Menopause hormone therapy (HT), also known as hormone replacement therapy or HRT, has many benefits for perimenopausal and menopausal women, including reducing hot flashes, night sweats, brain fog, and vaginal dryness, as well as improving mood, sleep, and long-term bone health.
However, there have been decades of controversy regarding this therapy. In the early 1990s, HT was very popular and in 1993, the National Institutes of Health launched the Women’s Health Initiative (WHI), a clinical trial to evaluate the impact of hormone therapy on the risk of chronic disease, particularly heart disease, stroke, cancers, and bone fractures. In this landmark study, more than 16,000 healthy postmenopausal US women with an intact uterus aged 50 to 79 (average age 63) were put on a protocol of estrogen and progesterone, and roughly 11,000 who had had a hysterectomy were placed on estrogen alone.
Enrollment proceeded from 1993 to 1998. In 2002 the combined group of the trial was stopped three years early, and in 2004 the estrogen-alone group was stopped one year early. The trials came to a halt when the risks of invasive breast cancer, blood clots, heart disease, and stroke exceeded the benefits for prevention of bone fractures and colon cancer. These outcomes instilled a general fear in the public and medical community that HT increases the risk of breast cancer and/or cardiovascular disease.
But, in May 2024, WHI researchers published their 20-year follow-up data that showed no increase in deaths from breast cancer or cardiovascular disease in the women in the trials. The follow-up report also showed a decrease in all-cause mortality when HT was started under age 60 or less than 10 years after the final menstrual period, illustrating that hormone therapy can be beneficial for many women.
Regarding breast cancer risk specifically, in the WHI trial, there were only eight cases of breast cancer per 10,000 women per year in the combined group and a decrease in breast cancer rates in women on estrogen-alone therapy. “Obesity, a sedentary lifestyle, and alcohol use pose much greater risks for breast cancer than HT,” says Karen Adams, MD, Stanford clinical professor of obstetrics and gynecology.
“There’s a lot of fear and misinformation around HT, and one of the biggest myths is that HT is a highly significant cause of breast cancer,” says Dr. Adams. “Today, only around three percent of women who are candidates for hormone therapy are actually taking it because they’re afraid.”
Dr. Adams is the founder and director of the Stanford Menopause & Healthy Aging program, a multidisciplinary team of women’s health experts that aims to educate providers in the use of HT since many medical schools stopped teaching the treatment after the WHI results. Since providers were not prescribing HT, an entire generation of women (now aged 65 to 80) did not receive or benefit from the therapy.
“It’s important that we get the message out there that we have learned how to individualize HT for each woman’s situation. Risks and benefits regarding hormone therapy are different for each person, and many women will gain significant benefits from hormone use, especially if they are under age 60,” says Dr. Adams.
Reducing Fears About Menopausal Hormone Therapy
In the last 20 years, results from follow-up studies of the original WHI trial and other studies have shown that HT is safer when specific guidelines are followed, such as making sure women start HT at the right age, and the treatment is administered in the proper form.
When Should I Start Hormone Therapy?
The first safety guideline is starting hormone therapy at the right age. Analyses of the WHI trial data found that heart attacks and strokes occurred primarily in women who started HT over the age of 65, meaning that age made a difference in how women responded to the hormones.
This finding has led to the current recommendation of starting HT within 10 years of menopausal onset. In other words, if a woman’s last period occurred at age 50, she should start treatment by 60.
“There is a window of greatest opportunity to start hormones. If you start within 10 years of your last period, you almost always get benefits. But, if you start after 10 years, or after the age of 60, possibly not,” says Dr. Adams.
Also, Dr. Adams shares that many women are starting HT in their 40s to relieve perimenopausal symptoms. Unpredictable hormone fluctuations can cause irregular periods during the years leading up to menopause, sometimes resulting in Perimenopausal Mood Instability or PMI.
“Everyone knows about PMS, but no one talks about PMI because the conditions that women have in midlife aren’t talked about enough … and PMI is like PMS on steroids,” says Dr. Adams. “Starting hormone therapy during perimenopause can be incredibly helpful to stabilize the ups and downs of hormone levels that can cause hot flashes, night sweats, and changes in mood.”
Dr. Adams explains that HT offers a lower level of hormones than birth control pills, so it does not prevent pregnancy. Therefore, many of her patients in perimenopause (where pregnancy is still possible) opt for birth control pills if they are sexually active to provide both symptom relief and contraception. But, if patients are using another mode of birth control, HT could be a good option to relieve perimenopausal symptoms.
What Forms of Hormone Therapy Should I Take?
The second safety guideline is knowing the best way to take the hormone. Research has shown that when estrogen is taken in pill form, the liver releases clotting factors, which can result in blood clots and other cardiovascular conditions. But, if estrogen is administered non-orally, such as through a skin patch or gel, the hormone is delivered directly into the blood stream without going through the digestive system, which takes the clotting risk back to baseline.
“This study is helpful for providers to understand whether HT is a good idea for a particular patient in that it divides people into low, moderate, and high risk for cardiovascular disease,” says Dr. Adams, referring to Figure 5 of the study. “If a patient is at high risk for cardiovascular disease, HT would not be recommended.”
Even though estrogen should be administered non-orally to prevent blood clotting, Dr. Adams recommends taking progesterone as a pill that is swallowed at night, since sleepiness is a convenient side effect. The purpose of progesterone is to protect the lining of the uterus. Estrogen typically thickens the uterine lining, which can cause irregular bleeding, and even pre-cancer or cancer of the lining. If a woman has had a hysterectomy, she does not have this risk and therefore she does not need to take progesterone.
Lastly, the WHI trial administered chemical forms of estrogen and progesterone, but Dr. Adams emphasizes the importance of taking bioidentical forms so that the body “recognizes” them. “The hormones we now use are bioidentical, meaning they are the same forms that were circulating in your body in your reproductive years,” she says. “They are much less inflammatory than the chemical forms that were studied in the WHI. Since inflammation increases our risk for all age-related diseases, less inflammation is always a good thing.”
What are the Benefits of Menopause Hormone Therapy?
At the Stanford Menopause & Healthy Aging clinic, HT is tailored to the patient’s needs and includes transdermal estrogen (via a patch) and micronized progesterone (via a pill) for those with a uterus. The primary use of hormone therapy is for management of menopausal symptoms, which can be distressing and can last for years.
Benefits of Hormone Therapy:
- Reduction of hot flashes
- Reduction of night sweats
- Reduction of vaginal dryness that can cause painful sex
- Reduction of joint pain
- Reduction of brain fog
- Mood stabilization
- Sleep improvement
“Hormone therapy takes hot flashes and night sweats away in about three to four weeks. Regarding painful sex, the vagina gets more stretchy, moist, and flexible with estrogen,” says Dr. Adams. “HT also provides a small but measurable impact on lean body mass and can help to mitigate the ‘spare tire’ that women see in midlife.”
Long-term Benefits of Hormone Therapy:
- Reduced risk of osteoporosis and bone fracture
- Reduced risk of colorectal cancer
“Women take HT to not only relieve current menopause-related symptoms but also for improved long-term bone health. HT helps keep your bones strong and can potentially prevent osteoporosis,” says Dr. Adams. “Regarding heart health, we see a slowing of calcium deposition in the coronary arteries when HT is started under age 60, which may lead to a lowered risk for cardiovascular disease long-term.”
Benefits of Testosterone:
- Improved sex drive
“Testosterone is not part of a standard HT protocol since it’s not FDA approved for women. For that reason, insurance will not reimburse for it. The best data supports the use of testosterone in postmenopausal women with low sex drive. In those women we see small increases in desire, arousal, and orgasm, so some HT clinics do offer it for this purpose and follow a national guideline for administration,” says Dr. Adams. “Regarding improvements in muscle mass and energy, we don’t have enough data currently to conclude that testosterone mitigates the sarcopenia of aging or increases energy in women, but this may come in the future.”
Who Should Not Take Hormone Therapy?
Dr. Adams explains that people with the following conditions should not take hormone therapy:
- Women with a hormone-sensitive cancer, such as estrogen or progesterone positive breast cancer.
- People who have had a heart attack, stroke, or a blood clot in their leg, lung, or brain.
- People with gallstones, liver disease, gallbladder disease, or undiagnosed vaginal bleeding or pregnancy.
“It’s an exciting time to be a menopause specialist because there has been more attention being paid to menopause in recent years, which is great and long overdue,” says Dr. Adams.
“I want to send a message of hope. Once they figure out how to manage their menopausal symptoms, most women are happier than they’ve ever been in their lives. They are more confident, and their relationships tend to improve because they know themselves well. So, you just need to navigate these choppy waters of perimenopause to get to a time of life that is called ‘menopausal zest’. That is out there waiting for you, and it’s wonderful,” says Dr. Adams.
Learn more about Dr. Karen Adams’ recommendations for women’s healthy aging:
TED Talk: Sleep, Sex, and Menopausal Zest
SHE Talk: Taboos and Truths – A Frank Talk About Women’s Health
Marcia L. Stefanick, PhD has spent her career changing the way medicine understands both the differences and similarities in health across sex and gender. A professor of medicine at Stanford and a leading researcher in women’s health and sex differences, she has dedicated decades to advocating for the inclusion of women in clinical trials and challenging outdated medical norms. As a principal investigator in the landmark Women’s Health Initiative (WHI) and co-founder of Stanford’s Women’s Health and Sex Diversity in Medicine (WHSDM) Center, Dr. Stefanick has shaped public health policies and medical guidelines that continue to influence patient care all over the world.
“I’m interested in everything that relates to sex and gender across the life course,” says Dr. Stefanick. “My research has been very autobiographical—I first studied the menstrual cycle, then pregnancy complications, then midlife and menopause, and now aging.”
Early Life and Career Path
Born in Western Pennsylvania into a family of seven children, Dr. Stefanick developed an early curiosity about sex differences—wondering why puberty affected her brothers differently and why societal expectations varied by gender.
“I was always trying to figure out—when my brothers went through puberty, is that going to happen to me? Why do they get to do certain things, and I don’t? That made me interested in both biology and gender norms,” says Dr. Stefanick.
After spending a year in Germany as a Rotary International Exchange student, she pursued a degree in biology from the University of Pennsylvania, where she became interested in sex differences, particularly in primate behavior.
“When I graduated, I had hoped to study lowland gorillas in Africa, which led me to the Oregon Regional Primate Center. There, I became a research assistant in a sex hormone laboratory and developed a deeper interest in hormones and behavior and neuroendocrinology. This motivated me to pursue a PhD in Physiology with Julian Davidson at Stanford,” says Dr. Stefanick.
During graduate school, she realized she was not meant to be an animal researcher. Seeking a new direction, she connected with researchers at the Stanford Prevention Research Center (SPRC) who were focusing on physical activity and heart disease prevention.
Breaking Barriers in Research
At the SPRC, Dr. Stefanick’s research in the early 1990s primarily focused on body composition, weight loss, and exercise’s impact on cardiovascular risk. At the time, clinical trials were overwhelmingly conducted on men.
Her first two trials—one on exercise and HDL cholesterol and the other on diet, exercise, and weight loss—only included men because that was all that was funded. Frustrated by this, she refused to conduct another male-only study, successfully pushing for the inclusion of pre-menopausal and post-menopausal women in subsequent research.
“I told them, ‘I’m not doing another study without women. We have to include women in our research and not only study men’,” says Dr. Stefanick.
Her interest in sex and hormones led her to take on a National Institutes of Health (NIH) request for applications to study menopausal hormones and heart disease. At the time, doctors were widely prescribing menopausal hormone therapy (HT), often referred to as hormone replacement therapy (HRT), for older women despite a lack of research on its effects. Dr. Stefanick and her colleagues designed one of the first studies to examine these treatments.
This resulted in the Postmenopausal Estrogen/Progestin Interventions Trial (PEPI), published in 1995, which was the first clinical trial by the National Heart, Lung, and Blood Institute (NHLBI) conducted exclusively on women. “It was the first trial done by NHLBI that had only women in it,” says Dr. Stefanick with pride.
Women’s Health Initiative: A Landmark Study
Dr. Stefanick’s PEPI trial laid the foundation for the Women’s Health Initiative (WHI)—the largest study of women’s health ever conducted. Launched in the 1990s, WHI enrolled nearly 162,000 women at 40 clinical centers nationwide to study menopausal hormone therapy, diet and cancer risk, and calcium and vitamin D supplementation.
WHI is still ongoing, and Dr. Stefanick serves as Principal Investigator of the Western Regional Center. “It’s the biggest study of women’s health ever done—and it’s still going on,” says Dr. Stefanick.
The WHI hormone trials, published in 2002 and 2004, challenged long-held medical beliefs. Doctors were prescribing menopausal hormone therapy for older women to prevent heart disease, but the study found that HT actually increased the risk of strokes, heart attacks, breast cancer, and dementia. Within a year of publication, HT prescriptions in the US dropped from 20 million to 6 million. “Doctors became afraid to prescribe hormones for menopause management. Women now ask, ‘Why won’t anyone treat my menopause symptoms?’ There are alternative estrogen therapies that don’t carry the same risks, but they remain underutilized,” says Dr. Stefanick.
Dr. Stefanick is currently leading the largest-ever study on whether physical activity prevents heart disease—a question that, despite decades of research, has never been definitively proven.
“We’ve never actually proven that physical activity reduces heart disease. All our data is based on surrogate markers—blood pressure, cholesterol, glucose tolerance—but we haven’t studied enough men or women (or nonbinary people) to say for sure,” says Dr. Stefanick.
The WHSDM Center: Advancing Sex Differences Research
Dr. Stefanick believes that one of the biggest problems in sex differences research is the overemphasis on sex hormones while ignoring other biological factors and broader sociocultural influences. “People tend to believe it’s all about estrogen and testosterone, but the biggest biological difference is probably the X chromosome. Every cell in an XX (female) body is different from every cell in an XY (male) body and some people have other variations of X and Y combinations,” says Dr. Stefanick.
For example, women have a stronger immune response than men, yet medical studies rarely adjust for these differences. Even in vaccine development, the COVID-19 vaccine was given at the same dose to men and women, despite evidence that women may need much lower doses.
“We don’t need to treat women like men. We are not men. We need to treat women like women—XX people with estrogen between puberty and menopause and with low estrogen after menopause, which may be over a third of our lives,” says Dr. Stefanick.
To address these gaps, Dr. Stefanick co-founded the WHSDM Center at Stanford, which serves as a hub for sex and gender research in medicine. The center funds studies, ensures that departments consider sex and gender in research, and promotes the inclusion of underrepresented groups in medical studies.
“Our goal at the WHSDM Center is to encourage researchers to study sex differences at every level—cells, tissues, animals, people, and populations,” says Dr. Stefanick.
Future Research Priorities
Dr. Stefanick continues to advocate for more inclusive research in several key areas:
- Menopause and why some women have more severe symptoms than others and how to treat these more serious cases
- Adverse pregnancy outcomes and their link to increased risk of diabetes and premature heart attack
- Aging in women and why women live longer than men in many parts of the world
- LGBTQ+ health research and the need for broader representation
“Women are incredibly resilient,” says Dr. Stefanick. “Our culture doesn’t value women in the same way it values men, yet women persist. I just love women. Women are incredible.”