitivity to the insulin in combination with elevated LH concentration, brings about thecal hyperplasia, increased androgen secretion, arrest of follicular development, and therefore anovulation along with menstrual disturbance.
Overall obesity is present in approximately 44% of women with PCOS (2). When obesity is present insulin resistance is worsened. The obesity of PCOS, because of hyperandrogenism and insulin resistance, is of the android (central) type (2). Android type obesity results in an increased waist to hip ratio. This ratio is highly associated with diabetes mellitus and increased cardiovascular risk.
Due to the insulin resistance, many patients with PCOS have many features of metabolic syndrome. Increased awareness of this overlap between PCOS and metabolic syndrome advocates therapies that improve insulin resistance and often ameliorates PCOS symptoms. Many women with PCOS have multiple metabolic abnormalities and receive inadequate treatment for risk factors for heart disease and diabetes. The metabolic syndrome has largely asymptomatic risk factors. PCOS patients often come to their health care providers with the troublesome symptoms of hirsutism and acne. This brings women to their providers’ attention. This gives providers the opportunity to intervene early with counseling and medications to alter the risk profile for later development of the metabolic syndrome if needed. It is important for providers to be aware of the high risk that PCOS patients have of developing the metabolic syndrome or of the possibility that the metabolic syndrome is already present. Providers need to be aware of treatment options that may help these patients. Patients need to be educated and managed for the continuing health risk of insulin resistance throughout their lives.
Metabolic Syndrome Associated with PCOS
The metabolic syndrome has been defined by a constellation of risk factors for cardiovascular disease. Insulin resistance being the key pathogenic factor in PCOS, it also appears to play a pathogenic role in the metabolic syndrome. The criteria for the diagnosis of the metabolic syndrome are found in table 2 (6).
Table 2. Criteria for the diagnosis of the metabolic syndrome in women
Dyslipidemia (HDL-C level <45mg/dl, or triglyceride level >150mg/dl
Waist/hip ratio >.85
Waist circumference >88cm (35 inches)
Waist circumference >88cm (35 inches)
Type 2 diabetes or IGT
Fasting Blood Glucose level >110mg/dl
Impaired fasting blood glucose level (110mg/dl) or type 2 diabetes
Microalbuminuria (overnight urinary albumin excretion rate >20 mg/min
Insulin resistance (hyperinsulinemia relative to glucose levels) or acanthosis nigricans
Requirements for diagnosis
Confirmed type 2 diabetes or IGT and any 2 of the above criteria. If normal glucose tolerance, must demonstrate 3 of the above criteria.
Any 3 of the above disorders
Consider any minor criteria including hypercoagulability, PCOS, vascular or endothelial dysfunction, microalbuminuria, and coronary heart disease
WHO (World Health Organization); NCEP ATP III (National Cholesterol Education Program Adult Treatment Panel III); AACE (American Association of Clinical Endocrinology).
The metabolic syndrome is more prevalent in women with PCOS than in the general U.S. population, even when matched for both age and body mass index (1). One study found that the prevalence of the metabolic syndrome in women with PCOS was 43%, which is nearly 2-fold higher than the age-adjusted prevalence rate of 24% in women nationally (1). The analyses in one study were most notable for the finding that fully one third of nondiabetic women with PCOS have developed the metabolic syndrome well before the end of their fourth decade, and usually before the end of their third decade of life (4). This places PCOS patients at a high risk for cardiovascular disease and diabetes at an earlier age. One study found that waist circumference exceeded 88 cm in 80% of the PCOS patients in the study, HDL cholesterol was less then 50 mg/dl in 66%, triglycerides were 150 mg/dl or greater in 32%, and blood pressure was 130/88mmHg or greater in 5% (4).
Cardiovascular disease is more common in patients with PCOS. It has been calculated that based on the risk profile, women with PCOS have a 7-fold increased risk for myocardial infarction (2). Visceral distribution of body fat is of greater consequence to the metabolic effects of insulin resistance then obesity per se (7). Central obesity and insulin resistance lead to an altered lipolytic response to insulin, with impaired suppression of release of free fatty acids from adipose tissue. An increase flux of free fatty acids from central sites enter the portal circulation, increasing the availability of substrate to the liver for triglyceride production.
PCOS women also have impaired fibrinolytic activity with increased circulatory levels of plasminogen activator inhibitor PAI-1. Elevated PAI-1 levels are associated with insulin resistance and are considered to be an independent cardiovascular risk factor by increasing the risk of intravascular thrombosis. In PCOS, increased PAI-1 levels are also associated with insulin resistance (2).
Also, women with PCOS exhibit increased activity of hepatic lipase, an enzyme responsible for the conversion of large lipoprotein particles to smaller, more atherogenic species (16). This explains why PCOS patients exhibit reduced concentrations of high density lipoprotein cholesterol and increased levels of atherogenic, small, low density lipoprotein. The combination of decreased HDL and increased LDL is strongly linked with cardiovascular disease. Most of the metabolic and other abnormalities discussed previously are likely to contribute to this risk. Due to the high incidence of PCOS in the general population, and because cardiovascular disease is the major cause of death in older women, the prevention of cardiovascular disease in women with PCOS should be a serious public health priority.
The metabolic syndrome population has a higher prevalence of glucose intolerance. PCOS patients, because of insulin resistance are at a high risk of glucose intolerance, thereby making them more vulnerable to fit into this metabolic syndrome population. One study found that 31% of reproductive age women with PCOS have impaired glucose tolerance and 7.5 % have diabetes. Therefore, patients with PCOS and the metabolic syndrome are at an increased risk for the development of type 2 diabetes. In the presence of peripheral insulin resistance pancreatic B-cell insulin secretion increases in a compensatory fashion. Non-insulin dependant diabetes develops when the compensatory increase in insulin levels is no longer sufficient to maintain euglycemia (3). Diabetes prevention should be considered for these patients.
Current and Future Treatments
The cheapest and safest therapy that has shown benefit in PCOS is lifestyle modification and weight loss. Weight loss through diets that are low in fat or low in carbohydrates may be beneficial. Weight loss causes a reduction in insulin resistance, which improves metabolic consequences of PCOS. There may be extra benefits to following a diet low in carbohydrate. Many of the indicators of the metabolic syndrome respond to reduction in dietary carbohydrate. Carbohydrate restriction is one of several strategies for reducing body mass but even in the absence of weight loss or in comparison with low fat alternatives, carbohydrate restriction is effective at ameliorating high fasting glucose and insulin, high plasma triglycerides, low HDL and high blood pressure (14). In addition, low fat, high carbohydrate, diets have been long known to raise plasma triglycerides, lower HDL, and in the absence of weight loss, may worsen glycemic control (14). Data from the literature suggests that a patient with more then two of the criteria for the metabolic syndrome or the combination of high TAG/HDL ratio should try carbohydrate restriction as a first strategy. Patients need to be educated on these findings.
Physical exercise, as a lifestyle modification, can benefit PCOS patients by helping sustain weight loss as well as increasing glucose disposal and muscle sensitivity to insulin. The Diabetes Prevention Program performed a study where the effect of lifestyle modification was compared to placebo in obese patients with impaired glucose tolerance. The lifestyle modification in the study involved approximately a 7% weight loss and 20 minutes of brisk walking each day. This modest lifestyle modification reduced the risk of diabetes by 58% (12). A 3 to 6 month trial of aggressive lifestyle modification may be a prudent first step before considering an insulin sensitizer (12).
Weight loss may be difficult to achieve and maintain as evidenced by millions of obese children and adults. The American Obesity Association states that 64.5 % of US adults are overweight, and 30.5 % are obese. Increased physical activity and dietary modification are the cornerstones to successful weight loss and cardiovascular risk reduction (12). It is important to guide patients to implement both of these strategies simultaneously. Patients should also be prompted to reduce sedentary behaviors. In a 1997 survey, adult women spent an average of 34 hours per week watching television (12). In one study, each 2 hour/day increment in television watching was associated with a 23% increase in obesity and a 14% increase in the risk of type 2 diabetes mellitus over 6 years (12).
Insulin sensitizing agents have been studied in the treatment of PCOS because insulin resistance seems to play such a dominant role in both PCOS and the metabolic syndrome. There may be potential utility in using insulin sensitizers to delay or prevent the onset of type 2 diabetes in PCOS patients. A biguanide, metformin, has been the most commonly used. Metformin is also used in the treatment of noninsulin dependent diabetes. Metformin increases peripheral glucose uptake and decreases hepatic glucose production. One study suggests that metformin could result in subtle improvements in both hepatic insulin extraction and insulin sensitivity in PCOS subjects, which together could lead to a significant decrease in hyperinsulinemia (11). Another study found that after metformin treatment, fasting plasma insulin showed a decrease and serum HDL cholesterol was significantly increased (10). Metformin is a beneficial drug, because it does not cause weight gain like the thiazolidinediones (9). The beneficial effects of metformin were independent of changes in body weight. Authors of a metformin study performed the study in both obese and nonobese PCOS patients, indirectly confirming that effects of metformin were not dependent on weight loss (10).
The thiazolidinedione class consists of troglitazone, pioglitazone, and rosiglitazone. This class has also been studied. The thiazolidinedione class works at the level of the peroxisome proliferators-activated receptor gamma to directly improve insulin action (13). These drugs decrease insulin resistance and hyperinsulinemia and improve dyslipidemia as well as blood pressure in patients with impaired glucose tolerance or diabetes. Troglitazone improves muscle insulin sensitivity, but was taken off the market because of adverse effects on hepatic function (hepatotoxicity). Troglitazone was beneficial in PCOS patients because the drug improved hyperandrogenemia, and insulin resistance despite an average 1 kg weight gain (13). In a study, troglitazone resulted in significant improvements in insulin action in PCOS women. Increases in insulin sensitivity were significant at both a 200 and 400 mg dose, but were much more marked at the 400 mg dose then at the 200 mg dose (3). The newer congeners, pioglitazone and rosiglitazone are effective for the metabolic syndrome.
Polycystic ovarian syndrome is a commonly encountered endocrinopathy in women of reproductive age. With the appreciation of the important role insulin resistance play in PCOS, proper identification has become increasingly important. Patients with polycystic ovarian syndrome are at high risk for the metabolic syndrome. Providers do not often appreciate that the syndrome is associated with significant morbidity in terms of reproductive as well as nonreproductive events (2). These patients are at an increased risk for cardiovascular disease and type 2 diabetes. Providers need to be aware of the prevalence of the metabolic syndrome in these patients in order to use precautionary measures to prevent cardiovascular disease and type 2 diabetes. If diagnosed early and properly managed with lifestyle modification and/or insulin sensitizers, the onset of cardiovascular disease and/or type 2 diabetes may be delayed or prevented.
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