Estrogen affects bone and heart health before menopause, but the timing and duration of hormone replacement therapy during and after menopause have been controversial. Women going through menopause today have many questions about whether it is advisable to consider estrogen therapy and for how long. Does hormone therapy help reduce cardiac risks? Is this benefit offset by introducing new stroke and gallbladder risks? Can we sidestep the whole question by using plant-based estrogen supplementation?
Menopause hormone therapy (MHT) is most beneficial when started around menopause (before 60 years of age and within 10 years of menopause symptom onset).
Women older than 60 can start MHT but their risks of cardiovascular disease, breast cancer, and osteoporosis should be considered in the decision-making matrix.
Therapy does not necessarily need to be discontinued when a woman reaches 60 or 65.
Taking the lowest dose possible and using non-oral routes (avoiding pills) may help reduce the risk of developing clots or strokes.
More randomized, controlled trials (RCTs) must be run to evaluate differences in the timing of MHT initiation, formulation, dose, and duration.
Overall, the benefit-risk ratio for women younger than 60 or within 10 years of menopause onset looks favorable for MHT to prevent bone loss and fractures and may be favorable for cardiovascular disease depending on personal and family risk factors.
Before menopause, estrogen plays an important role not only in preparing the uterine lining for pregnancy, but it is also responsible for helping maintain the skeleton and cardiovascular system throughout life. After menopause, estrogen levels decline, and women can experience bone loss resulting in osteoporosis and fractures. Declining estrogen also affects cardiovascular health by maintaining pliable blood vessels, controlling cholesterol, and managing inflammation.
For women going through menopause today, it is important to sift through several decades-old controversies which influenced the treatment of menopause for our mothers. Thanks to a very large study begun in 1992 — the Women’s Health Initiative (WHI) — we know a bit more about the importance of estrogen for bone and heart health, improvements to the quality of life, and the optimal timing for estrogen replacement therapy. A second major trial began in 1994 — The heart and Estrogen/Progestin Replacement Study (HERS) found no effect of estrogen therapy on cardiovascular outcomes but found a higher risk of stroke and gallbladder disease. Still, these findings must be interpreted with age at the start of hormone therapy in mind. A third large study — the Nurses’ Health Study (NHS) — is ongoing in nearly 60,000 women and has yielded evidence that suggests hormone therapy reduces the risk of major coronary disease by about half.
These studies have left women and their doctors in a quandary of complicated risk-benefit conversations, but new interpretations are beginning to shed some light on who benefits most from menopause hormone therapy (MHT).
The importance of estrogen for cardiovascular health has been known for more than five decades. Many mechanisms have been proposed to describe the precise role of estrogen in promoting heart health. Some include helping to manage the lipid profile (the so-called “good” HDL and “bad” LDL cholesterol levels), as well as anti-clotting and antioxidant effects.
It is unfortunate that the first analyses of both WHI and HERS reported cardiovascular events in the first year after starting therapy but failed to account for the age and underlying risk factors of the women who experienced these negative outcomes. Women who had a cardiovascular event tended to start estrogen at least 10 years after menopause and had pre-existing risk factors for a cardiac event. The HERS trial was stopped for this reason. In other words, they already had a history of heart attacks or chest pain and were at risk for that getting worse. The type of estrogen they received, too, tipped the scales toward increasing their risk due to an increase in liver proteins, even though it helped with their lipids.
Follow-on studies to understand why timing matters with estrogen therapy were conducted on animal models (monkeys). Although estrogen does not reverse plaque buildup in the blood vessels, it can help prevent plaque from developing by coating the molecules which would otherwise tend to stick together. The benefits of an earlier start on coronary artery thickness were later studied and confirmed by the ELITE Research Group.
Estrogen also allows the blood vessels to stay more elastic and expand as the heart pumps blood through. When the vessels lose this elasticity, blood pressure goes up causing hypertension.
Breast and uterine cancer
This may be one of the top concerns of women considering hormone therapy. The WHI found an increased risk of breast cancer in women taking combination therapy (estrogen and progesterone), but it was low (1 excess case per 1000 women); those taking estrogen alone seemed to have a reduction in breast cancer. The North American Menopause Society released a literature review and position statement in 2022 on this and myriad MHT concerns. The excess risk of breast cancer with MHT appears to be similar to other modifiable risks, such as drinking two or more alcoholic beverages a day, obesity, and low physical activity.
Cancer of the endometrium is the most common gynecologic cancer in the U.S., and taking estrogen without progestin (or “unopposed” estrogen) can increase the risk of this cancer depending on what dose is taken and for how long. Adding progesterone (e.g. “combined” therapy) significantly reduces this risk.
Early (premature) menopause
Women who go through early menopause (between ages 40 and 45) due to surgery or premature menopause may have an increased risk of fracture, cardiovascular disease, and overall mortality. Multiple professional medical society guidelines strongly recommend starting hormone therapy for these women and continuing through the age of natural menopause.
When to start hormone therapy?
There is now consensus that MHT should be started as close to menopause as possible — either using chronological age or the onset of menopausal symptoms as a guide — for women without any cardiovascular risk factors. For women who do have cardiovascular risk factors (hypertension, elevated cholesterol, or metabolic syndrome), screening is important before starting MHT.
What to take?
The American College of Obstetricians and Gynecologists (ACOG) recommends estrogen therapy for the management of menopausal symptoms and heart health; women who have a uterus must take progestin as well. The hormones can be taken via pills, patches, sprays, creams, and rings.
What is the evidence for plant-based estrogen?
While certain foods, such as alcohol, may increase the risk of breast cancer, epidemiological studies have suggested that plant-based estrogens such as soy may be protective. However, studying this over the long term is complicated and better-quality data is still needed. A meta-analysis concluded that there is still insufficient scientific evidence that soy intake can reduce the risk of breast cancer.
When to stop?
The benefits of MHT for women appear to continue accruing over time, and there are other potential benefits related to cognition and dementia. Unfortunately, there is scant published data on prospective trials which can definitively sort out when women should stop taking MHT. The benefits to the heart begin if women start within 10 years of menopause, and continued bone and metabolic benefits appear to continue. Research is ongoing to better understand what type of hormone therapy is best, in what formulation, and for how long.
Is there any new data on how to reduce risks?
A study published in June 2022 was conducted among more than 40,000 women in the U.K. The purpose of the study was to look for any link between hormone therapy and breast cancer. Estrogen had no relationship to the odds of developing breast cancer, but synthetic progestin did seem to increase the risk. When taking combined therapy, micronized progesterone may be preferable to synthetic progestin. According to the ACOG, the small risk of stroke and blood clots from deep vein thrombosis (DVT) may be lessened by using hormone delivery via patch, spray, or ring than a pill by mouth.
Where does all of this nuanced science leave women going through menopause today? In her popular newsletter, Dr. Lucy McBride, an internal medicine physician in Washington, D.C. summarizes the complicated evidence base nicely for her patients. “Luckily, estrogen therapy after menopause is safe for the overwhelming majority of women. It’s particularly safe when started within 10 years of menopause or before the age of 60 and when paired with careful management of underlying medical conditions that predispose patients to poor outcomes.”
- NIH. Cardiovascular health and the menopausal woman: the role of estrogen and when to begin and end hormone treatment.
- Endocrine Reviews. Hormone Therapy in Menopause: Concepts, Controversies, and Approach to Treatment.
- NIH. ACOG Practice Bulletin No. 141: management of menopausal symptoms.
- ACOG. Hormone Therapy for Menopause.
- NAMS POSITION STATEMENT. The 2022 hormone therapy position statement of The North American menopause Society.