Testosterone and Aging Clinical Research Directions (2004) / Chapter Skim
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3 Future Research Directions
3 Future Research Directions
Pages 112-158
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From page 112... ...
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~.
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From page 113... ...
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)
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From page 114... ...
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.
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From page 115... ...
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.
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From page 116... ...
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.
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From page 117... ...
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.
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From page 118... ...
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)
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From page 119... ...
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)
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From page 120... ...
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.
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From page 121... ...
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]
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From page 122... ...
Measuring Testosterone Levels Measurements of testosterone levels are of critical importance because these determinations are involved in the selection of participants for inclusion in clinical trials, the dosing of testosterone preparations, and the evaluation of the effects of testosterone treatment on outcomes. As discussed in Chapter 1, there are several different forms of testosterone that
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From page 123... ...
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.
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From page 124... ...
In general, the forms of testosterone administration should be chosen based upon the effectiveness of achieving physiological target serum levels; minimization of sideeffects 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.
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From page 125... ...
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.
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From page 126... ...
. 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~.
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From page 127... ...
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.
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From page 128... ...
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 (luul and Skakkebaek, 2002~.
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From page 129... ...
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; lannini 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.
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From page 130... ...
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.
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From page 131... ...
. 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~.
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From page 132... ...
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~.
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From page 133... ...
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 healthrelated quality of life have been reported, in general, results have been inconsistent, with no clear patterns emerging regarding overall health improvement with testosterone therapy.
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From page 134... ...
; · 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)
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From page 135... ...
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.
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From page 136... ...
. If those effects of therapy also occurred in older men with low testosterone levels, bone strength and fracture resistance could be improved.
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From page 137... ...
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)
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From page 138... ...
. 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.
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From page 139... ...
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)
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From page 140... ...
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~.
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From page 141... ...
MalesC Males Males Males 40 0-2.5 0-2.4 0-2.5 0-2.0 50 0-3.5 0-6.5 0-3.5 0~.0 60 0~.5 0-11.3 0-3.5 0~.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.
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From page 142... ...
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.
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From page 143... ...
In addition, the effect of testosterone administration on occult or incidental prostate cancer is unknown, although current studies suggest minimal risk (Brewer, 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.
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From page 144... ...
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.
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From page 145... ...
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~.
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From page 146... ...
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.
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From page 147... ...
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.
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From page 148... ...
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 twostage informed consent process.
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From page 149... ...
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.
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From page 152... ...
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.
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From page 153... ...
1993. Sexual function does not change when serum testosterone levels are pharmacologically varied within the normal male range.
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From page 154... ...
1990. Prostate cancer detection in a clinical urological practice by ultrasonography, digital rectal examination, and prostate specific antigen.
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From page 155... ...
2002. Effects of transdermal testosterone on cognitive function and health perception in older men with low bioavailable testosterone levels.
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From page 156... ...
2003. Predictors of prostate cancer on repeat transrectal ultrasound-guided systematic prostate biopsy.
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From page 157... ...
1994. Rate of change in serum prostate specific antigen levels as a method for prostate cancer detection.
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From page 158... ...
2003. The influence of finasteride on the development of prostate cancer.
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