New pharmaceuticals and new uses for existing pharmaceuticals will continue to offer the promise of safe and effective treatments for acute and chronic diseases, many of which are associated with the aging process. However, the interest and excitement regarding these prospects must always be tempered by appropriate concerns about safety, which can only be addressed through carefully designed research and critical review of the resulting empirical evidence. Collecting such evidence can take many years, with knowledge gained through iterative and incremental steps.
Experience with the use of postmenopausal hormone therapy in women and the growing body of scientific evidence about its risks and potential benefits provides an apt and timely example of the need for sustained, systematic analysis of short- and long-term effects of new treatments and the caution that must be exercised in widely prescribing drugs as preventive measures. In the meantime, clinicians are searching for therapies, and an enthusiastic and perhaps overly optimistic citizenry is eager to not only treat diseases associated with aging but also possibly delay the timing of their initial onset.
NEED FOR EFFICACY STUDIES IN OLDER MEN
There are several health outcomes for which preliminary evidence indicates that testosterone may improve the health of older men. Although the committee was unable to find conclusive evidence regarding the efficacy of testosterone therapy for older men with symptoms of androgen
deficiency, there are some suggestions that testosterone may have benefits for certain conditions in older men. In addition, the committee found no compelling evidence of major adverse side effects to testosterone therapy, but the evidence is far from adequate to document safety. Once more, the experience of the Women’s Health Initiative (WHI) and studies of hormone therapy in women provide stark evidence of the danger of prematurely asserting the safety of a drug, particularly when it is being prescribed to prevent illness that might never occur or to confer unproven protective effects, rather than treat clinically evident symptoms or disease.
In the case of postmenopausal hormone therapy, a substantial body of observational data existed on indicated potential benefits, such as reduced risk of cardiovascular outcomes, and there was a rapid rise in the use of hormone products from the 1970s through the 1990s (OTA, 1992). Only recently have the results from clinical trials (such as WHI) showed increased risk of cardiovascular outcomes among women taking the estrogen-progestin combination therapy, the opposite of expectations (Hulley et al., 1998; Rossouw et al., 2002; Rapp et al., 2003). Quality of life measures (in women who had no hot flashes) have not been found to differ between women assigned to estrogen-progestin therapy versus placebo (Hlatky et al., 2002).
Efficacy trials of testosterone therapy must be fielded to assess potential benefits, particularly in the older male population, which is more likely to exhibit low testosterone levels and experience symptoms that could benefit from treatment. These smaller more focused trials may additionally provide important information regarding dose regimen and delivery methods as well as inform decisions regarding study power for potential long-term studies. To collect reliable data on adverse events, monitoring must be conducted in a uniform and systematic manner.
Until the safety and efficacy of testosterone therapy in older men is established, the committee believes that its use is appropriate only for the indications approved by the FDA (the primary indication is the treatment of hypogonadism) and inappropriate for wide-scale use to prevent possible future disease or for enhancing strength or mood in otherwise healthy older males. Despite the increasing popularity of testosterone treatment, there is not a large body of data to suggest the efficacy of testosterone therapy in older men who do not meet the clinical definition of hypogonadism. Moreover, the effects of testosterone on the prostate, and its implications for cancer, warrant caution in extensive nontherapeutic use.
Establishing efficacy, with appropriate attention to safety, is the only way to justify widespread testosterone therapy. As outlined in Chapter 3, if smaller efficacy studies yield promising results, then it would be appropriate to field a larger study that could be statistically powered to assess
both long-term efficacy and safety. If efficacy cannot be clearly established, such long-term studies will be unnecessary.
Given the size and projected growth of the aging male population, it is important to know the effects of testosterone therapy before more men are treated at considerable cost and uncertain benefit or safety. Research on testosterone therapy is at the point where therapeutic benefits in older men need to be established or refuted so that informed decisions can be made. Randomized clinical trials provide the best possible assessment of risk and benefits, evaluations that years of observational data cannot necessarily predict. In recommending such studies, the committee acknowledges the concerns about potential adverse effects and the unique dilemmas posed by detecting prostate cancer in populations of older men in which subclinical cancers may otherwise go undetected and not become a health concern. This area is made exceedingly complex by controversies and trade-offs about when and how to intervene. After carefully examining the issues and weighing the ethical considerations, the committee determined that older men participating in clinical trials of testosterone therapy can be fully informed, provide voluntary consent to participate, and be adequately protected against potential adverse effects.
CLINICAL STUDIES IN MIDDLE-AGED MEN
As a final point, although the focus of this report is on testosterone therapy in older men, the committee realized that the large and growing population of middle-aged men using testosterone products also raises important public health concerns about the benefits and risks in this age group. The motivation for younger men in using testosterone therapy appears to have relatively little to do with increased bone mineral density and decreased fracture risk, but it is mainly sought to improve strength, body image, sexual function, and vitality. Some of the results of trials in older men should shed light on the possible benefits in these areas of testosterone therapy in younger men.
However, information about some putative risks—for example, prostate cancer and cardiovascular morbidity—associated with testosterone therapy for older men may not be very informative about the risks in younger men, in part because of the lower incidence of disease in younger men, but also because the longer expected survival in younger men implies that long-term risks (for example, beginning 15 or more years following initiation of testosterone therapy) would have a greater impact. Thus, for example, demonstration of an increased risk of prostate cancer incidence in older men could suggest a risk in younger men, but failure to demonstrate an increased risk in older men would not necessarily provide convincing evidence of a lack of long-term risk in younger men. Relatively small clinical trials of the benefits of testosterone therapy in middle-
aged men could readily be fielded as additional arms of the efficacy trials recommended in Chapter 3. However, studies of longer-term risks could be much more difficult, and observational studies may be of only limited value because of their uncontrolled nature and possible selection biases. Randomized clinical trials would be the most reliable method for assessing the long-term risks associated with testosterone therapy in middle-aged men. However, because of the low incidence of morbidity in this population, such trials would likely need to be very large and of long duration. For example, the estimated 10-year cumulative incidence of prostate cancer in 50-year-old men is 2.13 percent (NCI, 2003). Thus, for example, a randomized trial with 90 percent power to detect a 50 percent increase in the incidence rate of prostate cancer, based on a 2-sided Type I error of 0.05, would require 10,000 subjects and take 12.9 years to complete based on an annual accrual of 2,000 men. Smaller trials could be designed with the same power, but these would require even longer duration. The logistical complications in a trial of such duration would likely be formidable because of challenges in retaining participants and in accurately documenting the use of testosterone therapy as well as concomitant medications that might also be related to cancer risk.
Because of these considerations, the committee’s recommendation for a set of clinical trials in older men could be considered an initial step that would provide information on benefits from testosterone therapy in older men and speculative data on similar benefits in middle-aged men. Because of the considerable challenges in assessing long-term risk in younger men, it may be prudent to await the results of such studies in older men. At the present time a large-scale clinical trial in middle-aged men does not appear to be the logical next step in testosterone therapy research.
It may be feasible and useful to use other research approaches to obtain information on testosterone therapy in middle-aged men. In particular, information about the age-specific rate of initiation and duration of use of testosterone therapy, as well as how this changes with calendar time, would provide a valuable basis for assessing the possible health impacts of long-term testosterone administration. Other options could include incorporating questions about testosterone use into existing large-scale studies of middle-aged men or adding measures of testosterone levels as one of the secondary outcome measures to future research efforts, thereby gaining useful data with relatively minimal expense, particularly as compared to a large-scale clinical trial.
In addition, a new class of compounds—selective androgen receptor modulators (SARMs)—may provide an alternative to the use of testosterone as they appear to have androgenic effects similar to testosterone on muscle mass, sexual function, and bone density in animal models, while apparently causing little or no harm to the prostate (Orwoll, 2001).
The goal of this report was to assess the current state of knowledge regarding the potential risks and benefits of testosterone therapy and provide recommendations on directions for further clinical research on testosterone and its effects on human health. In addressing these issues, the committee found a paucity of randomized placebo-controlled clinical trials in older men. The trials that have been conducted do not show definitively that there are benefits of testosterone therapy for older men; however, there are some areas that need to be further examined. The committee recommends short-term efficacy trials to determine if there are benefits of testosterone therapy in older men. If benefits are established, then long-term trials would be appropriate.
Clearly, empirical evidence about testosterone therapy is needed. Currently testosterone therapy is an attractive option as speculation abounds regarding its potential. What is needed is the research to determine if testosterone therapy is also a rational option for older men.
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