#253 ‒ Hormone replacement therapy and the Women’s Health Initiative: re-examining the results, the link to breast cancer, and weighing the risk vs reward of HRT | JoAnn Manson, M.D.

JoAnn Manson is a world-renowned endocrinologist, epidemiologist, and Principal Investigator for the Women’s Health Initiative (WHI). In this episode, she dives deep into the WHI to explain the study design, primary outcome, confounding factors, and nuanced benefits and risks of hormone replacement therapy (HRT). JoAnn reflects on how a misinterpretation of the results, combined with sensationalized headlines regarding an elevated risk of breast cancer, led to a significant shift in the perception and utilization of HRT. From there, they take a closer look at the breast cancer data to separate fact from fiction. Additionally, JoAnn gives her take on how one should weigh the risks and benefits of HRT and concludes with a discussion on how physicians can move towards better HRT practices. 

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We discuss:

• The Women’s Health Initiative: the original goal of the study, hormone formulations used, and potential confounders [4:15];
• Study design of the Women’s Health Initiative, primary outcome, and more [16:00];
• JoAnn’s personal hypothesis about the ability of hormone replacement therapy to reduce heart disease risk prior to the WHI [26:45];
• The relationship between estrogen and breast cancer [30:45];
• Why the WHI study was stopped early, and the dramatic change in the perception and use of HRT due to the alleged increase in breast cancer risk [37:30];
• What Peter finds most troubling about the mainstream view of HRT and a more nuanced look at the benefits and risks of HRT [45:15];
• HRT and bone health [56:00];
• The importance of timing when it comes to HRT, the best use cases, and advice on finding a clinician [59:30];
• A discussion on the potential impact of HRT on mortality and a thought experiment on a long-duration use of HRT [1:03:15];
• Moving toward better HRT practices, and the need for more studies [1:10:00]; and
• More.

The Women’s Health Initiative: the original goal of the study, hormone formulations used, and potential confounders [4:15]

What is the h-index, and how is it calculated? 

• The h-index is calculated from the number of publications you have that are highly cited
  • If, for example, you have an h-index of 100, that would mean that you have at least 100 publications that have 100 or more citations each
  • An h-index of 200 would be 200 publications that each have at least 200 citations that are referenced in other publications
    • These are epic h-indexes
    • A person with a h-index of 100 has done 10 people’s lifetime work in their lifetime
• Last time Peter checked, JoAnn’s h-index was 305
  • She’s in the top 3 h-index rankings in the history of biomedical science
  • JoAnn clarifies, “It means I have wonderful colleagues in collaborations going on throughout the world”

The goal of the Women’s Health Initiative (WHI) 

• JoAnn was one of the principal investigators on the WHI
• Looking back, 20 years later, this study wasn’t interpreted in the best way, from a public health perspective
• This was a randomized experiment designed in the early 1990s to test what was being found in the Nurses Health Study and other epidemiologic studies
• In the 1980s and 1990s there were several large observational studies of women on hormone therapy
  • Compared to women not on hormone therapy, they tend to have lower rates of heart disease in those studies compared to women not using hormone therapy, less cognitive decline, lower all-cause mortality

“We often say that observational studies of this nature cannot prove a cause and effect relationship, but they can generate hypotheses to be tested in randomized clinical trials”‒ JoAnn Manson 

• Before the randomized clinical trials were launched in the early 1990s, there was already an increasing practice in clinical medicine to prescribe hormone therapy for the express purpose of trying to prevent heart disease, cognitive decline, and other chronic diseases
  • This was a trend not only in recently menopausal women, or when women had hot flashes and night sweats and were in early menopause
  • Many clinicians were starting to prescribe these hormones for women who were well over a decade, 10, 20, 30 years after the onset of menopause

It was very important to understand whether this practice of prescribing menopausal estrogen therapy or estrogen plus progestin therapy was advisable when used for prevention of chronic diseases 

• This was a very different question from, “Does hormone therapy reduce hot flashes, night sweats, and should women in their 40s, early 50s who are just starting to go through menopause take hormone therapy to treat those symptoms?”
• It was accepted that hormone therapy is effective for treating hot flashes and night sweats
  • It’s actually FDA approved for that purpose
  • It has an indication for treatment to reduce hot flashes and night sweats
• But the question of its use for prevention of heart disease, stroke, cognitive decline, other chronic diseases had never been tested in a randomized clinical trial, and that was the goal of the Women’s Health Initiative (WHI) 
• Despite the fact that the epidemiology suggested benefits in all of those arenas, people who listen to this podcast are no strangers to the different types of biases that can creep in
  • Like the healthy user bias—It could easily be the case that the women who were provided hormones had access to the type of physicians who maybe were more knowledgeable or provided better care
• There was no doubt that an RCT was going to be essential to elucidate the causality here

The history of hormone formulations [11:00]

• The idea of replacing estrogen in menopausal woman began in the 1960s
• The most common formulations were conjugated estrogen with and without medroxyprogesterone acetate
  • Women who had a hysterectomy could use estrogen alone, but women with an intact uterus needed to take what we call a progestogen
• Progestogen counteracts the effect of estrogen on increasing the thickness of the uterine lining, the endometrium
  • If women who have an intact uterus take estrogen alone, they have a very high risk of developing endometrial cancer
    • Early on, they will just have proliferation and of the lining of the uterus and increased of vaginal bleeding related to taking estrogen without the progestogen
• Those two formulations (conjugated estrogen with and without medroxyprogesterone acetate) were very commonly used, and they had been extensively studied in the observational studies where the results had looked very promising for a lower risk of heart disease and cognitive decline all cause mortality

It was important to test the formulations that had contributed so much to the observational study findings 

Potential confounding factors of observational studies 

• Women who were taking hormone therapy in the observational studies tended to be a higher socioeconomic status, more highly educated, and more health conscious
  • These may have contributed to their lower risk of chronic diseases
• However, it’s also important to note that in observational studies, the women who were being prescribed hormone therapy were still largely women in early menopause
  • Hormone therapy was started in early menopause, even if they continued into mid and later menopause
  • That’s another important perhaps biological difference between the women in the observational studies and women in randomized trials, in the Women’s Health Initiative (WHI)  
• The average age of participants in the WHI was 63, or more than a decade past onset of menopause when the hormone therapy was being started

Do we know if the age of menopause is moving over time? 

• We know that girls are getting their periods earlier and earlier, even over just two decades
• JoAnn doesn’t know if that has been rigorously studied
• The average age of menopause is 51, and that has stayed relatively constant for quite a while

Why were conjugated equine estrogen and MPA synthetic progestogen the dominant forms of these hormones used in the 80s and in the 90s, which of course then became the precursor for the epidemiology? 

Do we know why there was not just a bioidentical estradiol and progesterone? 

• One theory is that a pharmaceutical company developed the conjugated estrogens
• Originally, they derived from the pregnant mare’s urine
  • This is true even for many of the forms today
• This pharmaceutical company really became the dominant force in terms of hormone therapy
• Synthesis of estradiol from plants is a more complicated process that really did not get going on a large scale until more recent decades
• For quite a long time (more than 50 years), only conjugated estrogen available

Study design of the Women’s Health Initiative, primary outcome, and more [16:00]

How many lead investigators were on the WHI?

• In the overall Women’s Health initiative there were initially 16 clinical centers and then expanded to 40 clinical centers for most of the duration of the WHI
• There were actually 40 Principal Investigators throughout the country

Were women who were having vasomotor symptoms excluded? 

{end of show notes preview}

JoAnn Manson, M.D.

JoAnn Manson earned her Bachelor of Arts degree from Harvard. She went on to Case Western Reserve School of Medicine for her MD, then returned to Harvard School of Public Health to earn her MPH and DrPH. 

Dr. Manson is an endocrinologist, epidemiologist, and Principal Investigator of several research studies, including the Women’s Health Initiative, the cardiovascular component of the Nurses’ Health Study, the VITamin D and OmegA-3 TriaL (VITAL), the COcoa Supplement and Multivitamin Outcomes Study (COSMOS), and others. Her primary research interests include randomized clinical prevention trials of nutritional and lifestyle factors related to heart disease, diabetes, and cancer and the role of endogenous and exogenous estrogens as determinants of chronic disease. Currently, she serves as the Chief of the Division of Preventive Medicine at Brigham and Women’s Hospital. She is a Professor of Medicine and Michael and Lee Bell Professor of Women’s Health at Harvard Medical School, and she is a Professor of Epidemiology at Harvard T.H. Chan School of Public Health.

Dr. Manson has received numerous honors, including the American Heart Association’s (AHA) Population Research Prize, the AHA’s Distinguished Scientist Award, AHA invited lectureships (Ancel Keys and Distinguished Scientist lectures), election to the Institute of Medicine of the National Academies (National Academy of Medicine), membership in the Association of American Physicians (AAP), fellowship in AAAS, the Woman in Science Award from the American Medical Women’s Association, the Bernadine Healy Award for Visionary Leadership in Women’s Health, and the Massachusetts Medical Society awards in both Public Health and Women’s Health Research. She served as the 2011-2012 President of the North American Menopause Society. 

Dr. Manson has published more than 1,200 articles and is the author or editor of several books and textbooks. She was also one of the physicians featured in the National Library of Medicine’s exhibition, History of American Women Physicians. [Brigham and Women’s Hospital]