HRT UPDATE

Ruth K Weinberg, MD, Jack Imig, MD, Sherburne Macfarlan, MD, Lissa Mcintyre, MD, Molly Yardley, MD, Saul Snowise, MD
7/30/2002

You have probably heard a great deal through the media about the recent study on hormone replacement therapy and the controversy that has been stimulated by it. We wanted to give you some written feedback about how we are counseling our patients at this time.

Details of the Study

The Women's Health Initiative (WHI) is a study trying to look at several outcomes from hormone replacement therapy (HRT), there were 161,809 women enrolled. These were divided up into 2 main arms of the study; in one arm half of the women were randomly assigned to take Prempro (a combination of Premarin and Provera) and the other half were on a placebo pill (no hormones). In the other arm, half of the women were randomly assigned to take Premarin alone and the other half took placebo. The women in the second arm of the study had had hysterectomies, so they did not need to take Provera.

The Prempro arm of the study was stopped after about 5 years because of an increased rate of cardiovascular events (heart attack and stroke) and an increased rate of breast cancer seen in the women on Prempro compared to placebo. The Premarin alone arm is still continuing, since no increased risks have been shown to date.

Lets deal with these issues separately first.

Cardiovascular risk

• There was a 39% increased risk of heart attack on Prempro versus placebo, which translates to 37 heart attacks per 10,000 women per year in the Prempro group compared to 30 heart attacks per 10,000 women per year in the placebo group.
• There was a 41% increase risk of stroke on Prempro versus placebo, which translates to 29 strokes per 10,000 women per year in the Prempro group as compared to 21 strokes per 10,000 women per year in the placebo group.

Two criticisms of the study that have been raised:

• The average age of the women starting the study was 63 & 21% of the women were in their 70's. Maybe the older women had already developed some heart disease before starting the estrogen, a better way to see if estrogen really prevents heart attacks would have been to just look at women who started estrogen in their early 50's when they just started menopause.
• There was no record of what other medication the women in the placebo group were on. If they were started on statin drugs, like Lipitor or Zocor, their heart attack risk would be expected to go down compared to the women on Prempro.

What may be going on here is that the risk factors for heart disease that we look for in men may be different than the risk factors in women. Also, maybe not all estrogens are created equal as far as heart disease. For instance, some of the newer data about heart disease risk in women imply that Triglycerides (TG) may be more of a factor than we thought and just watching LDL (low-density lipoproteins) may not be enough. Estrogens decrease LDL but raise Triglycerides. Maybe some types of estrogen don't raise TG as much as others. Evista is a selective estrogen receptor modulator that lowers LDL and TG. Future studies will hopefully clarify these issues.

Our conclusions:

• If you have existing cardiovascular disease, there is no benefit to starting or continuing HRT.
• If you are taking HRT just to prevent cardiovascular disease, this study has called that into question, and perhaps a statin drug would be a better choice.
• If you have few risk factors for cardiovascular disease and you like the other benefits of estrogen, than it may still be a good choice.
• If you develop elevated Triglyceride levels on HRT, we might recommend changing over to a statin drug or Evista.

Breast Cancer Risk:

The rate of breast cancer in the women on Prempro was slightly higher than the women on no hormones, but the difference was not statistically significant. This means we cannot be sure the difference isn't due to chance or factors other than estrogen. This is very similar to the other studies about estrogen and breast cancer. There was a 25% increased risk of invasive breast cancer in the women on Prempro, which translates to 38 cancers per 10,000 women per year in the Prempro group compared to 30 cancers per 10,000 women per year in the placebo group.

Criticisms:

Growth of breast tumors is slow. It takes 10 years for a malignant cell to become clinically detectable at 1 cm. If estrogen stimulates growth of already existing tiny tumors we should catch them sooner in estrogen users. So if the study had continued, the same number of breast cancers might have been found in the other group, but they would have been detected later and the cancers may have been more aggressive by then. Other studies have shown a decreased risk of dying from breast cancer if it is diagnosed while on HRT, perhaps we catch it when the tumors are smaller and appear less aggressive. Interestingly, the week before this WHI study report, a large study in the New England Journal of Medicine showed no increased risk of breast cancer in birth control pill users, this is an example of conflicting results of studies looking at hormones and breast cancer.

Thromboembolism:

Thromboembolism is the formation of blood clots. This includes deep vein thrombosis, which is a clot in the deep veins of your leg, and pulmonary embolism, which is when a blood clot breaks off and floats to your lungs. Estrogen & Evista slightly increase the bloods tendency to clot. A similar change occurs during pregnancy and on birth control pills. This is a known risk of taking estrogens or Evista, although it is a small risk. There was a 211% increase of deep vein thrombosis on Prempro, which translates to 34 cases per 10,000 women per year in the Prempro group compared to 16 cases per 10,000 women per year in the placebo group.

Osteoporosis:

Finally some good news about estrogen! There were 5 less hip fractures per 10,000 women per year in the women on estrogen. So estrogen does appear to protect against osteoporosis.

Colon Cancer:

There were 6 less cases of colon cancer per 10,000 women per year in the women on estrogen. So estrogen does appear to protect against colon cancer.

Summary:

So how do we put this all together? The decision about hormone replacement therapy is still a complicated and individual one. Each medication option has its pros and cons, and even deciding not to take any of them has risks and benefits. Some of these medications have additional risks and benefits that weren't addressed in this study. Some factors may be more of an issue than others for you. We have to take into account your chances of developing certain diseases, as well as your concerns about risks of the medications, and of course your symptoms.

We have constructed a table that we think helps compare the drugs that are options after menopause. Please feel free to look it over and see if it helps you in your decision-making. We would be happy to have your come in for a consultation appointment to discuss the options and the recommendations in your particular case.

* Controversial - Estrogen plus progesterone may be different than estrogen alone, and different types of estrogen may act differently.