The Women’s Health Initiative (WHI) studies were the first large-scale, double-blind, placebo-controlled clinical trial of Hormone Replacement Therapy in healthy, postmenopausal women. This type of study is considered the gold standard for clinical research. The hormone medication used by women in the estrogen-plus-progestin part of the trial was Prempro, a single pill that combined conjugated estrogen and progestin. The WHI had two separate parts: one part designed for hysterectomized women who were given a pill that contained estrogen but not progestin, and a second part that included women with their uterus intact who received a combination pill (Prempro) containing estrogen and progestin.
The End of the Trial
The WHI estrogen-plus-progestin trial and estrogen-alone trial of hysterectomized women were both halted early (in July 2002 and February 2004 respectively) because study results indicated that the health risks of Prempro (conjugated equine estrogen and progestin) exceeded the benefits.
The first published report on the interrupted, estrogen-plus-progestin study came out in July 2002. It reported on over 16,000 women followed for an average of 5.2 years. Half of the women took a placebo, and the other half a combination of progestin medroxyprogesterone acetate and conjugated equine estrogens. The study found statistically signficant increases in rates of breast cancer, coronary heart disease, strokes and pulmonary blood clots in the women treated with the synthetic hormones. Analysis of the data also showed statistically significant decreases in rates of hip fractures and colorectal cancer. A year later, a new analysis of data from the trial indicated that taking estrogen plus progestin also increases risks of dementia. The conclusion of this study was that the hormone combination in Prempro presented risks that outweighed benefits.
The risks of coronary heart disease in women subjects varied with their age and the number of years from the onset of menopause. Women aged 50 to 59 using HRT showed a small trend towards lower risk of coronary heart disease, as did younger women who were within five years of reaching menopause.
The adverse cardiovascular outcomes may only apply to oral dosing with progestin and equine estrogens, as other types of HRT such as topical estradiol and estriol, used in bio-identical hormone therapies for menopause, may not produce the same risks. Results from other studies suggest that when estrogen is administered orally, liver function is altered and the risk of blood clots is increased.
WHI preliminary results reported in 2004 found a non-significant trend in the estrogen-alone clinical trial towards a reduced risk of breast cancer. Updated in 2006, researchers concluded that use of estrogen-only for 7 years does not increase the risk of breast cancer in postmenopausal women who have had a hysterectomy. The results of the WHI estrogen-alone trial suggest that the progestin in the WHI estrogen-plus-progestin trial increased the risk for breast cancer above that associated with estrogen alone. Estrogen-alone HRT (”unopposed estrogen”) poses unacceptable cancer risks to women who have not had a hysterectomy.
No Heart Benefit for Older Women
Another recent randomized, controlled trial found that HRT may actually prevent the development of heart disease and reduce the incidence of heart attack in women between 50 and 59, but not in older women. The mechanism may have something to do with the contradictory effects of increasing propensity for clotting, versus improving both “good” and “bad” cholesterol concentrations in the blood (which would have a protective effect). Followup studies are underway which are intended to confirm these findings. The increased risk of breast cancer remains a major cause for concern.
Breast Cancer Risk Confirmed in UK Study
A national study of women’s health in the UK, involving more than one million British women aged 50 and over, was undertaken to answer questions about about factors affecting women’s health in this age group. One of the questions the study attempted to answer was the safety, risks, and benefits of hormone treatments for menopause. The Million Women Study was set up with the aim of recruiting 1,000,000 women in the UK into an ongoing cohort study, to provide answers to the following questions:
- What effects do combined estrogen and progestagen (a synthetic form of progesterone) hormone replacement therapy (HRT) preparations have on breast cancer risk?
- Are breast cancers detected at screening in women who have used HRT or oral contraceptives different in terms of size and invasiveness from cancers detected in women who have never used these hormones?
- How does HRT use affect the efficacy of breast cancer screening?
- How does HRT use affect mortality from breast cancer and other conditions?
Follow-up of over 1 million women in the Million Women Study confirmed findings from other recent studies that women currently using HRT are more likely to develop breast cancer than those who are not. Past users are not at increased risk. The study was able to show that this effect is substantially greater for combined (estrogen-progestagen) HRT than for estrogen-only, and that the effects were similar for all types and doses of estrogen and progestagen, oral, transdermal and implanted HRT, and for continuous and sequential patterns of use. Current users of estrogen-progestagen HRT were at 2-fold increased risk of developing breast cancer, and current users of estrogen-only were at 1.3 fold risk. Use of HRT by women aged 50-64 in the UK in the decade from 1993-2003 resulted in an estimated 20,000 extra breast cancers.
These results are yet to be studied in the context of the three most common cancers in women: breast, endometrial (womb), and ovarian cancer. Together, these cancers account for about 4 of 10 cancers in UK women. The findings of the WHI show that in women aged 50-69, about 19 will develop cancers over 5 years in every 1000 women not taking HRT. In women taking HRT the estimate is for the number of cancers to be increased to about 31. The overall increased risk is higher in women using combined estrogen-progestagen HRT than in women using estrogen-only, and most of the overall increase is due to an increase in breast cancer. Users of combined HRT have a higher risk of breast cancer than users of estrogen-only HRT.
HRT Significantly Increases Stroke Risk
In April, 2008, a new analysis of data from the Nurses Health Study by Harvard researchers showed that hormone replacement therapy (HRT) can increase post-menopausal women’s stroke risk regardless of when the HRT began. While the risk for stroke seems to be lower in younger women taking HRT and in women taking the lowest doses of estrogen, Harvard researchers say women who took the high hormone doses used in the WHI experienced an increased stroke risk by as much as 62 percent.
HRT Increases Benign Breast Disease
In April, 2008, researchers at the Albert Einstein College of Medicine in New York City discovered that women who took a common form of estrogen as hormone replacement therapy (HRT) during menopause more than doubled their risk for certain types of benign breast disease, for example, benign proliferative breast disease, as compared with women who took a placebo, over an average of about seven years. Benign proliferative breast disease is relatively common and has been linked with increased risk of breast cancer.
Prempro Increases Dementia in Older Women
A study to determine if the combination of estrogen and progesterone therapy taken by older, postmenopausal women would improve cognitive functioning and protect them from mental impairment, published in the J. of the American Medical Association (May, 2003), found that the combination drug doubled the chances women would develop dementia, compared with women who didn’t take the drug. Researchers concluded that because of possible harm and lack of demonstrated benefits, the combination therapy (Prempro) should not be prescribed for older, postmenopausal women to improve or maintain cognitive functioning.
German Study Confirms Breast Cancer Link
In May, 2008, A study out of Germany found hormone replacement therapy (HRT) drugs – inlcuding Prempro and Premarin – taken for more than five years, increases one’s breast cancer risk, confirming earlier findings out of the United States. Over 10,000 German women between 50 and 74 were studied for over six years. Of these,:3,464, approximately, 4 out of 10 women, became breast cancer patients and 6,657 remained healthy. The German survey was prompted by the “MARIE” case-control study carried out by the German Cancer Research Center.
As a result of the WHI trial experience, the FDA now requires a warning label on the menopause drug Prempro.
You must log in to post a comment.