In Tolkien’s classic tale The Lord of the Rings, at one point the creature Gollum falls off a cliff trying to go too fast, all the while telling himself, “Less haste, more speed.” It is to be hoped that we are not as possessed by the possibilities of human growth hormone (HGH) as Gollum was by visions of the One Ring. Nevertheless, in dealing with this controversial issue, it is worth noting that a degree of caution is advisable to get us where we need to go.

More than 30 years ago, growth hormone from human pituitary extract was used to treat children of short stature with congenital growth hormone (GH) deficiency. In a study of 12 patients treated with GH compared with 9 untreated controls, conducted in a veterans’ hospital in Milwaukee, WI, in 1990, Rudman demonstrated that many dramatic, positive physiologic changes occurred in normal, elderly patients. He stated, “the effects of six months of human growth hormone on lean body mass and adipose-tissue mass were equivalent in magnitude to the changes incurred during 10 to 20 years of aging.” In a subsequent paper he concluded, “The overall deterioration of the body that comes with growing old is not inevitable. We now realize that some aspects of it can be prevented or reversed.” Since then, the use of HGH has accelerated beyond its classic indication for the treatment of hypothalamic pituitary disease in children and adults with GH deficiency to encompass administration to normal, healthy, aging adults as part of the evolving field of antiaging medicine.

The term antiaging has itself become a source of controversy Some take it to mean reversing aging, some interpret it as slowing aging, and others consider it a synonym for wasted effort. Aging has been defined as longevity in conjunction with survival (minimal heart, lung, and brain function); wellness (being able to participate in activities of daily living and self-care); physical fitness (push-ups, sit-ups, reaction time, visual acuity, running, etc); cell function (accumulation of lipid waste products in the brain, mitochondrial function), and myriad other categories. As outlined in the essay “No Truth to the Fountain of Youth,” biologists accurately argue that aging and degeneration of cells occur fundamentally at the cellular level in spite of any medical, hormonal, vitamin, supplement, or other macroscopic therapy.In spite of eager optimism on the part of some practitioners, we simply don’t have a mechanism to characterize, much less modulate, aging at the cellular level.

There is no doubt of the physiologic effects of HGH. Innumerable studies of the last decade have demonstrated unequivocally that a person’s clinical function can be improved to mirror that of someone years younger. Moreover, guarded optimism is appropriate with respect to any association between HGH administration and cancer; at least to date, there are no data to suggest an increased incidence of cancer resulting from long-term HGH treatment.However, in the evaluation of the healthy patient for HGH administration, the efficacy of treatment remains highly problematic. Controlled clinical trials are the gold standard in the medical literature and should be applied to assess the results of HGH treatment. The study of several hundred patients over a few years in a controlled trial may be required to delineate more precisely the benefits of HGH therapy. In the years to come, understanding of the human genome will guide us in our tracking of outcome at the cellular level. [9] All studies conducted thus far have been longitudinal, without appropriate matched controls, and have been largely based on clinical, not cellular, evaluations. Longitudinal studies lack the power of controlled trials and require many more participants over a much longer period to obtain meaningful data. The data produced are neither strong nor cogent for changes at the cellular level. The widespread off-label use of HGH and the pecuniary temptations for physicians managing large clinics for an aging baby-boomer population hungry to stay young make its judicious clinical use in the face of patient demands extremely difficult, if not impracticable. The cost of hundreds of millions of dollars to achieve a new Food and Drug Administration clinical indication for the use of a drug and the expiration of patent protection within the next several years make the expenditure of research dollars by the pharmaceutical industry highly unlikely.

In the disease approach to health care, a drug has specific clinical indications for its use, such as systolic blood pressure or white blood cell count. In the wellness approach to health care, the indication may simply be “improvement” of a clinical assessment. Demonstrated indications for HGH include improvement with respect to visceral body fat, percentage of body fat, muscle mass, strength, bone density, cardiac output, sense of well-being, cholesterol levels, and improvements in many other health or fitness characteristics of a certain biodemographic age group. These may be used as biomarkers of fitness, and are subject to intervention through diet, exercise, nutrition, supplements, and sleep, as well as HGH. They are not specifically markers of aging. Good medical practice dictates implementation of less invasive, safer, and better understood interventions as first-line therapy. If these treatments fail, second-line, less understood therapies, such as HGH, may be indicated.

Should HGH therapy be continued lifelong in the healthy, 6 days on and 1 day off per week? The measurement of parameters is relatively straightforward, but identifying specific endpoints, clinical outcomes, or goals is more problematic. The list of clinical factors could include many of the following: hitting a golf ball farther, being able to stand in the operating room for increased hours with better concentration, having more energy to participate in family life and community affairs, enjoying a better sex life, losing weight and gaining muscle mass, improving memory, and avoiding future fractures. Are these goals sufficient to warrant a more aggressive and invasive (and expensive) intervention over the safe, effective, less costly conservative ones, given that the delay of old age and longer life through HGH therapy are unproven and, with current technology, unlikely, if not unattainable?.

Although there are many anecdotal reports of HGH abuse in competitive athletes, no responsible physician wisely argues for the “pharmacologic” or superphysiologic replacement of HGH to many times the natural levels produced by a healthy 25-year-old. We do not have an appropriate set of goals or endpoints other than the physiologic replacement of HGH levels to the upper quartile of the natural levels produced in the healthy 25-year-old. This is an important and acceptable first step. However, it is essential that we develop a comprehensive set of goals for patients in controlled clinical trials and measure them prospectively. Only then will we be able to identify suitable patients on the basis of specific biomarkers and measure efficacy in the wellness approach to health care. Researchers may have definitive answers for us in a few years; we have reason to be highly cautious in our approach but optimistic about our ability to find the answer.