‘What’s normal has changed’: Navigating menopausal hormone therapy as CVD risk grows
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For women experiencing disruptive, bothersome hot flashes, the use of menopausal hormone therapy — a one-time standard but later feared treatment option — is far from straightforward.
Decades after two landmark studies suggested HT may increase cardiovascular disease and cancer risk, followed by analyses that demonstrated the risk depended on factors including age and time since menopause onset, confusion persists about the risks and benefits of menopausal HT for treatment of moderate to severe vasomotor symptoms. As heart disease incidence among young women in the U.S. continues to rise, that confusion can be compounded for women with CV risk factors.
“Having lived through all these decades of being an estrogen cheerleader and moving to, ‘Yikes, maybe we were wrong,’ I think people are still afraid because the early release of the 2002 Women’s Health Initiative results scared people so much,” Cynthia A. Stuenkel, MD, MSCP, clinical professor in the department of medicine at the University of California, San Diego, told Healio | Endocrine Today. “Estrogen was the highest prescribed drug in America in the late 1980s and early 1990s, back when we thought that estrogen was going to prevent heart disease for all women at any state, even among those with heart disease. Now, clinicians are still afraid. More concerning, programs have stopped teaching about menopause and HT. We have 20 years now of young clinicians not learning about this.”
Recent data suggest menopausal HT for bothersome vasomotor or other symptoms is safe and appropriate for most women at low atherosclerotic CVD risk, whereas a nuanced approach is needed for intermediate-risk women. Yet, many clinicians are reluctant to prescribe HT for patients with symptoms of menopause due to uncertainty around evidence-based guidelines that support hormone use.
“The pendulum has swung widely on HT over the last several decades and this has created a lot of confusion,” JoAnn E. Manson, MD, DrPH, MACP, FAHA, chief of the division of preventive medicine at Brigham and Women’s Hospital and professor of medicine and the Michael and Lee Bell Professor of Women’s Health at Harvard Medical School, told Healio | Endocrine Today. “Even though the pendulum has come to rest in a much more appropriate place now, many clinicians, women and the lay public often are not aware of the new information.”
Changing HT guidance
At one time, menopausal HT was almost universally recommended, Leslie Cho, MD, director of the Cleveland Clinic’s Women’s Cardiovascular Center, and colleagues wrote in a review published in February in Circulation. With the publication of the Heart and Estrogen/progestin Replacement Study (HERS) and the WHI trial, both of which reported excess CV risk with HT, use of HT declined substantially.
For the WHI, researchers randomly assigned women aged 50 to 79 years without CVD to continuous combined oral conjugated equine estrogen (CEE) with medroxyprogesterone acetate or placebo; women without a uterus were randomly assigned to CEE alone or placebo. The initial findings suggested that compared with placebo, risks for coronary heart disease, stroke and venous thromboembolism, including pulmonary embolism, were increased with HT.
“You can’t un-ring a bell,” said Manson, a principal investigator for the WHI. “In 2002, when the WHI main findings for estrogen plus progestin were reported, there was tremendous alarm and confusion about the results. Many of those views and feelings have persisted. The rate of HT use declined by as much as 80%. At that time, many medical schools stopped teaching about menopausal HT in their curricula. Women and the general public have often had difficulty finding a clinician who has training and expertise in decision-making about HT.”
Subsequent analyses of the WHI, which were age-stratified with longer cumulative follow-up (median duration, 13 years) supported a more nuanced approach to HT, Cho said.
“The WHI initially showed that HT increases risk. That trial included women of all ages, women older than 60 years, those more than 10 years after menopause,” Cho said. “That scared everyone. But what we have learned since then — almost 20 years later — is that starting HT for younger women, and being mindful of HT type and for the shortest duration possible for symptom relief is actually quite safe. The nuanced approach is an important message to convey.”
During the past 20 years, the relationship of CVD risk with timing of menopause, initiation of HT and route of HT delivery has been better understood. Four major North American medical societies — the American College of Obstetricians and Gynecologists, American Association of Clinical Endocrinology, the Endocrine Society and The Menopause Society — now recommend HT for appropriate patients for the management of menopausal symptoms.
“No one recommends hormones for CVD prevention,” Cho said. “HT does not impact weight or lower heart disease risk. HT is recommended for bothersome menopausal symptoms.”
The Circulation review, led by the American College of Cardiology Cardiovascular Disease in Women Committee, along with leading gynecologists, women’s health internists and endocrinologists, states that ideal candidates for menopausal HT are women who are younger than 60 years or within 10 years of menopause onset, who have a 10-year estimated atherosclerotic CVD risk of less than 5% and do not have an increased risk for breast cancer or history of VTE.
“In the WHI, we did find evidence that younger and more recently menopausal women tended to have a more favorable benefit/risk profile with HT,” Manson said. “Women who were below the age of 60 years and within 10 years of menopause onset tended to have no excess risk for heart disease with HT, and, for estrogen alone, there was even a signal for lower risk for myocardial infarction and total coronary heart disease. The younger women given estrogen alone also tended to have a favorable pattern for all-cause mortality as well as the global index, which is the summary measure of all of the benefits and risks of HT.”
Options for intermediate-risk women
A more nuanced approach for HT is recommended for women at intermediate CVD risk, defined as those who have diabetes, who smoke or who have hypertension, obesity, metabolic syndrome or an autoimmune disease, among other risk factors.
Increasingly, the group of women who would be characterized as “intermediate risk” for CVD is becoming larger, according to Gina Lundberg, MD, FACC.
“Many people think they are low-risk women and they are not,” Lundberg, clinical director of the Emory Women’s Heart Center and professor of medicine at Emory University School of Medicine, told Healio | Endocrine Today. “About 90% of the people I talk to as a preventive cardiologist consider themselves ‘healthy,’ and it will be a postmenopausal woman who is overweight with high blood pressure, elevated cholesterol and a family history of CVD. I just counted five risk factors. How we determine risk as a physician is not always how the patient sees their risk.”
The presence of CVD risk factors alone does not preclude the use of HT, but a patient’s worsening CV risk profile around the menopause transition emphasizes the need to optimize primary prevention efforts, including lifestyle and pharmacologic management, Cho said.
“There are many HT formulations, including systemic hormones, transdermal estrogen and progesterone, vaginal estrogen,” Cho said. “The lowest risk is vaginal estrogen because it is minimally systemically absorbed. Transdermal HT seems to be associated with less of an increase in cholesterol and blood pressure and less risk for development of clots.”
Guidance does not recommend the use of non-FDA approved compounded bioidentical hormones, which are not FDA-regulated, Cho said.
“Women at intermediate risk — women with metabolic syndrome, hypertension that is treated, maybe prediabetes or well-controlled type 2 diabetes — our recommendation is that group, if they are within 10 years of menopause, would do best on a transdermal HT formulation,” Stuenkel said. “We suggest transdermal because we avoid first-pass metabolism by the liver, which can increase clotting factors, bump up blood pressure, triglycerides and C-reactive protein in women, which contributes to inflammation. That is increasingly more and more women in our population. What’s ‘normal’ has changed. Our new normal is women with all of these cardiometabolic conditions.”
How to assess CV risk
CVD is on the rise among women and at younger ages and increases with menopause. This makes risk stratification increasingly important when choosing therapies for menopausal symptoms, according to Stuenkel.
“Just as with decisions regarding lipid-lowering therapies, it seems reasonable to review and discuss with the patient the growing list of risk-enhancing factors when considering menopausal HT,” Stuenkel said, noting these have expanded to include adverse pregnancy outcomes and rheumatologic diseases.
Cho said CVD risk should be assessed via careful ascertainment of history and with a validated risk calculator to measure 10-year atherosclerotic CVD risk, such as the pooled cohort equation, which is the most commonly used.
“Women do not get CV risk assessments regularly,” Cho said. “They should be getting assessments just like men. This includes annual cholesterol testing, blood pressure checks, glucose testing, and questions about adverse pregnancy outcomes, which increase the risk for CVD. Ask, ‘Did you have gestational diabetes, preeclampsia or an early delivery?’”
Additionally, women should receive a weight check and undergo counseling on smoking cessation.
“These are common sense things, but unfortunately, most women get things like mammograms and OB/GYN checkups but not CVD screenings,” Cho said. “Yet, we know that the No. 1 killer for women is heart disease and not breast cancer or gynecological cancers.”
An evolving area is the concept of further risk refinement using a coronary artery calcium (CAC) score to assess coronary artery calcification, Michael Honigberg, MD, MPP, FACC, a cardiologist and researcher at Massachusetts General Hospital and assistant professor of medicine at Harvard Medical School, told Healio | Endocrine Today.
“This allows us to move beyond population-based risk calculators to the individual patient sitting in front of us,” Honigberg said. “It can be helpful if someone has zero to very minimal calcification; that implies, generally, fairly low short-term risk for coronary events. Then, you can feel better safely prescribing HT for symptom management. Secondarily, CAC is really helpful to determine whether someone would benefit from being on a statin. Exactly how CAC should be incorporated in HT assessment has not been rigorously tested or quantified.”
CV guidelines endorse using a CAC score for people in the “gray zone” for CV risk, considered to be between 5% and 20% risk over the next 10 years, Honigberg said.
“For that group, the guidelines say if there are uncertainties, consider a CAC score,” Honigberg said. “To apply that paradigm to HT, one might consider using CAC score for women who fall within the 5% to 10% risk group or the 5% to 20% risk group, particularly if there is any uncertainty. It can also be helpful for people with risk factors that may not be as readily captured. We preventive cardiologists often see patients with a scary family history of early-onset heart disease, for example. They may appear pretty low risk, by the calculators, but they have other risk factors that are not included in standard risk calculators, like high lipoprotein(a). For patients where you are worried there might be a mismatch between the [CV] risk calculator and other risk factors, CAC can be particularly helpful.”
Options for high-risk women
Menopausal HT remains the most effective treatment for vasomotor symptoms and should be considered in women at or around the time of menopause without contraindications; however, some women may not choose to or may not be candidates for HT.
Women who may not be good candidates for HT include those with prior estrogen-sensitive cancers; previous stroke, MI or pulmonary embolism; or severe active liver disease.
An updated position statement on non-HT options from The Menopause Society, published in May, includes several new recommendations and changes to reflect new evidence, namely the FDA approval of fezolinetant (Veozah, Astellas) to treat moderate to severe vasomotor symptoms caused by menopause. Fezolinetant is the first neurokinin 3 receptor antagonist approved by the FDA for treatment of moderate to severe vasomotor symptoms.
“Keep in mind we do not have a long-term track record on safety for fezolinetant yet,” Manson said. “However, it does seem to be safe. It does require monitoring of liver function; this may deter some people. But it seems to be safe and works through the hypothalamus. It inhibits the KNDy neurons, which are involved in vasomotor symptoms.”
In addition to fezolinetant, recommended treatments include cognitive-behavioral therapy, clinical hypnosis, selective serotonin reuptake inhibitors/serotonin-norepinephrine reuptake inhibitors, gabapentin, oxybutynin, weight loss, and stellate ganglion block for select patients.
“None of these nonhormonal treatments are quite as effective as estrogen; however, they are effective, and they are good alternatives, and it is great that there are nonhormonal options for women,” Manson said. “Many women are not candidates for HT, and some women just do not want to take hormones. They have anxiety about it or may be concerned about a family history they have.”
Shared decision-making key
Clinical guidance on menopausal HT is useful but should be paired with an individualized clinical approach, Stuenkel said. Assess patient symptoms, personal preferences and overall health status with three overarching questions:
- How bothered is she?
- What does she want?
- Will therapy be safe?
“One of the things we need to continue to work toward is cross-specialty, interdisciplinary focus on this,” Stuenkel said. “The cardiologist brings something. I like to think we in the menopause world bring something. These are important collaborations.”
Lundberg said women deserve to have the most up-to-date data on menopausal HT, coupled with well-informed shared decision-making, to make the best choice for their well-being.
“What I tell women is there is quality of life, and shared decision-making is at the heart of it,” Lundberg said. “I have women at higher risk, and they know they are. They are well informed, and we are still using a low dose of hormones to help them have a better quality of life. Too often, when we say, ‘This is the guideline,’ people think it is the law. I even have patients who had breast cancer who choose to take estrogen because of their quality of life. It is scary and we watch them closely, but these are women who say, ‘I don’t care if I live longer if I am miserable every day.’”
“We do need more options,” Lundberg said. “If we could find a vaccine for COVID-19 in 9 months, can’t we find something for menopause? Women’s health is not prioritized in the pharmaceutical industry. Guidelines are important. They are there to protect us. But quality of life and your decision-making trumps that. You must find the best outcome for each patient, as long as they are informed and understand risks.”
- References:
- Cho L, et al. Circulation. 2023;doi:10.1161/CIRCULATIONAHA.122.061559.
- “The 2023 Nonhormone Therapy Position Statement of The North American Menopause Society” Advisory Panel. Menopause. 2023;doi:10.1097/GME.0000000000002200.
- Truong SR, et al. J Gynecol Obstet. 2019;doi:10.11648/j.jgo.20190702.11.
- For more information:
- Leslie Cho, MD, can be reached at chol@ccf.org.
- Michael Honigberg, MD, MPP, can be reached at mhonigberg@mgh.harvard.edu; X (Twitter): @mchonig.
- Gina Lundberg, MD, FACC, can be reached at gina.lundberg@emory.edu; X (Twitter): @gina_lundberg.
- JoAnn E. Manson, MD, DrPH, MACP, FAHA, can be reached at jmanson@bwh.harvard.edu; X (Twitter): @BrighamWomens.
- Cynthia A. Stuenkel, MD, MSCP, can be reached at castuenkel@health.ucsd.edu.
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