METABOLIC SYNDROME

The metabolic syndrome in postmenopausal women

By Benjamin J. Ansell, MD

Although nearly 40% of women have metabolic syndrome and the incidence is rising, the condition remains underdiagnosed. Clinicians who treat postmenopausal women should increase their awareness of the metabolic derangements associated with the syndrome and consider them when weighing hormone therapy options.

Coronary heart disease (CHD) is the number one killer of American women, and yet most women do not perceive themselves to be at risk. The prevention of CHD in women is usually made more difficult by the absence of symptoms prior to a myocardial infarction (MI) and a relatively high risk of sudden death as the initial presentation of the disease.¹ Furthermore, our prevention and treatment strategies have focused on a paradigm reflecting the presentation of coronary disease in men. While men experience slightly greater risk of MI prior to age 65, women surpass men in coronary risk after this age.² Overall now, American women have slightly more heart attacks than men, and a slightly higher fraction of women than men die from heart disease.^2,3 The relative importance of CHD is evident when one considers that heart disease kills 37% more American women than all types of cancers combined, including about 10 times more than die from breast cancer.³

At any age, an American woman is more likely to die from heart disease than from breast cancer. Still, many women do not feel themselves to be at risk for heart attack. A Gallup poll conducted for the National Center for Health Statistics showed that 40% of women perceive breast cancer as their greatest health threat, compared with just 4% who expect to die from heart disease.⁴ The Acquired Immune Deficiency Syndrome (AIDS) presents as great an apparent health concern as CHD, cited by 4% of the respondents. In reality, the cause of death for 30% of women is heart disease, compared with 4% from breast cancer and fewer than 1% from HIV.³

Likely contributing to the low perception of CHD risk in women are a number of asymptomatic risk factors that are more predictive of CHD in women than in men. These include type 2 diabetes mellitus, low levels of high-density lipoprotein (HDL) cholesterol, and elevated serum triglycerides.⁴ Furthermore, more than half of women over age 45 have elevated blood pressure. Smoking rates are also declining more slowly in women than in men.⁴ Given that coronary disease is especially likely to present with sudden death in women, primary prevention is particularly critical.⁵

The metabolic syndrome

One of the major predisposing factors for CHD is the metabolic syndrome, a myriad of subtle risk markers especially common in postmenopausal women highlighted in the recently updated National Cholesterol Education Program Adult Treatment Panel III (ATP-III) guidelines.⁶ The syndrome is characterized by mild abnormalities in three or more of the following parameters: abdominal girth, blood pressure, fasting glucose, triglycerides, and HDL cholesterol (Table 1). Other factors common in the metabolic syndrome include abnormal markers of inflammation and coagulation. Together, these multiple subtle risks portend an increased risk that approaches that seen with hyperlipidemia.⁷ In many ways, the metabolic syndrome is a precursor to the development of frank diabetes, and abnormalities of insulin function, insulin secretion, and serum glucose levels are among the earliest manifestations of both conditions.⁸

TABLE 1
Clinical characteristics of the metabolic syndrome as defined in NCEP ATP-III

Because the metabolic syndrome is defined by a collection of risk factors, it can present in a varied fashion among different patients. Some display obvious hypertension, others have abnormalities of fasting glucose, while still other populations manifest the polycystic ovarian syndrome. Although there is some variation in the phenotypic patterns of the metabolic syndrome, obesity is present in nearly all affected individuals.⁹

As the epidemic of obesity in America worsens, the prevalence of the metabolic syndrome continues to rise. Overall, 47 million people—or 24% of the adult population—have the metabolic syndrome, and by age 60 nearly 40% of women have the condition.⁹

Lipids at menopause

At menopause, most women experience a worsening in their lipid profile, manifested by increasing levels of low-density lipoprotein (LDL) cholesterol and triglycerides, and decreasing concentrations of HDL cholesterol.^10-12 While some features of the metabolic syndrome worsen with traditional forms of hormone replacement therapy (HRT), effects on the lipid profile are variable among different regimens.^13,14 Most hormone formulations raise levels of serum triglycerides, a risk factor for CHD especially predictive among women in the Framingham Heart Study.¹⁵

The assessment of CHD risk associated with hypertriglyceridemia is difficult given several different populations of triglyceride-rich particles (including very-low-density lipoprotein [VLDL] and chylomicrons), controversy as to whether postprandial or fasting levels of triglycerides are more representative of risk, and association between elevated triglycerides, hypertension, insulin resistance, and low levels of HDL cholesterol. Furthermore, most patients with serum triglyceride concentrations exceeding 100 mg/dL display smaller, denser LDL cholesterol particles.¹⁶ Small, dense LDL cholesterol appears to contribute to excess CHD risk by increased susceptibility to oxidation (an initiating step in atherosclerosis), increased vascular permeability to LDL cholesterol (allowing incorporation into plaques), and decreased affinity for the LDL receptor in the liver (limiting LDL clearance and reverse cholesterol transport).¹⁷

Although not characterized as an independent risk factor in the ATP-III guidelines, hypertriglyceridemia is nonetheless recognized as an important target for intervention. Clinical trials such as the Helsinki Heart Study and the Veterans Administration HDL-Intervention Trial that achieved coronary risk reduction in association with significant reductions in hypertriglyceridemia provide the basis for this recommendation.^18,19 ATP-III classifies optimal serum triglyceride levels as less than 150 mg/dL, a more strict definition than previous guidelines offered. When serum triglycerides are elevated above 200 mg/dL, ATP-III recommends a secondary goal of reducing "non-HDL" cholesterol (equal to the total minus the HDL cholesterol concentration) to a level no more than 30 mg/dL above an individual's LDL target. This additional objective recognizes the importance of all apolipoprotein B-associated cholesterol particles, most especially VLDL, in potentiating atherosclerosis.

Implications for HRT

The role of HRT in prevention of CHD, long considered obvious given multiple supportive lines of epidemiologic evidence, is being challenged by recent clinical trial data. Numerous studies have shown an early hazard of MI in the first 6 to 12 months after the initiation of HRT in postmenopausal women.²⁰ This was also seen in two placebo-controlled trials: the Heart and Estrogen Replacement Study (HERS) evaluating conjugated equine estrogen (CEE)/medroxyprogesterone (MPA) in CHD patients and the CEE/MPA arm of the Women's Health Initiative.^21,22 Two other trials showed no significant effect on coronary event rate: (1) a randomized, controlled (but not blinded) trial showed a 49% increased risk (not reaching statistical significance) of coronary events in women with angiographic ischemic heart disease when treated with transdermal HRT, and (2) the Estrogen Replacement and Atherosclerosis (ERA) trial assessing CEE with/ without MPA versus placebo, showing similar atherosclerotic progression and event rates in all three treatment groups.^23,24

The sobering realization that HRT is not, as once thought, the optimal CHD prevention strategy in postmenopausal women is made worse by the recognition that well-defined risk reduction strategies are underutilized in this population. For example, most dyslipidemia went untreated in HERS.²⁵

At the same time, it is important to ensure that appropriate usage of HRT for management of postmenopausal symptomatology does not itself jeopardize coronary risk. Toward that end, newer HRT regimens are showing promise in producing favorable effects on blood lipids (especially triglycerides) and blood pressure. Transdermal preparations have more favorable lipid effects than oral options, especially relating to triglycerides. For example, a recent study showed that a once-weekly patch containing a combination of 17ß-estradiol (E₂) and levonorgestrol lowered total cholesterol, LDL, and triglyceride concentrations by 12% to 22%, 4% to 12%, and 13% to 26%, respectively. HDL cholesterol also fell 2% to 5% with this regimen.²⁶ This compares favorably with transdermal E₂ alone, which produced no significant change in total cholesterol, HDL, LDL, or triglycerides in the same trial.

Similarly, the novel oral progestin drosperinone reduces serum triglycerides by 6% to 11%, even when used in combination with oral estradiol.²⁷ The combination with drosperinone, which also has antimineralocorticoid activity, is associated with a 9- to 13-mm Hg reduction in systolic blood pressure as well. Preliminary data also suggest that the selective estrogen-receptor modulator raloxifene in women with osteoporosis reduces the risk of coronary events.²⁸ Cardioprotective effects of this agent in a population with better-defined coronary disease risk factors are not known. Aggressive nonhormonal risk reduction strategies, typically involving statins, ACE inhibitors, and aspirin, are justified in all women at high risk for CHD.

Based on available data, HRT does not appear to be an appropriate strategy to reduce vascular risk. However, when HRT is used for other indications in women at lower cardiovascular risk, careful selection is required of both the regimen and the route of delivery to ensure that dyslipidemia and/or blood pressure is not worsened. The careful selection of women for HRT requires attention to a spectrum of often-subtle cardiovascular risk factors, such as the metabolic syndrome.

Conclusions

The metabolic syndrome often complicates the many physiologic consequences of menopause. While there is variability in presentation, the syndrome usually manifests with features of insulin resistance, a proinflammatory state, hypercoagulability, dyslipidemia with elevated triglycerides, depressed HDL-C, and small, dense LDL-C. In combination, these characteristics are associated with a 40% to 50% increased CHD risk, even though the definitions of these abnormalities encompass many patients with near-normal values. The metabolic syndrome illustrates how multiple, subtle risk factors predict a significant overall CHD risk. It also challenges the clinician to adopt strategies to manage menopause that do not exacerbate these metabolic derangements in women, and, if possible, improve them.

Dr. Ansell is on the speaker's bureau for Berlex Laboratories.

REFERENCES

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18. Frick MH, Elo O, Haapa K, et al. Helsinki Heart Study: primary-prevention trial with gemfibrozil in middle-aged men with dyslipidemia. Safety of treatment, changes in risk factors, and incidence of coronary heart disease. N Engl J Med. 1987;317:1237-1245.

19. Rubins HB, Robins SJ, Collins D, et al. Gemfibrozil for the secondary prevention of coronary heart disease in men with low levels of high-density lipoprotein cholesterol. Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial Study Group. N Engl J Med 1999;341:410-418.

20. Nelson HD, Humphrey LL, Nygren P, et al. Postmenopausal hormone replacement therapy: scientific review. JAMA. 2002;288:872-881.

21. Hulley S, Grady D, Bush T, et al. Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. Heart and Estrogen/progestin Replacement Study (HERS) Research Group. JAMA. 1998;280:605-613.

22. Rossouw JE, Anderson GL, Prentice RL, et al. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women's Health Initiative randomized controlled trial. JAMA. 2002;288:321-333.

23. Herrington DM, Reboussin DM, Brosnihan KB, et al. Effects of estrogen replacement on the progression of coronary-artery atherosclerosis. N Engl J Med. 2000;343:522-529.

24. Clarke SC, Kelleher J, Lloyd-Jones H, et al. A study of hormone replacement therapy in postmenopausal women with ischaemic heart disease: the Papworth HRT atherosclerosis study. BJOG. 2002;109:1056-1062.

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26. Shulman LP, Yankov V, Uhl K. Safety and efficacy of a continuous once-a-week 17 beta-estradiol/levo-norgestrel transdermal system and its effects on vasomotor symptoms and endometrial safety in postmenopausal women: the results of two multicenter, double-blind, randomized, controlled trials. Menopause. 2002;9:195-207.

27. Data on file with Berlex Laboratories.

28. Barrett-Connor E, Grady D, Sashegyi A, et al. Raloxifene and cardiovascular events in osteoporotic postmenopausal women: four-year results from the MORE (Multiple Outcomes of Raloxifene Evaluation) randomized trial. JAMA. 2002; 287:847-857.

Dr. Ansell is Director, UCLA Center for Primary Care-Based Cardiovascular Disease Prevention, Los Angeles, Calif.

Key points

• The metabolic syndrome, which is common in postmenopausal women, is a major predisposing factor for coronary heart disease.

• A patient with metabolic syndrome may present with a variety of subtle risks, such as hypertension, abnormalities in fasting glucose, and polycystic ovarian syndrome. Virtually all such patients are obese.

• Aggressive nonhormonal risk reduction strategies such as statins, ACE inhibitors, and aspirin, are justified in all women at high risk for CHD.

• When selecting candidates for HRT, consider the impact of often-subtle cardiovascular risk factors, such as the metabolic syndrome.

Benjamin Ansell. The metabolic syndrome in postmenopausal women.

Contemporary Ob/Gyn

May 1, 2003;48:77-83.