By Sarah L. Berga, MD
One of the benefits that has come from the release of the data from the Prempro® arm of the Women’s Health Initiative (WHI) has been a re-evaluation of the pros and cons of menopausal hormonal therapy. In undertaking this appraisal, one inevitably asks what are rational alternatives to hormone use. It is a very logical question. I think we have to accept that many, if not most, women and men want to do what they can to remain as well as possible for as long as possible. Aging gracefully is a worthy pursuit, and we need to find ways to aid those who attempt it. After all, it is a sign of mental health that one wants to minimize age-related disability and disease. However, it is not trivial to outline acceptable alternatives. Consider the following issues.
To delineate alternatives to postmenopausal estrogen or progestin use, one must first understand the benefits and risks of its use. The difficulty inherent in comparing postmenopausal hormone therapy with various alternatives is highlighted by the fact that hormone therapy does not constitute a single therapy. Indeed, although it is not commonly appreciated that each estrogen preparation has unique molecular and tissue effects, the same dose of a given estrogen or progestin does not lead to the same circulating levels in all women or in all tissues within that woman, and not all women stand to benefit equally or suffer the same risks and side effects from postmenopausal estrogen use. Further, progestins differ in their molecular and clinical profiles.
Given this enormous complexity and ever-burgeoning molecular insights, clinicians may feel stymied by a lack of reliable clinical data upon which to guide treatment decisions. Further, the adequacy and acceptability of alternatives to postmenopausal hormone use depend in part on the expectations and goals of therapy. If goals are circumscribed (such as treatment of osteoporosis), then it is easier to delineate several acceptable alternatives. If the goal is to produce in all tissues of relevance an estrogenic effect, but with an absence of estrogen action in tissues in which this effect is deemed deleterious, then that is a much more ambitious undertaking. In asking what might constitute acceptable alternatives to postmenopausal estrogen therapy, one could simply advocate a good lifestyle with an appropriate amount of exercise and an acceptable diet. Or one could advocate a good lifestyle plus periodic surveillance for disorders for which we have good treatment options, such as statins for dyslipidemia. This strategy involves waiting for a disease process to announce itself and then trying to intervene.
The problem is that most health-conscience individuals want to ward off age-related disease and disability before it becomes evident. This means prevention and prophylaxis. The ultimate goal is to retard the aging process. This is also a much more complex task than commonly assumed. While we can enumerate age- related disabilities and diseases, we still don’t really understand what aging means at the molecular level. It is hard to imagine how we could reverse or retard a process that is so poorly understood. Fortunately we are making progress in understanding that ontogenic process we call aging. For those aficionados who love science at its best, try reading the Feb. 28, 2003, issue of Science, which is devoted to illuminating the many dimensions of aging. In that issue, Juengst and colleagues urge that our scientific institutions must take the lead in ensuring that public discussion of anti-aging research is as deliberate and farsighted as the research itself.1 If there is one thing we learned from the WHI, it is that strategies advocated for retarding aging hold both promise and peril.
Agents commonly considered as alternatives to postmenopausal estrogen use for preventing age-related disability include selective estrogen receptor modulators (SERMs), phytoestrogens, black cohosh, other herbal agents, and some vitamins. Other "anti-aging" hormones include dehydroepiandrosterone (DHEA), androstenedione (Andro), melatonin, and growth hormone and its analogs. Although acceptance of postmenopausal estrogen therapy has been constrained by recent evidence from the WHI, acceptance of alternatives often is buoyed by hypothetical benefits based on reductionistic assumptions about tissue effects or pathogenetic mechanisms, known benefit in a particular tissue such as bone without demonstrated efficacy in other tissues, and/or lack of long-term data regarding clinical outcomes. Indeed, the more an agent is studied, the more we find out about its risks and side effects. Often, putative benefits do not stand the test of time. The availability of untested or insufficiently tested agents coupled with negative perceptions regarding pharmaceutical estrogens makes counseling menopausal women a challenging task.
Despite the limitations of current strategies, our increasing longevity makes it imperative that we continue to search for ways to reduce the burdens of aging. Although we don’t quite know why, there can be no doubt that we are on average living longer and longer. Although the field of anti-aging is in its infancy and our initial attempts look as clumsy as the first car or early computers, this line of investigation and intervention is here to stay. Today’s task is to help patients understand the gap between expectations and our limited fund of knowledge. It is important for physicians and patients to recognize that we will be forever refining our approaches. Whatever strategies are undertaken will hold both promise and peril, because there is no easy and rapid way to acquire the knowledge needed to hold back the ravages of aging.
Dr. Berga is Professor and Director, Division of Reproductive Endocrinology and Infertility, University of Pittsburgh.
Reference
1. Juengst ET, et al. Aging. Antiaging research and the need for public dialogue Science 2003;299:1323.
Berga SL. Alternatives to menopausal hormone therapy. Altern Ther Women's Health 2003;5(9);70-71.
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