ERT: If It's So Great, Why Aren't We All On It? Part II

by Jane Sprague Zones and Susan Rennie

This article includes excerpts from presentations on heart disease and Alzheimer's which were part of a panel discussion of ERT organized by the Network. Part I was published in NNJan/Feb 1997.

Will ERT Save Our Minds?
 Headlines in recent months have  proclaimed "The Brainiest Reason toConsider Estrogen," or "Estrogen Aids Brain." Although most menopausal and post-menopausal women have resisted the nearly universal urging of the medical community to start taking estrogen replacement therapy (ERT) in middle age, a new and seductive benefit—that ERT delays or lowers the risk of memory loss—has increased its allure among women who have previously considered ERTs risks and benefits and decided against its use. We know we can take active steps to reduce our chances of developing osteoporosis and heart disease by diet, exercise and other means, but no one seems to know when and why some people lose their memory and others do not.

Memory and Dementia
Recently, estrogen "deficiency" has been associated with memory loss, and dementia, (especially the type of dementia known as Alzheimer's Disease (AD). Biological theories about estrogen's effects on the brain include increasing blood flow and nerve cell growth. Few studies have considered the effect of progesterone, which may counteract estrogen's action in the brain. Research on the relationship between ERT and cognitive functioning (including AD), reports inconsistent findings. A research team at the University of Washington found no differences in ERT use in a study of 107 women with AD and 120 age-matched, randomly selected female controls from a managed care organization. However, they did find that while 61% of controls had more than a high school education, only 35% of the AD cases were in the higher education category.

On the other hand, Annlia Paganini- Hill and her colleagues, who conduct continuing studies at Leisure World, an upper middle class retirement community in Southern California, compared 138 women who had died of AD and other dementias with four times as many age-matched female controls who had died of other causes. They found that the risk of dementia (including AD) for ERT users was only about 65% of those who had never used ERT. Interestingly, however, there was a much higher rate of ERT use in 33 cases whose death certificates indicated they died of senility.

A more recent study which found a benefit for estrogen users was reported last year in The Lancet. A group of researchers at Columbia University studied 1124 elderly women initially free of AD taking part in a longitudinal study of aging and health. In their initial survey, subjects reported on their use of estrogen and age at menopause. They were followed up 1 to 5 years later. Those who developed AD were an average of five years older than those who did not, and had an average of three fewer years of education. Duration of ERT use was related to a lower risk of developing AD.

Problems With Current Research
The failure to control for socio-economic status (SES) in the conduct of this research is its greatest shortcoming. Lower SES is associated with higher rates of AD. It is also associated with lower prescriptions for ERT. ERT is a daily or almost daily drug, which women are being encouraged to take for the several decades of life at and after menopause, costing thousands of dollars per woman over her lifetime. To the extent that researchers do not control for social status in their studies, they may be observing a false relationship between ERT and AD, in that those who were more likely to get AD anyway were also those least likely to use ERT because of access and expense. It is possible that environmental or other factors related to social class may be at play in the development of AD.

Age is a similar confounding factor. People are more likely to develop AD as they grow older, and older women are also less likely to take ERT than middleaged women.

Research in this field is heavily subsidized by grants from pharmaceutical companies with a vested interest in hormone sales. Paganini-Hill's research, for example, which lends the strongest published support to the connection between ERT and lowered risk fordementia, is sponsored in part by Wyeth-Ayerst, makers of Premarin, the most commonly used estrogen product at Leisure World (the research site), and the top-selling prescription drug in the U.S. And the new Women's Health Initiative satellite study on ERT/HRT and Alzheimer's is completely funded by Wyeth-Ayerst.

Alternative Explanations
Environmental and social factors need to be explored as they affect the development of AD, dementia, and cognitive functioning. A September 1996 study reported that the risk of AD is nearly twice as high for men of Japanese heritage in Hawaii compared to Japanese men living in Japan. The risk of Japanese in Hawaii approached the prevalence of Americans of European ancestry. And a group of French Canadian researchers found a significant excess of AD cases in those bom in a rural area Compared with an urban-bom population.

We need to examine the effects of agism upon cognitive function. Levy and Langer studied short-term memory and attitudes toward aging in older (50- 90) and younger (15-30) people from mainland China, deaf Americans, and hearing Americans. Memory loss was greatest in the older Americans without hearing impairment. Among the mainland Chinese, the elders performed very similarly to the young adults. For all of the older groups, performance on shortterm memory tests was directly related to attitude toward aging. The authors surmise that the ways we buy into the expectations of loss of functioning with age are possibly self-fulfilling.

Conclusion
Sandra Coney, author of The Menopause Industry, argues that the attention n improved benefits of ERT is part of the rehabilitation of ERT, which suffered sales losses in the 1970s when it was found to increase cancer risk. Finding that ERT prevents Alzheimer's disease would expand the market for this very lucrative product. The ERT-AD connection is also an extension of a 30-year effort to focus attention on AD that has been conducted by NIH scientists in conjunction with a consumer movement largely created and choreographed by these scientists. What we are witnessing now is a redefinition of Alzheimer's Disease as a female disorder, when in fact there is not convincing evidence to show that women are more likely to develop AD than men. In a fashion similar to osteoporosis, women's fears about risk have been heightened by exaggerated claims of incidence which increase demand for potential remedies.

The research is not conclusive on the relationship between ERT and mental function. What research exists is very much influenced by profit motives. We may need to wait for the conclusion of the Women's Health Initiative—and hope that its independent oversight committee does its job!—to get more valid outcomes. Finally, it is possible that environmental and cultural factors play important roles in pur cognitive functioning as we age, and more attention should be paid to these factors.

ERT, Heart Disease, and Non-Compliance
Many women who talk to their clinicians about ERT or HRT are told that the most important reason to take hormone "replacement" therapy is the prevention of heart disease. Heart disease, the leading cause of death for American women of all racial and ethnic groups, is responsible for over thirty percent of all deaths. The majority of studies of ERT and heart disease have shown a substantial reduction in risk. And yet, the majority of postmenopausal women are not on long-term hormone therapy. This apparent contradiction has led to tremendous frustration on the part of some physicians who believe that ERT/HRT is good preventive medicine. These physicians often talk and write about ways to deal with what they consider to be the problem of "non-compliance"— a phrase more typically used to describe patients who cannot or will not follow instructions for adequate treatment of a medical problem.

It is important to take another look at "non-compliance," first by carefully reviewing the evidence on ERT/HRT and heart disease. There is no evidence from large, long-term randomized studies that estrogen prevents heart disease. The evidence doesn't exist because the studies addressing this aren't finished— in fact they only started a few years ago. After years of pressure by the Network, the federal government finally started the Women's Health Initiative in 1993 which will eventually enroll 25,000 women in a 9-year study of ERT vs. HRT vs. placebo. This lack of information from randomized controlled trials is very important because it is the standard to which treatments are usually held before being considered effective. All cholesterol-lowering drugs have gone through randomized trials before approval, and even aspirin, which is available over-the-counter, was tested in a lengthy randomized trial to determine whether or not it could prevent heart attacks. It is true that there are several observational trials which have found 30-50% less heart disease in women who use ERT, but these trials aren't able to control for other differences between users and non-users, and there is good reason to think that to some extent, rather than ERT preventing heart disease, women who are less likely to develop heart disease are more likely to choose ERT. We need to question why physicians who looked for evidence from randomized trials before they recommended heart disease prevention drugs to men were willing to accept a lower standard of proof for estrogen and heart disease in women.

Many physicians downplay the risk of breast cancer, often talking about it only in terms of women's "fear" of breast cancer as if that fear were completely irrational. Actually, the evidence linking estrogen to breast cancer is consistent— the more estrogen a woman is exposed to, the more likely she is to develop breast cancer. Estrogen probably doesn't cause cancer, but seems to act as a promoter. While studies which compare women who have never used ERT to women who ever used ERT often find no increased risk of breast cancer, studies which look at long-term use and current use consistently find an increased risk of about 30%. The level of evidence for ERT and breast cancer is about the same as the evidence for ERT and heart disease— probable, but not completely proven, and the strength of the effect can't be pinned down until randomized trials are completed.

Some physicians try to address women's concerns about ERT and breast cancer not by downplaying the risk but by trying to persuade women that it is worth trading an increased risk of breast cancer for a decreased risk of heart disease, because heart disease is so much more common. Some physicians ignore a statistic that women seem to know—although breast cancer may be less likely to kill you than heart disease, when it does, it robs women of many more years than heart disease. Women who die of heart disease lose an average of eight years of life. Women who die of breast cancer lose 19 years. Another way of putting that same statistic is that, at least according to the experience of women in the Nurses Health Study, up to age 71 there are three times as many cases of breast cancer as heart attacks.

Women are faced with trying to balance probable risks which occur at a younger age versus probable benefits which occur at an older age. Many women, reasonably enough, chose to forgo ERT and use health-enhancing heart disease prevention strategies such as exercise and changes in their diet. Is this non-compliance or a positive, non-pharmaceutical approach to aging, healthfully?

Susan Rennie and Jane Sprague Zones have recently completed their terms as members of the Network's Board of Directors. A longer version of Jane Zones' article on ERT & Alzheimers is available from the Network Clearinghouse, as are "Taking Hormones and Women's Health" ($8.00) and packets on Menopause, ERT/HRT and Alternative Treatments ($6.00 each).