Study Finds 5-7 Years Post-Menopausal Hormone Therapy Not Associated with Increased Risk of Mortality Interview with:

JoAnn E. Manson, MD, DrPH Chief, Division of Preventive Medicine Brigham and Women's Hospital Professor of Medicine and the Michael and Lee Bell Professor of Women's Health Harvard Medical School Boston, Massachusetts  02215

Dr. Manson

JoAnn E. Manson, MD, DrPH
Chief, Division of Preventive Medicine
Brigham and Women’s Hospital
Professor of Medicine and the
Michael and Lee Bell Professor of Women’s Health
Harvard Medical School
Boston, Massachusetts  02215 What is the background for this study?

Response: The current report provides new information on total mortality and the rates of death from specific causes (cardiovascular disease, cancer, other major illnesses) over 18 years of follow-up in the Women’s Health Initiative (WHI) randomized trials of hormone therapy (estrogen + progestin and estrogen alone). This is the first WHI report to focus on all-cause and cause-specific mortality. It includes all of the 27,347 women in the 2 hormone therapy trials with >98% follow-up over 18 years, during which time 7,489 deaths occurred. This is more than twice as many deaths as were included in earlier reports. The report also provides detailed information on differences in results by age group (ages 50-59, 60-69, 70-79) at time of study enrollment. Why look at all-cause mortality?

Response: All-cause mortality provides a critically important summary measure for an intervention such as hormone therapy that has a complex pattern of benefits and risks. Mortality rates are the ultimate “bottom line” when assessing the net effect of a medication on serious and life-threatening health conditions. Menopausal hormone therapy (HT) is known to have several benefits (reducing hot flashes and menopausal symptoms, decreasing risk of hip fractures and other fractures), but it also has several risks (venous blood clots, stroke, and [for estrogen + progestin] an increased risk of breast cancer.  But what is the net effect of treatment, especially over long-term follow up? —  how does HT affect mortality rates compared with placebo?  Also, does the effect of HT on mortality differ by age group?  Is there evidence for a more favorable effect in younger, compared to older, women? What are the main findings?

Response: For the overall study population (women aged 50-79, mean age 63 at the start of the trials), hormone therapy was not associated with an increase or decrease in total mortality, or deaths from cardiovascular disease or cancer, during the 5-7 yr treatment period or during 18 years of cumulative follow-up.  Over 18 years, the RR was 0.99 in the 2 trials pooled.  However, when examined by 10-year age groups, mortality outcomes were more favorable with hormone therapy in younger than older women.  During the 5-7 years of treatment, the death rates in the women aged 50-59 tended to be lower with hormone therapy than with placebo (a statistically significant 31% lower risk in the 2 trials pooled, p-value for trend by age =0.01).  However, for women in their 60s and 70s at enrollment, neutral results for hormone therapy and mortality were seen.  With extended follow-up for 18 yrs (which included 10-12 years after stopping HT), the differences by age group diminished and were no longer statistically significant. Over 18 years, mortality rates with HT were neutral for the overall study population and were not increased or decreased for all-cause mortality or for deaths from cardiovascular disease or cancer. Were you surprised by any of your findings?

Response: Deaths from Alzheimer’s disease and other forms of dementia were lower with estrogen-alone than with placebo during 18 years of follow up (26% reduction, p-value =0.01).  This finding needs further study and we consider it exploratory.  Estrogen + progestin did not increase or decrease dementia mortality. It is also surprising, given concerns about hormones and cancer, that total cancer mortality was not significantly increased by either  hormone therapy regimen. What should clinicians and patients take away from your report?

Response: Women seeking treatment for distressing hot flashes, night sweats, or other menopausal symptoms in early menopause may find the mortality results reassuring. The findings of a trend toward reduced mortality in younger women (aged 50-59) taking  hormone therapy and neutral effects in older women provide support for clinical guidelines for HT from several professional societies, which endorse HT use for the management of bothersome hot flashes and other menopausal symptoms.  However, the findings would not provide support for the use of  hormone therapy  for prevention of cardiovascular disease or other chronic diseases, given the neutral effect on mortality over 18 yrs (especially among women in their 60s and 70s). What recommendations do you have for future research as a result of this study?

Response: The WHI HT trials addressed the benefits and risks of the most common formulations of HT being used at the time the trials started. These medications are still in use However, in current clinical practice, lower doses and different formulations of HT (estradiol, micronized progesterone) and transdermal routes of administration are increasingly common.  We need additional research on the long-term benefits and risks of these newer treatments. 

No relevant disclosures for me. Some coauthors have listed disclosures. Thank you for your contribution to the community.


Manson JE, Aragaki AK, Rossouw JE, Anderson GL, Prentice RL, LaCroix AZ, Chlebowski RT, Howard BV, Thomson CA, Margolis KL, Lewis CE, Stefanick ML, Jackson RD, Johnson KC, Martin LW, Shumaker SA, Espeland MA, Wactawski-Wende J, for the WHI Investigators. Menopausal Hormone Therapy and Long-term All-Cause and Cause-Specific MortalityThe Women’s Health Initiative Randomized TrialsJAMA.2017;318(10):927–938. doi:10.1001/jama.2017.11217

Note: Content is Not intended as medical advice. Please consult your health care provider regarding your specific medical condition and questions.

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Last Updated on September 13, 2017 by Marie Benz MD FAAD