Menopausal Medicine: For clinicians who provide care for women

The Metabolic Syndrome: Impact on women and considerations for treatment

Department of Obstetrics and Gynecology, Division of Reproductive Endocrinology and Infertility, University of Alabama at Birmingham, Birmingham, Alabama

Introduction

Metabolic syndrome (MetS) refers to a constellation of factors that increase an individual’s risk of cardiovascular morbidity and mortality as well as type 2 diabetes mellitus (T2DM). The term MetS is relatively new but appears to have been initially defined, in a formal way, by the Swedish physician Eskil Kylin. In 1923, Dr Kylin reported on a metabolic disorder characterized by hypertension, hyperglycemia, and hyperuricemia.¹ More recently, in 1988, Gerald Reaven and his colleagues identified a clustering of risk factors that they coined Syndrome X.² Reaven was among the first to suggest that insulin resistance and obesity were directly linked to this clustering of metabolic risk factors that predispose an individual to cardiovascular disease (CVD) and T2DM.

In the late 1990s, the World Health Organization formally defined MetS but the criteria that appear to have gained the widest acceptance are those set forth by the National Cholesterol Education Program (NCEP) Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III, or ATP III).³ The American Association of Clinical Endocrinology (AACE) and the International Diabetes Foundation (IDF) have also defined MetS based on their differing opinions regarding what constitutes the absolute thresholds for the various criteria, such as waist circumference or lipid level.

There is also a lack of agreement regarding which of the criteria are most clinically relevant to provide a diagnosis of MetS. Nevertheless, each organization agrees on 4 distinct criteria for making the diagnosis of MetS. These include central adiposity, hypertension, glucose intolerance, and dyslipidemia. TABLE 1 shows the most widely used criteria as defined by NCEP-ATP III, including new ethnic-specific criteria.⁴

NCEP-ATP III Guidelines for Diagnosis of MetS

Importance of diagnosis

It has been suggested that the importance of diagnosing MetS is to identify and reduce or negate its effects on the development of CVD and T2DM. The value of collating these individual risk factors into a single entity appears to be its ability to assist the clinician in identifying and intervening in that segment of the population at increased risk of CVD (eg, coronary heart disease [CHD], peripheral vascular disease, and stroke) and T2DM.

The question has been raised as to whether the risk of atherosclerotic CVD associated with MetS is greater than the sum of its risk factors. Epidemiologic studies strongly suggest that multiple risk factors, such as those that comprise MetS, raise an individual’s health risks more than the sum of the accompanying single risk factors.⁵ Additionally, several metabolic risk factors (prothrombotic state, proinflammatory state, and elevated triglycerides) are not included in standard algorithms but undoubtedly are independent risk factors for cardiovascular events. Since MetS is often progressive and culminates in CVD and T2DM, the syndrome’s long-term risk is likely underestimated at any one time. It seems, then, that the risk accompanying MetS is greater than the sum of its measured components.⁵

MetS vs 10-year risk assessment

MetS, however, is not a reliable tool for global risk assessment for atherosclerotic CVD in the short term (such as 10-year risk). It does not account for all of the risk factors involved in the standard risk-prediction algorithms (age, gender, total cholesterol, and smoking status). Thus, algorithms such as the Framingham risk scoring system better determine a 10-year risk assessment.⁵ The British Regional Heart Study showed that MetS was inferior to the Framingham Risk Score in predicting total CHD or major CVD over 20 years but was superior in predicting T2DM.⁶ Jassal et al examined the sex-specific contributions of MetS and microalbuminuria to CVD and CHD mortality.⁷ In their cohort, they found that microalbuminuria and MetS together was a more powerful predictor of CVD mortality than either alone in women but not in men. This study provided new evidence that screening for microalbuminuria in older women (>40 years) may identify more patients at high risk of CVD mortality than can be identified by risk factors included in MetS alone.⁷

The CVD and MetS connection

CVD is the number one cause of mortality in women. Studies have shown an association between the diagnosis of MetS and an increase in an individual’s risk for CVD.⁸ The San Antonio Heart Study highlighted gender differences in CVD risk in patients diagnosed with MetS. The hazard ratios for cardiovascular mortality in patients with ATP III-defined MetS were 4.6 (95% confidence interval [CI], 2.35-9.21) in women and 1.82 (95% CI, 1.14-2.91) in men. Clear gender-specific differences have been shown in MetS prevalence, presentation, and risk, with women having more negative CVD outcomes.^8-14 Of great interest is whether the diagnosis of MetS in menopausal women is affected by events that occurred in their reproductive years. Unique modifiers of MetS exist for women and may include pregnancy, lactation, gestational diabetes mellitus (GDM), preeclampsia, hormonal contraceptive use, polycystic ovary syndrome (PCOS), and menopause.⁹

Prevalence

According to US Census 2000 data, MetS is present in 47 million residents.¹⁵ Although the age-adjusted prevalence was similar in men (24%) and women (23%), gender equality was lost when comparisons were made within ethnic groups.⁹ Whereas Caucasian women were found to have a lower prevalence of MetS than do Caucasian men, this trend did not hold true for either African American or Mexican American women.¹⁵ The Census 2000 data revealed that 57% more African American women and 26% more Mexican American women have MetS than do men in the same ethnic group (FIGURE 1).⁹

When the National Health and Nutrition Examination Survey (NHANES) data from 1988-1994 were compared with NHANES data from 1999-2000, it was noted that the age-adjusted prevalence of MetS increased by 23.5% among women (P=.021) and 2.2% among men (P=.831). Based on the increasing prevalence of MetS in women, it appears that the similarity in age-adjusted prevalence between men and women, regardless of ethnicity, will likely be lost over time.⁹ Ford et al evaluated the causes of the increasing prevalence of MetS among women in the United States and found that increases in blood pressure, waist circumference (surrogate for central adiposity), and triglycerides have occurred.¹⁶

The American Heart Association (AHA) reports that 1 out of every 2 women will develop some form of CVD during their lifetime.¹³ As previously stated, CVD is the number one killer of women in the United States and has been estimated to affect approximately 42 million US women over the age of 20. It is disconcerting to think that two-thirds of cardiac deaths (66%) occur without individual awareness of the risk of CVD. To gain some perspective regarding the significance of CVD in women, the 2008 update of the AHA Heart Disease and Stroke Statistics showed that 1 in 30 female deaths were attributed to breast cancer, whereas 1 in 2.6 women died of CVD.¹³ Put another way, CVD claims more lives each year than the next 5 leading causes of death (cancer, Alzheimer’s disease, chronic respiratory disease, accidents, and diabetes mellitus) combined.¹³

Presentation of MetS in women

Obesity

Abdominal obesity, or central adiposity, is the manifestation of increased visceral storage of adipose tissue and is highly associated with MetS.^11,17 Clinically, obesity most recently has been defined by the body mass index (BMI) which is simply the person’s weight (kilograms) divided by her squared height (meters²) [BMI <24.9, normal weight; >25 but <29.9, overweight; and >30, obese]. BMI, however, does not account for the actual distribution of fat mass in an individual; it is this distribution of fat, one’s “body composition,” which determines metabolic risk.¹⁸ Abdominal visceral fat is thought to be the most deleterious from a metabolic standpoint, with abdominal subcutaneous fat imposing an intermediate risk. Notably, lower extremity adiposity may actually confer “metabolic protection.”¹⁹ Visceral fat, when compared to subcutaneous fat, is less sensitive to the action of insulin and causes the body to undergo lipolysis, releasing free fatty acids into the circulation; this ultimately leads to elevated serum levels of cholesterol and low-density lipoprotein (LDL), known to be independent risk factors for CVD.¹⁹

Premenopausal women tend to have a gynoid or “pear” shape, characterized by fat accumulation in the subcutaneous gluteal/femoral regions (buttocks/hips). It has been suggested that with the loss of estrogen at menopause, a woman’s body shape begins to change and becomes more android, or “apple,” in appearance. Although menopausal women are noted to have an increase in total body fat, with adipose distribution occurring between both visceral and subcutaneous depots, it is the visceral depot that preferentially gains a greater percentage of total fat.¹⁸ Older women gain approximately 1 pound of weight per year in the aging process, which occurs simultaneously with menopause. Studies show that women with an android body composition (increased central adiposity) have an increased risk of cardiovascular mortality and associated metabolic abnormalities such as glucose intolerance, insulin resistance, increased risk of T2DM, and dyslipidemia.^20,21

Central adiposity has been quantified in a variety of ways, including dual x-ray absorptiometry (DXA) and computed tomography (CT). Although both DXA and CT can provide accurate measures of central adiposity, these modalities are labor- intensive, time-consuming, costly, and of limited availability in the office setting. Waist circumference has been shown to directly predict MetS²² and act as a surrogate marker for central adiposity. Waist circumference greater than 88 cm (34 inches) in a woman satisfies the MetS criterion as defined by the ATP III.

Over the past 20 years, the percentage of women with abdominal obesity has increased from 47.0% to 61.3% (P<.001).²³ The San Antonio Heart Study presents data that suggest that increases in BMI and waist circumference increase the risk of developing MetS to a greater degree in women than in men.²² Thus it appears that both the aging process and menopause result in an increase in total body fat as well as a change in body composition, which favors the development of MetS.

Hypertension

Hypertension increases the risk of CVD; its prevalence increases as a woman ages. Studies have shown an increase in hypertension in menopausal women even after correcting for age and body weight.¹⁴ The prevalence of hypertension in menopausal women also exceeds that of age-matched men.^10,24 There are several physiologic mechanisms that help to explain this phenomenon of increasing blood pressure in menopausal women.

It is known that estrogen prevents the conversion of angiotensin I to angiotensin II and decreases the sensitivity of angiotensin receptors, which favors vasodilatation.²⁵ With declining estrogen levels at menopause, the conversion of angiotensin I to angiotensin II is increased. Both plasma renin activity and sympathetic activity are also increased, which favors vasoconstriction and results in increased blood pressure.¹² Estrogen also enhances nitric oxide synthesis, promoting vasodilatation. In an estrogen-deficient state (menopause), this blood pressure–lowering mechanism would be lost. Thus, menopause may promote hypertension, contributing to MetS and the risk of CVD.

Glucose intolerance

Insulin resistance is defined as the inability of insulin to promote the uptake of glucose into skeletal muscle. Many investigators have suggested that insulin resistance is of greater significance than obesity in the pathogenesis of MetS.¹² However, insulin resistance is directly related to obesity, and hyperglycemia increases with increasing body fat.¹² Overt diabetes increases the risk of atherosclerosis to a greater degree in women than in men, secondary to worsening lipid profiles. Women with diabetes have greater increases in triglycerides and LDL with lower levels of high-density lipoprotein (HDL) compared to diabetic men.¹² Of note, premenopausal diabetic women have the same cardiovascular risk profile as diabetic men. With the decline in estrogen at menopause, women have a greater degree of insulin resistance. However, insulin sensitivity and glucose intolerance are not entirely explained by a woman’s hormonal status. There are now data showing that weight gain in women is a stronger predictor of impaired glucose tolerance than is menopausal status.¹²

Dyslipidemia

Premenopausal women have higher HDL levels than their age-matched male counterparts and, thus, are less likely to satisfy this criterion of MetS. Estrogen deficiency is associated with a more atherogenic lipid profile and is thought to be responsible for the increased CVD seen in menopausal women.¹² The decline in estrogen is known to result in increased triglycerides and increased total and LDL cholesterol, with a concomitant decline in HDL cholesterol. Thus, the increase in dyslipidemia after menopause increases the risk of development of MetS.

Polycystic ovary syndrome

PCOS is a disorder that is diagnosed in approximately 5% of reproductive-aged women. The accepted criteria for diagnosing PCOS are still undergoing debate. PCOS is defined in women with oligo- or anovulation, clinical or laboratory evidence of hyperandrogenism, and the exclusion of other endocrine disorders. Ultrasonographic finding of “multicystic ovaries” has recently been added to the criteria for PCOS.²⁶ The etiology of PCOS has not been elucidated fully at this time. Patients with PCOS are known to have many of the characteristics of MetS, including obesity, glucose metabolism abnormalities, and dyslipidemia. The prevalence of MetS in women with PCOS is twice as high as that of the age- and BMI-matched controls. Women with PCOS also have a higher risk of T2DM and hypertension. Central obesity and dyslipidemia (including low serum HDL levels) are routinely found in women with PCOS. Thus, the diagnosis of PCOS during a woman’s adolescent and reproductive years places her at an increased risk of MetS throughout her lifetime.¹²

Treatment options for menopausal women with MetS

Lifestyle interventions

The increasing prevalence of obesity in menopausal women would seem to suggest that weight loss is a straightforward means of preventing MetS. One simply must create a negative energy balance; that is “burn more, eat less,” but this is quite difficult in practice. Estrogen deficiency brings about changes in fat distribution that increase the risk of MetS, T2DM, and CVD. The AHA published evidence-based guidelines in 2007 for CVD prevention in women. The cornerstone is lifestyle interventions, including smoking cessation, dietary modifications that “result in weight loss,” and an increase in physical activity. CVD risk can be reduced by as much as 82% by maintaining a healthy diet and body weight while engaging in regular physical activity. Dietary recommendations include a diet low in both saturated and trans saturated fat as well as a carbohydrate-controlled diet. Many of the risk factors associated with MetS are attenuated with weight loss. The Diabetes Prevention Program demonstrated that reducing body weight by only 7% was associated with a 58% reduction in T2DM.³⁰

Pharmacologic interventions

Targeted pharacologic interventions can address other major risk factors, such as insulin resistance, elevated blood pressure, and an abnormal lipid profile. Lowering of blood pressure with antihypertensive agents effectively reduces CVD risk in women. The pharmacologic treatment of dyslipidemia with fibrate or statin therapy is also beneficial in women for prevention of heart disease. For example, when a practitioner prescribes a statin for the treatment of hypercholesterolemia, it is recommended that use of the medication be combined with lifestyle changes such as diet and exercise, which will affect other risk factors. In addition, there is some evidence to suggest that statins, which are known to reduce inflammation, may also increase adiponectin levels (marker of insulin sensitivity),³¹ so in this way, other risk factors may be treated as well (TABLE 2).

A meta-analysis published in 2006 demonstrated global improvement in the individual components of MetS in menopausal women receiving hormone therapy (HT).³² A reduction in abdominal obesity, insulin resistance, and new-onset diabetes as well as improvement in the lipid profile and blood pressure in menopausal women receiving HT was noted. Menopausal women with T2DM who received HT were also found to experience an improvement in their insulin resistance and fasting glucose levels. However, this meta-analysis was limited in that various hormone preparations and doses were combined for analysis. Also, criterion measures were not used to assess body fat distribution and insulin sensitivity.

In a 2-year, randomized trial of postmenopausal women without diabetes, combined estrogen/progestin did not significantly affect visceral fat, subcutaneous abdominal fat, total body fat, or lean body mass. The trial used CT scans to assess body fat distribution and euglycemic hyperinsulinemic clamps to measure insulin sensitivity. Insulin sensitivity worsened by 17%, but this was reversed after discontinuing HT.³³ It is important to remember that HT is not currently indicated for prevention of chronic disease, including CVD and MetS.

Recommended Treatment Options for MetS

Future treatment for MetS

In the future, postmenopausal women may have new options for preventing MetS. Supplementation with soy isoflavones reduces the gain in subcutaneous abdominal fat in post-menopausal women.³⁴ Chromium picolinate supplementation attenuates body weight gain and visceral fat accumulation, while improving insulin sensitivity and glucose control in patients with T2DM.³⁵ Studies in rodents report that some botanicals may also improve components of MetS. Specifically, the botanical Russian tarragon reduces cholesterol and blood glucose levels. In addition, the botanical anthrocyanin (found in berries) improves insulin sensitivity, reduces fat deposition, and improves fatty acid uptake and oxidation in peripheral tissues.³⁶

Further studies are needed on these supplements and botanicals in perimenopausal and postmenopausal women before definitive recommendations can be made on their use in the prevention of MetS, optimal doses, and long-term safety (TABLE 3).

Recommended Treatment Options for MetS

Summary

Many features of MetS arise or worsen with the onset of menopause. Estrogen deficiency has been shown to negatively impact many of the criteria used to diagnose MetS. Estrogen deficiency appears to play a role in increasing central adiposity with or without actual weight gain. Menopausal women have a higher incidence of hypertension, dyslipidemia, and insulin resistance.

MetS is an increasingly prevalent disorder known to significantly enhance the risk of developing cardiovascular disease and diabetes. The syndrome is defined by a constellation of cardiac risk factors that include obesity, atherogenic dyslipidemia, hypertension, and insulin resistance. There are several unique features of MetS in women. An insulin-resistant state associated with both PCOS and increased abdominal fat may contribute to the development of MetS and increase cardiovascular risk. Menopause heralds a decline in circulating estrogen levels, which may increase cardiovascular risk through effects on adiposity, lipid metabolism, and prothrombotic state.

The key elements involved in managing MetS are dietary and lifestyle modification. Managing individual cardiac risk factors with the use of antihypertensive and lipid-modifying agents is also appropriate. Although HT could have beneficial effects on the components of MetS, current recommendations do not include HT for either primary or secondary prevention of CVD or for prevention of MetS. In the future, some supplements and botanicals (soy isoflavones, chromium picolinate, Russian tarragon, and anthrocyanins) may provide alternatives for preventing MetS in menopausal women.

Sexuality, Reproduction & Menopause ©2008 Quadrant HealthCom Inc.