Do Hormones Cause Breast Cancer?

Do the results of this study mean I should stop my hormone replacement therapy?

I received an e-mail with this question from a patient citing the CBS and PBS News broadcasts last night in which the results of this study were offered as further evidence that women should not take HRT at all, or only for the severest of symptoms and for the shortest length of time. Given the way this publication is being reported, I am sure to receive quite a few more.

The paper reported on the breast cancer risk of 12,788 out of the 16,608 women in the Women’s Health Initiative (WHI) study who had not had a hysterectomy and therefore took Premarin and Provera for a mean of 5.6 years. While I could quibble with their intention-to-treat analysis given that there was only an 83% follow up rate, let’s assume the results are correct. They found that after 11 years of follow up, women taking Premarin and Provera had an increased risk compared to those taking a placebo of invasive breast cancer (0.42% vs. 0.34% per year), and death attributable to breast cancer (0.026% vs. 0.013%). These are small numbers, working out to about one more case of invasive breast cancer per 1,000 women per year and a little over one more death per 10,000 women per year. While we would like to avoid each of these deaths, when described in these absolute risk terms it does not have nearly the same impact as the headlines you have heard, also true, that the relative risk of death doubled (going from 0.013 to 0.026%).

A perhaps more misleading problem with this report lies not in the statistics, but in the title. It would be more accurate and less misleading if it read, “Premarin Plus Provera and Breast Cancer Incidence and Mortality in Postmenopausal Women,” not the more generic ‘Estrogen Plus Progestin’, because there is much evidence to support the statement that not all progestins are alike in their effect on breast cancer risk. It is astonishing to me that the authors of the Women’s Health Initiative Study (WHI) papers still engage this “class effect” thinking about the results of their investigations into one type of estrogen and progestin — Premarin and Provera.

‘Provera’ is medroxyprogesterone acetate (MPA), a synthetically altered form of the molecule that naturally occurs in a woman’s body called ‘progesterone.’ Both are progestins in that they have the effect stabilizing the lining of the uterus after it has been stimulated to thicken under the influence of an estrogen. ‘Premarin’ is the name for a group of estrogens derived from pregnant mare urine, whereas ‘estradiol’ is the name of the form of estrogen naturally occurring in a woman’s body. Both are estrogens because they stimulate the lining of the uterus to thicken, but they are not molecularly identical and have different effects in other tissues. Thus, menopausal therapy with estradiol and progesterone is called ‘bio-identical’ HRT or ‘BHRT.

While Premarin is not the ideal form of ERT (not molecularly identical and orally administered), the WHI investigators also reported that women with a hysterectomy who took only Premarin alone had a 23% decreased risk of breast cancer compared to placebo(1). Although this decrease was not quite statistically significant, it certainly at least reassures one that Premarin alone does not increase the risk of breast cancer after over 5 years of use. If you take this fact along with the increased risk of breast cancer in women taking Premarin and Provera, the logical conclusion should be that Provera is the culprit, not HRT overall. But in the United States, probably because prior to the WHI 90% of women on HRT took Premarin and Provera, the class effect mentality continues despite significant evidence that it is flawed thinking.

In Europe, where Premarin and Provera have not dominated the market the medical thinking is different. The very large E3N study that followed 80,377 women on various progestin/estrogen combination (none on MPA) for 10 years found no increased risk of breast cancer in women taking progesterone and an estrogen over 35,000 person years of follow up(2). This study focused on women going through the menopause in real life conditions as opposed to older women being placed on Premarin and Provera an average 13 years after menopause. In vitro evidence also supports the difference between various progestins as well. In a study that looked at the effect of various progestins on the proliferation of breast cancer cells found that progesterone had an inhibitory effect whereas Provera did not(3).

The bottom line: not all progestins are alike; results from a study with one progestin should not be generalized to all progestins. Therefore, these results should have no impact on your decision to continue with estradiol and progesterone for the signs and symptoms of menopause. We have substantial real-world evidence for the safety of taking the form of HRT you are currently on and await the results of randomized controlled trials from the Kronos Early Estrogen Prevention Study (KEEPS)(4) and the Early versus Late Intervention Trial with Estradiol (ELITE) to further clarify the cardiovascular and cognitive benefits of bio-identical HRT.

1. Anderson GL, Limacher M, Assaf AR, et al. Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Women's Health Initiative randomized controlled trial. JAMA. Apr 14 2004;291(14):1701-1712.

2. Fournier A, Berrino F, Riboli E, Avenel V, Clavel-Chapelon F. Breast cancer risk in relation to different types of hormone replacement therapy in the E3N-EPIC cohort. Int J Cancer. Apr 10 2005;114(3):448-454.

3. Seeger H, Wallwiener D, Mueck AO. The effect of progesterone and synthetic progestins on serum- and estradiol-stimulated proliferation of human breast cancer cells. Horm Metab Res. Feb 2003;35(2):76-80.