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Getting in Nature’s Way

But no matter its other presumptive advantages, the emphasis was always on HRT’s benefits in reversing, or at least holding off, the aging process. Though the women who took hormones may initially have been attracted by their effect on menopausal symptoms, most of those who continued treatment were more interested in how they looked, the texture of their skin, and the revitalization of their energies. To many of them and to their doctors as well, aging was a disease, unnecessary and henceforth treatable. If taking a few pills every day could enhance the quality of life without any dangers, as the press and television proclaimed with the wide agreement of the medical profession, why not try them out?

Some foresighted gynecologists warned that estrogen’s potential for encouraging tissue growth might promote the development of cancer, but calls for specific studies of that possibility went unheeded. And then in 1971, it became apparent that women whose mothers had taken the synthesized estrogen compound diethyl stilbestrol (DES) during the first trimester of pregnancy had a distinctly higher risk of developing adenocarcinoma of the vagina, a relatively rare malignancy. A few years later, two studies were published describing a several-fold increase in endometrial cancer, a cancer of the uterus, among women who had been on HRT. The medical profession’s response was to change the treatment, adding progesterone, a steroid hormone, and emphasizing the preventive aspects of the hormones, especially the well-documented improvement in bone density for those women at risk for osteoporosis. It is estimated that more than a third of post-menopausal American women were having hormonal therapy by the end of the 1990s. Meanwhile, further investigations had failed to confirm that it lowered the incidence of Alzheimer’s disease.

Finally in July 2002, a study by the US government–funded Women’s Health Initiative comparing 65,000 women on hormones to 100,000 controls was stopped because it had become obvious that those on HRT were having more coronary events, strokes, blood clots in the lung, and invasive breast cancers. Though they had fewer colorectal cancers and hip fractures than the control group, the decision about HRT was expressed as follows in an editorial in the Journal of the American Medical Association: “Do not use estrogen/progestin to prevent chronic disease.”

Of course, there is still a place for HRT in the lives of many women who, having considered the risks and benefits with their doctor, may find it useful to take the hormones for their own distinctive physical situation. Some, for example, have such distressing menopausal symptoms that they feel justified in accepting the added possibility of danger; so do women who by family history or for some other reason are at such a high risk of developing osteoporosis that the benefits would seem to outweigh any other considerations. But at least the word has spread that such treatments do not guarantee a life of youthfulness and that decisions about chemicals whose primary purpose is enhancement must be made individually by each patient and her doctor. The real question for physicians and consumers, though, as posed by the Rothmans, is whether the kind of careful testing by the Women’s Health Initiative that limited the use of HRT will be applied to other treatments. “Will they now use HRT as the model for guiding their use of plastic surgery and liposuction? Will they use the story of estrogen as a template for evaluating future genetic enhancements?”

To respond to the first question, there is no evidence that the demand for liposuction has slowed down. Over 400,000 such procedures to remove fatty tissue were performed in 2001 (of which 20 percent were done on men) and the number grows ever larger. This in spite of statistics indicating that some eighty of those patients died as a result of the operation, a mortality rate exceeding that for adult hernia repair by a factor of almost seven. Hundreds of thousands of Americans are subjecting themselves to a possibility of postoperative complications and death that surgeons would find unacceptable for any other elective procedure. It is ironic that the doctors who choose to perform an operation that is solely cosmetic are willing to accept mortality and complication rates significantly higher than those who restrict their interventions to those required for the treatment of disease. Perhaps this says something about the standards observed by cosmetic surgeons. Yet we can expect, as the authors write, that liposuction will continue to “go forward without significant attention to risks.”

Ironically, the earliest of all hormonal manipulations has never established itself as either popular or particularly useful. Though hormone treatment for testosterone-deficient young men is an established medical intervention, the notion that it will rejuvenate the elderly or improve their sexual functioning has found little support in unbiased studies. Following decades of initial optimism, there seems far less interest in it on the part of either doctors or patients. One nowadays finds only infrequent glowing testimonials to testosterone of the sort that were common in women’s magazines to boost the sales of HRT. There was a burst of advertising for testosterone by drug companies in the decades following World War II, but this has significantly decreased in recent years.

The reasons for the falling off of enthusiasm for testosterone supplements go beyond the fact that they have not been shown to accomplish the purpose for which they were initially touted. Because there is no male equivalent to the dramatic changes of menopause, symptoms requiring urgent amelioration—insomnia, hot flashes, weight gain, etc.—do not occur and the changes in appearance set in gradually. Moreover, middle-aged men tend not to be as intent on maintaining youthfulness, whether in appearance or physiology, as women of the same age. When they get a medical checkup, they are more likely to have it done by an internist than are women, who frequently use their gynecologist as a general practitioner. A visit to a specialist in urology, who would be far more likely to recommend testosterone therapy, only occurs if the actual symptoms overcome the man’s greater reluctance to seek medical attention.

And then there is the question of cancer. Like estrogen’s effect on breast tissue, testosterone can stimulate cellular proliferation in the prostate. Studies have not been extensive enough to prove an association beyond doubt, but contrary to the experience with estrogen, physicians are hesitant to prescribe a therapy with such potential when there is no proven benefit. The National Cancer Institute and the National Institute on Aging, concerned that steadily increasing use of testosterone compounds might result in a greatly heightened incidence of prostate cancer, recently asked for advice from the Institute of Medicine of the National Academy of Sciences on how to convince the public of the hormone’s lack of benefit and its potential dangers. The academy has suggested small clinical trials to provide evidence of risk. Should the results of such investigations prove unrevealing, large, long-term studies could then be undertaken.

And yet, some physicians continue to prescribe male hormones. Though the FDA prohibits the marketing of testosterone as an anti-aging therapy, there are enough hints in the advertising of such products and in occasional articles appearing in the popular press that many physicians will prescribe it for selected patients. Moreover, the hormone is a staple—along with other kinds of hormones, fetal cells, and numerous antioxidants—of the hundred or more so-called “rejuvenation clinics” that have sprung up throughout the country. The result is that anyone who wants testosterone without his doctor’s knowledge can get it, whether by answering an advertisement or by going on-line to a Web site that provides the names of doctors who treat “testosterone deficiency.”

Among the rationalizations for giving testosterone to older men is that their natural levels of the hormone wane with age: it would seem logical to use replacement therapy even though it seems to provide no benefits. Something of the same logic has been used to justify injections of growth hormone, whose blood levels were also found to decline with the passing of years. Growth hormone treatments, often administered to children with a deficiency of the hormone, had been a source of contention for decades, not only because a number of cases of the neurologically crippling Creutzfeldt-Jakob disease were found among children to whom it was given, but also because of the vexing question of which children should receive it. Should a short but not hormone-deficient child be treated? How short is short? Where does treatment end and enhancement begin? Because the use of growth hormone in some children resulted in stronger bones, increased muscle strength, and reduced body fat, researchers thought it might reverse some of the common problems of aging, namely osteoporosis, muscle weakness, and the accumulation of fatty tissue. Not only have the results been ambiguous, but significant side effects have occurred, such as joint pain, numbness, and swelling of the legs. In addition, experimental work indicated that mice injected with growth hormone did not live as long as those without it.

None of this has deterred the rejuvenation clinics and many physicians from prescribing growth hormone. Though not approved by the FDA to treat the symptoms of old age, there is no law against such use, and so-called “off-label” prescribing for older men is common. “All of which,” conclude the Rothmans, “helps explain why enhancement technologies, whatever their putative benefits or demonstrated risks, will have significant space in our future.”

And, they add, “there is no holding back the enterprise.” Research will go forward, and there will be great pressure for its clinical application:

As this history of enhancement has demonstrated time and again, routine methods of oversight will not be adequate, nor will the advice of individual physicians or professional medical societies or government regulators. What is required is an intimate understanding of the nature of the research and the reliability of the results. Only with this information at hand will consumers be able to calculate potential risks and benefits to know whether to join the line outside the doctor’s office, or to demur.

This is wise advice, and the Rothmans have built a powerful case for it. But it is far more easily given than taken. In the long run knowledge guarantees neither wisdom nor sound judgment. Seeking out every available fact about some method of enhancement—or any other medical intervention, for that matter—does not give the perspective that can only come from professionally trained authorities with experience in the distinctive variety of critical thinking that is called clinical judgment. The fact that the clinical judgment of physicians has been woefully inadequate in the situations so well described by the Rothmans does not mean that it should be discarded.

What it does mean is that some of the strangers previously mentioned do have a place at the bedside. Decisions which in decades past were considered strictly clinical must now be recognized as having a moral, an ethical, a philosophical, and a legal aspect, and even a bearing on public policy. Ideally, the therapeutic implications of every coming medical advance should be scrutinized with these perspectives in mind. When that becomes the norm, society and individual patients—and the Rothmans—will need no longer fear that practitioners, medical societies, or government will abdicate their responsibility. What might be proposed for such scrutiny is a variation on today’s bioethics committees, in the best of which physicians and nurses with scientific or clinical expertise join with ethicists, lawyers, the clergy, and community representatives to recommend a course of action that arises from the consensus of the group. The makeup of such committees might vary with the therapy being evaluated and its possible implications. While no system of oversight can be flawless, such committees may not only discover and publicly communicate problems that might arise with new technology but also bring attention to matters that should be considered by more specialized advisers.

The evidence that such a state of affairs may be attainable comes from American experience with end-of-life care. Since the Karen Ann Quinlan case in 1976, there have been many changes in the way decisions are made during every phase of the process of dying. The current wide availability of hospice care is an example of that, as are the frequent use of such legal strategies as durable power of attorney or the appointment of a health care proxy, vast improvements in palliative care, not to mention its being established as a distinct medical specialty, and the greatly increased involvement of families and patients.

In making such changes, the medi-cal community has by and large responded with heightened sensitivity to the advice of philosophers, bioethicists, and even lawyers. My own impression is that clinicians are far more understanding, empathetic, and skilled in dealing with dying patients than they were a quarter-century ago. Pointing this out is not to imply that the demands of patients and families do not have a decisive effect, but we know that the impetus for change could not have been accomplished without the involvement of the experts and advisers I have mentioned.

I wonder whether it is true, as the Rothmans claim, that “there is no holding back the enterprise.” It is just possible—now for the first time in the history of modern science—that the moment has finally come when society might reconsider whether the curiosity and enthusiasm of scientists alone should determine the direction of research into certain technologies. As biomedical investigation moves into the forms of enhancement that will affect personality, intelligence, memory, organic structure, and longevity, perhaps we ought to make use of our experience with those strangers at the bedsides, and bid them visit not only the clinic but the laboratory too.

To calculate what the Rothmans call “potential risks and benefits” is praiseworthy, but in order to do that one must have better knowledge of those risks. The misadventures that these writers portray in their important book prove that we enhance ourselves at our own peril, and much of that peril is yet to be discovered.

To accomplish the feats of genetic improvement predicted with such assurance by Gregory Stock and William Haseltine is to forget the admonition of Francis Bacon, who was, after all, the father of the scientific method: “Nature, to be commanded, must be obeyed.” Two centuries earlier, Michel de Montaigne had warned of the dangers of doing otherwise when he pointed out that we should not get in nature’s way, because “she knows her business better than we do.” Long before the Rothmans, such philosophers were putting us on notice.

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