How Oral Estrogen Impacts Cardiovascular Risk After Menopause

Menopause often includes a range of unpleasant symptoms, like hot flashes, night sweats, sleep disturbances, and mood changes. Unfortunately, the change of life also brings a higher risk for heart disease. Estrogen therapy mitigates these effects, but not for every patient. In addition, some forms of estrogen come with more significant risks than others.

The Women’s Health Initiative (WHI) shed light on the pitfalls of aggressive menopause hormone therapy, particularly in older women with cardiovascular histories.¹ As a result, today’s physicians have more considerations to weigh before selecting the best treatment options.

Quantifying the Risks

Health care providers can reduce potential upticks in cardiovascular events by choosing the route of estrogen administration carefully. Although preferred by many patients, oral estrogen is associated with a 19% higher risk for hypertension than vaginal creams or suppositories and a 14% higher hypertension risk than transdermal estrogen creams.² Fortunately, these different forms of estrogen are equally effective, so providers can educate patients on choosing their safest option.¹

Cerebral stroke rates do not increase for women receiving menopause hormone therapy who are aged younger than 60 years or within 10 years of starting menopause.³ However, menopause hormone therapy does raise the risk for ischemic stroke, but not hemorrhagic stroke, in women aged over 60 years. As a result, experts advise transdermal administration and lower-dose menopause hormone therapy to mitigate this risk while still supplying patients with the benefits of estrogen therapy.

After age 60 years, the risk for venous thromboembolism increases for all women. Additional risk factors include BMI, history of thromboembolism, and genetic factors, particularly the factor V Leiden mutation.³ Menopause hormone therapy almost doubles the risk for venous thromboembolism in women aged 60 years and older, particularly during the first year of treatment. By increasing thrombin activity and downregulating plasmin activity, oral estrogen increases risk for thromboembolism for at-risk groups. Adding progesterone to estrogen therapy increases this risk more than estrogen alone.

There’s a marked discrepancy between the risk for coronary artery disease (CAD) and menopause hormone therapy for women of different age groups. While some studies suggest a preventative effect in those under the age of 60 (28% reduction), studies that included older patients showed no primary prevention and a 50% to 80% higher risk for CAD during the first year of treatment, which declined as treatment continued. Researchers concluded that menopause hormone therapy initiated within 10 years of menopause is associated with a 48% reduction in cardiovascular mortality.³ However, the reasons for initiating menopause hormone therapy should not be solely for CAD prevention.³

Studies on estrogen-only therapy show that conjugated equine estrogen promotes hypertension more than estradiol. In addition, longer durations and higher doses of estrogen increase hypertension risk.⁴ One of the most common complaints of menopause is vasomotor symptoms, including hot flashes. Low-dose menopause hormone therapy is similarly effective for this symptom as standard doses.³ An individualized and conservative approach to treatment during and after menopause should guide decisions about the proper duration, dosage, and administration of menopause hormone therapy. It all starts with appropriate screening.

Screening for the Right Menopause Treatments

When initiated during the first 10 years of menopause, menopause hormone therapy helps prevent diabetes, metabolic syndrome, and cardiovascular disease. It can also lower the risk for colon cancer and, potentially, Alzheimer’s.¹ However, certain patients may be risking cardiovascular events by using menopause hormone therapy. Therefore, some absolute contraindications to menopause hormone therapy related to the cardiovascular system include congenital coagulation disorders, acute myocardial infarction, acute stroke, and unstable hypertension.¹

Physicians must conduct a thorough examination before prescribing menopause hormone therapy. Aside from assessing the indications and contraindications, prescribers should evaluate alcohol and smoking history, along with significant family history (particularly for cardiovascular disease and venous thromboembolism).³ Lipid tests, blood pressure, height and weight, thyroid function tests, and blood glucose screenings can also help identify cardiovascular risk factors. Additionally, customized tests may be necessary for individual risk factors.

Follow-ups every 1 to 2 years can help catch any concerning changes and allow for adjustments. Instructing patients to monitor their health between appointments (such as by taking periodic blood pressure readings at home) can be a proactive and collaborative approach to managing risk.

According to a 2022 article in Global Health Journal, “To reduce the risk of venous thromboembolism and stroke, transdermal estradiol (gels, patches,) should be used, in free combination with progesterone or dydrogesterone as ‘golden standard’ in patients with increased risk.”¹ Because the liver doesn’t process transdermal estrogen, it is more suitable for women with diabetes, high blood pressure, and other cardiovascular risk factors.³ Ultimately, hormone therapy should be prescribed with adjunct therapies and lifestyle changes based on the severity and frequency of menopause symptoms to improve quality of life and minimize potential harm.³

Alternative Therapies to Consider

The ideal candidate for menopause hormone therapy is aged 60 years or younger, are 10 years or less from the onset of menopause, and otherwise healthy with no history of cardiovascular disease.⁵ This period is frequently called the “window of opportunity” for menopause hormone therapy. However, as any practicing physician knows, ideal patients are rare. Postmenopausal women need solutions to manage their symptoms, even if their age or medical history makes menopause hormone therapy too risky. As women live longer and obesity rates continue rising, heart health becomes an even more critical consideration for postmenopausal patients.⁶

Aside from recommending a non-oral route for estrogen administration, physicians can mitigate cardiovascular risks by exploring different options, including non-hormone-derived drugs and herbal supplements.¹ For instance, vasomotor menopause symptoms may improve with off-label use of citalopram, clonidine, desvenlafaxine, escitalopram, gabapentin, opipramol, paroxetine, and venlafaxine.

Tibolone is a combined steroid and derivative of 19-nortestosterone.³ After transformation in the liver and stomach, tibolone has characteristics of androgen, progesterone, and an estrogen metabolite. Tibolone is a selective tissue estrogen activity regulator because it reduces estrogen activity in the breast tissue, making it a safer option for those with a breast cancer risk or history. It helps with menopausal symptoms, including headache, libido, insomnia, osteopenia, hot flashes, urinary symptoms, and vaginal dryness. Tibolone also lowers total cholesterol and does not appear to increase the risk for venous thromboembolism or CAD in at-risk patients aged older than 60 years. However, older patients may still have a higher stroke risk.

The herbal product black cohosh (Cimicifuga racemosa) also helps through the activation of the serotonin transmitter system.¹ But health care professionals should be aware of the potential contamination of some preparations, which may warrant liver function monitoring with long-term use. Finally, other forms of Chinese Traditional Medicine, including acupuncture, may be effective menopause management tools in patients contraindicated for menopause hormone therapy.

Encouraging Successful Lifestyle Changes

It is no secret that regular exercise is essential, especially with aging. Encouraging patients to engage in consistent physical activity may improve both their postmenopausal symptoms and cardiovascular risk.⁶ Studies show that women who exercise regularly don’t experience the same age-related resting metabolic rate decline as their sedentary counterparts.⁶ In addition, weight loss interventions lower the incidence of hot flashes.⁶

Social support and accountability can make all the difference in a patient’s success with lifestyle interventions. Thinking beyond traditional one-to-one patient-provider counseling sessions offers opportunities for better outcomes, especially in patients for whom menopause hormone therapy is contraindicated. Therefore, group nutrition classes, walking programs, or stress management clinics are some additional ways beyond menopause hormone therapy for doctors to treat patients and promote heart health and well-being during menopause.