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Institute of Medicine (US) Committee on Assessing the Need for Clinical Trials of Testosterone Replacement Therapy; Liverman CT, Blazer DG, editors. Testosterone and Aging: Clinical Research Directions. Washington (DC): National Academies Press (US); 2004.

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Testosterone and Aging: Clinical Research Directions.

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2Testosterone and Health Outcomes

Research has been conducted to examine three basic questions regarding testosterone and health outcomes in aging males:

  • Do endogenous testosterone1 levels in males decline with aging?
  • If so, what are the impacts on health of age-related testosterone declines?
  • What are the health benefits and risks of testosterone therapy?

While the questions may seem simple, determining how and to what extent changes in testosterone levels cause or influence clinical outcomes is a complex research challenge. It requires untangling the effects of testosterone from intricately entwined physiologic pathways where multiple factors play a role, and accounting for other correlates of aging such as illness and inactivity. It is also difficult to determine if a change in testosterone levels results in (or contributes to) a health outcome, or the outcome results in decreasing testosterone levels, or both.

This chapter provides an overview of the research to date. The committee chose to focus on randomized placebo-controlled clinical trials, which provide the most methodologically strong and scientifically valid evidence. The chapter begins with a discussion of research findings on changes in endogenous testosterone levels with aging. The remainder of the chapter is then organized by health outcome. For each health outcome section there is a brief introduction on epidemiology, risk factors, and biological plausibility, followed by an overview of studies that have been conducted on the correlations between the outcome and changes in endogenous testosterone levels during aging. A description of the randomized placebo-controlled trials in older men is provided in each section, with detailed tables on the results specific to that outcome.

CHANGES IN ENDOGENOUS TESTOSTERONE LEVELS WITH AGING

Early studies of testosterone levels and aging found conflicting evidence regarding changes in endogenous testosterone levels, but recent studies have consistently reported declining levels with aging. Some of the earlier discrepancies have been attributed to various health conditions and inconsistent timing of sera drawn for testosterone measures (Tenover, 1994). Normal values of testosterone vary widely in older men, and the particular level that is considered to be abnormally low is not consistent in the literature. Additionally, whether total testosterone, free testosterone, bioavailable testosterone, or some combination is the most appropriate measure has been debated. This section highlights the results of several large cohort studies that have compared endogenous testosterone levels among various age groups (Box 2-1). Many of the studies are cross-sectional in design, with serum hormone level and age considered at the same point in time. Blood specimens for these studies (Table 2-1) were collected from participants in the morning.

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BOX 2-1

Major Cohort Studies Examining Endogenous Testosterone Levels and Health Outcomes. Baltimore Longitudinal Study of Aging (BLSA). An ongoing longitudinal study sponsored by the National Institute on Aging, the BLSA has collected data on more than 1,200 (more...)

TABLE 2-1. Selected Studies of Endogenous Testosterone Levels and Age.

TABLE 2-1

Selected Studies of Endogenous Testosterone Levels and Age.

Harman and colleagues (2001) examined changes in testosterone and sex hormone binding globulin (SHBG) levels over time among participants in the Baltimore Longitudinal Study of Aging (BLSA) (Table 2-1). During a 6-month period in 1995, sera from 890 participants' most recent and several previous visits (up to 10 samples per man) were retrieved. Cross-sectional plots of earliest total testosterone, SHBG, and free testosterone indices [(FTI) = total T/SHBG] versus age show a negative association with age for the two testosterone measures. An increase in SHBG with age was more apparent at older ages (>50 years) than among the younger decades of age. Longitudinal analysis based on all men with sera for at least two visits (N = 702) showed similar downward trends of testosterone for each decade of age from the 30s to the 80s; downward trends for FTI were found for each decade except the 80s (Figure 2-1). Multivariable analysis found age associated with a decrease in testosterone and FTI at a relatively constant rate, independent of obesity, illness, medications, cigarette smoking, or alcohol intake. Total testosterone decreased an aver age 0.110 nmol/L/year (3.17 ng/dL) in both the cross-sectional and longitudinal analyses.

FIGURE 2-1. Longitudinal effects of aging on date-adjusted testosterone and free testosterone index.

FIGURE 2-1

Longitudinal effects of aging on date-adjusted testosterone and free testosterone index. Linear segment plots for total T and free T index vs. age are shown for men with T and SHBG values on at least two visits. Each linear segment has a slope equal to (more...)

Two studies from the Massachusetts Male Aging Study (MMAS) cohort have correlated serum hormone levels and age. Gray and colleagues (1991a) examined sera from 1,709 men (ages 39 to 70) and found that the levels of 17 hormones, including total testosterone and free testosterone, were correlated with age among two groups of men: 415 men who were “apparently healthy,” according to several criteria, and 1,294 men with at least one “nonhealthy” criterion. The authors found a decline in testosterone with age at a similar rate between the two groups, with testosterone levels significantly lower among those in the unhealthier group. Free testosterone decreased about 1.2 percent per year of age, and total testosterone decreased about 0.4 percent per year of age in this cross-sectional analysis. Using follow-up sera, Feldman and colleagues (2002) reported a decrease in total testosterone of 0.8 percent per year; free and albumin-bound testosterone decreased about 2 percent per year in cross-sectional analysis. Apparent good health was associated with higher levels of several hormones, including total testosterone by 10 percent to 15 percent.

Among participants in the Multiple Risk Factor Intervention Trial (MRFIT), age and obesity were significantly correlated with plasma testosterone (Dai et al., 1981). Both testosterone and free testosterone were negatively correlated with age in a cross-sectional analysis (rtotal testosterone = −0.23; rfree testosterone = −0.30). Similarly, in a community-based study in Rancho Bernardo, California, levels of bioavailable testosterone and bioavailable estradiol decreased with age independently of covariates (Ferrini and Barrett-Connor, 1998) (Figures 2-2 and 2-3) (Table 2-2). Total testosterone and total estradiol decreased with age when confounders were controlled (body mass index [BMI], waist:hip ratio, alcohol intake, smoking, sample storage time, and caffeine intake). Total testosterone concentrations decreased by approximately 0.19 ng/dL per year of age, and bioavailable testosterone decreased by 1.85 ng/dL per year of age. Both the MRFIT and Rancho Bernardo studies examined hormone levels and age measured at the same point in time, that is, in cross-section.

FIGURE 2-2. Levels of endogenous total and bioavailable testosterone in 810 men aged 24 to 90, by 5-year age group, Rancho Bernardo, CA, 1984 to 1993.

FIGURE 2-2

Levels of endogenous total and bioavailable testosterone in 810 men aged 24 to 90, by 5-year age group, Rancho Bernardo, CA, 1984 to 1993. Data were adjusted for multiple covariates, including body mass index (weight (kg)/height2 (m2)), waist:hip ratio, (more...)

FIGURE 2-3. Levels of endogenous total and bioavailable estradiol in 810 men aged 24 to 90, by 5-year age group, Rancho Bernardo, CA, 1984 to 1993.

FIGURE 2-3

Levels of endogenous total and bioavailable estradiol in 810 men aged 24 to 90, by 5-year age group, Rancho Bernardo, CA, 1984 to 1993. Data were adjusted for multiple covariates, including body mass index (weight (kg)/height2 (m2)), waist:hip ratio, (more...)

TABLE 2-2. Total and Bioavailable (non-SHBG Bound) Testosterone Levels and Proportions Less Than Various Cut Points Among 827 Men, the Rancho Bernardo Study, 1984-1987.

TABLE 2-2

Total and Bioavailable (non-SHBG Bound) Testosterone Levels and Proportions Less Than Various Cut Points Among 827 Men, the Rancho Bernardo Study, 1984-1987.

A number of other cross-sectional studies have also found that testosterone levels are negatively associated with age (Maas et al., 1997; Kaufman and Vermeulen, 1997).

LITERATURE REVIEW

As discussed above, the focus of the remainder of this chapter is on health outcomes that may be affected by testosterone. Each of the health outcome sections discusses results from studies of endogenous testosterone levels, followed by a discussion of results from placebo-controlled randomized trials of testosterone therapy in older men. The overview of the literature on endogenous testosterone draws from extensive reviews on this topic and provides tables on selected studies. The selected studies are meant to serve as examples. This report does not provide an exhaustive review of the literature on endogenous testosterone.

The review of placebo-controlled trials focuses on those clinical trials that included older men. The committee focused its literature review on double-blinded placebo-controlled trials as they provide the best opportunity for obtaining accurate comparison data particularly for qualitative endpoints such as sexual function and quality of life. There is an additional body of literature (that is briefly discussed in this chapter and more fully described in Appendix C) consisting of studies of testosterone therapy that did not use placebo controls, did not have a control group, or focused on younger males.

Searches of the medical literature (described in Appendix A) resulted in 39 articles reporting the results of 31 placebo-controlled trials of testosterone therapy that were conducted in older or middle-aged men and were published from 1977 to 2003.2 Appendix B provides a table with the design characteristics of the placebo-controlled trials and includes information on the baseline testosterone levels in the study population and, where applicable, the entry criteria used for the trial regarding testosterone level. Placebo-controlled trials in older men have been conducted with small numbers of participants, ranging from 6 to 108 individuals, and most are of limited duration, ranging from 1 to 36 months. Of the 31 randomized trials, 18 administered testosterone intramuscularly, 5 used oral preparations, 5 used a testosterone patch, and 3 used testosterone gel. Many of the randomized trials have examined healthy, community-dwelling elderly men. There have been three trials of institutionalized populations: surgical patients, rehabilitation unit patients, and nursing home patients. The remainder of the trials studied men with chronic diseases. Many of the trials assessed multiple outcomes and are discussed in several of the health outcome sections.

In subsequent tables in the chapter the results for the placebo-controlled clinical trials are sorted by the mean baseline total testosterone level of study participants and by testosterone preparation used in the trial. Because of the difficulty in assessing the physiologic effects of exogenous testosterone, the lack of definitions of normal ranges in older age groups, and differing variance around the mean testosterone levels in different clinical trials, the groupings are provisional and the borders between them are not sharp. Some of the trials did not report baseline testosterone levels. The rest of the trials were divided into three groups. These groups include trials that enrolled:

  • Men with baseline testosterone levels that were frankly low, even for older males, usually with means less than 250 ng/dL;
  • Men with baseline testosterone levels in the low to low-normal range, with means in the 250 to 400 ng/dL range; and
  • Men with baseline testosterone levels in the normal range, with mean levels greater than 400 ng/dL.

BONE

Aging has major effects on bone strength. Men undergo a gradual reduction in bone mass in early to mid adulthood. Although they do not experience the rapid bone loss that occurs in women during early menopause, after ages 65 to 70, men and women lose bone mass at approximately the same rate (NIH, 2003). An estimated 2 million men in the United States have osteoporosis (primarily at the hip), and it is estimated that 1 in 8 men over age 50 will have an osteoporosis-related fracture (NIAMS, 2003). Risk factors for bone loss in men include family history of osteoporosis, suboptimal bone growth during childhood and adolescence, smoking, excessive alcohol intake, physical inactivity, use of some medications (such as corticosteroids and anticonvulsants), vitamin D deficiency, poor nutrition, inadequate calcium intake, and low testosterone levels (Matsumoto, 2002; NIAMS, 2003).

Aging in men is associated with reduced levels of the gonadal sex steroids, testosterone and estradiol, and it is clear that major reductions in sex steroid levels result in bone loss in men. For instance, androgen deprivation therapy for the treatment of prostate cancer has been shown to result in rapid bone loss, and osteopenia and osteoporosis are common in men undergoing this therapy (Dawson, 2003; Smith, 2003). Despite this clear clinical effect, the mechanisms that underlie bone loss in hypogonadal men are uncertain. There are many unknowns regarding the role that testosterone—as compared with its metabolites, particularly estradiol—plays in this loss of bone mass. A recent review by Khosla and colleagues (2002) summarized research indicating that estrogen compounds play a major role in the regulation of male bone metabolism. Male mice with the aromatase gene knocked out develop osteopenia (decreased calcification or density of bone), and men with inactivating mutations of the aromatase gene have low bone mass that improves with estradiol therapy (Khosla et al., 2002). In men treated with a gonadotropin releasing hormone (GnRH) agonist to induce short-term gonadal insufficiency, estradiol replacement greatly reduced the expected abnormalities in bone remodeling (Khosla et al., 2002).

However, in addition to serving as a substrate for aromatization to estradiol, testosterone also appears to have independent effects on both bone resorption and bone formation. Testosterone may act directly on androgen receptors in bone cells or indirectly by affecting growth factor metabolism or the action of cytokines (Finkelstein, 1998; Wergdal and Baylink, 1996). Animal studies have found that decreased androgen action (e.g., with administration of an androgen receptor antagonist) results in a loss of bone mass (Bhasin and Buckwalter, 2001), and androgen-receptor-gene knockout mice have reduced bone mass. In men with GnRH-induced hypogonadism, androgens appear to have effects on bone resorption and formation. In sum, both androgens and estrogens appear to affect bone metabolism in men, and both are reduced in hypogonadism and with aging.

Studies of Endogenous Testosterone Levels and Bone-Related Outcomes

Changes in bone mineral density (BMD) occur in men as they age; but it is not clear to what extent age-related decreases in testosterone (that tend to be of lesser magnitude than the reductions seen in men with established hypogonadism) are related to decreased BMD, or if there is some threshold below which risk for osteoporosis increases.

There are inconsistent findings in studies that have examined associations between endogenous testosterone levels and bone mineral density or fracture risk (reviewed in Kaufman and Vermeulen, 1998; Matsumoto, 2002). Several studies with large sample sizes that controlled for age and other potential confounding factors found that lower levels of bioavailable testosterone were associated with lower bone density and that bioavailable estradiol levels were a stronger predictor of BMD, but the associations between bone density and each sex steroid were relatively weak (Table 2-3) (Greendale et al., 1997; Khosla et al., 1998, 2001). Measures of total testosterone were either not associated with BMD (Greendale et al., 1997) or had weaker correlations than bioavailable testosterone (Khosla et al., 1998). In one study, free testosterone levels were found to be a weak predictor of lower lumbar spine BMD but were not associated with femoral neck BMD (Center et al., 1999). A recent review found that in a number of studies the correlations between estradiol levels and bone loss were stronger than the correlations with testosterone levels (Matsumoto, 2002).

TABLE 2-3. Selected Studies of Endogenous Testosterone Levels and Bone Outcomes.

TABLE 2-3

Selected Studies of Endogenous Testosterone Levels and Bone Outcomes.

Low testosterone levels have been identified as a risk factor for hip fractures in older men (reviewed in Kaufman and Vermeulen, 1997; Matsumoto, 2002); studies of vertebral fractures have not shown similar results (Barrett-Connor et al., 2000). For example, a case-control study of 17 patients 65 years of age or older with minimal trauma hip fracture found an association with hypogonadism, defined as free testosterone <9 pg/mL (Stanley et al., 1991). A study of 353 men (median age of 66 years) in the Rancho Bernardo cohort who were diagnosed with vertebral fractures found that total and bioavailable estradiol levels were associated with fracture prevalence, but there was no association with testosterone levels (Barrett-Connor et al., 2000).

Clinical Trials of Testosterone Therapy and Bone-Related Outcomes

Four published, placebo-controlled trials have reported the effect of testosterone therapy on bone turnover markers and bone density in older community-dwelling men with low to low-normal baseline testosterone levels (Table 2-4). These trials included 13 to 108 men treated from 3 to 36 months. Testosterone was administered by intramuscular injection or transdermal patch. For the most part, administering testosterone under these conditions was not associated with major effects.

TABLE 2-4. Randomized Placebo-Controlled Trials of Testosterone Therapy and Bone Outcomes in Older Men.

TABLE 2-4

Randomized Placebo-Controlled Trials of Testosterone Therapy and Bone Outcomes in Older Men.

Several trials reported that testosterone treatment had no effect on bone markers or BMD. One trial found that testosterone therapy decreased urinary excretion of hydroxyproline, a nonspecific marker of bone resorption, but did not change measures of nine other bone turnover markers (Tenover, 1992). Kenny and colleagues (2001) found that testosterone therapy improved bone density at the femoral neck but not at four other measurement sites. In the study of longest treatment duration and with the largest sample size, Snyder and colleagues (1999a) found no difference in BMD between treatment and control groups of healthy elderly men with low-normal testosterone levels treated for up to 36 months with a scrotal testosterone patch. The authors noted, however, that in posthoc analyses, the men with lower pretreatment testosterone levels experienced increases in lumbar spine BMD while receiving testosterone. In another study thus far reported only in abstract form, older men treated with intramuscular testosterone experienced a clear increase in BMD compared to men receiving placebo injections (Bebb et al., 2001). None of the trials examined the effect of testosterone treatment on fracture rates.

Multiple studies have examined the effect of treatment with testosterone on bone outcomes in hypogonadal males (primarily young adults) (Appendix C). These studies are generally not placebo controlled, but consistently report improvement in bone mass with testosterone therapy. These studies are not included in Table 2-4 because they did not include a placebo control group or were conducted in younger age groups.

From the available clinical trials, it is not possible to establish a level of testosterone that is necessary to achieve a positive effect on the skeleton. Moreover, treating men with testosterone results in higher testosterone levels as well as in increased estradiol levels via aromatization of testosterone. Thus, it is not clear to what extent skeletal effects of testosterone therapy are due to androgen or to estrogen actions.

BODY COMPOSITION AND STRENGTH

Normal aging is associated with a decline in fat-free mass and strength along with an increase in total body fat. Additionally, abdominal visceral adipose tissue generally increases with age as fat is redistributed from peripheral locations (Mårin, 2002). The extent and nature of these changes is influenced by multiple factors including genetic, hormonal, metabolic, and nutritional factors as well as by physical activity and illness. Muscle is a major component of fat-free mass, and research has shown that there are age-related declines in both muscle cell mass and the capacity of muscle to generate force, potentially related to atrophy of type IIa muscle fibers (Frontera et al., 2000). It is estimated that a cumulative 35 percent to 40 percent decline in skeletal muscle mass occurs between the ages of 20 and 80 (Bhasin and Buckwalter, 2001). Sarcopenia, age-related loss in skeletal muscle, is especially problematic as it is associated with loss in strength and endurance and thereby can increase the risk of falls, frailty, and loss of mobility (Roubenoff and Hughes, 2000). It is important to note that sarcopenia develops even in successfully aging adults (Roubenoff et al., 2002).

The mechanisms by which testosterone affects changes in fat-free mass, muscle mass, or muscle strength are not fully understood. Additionally, the potential interactive effects between testosterone and exercise have not been fully explored. Studies of androgen administration to castrated male animals have shown the nitrogen-retention properties of androgens (Bhasin et al., 1998a). Several studies have shown that administering testosterone results in muscle hypertrophy by increasing muscle protein synthesis (Griggs et al., 1989; Urban et al., 1995; Brodsky et al., 1996). The extent of the relationship between supraphysiologic doses of testosterone and athletic performance (particularly endurance, fatigability, and power) is an issue of continuing debate (Bhasin et al., 2001).

There are terminology and measurement issues regarding body composition that deserve careful consideration in future clinical trials of testosterone therapy. At the molecular level, two main components of body weight are recognized: fat and fat-free mass. Fat-free mass includes water, protein, and minerals, including those from bone. Methods such as skin-folds and underwater weighing usually provide estimates of fat and fat-free mass. Dual-energy X-ray absorptiometry, used in several of the randomized trials, provides estimates of fat and partitions fat-free mass into lean soft tissue and bone minerals. Imaging methods such as computed tomography and magnetic resonance imaging evaluate subcutaneous and visceral adipose tissue and adipose-tissue free-mass components such as skeletal muscle. In descriptions of the individual randomized trials (and in Tables 2-5 and 2-6), the committee uses the terminology as reported by the authors of the publication. It is hoped that future studies will explicitly define and explain the components measured and terms applied.

TABLE 2-5. Selected Studies of Endogenous Testosterone Levels and Body Composition and Strength.

TABLE 2-5

Selected Studies of Endogenous Testosterone Levels and Body Composition and Strength.

Studies of Endogenous Testosterone Levels and Body Composition and Strength

The relationship between changes in body composition seen in the aging process and naturally decreasing levels of testosterone with age is not well understood. Research findings regarding testosterone and various body composition measures have been inconsistent, although many studies find an increase in total or abdominal fat mass with decreases in testosterone levels (Table 2-5) (reviewed in Matsumoto, 2002). For example, a cross-sectional study evaluating hormone levels in 1,241 men in the Massachusetts Male Aging Study (38 to 70 years of age) found that low testosterone levels were associated with higher body mass index, controlling for age and smoking (Field et al., 1994).

The few studies examining associations between endogenous testosterone levels and measures of strength have had inconclusive results (reviewed in Matsumoto, 2002). For example, a small cross-sectional study conducted in Finland compared strength measures and testosterone levels in 9 men 44 to 57 years of age with 11 men 64 to 73 years of age and did not find an association between testosterone levels and muscle strength (Hakkinen and Pakarinen, 1993).

Clinical Trials of Testosterone Therapy and Body Composition and Strength

Body Composition

Twelve placebo-controlled trials have examined body composition measures in response to exogenous testosterone. In seven of the clinical trials the treatment was administered for 6 months or longer, and only three of the trials were conducted for 12 months or longer. Sample sizes ranged from 12 to 108 individuals, and the age ranges were broad. In seven of the placebo-controlled trials examined by the committee, the mean age is stated or appears to be over 60 years. In most of the trials the participants were healthy community-dwelling middle-aged or older men. Two of the trials examined the effects of testosterone in participants who were abdominally obese. The clinical trials used a variety of delivery methods: five administered intramuscular injections of testosterone enanthate or cypionate, three studies used transdermal patches, three studies used transdermal gels, and one used oral testosterone undecanoate.

Findings from randomized placebo-controlled trials of testosterone therapy have generally included increases in fat-free mass (lean body mass) and decreases in fat mass associated with a variety of testosterone interventions (Table 2-6). In some cases, improvements were seen in body composition measures when the data on testosterone-treated group members were compared to their baseline measures but not when compared with the placebo controls. Randomized trials of men with frankly low baseline total testosterone levels did not find significant changes in body composition measures, but this may be due to small sample sizes.

TABLE 2-6. Randomized Placebo-Controlled Trials of Testosterone Therapy and Body Composition and Strength in Older Men.

TABLE 2-6

Randomized Placebo-Controlled Trials of Testosterone Therapy and Body Composition and Strength in Older Men.

Mårin and colleagues (1993, 1995) conducted two clinical trials involving abdominally obese men and examining gel or oral testosterone preparations. Both studies found a significant decrease in visceral adipose tissue mass in the testosterone-treated group versus controls, with no significant change in total or subcutaneous adipose tissue mass or fat-free (lean body) mass.

Two studies provided insights at the cellular level into possible mechanisms for these changes. Ferrando and colleagues (2003) measured protein metabolism and found evidence of decreased muscle protein breakdown (but not of increased protein synthesis) in testosterone-treated men. Mårin and colleagues (1995) used needle biopsies to measure turnover in radioactively labeled triglycerides. They documented a significant increase in the turnover rate of triglycerides in abdominal, but not in femoral, subcutaneous fat, which may provide insights into the differential effects of testosterone on different fat depots in the body.

Muscle strength. Ten placebo-controlled trials assessed changes in muscle strength with testosterone treatment, including many of the clinical trials discussed above. Thus, the populations, sample sizes, duration of treatment, and types of interventions were similar to those that examined body composition outcomes (Table 2-6). In addition, a study by Bakhshi and colleagues (2000) assessed the effect of testosterone therapy on strength in older men admitted to a rehabilitation unit.

Eight of the 10 randomized trials did not find a change in measures of strength when comparing the testosterone- and placebo-treated groups. The two clinical trials noting improvements were in men with low to low-normal baseline testosterone levels. Ferrando and colleagues (2002) found significant improvement in leg and arm muscle strength, and Sih and colleagues (1997) noted improvement in grip strength. The study of 15 older men admitted to a rehabilitation unit found that those who received intramuscular testosterone had a significant increase in grip strength after up to eight weeks of treatment when compared with baseline but not compared with placebo controls (Bakhshi et al., 2000).

Testosterone therapy has also been explored to treat diseases involving weight loss or muscle wasting resulting from specific diseases, e.g., HIV, with generally positive results (Appendix C). There is little information on the duration of improvements in body composition after treatment has ceased.

PHYSICAL FUNCTION

Decrements in muscle strength with aging are part of a continuum, which for some older adults may lead to declines in physical function and potentially to decreases in the ability to perform many activities of independent living. As noted above, aging is associated with a loss of muscle mass and muscle function, leading to reductions in muscle strength, power, and endurance with age. Loss of muscle mass leads to a decrease in the contractile tissue volume available for locomotive and metabolic functions. Sarcopenia, or loss of muscle mass, with resulting declines in strength, is thought to be central to frailty, a wasting syndrome associated with decreased strength, reduced exercise tolerance, walking speed, and declines in both energy output (in terms of physical activity) and energy intake (in terms of dietary intake) (Fried et al., 2001). Frail older adults are at high risk of developing disability in mobility and in the activities of daily living (which in themselves further predict dependency, falls, and mortality). Consequences of loss of strength include balance problems and decreased exercise tolerance as well as frailty, functional limitations (such as slowing of walking and stair climbing speed), and difficulty with tasks dependent on general strength and exercise tolerance (such as ambulation, housework, or shopping). Thus, loss of strength is a component of frailty, and both loss of strength and the aggregate frailty syndrome independently predict the development or progression of physical disability and dependency in older adults.

A recent study of more than 5,000 community-dwelling men and women aged 65 and older found that 7 percent were frail, and that the incidence of frailty increased rapidly with aging (Fried et al., 2001). Frailty is twice as likely to develop in women as in men. However, 4.3 percent of community-dwelling older men have 3 or more symptoms or signs consistent with frailty (Fried et al., 2001).

Frailty is often closely associated with disability, particularly with difficulties in independently performing some of the activities of daily living. Men aged 70 and older report high rates of disability (Table 2-7) as measured by self-reported difficulty or dependency in walking, and in performing Instrumental Activities of Daily Living (tasks of household management essential to independent living, including shopping and meal preparation), and Activities of Daily Living (basic self-care tasks, including bathing, dressing, walking across a small room, and using the toilet.) Thus, both frailty and disability are frequent adverse health outcomes for older men as well as older women.

TABLE 2-7. Physical Functioning in Community-Dwelling Men, 70 Years and Older, U.S.

TABLE 2-7

Physical Functioning in Community-Dwelling Men, 70 Years and Older, U.S.

There is increasing evidence to suggest that declines or dysregulation of function of multiple biologic systems with age, including hormones, contribute to the loss of physiologic reserves and the ability to maintain homeostasis that underlie the development of resulting frailty (Wagner et al., 1992; Walston et al., 2002; Fried and Walston, 2003). While it is biologically plausible that testosterone plays a role in the development of frailty as well as in the loss of strength and in increased physical disability in older men, it is likely one of numerous dysregulated systems that is responsible.

Clinical Trials of Testosterone Therapy and Physical Function

Five placebo-controlled trials have examined physical function outcomes in studies of testosterone therapy in older men (Table 2-8). Three of the trials were conducted in populations of healthy older men with mean ages of 70 and older. The other two trials evaluated testosterone therapy in men with coronary artery disease and in men admitted to a rehabilitation unit. The studies were small (ranging from 15 to 108 participants) and of short duration. Three of the trials administered testosterone for three months or less. Transdermal patches were the route of testosterone administration in three of the trials, and intramuscular injections of testosterone enanthate were used in two trials.

TABLE 2-8. Randomized Placebo-Controlled Trials of Testosterone Therapy and Physical Function in Older Men.

TABLE 2-8

Randomized Placebo-Controlled Trials of Testosterone Therapy and Physical Function in Older Men.

The results of the randomized trials are mixed. The two trials noting improvement in the testosterone-treated group, as compared with placebo controls, were in men with low testosterone levels at baseline or men who were ill. In the two clinical trials that used the Functional Independence Measure, only slight improvements were seen when compared with placebo controls. Improvements were noted by Amory and colleagues (2002) in a postoperative assessment of the administration of supraphysiologic doses of testosterone 21 days to 1 day prior to surgery. Inconsistent results were found in the three trials that used the SF-36, a scale assessing eight physical function and quality-of-life related domains. The two trials of longer duration (12 and 36 months) did not find strong improvements in the SF-36 assessment of physical function. Snyder and colleagues (1999b) also assessed walking and stair climbing and did not find differences between the placebo and testosterone-treated groups.

Physical function is an area that has not been widely studied in relationship to testosterone therapy, and although the results of the few randomized trials to date are inconsistent, this is an area that deserves further exploration as it is an important outcome to aging men and is related to several potential intermediates of the effects of testosterone such as strength (as well as many other risk factors).

COGNITIVE FUNCTION

Cognitive function includes multiple domains such as memory, language, mathematics, spatial ability, and judgment that can be measured with a variety of standardized tests. Memory is the most common cognitive function that is impaired with aging. It has been estimated that moderate or severe memory impairment affects about 4 percent of adults ages 65 to 69 and about 35 percent of people ages 85 and older (Federal Interagency Forum on Aging-Related Statistics, 2002).

While it is known that testosterone and other sex hormones play an important role in the prenatal development of cognitive and behavioral differences between males and females (IOM, 2001), it is not clear if changes in testosterone levels affect cognitive function in adult men. An effect of testosterone on cognition is biologically plausible based on animal studies. Male rats demonstrate enhanced memory and learning after testosterone administration, and enhanced spatial learning after administration of estradiol (Alexander, 1996; Frye and Seliga, 2001). Testosterone may exert its actions through androgen receptors in the brain; further, testosterone has been shown to affect serotonin, dopamine, acetylcholine, and calcium signaling (Bhasin and Buckwalter, 2001).

Studies of Endogenous Testosterone Levels and Cognitive Function

Several studies have found correlations between bioavailable testosterone levels and general or spatial cognitive function, although there are few studies in older men (reviewed in Vermeulen, 2001; Matsumoto, 2002). For example, in a prospective study of the Rancho Bernardo cohort, higher bioavailable testosterone was associated with better scores on 2 of 12 cognitive function tests after adjustment for age and education (Table 2-9) (Barrett-Connor et al., 1999a). Higher total or bioavailable testosterone levels tended to be associated with better performance on tests of verbal memory and mental control.

TABLE 2-9. Selected Studies of Endogenous Testosterone Levels and Cognitive Function.

TABLE 2-9

Selected Studies of Endogenous Testosterone Levels and Cognitive Function.

Clinical Trials of Testosterone Therapy and Cognitive Function

Five placebo-controlled trials in older men have examined the effect of treatment with testosterone on cognitive function (Table 2-10). The trials were small and of short duration, including 19 to 56 participants followed for 12 months or less. Three of the trials used intramuscular injections of testosterone enanthate or cypionate and two used transdermal patches. Most participants were in their late 60s, and all were generally healthy.

TABLE 2-10. Randomized Placebo-Controlled Trials of Testosterone Therapy and Cognitive Function in Older Men.

TABLE 2-10

Randomized Placebo-Controlled Trials of Testosterone Therapy and Cognitive Function in Older Men.

The results of the randomized trials are mixed. Three of the studies found better memory or spatial function in the testosterone-treated men compared with those receiving a placebo, but no better scores on other cognitive domains. Given that multiple tests were performed, some differences between treatment groups may have occurred by chance. There is no clear evidence that specific doses, routes of administration, or types of testosterone were more effective than others. One trial among men with frankly low baseline testosterone levels found that 12 months of intramuscular testosterone treatment did not result in better scores on tests of memory, recall, or verbal fluency (Sih et al., 1997). Wolf and colleagues (2000) found some negative cognitive effects in a study of 30 elderly men who were tested 5 days after they received a single injection of testosterone or placebo. Those who received testosterone had a significant block of practice effect in verbal fluency. No effect was found on spatial or verbal memory.

Other studies have assessed cognitive function before and after testosterone administration, but the results are not informative because of opportunities for improved scores due to practice effects (Appendix C). No randomized trials have evaluated the effect of testosterone therapy among men with impaired cognitive function or at risk for developing dementia.

The committee recognized the need for larger, longer duration randomized trials using standardized, domain-specific measures to study the effect of testosterone therapy on cognitive function. The appropriate population for study, the dose and type of testosterone, and the duration of therapy required to produce optimal beneficial effects on cognitive function remain to be determined.

MOOD AND DEPRESSION

Although depression is not a normal part of aging, certain medical conditions such as stroke, cancer, diabetes, heart disease, and Parkinson's disease are associated with increased risk for depression (NIMH, 2003b). Additionally, some of the stresses of aging, such as the loss of a spouse or financial pressures can trigger depressive symptoms. There are genetic, psychological, and environmental risk factors for depression. It has been estimated that 5 million Americans over age 65 have subsyndromal depression and that another 2 million older Americans have a depressive illness (NIMH, 2003b). A number of recent advances in pharmacotherapeutic approaches, including selective serotonin reuptake inhibitors, target the neurotransmitters involved in depression. It has been estimated that 80 percent of older adults with depression improve when they receive treatment with antidepressant medication, psychotherapy, or both (NIMH, 2003a).

There is biologic plausibility for testosterone's effects on mood and depression, as testosterone is known to act through androgen receptors in the brain and can affect the serotonin and dopamine pathways (Bhasin and Buckwalter, 2001). Recent studies have examined a potential genetic component that may put some men at higher risk of depressed mood with decreasing testosterone levels during aging. For example, several reports suggest that the relationships between aging, declining testosterone, and increasing dysphoria are associated with polymorphisms in exon 1 of the androgen receptor (Seidman et al., 2001a; Harkonen et al., 2003).

The associations between mood, sexual desire parameters, and testosterone are unclear. Further, there are many unknowns regarding the relationship between testosterone levels and aggression (Christiansen, 1998).

Studies of Endogenous Testosterone Levels and Mood and Depression

The relationship between declining endogenous testosterone levels with aging and changes in mood has not been studied extensively, and findings have been inconsistent (reviewed in Tenover, 1994) (Table 2-11). For example, in a cross-sectional study of the Rancho Bernardo cohort, information on depressed mood was obtained using the Beck Depression Inventory (BDI) (Barrett-Connor et al., 1999b). A significant increase in BDI (indicating greater depressed mood) was reported with decreasing bioavailable testosterone after controlling for age, change in body weight, and regular exercise; however, no significant associations were found between BDI scores and total testosterone.

TABLE 2-11. Selected Studies of Endogenous Testosterone Levels and Mood and Depression.

TABLE 2-11

Selected Studies of Endogenous Testosterone Levels and Mood and Depression.

In the Massachusetts Male Aging Study, Gray and colleagues (1991b) found no significant correlation between testosterone levels and acting aggressively when angry, frequency of expression/suppression of anger, or ability to control anger. Free testosterone was negatively correlated with the personality characteristic of not expressing angry feelings, and both albumin-bound testosterone and free testosterone correlated positively with the characteristic of dominance.

Clinical Trials of Testosterone Therapy and Mood and Depression

Eleven placebo-controlled trials in older men have examined the effect of testosterone therapy on mood and depression (Table 2-12). In 9 of the 11 randomized trials, testosterone was administered for 3 months or less. The sample sizes in the studies were small, ranging from 6 to 77 participants. Eight of the studies used intramuscular injections of testosterone enanthate or cypionate, and there was one study each that used gel, patch, and oral delivery methods. The mean age of participants varied greatly and many of the participants were young (in their 40s and 50s); in most studies the participants were healthy. Three of the trials were in populations with chronic diseases (HIV or depression), and one study involved participants from a nursing home rehabilitation unit.

TABLE 2-12. Randomized Placebo-Controlled Trials of Testosterone Therapy and Mood and Depression in Older Men.

TABLE 2-12

Randomized Placebo-Controlled Trials of Testosterone Therapy and Mood and Depression in Older Men.

Although there are mixed results, there are some indications that the groups likely to show an improvement in mood are those who are already depressed or who are ill and frail. For example, in a study of 19 men with low baseline testosterone levels being treated for refractory depression, Pope and colleagues (2003) found that those using testosterone gel had greater improvements in measures of mental health as assessed by the Hamilton Depression (Ham-D) scores and the Clinical Global Impression score than placebo controls, although improvement was not seen in the Beck Depression Inventory. Rabkin and colleagues (1999) found similar improvements in depression measures in studies of HIV-positive men with sexual dysfunction symptoms. Bakhshi and colleagues (2000) found that among 15 frail men admitted to a rehabilitation unit, those who received testosterone had greater improvements in depression measures than placebo controls. Assessment of mood and depression measures in many randomized trials of healthy older males did not differ between testosterone-treated participants and placebo controls. It does not appear that testosterone's effects on mood and depression differ by the delivery method or dose, although the studies are small and of short duration.

Non-placebo-controlled studies have reported improvements in hypogonadal males in measures of mood and depression (Appendix C). Studies in which testosterone was administered to normal eugonadal males (in some cases using supraphysiologic doses) to assess mood and aggressive responses found mixed results, with some studies indicating increased aggressive responses.

SEXUAL FUNCTION

Multiple physiological, psychological, interpersonal, and behavioral factors play a role in sexual function, and the causes of sexual dysfunction in the adult male can be physical and/or psychological. A demographically representative survey of U.S. adults ages 18 to 59 years found that 31 percent of men reported experiencing sexual dysfunction, defined broadly to include lack of desire for sex, problems with arousal or orgasm, and concerns about sexual performance (Laumann et al., 1999). In the analysis of this survey, sexual dysfunction was generally associated with poor physical and emotional health.

Erectile dysfunction (ED) is an example of sexual dysfunction that illustrates the complex etiology of these outcomes. About 70 percent of ED cases are associated with diseases such as diabetes, hypertension, kidney disease, chronic alcoholism, multiple sclerosis, atherosclerosis, and neurologic disease (Bacon et al., 2003; NIDDK, 2003a). ED may also be a side effect of common medications; related to smoking, injury, or hormonal abnormalities; or associated with psychological factors such as stress, anxiety, hostility, or depression. About 5 percent of 40-year-old men and between 15 percent and 25 percent of 65-year-old men experience erectile dysfunction (NIDDK, 2003a).

Androgens play a key role in most aspects of male sexual development and function. While testosterone is primarily associated with effects on sexual interest, desire, and motivation, the role of testosterone in the erection reflex is not yet clear (Bhasin and Buckwalter, 2001). Testosterone may be important in the central nervous system control of sexual motivation and sleep erections, rather than a crucial aspect of erections during waking sexual activity. Schiavi and colleagues (1993) found that testosterone levels correlated with nocturnal penile tumescence in 67 healthy men over age 45. A study by Luboshitzky and colleagues (2002) found that men with sleep apnea secrete less testosterone and LH than men without sleep disorders, which may explain their common complaint of low sexual desire. Testosterone does not appear to enhance penile sensation (Rowland et al., 1993). Testosterone may have a direct vascular effect in the corpora cavernosa, mediating the ability of nitric oxide to relax corporal tissue and allow increased penile blood flow (Aversa et al., 2003).

Although a typical estimate of the testosterone levels needed to maintain normal sexual function in a healthy, young man is 300 ng/dL, studies that manipulated serum testosterone by using GnRH agonists and then added back testosterone at various levels suggest that may be an overestimate, particularly when the target behaviors are sexual activity and function, rather than the frequency of sexual fantasies or desire (Buena et al., 1993; Christiansen, 1998). Further, research suggests that there may be a threshold level of circulating testosterone, above which sexual function is not improved (Vermeulen, 2001). There is some research showing that testosterone levels may also rise in response to sexual stimulation and activity and decline during prolonged celibacy (Rowland et al., 1987; Jannini et al., 1999; Exton et al., 2001).

Studies of Endogenous Testosterone Levels and Sexual Function

As mentioned above, the testosterone concentrations needed to maintain normal sexual activity appear to be low, and it is therefore not unexpected that only a weak correlation has been found between testosterone levels and libido or sexual activity in many studies of healthy men (reviewed in Matsumoto, 2002). In general, studies report stronger associations between measures of sexual frequency, desire, and erections with aging, than with sex hormone levels (including total testosterone and free testosterone) among community dwelling, healthy men (Table 2-13). For example, a study of 1,290 men in the Massachusetts Male Aging Study found that of 17 hormone levels measured, only dehydroepiandrosterone sulfate (DHEAS) levels correlated with sexual function status (a composite measure of erectile dysfunction, frequency of partner sex, and sexual satisfaction). However, other variables, such as age, health status measures, depression, submission, and anger showed positive correlations with sexual dysfunction (Feldman et al., 1994).

TABLE 2-13. Selected Studies of Endogenous Testosterone Levels and Sexual Function.

TABLE 2-13

Selected Studies of Endogenous Testosterone Levels and Sexual Function.

Studies have also been conducted among men presenting with erectile dysfunction in a clinical setting (Buvat and Lemaire, 1997; Fahmy et al., 1999; Ansong and Punwaney, 1999) or among men with other clinical complaints, such as sleep apnea (Luboshitzky et al., 2002). In general these studies and others (reviewed in Kaufman and Vermeulen, 1997; Maas et al., 1997) have not found a significant association between endogenous testosterone levels and erectile dysfunction in studies of older men. Furthermore, supplementing testosterone in men with low levels was only successful in improving sexual function in 10 percent to 30 percent of cases (Buvat and Lemaire, 1997; Fahmy et al., 1999).

Clinical Trials of Testosterone Therapy and Sexual Function

Measures of sexual function have been studied in 10 placebo-controlled trials of testosterone therapy (Table 2-14). Eight of the trials administered testosterone for five months or less. Sample sizes were generally small, ranging from 6 to 108 participants. The clinical trials used a variety of delivery methods: three studies administered oral testosterone undecanoate, six used intramuscular injections of testosterone enanthate or cypionate, and one trial used the scrotal patch. The study populations were often relatively young; in 4 trials the mean age was 52 or less.

TABLE 2-14. Randomized Placebo-Controlled Trials of Testosterone Therapy and Sexual Function in Older Men.

TABLE 2-14

Randomized Placebo-Controlled Trials of Testosterone Therapy and Sexual Function in Older Men.

Improvements in sexual function were seen in clinical trials of men with low baseline testosterone levels. Studies in men with normal baseline levels had mixed results. For example, Nankin and colleagues (1986) studied 10 men (ages 51 to 74) with erectile dysfunction and low total testosterone levels and found that those receiving intramuscular testosterone reported a significant increase in sexual activity, urge for sex, morning and sleep erections, potency, and libido. However, a study of men with erectile dysfunction but normal baseline testosterone levels found no change in sexual function (Benkert et al., 1979). Since both trials are small and used different testosterone interventions, it is not possible to reach definitive conclusions on the effect of testosterone therapy on erectile dysfunction.

A number of additional studies have found increases in measures of sexual interest, arousal, and other aspects of sexual function with testosterone therapy (Appendix C). Most of these studies have focused on young hypogonadal men and are not placebo-controlled. Studies in normal young males administered supraphysiologic levels of testosterone have generally found increases in sexual awareness and measures of arousal, but no change in overt sexual behavior (Appendix C).

Overall, there is some suggestion that testosterone therapy may be beneficial to men with low baseline testosterone levels. The dose and type of testosterone and the duration of therapy required to produce optimal beneficial effects on sexual function remain to be determined.

HEALTH-RELATED QUALITY OF LIFE

Health-related quality of life is a broad concept that has been defined as encompassing five domains: survival, impairment, functional status (social, psychological, and physical), health perception, and opportunities (Patrick and Erickson, 1993). Although the percentage of adults reporting poor health increases with advancing age, it is important to note that 73 percent of Americans aged 65 years and older reported their health status as good, very good, or excellent in a 2000 survey (NCHS, 2003). Of the respondents 65 and 75 years and older, only 27 and 32.2 percent reported fair or poor health respectively. Chronic health conditions impact older adults disproportionately, and as age increases, the probability of having multiple chronic illnesses also increases (Hobbs and Damon, 1999). Visual and hearing impairments also increase. Many of the factors involved in quality of life have been described in other sections of this chapter. This section describes results for studies that have looked at overall quality of life measures, or changes in levels of vitality, energy, or sense of well-being. In the review of the literature, the committee did not identify studies of changes in endogenous testosterone levels with aging that examined quality of life and well-being issues.

Clinical Trials of Testosterone Therapy and Health-Related Quality of Life

Nine placebo-controlled trials reported on quality of life using a variety of measures.The studies were generally of short duration (6 of the 9 clinical trials administered testosterone for 3 months or less) and involved small numbers of participants (13 to 108 men) (Table 2-15). The study populations were quite varied, with several groups selected because of chronic conditions (e.g., obesity, HIV). A variety of interventions were used: four trials used intramuscular injections of testosterone enanthate or cypionate, four studies used transdermal patches, and one study administered testosterone undecanoate in oral form.

TABLE 2-15. Randomized Placebo-Controlled Trials of Testosterone Therapy and Quality of Life in Older Men.

TABLE 2-15

Randomized Placebo-Controlled Trials of Testosterone Therapy and Quality of Life in Older Men.

Because varied tests and questionnaires were used in the different clinical trials, it is difficult to generalize the results. Further, many of the measures, such as the SF-36, are also used to assess physical function, mood, and other outcomes. The only randomized trial that focused on health-related quality of life assessment was a pilot study of healthy older males conducted by Reddy and colleagues (2000). The men received either 200 mg of testosterone enanthate (14 men) or a placebo (8 men) intramuscularly every 2 weeks for 4 doses and were assessed at baseline, week 8, and then 6 weeks after the last dose. The study found similar scores between the testosterone- and placebo-treated groups on health-related quality of life measures as assessed by the SF-36 and the Psychological General Well-Being scales. Although 4 randomized trials found suggestively positive results, in 2 of these trials, this was based on improvements noted in only 1 of 8 domains of the SF-36.

Several additional studies in hypogonadal males using comparison with baseline measures found improvements in quality of life indicators, but did not use placebo controls (Appendix C; Wang et al., 1996; Snyder et al., 2000; Cutter, 2001).

The randomized trials that found positive results were conducted in populations of men with chronic health concerns or low baseline testosterone levels. As this is an area in which it could be speculated that testosterone's effects on multiple body systems may result in an overall improvement in health-related quality of life, the committee felt that additional placebo-controlled trials are needed.

CARDIOVASCULAR AND HEMATOLOGIC OUTCOMES

Cardiovascular disease is the number one cause of death for men in the United States (260,574 deaths due to coronary heart disease in 2000) and generally affects men at a younger age than women (AHA, 2003). One in five men in the United States has a diagnosis of cardiovascular disease (AHA, 2003). Heart and vascular diseases have a complex multifactorial etiology, and the role of testosterone in this mix has not yet been determined.

In considering the role of testosterone in risk for cardiovascular disease, most human studies have examined the effect of testosterone on lipid profiles and hematocrit because these measures are relatively easy and inexpensive to perform. Additionally, studies have measured the association of testosterone and glucose tolerance and insulin sensitivity. There have not been long-term studies of the effect of treatment with testosterone on cardiovascular morbidity and mortality including stroke, deep vein thrombosis, or myocardial infarction.

Researchers have used cholesterol-rich diets to develop animal models of atherosclerosis to test the effects of testosterone administration. However, differences in the plasma lipoprotein responses to diet and to exogenous hormone administration make it difficult to extrapolate from animals to humans (Alexandersen, 2002). Further, many of the past studies have been conducted using ovariectomized female cynomolgus monkeys and results may not generalize to male animals.

Animal and in vitro studies have shown effects of testosterone in increasing red blood cell mass by stimulating endogenous erythropoietin and directly acting on erythopoietic stem cells in bone marrow (Levere and Gidari, 1974; Ferenchick, 1996). 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). However, there are still many unknowns regarding the association between testosterone and thrombosis in humans.

Studies of Endogenous Testosterone Levels and Cardiovascular and Hematologic Outcomes

Studies of endogenous testosterone levels have looked at a variety of cardiovascular risk factors with mixed results (Table 2-16). A number of epidemiologic studies have found positive correlations between total or free testosterone levels in the physiologic range and high density lipoprotein (HDL) cholesterol and inverse relationships between testosterone levels and hypertension, an atherogenic lipid profile, and prothrombotic factors (reviewed in Alexandersen et al., 1996; Kaufman and Vermeulen, 1997; Matsumoto, 2002). In a prospective study, Contoreggi and colleagues (1990) evaluated levels of testosterone, estradiol, and DHEAS between two groups of men in the Baltimore Longitudinal Study of Aging. The comparison of 46 men (ages 41 to 92) classified as having coronary artery disease (CAD) with 124 men (ages 31 to 85) without CAD found that total and free testosterone and estradiol levels did not differ between the groups. In multivariable analysis, only systolic blood pressure, cholesterol, and age predicted CAD. Blood sera from the visit prior to CAD determination (about two years) were used to obtain sex hormone levels.

TABLE 2-16. Selected Studies of Endogenous Testosterone Levels and Cardiovascular Risk Factors and Diabetes.

TABLE 2-16

Selected Studies of Endogenous Testosterone Levels and Cardiovascular Risk Factors and Diabetes.

Epidemiologic studies have generally found that low endogenous testosterone levels are correlated with an increased risk of developing type 2 diabetes (reviewed in Matsumoto, 2002). For example, in a cross-sectional analysis of men (age 53 to 88) in the Rancho Bernardo study, plasma androgen levels were compared in 44 men with untreated diabetes mellitus and 88 age-matched men who had a normal glucose tolerance. Lower levels of free testosterone and total testosterone were associated with the presence of diabetes (Barrett-Connor, 1992). A later prospective study of the Rancho Bernardo cohort found that low total testosterone was associated with risk of developing diabetes (OR = 2.7 for lowest compared to top three quartiles of testosterone; 95% CI 1.1, 6.6), but low bioavailable testosterone was not (Oh et al., 2002).

Studies that have examined cardiovascular morbidity or mortality outcomes have generally not observed associations with testosterone levels, although results are mixed. Cauley and colleagues (1987) found that sex hormone levels were not associated with major coronary events in participants of the MRFIT study. Similarly, in a prospective five-year fol-low-up study of 2,512 men in England, Yarnell and colleagues (1993) found that testosterone levels were similar in those who did and did not have ischemic heart disease events (fatal or nonfatal) during follow-up. An analysis of the Rancho Bernardo cohort found that none of the sex hormones measured, including testosterone, was significantly associated with risk for cardiovascular mortality or ischemic heart disease morbidity or mortality after 12 years of follow-up (Barrett-Connor and Khaw, 1988). However, in men from the same cohort, those with hypertension had significantly lower testosterone levels than nonhypertensives (N = 1,132, ages 30 to 79 years) (Khaw and Barrett-Connor, 1988).

Clinical Trials of Testosterone Therapy and Cardiovascular and Hematologic Outcomes

The higher prevalence of heart disease in men compared to premenopausal women has led to an historical identification of the lack of estrogen and the presence of testosterone as risk factors for coronary artery disease. Seventeen placebo-controlled randomized trials assessed cardiovascular or hematologic outcomes among men treated with testosterone. Similar to the range of clinical trials for other health outcomes, the trials were generally small (ranging from 12 to 108 participants) and of short duration (4 weeks to 36 months). Most of the trials were in healthy, community-dwelling populations of older men. The trials used a variety of interventions and assessed a number of different cardiovascular risk factors or hematologic measures.

Lipid Profile

Thirteen randomized trials have compared various measures of cholesterol levels in older men treated with testosterone or placebo with mixed results. Eight of the 13 trials found no effect on the lipid profile in comparisons of the testosterone-treated group with their baseline measures or with controls. Four trials found that testosterone treatment resulted in lower levels of total and low density lipoprotein cholesterol levels. The trial by Kenny and colleagues (2002b) was the only one to observe a negative effect on the lipid profile. Compared to the placebo group, treatment with testosterone resulted in lower HDL, particularly in the HDL2 subfraction.

There are multiple uncontrolled trials of the effect of treatment with testosterone on cardiovascular endpoints in eugonadal or hypogonadal males (Appendix C). Several studies of eugonadal males found significant decreases in HDL with supraphysiological doses of intramuscular testosterone injections (Bagatell et al., 1994; Anderson et al., 1995; Meriggiola et al., 1995; Kouri et al., 1996; Anderson et al., 1996), but the uncontrolled design of these studies makes the results unreliable.

Red Blood Cell Measures

A commonly reported side effect of testosterone treatment is an increase in red blood cells, as measured by hematocrit, hemoglobin, or red cell counts. For this reason, many studies excluded men with high blood counts. Fourteen trials, listed in Table 2-17, examined changes in red blood cell count with testosterone treatment, but not all reported details or performed statistical tests of between group differences. Ten of these studies reported increases in hematocrit or in hemoglobin levels, although in several of the studies the results are reported for the testosterone-treated group compared with baseline levels, and there was not an analysis of the comparison with controls. The study by Snyder and colleagues (1999a) found that hematocrit increased in the first 6 months and then leveled off for the remainder of the 36-month study.

Acute Effects

The effects of intravenous administration of testosterone on coronary artery flow have been examined in several placebo-controlled clinical trials (Rosano et al., 1999; Webb et al., 1999a,b; White et al., 1999; Ong et al., 2000; Thompson et al., 2002). Of the six trials reviewed, four found a positive effect on coronary artery dilation and myocardial perfusion in the testosterone-treated group. These trials were not reviewed in depth by the committee as they examined acute effects using a supraphysiologic dose via an intravenous route.

Summary

Overall, a positive or negative effect of testosterone therapy on blood lipids has not been demonstrated conclusively. The trials are generally of short duration with a limited number of participants, and, therefore, could not provide data on cardiovascular morbidity or mortality. Most studies found increases in hematocrit, which is an effect of testosterone therapy that could have positive or negative implications, depending on baseline levels.

PROSTATE OUTCOMES

Concerns regarding the risks of testosterone therapy have focused primarily on the potential for increased incidence of prostate cancer and benign prostatic hyperplasia (BPH). In the United States, prostate cancer is the most common cancer in men, excluding skin cancers, with an estimated 220,900 new cases and 28,900 deaths expected in 2003 (NCI, 2003; ACS, 2003). Almost one-fifth of men in the United States will be diagnosed with prostate cancer during their lifetime; however, only 3 percent of men are expected to die of the disease (NCI, 2003). The greatest risk factor for prostate cancer is age; more than 75 percent of new diagnoses are in men over the age of 65 (NCI, 2003). Other risk factors include family history of prostate cancer, race (African American men have the highest incidence of prostate cancer in the United States), and a high-fat diet (Reiter and deKernion, 2002; NCI, 2003). Studies in twins have shown a stronger hereditary component in prostate cancer than in other types of cancer (Nelson et al., 2003).

Benign prostatic hyperplasia is a noncancerous enlargement of the prostate that can cause the gland to press against the urethra and bladder, potentially causing obstruction to urine flow and other related problems. The prostate begins to enlarge during puberty and continues to grow during most of a man's adult life. However, enlargement does not usually begin to cause problems until late in life (NIDDK, 2003b). More than half of men in their sixties and as many as 90 percent of those in their seventies and eighties have some symptoms of BPH (NIDDK, 2003b). In addition to age, risk factors for BPH include a high-fat diet and family history (NIDDK, 2003b).

TABLE 2-17. Randomized Placebo-Controlled Trials of Testosterone Therapy and Cardiovascular or Hematologic Outcomes in Older Men.

TABLE 2-17

Randomized Placebo-Controlled Trials of Testosterone Therapy and Cardiovascular or Hematologic Outcomes in Older Men.

Prostate cancer is an extremely common neoplasm in older men that is not always evident or detectable by clinical or laboratory methods, particularly in the early stages. Autopsy studies have documented the histological prevalence of prostate carcinoma in more than 30 percent of men older than 60 years, and higher rates with advancing age (Holund, 1980; Sakr et al., 1993; Etzioni et al., 2002; NCI, 2003). The complexities that subclinical prostate cancers present for conducting clinical trials of testosterone therapy in older men are discussed in Chapter 3.

Although androgens are necessary for the development and normal function of the human prostate, the role of testosterone in the progression of prostate cancer and BPH is not yet clear and is an issue that continues to be debated and explored. Since this is an area of particular concern with testosterone therapy, the committee provides a more in-depth review of the biological plausibility literature than for the other health outcomes discussed.

Testosterone undergoes rapid 5α-reductase conversion to dihydrotestosterone (DHT) in the prostate. Androgens regulate multiple diverse physiological processes in the mature prostate including cellular differentiation, proliferation, metabolism, and secretory function. Importantly, prostate epithelial cell-specific processes such as the production of prostate secretory proteins (e.g., prostate specific antigen [PSA]) are under androgenic control.

Animal models have demonstrated that testosterone and DHT can cause and maintain BPH and prostate cancer. The long-term administration of testosterone has been shown to induce the development of prostate adenocarcinoma in several, but not all, rat strains (Noble, 1977; Bosland, 2000). Thus, testosterone alone can act as a complete carcinogen in the rat prostate. If testosterone is given in combination with chemical carcinogens, such as N-methyl-N-nitrosourea (MNU) or N-nitrosobis(2-oxypropyl)amine (BOP), the incidence of prostate cancer increases dramatically to rates of 66 percent to 88 percent (Bosland, 2000). In these studies, a steep dose-response curve was observed for testosterone with a slight (less than 1.5-fold) increase in circulating testosterone levels, resulting in a near-maximal induction of tumor development. Further support for the hypothesis linking androgens and the androgen-signaling network in the process of prostate carcinogenesis is provided by a study describing transgenic mice with targeted overexpression of the androgen receptor (AR) in the mouse prostate (Stanbrough et al., 2001). These mice developed histological findings consistent with prostate intraepithelial neoplasia (PIN), a lesion thought to be a precursor to prostate adenocarcinoma. The conclusions drawn from studies in laboratory animals is that testosterone is a weak complete carcinogen, but acts as a strong tumor promoter at near physiological plasma levels (Bosland, 2000). The direct relevance of these studies for humans is not certain (Cunningham, 1996).

A causal relationship between androgenic hormones and human prostate carcinogenesis is plausible because prostate carcinoma develops from an androgen-dependent epithelium and is usually androgen-sensitive at early disease stages. Hypotheses postulating mechanistic roles for androgenic hormonal pathways as risk factors for prostate neoplastic growth include a) variations in circulating concentrations of testosterone and other hormones; b) variations in intraprostatic androgen levels (e.g., DHT); c) differences in activities of androgen-metabolizing enzymes (e.g., 5-α-reductase or CYP17 polymorphisms); and d) AR polymorphisms leading to altered AR activity (e.g., polyglutamine repeat length). An extensive overview of numerous molecular and epidemiological studies examining these factors is detailed by Bosland (2000). Surprisingly, with a few minor exceptions and caveats, the conclusions from these studies provide few clear or consistent results to support a role for any of these factors in the genesis of human prostate carcinoma. A major caveat to these conclusions is that the most relevant measurements may not have been obtained: the determination of hormone and enzyme levels within the prostate epithelial cell and its immediate environment and the elements of the prostate stroma. In addition, the rodent studies described above indicate that small increases in circulating androgen levels may be sufficient for prostate tumor-promoting effects. These small increases may not have been measurable or recognized in the human studies. Together, these studies of androgen involvement in human prostate carcinogenesis suggest that androgens act as strong tumor promoters via AR-mediated mechanisms to enhance the carcinogenic activity of strong endogenous and weak exogenous (environmental) genotoxic carcinogens.

Despite a lack of evidence implicating androgens and the androgen receptor as early initiating factors in carcinogenesis, it is clear that 1) prostate cancer does not develop in an environment devoid of androgens; and 2) the vast majority of prostate carcinoma cells require androgens for their continued growth and avoidance of programmed cell death. At diagnosis, the majority of prostate cancers are dependent on androgens for growth, and the elimination of AR ligands by surgical or chemical castration leads to marked tumor regression through a mechanism of apoptosis (Denmeade et al., 1996). The manipulation of the AR pathway has been used in clinical medicine since the 1940s as the primary treatment of advanced prostate cancer. However, this therapy is palliative, not curative, and eliminates the potential beneficial effects of androgen-induced cellular differentiation. Surviving cancer cells lose their dependency on androgens over time and are capable of proliferation in the absence of serum androgens, leading to relapse with clinically defined androgen-independent disease (Isaacs, 1996; Debes and Tindall, 2002).

Despite the extensive in vitro and in vivo data supporting a role for testosterone as a contributing factor in prostate carcinogenesis, there is also strong evidence indicating that the androgen signaling system in the prostate may also be associated with inhibiting cancer cell growth and resulting in tumor suppression. This dual role of androgens would not be unexpected because androgens are responsible for differentiation of the prostate epithelium. Evidence for suppression of tumor growth by androgens is supported by studies inserting a wild type AR into AR-null, androgen-independent human prostate cell lines resulting in a marked slowing of cell proliferation and tumor growth (Yuan et al., 1993). Second, at the time of invasion or metastasis mutations in the AR frequently occur, suggesting that a normal AR is protective from progression. Third, several androgen-regulated genes have been demonstrated to be associated with an AR-mediated proliferative “shut-off” function in LNCaP prostate cancer cells (Kokontis et al., 1998). Fourth, administering androgen to castrated rodents causes elevation of prostatic cell proliferation, but the increase in proliferation caused by testosterone is only transient, and after a few days, cell turnover returns to its normal very low levels (Bosland, 2000). Continuing to treat rodents with androgen does not result in permanently elevated cell proliferation rates in the prostate, but rather appears to support differentiation. Furthermore, DHT may even suppress prostatic cell proliferation in intact rats (Leav et al., 1989). Finally, both human and in vitro studies suggest that there may be a survival benefit from maintaining an androgen-responsive cohort of prostate tumor cells (Sato et al., 1996).

In mouse model systems of prostate carcinoma, androgen-independent cancers developing in castrated animals metastasized at twice the rate of androgen-independent cancers developing in littermates with normal serum androgen levels (Han et al., 2001). This concept has also been studied in the LNCaP cell system by comparing the rate of tumor growth in castrated mice followed either without further therapy or with intermittent androgen replacement. The rate of tumor growth was slower in animals treated with intermittent androgen supplementation compared with those maintained in the castrated state.

Clinical observations also support a role for the inhibitory effects of androgens toward prostate carcinoma. Population-based studies clearly document the relationship between aging and both increases in prostate cancer incidence rates and decreases in circulating testosterone levels. While this relationship does not equal causality, the findings do raise intriguing hypotheses regarding the influence of testosterone on inhibiting prostate carcinogenesis (Prehn, 1999). Several studies have reported that low levels of pretreatment serum total testosterone are associated with more aggressive disease and worse prognosis in patients diagnosed with prostate cancer (Daniell, 1998; Hoffman et al., 2000; Schatzl et al., 2001), and a recent report found that pretreatment total testosterone was also an independent predictor of extraprostatic disease in patients with localized prostate cancer; patients with lower testosterone levels had an increased likelihood of cancer spreading outside of the prostate (Massengill et al., 2003).

In summary, the influence of testosterone on prostate carcinogenesis and other prostate outcomes remains poorly defined, but could greatly influence the risk-benefit ratio for supplementation in both young and elderly populations. The results of the recently completed Prostate Cancer Prevention Trial (PCPT) support the potential for testosterone to influence prostate carcinogenesis in both positive and negative ways. Men treated with the 5-α-reductase inhibitor finasteride, which acts to reduce intraprostatic DHT levels, had a 24.8 percent reduction in the overall incidence of prostate carcinoma relative to placebo (Thompson et al., 2003). However, there was a higher incidence of high grade or aggressive prostate cancers detected in the finasteride arm—in an environment of lowered intraprostatic androgens (Scardino, 2003). These results support the need for continued research aimed toward a clear delineation of the positive and negative effects of testosterone and testosterone metabolites on prostate carcinoma.

Studies of Endogenous Testosterone Levels and Prostate Outcomes

A number of epidemiological studies have examined the risk of prostate cancer associated with a variety of factors, including serum hormone levels (Table 2-18). Many of these are case-control studies with different criteria used to select controls. Results of these studies have been inconsistent for an association with serum hormone levels, as described in a review by Bhasin and colleagues (2003) and a meta-analysis conducted by Shaneyfelt and colleagues (2000). Additionally, Bhasin discusses the findings of a quantitative review by Eaton and colleagues (1999), in which the authors conclude that there are no large differences in endogenous hormone levels among those who develop prostate cancer compared with those who do not. Several prospective studies of older men with testosterone measures obtained prior to developing prostate cancer found no association between testosterone levels and prostate cancer (Table 2-18). Most studies have been conducted with small numbers of men.

TABLE 2-18. Selected Studies of Endogenous Testosterone Levels and Prostate Outcomes.

TABLE 2-18

Selected Studies of Endogenous Testosterone Levels and Prostate Outcomes.

In one larger case-control study, investigators found evidence of the association of testosterone levels with a risk of prostate cancer (Gann et al., 1996). This study—part of the follow-up of 22,071 male physicians in the Physicians Health Study—identified 520 cases of prostate cancer by 1992, of which 222 men had plasma samples stored that were sufficient for sex hormone determination. Quartile cutpoints of hormone levels for control subjects were used to assign cases to a quartile. The odds ratios for each testosterone quartile, compared to the lowest testosterone quartile were: ORquartile 2 = 1.44, ORquartile 3 = 1.94, ORquartile 4 = 2.36 with a statistically significant test for trend. The 95 percent CI estimates for the odds ratio of the 3rd and 4th quartiles did not include 1.0. These estimates were adjusted for SHBG and estradiol. When the analysis was stratified by age (62 years of age or older and 61 years of age or younger), the association between prostate cancer and testosterone levels was strongest among older men.

Clinical Trials of Testosterone Therapy and Prostate Outcomes

Because of concerns regarding prostate-related problems, most randomized trials excluded men from participating in the study if they had an elevated PSA level, prostate-related symptoms, or prostate findings on digital rectal examination. Eighteen trials reported prostate-related outcomes (Table 2-19).

TABLE 2-19. Randomized Placebo-Controlled Trials of Testosterone Therapy and Prostate Outcomes in Older Men.

TABLE 2-19

Randomized Placebo-Controlled Trials of Testosterone Therapy and Prostate Outcomes in Older Men.

As discussed for other health outcomes, the number of the participants in these trials is small (trials examining prostate outcomes ranged from 12 to 108 participants), and the duration of follow-up is short (12 of the 18 trials were for 6 months or less, and all but one were completed after a year or less). The trials were generally in healthy older men and, as noted above, most studies had prostate outcome exclusion criteria. In six of the trials, the mean age was less than 60, a consideration in assessing an outcome with a long latency period and a higher incidence in older men. Several delivery methods were used: 8 trials used intramuscular injections of testosterone enanthate or cypionate, 4 studies used transdermal patches, 3 studies administered testosterone undecanoate orally, and in 3 studies, testosterone gel was used.

In most randomized trials in older men, no significant differences were seen in the magnitude of the changes in PSA levels between the testosterone- and placebo-treated groups. In some of the clinical trials, PSA levels were higher at the end of the study compared to baseline. However, PSA increases were generally seen in both groups, and the comparison between the treatment groups found that the extent of the changes was similar. As noted above, the durations of the trials were short, in most cases less than one year.

The longest and largest randomized trial in older men evaluated PSA levels at three months, six months, and then every six months for the three-year study (Snyder et al., 1999a). PSA levels increased significantly in the testosterone-treated group by six months and then leveled off. No significant increase was seen in the placebo group. Three men receiving testosterone therapy and one receiving placebo had persistent increases in PSA levels above 4.0 ng/mL and required a biopsy. One prostate cancer case was found in the testosterone group.

Five randomized trials measured prostate volume by ultrasound. Two found a significant increase in prostate volume in the testosterone-treated group compared to baseline, each after eight months (Mårin et al., 1992; Holmäng et al., 1993). The others (Tenover, 1992; Ferrando et al., 2002; Mårin et al., 1993) found no significant change in size after three, six, and nine months, respectively. There were no reports of an overall increase in prostate-related symptoms. Since the trials to date have been short, with small numbers of participants, it is not expected that effects on long-term prostate outcomes would be evident. As discussed in detail in Chapter 3, future clinical trials, particularly long-term trials, will require extensive monitoring and follow-up.

OTHER HEALTH OUTCOMES

There are several additional health outcomes that have been examined in association with testosterone: sleep apnea, water and sodium retention, gynecomastia, and suppression of sperm production. Sleep apnea is a breathing disorder in which breathing stops for 10 seconds or more, sometimes more than 300 times during the night (NINDS, 2001). It is estimated that up to 18 million Americans have sleep apnea, which occurs more often in men than in women (NHLBI, 2003). Other risk factors include having a family history of sleep apnea, being overweight, having high blood pressure, or having a physical abnormality of the nose or upper respiratory pathways (NHLBI, 2003).

Only one randomized trial (Snyder et al., 1999a) evaluated sleep apnea as a potential adverse effect of exogenous testosterone and found no significant difference between the mean number of apneic/hypopneic episodes per hour in the placebo and testosterone groups at baseline or after 36 months. Several noncontrolled studies of hypogonadal men found some evidence of increases in disordered breathing events during testosterone therapy but with wide variability in the extent of sleep disturbances between individuals (Appendix C). The other outcomes (water and sodium retention, gynecomastia, and suppression of sperm production) have been examined in older men in nonplacebo-controlled studies.

MULTIPLE OUTCOMES

Testosterone affects multiple health outcomes and, as is evident in the tables throughout this chapter, a number of randomized placebo-controlled trials have reported results on more than one outcome measure. The committee decided to select four of the trials to provide a brief overview of the results across multiple outcomes. The four trials in Table 2-20 were selected based on the length of the trial, the number of participants, the use of a study population of healthy community-dwelling older men, and the number of outcomes examined.

TABLE 2-20. Selected Randomized Placebo-Controlled Trials of Testosterone Therapy and Multiple Outcome Measures.

TABLE 2-20

Selected Randomized Placebo-Controlled Trials of Testosterone Therapy and Multiple Outcome Measures.

SUMMARY

Endogenous testosterone levels clearly decline with aging, but it is not clear if lower levels of serum testosterone affect health outcomes in older men. Much remains unknown regarding how physiologic pathways are affected by changes in endogenous testosterone levels or by the administration of exogenous testosterone.

A systematic review of the medical literature on testosterone therapy, particularly placebo-controlled trials in older men, demonstrated that there is not clear evidence of benefit for any of the health outcomes examined. The placebo-controlled trials are generally of short duration (only 3 of the 31 placebo-controlled trials administered testosterone for 12 months or longer) and involve a small number of participants (6 clinical trials had 50 or more participants and only 1 trial had more than 100 participants). The findings regarding testosterone's effects on specific health outcomes are generally mixed.

For several health outcomes, results of these trials suggest a potential benefit from testosterone therapy. These areas—including beneficial effects on body composition, strength, bone density, frailty, cognitive function, mood, sexual function, and quality of life—deserve further exploration, particularly those areas for which safe and effective pharmacologic treatments are not already available. Testosterone treatment increases hematocrit, but there is no definitive evidence of other risks. The potential for testosterone therapy to increase risk for symptomatic prostatic hypertrophy and prostate cancer is of major concern, but quantifying these risks will require randomized trials that include large numbers of men followed for multiple years. Future large-scale trials should be inclusive of multiple racial groups. To date, placebo-controlled trials have not examined if there is a differential response.

Most of the placebo-controlled trials used doses of testosterone that raised levels to the normal physiologic range for young adult males. However, the results of the clinical trials are not easily compared because of differences in route of administration and types of testosterone used. Most of the randomized trials used intramuscular injections of testosterone enanthate or cypionate. Testosterone patches and gels have more recently received FDA approval and therefore have been used in a smaller number of randomized placebo-controlled trials. Summarizing the results of published research is also difficult because of wide variations in the age ranges and baseline testosterone levels of the populations studied.

Clinical research on testosterone therapy in older men has produced suggestions of benefit and of risk, but little definitive evidence. Additional placebo-controlled trials of testosterone therapy are needed to determine the nature and extent of therapeutic benefits for older men.

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Footnotes

1

Endogenous hormones are produced or synthesized within the organism. Exogenous hormones are those administered or introduced from outside the organism.

2

Additional short-term placebo-controlled trials have examined the effects of cognitive and cardiovascular outcomes using a one-time or intravenous dose of testosterone. These trials are described in the relevant health outcome sections.

Copyright 2004 by the National Academy of Sciences. All rights reserved.
Bookshelf ID: NBK216175

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