3
Future Research Directions

As an FDA-approved treatment for male hypogonadism, testosterone therapy has been found to be effective in ameliorating a number of symptoms in markedly hypogonadal males. Researchers have carefully explored the benefits of testosterone therapy in this population. However, there have been fewer studies, particularly placebo-controlled randomized trials, in populations of middle-aged or older men who do not meet all the clinical diagnostic criteria for hypogonadism but who may have testosterone levels in the low range for young adult males and show one or more symptoms that are common to both aging and hypogonadism. Further, studies of testosterone therapy in older men generally have been of short duration, involving small numbers of participants, and often lacking adequate controls (Chapter 2). Therefore, assessments of risks and benefits have been limited, and uncertainties remain about the value of this therapy for older men.

Of particular importance is identifying potential benefits that are unique to testosterone, which could make it preferable to an already established, safe, and effective medication or treatment. Further, more must be known about the optimum dose, duration, and delivery method of testosterone therapy, and few studies have examined the duration of testosterone’s effects after therapy ends. Some research findings suggest that for certain health effects, there might be threshold levels of testosterone above which the beneficial effects could plateau and no further improvement would be realized. However, this is still a hypothesis needing further evaluation. Additionally, in the midst of the many unknowns about testosterone therapy, there are prospects in the drug development



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Testosterone and Aging: Clinical Research Directions 3 Future Research Directions As an FDA-approved treatment for male hypogonadism, testosterone therapy has been found to be effective in ameliorating a number of symptoms in markedly hypogonadal males. Researchers have carefully explored the benefits of testosterone therapy in this population. However, there have been fewer studies, particularly placebo-controlled randomized trials, in populations of middle-aged or older men who do not meet all the clinical diagnostic criteria for hypogonadism but who may have testosterone levels in the low range for young adult males and show one or more symptoms that are common to both aging and hypogonadism. Further, studies of testosterone therapy in older men generally have been of short duration, involving small numbers of participants, and often lacking adequate controls (Chapter 2). Therefore, assessments of risks and benefits have been limited, and uncertainties remain about the value of this therapy for older men. Of particular importance is identifying potential benefits that are unique to testosterone, which could make it preferable to an already established, safe, and effective medication or treatment. Further, more must be known about the optimum dose, duration, and delivery method of testosterone therapy, and few studies have examined the duration of testosterone’s effects after therapy ends. Some research findings suggest that for certain health effects, there might be threshold levels of testosterone above which the beneficial effects could plateau and no further improvement would be realized. However, this is still a hypothesis needing further evaluation. Additionally, in the midst of the many unknowns about testosterone therapy, there are prospects in the drug development

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Testosterone and Aging: Clinical Research Directions pipeline—selective androgen receptor modulators—that act on androgen receptors in a similar manner to testosterone and yet do not appear to be associated with adverse prostate outcomes. For reasons described throughout this report, research on testosterone and its potential therapeutic use presents challenges to clinical researchers. Any clinical trial or set of trials designed to assess the risks and benefits of testosterone therapy in aging men must account for multiple, complex aspects of health and behavior across the lifespan. Because testosterone is a critical hormone in many physiological and anatomic systems, there are numerous health endpoints that could be studied. Each of these endpoints, in turn, is affected by a complex set of variables other than testosterone, including genetics, environment, lifestyle factors, comorbid conditions, and the use of other medications and therapies. STRATEGY FOR FUTURE CLINICAL TRIALS IN OLDER MEN After examining the research on endogenous and exogenous testosterone, and discussing the research questions that remain to be explored, the committee determined that this is an area in which further clinical trials are needed. This chapter provides the committee’s recommendations on future research directions with a focus on clinical trials of testosterone therapy in older men. To guide its recommendations on a research strategy, the committee developed a central hypothesis that provides a general premise for future clinical trials and a set of key conclusions and considerations that serve as a rationale for the recommended research approach. Central Hypothesis Aging in men is associated with a progressive decline in median bioavailable testosterone levels such that concentrations in many septuagenarians and especially octogenarians are at or below the levels associated with clear-cut hypogonadism in young men. Aging in men is also associated with progressive declines in fat-free mass (including muscle mass) and an increase in adipose mass, especially central visceral adiposity. Male aging is also associated with a decline in sexual function and, in some individuals, with a decline in affect and cognition. Many of these aging-associated changes begin in middle age and progress with advancing age such that muscular weakness, osteopenia, osteoporosis, sexual dysfunction, depression, and cognitive dysfunction are seen in a number of older men. These multiple deficiencies frequently coexist, resulting in diminished vitality, and often converge to reduce quality of life and lead to frailty, which threatens independence and life in old age.

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Testosterone and Aging: Clinical Research Directions Young men with hypogonadism represent a vastly premature phenocopy of many aspects of this geriatric syndrome. These individuals demonstrate weakness, central obesity, diminished bone mineral content, sexual dysfunction, and apathy, which are improved when testosterone therapy is initiated and testosterone levels are raised to concentrations that are at the median in eugonadal men of comparable age. Therefore, the central hypothesis for clinical trials in older men is that changes in body composition, strength, sexual function, cognition, and vitality in aging men are associated with a decrease in bioavailable testosterone. Moreover, this hypothesis predicts that there will be improvements in these outcomes in older men when exogenous therapy raises testosterone levels to concentrations comparable to those in young eugondal men. Key Conclusions and Considerations Before weighing the options for future research directions, the committee reached several general conclusions that serve as the rationale for its recommendations. As discussed above and in Chapter 2, there are insufficient scientific data on the efficacy1 of testosterone therapy in improving the health of older men. Most of the research conducted in older populations has not been conducted with placebo controls, which is particularly problematic when evaluating qualitative endpoints (e.g., sexual function, quality of life). The committee felt that the first and most immediate goal is to establish whether treatment with testosterone results in clear benefits in aging men. In the committee’s determination, this could be accomplished in a set of efficacy trials with a study population of older men (65 years of age and older) who have clinically low testosterone levels and at least one symptom that might be related to low testosterone. Secondly, given the potential risks of testosterone therapy and the availability of other safe and effective therapeutic intervention options for some of the diseases and conditions it is intended to treat (e.g., bisphosphonates for osteoporosis), the committee felt that testosterone should be considered as a therapeutic, not a preventive, measure. Thus, 1   Efficacy is defined as “the extent to which a specific intervention … produces a beneficial result under ideal conditions (Stedman’s Medical Dictionary, 2000).” The committee chose specifically to use this term because establishing the efficacy of an intervention is a first step in determining if the intervention has therapeutic benefit by examining its use in a specific population and following a well–defined research protocol. Most randomized placebo-controlled trials would result in findings regarding the efficacy of the intervention. Effectiveness denotes finding benefit in an average clinical setting in which there is a more varied population, the potential for less strict adherence to the dosing regimen, etc.

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Testosterone and Aging: Clinical Research Directions trials of testosterone therapy should be conducted in men with symptoms or conditions that might benefit from a therapeutic intervention. A third consideration focused on using resources most effectively. A fundamental challenge in assessing the possible benefits and risks of testosterone therapy is that the sample size and follow-up time needed to assess efficacy for potential benefits such as improvements in strength, cognition, mood, and sexual function are substantially less than those needed to assess the risks of prostate cancer and cardiovascular disease. For example, studies to assess the potential benefit of testosterone therapy in elderly men who are frail and testosterone-deficient would likely require fewer than 500 persons followed for one year. In contrast, a study that would provide the information needed to assess a moderate increase in the risk of prostate cancer might require 5,000 men followed for 3 to 5 years. In the committee’s opinion, it is important to firmly establish benefit in the target population before expending the time and effort necessary to study the potential for long-term risks and benefits of testosterone therapy. Trials of efficacy can by accomplished in smaller populations and in shorter time frames. Although the research to date shows suggestions of outcomes in which testosterone may show efficacy, the benefits of testosterone therapy in older men have not been clearly established. If clear efficacy cannot be demonstrated, then large scale trials are not indicated. Fourthly, the committee determined that clinical trials should focus on those health outcomes and conditions among older men for which there is preliminary evidence of the efficacy of testosterone therapy and for which safe and effective therapeutic options are not currently available. The most promising potential benefits of testosterone therapy, in the opinion of the committee, are improvement of weakness, frailty, and dis- BOX 3-1 Key Conclusions and Considerations Focus on the population most likely to benefit. Use testosterone as a therapeutic intervention, not as a preventive measure. Establish a clear benefit before assessing long-term risks. Focus on clinical outcomes in which there is a preliminary suggestion of efficacy and for which safe and effective therapeutic options are not currently available. Ensure safety of the research participants.

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Testosterone and Aging: Clinical Research Directions ability; sexual dysfunction; cognitive dysfunction; and vitality, well-being, and quality of life among older men with low testosterone levels. Lower priority should be placed on establishing benefit for conditions in which there is already effective pharmacotherapy, such as fracture prevention. Finally, and most importantly, in any clinical trial, the utmost consideration is minimizing risks to research participants. The committee believes that it is possible to ethically and safely conduct clinical trials of testosterone therapy in older men as long as strict exclusion criteria are developed and implemented and monitoring practices are carefully followed. Overview of Recommended Clinical Trials In implementing the general conclusions and rationale discussed above, the committee encourages clinical research efforts to initially focus on determining benefits of testosterone therapy in older men as compared with placebo controls and then, contingent upon finding benefit(s), focus on assessing long-term risks and benefits. This rationale will determine that testosterone is a viable therapeutic option in older men before expending the time and resources to determine long-term risks. As described later in this chapter, the committee recommends that the initial short-term efficacy trials focus on examining whether testosterone improves one or more of the following clinical outcomes: strength/frailty/disability; cognitive function; sexual function; or vitality/well-being/quality of life. Additionally, as part of this initial research effort, data should be collected on adverse effects and other health measures. The initial efficacy effort could be designed as a coordinated set of trials structured through a cooperative agreement or other similar mechanism. Such a coordinated approach would provide for standardization of data collection methods across study sites to ensure that the results on common study endpoints can be analyzed in aggregate. In this way, all participants would contribute to the short-term assessment of risk, and more information would be gathered on potential benefits as well. If adequate benefits are observed in the initial trials, the next effort would involve a larger scale and longer-term study that would require careful planning to most effectively protect research participants. The committee’s recommendations are listed below to provide the reader with the research strategy recommended by the committee. The remainder of the chapter provides justification and further explanation of each of the recommendations.

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Testosterone and Aging: Clinical Research Directions RECOMMENDATIONS Recommendation 1. Conduct Clinical Trials in Older Men. The committee recommends that the National Institute on Aging and other research agencies and institutions conduct clinical trials of testosterone therapy in older men with low testosterone levels. Initial trials should be designed to assess efficacy. Studies to assess long-term risks and benefits should be conducted only if clinically significant benefit is documented in the initial trials. Recommendation 2. Begin with Short-Term Efficacy Trials to Determine Benefit. The committee recommends an initial focus on conducting short-term randomized double-blind, placebo-controlled efficacy trials of testosterone therapy in older men to determine potential health benefits and risks. Consideration should be given to the following issues in designing the initial trials: Recommendation 2a. Study Population for Initial Trials. Participants in the initial trials should be men 65 years of age and over with testosterone levels below the physiologic levels of young adult men and with one or more symptoms that might be related to low testosterone. Recommendation 2b. Testosterone Preparation and Dosages. Routes of testosterone administration and dosages should achieve testosterone levels that do not exceed the physiologic range of a young adult male. When feasible, multiple dose regimens and types of interventions should be compared. Recommendation 2c. Primary Outcomes. The primary outcomes to be examined in the initial trials should be clinical endpoints for which there have been suggestions of efficacy, particularly where there are not clearly effective and safe alternative pharmacologic therapies. These outcomes include weakness/frailty/disability; sexual dysfunction; cognitive dysfunction; impaired vitality/well-being/quality of life. Recommendation 2d. Coordination of Clinical Trials. Initial and subsequent trials should be coordinated under a cooperative agreement or similar mechanism to produce a common core data set that would maximize the information obtained from the different studies.

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Testosterone and Aging: Clinical Research Directions Recommendation 3. Conduct Longer-Term Studies if Short-Term Efficacy Is Established. The committee recommends that if clinically significant benefits of testosterone therapy are seen in the initial studies of older men, then larger-scale clinical trials should be conducted to assess the potential for long-term risks and benefits. The targeted population for these studies, their duration, and the long-term risks and benefits to be assessed would vary depending on the findings of the initial studies. Recommendation 4. Ensure Safety of Research Participants. The committee recommends a system for minimizing risk and protecting participants in clinical trials of testosterone therapy. The committee recommends: Strict exclusion criteria, such as for men who are at high risk for developing prostate cancer or for requiring an intervention to treat benign prostatic hyperplasia (BPH); Careful participant monitoring for changes in prostate specific antigen (PSA) levels or in the digital rectal examination (DRE) and for other adverse effects; Incorporating into the trial design the interim monitoring of trial results, stopping guidelines, and other measures deemed appropriate, particularly for long-term studies; Careful planning to address prostate risk issues. In long-term clinical trials, the primary safety endpoint will be increased incidence of prostate cancer. Ascertaining such an increase could be complicated by prevalent occult prostate cancer and detection bias associated with testosterone-induced PSA elevation leading to an increased number of biopsies. There should be careful consideration of these issues in the planning of long-term trials of testosterone therapy. Attention to communicating risks and benefits to study participants, particularly in light of multiple outcomes and the potential for long-term risks. This will be especially important for long-term clinical trials. Recommendation 5. Conduct Further Research. In addition to the research strategy for clinical trials recommended above, the committee recommends further investigator-initiated research on such issues as physiologic regulation of endogenous testosterone levels, mechanism of action of testosterone, and age-related changes in testosterone levels.

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Testosterone and Aging: Clinical Research Directions INITIAL EFFICACY TRIALS IN OLDER MEN As outlined above, short-term efficacy trials are recommended as a next step in clinical research on testosterone therapy in older men. These trials could also provide insights on the optimum types of intervention and dosages, as well as on the most accurate and relevant testosterone measures and methods of measurement. An additional advantage could be gained by coordinating the trials as described below. Coordination of Initial Efficacy Trials The committee felt there would be distinct advantages in planning and coordinating the initial efficacy trials and any subsequent long-term trials to comprehensively address the potential benefits and risks of testosterone therapy and to maximize the evidence obtained. To date, the largest placebo-controlled randomized trial of testosterone therapy in older men involved only 108 participants (Snyder et al., 1999a,b, 2001). Aggregated data would provide information on a larger number of participants, allowing greater insights into potential benefits and risks of testosterone therapy and enhancing the utility of the information collected. Planning and coordinating the initial efficacy trials might include: one expert advisory committee for all of the trials; the same statistical coordinating center for all planned trials; the same type, dose, and route of administration of testosterone or different preparations carefully chosen to identify differences in efficacy and adverse effects; common methods for measuring laboratory and clinical tests, outcomes, and adverse effects across all studies or a subset of studies (e.g., measures of endogenous testosterone, body composition, strength, frailty, cognitive function, sexual function, lipid and carbohydrate metabolism and cardiovascular risk, hematologic indices, bone metabolism and density, inflammation, other hormonal markers and growth factors, prostate outcomes, and genetic determinants of sex steroid action); a coordinated approach to safety assessment (including PSA and DRE), including safety assessment at a fixed time after discontinuing study medication; the same data collection instruments for common endpoints; a single data and safety monitoring board for all planned trials; timely analyses of the results of early trials to inform the data and safety monitoring board and provide data for the design of subsequent trials; and analyses of efficacy and adverse effects based on data from indi-

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Testosterone and Aging: Clinical Research Directions vidual trials and on pooled data or weighted mean analyses from several of the trials. Using the same testosterone preparation would allow assessment of efficacy in various populations. Alternatively, coordinated use of different testosterone preparations might allow assessment of differences in efficacy and adverse effects. For those endpoints that are evaluated in multiple trials, using the same data collection instruments will allow for pooled or weighted summary analyses across studies and would maximize power to address uncommon outcomes. Primary endpoints could be examined in depth at research centers with specialized expertise, but a subset of information could be collected in all centers. Coordination of these initial trials could be implemented through an NIH cooperative agreement or other similar mechanism that would provide for an infrastructure to plan and organize the trials and design the components that should be standardized or coordinated. The committee believes that the semi-independent efficacy trials may work best but acknowledges that other options could be considered. Studies that have used a similar approach include the Frailty and Injuries–Cooperative Studies of Intervention Techniques (FICSIT). FICSIT was a linked set of eight clinical trials sponsored by the National Institute on Aging and the National Institute for Nursing Research that focused on the benefits of exercise in older men and women (Schechtman and Ory, 2001). The set of trials was preplanned so that data could be analyzed through aggregated analyses. Design and Implementation Issues Several issues should be considered in the design and implementation of the recommended trials, including inclusion criteria, the measurement of testosterone levels, testosterone formulation and dose, and sample size(s). Inclusion Criteria As recommended above, the initial efficacy trials should focus on older men (age 65 years and over) with low testosterone levels and with one or more symptoms of possible testosterone deficiency or hypogonadism. Implementing these inclusion criteria raises several issues regarding determining the testosterone level to be used as an entry criterion. There are no specific clinical symptoms or generally accepted cut-off values for testosterone levels that easily define androgen deficiency in the elderly male. Additionally, in a population of older men, the tes-

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Testosterone and Aging: Clinical Research Directions tosterone levels are quite variable. For example, in a study of 300 healthy men ages 20 to 100, Vermeulen and colleagues found that while 20 percent of men over 60 years of age had subnormal testosterone levels, 15 percent of men over 80 years of age had testosterone levels in the upper normal range for young men (defined in this study as over 576 ng/dL [20 nmol/L]) (Kaufman and Vermeulen, 1997). Other laboratory parameters such as measures of gonadotropins have not proven to be of clear benefit in the diagnosis of testosterone deficiency in older men. The decline in testosterone levels associated with aging has both a central (characterized by a decrease in the amplitude of luteinizing hormone [LH] pulses) and testicular (decreased Leydig cell number) origin (Vermeulen and Kaufman, 1995). Thus, many older men with low testosterone have normal LH levels. Additional factors complicating the determination of androgen-deficiency states in older men include poorly defined, yet complex, interrelationships between testosterone, other sex hormones, (e.g., DHEAS, estrogens) and non-sex hormone systems (e.g., growth hormone, insulin-like growth factor). Acute illness and common chronic diseases of aging such as cancer, cardiovascular disease, diabetes, depression, hyperlipidemia and arthritis, and other factors such as obesity, tobacco and alcohol use, and nutritional deficiencies can also affect testosterone levels (Kaufman and Vermeulen, 1997). Further, it is unknown if the androgen-target tissues in older men require the same androgen levels as those of younger men (e.g., altered cellular testosterone sensitivity, a feedback system, or alterations in androgen receptor numbers). In the absence of a reliable, clinically useful biological parameter of the effects of testosterone, the criteria for defining and treating testosterone deficiency in the aging male are somewhat arbitrary. Thus, as a starting point, it is reasonable to base criteria for clinical intervention on benchmarks established for a condition (hypogonadism in young men) in which the intervention (testosterone therapy) has been proven to reverse the clinical and biochemical manifestations of the disease. One approach to setting entry-level criteria is to select a range that is two or more standard deviations below the mean testosterone level for normal young men. For example, in a study of 150 young adult males (ages 20 to 40), Vermeulen (2001) found that the mean level for total testosterone was 627 ng/dL (21.8 nmol/L). At two standard deviations from the mean, the range would be 365 to 889 ng/dL (12.6 to 30.8 nmol/L), and at 2.5 standard deviations, the range would be 319 to 935 ng/dL (11 to 32.4 nmol/L). Using these parameters as entry criteria for a clinical study, a serum total testosterone level less than 320 ng/dL (approximately 11 nmol/L) appears to be a reasonable discriminatory level. Many studies defining testosterone deficiency states in older men have used similar values (Chapter 2, Appendix B).

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Testosterone and Aging: Clinical Research Directions Increasing the stringency for defining testosterone deficiency could be achieved by setting the threshold testosterone level even further from the mean (e.g., 3 standard deviations [SD]), but at the expense of screening a larger number of individuals to identify a study cohort. As discussed below, other forms of testosterone such as free and bioavailable testosterone are measurable in serum. While data demonstrating the clear superiority of these measures over total testosterone in the context of clinical trials is lacking, some studies have shown correlations between a clinical parameter (e.g., depressed mood) and bioavailable testosterone where no association was found with total testosterone (Barrett-Connor et al., 1999a). As with total testosterone, an approach for the use of free or bioavailable testosterone levels as study entry criteria could be employed based upon standard deviations from mean population values. Due to aging-related changes in sex hormone-binding globulin (SHBG), a larger percentage of individuals at each age category would be defined as testosterone deficient (relative to measures in young adult men) if free testosterone or bioavailable testosterone levels are selected for stratification. Another factor to be considered is the stability of testosterone measures in the same individual over time. Because testosterone is secreted into plasma in a pulsatile fashion every 60 to 90 minutes, the level of deficiency may not be conclusively established by a single measure (single point in time). A pool of three samples spaced 15 to 20 minutes apart will likely provide a more accurate assessment than a single sample (Griffin and Wilson, 2001). Further, testosterone levels can transiently waver from the normal ranges in men who have long interpulse intervals of luteinizing hormone (Griffin and Wilson, 2001). However, this caveat must be balanced by the practical utility of screening large numbers of men in an efficient and cost-effective fashion. As older men generally attenuate the diurnal variation in testosterone secretion, it seems reasonable to consider one measurement in the low range as an entry criterion for the studies. It is likely that the treatment and placebo groups in a randomized trial would have similar degrees of variation in testosterone levels. The statistical likelihood of including men that are not truly testosterone deficient (based on natural fluctuations in testosterone levels and methodological errors of measurements) could be built into sample-size calculations. Measuring Testosterone Levels Measurements of testosterone levels are of critical importance because these determinations are involved in the selection of participants for inclusion in clinical trials, the dosing of testosterone preparations, and the evaluation of the effects of testosterone treatment on outcomes. As discussed in Chapter 1, there are several different forms of testosterone that

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Testosterone and Aging: Clinical Research Directions enters a research protocol. The combination of age with potential illness, mood disorders, or cognitive deficits among men who are included in the subject cohort may also increase the vulnerability of this research population. The potential for participants to be confused by the complex and uncertain risks or the benefits of research could be high. A general assessment of cognitive skills and screening for dementia might be indicated as a prelude to study enrollment for some subjects and may require a two-stage informed consent process. For others, as past National Research Council studies have recommended, special efforts directed toward ensuring maximum appreciation of study risks will be required (NRC, 2002). Not only risks, but also potential benefits will need to be carefully explained. Because there is the potential for improvements to be seen in multiple measures, it will be important for participants to fully understand the range of potential outcomes and the nature of the tests and assessment tools. Some of the risks inherent in trials of testosterone therapy will be exacerbated by the possibility that study participants will not understand clearly their role in the search for scientific conclusions. Investigators should understand that “therapeutic misconception” is a problem common to the conduct of human research, and they should take it seriously. Patients who meet a doctor in a medical setting expect that the doctor’s primary role is to provide the most appropriate treatment that will lead to a cure. Often, patients do not fully understand that a physician may also fill the role of researcher—presenting new, experimental interventions with the hope that they will prove effective as future treatments. Those patients may be unaware that an experiment is designed primarily to produce scientific information rather than cure any specific research subject. Research has shown that the therapeutic misconception is so prevalent and so strong that some patients are unaware they are receiving an experimental treatment, even though research consent forms they have signed specifically describe the clinical intervention as “research” (Advisory Committee on Human Radiation Experiments, 1996). For trials of testosterone therapy, men may have misconceptions about the strength of the association between testosterone and virility or muscle-building. In light of this potential “misconception,” the importance of voluntary and fully informed consent is critical. Not only must subjects have the opportunity to volunteer or refuse to participate in research, their consent must be “informed” by an accurate assessment of the potential benefits of the research and the potential harms it may pose. A clear explanation of the alternatives to participating in research is also necessary, so that patients who could choose a proven cure are not misled into picking an experimental intervention that can provide, at best, specu-

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Testosterone and Aging: Clinical Research Directions lative benefits. For the initial efficacy trials, the committee is recommending that the participants be “patients” rather than healthy volunteers, inasmuch as they would have one or more symptoms that may be related to low testosterone levels. In summary, it is imperative that any future clinical trials of the efficacy of testosterone therapy should focus attention on the complexities inherent in communicating the risks and benefits of a trial to older research participants. Design of the informed consent process for such trials should take into account the existing uncertainties in available diagnostic tests for prostate cancer; specific vulnerabilities in the likely subject population that could require additional assessment prior to study enrollment; the need to assess a participant’s understanding of medical terms that describe the side effects of prostate surgery and the poor quality of life outcomes that sometimes accompany surgery and other therapies; the prevalence of the “therapeutic misconception;” and the potential need to monitor research consent. Summary on the Protection of Research Participants There are various ways to protect the safety of individuals who are participating in clinical trials of testosterone therapy or who are being screened for participation. Stringent exclusion criteria will ensure that those men entering the trial are not at high risk for developing complications. At the onset of trial recruitment, communication of risks and benefits is critical, as those considering the trial need to have accurate information presented in a manner that is easily understood and in a research setting that is conducive to asking questions about issues that need further clarification. Further, throughout the course of the trial, a number of measures should be used to monitor adverse events and provide follow-up care as needed. The data and safety monitoring board is vitally important in ensuring the safety of participants through interim monitoring of trials results and implementation of stopping guidelines if deemed necessary. All of these considerations are, of course, integral to the ethical norms for the standard conduct of clinical trials, as regulated by human research protection regulations and applied by institutional review boards (IOM, 2003b). However, the committee felt it was important to emphasize these practices and provide detailed discussion, as testosterone therapy in older men is an area of research that is made complex, and at times controversial, by ethical considerations regarding the safety of research participants.

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Testosterone and Aging: Clinical Research Directions BOX 3-2 Recommendations Recommendation 1. Conduct Clinical Trials in Older Men. The committee recommends that the National Institute on Aging and other research agencies and institutions conduct clinical trials of testosterone therapy in older men with low testosterone levels. Initial trials should be designed to assess efficacy. Studies to assess long-term risks and benefits should be conducted only if clinically significant benefit is documented in the initial trials. Recommendation 2. Begin with Short-Term Efficacy Trials to Determine Benefit. The committee recommends an initial focus on conducting short-term randomized double-blind, placebo-controlled efficacy trials of testosterone therapy in older men to determine potential health benefits and risks. Consideration should be given to the following issues in designing the initial trials: Recommendation 2a. Study Population for Initial Trials. Participants in the initial trials should be men 65 years of age and over with testosterone levels below the physiologic levels of young adult men and with one or more symptoms that might be related to low testosterone. Recommendation 2b. Testosterone Preparation and Dosages. Routes of testosterone administration and dosages should achieve testosterone levels that do not exceed the physiologic range of a young adult male. When feasible, multiple dose regimens and types of interventions should be compared. Recommendation 2c. Primary Outcomes. The primary outcomes to be examined in the initial trials should be clinical endpoints for which there have been suggestions of efficacy, particularly where there are not clearly effective and safe alternative pharmacologic therapies. These outcomes include weakness/frailty/disability; sexual dysfunction; cognitive dysfunction; impaired vitality/well-being/quality of life. Recommendation 2d. Coordination of Clinical Trials. Initial and subsequent trials should be coordinated under a cooperative agreement or similar mechanism to produce a common core data set that would maximize the information obtained from the different studies.

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Testosterone and Aging: Clinical Research Directions Recommendation 3. Conduct Longer-Term Studies if Short-Term Efficacy Is Established. The committee recommends that if clinically significant benefits of testosterone therapy are seen in the initial studies of older men, then larger-scale clinical trials should be conducted to assess the potential for long-term risks and benefits. The targeted population for these studies, their duration, and the long-term risks and benefits to be assessed would vary depending on the findings of the initial studies. Recommendation 4. Ensure Safety of Research Participants. The committee recommends a system for minimizing risk and protecting participants in clinical trials of testosterone therapy. The committee recommends: Strict exclusion criteria, such as for men who are at high risk for developing prostate cancer or for requiring an intervention to treat BPH; Careful participant monitoring for changes in PSA levels or in the DRE and for other adverse effects; Incorporating into the trial design the interim monitoring of trial results, stopping guidelines, and other measures deemed appropriate, particularly for long-term studies; Careful planning to address prostate risk issues. In long-term clinical trials, the primary safety endpoint will be increased incidence of prostate cancer. Ascertaining such an increase could be complicated by prevalent occult prostate cancer and detection bias associated with testosterone-induced PSA elevation leading to an increased number of biopsies. There should be careful consideration of these issues in the planning of long-term trials of testosterone therapy. Attention to communicating risks and benefits to study participants, particularly in light of multiple outcomes and the potential for long-term risks. This will be especially important for long-term clinical trials. Recommendation 5. Conduct Further Research. In addition to the research strategy for clinical trials recommended above, the committee recommends further investigator-initiated research on such issues as physiologic regulation of endogenous testosterone levels, mechanism of action of testosterone, and age-related changes in testosterone levels.

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Testosterone and Aging: Clinical Research Directions ADDITIONAL AREAS OF RESEARCH There is still much to be learned about changes in endogenous testosterone levels associated with aging and the impact of those changes on health outcomes. Research has shown that testosterone levels in men decline with age, but more research is needed to determine how declining endogenous testosterone levels are associated with health outcomes during aging. It is unclear whether low testosterone levels are a marker of poor health or a contributing factor, or both. There are many research challenges in sorting out the role of testosterone and how testosterone interrelates with other hormones and with the myriad of other genetic, environmental, and biologic factors occurring during aging. Therefore, the committee believes that further investigator-initiated research should be pursued on a range of areas regarding endogenous and exogenous testosterone. RECOMMENDATIONS The recommendations were provided earlier in the chapter to present the committee’s research strategy. Summarized in Box 3-2, the recommendations emphasize an approach that the committee believes will most effectively and efficiently determine if testosterone is a therapeutic option for older men, taking into consideration its relative risks and benefits. REFERENCES Adamson J, Longo DL. 2001. Anemia and polycythemia. In: Braunwald E, Fauci AS, Kasper DL, Hauser SL, Longo DL, Jameson JL, eds. Harrison’s Principles of Internal Medicine. 15th ed. New York: McGraw Hill. Pp. 348–354. Advisory Committee on Human Radiation Experiments. 1996. The Human Radiation Experiments: Final Report of the Advisory Committee. New York: Oxford University Press. Pp. 474–476. Albert DJ, Walsh ML, Jonik RH. 1993. Aggression in humans: what is its biological foundation? Neuroscience and Biobehavioral Reviews 17(4):405–425. Amory JK, Chansky HA, Chansky KL, Camuso MR, Hoey CT, Anawalt BD, Matsumoto AM, Bremner WJ. 2002. Preoperative supraphysiological testosterone in older men undergoing knee replacement surgery. Journal of the American Geriatrics Society 50(10):1698–1701. Anderson RA, Bancroft J, Wu FC. 1992. The effects of exogenous testosterone on sexuality and mood of normal men. Journal of Clinical Endocrinology and Metabolism 75(6):1503–1507. Archangeli CG, Ornstein DK, Keetch DW, Andriole GL. 1997. Prostate-specific antigen as a screening test for prostate cancer. Urologic Clinics of North America 24(2):299–306. Aversa A, Isidori AM, Spera G, Lenzi A, Fabbri A. 2003. Androgens improve cavernous vasodilation and response to sildenafil in patients with erectile dysfunction. Clinical Endocrinology 58(5):632–638.

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