2007

Estrogen and the Heart Revisited: Resolving Conflicting Messages About Cardiovascular Risk and the Role of Estrogen Therapy in Menopause

Points to Remember

• Recent data suggest that timing of initiation of hormone therapy is an important determinant of benefits and risks.
• Estrogen therapy started early in menopause appears to be associated with fewer coronary heart disease risks and with potential heart protection.
• Recommendations are to prescribe the lowest dose for the shortest duration needed for goals of therapy.
• Mayo Clinic is 1 of 9 centers in the United States investigating estrogen's effects on heart disease in early menopausal women through the Kronos Early Estrogen Prevention Study, or KEEPS.

The Challenge

In recent years, conflicting reports have confused health care providers and patients about the role of estrogen therapy in managing menopausal symptoms. Where once estrogen was routinely prescribed to women in early menopause, reports in 2002 and 2003 from the Women's Health Initiative presented an estrogen risk profile of increased cardiovascular events in women given combination estrogen-progestin therapy. The fact that the study population was older and many years postmenopausal was often not conveyed fully in media reports of the data, and few women early in menopause were included in the trial. As a result, confusion arose over the role of hormone therapy for the typical woman considering estrogen for menopausal symptom relief.

Extracting Clarity From Confusion

A "unifying hypothesis" has emerged that reconciles data from recent clinical trials with past observational studies, clinical trials, and animal and basic science data. When evaluating the potential impact of hormone therapy on coronary heart disease (CHD), the main impressions based on this hypothesis are 2-fold:

• When hormone therapy is started years after the onset of menopause, it can increase CHD events early, likely due to vulnerable plaque, followed later by benefit, due to remodeling of stable plaque.
• When hormone therapy is started early in menopause — the period during which vulnerable plaque is usually less extensive — a decline in CHD is expected.

This hypothesis is now being tested directly in a clinical trial.

The Multicenter KEEPS Trial

Mayo Clinic is 1 of 9 centers in the United States investigating estrogen's effects on heart disease in women early in menopause through the Kronos Early Estrogen Prevention Study. KEEPS has enrolled women between the ages of 42 and 58 years who are within 6 months to 3 years of their last menstrual period and in good health. They are randomly assigned to intervention with estrogen pill, estrogen patch, or placebo. Those assigned to estrogen also take micronized progesterone pills by mouth. Investigators will measure multiple cardiovascular, bone, and neurologic parameters, including coronary artery calcification, carotid artery intimal medial thickness, bone density testing by dual-energy x-ray absorptiometry, cognition, blood coagulation, and sleep measures over 4 years of the study.

Tips for Customizing Hormone Therapy in Early Menopause

• Timing of initiating therapy is key. Starting it in early menopause seems to provide more benefit; starting it later in life is associated with greater risk.
• One dose does not fit all. The dose should be adjusted to symptom response and goals of therapy. Signs of excess estrogen include nausea, headaches, breast tenderness, and abdominal bloating. Signs of insufficient estrogen include inadequate symptom relief.
• Customize therapy. The availability of very low-dose estrogen products as well as different routes of administration, including pill, patch, cream, gel, and vaginal ring, provide greater flexibility for individualized therapy.
• Reduce risk for venous thromboembolism. Transdermal estradiol is often preferred over oral formulations because of its reduced risk for venous thromboembolism compared with oral estrogen and more even estrogen dosing. Also it does not elevate triglyceride levels.
• Use the lowest dose. US Food and Drug Administration (FDA) guidelines are to prescribe the lowest dose of estrogen for the shortest duration needed for treatment goals; follow up regularly, adjust the dose, and monitor for potential adverse effects.
• Bioidentical hormones are options to consider. Frequently women request "bioidentical" hormones. There are multiple conventional, FDA-approved hormone therapy formulations that are plant-based and biochemically identical ("bioidentical") to endogenous hormones, including some oral and most transdermal estradiol formulations and oral micronized progesterone.