The Women’s Health Initiative (WHI) study was initiated in 1991 and aimed to assess if hormone replacement therapy (HRT) has a preventive effect on cardiovascular outcomes in healthy postmenopausal women. The study found that the risk of using preventive HRT exceeds the benefits.
These results caused a huge shift in the perception of HRT, leading to a major reduction of HRT use for the treatment of menopausal symptoms and a “bad reputation” for HRT in the general public. In this blog, we will discuss what were the exact outcomes of the WHI and why they should be regarded with caution.
What was assessed in the WHI study?
The study included 16’608 healthy postmenopausal women with a median age of 63 years that either received oral estrogen and progestin (n=8506) or placebo (n=8102) as a preventive treatment. The combination of estrogen and progestin was the most commonly used HRT at that time.
On average, these women were observed for 5.2 years and cases of chronic heart disease (primary outcome), breast cancer, stroke, pulmonary embolism, colorectal cancer, endometrial cancer, hip fractures and deaths were detected.
What are the main outcomes of the WHI study?
The trial was stopped in 2002, after the data and safety monitoring board noticed an increase in breast cancer risk and a small increase in the risks for cardiovascular disease, stroke, and pulmonary embolism. These risks were not outweighed by observed benefits in risks of fractures and colon cancer among women who had received HRT.
In the final analysis, 29% more cases of cardiovascular disease, 26% more cases of breast cancer and 41% more cases of stroke were reported in women who had received preventive HRT. On the contrary, cases of colorectal cancer were reduced by 37% and cases of hip fractures were reduced by 34% for women on hormone therapy. Overall deaths were similar in both treatment arms.
It is important to note that although these numbers sound very alarming, the absolute difference between treatment arms is not very high since the total number of cases was low. For example, the 26% increase in breast cancer cases relates to a total number of 8 additional cases in 10’000 patient years*.
Why are the results controversial?
It is important to understand that the WHI study was designed to assess the benefits and risks of treatment with estrogen and progestin for prevention. The women included, were healthy, most of them were well past menopause and HRT was not used to treat menopausal symptoms. In fact, women with menopausal symptoms were specifically excluded from the study. The risks of preventive HRT use reported in this study cannot be directly translated into a risk of HRT as a treatment for menopausal symptoms.
As mentioned above, the high numbers for the increase in risk are misleading. For breast cancer, the absolute number of cases observed in 10’000 patient years were 38 cases in women who had received preventive HRT versus 30 cases in women who have not. This translates into an absolute increase in risk for breast cancer of 0.08%.
Moreover, only oral estrogen and progestin combinations were used in the study, which does not allow conclusions on other hormone regimens. In fact, a lot of development regarding dosing and preparations has happened throughout the last 20 years. Newer preparations such as creams and patches have been associated with a lower risk for adverse effects. Therefore, the results of the WHI are not directly applicable for today’s HRT use.
What do we know now?
Over the last two decades, several efforts were undertaken to reevaluate the WHI data and create new insights. Studies showed that the age at HRT use plays an important role. In younger females and women who just entered menopause, the benefits of HRT use do outweigh the risks significantly and HRT has been shown to reduce the cardiovascular risk in these women.
these findings and the continuous controversial discussion of the WHI study outcomes, the fear of HRT persisted. Therefore, it is important to have a comprehensive understanding of the study and its limitations when considering hormone therapy options. Consulting with a healthcare professional who can provide a balanced assessment based on individual circumstances is crucial.
*Patient years is a unit of measure used in medical research to describe the total amount of time that patients in a study were observed. It is calculated by multiplying the number of patients with the time they have been observed. For example, if 2’000 patients have been observed for 5 years, this relates to 10’000 patient years. Patient years can be used to compare the incidence of diseases over time.
