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Testosterone and Aging: Clinical Research Directions (2004)

Chapter: 3 Future Research Directions

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Suggested Citation:"3 Future Research Directions." Institute of Medicine. 2004. Testosterone and Aging: Clinical Research Directions. Washington, DC: The National Academies Press. doi: 10.17226/10852.
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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

Suggested Citation:"3 Future Research Directions." Institute of Medicine. 2004. Testosterone and Aging: Clinical Research Directions. Washington, DC: The National Academies Press. doi: 10.17226/10852.
×

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.

Suggested Citation:"3 Future Research Directions." Institute of Medicine. 2004. Testosterone and Aging: Clinical Research Directions. Washington, DC: The National Academies Press. doi: 10.17226/10852.
×

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.

Suggested Citation:"3 Future Research Directions." Institute of Medicine. 2004. Testosterone and Aging: Clinical Research Directions. Washington, DC: The National Academies Press. doi: 10.17226/10852.
×

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.

Suggested Citation:"3 Future Research Directions." Institute of Medicine. 2004. Testosterone and Aging: Clinical Research Directions. Washington, DC: The National Academies Press. doi: 10.17226/10852.
×

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.

Suggested Citation:"3 Future Research Directions." Institute of Medicine. 2004. Testosterone and Aging: Clinical Research Directions. Washington, DC: The National Academies Press. doi: 10.17226/10852.
×

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.

Suggested Citation:"3 Future Research Directions." Institute of Medicine. 2004. Testosterone and Aging: Clinical Research Directions. Washington, DC: The National Academies Press. doi: 10.17226/10852.
×

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.

Suggested Citation:"3 Future Research Directions." Institute of Medicine. 2004. Testosterone and Aging: Clinical Research Directions. Washington, DC: The National Academies Press. doi: 10.17226/10852.
×

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-

Suggested Citation:"3 Future Research Directions." Institute of Medicine. 2004. Testosterone and Aging: Clinical Research Directions. Washington, DC: The National Academies Press. doi: 10.17226/10852.
×

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-

Suggested Citation:"3 Future Research Directions." Institute of Medicine. 2004. Testosterone and Aging: Clinical Research Directions. Washington, DC: The National Academies Press. doi: 10.17226/10852.
×

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).

Suggested Citation:"3 Future Research Directions." Institute of Medicine. 2004. Testosterone and Aging: Clinical Research Directions. Washington, DC: The National Academies Press. doi: 10.17226/10852.
×

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

Suggested Citation:"3 Future Research Directions." Institute of Medicine. 2004. Testosterone and Aging: Clinical Research Directions. Washington, DC: The National Academies Press. doi: 10.17226/10852.
×

could be considered (total, bioavailable, and free) and a variety of methods for obtaining the measurements.

It has not been determined which form of testosterone most accurately represents the androgen-deficient state in older men. Free testosterone and bioavailable testosterone levels have been shown to decrease with age to a greater extent than total testosterone, in part due to the influence of higher serum SHBG levels. The initial efficacy trials may provide an opportunity to obtain measurements of all three and compare their usefulness in assessing associations between testosterone levels and biological effects.

In this field there is an obvious need for reproducible, accurate, and standardized laboratory assays of testosterone that can be efficiently conducted by local laboratories. While there are some validated measures of total testosterone, improved methods for determining bioavailable and free testosterone levels are needed. Bioavailable levels are of particular interest for studies in aging populations because amounts of the major testosterone binding protein (sex hormone binding globulin, SHBG) rise with age, resulting in less testosterone available to the tissues. Currently, readily available measures of free testosterone have not been found to be accurate across laboratories or when results are compared to more time-consuming methods (Chapter 1). It is important that the expertise of this field be brought to bear on addressing this issue and that standardized methods be endorsed by the appropriate professional organizations. One suggestion presented at the committee’s workshop was for a working group to be convened (possibly by the American College of Pathologists) to set reference standards and validation requirements (Rosner, 2003). To move the field forward, it is important for accurate validated measures to be established and used in all peer-reviewed research and publication.

Whatever assay(s) and measure(s) are selected, using standardized methods (including timing and number of samples) across the set of efficacy trials would be of paramount importance. Whenever possible the studies should be designed to assess the relative usefulness of these various methods in determining biological effects.

Testosterone Formulation and Dose

As described in Chapter 1, testosterone has been formulated for delivery via a number of routes including oral, injectable, transbuccal, and transdermal (patch and gel) preparations. However, the optimum route and dose are not clear, and dose-response characteristics for the effects of testosterone intervention on specific tissues or clinical outcomes are not well defined in older populations. The proposed initial efficacy trials would provide an opportunity to study more than one delivery method

Suggested Citation:"3 Future Research Directions." Institute of Medicine. 2004. Testosterone and Aging: Clinical Research Directions. Washington, DC: The National Academies Press. doi: 10.17226/10852.
×

and dose regimen as well as contributing to the understanding of dose-response relationships. However, if more than one formulation is used, there will need to be careful consideration of how this will impact the interpretation of the results as there are significant variations between the different formulations regarding the consistency of dose levels and the timing needed to achieve and maintain target levels. In general, the forms of testosterone administration should be chosen based upon the effectiveness of achieving physiological target serum levels; minimization of side-effects related to administration; ease of dose-adjustment; and cost.

Using the rationale discussed above for determining the entry testosterone level criteria, a reasonable target for testosterone levels during therapy are concentrations in the normal range of serum testosterone in young adult males. Using a target range of 2 standard deviations from mean serum levels should generally provide adequate concentrations for affecting androgen-influenced biochemical processes, and should minimize toxicities associated with high androgen levels (e.g., erythrocytosis). This range (320 to 930 ng/dL [11 to 32 nmol/L]) (Vermeulen, 2001) provides considerable latitude in designing studies to assess dose-response relationships for specific clinical outcomes. The attainment of the target serum levels should be verified shortly after the initiation of treatment and throughout the trial at regular intervals to maintain concentrations within a defined normal range. The exact reference range of serum testosterone must be determined at the start of the trials by a central laboratory using the most accurate and precise, fully validated method available.

Sample Size

Considerations regarding the sample size for the individual efficacy trials will involve a range of factors including the number of interventions being examined, the duration of the trial, and the outcome measures being used. Trials involving a single testosterone and placebo group should be designed to have high power (e.g., 90 percent power) to detect any differences in efficacy that develop within three to nine months, and with magnitude that is judged to be clinically significant. Trials that include multiple dosages of testosterone should, in addition, have high power to detect clinically meaningful differences in efficacy between adjacent dosage groups and/or a monotone dose-response relationship. The size of these studies should be adjusted to account for losses in power due to premature treatment discontinuation and losses to follow-up.

For measured outcomes, the required sample sizes of such trials will likely be between 200 and 500 for standardized differences between treatment groups of 0.5 to 0.3; that is, for differences in population means that

Suggested Citation:"3 Future Research Directions." Institute of Medicine. 2004. Testosterone and Aging: Clinical Research Directions. Washington, DC: The National Academies Press. doi: 10.17226/10852.
×

are 50 percent to 30 percent of the standard deviation of individual responses within a group. For most endpoints, therefore, sample sizes less than 500 should be adequate to achieve the desired power. It is important to note that aggregating the data from the common study endpoints in individual trials may provide information on a population of 800 or more older men. Thus, the aggregated analysis would be on a much larger population of older men than previously studied.

Primary Health Outcomes

In considering the outcomes that should be the primary focus of clinical trials of testosterone therapy in older men, the committee discussed several general principles. As outlined above, the committee focused on those outcomes for which there is preliminary evidence of testosterone’s benefit but where there is not an acceptable alternative treatment option, or where there may be subsets of older men for whom testosterone therapy might offer a second stage option or synergistically beneficial therapy. For those outcomes with other approved safe and effective treatments, testosterone—with its potential for adverse effects—may not be the first treatment of choice. An important facet of this consideration involves focusing on the health outcomes that older men and their physicians are concerned most about and those outcomes that are leading them to seek or consider testosterone therapy.

Additionally, the committee determined that the primary outcomes of future clinical trials should be clinical endpoints and not laboratory measurements. This does not diminish the need for laboratory measures; the next section discusses the wealth of information that could be learned from a range of laboratory tests. However, in choosing primary outcomes, the committee focused on those that would directly affect the health or physical functioning of older men.

After considering the many potential primary outcomes, the committee recommends focusing on strength/frailty/disability; cognitive function; sexual function; and a composite of well-being/quality-of-life/vitality. Additionally, there are other outcomes of some interest (discussed later in the chapter) such as bone mineral density, that could be examined across the set of trials or that could be the focus of specific substudies.

Strength, Frailty, Disability

One of the benefits of testosterone therapy in older men may be seen in improvements in strength, frailty, and disability outcomes. However, existing evidence is largely suggestive in terms of the nature and extent of

Suggested Citation:"3 Future Research Directions." Institute of Medicine. 2004. Testosterone and Aging: Clinical Research Directions. Washington, DC: The National Academies Press. doi: 10.17226/10852.
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FIGURE 3-1 Continuum of diminished physical function and disability.

potential benefits and the optimum target populations, method of administration, dose, and duration of therapy.

As discussed in Chapter 2, sarcopenia, or loss of muscle mass, with resulting declines in strength, is thought to be central to the development of frailty, which in turn may contribute significantly in many older adults to disability and reductions in the ability to perform daily activities (Figure 3-1). The extent to which declines in testosterone levels with aging contribute to frailty and disability remains to be determined, as does the potential for testosterone therapy in alleviating these outcomes. Moreover, the relationship between testosterone therapy and resistance exercise in enhancing strength in older men remains to be defined. Is testosterone therapy effective without concurrent resistance exercise training or additive to or even synergistic with resistance exercise in enhancing strength in older men?

Research findings indicate that testosterone therapy in hypogonadal younger men increases fat-free mass, and in some studies decreases fat mass as well (Appendix C). Because of the parallels between changes in body composition that occur due to hypogonadism and those changes seen with aging, clinical trials have been conducted in older men to assess the impact of testosterone therapy on body composition, strength (as a likely outcome of improvements in skeletal muscle mass), and physical function (as an hypothesized outcome of improvements in strength).

As discussed in Chapter 2, findings from studies of healthy older men with low testosterone levels suggest that testosterone therapy is associated with increases in muscle mass, in some cases accompanied by declines in fat mass, and there is evidence from one small study of an increased muscle protein net balance underlying this outcome (Ferrando et al., 2003). However, placebo-controlled randomized trials of testosterone therapy in older men have found only weak evidence of improved strength (Table 2-6). No conclusion can be drawn as yet regarding the effect of testosterone treatment on strength in men with low serum testosterone or in ill men receiving rehabilitative exercise.

Ultimately, to be of clinical value, the impact of testosterone therapy should be demonstrable in terms of prevention or amelioration of frailty or physical disability. There have been no assessments to date of testosterone therapy in older men with frailty. Placebo-controlled clinical trials that have assessed physical disability-related measures in older men have

Suggested Citation:"3 Future Research Directions." Institute of Medicine. 2004. Testosterone and Aging: Clinical Research Directions. Washington, DC: The National Academies Press. doi: 10.17226/10852.
×

produced mixed results (Table 2-8). The trials that reported improvement in the testosterone-treated group as compared to placebo controls were conducted in men with low testosterone levels at baseline or men who were ill (English et al., 2000; Amory et al., 2002). Two trials of longer duration (12 and 36 months) did not find strong improvements in the SF-36 assessment of physical function (Snyder et al., 1999b; Kenny et al., 2001). Snyder and colleagues (1999b) showed a significant improvement in one domain of SF-36, perception of physical function, but no significant differences between the testosterone and placebo-treated groups in performance-based measures assessing walking and stair climbing.

There are several issues that need to be addressed in future clinical trials of testosterone therapy related to strength, frailty, and disability outcomes. First, sensitive outcome measures are needed. The results of clinical trials in older men show a potential for improvements in strength and physical function with testosterone therapy. However, the results to date have been inconsistent, indicating either that testosterone has a weak impact on these outcomes or that the outcome measures employed to date are insensitive to testosterone’s effects. Because measurement insensitivity could be an issue, it will be important to critically evaluate the outcome measures to be used in future clinical trials. The choice of outcome measures should be hypothesis-based and include frailty measures and/ or physical function measures that include tasks along a spectrum of strength and exercise tolerance demands. Future trials could examine whether testosterone affects muscle strength uniformly throughout the body, as trials to date have not shown conclusive evidence. Further, measures should be tailored to focus on likely areas or levels of improvement in the population studied.

A second consideration involves the careful selection of appropriate target groups. Evidence to date suggests that the greatest benefit for chronic therapy may be in men with low baseline testosterone levels. There is little evidence for benefit in healthy men with normal testosterone levels. Issues to be considered include the baseline level of endogenous testosterone in the study population, health status, baseline muscle strength, or degree of frailty or disability. Further, it is important to consider whether the clinical trial will address chronic weakness versus acute recovery needs. Consideration should be given to substudies that would include populations of men who are weak or frail. Those with acute rehabilitation needs might also be a group of interest. It is essential that the method of administration, dose, and duration of therapy be carefully tailored to the target group.

It will also be important to consider alternative therapeutic options and cost-benefit relationships. Exercise, particularly resistance exercise, has been shown to increase fat-free mass, strength, and performance mea-

Suggested Citation:"3 Future Research Directions." Institute of Medicine. 2004. Testosterone and Aging: Clinical Research Directions. Washington, DC: The National Academies Press. doi: 10.17226/10852.
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sures in even the frailest older adults (Fiatarone et al., 1994). The study by Kenny and colleagues (2001) suggests that vitamin D (with calcium) treatment contributed to the increase in strength in both the testosterone and placebo groups of healthy older men with low testosterone, indicating that this alternative or complementary approach may be efficacious. Given that many approved pharmacologic or other therapeutic options are likely to have low adverse effects relative to benefits, it is critical that the rationale for administering testosterone be explicitly articulated and that trials comparing testosterone to other treatment options be considered.

In conclusion, the efficacy of testosterone therapy for the prevention or amelioration of frailty and resulting disability shows potential in older men with low testosterone or who are ill and in rehabilitation, and this warrants further evaluation. Additional small to medium-sized studies are indicated at this point to determine optimal target groups, outcome measures, and dose, duration, and mode of administration.

Sexual Function

There is much to be learned about the effect of testosterone therapy on sexual function in older males. Endogenous testosterone levels have at best a weak relationship with sexual satisfaction and function, and the relationship between androgen hormones and the ability to experience pleasure, erections, and orgasm appears to be quite complex. Young men who become hypogonadal typically experience decreased desire for sex within three or four weeks, yet some maintain relatively normal sexual activity with their partners (Juul and Skakkebaek, 2002). When men with advanced prostate cancer are treated with luteinizing hormone-releasing hormone (LHRH) agonists or medications that block circulating androgens, approximately 20 percent continue to function sexually, albeit with a need for more intense stimulation (Fossa et al., 1997; Smith et al., 2000; Potosky et al., 2002).

When exogenous testosterone is given to healthy young men, it appears that only a relatively low threshold level of androgens is needed to maintain normal sexual desire and that supraphysiological levels have little influence on the frequency or enjoyment of sexual activity (Anderson et al., 1992; Buena et al., 1993; Bagatell et al., 1994). Testosterone therapy combined with sildenafil had better results in a study by Aversa and colleagues (2003) than sildenafil alone in a selected group of men with erectile dysfunction and hypogonadism.

As discussed in Chapter 2 and Appendix C, several small studies in young hypogonadal men have found increases in sexual desire and function with testosterone therapy. Additionally, several non-placebo-controlled studies in larger samples of older men have shown improvements

Suggested Citation:"3 Future Research Directions." Institute of Medicine. 2004. Testosterone and Aging: Clinical Research Directions. Washington, DC: The National Academies Press. doi: 10.17226/10852.
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in sexual motivation, sexual performance, and mood as compared with baseline (Wang et al., 2000; McNicholas et al., 2003). Only a limited number of randomized placebo-controlled trials have examined the effects of testosterone therapy on sexual function in older men with mixed results (see Table 2-14 in Chapter 2).

The prominence of large placebo effects in trials of testosterone therapy was recently demonstrated in a randomized trial of the use of testosterone patches in treating sexually dysfunctional women (Shifren et al., 2000). In considering new research on testosterone therapy in older men, it will be crucial to conduct double-blind, randomized, placebo-controlled trials, and to measure the outcome by using well-validated, standardized self-report questionnaires that assess components of sexual function and satisfaction separately, including desire, pleasure, erectile function, and ability to have intense orgasms (Rosen et al., 1997). Sample sizes required depend on the effect sizes that would indicate clinically meaningful change on such outcome measures. It would be important to be able to analyze the results by pretreatment frequency of sex, age, and the availability of a functional sexual partner. This could be accomplished either by stratification (at randomization) or as an adjustment variable during the analysis. Investigators should consider measuring baseline testosterone before and after a period of several weeks of sexual abstinence, or compare changes in men who are treatment successes versus failures, since there is evidence that sexual activity itself increases endogenous testosterone levels (Dabbs and Mohammed, 1992; Jannini et al., 1999; Carosa et al., 2002). Hormonal treatment should be continued for enough time to determine if improvements in sexual function continue to increase or plateau after testosterone levels reach the normal range for young adult males. Supraphysiologic levels of testosterone should be avoided.

The associations between sexual desire, other mood parameters, and testosterone are unclear. Although both mood and sexual desire co-vary with testosterone levels, the directionality and causality remain to be defined. It would be advisable that any randomized trial of testosterone therapy include simultaneous self-report measures of mood and sexual function so that the relationships between these variables can be better understood. For men who have a committed relationship, it is very helpful to include measures of the partner’s sexual satisfaction and function. Having a partner who can still enjoy sex was an important factor in men’s ultimate sexual function and satisfaction in a large cohort of prostate cancer survivors (Schover et al., 2002).

There are several measures of sexual function that could be used in randomized trials of testosterone therapy. The International Index of Erectile Functioning (IIEF) includes five subscales: erectile function, orgasmic function, sexual desire, intercourse satisfaction, and overall sexual satis-

Suggested Citation:"3 Future Research Directions." Institute of Medicine. 2004. Testosterone and Aging: Clinical Research Directions. Washington, DC: The National Academies Press. doi: 10.17226/10852.
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faction (Rosen et al., 1997). One item also measures the frequency of sexual activity. The internal consistency of each scale is quite satisfactory, as is four-week test-retest reliability. The IIEF has been found to have excellent discriminant validity between men with sexual dysfunctions and controls and is not correlated significantly with measures of social desirability. Additionally, its 15 items take only a short amount of time (perhaps 5 minutes) to complete. The erectile function subscale also has norms for erectile functioning that allow comparison with many other samples (Cappelleri et al., 2000; Schover et al., 2002).

It would be helpful to also include an assessment of partner sexual function and satisfaction in testosterone therapy trials. For the majority of partners who are female, the Female Sexual Function Index (FSFI) was developed by the same team as the IIEF, and is a 19-item multiple-choice questionnaire measuring five female sexual function domains (Rosen et al., 2000). Validation studies of this measure have demonstrated excellent internal consistency and two-to-four week test-retest reliability for each subscale. It takes about 10 minutes to fill out and could be completed by women at each assessment point. Women could also complete a 3-item Partner Questionnaire on the husband’s erectile function and the woman’s overall satisfaction with the couple’s sex life. In a validation study comparing results from these questions with the man’s IIEF scores for 389 couples, good agreement, and internal consistency was observed for this brief scale (Mathias et al., 1999). Both the IIEF and FSFI ask about the past four weeks, a time period recent enough to promote accuracy and long enough to provide an adequate sample of behavior. Since these measures are designed to examine sexual activity within the past 1 to 4 weeks, supplemental questions may need to be added for older people who do not have a partner or who are not currently sexually active. Additionally, a new questionnaire that measures the specific psychological impact of erectile function on a man’s sexual experience and emotions looks promising (Latini et al., 2002). The development of a self-report inventory with adequate psychometric properties and norms to specifically measure a man’s sexual desire and arousability would be a valuable addition to the field. Consideration should also be given to further psychophysiological measurement of the relationship between testosterone, desire, subjective arousal, and erections, using both nocturnal penile tumescence and visual erotic stimulation under laboratory conditions.

Daily or event-related diaries offer another approach to measuring sexual function and activity. The Sexual Experience Profile includes seven multiple-choice questions about the sexual encounter and has been useful in recent studies of phosphodiesterase type 5 inhibiting drugs to treat erectile dysfunction (Hellstrom et al., 2003). A Partner Encounter Profile can also be included to provide further validation of the man’s self-report.

Suggested Citation:"3 Future Research Directions." Institute of Medicine. 2004. Testosterone and Aging: Clinical Research Directions. Washington, DC: The National Academies Press. doi: 10.17226/10852.
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Consideration must be given to the potential for inaccuracies that occur when participants fill out diaries. A potentially more reliable method of measuring behavior change is to use handheld computers or other small electronic devices to record behavior in real time, a method called ecological momentary assessment. Although this method has not yet been used to measure sexual behavior, it could be particularly useful to measure positive and negative sexual thoughts and emotions that occur during daily life activities (Stone and Shiffman, 2002).

Cognitive Function

There are several studies suggesting that higher levels of endogenous testosterone are associated with improved cognitive function. In one population-based study, older men with higher bioavailable testosterone exhibited higher scores on tests of verbal memory and mental control (Barrett-Connor et al., 1999b). In another study, bioavailable testosterone levels correlated with cognitive abilities, including tests of visual and verbal learning, memory, and naming ability (Morley et al., 1997).

As discussed in Chapter 2, placebo-controlled trials provide evidence suggesting that testosterone therapy may be of some value in improving certain cognitive abilities in older men (Table 2-10). From these trials it appears that the aspects of cognition and brain systems that are most likely to be affected by testosterone are what some call “fluid” intelligence. Fluid intelligence refers to abilities involved in novel problem solving, in contrast to crystallized intelligence, which refers to abilities and information learned through exposure to education and life experience. For example, Cherrier and colleagues (2001) found that supplementary testosterone given via intramuscular injections improved spatial memory (such as recall of a walking route), spatial ability (such as block construction), and, to some extent, verbal memory in men with normal baseline testosterone levels. Janowsky and colleagues (2000) found that testosterone therapy improved working memory (that is, the ability to “hold in mind” and flexibly manipulate information over brief periods of time in order to make a response) in older men with low baseline testosterone levels. Kenny and colleagues (2002) found that transdermal testosterone therapy improved scores on the Digit Symbol test in both the testosterone- and placebo-treated groups (both with normal testosterone levels) compared to their baseline measures and did not find significant differences in the scores on the Trailmaking B tests when the two groups were compared. These results are preliminary and the effect of testosterone on cognitive functioning remains largely unknown. Low testosterone could lead to a wide variety of cognitive deficits as well as emotional changes, though none of these changes may be dramatic. Testosterone therapy could im-

Suggested Citation:"3 Future Research Directions." Institute of Medicine. 2004. Testosterone and Aging: Clinical Research Directions. Washington, DC: The National Academies Press. doi: 10.17226/10852.
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prove cognition and mood across a broad spectrum yet the improvement may be subclinical; or testosterone therapy could even be detrimental. Future studies are needed to more clearly determine the neurochemistry and neuropharmacology of low testosterone and testosterone therapy. These studies should progress in parallel with clinical trials in promising areas, such as improved memory.

Fluid intelligence is the aspect of cognition most sensitive to the changes of aging. Yet it is unclear how a decrement in fluid intelligence actually affects the quality of life of older men (Janowsky, 2003). Most activities of daily life involve daily habits, automatic processes, and overlearned rote information—aspects of crystallized intelligence. Changes in fluid intelligence may have little impact on ordinary daily function, such as going to the store to buy groceries. Most older adults who experience problems with fluid intelligence compensate for those problems. For example, an older adult who cannot remember 10 items needed at the store will typically make a shopping list and refer to it when purchasing those items.

The current evidence of testosterone’s effect on cognition gives little reason to recommend clinical trials of testosterone therapy for the treatment of moderate to severe dementias such as Alzheimer’s disease. The preliminary data available give only weak support to the hypothesis that testosterone could be a reasonable treatment for these dementias. There may be theoretical (but no empirical) reasons for considering testosterone along with existing therapies, but given the potential adverse effects of testosterone, trials of testosterone as an augmenting therapy do not appear warranted. In addition, therapies are available that have been demonstrated in large clinical trials to be effective in the treatment of moderate to severe Alzheimer’s disease, and there is no reason to believe that testosterone would be an improvement over these therapies (Small et al., 1997; Emilien et al., 2000).

Much attention in recent years has been directed toward the prevention of Alzheimer’s disease by treating what has come to be labeled “mild cognitive impairment.” Mild cognitive impairment is diagnosed in individuals whose memory or other cognitive abilities are below normal but who do not meet conventional criteria for dementia (Bennett et al., 2002). There is no established method for defining mild cognitive impairment, but generally the condition is evaluated by use of a battery of psychological tests, including the Mini-Mental State Examination (Folstein et al., 1975), word list recall, naming tests, memory of digits forward and backward, and tests of language, such as category fluency. In one study over an average of 4.5 years of follow-up, the risk of death for subjects with mild cognitive impairment was nearly two-fold compared to controls, and the risk of meeting criteria for Alzheimer’s disease was three-fold com-

Suggested Citation:"3 Future Research Directions." Institute of Medicine. 2004. Testosterone and Aging: Clinical Research Directions. Washington, DC: The National Academies Press. doi: 10.17226/10852.
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pared to controls (Bennett et al., 2002). At present, a large, multicenter trial is underway to determine if ginkgo biloba can prevent or retard the onset of Alzheimer’s disease among subjects with mild cognitive impairment. The number of subjects required for enrollment for this trial is 3,000 (NIH, 2002). The committee found no justification for fielding a large trial of testosterone therapy at present to investigate the impact on mild cognitive impairment.

The committee does recommend further clinical trials to assess potential changes in cognitive function with testosterone therapy. Given the relatively small number of subjects enrolled to date in testosterone therapy studies to determine changes in cognitive function, a larger double-blind, placebo-controlled trial over a longer follow-up could be implemented. A battery of psychological tests should be employed in such a study. This battery should be selected by the investigators fielding the study after careful review of the literature and in consultation with psychologists who have been involved in studies of testosterone therapy. The tests should include assessments of fluid and crystallized intelligence, memory, and function. Investigators must address the problem of multiple measures of cognition being examined simultaneously and the possibility of false positive results. It is quite possible that this study could be combined with other studies of testosterone therapy as recommended by the committee.

Well-Being, Quality of Life, Vitality

The committee was also interested in an assessment of the overall improvement in well-being that might be achieved with testosterone therapy. As discussed in Chapter 2, a number of randomized clinical trials have examined the association between various aspects of quality of life and testosterone therapy in older men. While some improvements in physical function, cognitive function, sexual function, mood, and health-related quality of life have been reported, in general, results have been inconsistent, with no clear patterns emerging regarding overall health improvement with testosterone therapy.

Randomized trials to date have had small numbers of participants and have used a variety of measures. Sensitivity of the instrument could influence interpretations because broader more diffuse measures might be less likely to demonstrate an effect from testosterone therapy (discussed above in the section on strength, frailty, and disability). A pilot study of 22 healthy older males (ages 65 years and older) found similar scores between the treated and untreated groups on health-related quality of life (Reddy et al., 2000). Two studies that looked at hospitalized or rehabilitation patients found some improvements in the Functional Independence

Suggested Citation:"3 Future Research Directions." Institute of Medicine. 2004. Testosterone and Aging: Clinical Research Directions. Washington, DC: The National Academies Press. doi: 10.17226/10852.
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Measure (FIM) such as improved walking, stair climbing, and decreased hospital stay (Bakhshi et al., 2000; Amory et al., 2002).

Improvements in quality of life, well-being, or vitality are—by their very complexity—quite challenging to assess. There are some physiological, clinical, or performance-based measures that could be used to provide an indication of ambulatory improvement or to assess other physical functions or changes in cognitive function. However, since the goal is to determine improvement in individuals, this is an area where an individual’s perception of his or her health status is best obtained by self-reports and self-evaluation. In the Women’s Health Initiative (WHI) study on the effects of estrogen plus progestin on health-related quality of life, multiple measures were assessed in a population of 1,511 women (Hays et al., 2003). The measures used in this study were:

  • the RAND 36-Item Health Survey (with subscales on general health; physical functioning; limitations on usual role-related activities due to physical health problems; bodily pain; energy, and fatigue; limitations on usual role-related activities due to emotional or mental problems; social functioning; and emotional or mental health);

  • an eight-item scale on depressive symptoms;

  • a five-item quality of sleep scale;

  • a four-point response scale on sexual functioning (ranging from “very unsatisfied” to “very satisfied”);

  • the Modified Mini-Mental State Examination; and

  • a checklist of menopausal symptoms.

A similar approach (with necessary adaptations) might be useful in assessing the endpoints of interest regarding testosterone therapy. Additionally, consideration could be given to including other measures that focus more specifically on vitality and well-being; these measures could be adapted from other validated instruments or may need to be developed.

Additional Outcome Measures

In addition to the major research priorities identified above, the committee recognized that a variety of supplementary questions concerning the effects of testosterone therapy remain unresolved. These questions involve intermediate outcomes that could provide both useful insights into the mechanisms of testosterone’s effects in older men as well as useful markers of sex steroid action in future studies. In designing studies of the effects of testosterone therapy, the committee recommends including assessments of variables that have been linked to these issues. Standard

Suggested Citation:"3 Future Research Directions." Institute of Medicine. 2004. Testosterone and Aging: Clinical Research Directions. Washington, DC: The National Academies Press. doi: 10.17226/10852.
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ization of the measures and methodologies will be important so that the results on common study endpoints in the initial efficacy studies can be analyzed as an aggregate data set. Additional outcomes to be considered are discussed briefly below.

Lipid and Carbohydrate Metabolism and Cardiovascular Risk

Although a formal test of the effects of testosterone therapy on cardiovascular-related morbidity or mortality was not considered by the committee to be appropriate at this time, a variety of intermediate outcomes could provide useful information (e.g., lipid and lipoprotein concentrations, homocysteine levels, carbohydrate metabolism and insulin sensitivity, blood pressure, intimal thickness, vascular reactivity).

Measures of Body Composition

Body composition can also be affected by androgens and is related to a variety of important outcomes, including functionality, carbohydrate metabolism, and cardiovascular risk. It would be useful to gather more data on the impact of testosterone therapy in older men on measures of body composition including fat mass, skeletal muscle mass, and adipose tissue distribution.

Hematologic Indices

Intermediate laboratory measures including red cell mass, coagulation and fibrinolytic factor levels, and platelet function would provide useful information.

Inflammation Measures

Additional information could be gained by assessing the effects of testosterone replacement on measures of immunity and inflammation (e.g., C-reactive protein levels, tumor necrosis factor levels, immune reactivity).

Other Hormonal Markers and Growth Factors

Other endocrine systems can be affected by testosterone therapy, and some of the alterations may play a role in the overall effects of testosterone administration. To better understand those interactions, additional information is needed on growth factor levels, concentrations of estrogen and androgens, effects on sex hormone binding globulin, etc.

Suggested Citation:"3 Future Research Directions." Institute of Medicine. 2004. Testosterone and Aging: Clinical Research Directions. Washington, DC: The National Academies Press. doi: 10.17226/10852.
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Genetic Determinants of Sex Steroid Action

It is highly likely that an individual’s response to androgen replacement is substantially influenced by genotype. The relationship between androgen-receptor polymorphisms and responses to androgens is not well defined. The acquisition of DNA and sera could be incorporated into the study design to facilitate analyses of genetic differences in the androgen receptor and the potential development of future biomarkers of androgen action.

Bone Metabolism and Density

One of the potential benefits of testosterone therapy in older men is a reduction in the risk of osteoporotic fractures. It is clear that testosterone therapy in younger hypogonadal men has positive effects on bone mineral density (potentially via aromatization to estrogen). If those effects of therapy also occurred in older men with low testosterone levels, bone strength and fracture resistance could be improved. In addition, non-skeletal actions of testosterone treatment (e.g., increased muscle strength) could also improve bone strength or lessen fall risk. The committee carefully considered the issues regarding clinical trials of bone-related outcomes. While there is much to be learned about testosterone’s effect on bone density and fractures, the committee outlines in the following discussion its reasons for not considering bone-related outcomes as primary outcomes in the initial set of short-term clinical trials.

First, the committee was most concerned about outcomes of direct concern to older men. Bone density is but a surrogate measure for fracture risk. The standard for evaluating the potential benefits of an intervention for osteoporosis is a trial with a fracture endpoint. There are important challenges in the design of a trial of testosterone therapy with sufficient power to detect a reduction in fracture risk. At present, it is unclear how much skeletal benefit would result from testosterone administration in older men. The reduction in fracture risk to be gained from non-skeletal effects of testosterone is unknown. Thus, a very large, lengthy trial may be necessary to adequately examine the potential anti-fracture effects of testosterone, and it would be faced with difficult recruitment goals.

Second, effective therapies for osteoporosis in men already exist. Bisphosphonates and parathyroid hormone are available and have been shown to increase bone density and to reduce fracture risk in men. Bisphosphonates, in particular, are associated with little risk of adverse outcomes. Moreover, these treatments appear to be effective in men with low testosterone levels. The likelihood that testosterone therapy would offer additional benefits is unclear. The availability of effective therapies

Suggested Citation:"3 Future Research Directions." Institute of Medicine. 2004. Testosterone and Aging: Clinical Research Directions. Washington, DC: The National Academies Press. doi: 10.17226/10852.
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raises ethical concerns concerning the design of a placebo-controlled trial of testosterone therapy in men with low bone density and at risk of fracture (Brody et al., 2003). It may not be ethical to withhold treatment (or treat with placebo) in men with low bone density at entry. It is likely that a trial to detect an effect of testosterone on fracture risk that is different from that resulting from an approved treatment would require a large sample size.

Finally, in the relatively near future other therapeutic approaches could reduce the attractiveness of testosterone treatment. For instance, androgen receptor modulators are in development that appear to have skeletal benefits without major effects on the prostate.

Despite all these considerations, the committee also recognizes that there may be some benefit from better understanding the effects of testosterone on bone mass and metabolism. A variety of assessments (e.g., bone mineral density and structure, markers of bone metabolism) could be very useful in understanding the skeletal effects of sex steroids and in planning subsequent evaluations of the effects of testosterone therapy. At least, it should be possible to include these measures as secondary outcomes in the studies recommended by the committee. For instance, it may be possible to gain very useful information concerning the effects of testosterone on skeletal measures by studying men with bone density that is low but not so severely reduced that others therapies are indicated.

Additional Outcome Measures

There are a number of other measures of potential interest including measures of mood and dysthmia.

PROTECTION OF RESEARCH PARTICIPANTS

Safety and Ethical Issues

It is an axiom of research ethics that risks to research participants be minimized and that risks are reasonable in proportion to the potential benefits of participating in the study.2 As outlined in a recent Institute of

2  

The Federal Policy for Protection of Human Subjects states: “In order to approve research … the IRB shall determine that all of the following requirements are satisfied: (1) risks to subjects are minimized: (i) by using procedures which are consistent with sound research design and which do not unnecessarily expose subjects to risk and (ii) whenever appropriate, by using procedures already being performed on the subjects for diagnostic or treatment risks and benefits: (2) Risks to subjects are reasonable in relation to anticipated benefits, if any, to subjects, and the importance of the knowledge that may reasonably be expected to result.”

Suggested Citation:"3 Future Research Directions." Institute of Medicine. 2004. Testosterone and Aging: Clinical Research Directions. Washington, DC: The National Academies Press. doi: 10.17226/10852.
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Medicine (IOM) report, a systems approach to protecting research participants—involving protection measures incorporated at many phases of the research process—is critical (IOM, 2003b). The committee discussed a range of measures to protect participants of future clinical trials of testosterone therapy, including appropriate exclusion criteria, careful monitoring and evaluation for prostate and other potential adverse effects, a well-refined plan for interim monitoring, and a thorough informed consent process.

Discussions of research ethics distinguish between benefits to the individual and benefits to society. Although there is little evidence that testosterone therapy produces therapeutic benefits in older men, the committee selected the primary outcomes based on preliminary evidence of potential therapeutic benefit in this population. Further, the committee focused on clinical outcomes (as contrasted with laboratory measures) as these outcomes would have the most relevance and direct impact if found to be beneficial to the health of older men. As outlined elsewhere in this report, the use of testosterone therapy is increasing rapidly, and there is a social need to determine testosterone’s efficacy. Although participants who receive the placebo will not directly benefit if testosterone is found to have beneficial effects, there is so little known about testosterone therapy in older men that those in the placebo arm of the trial will be making an important contribution to research efforts in this field. It is the committee’s belief that this major social benefit and the possible benefits to participants, combined with the stringent proposed measures for minimizing risks, justifies the claim that the resulting minimized risks are reasonable in relation to the benefits for the recommended trials.

Exclusion Criteria, Monitoring, and Follow-Up

Prostate Outcomes

Any clinical study designed to determine the efficacy of testosterone therapy in the aging male must manage the risk of prostate diseases, specifically benign prostatic hyperplasia (BPH) and prostate cancer (Bhasin et al., 2003). There remain many unknowns regarding the extent or mechanisms by which testosterone or its metabolite, dihydrotestosterone, may be involved in modifying the risk of adverse prostate outcomes. Nevertheless, concerns about possible adverse effects necessitate careful attention to exclusion criteria and adverse event monitoring to minimize risks to research participants. The committee believes that it is possible to conduct ethical clinical trials of testosterone therapy in older men as long as stringent monitoring practices are followed for all participants, and potential risks are thoroughly and carefully explained prior to enrollment.

Suggested Citation:"3 Future Research Directions." Institute of Medicine. 2004. Testosterone and Aging: Clinical Research Directions. Washington, DC: The National Academies Press. doi: 10.17226/10852.
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Exclusion criteria. There are a number of considerations in identifying men who are at increased risk for prostate cancer or for complications of BPH (such as acute urinary retention [AUR] or the need for surgical intervention) and who therefore should be excluded from trials of testosterone therapy.

It is estimated that 5 percent to 10 percent of all prostate cancer cases have a hereditary basis. Thus, while the average man has an 8 percent lifetime risk of prostate cancer, his risk rises to 35 percent to 45 percent if three or more of his first- or second-degree male relatives are affected (Bratt, 2002) (Table 3-1). Thus candidates for studies of testosterone therapy should be excluded if their father, brothers, or sons have been diagnosed with prostate cancer.

In developing exclusion criteria for a clinical trial involving older men, consideration must be given to reliable and practical methods for screening large numbers of men for prostate cancer or BPH. In this study population, the potential for occult prostate cancer (cancer not evident or detectable by clinical methods alone) raises complex issues, particularly regarding when to conduct biopsies and on what segment of the study

TABLE 3-1 Effect of Family History of Prostate Cancer on Lifetime Risk of Clinical Prostate Cancer

Family History

Relative Risk

% Absolute Risk

Negative

1

8

Father affected at 60 yrs. or older

1.5

12

One brother affected at age 60 yrs. or older

2

15

Father affected before age 60 yrs.

2.5

20

One brother affected before age 60 yrs

3

25

Two affected male relativesa

4

30

Three or more affected male relativesb

5

35-45

aFather and brother, or 2 brothers, or a brother and a maternal grandfather or uncle, or a father and a paternal grandfather or uncle.

bThe absolute lifetime risk for mutation carriers is probably 70% to 90% for high penetrance genes such as HPC1.

NOTE: The absolute lifetime risk of clinical prostate cancer for men with a negative family history is derived from Swedish studies, but the figures are approximately the same for other high incidence populations in northern Europe, North America, and Australia. The relative risks represent approximations based on a synthesis of published epidemiological studies, accounting for various kinds of bias. The relative risk of early onset prostate cancer and thereby death from prostate cancer for men with relatives with early onset disease is substantially higher than the risks shown in the table.

SOURCE: Bratt, 2002.

Suggested Citation:"3 Future Research Directions." Institute of Medicine. 2004. Testosterone and Aging: Clinical Research Directions. Washington, DC: The National Academies Press. doi: 10.17226/10852.
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TABLE 3-2 Chance of Cancer as a Function of Serum Prostate Specific Antigen Level and Digital Rectal Examination Findingsa

 

Chance of Cancer on Biopsy (%) PSA <4 ng/mL

Chance of Cancer on Biopsy (%) PSA >4 ng/mL

Study

–DRE

+DRE

–DRE

+DRE

Cooner et al., 1990

9

17

25

62

Hammerer and Huland, 1994

4

21

12

7

Ellis et al., 1994

6

13

24

42

Catalona et al., 1994

10

32

49

Schroder et al., 1998

13

55

aNote the similarity in findings between Cooner and colleagues (1990) (referral population from early PSA era) and Schroder and colleagues (1998) (screened populations from more current PSA era).

SOURCE: Carter and Partin, 2002.

population.3 Although transrectal ultrasound and prostate biopsy are recommended for follow-up and monitoring of prostate concerns (see section below on monitoring), they are not practical screening methods for entry into clinical trials.

Currently, the combination of digital rectal examination (DRE) and serum PSA is the most useful first-line test for detecting the presence of prostate cancer (Carter and Partin, 2002). The chance of cancer being found as a function of serum PSA and DRE is shown in Table 3-2. Since, these tests are complementary, the committee suggests that both DRE and PSA be used to screen for prostate cancer and BPH. Patients with an examination that is clinically suspicious for cancer (not those simply with benign enlargement) should be excluded from the trials.

For those men with a normal digital rectal exam, determining a precise cut point for exclusion that is based solely upon PSA is more problematic. The most common cut point has been 4 ng/mL based on the reference range for the tandem PSA assay (Hybritech, San Diego, CA) being 0–3.99 ng/mL.

3  

Occult prostate cancer has been shown to be present in as many as 27 percent of men in their 30s and the incidence increases with age (Schwartz et al., 1999). Despite utilizing transrectal ultrasound guidance at the time of initial prostate biopsy, repeat biopsies continue to uncover prostate cancer where none has been demonstrated on prior biopsy. In one study, cancer detection rates on biopsies 1, 2, 3, 4 were 22 percent, 10 percent, 5 percent, and 4 percent, respectively, in a group of 1,051 men with total PSA levels between 4 and 10 ng/ mL (Djavan et al., 2001). In another study, repeat biopsy revealed prostate cancer in 21 percent of the participants (Park et al., 2003).

Suggested Citation:"3 Future Research Directions." Institute of Medicine. 2004. Testosterone and Aging: Clinical Research Directions. Washington, DC: The National Academies Press. doi: 10.17226/10852.
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TABLE 3-3 PSA Thresholds Based on Age and Race

 

Normal PSA Ranges (ng/mL)

 

Based on 95% Specificitya

Based on 95% Sensitivityb

Age Decade (Years)

White Malesc

Black Malesd

White Malesd

Black Malesd

40

0–2.5

0–2.4

0–2.5

0–2.0

50

0–3.5

0–6.5

0–3.5

0–4.0

60

0–4.5

0–11.3

0–3.5

0–4.5

70

0–6.5

0–12.5

0–3.5

0–5.5

aUpper limit of normal PSA determined from 95th percentile of PSA among men without prostate cancer.

bUpper limit of normal PSA required to maintain 95% sensitivity for cancer detection.

cOesterling et al., 1993.

d Morgan et al., 1996.

SOURCE: Carter and Partin, 2002.

An alternative method of establishing upper limits of PSA in a healthy population has been to use 95th percentiles based upon age groups (Table 3-3). This approach encourages further tests (biopsy) in younger patients with PSA levels lower than 4 ng/mL and extends normal values in older men, thus avoiding unnecessary biopsies (Oesterling et al., 1993). However, there has been criticism of this approach for fear of underdiagnosing early-stage disease (Catalona et al., 1994).

In considering exclusion criteria related to BPH, it is now well established with data from the Proscar Long-term Efficacy and Safety Study (PLESS) that the risk of acute urinary retention and surgical intervention is markedly reduced by the long-term administration of the 5-α-reductase inhibitor, finasteride (McConnell et al., 1998). An important series of sub-analyses of the data has revealed that prostate size is a risk factor for acute urinary retention and surgical intervention and that PSA is a surrogate for prostate size, and hence a powerful predictor of AUR and the need for surgery (Roehrborn et al., 2000). The risk for these complications ranged from 8.9 percent to 22 percent when stratified for prostate size, and 7.8 percent to 19.9 percent when stratified by increasing PSA.

These variables were more powerful than the American Urological Association (AUA) urinary symptom score, urinary flow rates, and residual volume in predicting the risk of acute urinary retention. In this study, the upper tertile of the study population had PSA levels above 3.3 ng/mL and patients with AUA symptom scores greater than 21 had been excluded.

Suggested Citation:"3 Future Research Directions." Institute of Medicine. 2004. Testosterone and Aging: Clinical Research Directions. Washington, DC: The National Academies Press. doi: 10.17226/10852.
×

In developing exclusion criteria regarding prostate outcomes for future clinical trials of testosterone therapy, consideration should naturally be given to the most up-to-date research. Based on current research, the committee suggests that men should be excluded from participation in clinical trials of testosterone therapy if they have been diagnosed with prostate cancer or have immediate family members (father, brothers, or sons) with prostate cancer; have a prostate examination clinically suspicious for cancer (not simple benign enlargement); have a PSA greater than 4.0 ng/mL; or have an AUA symptom score greater than 21.

Monitoring. The risk of developing clinically-apparent prostate cancer or having growth of BPH requiring intervention in men taking testosterone is unknown, and therefore must be carefully monitored. In testosterone therapy studies in which prostate changes have been monitored (see Table 2-19 in Chapter 2) the changes appear modest. However, as discussed in Chapter 2, most of these studies had durations less than one year, with small sample sizes and a wide range in the age of the participants. Where PSA was measured, there was either a small increase or no change. In the longer term (36 months) randomized trial by Snyder and colleagues (1999a), the mean PSA concentration had a small but significant increase in the testosterone-treated group, with no change in the placebo group. The increase in PSA occurred in the first six months of treatment, after which the PSA levels remained stable. Four men had biopsies, with one biopsy detecting prostate cancer. In future studies of testosterone therapy, prostate outcomes should be carefully monitored, and when deemed appropriate, additional information including systematic biopsy is warranted.

It has been shown that short-term variations in PSA regularly occur (Eastham et al., 2003), and that PSA velocity or rate of change in PSA is a useful indicator of potential prostate cancer. Utilizing frozen sera from men enrolled in the Baltimore Longitudinal Study of Aging, PSA was measured years before the diagnosis of prostate disease in men with and without prostate cancer (Burris et al., 1992). In that study, 72 percent of men with a subsequent diagnosis of prostate cancer and only 5 percent of men without cancer had a PSA velocity of more than 0.75 ng/mL per year. These data pertained only to men with PSA values from 4 to 10 ng/ mL. A later study confirmed the validity of the 0.75 ng/mL value in men less than 70 years old with initial PSA values less than 4 ng/mL (Smith and Catalona, 1994). Studies have also indicated that PSA velocity is accurate only if determined over at least an 18-month period (Archangeli et al., 1997). Thus, a rate of change of PSA greater than 0.75 ng/mL per year appears to be a reasonable indication for prostate biopsy during testoster-

Suggested Citation:"3 Future Research Directions." Institute of Medicine. 2004. Testosterone and Aging: Clinical Research Directions. Washington, DC: The National Academies Press. doi: 10.17226/10852.
×

one therapy in addition to any new prostate findings suspicious for cancer on physical exam or an absolute PSA level greater than 4 ng/mL.

In addition, both the baseline PSA and its rate of change over time can be used to predict risk of complications of BPH. In an analysis of the Baltimore Longitudinal Study of Aging, risk stratification based on PSA identified men at greatest risk for adverse events over time due to BPH (Wright et al., 2002). These data are in concert with the PLESS analysis previously discussed.

Therefore, in order to monitor prostate status closely, men enrolled in studies of testosterone therapy should have a DRE and PSA test every six months during the course of the study. Urologic evaluation (including transrectal ultrasound) is indicated if the AUA symptom score is greater than 21; urologic evaluation (including transrectal ultrasound and biopsy of the prostate) is indicated if:

  • DRE reveals changes suspicious for prostate cancer; or

  • PSA >4 ng/mL; or

  • PSA velocity greater than 0.75 ng/mL/year measured over 12 months for men whose PSA levels rise above 4 ng/mL and over 18 months for men with PSA levels less than 4 ng/mL.

Follow-up. There are still many unknowns regarding the effect of testosterone treatment on prostate histopathology. It is known that testosterone or its metabolite, DHT, is required for the development of the prostate since males with 5-α-reductase deficiency do not develop a prostate. In addition, DHT plays a role in sustaining BPH, as is evident through the action of finasteride (a synthetic compound that inhibits the type II 5-reductase enzyme from converting testosterone to DHT), which reduces prostate size by 20 percent to 30 percent. However, the fact that significant glandular BPH persists following finasteride treatment shows that other factors are operative. In addition, the effect of testosterone administration on occult or incidental prostate cancer is unknown, although current studies suggest minimal risk (Brawer, 2003).

Thus, there is a great deal of information that could be obtained if histopathologic studies were conducted at the termination of any future long-term clinical trials of testosterone therapy. Biopsies at the termination of study were used in the Prostate Cancer Prevention Trial and revealed a 24.4 percent detection rate in the control group (Thompson et al., 2003). The use of an end-of-study biopsy would also eliminate the effect of verification bias, an issue of concern (Punglia et al., 2003; Schroder and Kranse, 2003).

Suggested Citation:"3 Future Research Directions." Institute of Medicine. 2004. Testosterone and Aging: Clinical Research Directions. Washington, DC: The National Academies Press. doi: 10.17226/10852.
×
Exclusion Criteria and Monitoring for Other Potential Adverse Health Outcomes

In addition to prostate outcomes, the design of future clinical trials of testosterone therapy in older men will need to carefully consider the development of exclusion criteria and monitoring protocols for other adverse health outcomes.

Polycythemia. As discussed in Chapter 2 and Appendix C, a number of randomized trials and other human studies found increases in hematocrit with testosterone therapy. Animal and human studies have shown that androgens have an erythopoietic effect in mammals—including increasing reticulocyte counts, elevating hemoglobin concentrations, and stimulating bone marrow erythropoietic activity (Shahidi et al., 2001).

For some older men whose baseline hemoglobin levels are low, testosterone treatment may bring their hematocrit into the normal range, with a resulting beneficial increase in oxygen-carrying capacity. However, other men may develop abnormally high hemoglobin levels, potentially resulting in increased blood viscosity, and possibly contributing to thromboembolic sequelae, such as strokes (Basaria and Dobs, 2001). Men with pre-existing polycythemia should be excluded from clinical trials of testosterone therapy.

During clinical trials of testosterone therapy, each subject’s hematocrit and hemoglobin should be closely monitored and testosterone administration stopped if polycythemia develops or hematocrit exceeds the normal ranges. For men, hematocrit levels that are greater than 50 percent are considered abnormally high (Adamson and Longo, 2001). Health concerns regarding the potential for thrombotic events, such as stroke, increase dramatically with hematocrits greater than 55 percent, as blood viscosity at those levels increases logarithmically (Adamson and Longo, 2001). Exogenous testosterone may be restarted if hematocrit levels drop to normal levels, but would require more frequent monitoring.

Cardiovascular and thromboembolic disease. Older men are generally at high risk of developing cardiovascular and thromboembolic disease, and some effects of testosterone therapy (e.g., polycythemia) may increase that risk. Thus, exclusion criteria should be similar to those for other clinical trials in this population and may include excluding men with previous stroke or who have had a myocardial infarction within the past three to six months.

As discussed in Chapter 2, there is inconsistent evidence regarding testosterone’s effects on lipid profiles or on the risk for atherosclerotic heart disease. There is some evidence that thromboembolic and coronary

Suggested Citation:"3 Future Research Directions." Institute of Medicine. 2004. Testosterone and Aging: Clinical Research Directions. Washington, DC: The National Academies Press. doi: 10.17226/10852.
×

artery disease in hypogonadal men are mediated by low levels of fibrinolytic activity (Winkler, 1996). In men, hypogonadism is accompanied by an elevation of fibrinolytic activity inhibition mediated by an increased synthesis of plasminogen activator inhibitor (PAI 1). There is also evidence that androgens modify platelet function (including platelet aggregation), affect plasma proteins involved in coagulation and fibrinolysis, and decrease the elasticity of vascular tissue (Ferenchick, 1996).

In future trials of testosterone therapy, participants should be warned of cardiovascular disease and venous thromboembolism risks in general and the potential for adverse effects related to testosterone therapy. Participants should be monitored for symptoms and signs of these diseases at their milestone evaluations.

Serious psychiatric illness and aggression. Testosterone administration has not been shown to invoke violence in humans, but rather may alter the likelihood of aggression in specific situations involving cues that are internal and external (Christiansen, 2001). Clinical use of androgen preparations reveals few adverse events regarding aggression. A pattern of association has been seen in some athletes between irritability, aggression, personality disturbance, and psychiatric diagnoses and the use of certain exogenous anabolic steroids (Bahrke et al., 1996). However, studies in which testosterone was administered to hypogonadal men or men with normal gonadal function did not report increased aggression with treatment (Albert et al., 1993; Christiansen, 1998).

Subjects with serious psychiatric disorders are not candidates for study due to compliance concerns and the potential behavioral and psychological effects of exogenously administered testosterone. Participants in future clinical trials of testosterone therapy should be monitored for potential psychological and behavioral effects.

Other exclusion criteria. There are other outcomes that investigators will need to consider as exclusion criteria. These may include male breast cancer, diabetes, uncontrolled sleep apnea, obesity, and alcohol and drug abuse. Prior androgen use may also be considered as one of the exclusion criteria.

Interim Monitoring of Trial Results and Stopping Rules

Well-designed clinical trials, particularly long-term trials, include an a priori plan for interim monitoring of the study outcomes and for early stopping of the trial if monitoring indicates it is appropriate to do so based on the primary endpoints and safety assessment (Pocock, 1996; Piantadosi, 2001).

Suggested Citation:"3 Future Research Directions." Institute of Medicine. 2004. Testosterone and Aging: Clinical Research Directions. Washington, DC: The National Academies Press. doi: 10.17226/10852.
×

Comparable to estrogen, testosterone can affect multiple biochemical pathways resulting in the potential for multiple beneficial or deleterious outcomes. Therefore, in developing a plan for interim monitoring, careful consideration should be given to including a global evaluation measure to assess the balance of potentially beneficial and potentially harmful effects of testosterone. An interim monitoring plan could be modeled after plans used in trials designed to evaluate the risks and benefits of postmenopausal hormone therapy and selective estrogen receptor modulators such as the Women’s Health Initiative, the Breast Cancer Prevention Trial, and the Study of Tamoxifen and Raloxifene (Freedman et al., 1996; Gail et al., 1999; Costantino, 2001). The global evaluation could be developed as an informal supplemental monitoring tool for use by the data and safety monitoring board as part of its considerations for continuing the trial, or it could be developed as part of the formal rules for stopping the trial. Outcomes to be considered for inclusion in the global evaluation include heart disease, stroke, pulmonary embolism, deep vein thrombosis, depression, symptomatic benign prostate hyperplasia, prostate cancer, and a key measure for each of the primary outcomes.

As one potential consequence of testosterone therapy may be prostate hypertrophy, it is possible that those receiving testosterone will require an elevated rate of prostate biopsy. Therefore, the stopping rules for the trial should include, as a separate consideration, an evaluation of the difference between the treatment and control groups in terms of the number of prostate biopsies and the balance of potential gains and morbidity risks associated with the consequences of an increased biopsy rate. Also, it would be important to recognize that an increase in biopsy rate among those receiving testosterone may cause a bias in the detection of prostate cancer that would have otherwise gone undetected and be of no health consequence to the individual. Thus, when considering the differential between the treatment and control groups for the rate of prostate cancer, the stopping rules should incorporate some predefined level of tolerance to account for a cancer detection bias among those in the group treated with testosterone. An independent data and safety monitoring board will provide this and a number of other oversight functions that are crucial to protecting the safety of participants during the course of the clinical trials.

Risk/Benefit Communication and Consent

The purpose of full disclosure of risks during the consent process is to ensure that subjects have an opportunity to perform a risk/benefit assessment independent of investigators. Often, the values and preferences of an individual subject will determine just how “reasonable” any risk actually is.

Suggested Citation:"3 Future Research Directions." Institute of Medicine. 2004. Testosterone and Aging: Clinical Research Directions. Washington, DC: The National Academies Press. doi: 10.17226/10852.
×

Effective communication of potential benefits and risks is a challenge for all areas of clinical research. Testosterone therapy research poses specific ethical challenges to investigators attempting to describe and catalogue risks, and to institutional review boards that must evaluate those risks in light of possible benefits. As noted above, early screening and regular monitoring for prostate cancer will be necessary for all study participants. This regimen of concentrated diagnostic attention may reveal cancers that would otherwise have remained latent and untreated. Early discovery will necessitate that study participants decide whether to accept treatment and determine how aggressively to pursue that treatment. This quandary will be faced even in control groups that receive no testosterone therapy.

The current lack of scientific consensus concerning the efficacy of PSA screening and the use of other diagnostic tools in an aging population complicates any attempt to provide truly informed consent to research. Men whose age might normally rule them out as candidates for PSA screening could find themselves subjected to repeated screenings as part of a research protocol. Increasing the rate of screening will undoubtedly increase the findings of higher levels of PSA; rates of follow-up biopsy to detect the presence of malignancy will increase in turn. As a result, radiation or surgery rates are likely to rise in the study population.

Accurate baseline rates of prostate malignancy in elderly men do not exist; neither does the ability to project with precision the natural growth rate of their tumors. For some, surgery may represent an unnecessary intervention. In that context, exposure to the potential discomfort of frequent examinations and the heightened likelihood for biopsy (and subsequent radiation or surgery) will need to be explained as a potential risk for study participants.

A recent IOM report emphasizes the need for participant-centered clinical research (IOM, 2003a). Currently, it is estimated that the average time spent obtaining informed consent may be as little as 10 minutes and in some cases consists solely of the participant reading and signing the informed consent form. There is a need—particularly in clinical trials with complex potential risks such as is evident in trials of testosterone therapy—for focused effort on ensuring that informed consent is a participatory process. The informed consent process should involve a conversation between the research staff and the participant, with the opportunity for educating potential participants and answering their questions.

Understanding the benefits or risks in testosterone therapy requires medical sophistication among potential research subjects. The lack of a medical vocabulary necessary for discussing and understanding potential side effects of prostate surgery (such as incontinence and/or impotence) could lead to a flawed assessment of what is at stake when any individual

Suggested Citation:"3 Future Research Directions." Institute of Medicine. 2004. Testosterone and Aging: Clinical Research Directions. Washington, DC: The National Academies Press. doi: 10.17226/10852.
×

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-

Suggested Citation:"3 Future Research Directions." Institute of Medicine. 2004. Testosterone and Aging: Clinical Research Directions. Washington, DC: The National Academies Press. doi: 10.17226/10852.
×

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.

Suggested Citation:"3 Future Research Directions." Institute of Medicine. 2004. Testosterone and Aging: Clinical Research Directions. Washington, DC: The National Academies Press. doi: 10.17226/10852.
×

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.

Suggested Citation:"3 Future Research Directions." Institute of Medicine. 2004. Testosterone and Aging: Clinical Research Directions. Washington, DC: The National Academies Press. doi: 10.17226/10852.
×

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.

Suggested Citation:"3 Future Research Directions." Institute of Medicine. 2004. Testosterone and Aging: Clinical Research Directions. Washington, DC: The National Academies Press. doi: 10.17226/10852.
×

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.

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Popular culture often equates testosterone with virility, strength, and the macho male physique. Viewed by some as an “antiaging tonic,” testosterone’s reputation and increased use by men of all ages in the United States have outpaced the scientific evidence about its potential benefits and risks. In particular there has been growing concern about an increase in the number of middle-aged and older men using testosterone and the lack of scientific data on the effect it may have on aging males. Studies of testosterone replacement therapy in older men have generally been of short duration, involving small numbers of participants and often lacking adequate controls. Testosterone and Aging weighs the options of future research directions, examines the risks and benefits of testosterone replacement therapy, assesses the potential public health impact of such therapy in the United States, and considers ethical issues related to the conduct of clinical trials. Testosterone therapy remains an attractive option to many men even as speculation abounds regarding its potential.

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