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Kenneth H. Cooper MD, MPH


Is Hormone Replacement Therapy for Menopause Symptoms Worth the Risk?

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Live well

Tuesday, Oct 10, 2017

Postmenopausal Hormone Replacement Therapy: to Take or Not to Take? Latest Findings from the Women’s Health Initiative  

Many women have moderate to severe symptoms when they reach menopause. These symptoms include, but are not limited to hot flashes, night sweats, difficulty sleeping, moodiness, forgetfulness, and weight gain. The issue of whether or not women should undergo hormone replacement therapy at menopause has had some interesting twists and turns over the past 2 decades. Very recent findings from the Women’s Health Initiative (WHI) have shed further important light on this topic. First, some background: The overall goal of the WHI was to determine the benefits and risks of hormone replacement therapy in postmenopausal women. Between 1993 and 1998, a total of 27,347 women who ranged in age between 50 and 79 years were recruited from 40 clinical centers across the U.S. The women were randomly assigned to one of four groups:   

  • Group 1. Women with a uterus who received estrogen and progesterone    
  • Group 2. Women with a uterus who received a placebo       
  • Group 3. Women who had undergone a hysterectomy who received estrogen   
  • Group 4. Women who had undergone a hysterectomy who received a placebo

The study was double-blinded, which means that during the study neither the women nor the researchers knew who was receiving hormone therapy or who was receiving the placebo. The study on the first two groups was halted early after 5.6 years because an increased risk of breast cancer in Group 1 and an overall finding that the risks of hormone therapy exceeded the benefits. The study on Groups 3 and 4 was halted early after 7.2 years due to an increased risk of stroke in Group 3. When I say that the study was halted, I mean that the women were told which group that they had been in and that they stopped taking study-related hormones or placebo at that point. A very small percentage of women (~3%) chose to use hormone therapy through their personal physician beyond this point.

If the study had truly ended at this time, the conclusion would have been that the risks of postmenopausal hormone therapy were greater than the benefits and that most women are not candidates for such therapy. However, the researchers wisely chose to continue to follow all of these women for all-cause mortality (death) and cause-specific mortality through 2014, which resulted in an average total follow-up period of 18 years. There were a total of 7489 deaths during follow-up. In the Figure below, we will compare the risks of mortality in the different groups. The intervention period is the amount of time that women were receiving hormone therapy or the placebo, while the cumulative period includes the intervention period plus the follow-up time beyond that point. Remember that the overwhelming majority of the women (~97%) stopped using hormone replacement therapy after the intervention period. In Figure 1, we see that there was no difference in all-cause mortality between the groups who received hormone therapy and the groups who received placebo during the intervention; 4% in each group died. During the cumulative period, there was also no significant difference in all-cause mortality between the hormone and placebo groups; just over 27% in each group died.      


Then the researchers carefully examined cause-specific mortality during the cumulative period in the groups. They found that there was no significant difference in cardiovascular disease (CVD) mortality; 8.9% of women in the hormone therapy group died from CVD as compared to 9.0% of the women in the placebo group. Similar findings were shown for total cancer mortality; 8.2% of women in the hormone group died from cancer as compared to 8.0% of women in the placebo group. Since October is Breast Cancer Awareness Month, we thought that it was important to report those findings as well. Among women who took estrogen plus progesterone, there was a higher risk of breast cancer death than in women who took a placebo. The difference in the breast cancer death rates between the two groups approached, but did not quite reach statistical significance. Women who took estrogen alone enjoyed a significant 45% reduction in risk of breast cancer death when compared to women who took a placebo.

This study is important because it represents nearly 500,000 woman-years of data* and focused on mortality risk. Previous WHI data reported primarily on morbidity (illness) during much shorter follow-up periods. So, I’d like to summarize the major takeaway messages from this latest data.

  • Many women suffer moderate to severe symptoms of menopause that interfere with quality of life.
  • Since every woman is different, all women should consult with their primary care physician at menopause regarding the risks and benefits of menopausal hormone therapy. He or she will be the best judge of whether or not you are a good candidate for hormone replacement therapy.
  • In women with moderate to severe symptoms of menopause, as long as contraindications for hormone therapy are not present, then the use of hormone therapy can provide substantial relief for many of these symptoms.
  • Also in such women, the use of hormone therapy for a period of 5-7 years neither decreases nor increases the risk of all-cause mortality during this period, nor does it have a significant effect on all-cause mortality during the subsequent ~13 year period.  

*death rates are often expressed in woman-years or man-years of data. If you follow 1 woman for 1 year, then you have 1 x 1 = 1 woman-year of data. If you follow 10 women for 10 years, then you have 10 x 10 = 100 woman-years of data.   


Manson, J. E., Aragaki, A. K., Rossouw, J. E.…Wactawski-Wende, J. (2017). Menopausal hormone therapy and long-term all-cause and cause-specific mortality. The Women’s Health Initiative Randomized Trials. JAMA, 318(10):927-938.  doi:10.1001/jama.2017.11217

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