While there are many concerning side effects of menopause—including hot flashes and weight gain—more than 1 million people nationwide who start this life phase each year face a more life-threatening problem: a sharply rising risk of cardiovascular disease.

“Cardiovascular disease is the leading killer in women, the same as men, but it’s underrecognized in women because the threat emerges later in life,” says Shadab Rahman, PhD, a lead investigator in the Brigham’s Division of Sleep and Circadian Disorders. “Many treatment guidelines are based on data collected primarily from men. And we’re recognizing more and more that men and women do not respond the same way to treatments.”

Rahman and his colleague Leilah Grant, PhD, specialize in research on the effects of sleep, circadian rhythms, and light on different aspects of health, from cognition to metabolism to women’s health. They have developed solutions that can be used in day-to-day life, healthcare settings, and even on space missions.

Compelled to learn more about how menopause affects women’s health, Rahman, Grant, and collaborators in the Mary Horrigan Connors Center for Women’s Health Research working on another large NIH-funded network are tracking down answers to important questions.

“We’re asking which aspects of women’s cardiovascular and metabolic health are negatively affected—and how much,” says Grant. “And we want to know how diet, medication, and other approaches could help overcome these problems.”

Sleep, hormones, and heart health

Rahman and Grant collaborated on a first-of-its-kind study with principal investigator Hadine Joffe, MD, MSc, executive director of the Connors Center. Together, they examined two major reasons women experience an elevated cardiovascular risk during menopause: the loss of the hormone estrogen, which protects heart health, and disruptions in sleep from hot flashes and other related symptoms. Assessing 16 cardiometabolic measures, from blood pressure and cholesterol to blood sugar and hunger hormones, they saw wide-ranging effects.

“We found that with estrogen loss and sleep fragmentation, which is the pattern of repeated sleep interruption from hot flashes, each have an independent adverse impact,” Rahman says. “When you combine the two, all of the cardiometabolic factors we examined were negatively affected. These were powerful, impactful results.”

Funded by the National Institutes of Health (NIH), the five-year study involved two parts. First, they brought pre-menopausal women under age 45 to a sleep lab to repeatedly wake them with a loud alarm overnight for three nights, imitating sleep interruptions caused by hot flashes, which affect about 70% of women. Next, researchers temporarily lowered participants’ estrogen levels for a few weeks to mimic menopause and participants returned to the lab to repeat the same sleep-interruption experiment.

“In this short period of time, we saw a problematic change of 14%, on average, across multiple cardiometabolic outcomes such as blood pressure, fasting glucose, and heart rate, and up to 50% change in individual cardiometabolic outcomes,” says Rahman. “And if you compound this, knowing that menopause symptoms and sleep disturbance can last for up to 10 years, you can imagine what could happen over a longer period.”

Most troubling to the researchers were the detrimental effects on participants’ lipid profiles and the increasing amount of fat, including cholesterol and triglycerides, circulating in the blood. When the scientists calculated a composite cardiovascular risk score including multiple risk factors, they discovered that on top of an elevated risk from estrogen loss, sleep interruption increased risk by an additional 35%.

The value of continuous sleep

While many other sleep studies have shortened the amount of time participants sleep overnight, Rahman notes this study’s unique approach enabled participants to get the total recommended 7.5 to 8 hours of sleep per night, even though sleep was disrupted. He says this underscores how essential uninterrupted sleep is to health, especially in women.

“Surveys have shown that less than 50% of women recognize what a big risk factor the menopausal transition is for cardiometabolic health,” Rahman says. “The main clinical complaint women have is sleep disturbance, but the link between sleep and cardiometabolic health during this time is even less well known. Sleep issues can be treated with a physician’s help, but many women are not reaching out because they are not aware of the cardiovascular link. We want to help improve awareness and knowledge.”

To find effective solutions, the scientists have been gauging whether sleep medications could help. An earlier clinical trial by Rahman and Joffe showed the medication suvorexant led to significant improvements in sleep disruption for postmenopausal women. Now, they are concluding a new clinical trial looking at whether the same medication could benefit women’s cardiometabolic health by improving their sleep.

Examining links between stress and health

“The study of menopause-related health problems has been persistently neglected, even though menopause impacts half the world’s population,” says Joffe, a past president of The Menopause Society and an expert in the field of women’s aging and neurocognitive health.

Joffe leads one of the Connors Center’s core research programs, the NIH-funded Reproductive Outcomes of Stress and Aging (ROSA) Center, which aims to advance new scientific understanding of women’s health and address crucial knowledge gaps. Through a multi-year competitive grant, the ROSA Center is one of 12 sites nationwide selected by the NIH as a Specialized Center of Research Excellence, a flagship program of the NIH Office of Women’s Health Research.

Joffe, Rahman, and leading investigators from Mass General Brigham and other Harvard-affiliated institutions are collaborating to focus on clinical conditions in midlife women that underlie susceptibility to cardiovascular disease and dementia. With the goal of developing new ways to improve women’s health through a coordinated approach, the interdisciplinary ROSA Center team is studying how stress is linked with and transmitted to induce hot flashes and sleep disturbance across the menopause transition, further disrupting health through cognitive and cardiometabolic problems.

“This national research center is dynamically propelling knowledge in the field of women’s aging health,” Joffe says. “We’re gaining important insights that will help transform clinical practice and the health of women.”

Innovative approach to improve heart health

Another key program of the Connors Center is the First.in.Women translational research platform, which includes IGNITE awards for junior faculty and postdoctoral trainees. Grant, who is a Connors BWH-MGB Collaborative Cardiovascular IGNITE Awardee, completed a clinical trial looking at how meal timing could boost women’s fat-burning capabilities, something that naturally decreases during menopause. In the earlier study of sleep fragmentation and estrogen loss, Grant saw about a 33% reduction in fat burning, showing changes in how the body metabolizes food. Combined with this, the hunger hormone is affected in some menopausal women, causing them to feel less satisfied after eating, which could lead to more food intake and more weight gain.

“During this time in women’s lives, they are gaining cardiovascular risk, so our question was, ‘Can we intervene during this upward trajectory, rather than waiting until later when they’ve already accumulated this risk?’” Grant says. “One way individuals can increase fat burning is by lengthening the duration of their overnight fast.”

Grant’s 8-week study included a mix of perimenopausal and recently postmenopausal women with obesity and high cholesterol, randomized into two groups. One group consumed calories during an 8-hour window of their choosing each day, following an intermittent fasting method called time-restricted eating, while the control group had no restrictions, eating whenever they wanted.

“We instructed the women not to change what they ate or how much—the focus was on timing,” Grant says.

By the end, the time-restricted group had a significantly greater reduction in fat mass and weight than the control group. Also, Grant was pleased to see the test group adhered to the time window about 90% of the time, showing this could be a sustainable strategy. While she did not see changes in lipid levels, the findings suggest potential benefits for symptoms like hot flashes and sleep disturbances. In future studies, she aims to extend the fasting intervention over more weeks to see if that will reduce cholesterol and other risk factors.

“This is my first time working more closely with a patient population, and I got a sense there’s a real need for better supports,” Grant says. “The participants were grateful for an outlet to speak with someone about all the changes they’re experiencing. What I want to see for women is that they can go to their doctors, be taken seriously for their concerns, and be matched up with the right help. I don’t think we’re quite there yet, but I’m hopeful studies like these can spark change.”

Did You Know?

During menopause—which usually starts between ages 45 and 55—the hormones estrogen and progesterone fluctuate and then decline, causing a variety of symptoms that last an average of 5 to 7 years. A woman is considered postmenopausal after 12 consecutive months without a menstrual period, marking the culmination of her reproductive years.