I’m sure most of you saw the news reports that came out subsequent to the publication of the ongoing Women’s Health Initiative study (the WHI) that was published in the October 20 issue of JAMA. The “reviews” varied from (and I paraphrase): “this shows that hormone therapy is a disaster” to “maybe hormone therapy should be limited” to “well, this study was a follow-up of women who had taken Prempro and it may not be relevant to other forms of hormone therapy”. I think that the conclusion should be somewhere in between all of these statements.

First, let’s look at the statistics: The original study included 16,608 women who ranged in age between 50 and 79. Unfortunately the age range skewed high; the average age of the women was 63. (Remember that they needed to include women who did not have horrific menopausal symptoms, otherwise if their severe hot flashes, night sweats and sleep disturbances were not relieved by the placebo pills the women as well as their doctors, would know that they were not taking “true” hormones and this would “unblind” the study. So many of the women were 10 or 15 years post- menopausal.)  To continue….basically the study group was given Premarin and a synthetic progestin (Provera) in the form of Prempro and the control women were given a placebo. The study was stopped after a mean of 5.6 years because the researchers found that the women on the hormone therapy did not receive health benefits that exceeded the risks, including the risk of invasive breast cancer.

This new JAMA article reported on the follow-up of most of the original women in the study for a total of 11 years. (Remember, the group of women on Prempro were instructed to stop taking it after 5.6 years.) After obtaining consent from most of the women to continue the follow-up, the researchers looked at whether the cancers the women had at diagnosis were advanced (ie had spread to the lymph nodes) and whether those who had taken Prempro and developed breast cancer were more likely to die of the disease or indeed die from any cause. They found that, indeed, the mortality from breast cancer was higher in the women who had taken Prempro. Here, however is where numbers do matter: The risk of death from breast cancer in women who had taken Prempro, when extrapolated to 10,000 women per year was calculated to be 2.6 (ie 2.6 women out of 10,000 women who took Prempro would ultimately die from their breast cancer.) This was compared to the risk of death from breast cancer in women who did not take Prempro. That number was 1.3 deaths per 10,000. Death after diagnosis with breast cancer from other causes (not from the actual cancer) was also higher in women who took Prempro. This was extrapolated to 5.3 deaths vs 3.4 deaths in women not on this hormone per 10,000 women per year.

Here is the summary in the official response from the American Congress of Obstetricians and Gynecologists (ACOG):  The study reported 25 deaths [0.03% per year] vs 12 deaths [0.01% per year], with a Hazard ratio of 1.96; 95% CI, 1.00-4.04; P=.049). This represents an absolute risk of 2.6 deaths from breast cancer (in the combined hormone group) vs 1.3 deaths (in the placebo group) per 10,000 women per year.

• There were more deaths from all causes occurring after a breast cancer diagnosis (51 deaths [0.05% per year] vs 31 deaths [0.03% per year]; HR, 1.57; 95% CI, 1.01-2.48; P=.045) in women taking combined estrogen and progestin compared with placebo.  This represents 5.3 vs 3.4 deaths per 10,000 women per year, respectively.

Summary:

• The recent report from follow-up to the WHI study demonstrates the risk of breast cancer for women taking combined estrogen plus progestin.  There is an increased risk of invasive breast cancer, breast cancers presenting with positive lymph nodes, and breast cancer mortality.  While the absolute risk of breast cancer mortality is small, it is significantly increased for women taking combined estrogen plus daily progestin.
• A 2004 report published in JAMA on the estrogen-alone component of the WHI found no increase in breast cancer risk among women with hysterectomy over an average of 7 years of randomized treatment.
• Women considering hormone therapy for relief of menopausal symptoms should continue to be counseled that they should use the lowest effective dose, for the shortest period of time.

Now I just want to add my take…We know that progestins can increase the growth and proliferation of blood vessels (angiogenesis). It’s possible that the women on Prempro (versus those on estrogen only) had small vessel growth in their breast tissue that led to spread of the cancer cells, hence they were more likely to have a somewhat more advanced disease at diagnosis. Moreover, hormone therapy with estrogen and progestin can increase breast tissue density, making it more difficult to detect an early cancer in mammogram….leading to a delay in diagnosis. Finally, it’s possible that this type of estrogen (Premarin) with the addition of this type of synthetic progestin (Provera) together have a greater impact on breast cancer mortality as well as other causes of disease (inflammation, atherosclerosis and coronary heart disease) that are unique. The WHI was not conducted on other forms of estrogen (estradiol) or more natural progesterone… the hormones our ovaries produce during our reproductive years.  When many physicians prescribe hormone therapy, they take this into account and try to limit doses of both as well as considering the type of estrogen and progesterone they prescribe.

In the end the decision to take hormone therapy depends on a woman’s menopausal symptoms. The risk of any medication should always be calculated and weighed against its benefits. There are myriad studies that show that early hormone use in menopause has a positive impact on heart disease and symptom control for the appropriate women. There is no other therapy as effective when it comes to treating severe menopausal symptoms.

The decision to begin hormone therapy has to be made on an individual basis and should be discussed with your physician. (If you are my patient, I hope we have had this discussion.) The absolute risk for breast cancer as a result of hormone therapy remains small but real. I echo the recommendations of ACOG and the FDA. Use the smallest dose for the shortest time to reach your treatment goals.