#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.
Dr. JoAnn Manson, a world-renowned endocrinologist and epidemiologist, discusses the Women's Health Initiative (WHI) study, its design, and the misinterpretation of its hormone replacement therapy (HRT) results. She clarifies the nuanced benefits and risks of HRT, emphasizing individualized decision-making.
Deep Dive Analysis
17 Topic Outline
Introduction to Dr. Joanne Manson and Her H-Index
Background and Rationale for the Women's Health Initiative (WHI)
Observational Studies and Pre-WHI Hypotheses for HRT Benefits
Hormone Formulations Used in the WHI
WHI Study Design, Participant Criteria, and Enrollment
Primary Outcomes and Power Analysis of the WHI
Understanding Oral Estrogen's Impact on Coagulability
Personal Hypotheses and Expectations Before WHI Results
Pre-WHI Understanding of Estrogen and Breast Cancer Link
WHI Findings on Breast Cancer and the Role of Progestin
Reasons for Premature Stoppage of the Estrogen Plus Progestin Arm
Misinterpretation and Public Reaction to WHI Results
Nuanced View of HRT Benefits and Risks Post-WHI
HRT and Bone Health Considerations
Importance of Timing for HRT and All-Cause Mortality
Moving Towards Better HRT Practices and Future Research Needs
How to Find a Knowledgeable Menopause Clinician
7 Key Concepts
H-index
The H-index is a metric used to quantify the productivity and citation impact of a scholar's publications. An H-index of 100 means a researcher has at least 100 publications that have each been cited 100 or more times.
Observational Studies
These are large studies that look at women who chose to be on hormone therapy or were prescribed it, observing associations between hormone use and health outcomes. They can generate hypotheses but cannot prove cause-and-effect relationships due to potential confounding factors like healthy user bias.
Randomized Clinical Trials (RCTs)
These are studies where participants are randomly assigned to receive an active treatment or a placebo, designed to prove a cause-and-effect relationship. The Women's Health Initiative (WHI) was an RCT designed to test hypotheses generated by observational studies.
Healthy User Bias
A type of confounding bias where individuals who choose to engage in healthy behaviors (like taking hormones in observational studies) may also have other healthy lifestyle factors or better access to care, making it appear that the intervention itself is beneficial when other factors are at play.
Estrogen Alone vs. Estrogen Plus Progestin
In hormone replacement therapy, women with an intact uterus must take a progestogen alongside estrogen to counteract estrogen's effect of increasing the thickness of the uterine lining, which would otherwise lead to a high risk of endometrial cancer. Women who have had a hysterectomy can safely take estrogen alone.
Relative Risk vs. Absolute Risk
Relative risk describes the proportional increase or decrease in risk between two groups (e.g., a 25% higher risk). Absolute risk describes the actual difference in the number of cases between groups (e.g., one extra case per thousand women), which can be very small even with a significant relative risk.
Timing Hypothesis (HRT)
This concept suggests that the benefits and risks of hormone therapy vary significantly based on a woman's age and time since menopause. Younger women in early menopause tend to have lower absolute risks and potentially more favorable outcomes compared to older women who start HRT many years after menopause.
13 Questions Answered
The H-index is calculated by finding the number of publications a researcher has that have been cited at least that many times. For example, an H-index of 100 means 100 publications with 100 or more citations each.
The WHI was launched to test the hypothesis, generated by observational studies, that hormone therapy could prevent heart disease, cognitive decline, and other chronic diseases in postmenopausal women, a practice that was becoming common in clinical medicine.
The WHI tested conjugated estrogen (CEE) alone for women with a hysterectomy, and conjugated estrogen plus medroxyprogesterone acetate (MPA) for women with an intact uterus, as these were the most common formulations at the time.
The average age of women in the WHI was 63, ranging from 50 to 79. Women with hot flashes were not excluded, although those with very severe symptoms often self-selected out as they were already taking HRT.
The primary outcome for both trials was coronary heart disease (nonfatal heart attack or fatal coronary disease), and the primary safety outcome was breast cancer.
It was understood that oral estrogen, similar to oral contraceptives, could increase the synthesis of clotting proteins by the liver, leading to an increased risk of deep vein thrombosis and pulmonary embolism, though this was believed to be rare and outweighed by benefits.
This arm was stopped after 5.6 years (3.3 years early) due to an increased risk of breast cancer, no reduction in heart disease, and an overall unfavorable risk-benefit ratio as determined by the global index of chronic conditions.
No, the WHI found no increased risk of breast cancer with estrogen alone; with longer follow-up, it actually showed a reduction in breast cancer incidence and a statistically significant reduction in breast cancer mortality.
The medical community was 'shell-shocked,' leading to a dramatic 70-80% reduction in HRT use. The results were often over-extrapolated, leading to a widespread belief that HRT was bad for all women due to breast cancer risk, even for those in early menopause with severe symptoms.
The current understanding is that HRT is beneficial for some but not all women, with the best candidates being women in early menopause (50-59 years old) who have moderate to severe hot flashes and night sweats and are in generally good health, as they experience quality of life benefits with minimal absolute risks.
HRT can reduce the incidence of hip fracture, but its benefits to bone mineral density dissipate quickly after stopping. Long-term use for bone health in older age would require prolonged HRT, which could increase other risks like breast cancer.
Yes, timing is crucial. Younger women (50-59) on HRT showed signals for about a 30% lower all-cause mortality, while older women (70-79) on estrogen alone showed a signal for a small increase in mortality risk.
Women can visit menopause.org, the website of the North American Menopause Society, and use the 'Find a Certified Menopause Practitioner' tab to locate clinicians with expertise in menopause management in their area.
15 Actionable Insights
1. Personalize HRT Decisions
Make hormone replacement therapy (HRT) decisions based on an individualized assessment of benefits and risks, considering a woman’s age, time since menopause, and underlying health status, through shared decision-making with a clinician.
2. Ideal HRT Candidates
The best candidates for HRT are women in early menopause (40s-50s) who experience moderate to severe or bothersome hot flashes and night sweats and are in generally good health, as they derive quality of life benefits with minimal absolute risk.
3. Seek Expert Menopause Clinician
If seeking HRT or menopause management, find a certified menopause practitioner through menopause.org by using their ‘Find a Certified Menopause Practitioner’ tab with your zip code, to ensure expert guidance and informed discussion of options.
4. HRT Timing is Key
Understand that the timing of HRT initiation is critical; absolute risks are much lower and potential benefits (e.g., for heart disease with estrogen alone) are more favorable when started in early menopause (50s) compared to later menopause.
5. Distinguish Absolute, Relative Risk
When evaluating medical information, understand the difference between relative and absolute risk, as relative risk can sound alarming (e.g., 25% increase) while the absolute risk may be very low (e.g., one extra case per 1,000 women per year).
6. HRT for Symptoms Only
Use HRT for treating bothersome menopausal symptoms like hot flashes and night sweats, for which it is FDA-approved and effective, but avoid using it for chronic disease prevention in mid to later menopause (average age 63+), as risks outweighed benefits in that context.
7. Progestogen with Intact Uterus
Women with an intact uterus must take a progestogen along with estrogen to counteract estrogen’s effect on the uterine lining and prevent a very high risk of developing endometrial cancer.
8. Prefer Bioidentical Hormones
Prefer transdermal estradiol and micronized progesterone (FDA-approved bioidentical formulations) over oral conjugated estrogen and medroxyprogesterone acetate, due to their potentially more favorable effects on clotting and cardiometabolic health.
9. MPA Linked to Breast Cancer
Recognize that the increased breast cancer risk observed in the Women’s Health Initiative was primarily linked to medroxyprogesterone acetate (MPA) when combined with estrogen, not estrogen alone.
10. Estrogen Alone & Breast Cancer
Estrogen-alone therapy (specifically conjugated equine estrogen) did not show an increased risk of breast cancer in the WHI and even showed a reduction with longer follow-up.
11. Consider Non-Hormonal Options
If HRT is not suitable or desired, explore non-hormonal options like SSRIs, SNRIs, or gabapentin for hot flashes, as these medications have been found to be quite effective, reducing symptoms by 40-50%.
12. Respect Patient HRT Fears
Respect a patient’s strong reluctance to take HRT, even if data suggests favorable absolute risks, as their emotional well-being and anxiety are crucial factors in the overall benefit-risk equation.
13. Bone Benefits Not Sustained
Be aware that HRT benefits for bone density are not sustained long-term after stopping the therapy; continuous use into later life would be needed for fracture prevention, which carries other risks.
14. Recognize Healthy User Bias
Be aware of healthy user bias when interpreting observational health data, as apparent benefits might be due to other healthy lifestyle factors rather than the intervention itself.
15. Progestogen Formulation Caution
Be cautious about breast cancer risk with longer duration of estrogen plus progestin, even with different progestogen formulations, due to limited large-scale randomized trial data on alternatives to medroxyprogesterone acetate.
5 Key Quotes
Your H-index, Joanne, last I checked, is 305. Is that correct? It may have crept up even higher. Yeah. Well, I would say that you are generally in the top three H-index rankings in the history of biomedical science.
Peter Attia
The medical community was shell-shocked. There was a sea change in clinical practice, a seismic shift in clinical practice.
Joanne Manson
Hormone therapy has very complex effects. It has a complex matrix of benefits and risks that vary according to a woman's age, her time since menopause, her underlying health status.
Joanne Manson
In the 1980s, 1990s, the perception was that hormone therapy was good for all women. And women were being routinely started on hormone therapy. Then after the WHI in the early 2000s, the pendulum was in the opposite direction, that hormone therapy is bad for all women. And now I think it is coming, the pendulum is coming to rest in a more appropriate place, that hormone therapy is good for some but not all women.
Joanne Manson
I still remain somewhat sad because I think there's a lost generation of women. I think there's 20 years of women who entered menopause who were denied HRT due to the ignorance of their physicians and the irresponsibility of the media.
Peter Attia
1 Protocols
Finding a Certified Menopause Practitioner
Joanne Manson- Go to the North American Menopause Society website: menopause.org.
- Find the 'Find a Certified Menopause Practitioner' tab.
- Enter your zip code to find clinicians in your area with expert training in menopause management and hormone therapy.