National Academies Press: OpenBook

Testosterone and Aging: Clinical Research Directions (2004)

Chapter: 2 Testosterone and Health Outcomes

« Previous: 1 Introduction
Suggested Citation:"2 Testosterone and Health Outcomes." Institute of Medicine. 2004. Testosterone and Aging: Clinical Research Directions. Washington, DC: The National Academies Press. doi: 10.17226/10852.
×

2
Testosterone 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

1  

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

Suggested Citation:"2 Testosterone and Health Outcomes." Institute of Medicine. 2004. Testosterone and Aging: Clinical Research Directions. Washington, DC: The National Academies Press. doi: 10.17226/10852.
×

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.

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-

Suggested Citation:"2 Testosterone and Health Outcomes." Institute of Medicine. 2004. Testosterone and Aging: Clinical Research Directions. Washington, DC: The National Academies Press. doi: 10.17226/10852.
×

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 men and women for more than 40 years. Follow-up medical and psychological examinations are conducted approximately every two years, and serum samples are drawn and stored at each follow-up visit.

Massachusetts Male Aging Study (MMAS). An ongoing study of a random sample of 2,300 men ages 39 to 70 identified from towns and cities in the Boston metropolitan area. The men were initially invited to participate from 1986 to 1989, and the overall response to the request to participate was 53.3 percent, with participants averaging 54.7 years of age at that time.

Rancho Bernardo Study. An ongoing community-based examination of aging and lifestyle factors, this study was begun 1972 to 1974 with ambulatory adults from the middle to upper-middle class community of Rancho Bernardo, California. From 1984 to 1987, 82 percent of surviving cohort members participated in a follow-up clinic visit, which included a questionnaire, physical examination, and blood samples drawn and stored.

Rochester Epidemiology Project. This population-based data resource is comprised of the inpatient and outpatient medical records of all Olmsted County, Minnesota residents for the entire duration of their residency in the county. The database covers the medical care health care that providers have delivered to county residents from 1909 through the present. The majority of the population is seen over any 3-year period.

Multiple Risk Factor Intervention Trial (MRFIT). Conducted from 1973 to 1982, this randomized prevention trial assessed the effect of altering or removing risk factors for cardiovascular morbidity and mortality in more than 12,000 men ages 35 to 57. One group received a special intervention, and the other received usual care.

Physician’s Health Study. The first phase of this randomized, double-blind, placebo-controlled trial assessed the effects of aspirin and β-carotene on cancer and cardiovascular disease among 22,071 male physicians in the United States, who were 40 to 84 years old in 1982. The study is currently in Phase II and is examining the effects of vitamins on cancer, cardiovascular disease, and age-related eye disease.

Suggested Citation:"2 Testosterone and Health Outcomes." Institute of Medicine. 2004. Testosterone and Aging: Clinical Research Directions. Washington, DC: The National Academies Press. doi: 10.17226/10852.
×

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

Reference

Study Population

Control Variables

Results

Prospective Studies

Harman et al., 2001

BLSA. 890 men (55 to 90 years of age); 782 men with 2 or more determinations

Storage time, age

Cross-sectional analysis: total T decreased linearly with age

 

 

Longitudinal analysis: significant downward progression of T at every age; no significant differences in rate of decline in T by decade of age

Cross-Sectional Studies

Dai et al., 1981

MRFIT study. 243 men at 4th annual exam (age 35 to 57)

Age, relative weight, physical activity, alcohol use, others

T and free T negatively correlated with age

(rTotalT = −0.23;

rfreeT = −0.30)

 

Age and relative weight were independent predictors of T and free T in multivariable analysis

Gray et al., 1991a

MMAS. Group 1:415 nonobese men with no excess alcohol consumption, self-reported chronic illness, prostatic hypertrophy, history of prostate surgery, prescription meds; Group 2:1,294 men with at least one of the above as true

Stratified by obesity

Hormones declined with age at similar slope in 2 groups

 

 

Free T ↓ 1.2%/yr; albumin-bound T ↓ 1%/yr; total T ↓ 0.4%/yr; SHBG ↑ 1.2%/yr

 

 

T levels significantly and consistently lower in Group 2

Suggested Citation:"2 Testosterone and Health Outcomes." Institute of Medicine. 2004. Testosterone and Aging: Clinical Research Directions. Washington, DC: The National Academies Press. doi: 10.17226/10852.
×

Reference

Study Population

Control Variables

Results

Feldman et al., 2002

MMAS. 1,709 men included at baseline (1984-1987); 1,156 men surviving and participating at follow-up (1995-1997). Ages 40 to 70.

Baseline age, health status indicator

Hormone levels differed by apparent good health, but trends did not

Cross-sectional: SHBG ↑ 1.6%/yr; Total T ↓ 0.8%/ yr; Free T and albumin-bound T ↓ about 2%/yr

Within subject: SHBG ↑ 1.3%/yr; Total T ↓ 1.6%/ yr; Bioavailable T ↓ 2%-3/yr

Apparent good health added 10%-15% to level of several hormones

Ferrini and Barrett-Connor, 1998

Rancho Bernardo study. 810 men, age; Bioavailable T ↓ 1984-1987

BMI, waist/hip ratio, cigarettes, alcohol, caffeine, exercise, sera storage time; 5-year age groups

Total T ↓ 1.9 pg/ml/yr ages 24 to 90 in 18.5 pg/ml/yr age; Total E ↓ 0.03 pg/ml/yr age; Bioavailable E2 ↓ 0.12 pg/ml/yr age

NOTE: BLSA = Baltimore Longitudinal Study of Aging; BMI = body mass index; E2 = estradiol; MMAS = Massachusetts Male Aging Study; MRFIT = Multiple Risk Factor Intervention Trial; SHBG = sex hormone binding globulin; T = testosterone.

SOURCE: E. Barrett-Connor, G. Laughlin, unpublished. Printed with permission.

age 0.110 nmol/L/year (3.17 ng/dL) in both the cross-sectional and longitudinal analyses.

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

Suggested Citation:"2 Testosterone and Health Outcomes." Institute of Medicine. 2004. Testosterone and Aging: Clinical Research Directions. Washington, DC: The National Academies Press. doi: 10.17226/10852.
×

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 the mean of the individual longitudinal slopes in each decade, and is centered on the median age, for each cohort of men from the second to the ninth decade. Numbers in parentheses represent the number of men in each cohort. With the exception of free T index in the ninth decade, segments show significant downward progression at every age, with no significant change in slopes for T or free T index over the entire age range (Harman et al., 2001). Reprinted with permission from The Endocrine Society. Copyright 2001.

Suggested Citation:"2 Testosterone and Health Outcomes." Institute of Medicine. 2004. Testosterone and Aging: Clinical Research Directions. Washington, DC: The National Academies Press. doi: 10.17226/10852.
×

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

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, alcohol intake (g/week), smoking (cigarettes/day), sample storage time (months), and caffeine intake (g/month) (Ferrini and Barrett-Connor, 1998). Reprinted with permission from Oxford University Press.

Suggested Citation:"2 Testosterone and Health Outcomes." Institute of Medicine. 2004. Testosterone and Aging: Clinical Research Directions. Washington, DC: The National Academies Press. doi: 10.17226/10852.
×

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, alcohol intake (g/week), smoking (cigarettes/day), sample storage time (months), and caffeine intake (g/month) (Ferrini and Barrett-Connor 1998). Reprinted with permission from Oxford University Press.

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.

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

Suggested Citation:"2 Testosterone and Health Outcomes." Institute of Medicine. 2004. Testosterone and Aging: Clinical Research Directions. Washington, DC: The National Academies Press. doi: 10.17226/10852.
×

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

Age (years)

50-59

60-69

70-79

80-89

p-value

N

141

210

322

154

 

Total Testosterone Levels

Mean (SD) ng/dL

302 (86)

305 (91)

312 (111)

306 (125)

ns

Percent of Study Population

% <288 ng/dL

45.4

47.1

46.6

46.8

ns

% <259 ng/dL

33.3

37.1

31.1

35.1

ns

% <230 ng/dL

19.1

24.8

22.2

26.0

ns

Bioavailable Testosterone Levels

Mean (SD) ng/dL

124 (31)

106 (27)

92 (29)

78 (31)

<0.001

Percent of Study Population

% <84 ng/dL

7.9

26.7

43.8

61.7

<0.001

% <66 ng/dL

2.9

5.6

17.7

31.2

<0.001

% <57 ng/dL

0

3.3

7.1

20.8

<0.001

NOTE: 288 ng/dL = 10 nmol/L, 259 ng/dL = 9 nmol/L, 230 ng/dL = 8 nmol/L, 84 ng/dL = 3 nmol/L, 66 ng/dL = 2.2 nmol/L, 57 ng/dL = 2 nmol/L (0.0347 used as the conversion factor, JAMA, 2001). ns = not significant.

SOURCE: E. Barrett-Connor, G. Laughlin, unpublished. Printed with permission.

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 tes-

Suggested Citation:"2 Testosterone and Health Outcomes." Institute of Medicine. 2004. Testosterone and Aging: Clinical Research Directions. Washington, DC: The National Academies Press. doi: 10.17226/10852.
×

tosterone therapy that were conducted in older or middle-aged men and were published from 1977 to 2003.2Appendix 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

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.

Suggested Citation:"2 Testosterone and Health Outcomes." Institute of Medicine. 2004. Testosterone and Aging: Clinical Research Directions. Washington, DC: The National Academies Press. doi: 10.17226/10852.
×

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.

Suggested Citation:"2 Testosterone and Health Outcomes." Institute of Medicine. 2004. Testosterone and Aging: Clinical Research Directions. Washington, DC: The National Academies Press. doi: 10.17226/10852.
×

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).

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

Suggested Citation:"2 Testosterone and Health Outcomes." Institute of Medicine. 2004. Testosterone and Aging: Clinical Research Directions. Washington, DC: The National Academies Press. doi: 10.17226/10852.
×

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

Reference

Study Population Duration of Follow-Up

Control Variables

Results

Prospective Studies

Khosla et al., 2001

Rochester Epidemiology Project. 315 men with more than one visit

Some analyses stratified by age; multivariable analyses control for other hormone levels

Rates of change in BMD correlated with bioavailable T at the radius and ulna; progressive ↓ BMD with age; after adjustment, free E2remained significant determinant of bone turnover

Greendale et al., 1997

Rancho Bernardo study. 534 white men, aged 50-89; followed for approximately 4 years

Age, BMI, alcohol and cigarette use, other variables

Total T, DHEAS, DHEA not associated with BMD; bioavailable T associated with BMD at ultradistal radius, lumbar spine, hip

Cross-Sectional Studies

Khosla et al., 1998

Rochester Epidemiology Project. 346 men aged 20 or older. All but 13 white. 280 controls

Age

Positive correlations were strongest between BMD and bioavailable testosterone and bioavailable estrogen

Center et al., 1999

437 community-dwelling men over age 60 followed for approximately 4 years

Age, weight, other hormones

Low E2, low free T predicted lumbar spine BMD

Fractures

Barrett-Connor et al., 2000

Rancho Bernardo study. 352 white men, median age of 66

Age

Association between increased total and bioavailable E2 and decreased vertebral fractures; no association with total or bioavailable T

Suggested Citation:"2 Testosterone and Health Outcomes." Institute of Medicine. 2004. Testosterone and Aging: Clinical Research Directions. Washington, DC: The National Academies Press. doi: 10.17226/10852.
×

Reference

Study Population Duration of Follow-Up

Control Variables

Results

Stanley et al., 1991

17 men with minimal trauma hip fracture; 61 controls identified among male nursinghome residents 65 or older

Age, race, alcohol and tobacco use, disorders or drugs that may affect bone metabolism

Hypogonadism associated with hip fracture: OR =6.5 (95% CI 2.0–20.6)

NOTE: BMD = bone mineral density; BMI = body mass index; DHEA = dehydroepiandrosterone; DHEAS = dehydroepiandrosterone sulfate; E2 = estradiol; OR = odds ratio; T = testosterone.

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.

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.

Suggested Citation:"2 Testosterone and Health Outcomes." Institute of Medicine. 2004. Testosterone and Aging: Clinical Research Directions. Washington, DC: The National Academies Press. doi: 10.17226/10852.
×

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

Reference

Population; Age (years)

N

Duration; Dosagea

Results

Δb

Studies of Men with Low to Low-Normal Baseline Total Testosterone Levels

Christmas et al., 2002

Age 65-88, healthy

72

26 weeks

100 mg TE

IM every two weeks

No significant difference in changes in bone biochemical markers or in BMD between groups

+/−

Tenover, 1992

Age 57-76, healthy

13

3 months

100 mg TE

IM weekly

Significant change in one biochemical marker (↓ in urinary excretion of hydroxyproline); no effect on 9 other bone turnover markers

+/−

Kenny et al., 2001

Age 65-87 (mean 76), healthy, all received vitamin D and calcium

44

12 months

Two 2.5 mg

patches daily

Less bone loss at femoral neck; no effect on bone loss at 4 other sites or in bone turnover markers

+

Snyder et al., 1999a

Age >65, mean 73, healthy

108

36 months

6 mg scrotal

patch daily

Similar increases in each group in BMD at L2-L4 (spine). No effect on BMD at any of 3 other sites, no effect on bone turnover markers

+/−

NOTE: BMD = bone mineral density; IM = intramuscular; T = testosterone; TE = testosterone enanthate.

aDoses are physiologic, unless otherwise noted.

bThis column is intended to provide an overall summary of whether testosterone therapy had positive changes on bone density or bone turnover markers (+); no significant changes (+/−); or negative changes (−) as compared with placebo therapy. This is an overall subjective assessment by the committee and is meant only to provide the reader with a brief overview of the results.

Suggested Citation:"2 Testosterone and Health Outcomes." Institute of Medicine. 2004. Testosterone and Aging: Clinical Research Directions. Washington, DC: The National Academies Press. doi: 10.17226/10852.
×

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-

Suggested Citation:"2 Testosterone and Health Outcomes." Institute of Medicine. 2004. Testosterone and Aging: Clinical Research Directions. Washington, DC: The National Academies Press. doi: 10.17226/10852.
×

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

Reference

Study Population

Control Variables

Results

Cross-Sectional Studies

Field et al., 1994

MMAS. 1,241 men

Age, BMI, smoking

Low T levels related to higher BMI

Abbasi et al., 1998

144 men, 60 to 80 years of age from communities of SE Wisconsin

Age

Total T and free T correlated with lean body mass and total adipose mass, with age partialled out of the correlation; hormones did not predict either measure in regression analysis

Baumgartner et al., 1999

121 male volunteers, 65-97 years old

Knee height

Free T associated with muscle mass

Couillard et al., 2000

217 healthy and sedentary men ages 17 to 64; 57 men age 50 or older

Waist girth

Higher BMI, % body fat, fat mass with lower T levels. T also negatively correlated with body fat in waist, hip, but not with visceral adipose tissue

NOTE: BMI = body mass index; MMAS = Massachusetts Male Aging Study; T = testosterone.

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.

Suggested Citation:"2 Testosterone and Health Outcomes." Institute of Medicine. 2004. Testosterone and Aging: Clinical Research Directions. Washington, DC: The National Academies Press. doi: 10.17226/10852.
×

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

Suggested Citation:"2 Testosterone and Health Outcomes." Institute of Medicine. 2004. Testosterone and Aging: Clinical Research Directions. Washington, DC: The National Academies Press. doi: 10.17226/10852.
×

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

Reference

Population; Age (years)

N

Duration; Dosage a

Studies of Men with Frankly Low Baseline Total Testosterone Levels

Sih et al., 1997

Mean age 65, healthy

22

12 months

200 mg TC

IM every 14-17 days

Bhasin et al., 1998b

Age 18-60, HIV positive

32

12 weeks

Two 2.5 mg patches daily

Simon et al., 2001

Mean age 53

18

3 months

125 mg gel at first, then adjusted

Studies of Men with Low to Low-Normal Baseline Total Testosterone Levels

Münzer et al., 2001;

Blackman et al., 2002

Age 65-88, healthy

74

26 weeks

100 mg TE

IM every two weeks

Clague et al., 1999

Age 60+, healthy

14

12 weeks

200 mg TE

IM every two weeks

Ferrando et al., 2002, 2003

Age 64-71, healthy

12

6 months

IM TE weekly for 1 month, then biweekly, adjusted doses

Tenover, 1992

Age 57-76; healthy

13

3 months

100 mg TE

IM weekly

Kenny et al., 2001

Age 65-87 (mean 76), healthy, all received vitamin D and calcium

44

12 months

Two 2.5 mg patches daily

Snyder et al., 1999b

Age >65, (mean 73), healthy

108

36 months

6 mg scrotal patch daily

Suggested Citation:"2 Testosterone and Health Outcomes." Institute of Medicine. 2004. Testosterone and Aging: Clinical Research Directions. Washington, DC: The National Academies Press. doi: 10.17226/10852.
×

Results

Body Comp Δb

Strength Δc

No difference in % body fat or BMI between groups; increase in grip strength

+/−

+

Increase in lean body mass compared to baseline in T-treated group but not controls; no change in weight; no difference in muscle strength between groups

+/−

+/−

No change in waist circumference or waist-to-hip ratio

+/−

NA

Decrease in subcutaneous fat compared to controls; no effect on visceral abdominal fat or total abdominal area; no significant difference in total muscle strength changes between groups

+

+/−

Increase in total body mass compared to baseline in T-treated group, no effect on lean body mass; no difference in strength measures between groups

+/−

+/−

Increase in total and leg lean body mass, decrease in muscle protein breakdown, decrease in body fat; increase in leg and arm muscle strength

+

+

Increase in lean body mass and in weight; no significant change in percent body fat, waist/hip ratio, body circumference measures, or hand-grip strength compared with baseline

+

+/−

Decrease in body fat compared to controls; increase in lean body mass in T-treated group vs. baseline; no difference in muscle strength improvements between groups

+

+/−

Increase in lean mass (in trunk) and decrease in fat mass (arms and legs) compared to controls; no significant differences in changes in strength measures (knee extension or flexion, hand grip strength)

+

+/−

Suggested Citation:"2 Testosterone and Health Outcomes." Institute of Medicine. 2004. Testosterone and Aging: Clinical Research Directions. Washington, DC: The National Academies Press. doi: 10.17226/10852.
×

Reference

Population; Age (years)

N

Duration; Dosage a

Pope et al., 2003

Age 30-65 (mean 47) with treated but refractory depression

19

8 weeks

10 g 1% gel daily, then adjusted

Studies of Men with Normal Baseline Total Testosterone Levels

Holmäng et al., 1993

Age 40-65 (median 52), slightly to moderately obese

23

8 months

80 mg oral TU twice daily

Mårin et al., 1992

Age >45 (mean 52d), abdominally obese

23

8 months

80 mg

oral TU twice daily

Mårin et al., 1993, 1995

Age 40-65 (mean 58), healthy, abdominally obese

27

9 months

5 g T gel dailye

Studies in Which the Baseline Testosterone Level Is Not Reported

Bakhshi et al., 2000

Age 65-90, ill, admitted to rehab unit

15

up to 8 wks

100 mg TE IM weekly

NOTE: BMI = body mass index; HIV = human immunodeficiency virus; IM = intramuscular; NA = not applicable; T = testosterone; TC = testosterone cypionate; TE = testosterone enanthate; TU = testosterone undecanoate.

aDoses are physiologic, unless otherwise noted.

bThis column is intended to provide an overall summary of whether there were positive improvements in body composition measures with testosterone therapy (+); no significant changes (+/−); or negative changes (−) as compared with placebo controls. Some studies did not measure body composition (NA). This is an overall subjective assessment by the committee and is meant only to provide the reader with a brief overview of the results.

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.

Suggested Citation:"2 Testosterone and Health Outcomes." Institute of Medicine. 2004. Testosterone and Aging: Clinical Research Directions. Washington, DC: The National Academies Press. doi: 10.17226/10852.
×

Results

Body Comp Δb

Strength Δc

No significant change in % body fat or muscle mass

+/−

NA

“Increased muscular energy” reported by 5 of 11 in T-treated group vs. 1 of 12 on placebo

NA

+/−

Decrease in visceral fat mass in T-treated group compared to baseline; no change in body mass, subcutaneous fat mass, or lean body mass in either group

+

NA

Decrease in visceral adipose tissue mass in T-treated group compared to baseline; no change in total or subcutaneous adipose tissue masses or in lean body mass from baseline. Decrease in uptake and significant increase in turnover rate of triglycerides in abdominal but not femoral subcutaneous adipose tissue

+

NA

Increase in grip strength compared with baseline in T-treated group

NA

+/−

cThis column is intended to provide an overall summary of whether there were positive improvements in strength measures with testosterone therapy (+); no significant changes (+/−); or negative changes (−) as compared with placebo controls. Some studies did not measure strength (NA). This is an overall subjective assessment by the committee and is meant only to provide the reader with a brief overview of the results.

dMean age for the testosterone-treated group.

eAs stated in the study, this dose corresponds to 125 mg of testosterone.

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

Suggested Citation:"2 Testosterone and Health Outcomes." Institute of Medicine. 2004. Testosterone and Aging: Clinical Research Directions. Washington, DC: The National Academies Press. doi: 10.17226/10852.
×

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

Suggested Citation:"2 Testosterone and Health Outcomes." Institute of Medicine. 2004. Testosterone and Aging: Clinical Research Directions. Washington, DC: The National Academies Press. doi: 10.17226/10852.
×

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.

There is increasing evidence to suggest that declines or dysregulation

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

 

Perform with Difficulty (%)

Unable to Perform (%)

Physical Activity

30.1

19.6

ADL

16.6

7.1

IADL

6.9

12.8

NOTE: ADL = Activities of Daily Living; IADL = Instrumental Activities of Daily Living

SOURCE: NCHS, 1999.

Suggested Citation:"2 Testosterone and Health Outcomes." Institute of Medicine. 2004. Testosterone and Aging: Clinical Research Directions. Washington, DC: The National Academies Press. doi: 10.17226/10852.
×

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

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

Reference

Population; Age (years)

N

Studies of Men with Low to Low-Normal Baseline Total Testosterone Level

Amory et al., 2002

Age 58-86 (mean 70), generally healthy, undergoing knee surgery

22

Kenny et al., 2002a

Age 65-87 (mean 76), healthy, all received vitamin D and calcium

44

English et al., 2000

Mean age 62, coronary artery disease

46

Snyder et al., 1999b

Age >65, mean 73, healthy

108

Studies in Which the Baseline Testosterone Level Is Not Reported

Bakhshi et al., 2000

Age 65-90, ill, admitted to rehab unit

15

NOTE: FIM = Functional Independence Measure; IM = intramuscular; T = testosterone; TE = testosterone enanthate.

aDoses are physiologic, unless otherwise noted.

bThis column is intended to provide an overall summary of whether testosterone therapy resulted in better physical function (+); decrements in physical function (−); or no significant effect (+/−) compared with placebo therapy. This is an overall subjective assessment by the committee and is meant only to provide the reader with a brief overview of the results.

Suggested Citation:"2 Testosterone and Health Outcomes." Institute of Medicine. 2004. Testosterone and Aging: Clinical Research Directions. Washington, DC: The National Academies Press. doi: 10.17226/10852.
×

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.

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

Duration; Dosage a

Results

Δb

4 weeks

600 mg TE IM 21, 14, 7, and 1 day(s) before surgeryc

Improvement in post-op FIM score: stood sooner vs. placebo post-op; trends toward improved walking and stair climbing

+

12 months

Two 2.5 mg patches daily

No differences on SF-36 scores between groups

+/−

12 weeks

Two 2.5 mg patches daily

Improvement in 1 of 8 SF-36 domains: role limitation resulting from physical problems

+

36 months

6 mg scrotal patch daily

Significant improvement in 1 of 8 SF-36 domains: perception of physical function; no significant change in physical function (walking, stair climbing)

+

up to 8 weeks

100 mg TE IM weekly

Increased FIM score compared to baseline in T-treated group; similar FIM scores between groups; no significant change in length of stay on rehab unit

+/−

cSupraphysiologic dose.

Suggested Citation:"2 Testosterone and Health Outcomes." Institute of Medicine. 2004. Testosterone and Aging: Clinical Research Directions. Washington, DC: The National Academies Press. doi: 10.17226/10852.
×

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,

Suggested Citation:"2 Testosterone and Health Outcomes." Institute of Medicine. 2004. Testosterone and Aging: Clinical Research Directions. Washington, DC: The National Academies Press. doi: 10.17226/10852.
×

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

Reference

Study Population

Control Variables

Results

Prospective Study

Barrett-Connor et al., 1999a

Rancho Bernardo study. 547 men (age 55-89); cognitive tests administered 4 to 7 years after sera collected for T levels.

Age, education in linear regression models; age, education, depression, alcohol, BMI, smoking, other hormones in multiple regression models

High total or bioavailable T predicted better performance on tests of verbal memory and mental control

NOTE: BMI = body mass index; T = testosterone.

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.

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.

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

Suggested Citation:"2 Testosterone and Health Outcomes." Institute of Medicine. 2004. Testosterone and Aging: Clinical Research Directions. Washington, DC: The National Academies Press. doi: 10.17226/10852.
×

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

Reference

Population; Age (years)

N

Studies of Men with Frankly Low Baseline Total Testosterone Levels

Sih et al., 1997

Mean age 65, healthy

22

Studies of Men with Low to Low-Normal Baseline Total Testosterone Levels

Janowsky et al., 2000

Age 61-75, healthy

19

Studies of Men with Normal Baseline Total Testosterone Levels

Cherrier et al., 2001

Age 50-80 (mean 67), healthy

25

Kenny et al., 2002a

Age 65-87 (mean 76), healthy

44

Janowsky et al., 1994

Age 60-75 (mean 67), healthy

56

NOTE: IM = intramuscular; TC = testosterone cypionate; TE = testosterone enanthate.

aDoses are physiologic, unless otherwise noted.

bThis column is intended to provide an overall summary of whether testosterone therapy resulted in better cognitive function (+); worse cognitive function (−); or no significant effect on cognitive function (+/−) compared with placebo therapy. This is an overall subjective assessment by the committee and is meant only to provide the reader with a brief overview of the results.

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

Suggested Citation:"2 Testosterone and Health Outcomes." Institute of Medicine. 2004. Testosterone and Aging: Clinical Research Directions. Washington, DC: The National Academies Press. doi: 10.17226/10852.
×

Duration; Dosage a

Results

Δb

12 months

200 mg TC

IM every 14- 17 days

No effect on memory, recall, or verbal fluency tests

+/−

1 month

150 mg TE

IM weekly

Improvement in working memory

+

6 weeks

100 mg TE

IM weekly

Better recall of walking route, block construction, and verbal memory

+

12 months

Two 2.5 mg patches daily

No effect when compared with placebo, improvement in one (Trailmaking B) of four cognitive tests vs. baseline

+/−

3 months

15 mg

scrotal patch 16 hours/day

Better spatial cognition, but no effect on 5 other cognitive tests

+

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 de-

Suggested Citation:"2 Testosterone and Health Outcomes." Institute of Medicine. 2004. Testosterone and Aging: Clinical Research Directions. Washington, DC: The National Academies Press. doi: 10.17226/10852.
×

pression 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.

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.

Suggested Citation:"2 Testosterone and Health Outcomes." Institute of Medicine. 2004. Testosterone and Aging: Clinical Research Directions. Washington, DC: The National Academies Press. doi: 10.17226/10852.
×

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

Reference

Study Population

Control Variables

Results

Cross-Sectional Studies

Barrett-Connor et al.,1999b

Rancho Bernardo study.

856 men, age 50-89

Age, weight change

(1972-1974 to 1984-1987),

physical activity

Depressed mood associated with decreasing bioavailable T, no significant association with total T

Gray et al., 1991b

MMAS. 1,709 men, aged 39 to 70 in 1986-1989

No control variables

No significant correlation between T levels (albumin-bound, free, or total T) and anger expression measures; positive correlation between dominance and albumin-bound T and free T

NOTE: MMAS = Massachusetts Male Aging Study; T = testosterone.

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.

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

Suggested Citation:"2 Testosterone and Health Outcomes." Institute of Medicine. 2004. Testosterone and Aging: Clinical Research Directions. Washington, DC: The National Academies Press. doi: 10.17226/10852.
×

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

Reference

Population; Age (years)

N

Studies of Men with Frankly Low Baseline Total Testosterone Levels

Davidson et al., 1979

Age 37-61

6

Sih et al., 1997

Mean age 65, healthy

22

Studies of Men with Low to Low-Normal Baseline Total Testosterone Levels

Janowsky et al., 2000

Age 61-75, healthy

19

Rabkin et al., 1999

Mean age 41, HIV positive with sexual dysfunction

77

Rabkin et al., 2000

Mean age 38, HIV positive with sexual dysfunction

70

Seidman et al., 2001b

Age 35-71 (mean 52)

29

Pope et al., 2003

Age 30-65 (mean 47) with treated but refractory depression

19

Studies of Men with Normal Baseline Total Testosterone Levels

Schiavi et al., 1997

Age 46-67 (median 60) with erectile dysfunction

12

Benkert et al., 1979

Age 45-75, erectile dysfunction

29

Suggested Citation:"2 Testosterone and Health Outcomes." Institute of Medicine. 2004. Testosterone and Aging: Clinical Research Directions. Washington, DC: The National Academies Press. doi: 10.17226/10852.
×

Duration; Dosage a

Results

Δb

5 months

100 mg or 400 mg TE

IM every 4 weeks

No change in mood measured by POMS

+/−

12 months

200 mg TC

IM every 14-17 days

No effects on Yesavage Geriatric Depression Scale

+/−

1 month

150 mg TE

IM weekly

No significant change in measures of mood

+/−

6 week discontinuation trial

200 mg TC IM once, then 400 mg TC IM biweekly, adjusted as needed

Participants randomized to placebo after 4 weeks of T treatment showed decrements in depression measures compared with during T treatment

+

6 weeks

200 mg TC IM once, then 400 mg TC IM biweekly, adjusted as needed

Significant improvement in measures of depression (Ham-D score and BDI)

+

6 weeks

200 mg TE

IM weekly

No difference in depression measures (Ham-D) between groups

+/−

8 weeks

10 g 1% gel daily, then adjusted

Improvement in mood and depression on Ham-D and CGI in T-treated group, but not on BDI

+

6 weeks

200 mg TE

IM biweekly

No effect on mood measured by POMS

+/−

8 weeks

120 mg TU orally daily

No difference in depression scores between groups

+/−

Suggested Citation:"2 Testosterone and Health Outcomes." Institute of Medicine. 2004. Testosterone and Aging: Clinical Research Directions. Washington, DC: The National Academies Press. doi: 10.17226/10852.
×

Reference

Population; Age (years)

N

Studies in Which the Baseline Testosterone Level Is Not Reported

Bakhshi et al., 2000

Age 65-90, ill, admitted to rehab unit

15

Janowsky et al., 1994

Age 60-75 (mean 67), healthy

56

NOTE: BDI = Beck Depression Inventory; CGI = Clinical Global Impression score; GDS-SF = Geriatric Depression Score, Short Form; Ham-D = Hamilton Depression Rating Scale; HIV = human immunodeficiency virus; IM = intramuscular; POMS = Profile of Mood States; T = testosterone; TC = testosterone cypionate; TE = testosterone enanthate; TU = testosterone undecanoate.

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 demographi-

Suggested Citation:"2 Testosterone and Health Outcomes." Institute of Medicine. 2004. Testosterone and Aging: Clinical Research Directions. Washington, DC: The National Academies Press. doi: 10.17226/10852.
×

Duration; Dosage a

Results

Δb

Up to 8 weeks

100 mg TE

IM weekly

Improvement in depression measures

+

3 months

15 mg scrotal patch

16 hours/day

No significant change in mood as self-rated or rated by wives

+/−

aDoses are physiologic, unless otherwise noted.

bThis column is intended to provide an overall summary of whether there were positive improvements in mood or depression with testosterone therapy (+); no significant changes (+/−); or negative changes (−) as compared with placebo controls. This is an overall subjective assessment by the committee and is meant only to provide the reader with a brief overview of the results.

cally 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

Suggested Citation:"2 Testosterone and Health Outcomes." Institute of Medicine. 2004. Testosterone and Aging: Clinical Research Directions. Washington, DC: The National Academies Press. doi: 10.17226/10852.
×

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).

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

Suggested Citation:"2 Testosterone and Health Outcomes." Institute of Medicine. 2004. Testosterone and Aging: Clinical Research Directions. Washington, DC: The National Academies Press. doi: 10.17226/10852.
×

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

Reference

Study Population

Control Variables

Results

Feldman et al., 1994

MMAS. 1,290 men, age 40-70

Age, health status, medication use, tobacco use

No significant correlations between total T or free T and self-reported impotence

Davidson et al., 1983

220 men age 40-93

Diseases and drugs; age strata

No significant correlations between total T and sexual behaviors; significant correlations between free T and orgasm, morning erections, and sexual thoughts did not remain consistently associated when stratified by age

NOTE: MMAS = Massachusetts Male Aging Study; T = testosterone.

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.

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 testoster-

Suggested Citation:"2 Testosterone and Health Outcomes." Institute of Medicine. 2004. Testosterone and Aging: Clinical Research Directions. Washington, DC: The National Academies Press. doi: 10.17226/10852.
×

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

Reference

Population; Age (years)

N

Studies of Men with Frankly Low Baseline Total Testosterone Levels

Davidson et al., 1979

Age 37-61

6

Skakkebaek et al., 1981

Age 22-50, chronically hypogonadal

11

Studies of Men with Low to Low-Normal Baseline Total Testosterone Levels

Nankin et al., 1986

Age 51-74, erectile dysfunction

10

Rabkin et al., 2000

Mean age 38, HIV positive with sexual dysfunction

70

Seidman et al., 2001b

Age 35-71 (mean 52)

29

Tenover, 1992

Age 57-76, healthy

13

Snyder et al., 1999b

Age >65, mean 73, healthy

108

Studies of Men with Normal Baseline Total Testosterone Levels

Schiavi et al., 1997

Age 46-67 (median 60)

12

Benkert et al., 1979

Age 45-75, erectile dysfunction

29

Holmäng et al., 1993

Age 40-65 (median 52), slightly to moderately obese

23

NOTE: HIV = human immunodeficiency virus; IM = intramuscular; T = testosterone; TC = testosterone cypionate; TE = testosterone enanthate; TU = testosterone undecanoate.

aDoses are physiologic, unless otherwise noted.

bThis column is intended to provide an overall summary of whether there were positive improvements in sexual function with testosterone therapy (+); no significant changes (+/−); or negative changes (−) as compared with placebo controls. This is an overall subjective assessment by the committee and is meant only to provide the reader with a brief overview of the results.

Suggested Citation:"2 Testosterone and Health Outcomes." Institute of Medicine. 2004. Testosterone and Aging: Clinical Research Directions. Washington, DC: The National Academies Press. doi: 10.17226/10852.
×

Duration; Dosage a

Results

Δb

5 months

100 mg or 400 mg TE

IM every 4 weeks

Increase in frequency of erection

+

4 months

80 mg TU orally twice daily

Improvement in sexual activity and desire

+

12 weeks

200 mg TC IM every 2 weeks

Increase in reported sexual activity, urge for sex, morning/sleep erections, potency, and libido

+

6 weeks

200 mg TC IM once, then 400 mg TC IM biweekly, adjusted as needed

Increased libido and morning erections

+

6 weeks

200 mg TE

IM weekly

Marginal improvement in sexual function, activity, and satisfactory measures

+

3 months

100 mg TE IM weekly

12 of 13 patients correctly predicted T therapy, in part because of an increase in libido

+/−

36 months

6 mg scrotal patch daily

No significant difference in responses to sexual function questionnaire between groups

+/−

6 weeks

200 mg TE

IM biweekly

Increase in reported ejaculation frequency; no effects on erection or sexual satisfaction

+

8 weeks

120 mg TU orally daily

No significant difference in reported erectile dysfunction

+/−

8 months

80 mg oral TU twice daily

Increased sexual desire reported by 5 of 11 in T-treated group versus 1 of 12 on placebo

+/−

Suggested Citation:"2 Testosterone and Health Outcomes." Institute of Medicine. 2004. Testosterone and Aging: Clinical Research Directions. Washington, DC: The National Academies Press. doi: 10.17226/10852.
×

one 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.

Suggested Citation:"2 Testosterone and Health Outcomes." Institute of Medicine. 2004. Testosterone and Aging: Clinical Research Directions. Washington, DC: The National Academies Press. doi: 10.17226/10852.
×

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.

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

Suggested Citation:"2 Testosterone and Health Outcomes." Institute of Medicine. 2004. Testosterone and Aging: Clinical Research Directions. Washington, DC: The National Academies Press. doi: 10.17226/10852.
×

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

Reference

Population; Age (years)

N

Studies of Men with Frankly Low Baseline Total Testosterone Levels

Bhasin et al., 1998b

Age 18-60, HIV positive

32

Studies of Men with Low to Low-Normal Baseline Total Testosterone Levels

Rabkin et al., 2000

Mean age 38, HIV positive with sexual dysfunction

70

Reddy et al., 2000

Age 65+, healthy

22

Seidman et al., 2001b

Age 35-71 (mean 52)

29

Tenover, 1992

Age 57-76, healthy

13

English et al., 2000

Mean age 62, coronary artery disease

46

Kenny et al., 2002a

Age 65-87 (mean 76), healthy

44

Snyder et al., 1999b

Age >65, mean 73, healthy

108

Studies of Men with Normal Baseline Total Testosterone Levels

Mårin et al., 1992

Age >45 (mean 52c), abdominally obese

23

NOTE: HRQoL = Health-related Quality of Life; HIV = human immunodeficiency virus; IM = intramuscular; PGWB = Psychological General Well Being scale; PSDI = Positive Symptom Distress Index; Q-LES-Q = Endicott Quality of Life Enjoyment and Satisfaction Questionnaire; SF-36 = Short Form 36 item; T = testosterone; TE = testosterone enanthate; TU = testosterone undecanoate.

aDoses are physiologic, unless otherwise noted.

Suggested Citation:"2 Testosterone and Health Outcomes." Institute of Medicine. 2004. Testosterone and Aging: Clinical Research Directions. Washington, DC: The National Academies Press. doi: 10.17226/10852.
×

Duration; Dosage a

Results

Δb

12 weeks

Two 2.5 mg patches daily

No significant differences in HRQoL scores between groups; improved role limitation due to emotional problems in T-treated group compared to baseline

+/−

6 weeks

200 mg TC IM once, then 400 mg TC IM biweekly, adjusted as needed

Improvement on the quality of life enjoyment measure (Q-LES-Q); trend toward significant improvement in fatigue scores

+

8 weeks

200 mg TE

IM every two weeks

No effect seen on health-related quality of life measures (SF-36, PGWB)

+/−

6 weeks

200 mg TE

IM weekly

No significant change in quality of life enjoyment (Q-LES-Q)

+/−

3 months

100 mg TE IM weekly

12 of 13 patients correctly predicted testosterone therapy, in part because of “a general increase in sense of well-being”

+/−

12 weeks

Two 2.5 mg patches daily

Improvement in 1 of 8 SF-36 domains: role limitation resulting from physical problems

+

12 months

Two 2.5 mg patches daily

No effect on health perception (SF-36)

+/−

36 months

6 mg scrotal patch daily

Improvement in 1 of 8 SF-36 domains: perception of physical function; no significant change in perception of energy

+

8 months

80 mg oral TU twice daily

Increase in “well-being,” trend toward “feeling of improved energy”

+

bThis column is intended to provide an overall summary of whether there were positive improvements in the assessment of health-related quality of life with testosterone therapy (+); no significant changes (+/−); or negative changes (−) as compared with placebo controls. This is an overall subjective assessment by the committee and is meant only to provide the reader with a brief overview of the results.

cMean age for men in the testosterone-treated group.

Suggested Citation:"2 Testosterone and Health Outcomes." Institute of Medicine. 2004. Testosterone and Aging: Clinical Research Directions. Washington, DC: The National Academies Press. doi: 10.17226/10852.
×

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

Suggested Citation:"2 Testosterone and Health Outcomes." Institute of Medicine. 2004. Testosterone and Aging: Clinical Research Directions. Washington, DC: The National Academies Press. doi: 10.17226/10852.
×

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

Reference

Study Description

Control Variables

Results

Cardiovascular Risk Factors and Outcomes

Prospective Studies

Contoreggi et al., 1990

BLSA. 124 men (age 31-85) with no coronary artery disease, compared with 46 men with CAD (age 41-92)

Continuous variables included age, BMI, total cholesterol, hormone levels

Groups did not differ on T levels; SBP, cholesterol, age differentiated groups

Zmuda et al., 1997

MRFIT. 66 men (age 41 to 61 years)

Lifestyle, anthropometric, psychosocial attributes

Type “A” baseline, greater decrease T at follow-up 1,009 men followed for an

Barrett-Connor and Khaw, 1988

Rancho Bernardo. 1,009 men average of 12 years for cardiovascular disease

Age, cigarette smoking, SBP, fasting plasma glucose, cholesterol, BMI

T levels not significantly associated with cardiovascular or ischemic heart disease either cross-sectionally or prospectively

Yarnell et al., 1993

Caerphilly Study. 2,512 men (age 45-59), followed for 5 years

Smoking, blood pressure, BMI, total triglycerides

No association found between T and ischemic heart disease

Cross-Sectional Studies

Khaw and Barrett-Connor, 1988

Rancho Bernardo. 1,132 men (age 30-79)

Age, BMI

Hypertensive men had lower T levels than nonhypertensives; SBP and DBP negatively correlated with T levels

van den Beld et al., 2003

403 men (73 to 94 years of age in 1996)

Age

IMT increased with decreased T

Suggested Citation:"2 Testosterone and Health Outcomes." Institute of Medicine. 2004. Testosterone and Aging: Clinical Research Directions. Washington, DC: The National Academies Press. doi: 10.17226/10852.
×

Reference

Study Description

Control Variables

Results

Case-Control Study

Cauley et al., 1987

MRFIT. 163 men who had a major coronary event. 163 controls. Follow-up in 6 to 8 years.

Matched for age, serum cholesterol level, randomization group, date, clinic

No difference between cases and controls for total T, free T, or estradiol levels

Diabetes

Prospective Studies

Oh et al., 2002

Rancho Bernardo study. 294 men, ambulatory, living locally 1992-1996

Baseline age, BMI, SBP

Low levels of total T predicted incident diabetes (OR = 2.7; 1.1, 6.6); incidence diabetes significantly higher in lowest quartile for total T

Stellato et al., 2000

MMAS. 54 incident cases of diabetes among men age 40-70, followed 7-10 years

Hypertension, heart disease, depression, BMI

OR free T = 1.58 (1.08- 2.29) per -1 SD; SHBG = 1.89 (1.14- 3.14) per -1 SD

Cross-Sectional Study

Barrett-Connor, 1992

Rancho Bernardo study. 44 cases noninsulin dependent DM; 88 controls 1984-1987

Tobacco and alcohol use; controls matched on age and time of visit

Diabetic men had significantly lower total T and free T controlling for tobacco and alcohol use

NOTE: BLSA = Baltimore Longitudinal Study of Aging; bp = blood pressure; BMI = body mass index; CAD = coronary artery disease; DBP = diastolic blood pressure; DM = diabetes mellitus; IMT = intima-media thickness; MMAS = Massachusetts Male Aging Study; MRFIT = Multiple Risk Factor Intervention Trial; OR = odds ratio; SHBG = sex hormone-binding globulin; SBP = systolic blood pressure; SD = standard deviation; T = testosterone.

Suggested Citation:"2 Testosterone and Health Outcomes." Institute of Medicine. 2004. Testosterone and Aging: Clinical Research Directions. Washington, DC: The National Academies Press. doi: 10.17226/10852.
×

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.

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 follow-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, com-

Suggested Citation:"2 Testosterone and Health Outcomes." Institute of Medicine. 2004. Testosterone and Aging: Clinical Research Directions. Washington, DC: The National Academies Press. doi: 10.17226/10852.
×

munity-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 tri-

Suggested Citation:"2 Testosterone and Health Outcomes." Institute of Medicine. 2004. Testosterone and Aging: Clinical Research Directions. Washington, DC: The National Academies Press. doi: 10.17226/10852.
×

als (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

Suggested Citation:"2 Testosterone and Health Outcomes." Institute of Medicine. 2004. Testosterone and Aging: Clinical Research Directions. Washington, DC: The National Academies Press. doi: 10.17226/10852.
×

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

Reference

Population; Age (years)

N

Duration; Dosage a

Studies of Men with Frankly Low Baseline Total Testosterone Levels

Sih et al., 1997

Mean age 65, healthy

22

12 months

200 mg TC

IM every 14–17 days

Bhasin et al., 1998b

Age 18-60, HIV positive

32

12 weeks

Two 2.5 mg patches daily

Simon et al., 2001

Mean age 53

18

3 months

125 mg gel at first, then adjusted

Studies of Men with Low to Low-Normal Baseline Total Testosterone Levels

Amory et al., 2002

Age 58-86 (mean 70) generally healthy, undergoing knee surgery

22

4 weeks

600 mg TE IM 21, 14, 7, and 1 day(s) before surgeryd

Blackman et al., 2002

Age 65-88, healthy

74

26 weeks

100 mg TE

IM every 2 weeks

Clague et al., 1999

Age 60+, healthy

14

12 weeks

200 mg TE

IM every 2 weeks

Drinka et al., 1995

Age 60-90 in nursing home

18

6 months

150 mg/70 kg T e

IM every 2 weeks

Ferrando et al., 2002

Age 64-71, healthy

12

6 months

IM TE weekly for 1 month, then biweekly, adjusted doses

Tenover, 1992

Age 57-76, healthy

13

3 months

100 mg TE

IM weekly

Uyanik et al., 1997

Ages 53-89 (mean 67), healthy

37

2 months

120 mg TU orally daily

Suggested Citation:"2 Testosterone and Health Outcomes." Institute of Medicine. 2004. Testosterone and Aging: Clinical Research Directions. Washington, DC: The National Academies Press. doi: 10.17226/10852.
×

Results

CV Δb

HemΔc

No effect on lipid profile (total cholesterol, LDL, HDL, TG); increased hemoglobin

+/−

No significant change in total cholesterol, LDL, HDL from baseline in either group; increase in red cell count and hemoglobin from baseline in T-treated group

+/−

No effect on lipid profile (total cholesterol, HDL, TG); increase in hematocrit and hemoglobin from baseline in T-treated group

+/−

No significant change in total cholesterol, LDL; trend toward decreased HDL after 14 days; increase in hematocrit

+/−

No significant hematocrit change in either group

NA

+/−

No effect on total cholesterol; increase in hemoglobin in T-treated group compared to baseline

+/−

2 of 8 men in T-treated group developed hematocrits >51%

NA

No effect on lipid profile (total cholesterol, HDL, LDL); increased hematocrit

+/−

Significant decrease in total cholesterol and LDL; nonsignificant trend to decreased HDL; increase in hematocrit, hemoglobin, red cell count at 3 months (2 men’s hematocrit >50%) with T therapy

+

Decrease in total cholesterol and LDL as compared to baseline in T-treated group; no effect on TG, HDL

+

NA

Suggested Citation:"2 Testosterone and Health Outcomes." Institute of Medicine. 2004. Testosterone and Aging: Clinical Research Directions. Washington, DC: The National Academies Press. doi: 10.17226/10852.
×

Reference

Population; Age (years)

N

Duration; Dosage a

English et al., 2000

Mean age 62, coronary artery disease

46

12 weeks

Two 2.5 mg patches daily

Kenny et al., 2001; 2002b

Age 65-87 (mean 76), healthy

44

12 months

Two 2.5 mg patches daily

Snyder et al., 1999a, 2001

Age >65 (mean 73), healthy

108

36 months

6 mg scrotal patch daily

Studies of Men with Normal Baseline Total Testosterone Levels

Mårin et al., 1992

Age >45 (mean 52f), abdominally obese

23

8 months

80 mg oral TU twice daily

Mårin et al., 1993, 1995

Mean age 58, abdominally obese

27

9 months

5 mg Tgel dailyg

Studies in Which the Baseline Testosterone Level Is Not Reported

Bakhshi et al., 2000

Age 65-90, ill, admitted to rehab unit

15

up to 8 weeks

100 mg TE IM weekly

Jaffe, 1977

Age 35-71 (mean 58) with heart disease

50

8 weeks

200 mg TC IM weeklyd

NOTE: HDL = high-density lipoprotein; HIV = human immunodeficiency virus; IM = intramuscular; LDL = low-density lipoprotein; Lp(a) = lipoprotein a; T = testosterone; TC = testosterone cypionate; TE = testosterone enanthate; TG = triglycerides; TU = testosterone undecanoate.

aDoses are physiologic, unless otherwise noted.

bThis column is intended to provide an overall summary of whether there were positive improvements in cardiovascular risk factors (most often lipid profiles) with testosterone therapy (+); no significant changes (+/−); or negative changes (−). Some studies did not assess lipid profile (NA). This is an overall subjective assessment by the committee and is meant only to provide the reader with a brief overview of the results.

Suggested Citation:"2 Testosterone and Health Outcomes." Institute of Medicine. 2004. Testosterone and Aging: Clinical Research Directions. Washington, DC: The National Academies Press. doi: 10.17226/10852.
×

Results

CV Δb

HemΔc

No effect on lipid panel; improvement in time to 1-mm ST depression on treadmill compared to controls, better in those with lower T; no effect on hemoglobin levels

+/−

+/−

Decrease in HDL; no effect on total cholesterol, LDL, or Lp(a), or in vascular reactivity (brachial artery); no effect on hematocrit or hemoglobin

+/−

No significant difference in changes in lipid profile (total cholesterol, HDL, Lp(a), LDL) between groups; no significant difference in cardiovascular events (but small number of events); increase in hematocrit and hemoglobin at 6 months, then stable (3 men’s hematocrit >52%) in T-treated group

+/−

Decrease in total cholesterol in T-treated group compared to baseline; no significant change in HDL or TG compared to baseline in either group

+

NA

Decrease in TG and total cholesterol in T-treated group compared to baseline, no effect on HDL

+

NA

No elevation in hemoglobin >15 mg/dL

NA

+/−

Decrease in sum of ST segment depression in multiple leads in T-treated group; increase in hematocrit and hemoglobin at 4 and 8 weeks in T-treated group

+

cThis column is intended to provide an overall summary of whether there were positive improvements in hematocrit with testosterone therapy (+); no significant changes (+/−); or negative changes (−). An increase in hematocrit is depicted as a negative change. Although the committee notes that for some older men with low baseline hematocrit, an increased hematocrit within normal ranges would be a positive outcome. Some studies did not measure hematocrit (NA). This is an overall subjective assessment by the committee and is meant only to provide the reader with a brief overview of the results.

dSupraphysiologic dose.

eTestosterone compound not specified.

fMean age for the testosterone-treated group.

gAs stated in the study, this dose corresponds to 125 mg of testosterone.

Suggested Citation:"2 Testosterone and Health Outcomes." Institute of Medicine. 2004. Testosterone and Aging: Clinical Research Directions. Washington, DC: The National Academies Press. doi: 10.17226/10852.
×

age, risk factors for BPH include a high-fat diet and family history (NIDDK, 2003b).

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

Suggested Citation:"2 Testosterone and Health Outcomes." Institute of Medicine. 2004. Testosterone and Aging: Clinical Research Directions. Washington, DC: The National Academies Press. doi: 10.17226/10852.
×

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

Suggested Citation:"2 Testosterone and Health Outcomes." Institute of Medicine. 2004. Testosterone and Aging: Clinical Research Directions. Washington, DC: The National Academies Press. doi: 10.17226/10852.
×

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

Suggested Citation:"2 Testosterone and Health Outcomes." Institute of Medicine. 2004. Testosterone and Aging: Clinical Research Directions. Washington, DC: The National Academies Press. doi: 10.17226/10852.
×

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.

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

Suggested Citation:"2 Testosterone and Health Outcomes." Institute of Medicine. 2004. Testosterone and Aging: Clinical Research Directions. Washington, DC: The National Academies Press. doi: 10.17226/10852.
×

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

Reference

Study Description

Control Variables

Results

Prospective Studies

Meigs et al., 2001

MMAS. 1,019 without prostate cancer at baseline followed for approximately 9 years

Age, free PSA, smoking, physical activity, SBP, heart disease, beta-blockers or antihypertensive or heart meds, marital status; waist/hip ratio, alcohol use

T not significantly related to subsequent BPH

Mohr et al., 2001

MMAS. 1,576 men followed for approximately 9 years

Age

No association found between T, free T, or albumin-bound T and prostate cancer at p = 0.01

Carter et al., 1995

BLSA. Of men over age 60, 16 men with no prostatic disease; 20 with BPH; 20 with prostate cancer

Age

No differences in measures and development of prostate diseases

Barrett-Connor et al., 1990

Rancho Bernardo study. 57 cases and 951 non-cases

Age, BMI

No association found between prostate cancer and T

Case-Control Studies

Gann et al., 1996

Physician’s Health Study. 222 cases over 10 years follow-up/390 sera from 1980s

T, SHBG, E2, BMI, alcohol use, exercise; frequency controls matched on age, smoking status

Highest quartile vs. lowest:, (ORT = 2.6); (OR SHBG = 0.46) Risks greater among older men with aggressive disease

Heikkila et al., 1999

Mobile Clinic Health Examination Survey. 166 cases of prostate cancer, 300 controls; maximum 24 years follow-up

Smoking, BMI; controls matched for age, municipality

No hormone variable predicted prostate cancer; RR = 1.27 (0.67–2.37) for highest/lowest T comparison

Suggested Citation:"2 Testosterone and Health Outcomes." Institute of Medicine. 2004. Testosterone and Aging: Clinical Research Directions. Washington, DC: The National Academies Press. doi: 10.17226/10852.
×

Reference

Study Description

Control Variables

Results

Hsing and Comstock, 1993

County cancer registry to identify 98 prostate cancer cases; prostate cancer diagnosed within 13 years after bloods drawn; 98 controls

Marital status, education, smoking, medications for hypertension at baseline

No differences in levels of T between groups

Nomura et al., 1988

Honolulu Heart Program. Japanese men born from 1900-1919, 98 cases; 98 controls

Age, time of exam, time of blood draw

No association found between T levels and prostate cancer

Vatten et al., 1997

Linkage of Norwegian National Cancer Registry and serum bank (approximately 28,000 men with blood samples); 59 incident prostate cancer cases and 180 controls identified 1973-1994

Controls matched on birth year (± 1), time of blood draw (± 6 months)

No differences in levels of T between groups; no increased risk of cancer with increased quartile of T; no trend of risk with increasing T levels

NOTE: BLSA = Baltimore Longitudinal Study of Aging; BMI = body mass index; BPH = benign prostatic hypertrophy; E2 = estradiol; MMAS = Massachusetts Male Aging Study; OR = odds ratio; PSA = prostate-specific antigen; RR = relative risk; SBP = systolic blood pressure; SHBG = sex hormone-binding globulin; T = testosterone.

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.

Suggested Citation:"2 Testosterone and Health Outcomes." Institute of Medicine. 2004. Testosterone and Aging: Clinical Research Directions. Washington, DC: The National Academies Press. doi: 10.17226/10852.
×

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).

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.

Suggested Citation:"2 Testosterone and Health Outcomes." Institute of Medicine. 2004. Testosterone and Aging: Clinical Research Directions. Washington, DC: The National Academies Press. doi: 10.17226/10852.
×

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.

Suggested Citation:"2 Testosterone and Health Outcomes." Institute of Medicine. 2004. Testosterone and Aging: Clinical Research Directions. Washington, DC: The National Academies Press. doi: 10.17226/10852.
×

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

Reference

Population; Age (years); Prostate Baseline

N

Studies of Men with Frankly Low Baseline Total Testosterone Levels

Sih et al., 1997

Mean age 65, healthy; no evidence of significant prostate disease, normal PSA and rectal exam

22

Bhasin et al., 1998b

Age 18-60, HIV positive

32

Simon et al., 2001

Mean age 53; no prostate disease and normal PSA value

18

Studies of Men with Low to Low-Normal Baseline Total Testosterone Levels

Amory et al., 2002

Age 58-86 (mean 70) generally healthy, undergoing knee surgery; no prostate cancer history

22

Blackman et al., 2002

Age 65-88, healthy; no prostate cancer history, normal PSA

74

Clague et al., 1999

Age 60+, healthy; normal PSA, rectal exam, and urine flow rate

14

Ferrando et al., 2002

Age 64-71, healthy; PSA<4.0, no history of prostate cancer

12

Tenover, 1992

Age 57-76, healthy; no history of prostate disease

13

Uyanik et al., 1997

Ages 53-89 (mean 67), healthy

37

English et al., 2000

Mean age 62, coronary artery disease; normal PSA

46

Kenny et al., 2001

Age 65-87 (mean 76), healthy; no high PSA

44

Suggested Citation:"2 Testosterone and Health Outcomes." Institute of Medicine. 2004. Testosterone and Aging: Clinical Research Directions. Washington, DC: The National Academies Press. doi: 10.17226/10852.
×

Duration; Dosagea

Results

Δb

12 months

200 mg TC IM every 14-17 days

No significant change in PSA levels compared to controls; no nodules detected

+/−

12 weeks

Two 2.5 mg patches daily

No significant change in PSA levels in either group; no difference between groups

+/−

3 months

125 mg gel at first, then adjusted

No significant change in PSA levels compared to controls; 1 case of benign nodular hypertrophy

+/−

4 weeks

600 mg TE IM 21, 14, 7, and 1 day(s) before surgeryc

No significant change in PSA level in either group; no increase in symptoms of urinary retention

+/−

26 weeks

100 mg TE IM every 2 weeks

No significant change in PSA levels in either groupd; no significant change in IPSS scores or reports of prostatism symptoms

+/−

12 weeks

200 mg TE IM every 2 weeks

No significant change in PSA levels in either group

+/−

6 months

TE IM weekly for 1 month, then biweekly, adjusted doses

No significant change in PSA levels in either group; no change in prostate volume or urinary flow rate

+/−

3 months

100 mg TE IM weekly

Increase in PSA from baseline in T-treated group; no significant change in prostate size or urine postvoiding residual measurements

2 months

120 mg TU orally daily

No patients complained of changes in urination patterns

+/−

12 weeks

Two 2.5 mg patches daily

No significant change in PSA levels in either group

+/−

12 months

Two 2.5 mg patches daily

Increase in PSA levels in T-treated group vs. baseline but not significant vs. controls; no change in DRE, IPSS scores, or reports of urinary retention

+/−

Suggested Citation:"2 Testosterone and Health Outcomes." Institute of Medicine. 2004. Testosterone and Aging: Clinical Research Directions. Washington, DC: The National Academies Press. doi: 10.17226/10852.
×

Reference

Population; Age (years); Prostate Baseline

N

Snyder, et al., 1999a

Age >65 (mean 73), healthy; no prostate cancer history, no palpable nodule, PSA<4, no prostate symptoms

108

Pope et al., 2003

Age 30-65 (mean 47) with treated but refractory depression; normal PSA and DRE

19

Studies of Men with Normal Baseline Total Testosterone Levels

Cherrier et al., 2001

Age 50-80 (mean 67), healthy; normal PSA, DRE, no history of prostate cancer

25

Holmäng et al., 1993

Age 40-65 (median 52), slightly to moderately obese

23

Mårin et al., 1992

Age >45 (mean 52f), abdominally obese; no enlarged prostate

23

Mårin et al., 1993, 1995

Mean age 58, abdominally obese; prostate not enlarged, PSA ≤ 3.0 µg/l

27

Studies in Which the Baseline Testosterone Level Is Not Reported

Bakhshi et al., 2000

Age 65-90, ill, admitted to rehab unit; PSA <4.5, no recurrent prostatitis

15

NOTE: DRE = digital rectal exam; HIV = human immunodeficiency virus; IM = intramuscular; IPSS = International Prostate Symptom Scale; PSA = prostate specific antigen; T = testosterone; TC = testosterone cypionate; TE = testosterone enanthate; TU = testosterone undecanoate.

aDoses are physiologic, unless otherwise noted.

bThis column is intended to provide an overall summary of whether testosterone therapy resulted in improvements in prostate outcomes (+); decrements in prostate outcomes (−); or no significant effect (+/−). This is an overall subjective assessment by the committee and is meant only to provide the reader with a brief overview of the results.

Suggested Citation:"2 Testosterone and Health Outcomes." Institute of Medicine. 2004. Testosterone and Aging: Clinical Research Directions. Washington, DC: The National Academies Press. doi: 10.17226/10852.
×

Duration; Dosagea

Results

Δb

36 months

6 mg scrotal patch daily

Increase in PSA levels in T-treated group not in controls; 4 men with persistent PSA increase (biopsies found 1 cancer in T-treated group); no change in urine flow rate, urine symptoms, or postvoid residual in either group

8 weeks

10 g 1% gel daily, then adjusted

Change in PSA level did not differ between groups; 1 patient dropped out because of urinary symptoms

+/−

6 weeks

100 mg TE IM weekly

Increase in PSA levels as compared with baseline in the T-treated groupe

8 months

80 mg oral TU twice daily

No significant changes in PSA levels in either group; increase in prostate volume in T-treated group compared to baseline

+/−

8 months

80 mg oral TU twice daily

No change in PSA level; increase in volume in T-treated group, no change in symptoms or flow

+/−

9 months

125 mg gel dailyg

No significant change in PSA level; no change in prostate volume or symptoms in either group

+/−

up to 8 weeks

100 mg TE IM weekly

No elevation in PSA level above 4.5 in any participant; no symptoms of obstructive uropathy

+/−

cSupraphysiologic dose.

dTwo subjects had (negative) biopsies when PSA increased >1.0 ng/mL.

eOne patient’s PSA increased from 3.5 to 4.1 ng/mL and was discontinued from the study.

fMean age for the testosterone-treated group.

gAs stated in the study, this dose corresponds to 125 mg of testosterone.

Suggested Citation:"2 Testosterone and Health Outcomes." Institute of Medicine. 2004. Testosterone and Aging: Clinical Research Directions. Washington, DC: The National Academies Press. doi: 10.17226/10852.
×

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

 

Snyder et al., 1999a,b, 2001

  • 36 months

  • 108 mena (age >65)

  • 6 mg scrotal patch daily

Blackman et al., 2002;

Münzer et al., 2001;

Christmas et al., 2002

  • 26 weeks

  • 74 menb (age 65-88)

  • 100 mg TE IM every 2 weeks

Kenny et al., 2001; 2002a,b

  • 12 months

  • 44 men (age 65-87)

  • Two 2.5 mg patches daily

Sih et al., 1997

  • 12 months

  • 22 men (mean age 65)

  • 200 mg TC IM every 14-17 days

Bone

+/−

+/−

+

NA

Body composition

+

+

+

+/−

Strength

+/−

+/−

+/−

+

Physical function

+

NA

+/−

NA

Cognitive function

NA

NA

+/−

+/−

Mood/depression

NA

NA

NA

+/−

Sexual function

+/−

NA

NA

NA

HRQoL

+

NA

+/−

NA

Lipid profile

+/−

NA

−(↓HDL)

+/−

Hematocrit

+/−

+/−

−(↑ hemoglobin)

Prostate

+/−

+/−

+/−

NOTE: HRQoL = health-related quality of life; IM = intramuscular; TC = testosterone cypionate; TE = testosterone enanthate. (+) = Significant improvement in the testosterone-treated group as compared with placebo group; (−) = significant decrement in the testosterone-treated group as compared with placebo group; (+/−) = outcome was examined in the study but no significant differences were seen between testosterone-treated and placebo groups; NA = no information available.

a96 men completed the entire 3 years of the study.

bMünzer et al., 2001 study, N = 64; Christmas et al., 2002 study, N = 72.

Suggested Citation:"2 Testosterone and Health Outcomes." Institute of Medicine. 2004. Testosterone and Aging: Clinical Research Directions. Washington, DC: The National Academies Press. doi: 10.17226/10852.
×

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.

Suggested Citation:"2 Testosterone and Health Outcomes." Institute of Medicine. 2004. Testosterone and Aging: Clinical Research Directions. Washington, DC: The National Academies Press. doi: 10.17226/10852.
×

REFERENCES

Abbasi AA, Mattson DE, Duthie EH Jr, Wilson C, Sheldahl L, Sasse E, Rudman IW. 1998. Predictors of lean body mass and total adipose mass in community-dwelling elderly men and women. American Journal of the Medical Sciences 315(3):188–193.

ACS (American Cancer Society). 2003. What Are the Key Statistics About Prostate Cancer? [Online]. Available: http://www.cancer.org [accessed April 2003].

AHA (American Heart Association). 2003. Men and Cardiovascular Disease: Statistical Fact Sheet. [Online]. Available: www.americanheart.org [accessed April 2003].

Alexander GM. 1996. Androgens and cognitive function. In: Bhasin S, Gabelnick HL, Spieler JM, Swerdloff RS, Wang C, Kelly C, eds. Pharmacology, Biology, and Clinical Applications of Androgens: Current Status and Future Prospects. New York: Wiley-Liss. Pp. 169–177.

Alexandersen P. 2002. Androgens and heart disease: evidence from animal models of atherosclerosis. In: Lunenfeld B, Gooren L, eds. Textbook of Men’s Health. Boca Raton, FL: Parthenon Publishing. Pp. 227–240.

Alexandersen P, Haarbo J, Christiansen C. 1996. The relationship of natural androgens to coronary heart disease in males: a review. Atherosclerosis 125(1):1–13.

Amory JK, Chansky HA, Chansky KL, Camuso MR, Hoey CT, Anawalt BD, Matsumoto AM, Bremner WJ. 2002. Preoperative supraphysiologic testosterone in older men undergoing knee replacement surgery. Journal of the American Geriatrics Society 50(10):1698–1701.

Anderson FH, Francis RM, Faulkner K. 1996. Androgen supplementation in eugonadal men with osteoporosis-effects of 6 months of treatment on bone mineral density and cardiovascular risk factors. Bone 18(2):171–177.

Anderson RA, Ludlam CA, Wu FC. 1995. Haemostatic effects of supraphysiologic levels of testosterone in normal men. Thrombosis & Haemostasis 74(2):693–697.

Ansong KS, Punwaney RB. 1999. An assessment of the clinical relevance of serum testosterone level determination in the evaluation of men with low sexual drive. Journal of Urology 162(3 Pt 1):719–721.

Aversa A, Isidori AM, Spera G, Lenzi A, Fabbri A. 2003. Androgens improve cavernous vasodilation and response to sildenafil in patients with erectile dysfunction. Clinical Endocrinology 58(5):632–638.


Bacon CG, Mittleman MA, Kawachi I, Giovannucci E, Glasser DB, Rimm EB. 2003. Sexual function in men older than 50 years of age: results from the health professionals follow-up study. Annals of Internal Medicine 139(3):161–168.

Bagatell CJ, Heiman JR, Matsumoto AM, Rivier JE, Bremner WJ. 1994. Metabolic and behavioral effects of high-dose, exogenous testosterone in healthy men. Journal of Clinical Endocrinology and Metabolism 79(2):561–567.

Bakhshi V, Elliott M, Gentili A, Godschalk M, Mulligan T. 2000. Testosterone improves rehabilitation outcomes in ill older men. Journal of the American Geriatrics Society 48(5):550–553.

Barrett-Connor E. 1992. Lower endogenous androgen levels and dyslipidemia in men with noninsulin-dependent diabetes mellitus. Annals of Internal Medicine 117(10):807–811.

Barrett-Connor E, Khaw KT. 1988. Endogenous sex hormones and cardiovascular disease in men. A prospective population-based study. Circulation 78(3):539–545.

Barrett-Connor E, Garland C, McPhillips JB, Khaw KT, Wingard DL. 1990. A prospective, population-based study of androstenedione, estrogens, and prostatic cancer. Cancer Research 50(1):169–173.

Barrett-Connor E, Goodman-Gruen D, Patay B. 1999a. Endogenous sex hormones and cognitive function in older men. Journal of Clinical Endocrinology and Metabolism 84(10):3681–3685.

Suggested Citation:"2 Testosterone and Health Outcomes." Institute of Medicine. 2004. Testosterone and Aging: Clinical Research Directions. Washington, DC: The National Academies Press. doi: 10.17226/10852.
×

Barrett-Connor E, Von Muhlen DG, Kritz-Silverstein D. 1999b. Bioavailable testosterone and depressed mood in older men: the Rancho Bernardo Study. Journal of Clinical Endocrinology and Metabolism 84(2):573–577.

Barrett-Connor E, Mueller JE, von Muhlen DG, Laughlin GA, Schneider DL, Sartoris DJ. 2000. Low levels of estradiol are associated with vertebral fractures in older men, but not women: the Rancho Bernardo Study. Journal of Clinical Endocrinology and Metabolism 85(1):219–223.

Baumgartner RN, Waters DL, Gallagher D, Morley JE, Garry PJ. 1999. Predictors of skeletal muscle mass in elderly men and women. Mechanisms of Ageing and Development 107(2):123–136.

Bebb R, Anawalt B, Wade J. 2001. A randomized, double-blind, placebo controlled trial of testosterone undecanoate administration in aging, hypogonadal men: effects on bone density and body composition [abstract]. Proceedings of the Endocrine Society 83rd Annual Meeting.

Benkert O, Witt W, Adam W, Leitz A. 1979. Effects of testosterone undecanoate on sexual potency and the hypothalamic-pituitary-gonadal axis of impotent males. Archives of Sexual Behavior 8(6):471–479.

Bhasin S, Buckwalter JG. 2001. Testosterone supplementation in older men: a rational idea whose time has not yet come. Journal of Andrology 22(5):718–731.

Bhasin S, Bross R, Storer TW, Casaburi R. 1998a. Androgens and muscles. In: Nieschlag E, Behre HM, eds. Testosterone: Action, Deficiency, Substitution. Berlin: Springer. Pp. 210–227.

Bhasin S, Storer TW, Asbel-Sethi N, Kilbourne A, Hays R, Sinha-Hikim I, Shen R, Arver S, Beall G. 1998b. Effects of testosterone replacement with a nongenital, transdermal system, Androderm, in human immunodeficiency virus-infected men with low testosterone levels. Journal of Clinical Endocrinology and Metabolism 83(9):3155–3162.

Bhasin S, Woodhouse L, Storer TW. 2001. Proof of the effect of testosterone on skeletal muscle. Journal of Endocrinology 170(1):27–38.

Bhasin S, Singh AB, Mac RP, Carter B, Lee MI, Cunningham GR. 2003. Managing the risks of prostate disease during testosterone replacement therapy in older men: recommendations for a standardized monitoring plan. Journal of Andrology 24(3):299–311.

Blackman MR, Sorkin JD, Munzer T, Bellantoni MF, Busby-Whitehead J, Stevens TE, Jayme J, O’Connor KG, Christmas C, Tobin JD, Stewart KJ, Cottrell E, St Clair C, Pabst KM, Harman SM. 2002. Growth hormone and sex steroid administration in healthy aged women and men: a randomized controlled trial. Journal of the American Medical Association 288(18):2282–2292.

Bosland MC. 2000. The role of steroid hormones in prostate carcinogenesis. Journal of the National Cancer Institute Monographs 27:39–66.

Brodsky IG, Balagopal P, Nair KS. 1996. Effects of testosterone replacement on muscle mass and muscle protein synthesis in hypogonadal men—a clinical research center study. Journal of Clinical Endocrinology and Metabolism 81(10):3469–3475.

Buena F, Swerdloff RS, Steiner BS, Lutchmansingh P, Peterson MA, Pandian MR, Galmarini M, Bhasin S. 1993. Sexual function does not change when serum testosterone levels are pharmacologically varied within the normal male range. Fertility & Sterility 59(5):1118–1123.

Buvat J, Lemaire A. 1997. Endocrine screening in 1,022 men with erectile dysfunction: clinical significance and cost-effective strategy. Journal of Urology 158(5):1764–1767.


Carter HB, Pearson JD, Metter EJ, Chan DW, Andres R, Fozard JL, Rosner W, Walsh PC. 1995. Longitudinal evaluation of serum androgen levels in men with and without prostate cancer. Prostate 27(1): 25–31.

Suggested Citation:"2 Testosterone and Health Outcomes." Institute of Medicine. 2004. Testosterone and Aging: Clinical Research Directions. Washington, DC: The National Academies Press. doi: 10.17226/10852.
×

Cauley JA, Gutai JP, Kuller LH, Dai WS. 1987. Usefulness of sex steroid hormone levels in predicting coronary artery disease in men. American Journal of Cardiology 60(10):771–777.

Center JR, Nguyen TV, Sambrook PN, Eisman JA. 1999. Hormonal and biochemical parameters in the determination of osteoporosis in elderly men. Journal of Clinical Endocrinology and Metabolism 84(10):3626–3635.

Cherrier MM, Asthana S, Plymate S, Baker L, Matsumoto AM, Peskind E, Raskind MA, Brodkin K, Bremner W, Petrova A, LaTendresse S, Craft S. 2001. Testosterone supplementation improves spatial and verbal memory in healthy older men. Neurology 57(1):80–88.

Christiansen K. 1998. Behavioral correlates of testosterone. In: Nieschlag E, Behre HM, eds. Testosterone: Action, Deficiency, Substitution. Berlin: Springer. Pp. 107–131.

Christmas C, O’Connor KG, Harman SM, Tobin JD, Munzer T, Bellantoni MF, St Clair C, Pabst KM, Sorkin JD, Blackman MR. 2002. Growth hormone and sex steroid effects on bone metabolism and bone mineral density in healthy aged women and men. Journals of Gerontology. Series A, Biological Sciences & Medical Sciences 57(1):M12–M18.

Clague JE, Wu FC, Horan MA. 1999. Difficulties in measuring the effect of testosterone replacement therapy on muscle function in older men. International Journal of Andrology 22(4):261–265.

Contoreggi CS, Blackman MR, Andres R, Muller DC, Lakatta EG, Fleg JL, Harman SM. 1990. Plasma levels of estradiol, testosterone, and DHEAS do not predict risk of coronary artery disease in men. Journal of Andrology 11(5):460–470.

Couillard C, Gagnon J, Bergeron J, Leon AS, Rao DC, Skinner JS, Wilmore JH, Despres JP, Bouchard C. 2000. Contribution of body fatness and adipose tissue distribution to the age variation in plasma steroid hormone concentrations in men: The HERITAGE Family Study. Journal of Clinical Endocrinology and Metabolism 85(3):1026–1031.

Cunningham GR. 1996. Overview of androgens on the normal and abnormal prostate. In: Bhasin S, Gabelnick HL, Spieler JM, Swerdloff RS, Wang C, Kelly C, eds. Pharmacology, Biology, and Clinical Applications of Androgens: Current Status and Future Prospects. New York: Wiley-Liss. Pp. 187–207.

Cutter CB. 2001. Compounded percutaneous testosterone gel: use and effects in hypogonadal men. Journal of the American Board of Family Practice 14(1):22–32.


Dai WS, Kuller LH, LaPorte RE, Gutai JP, Falvo-Gerard L, Caggiula A. 1981. The epidemiology of plasma testosterone levels in middle-aged men. American Journal of Epidemiology 114(6):804–816.

Daniell HW. 1998. A worse prognosis for men with testicular atrophy at therapeutic orchiectomy for prostate carcinoma. Cancer 83(6):11701173.

Davidson JM, Camargo CA, Smith ER. 1979. Effects of androgen on sexual behavior in hypogonadal men. Journal of Clinical Endocrinology and Metabolism 48(6):955–958.

Davidson JM, Chen JJ, Crapo L, Gray GD, Greenleaf WJ, Catania JA. 1983. Hormonal changes and sexual function in aging men. Journal of Clinical Endocrinology and Metabolism 57(1):71–77.

Dawson NA. 2003. Therapeutic benefit of bisphosphonates in the management of prostate cancer-related bone disease. Expert Opinions on Pharmacotherapy 4(5):705–716.

Debes JD, Tindall DJ. 2002. The role of androgens and the androgen receptor in prostate cancer. Cancer Letters 187(1–2):1–7.

Denmeade SR, Lin XS, Isaacs JT. 1996. Role of programmed (apoptic) cell death during the progression and therapy for prostate cancer. Prostate 28(4):251265.

Drinka PJ, Jochen AL, Cuisinier M, Bloom R, Rudman I, Rudman D. 1995. Polycythemia as a complication of testosterone replacement therapy in nursing home men with low testosterone levels. Journal of the American Geriatrics Society 43(8):899–901.

Suggested Citation:"2 Testosterone and Health Outcomes." Institute of Medicine. 2004. Testosterone and Aging: Clinical Research Directions. Washington, DC: The National Academies Press. doi: 10.17226/10852.
×

Eaton NE, Reeves GK, Appleby PN, Key TJ. 1999. Endogenous sex hormones and prostate cancer: a quantitative review of prospective studies. British Journal of Cancer 80(7):930–934.

English KM, Steeds RP, Jones TH, Diver MJ, Channer KS. 2000. Low-dose transdermal testosterone therapy improves angina threshold in men with chronic stable angina: a randomized, double-blind, placebo-controlled study. Circulation 102(16):1906–1911.

Etzioni R, Penson DF, Legler JM, di Tommaso D, Boer R, Gann PH, Feuer EJ. 2002. Overdiagnosis due to prostate-specific antigen screening: lessons from U.S. prostate cancer incidence trends. Journal of the National Cancer Institute 94(13):981–990.

Exton MS, Kruger TH, Bursch N, Haake P, Knapp W, Schedlowski M, Hartmann U. 2001. Endocrine response to masturbation-induced orgasm in healthy men following a 3-week sexual abstinence. World Journal of Urology 19(5):377–382.


Fahmy AK, Mitra S, Blacklock AR, Desai KM. 1999. Is the measurement of serum testosterone routinely indicated in men with erectile dysfunction? BJU International 84(4):482–484.

Federal Interagency Forum on Aging-Related Statistics. 2002. Federal Interagency Forum on Aging-Related Statistics (Forum). [Online]. Available: http://www.agingstats.gov/ [accessed May 2003].

Feldman HA, Goldstein I, Hatzichristou DG, Krane RJ, McKinlay JB. 1994. Impotence and its medical and psychosocial correlates: results of the Massachusetts Male Aging Study. Journal of Urology 151(1):54–61.

Feldman HA, Longcope C, Derby CA, Johannes CB, Araujo AB, Coviello AD, Bremner WJ, McKinlay JB. 2002. Age trends in the level of serum testosterone and other hormones in middle-aged men: Longitudinal results from the Massachusetts Male Aging Study. Journal of Clinical Endocrinology and Metabolism 87(2):589–598.

Ferenchick GS. 1996. Androgens and hemopoesis: coagulation and the vascular system. In: Bhasin S, Gabelnick HL, Spieler JM, Swerdloff RS, Wang C, Kelly C, eds. Pharmacology, Biology, and Clinical Applications of Androgens: Current Status and Future Prospects. New York: Wiley-Liss. Pp. 201–213.

Ferrando AA, Sheffield-Moore M, Yeckel CW, Gilkison C, Jiang J, Achacosa A, Lieberman SA, Tipton K, Wolfe RR, Urban RJ. 2002. Testosterone administration to older men improves muscle function: molecular and physiological mechanisms. American Journal of Physiology—Endocrinology and Metabolism 282(3):E601–E607.

Ferrando AA, Sheffield-Moore M, Paddon-Jones D, Wolfe RR, Urban RJ. 2003. Differential anabolic effects of testosterone and amino acid feeding in older men. Journal of Clinical Endocrinology and Metabolism 88(1): 358–362.

Ferrini RL, Barrett-Connor E. 1998. Sex hormones and age: a cross-sectional study of testosterone and estradiol and their bioavailable fractions in community-dwelling men. American Journal of Epidemiology 147(8):750–754.

Field AE, Colditz GA, Willett WC, Longcope C, McKinlay JB. 1994. The relation of smoking, age, relative weight, and dietary intake to serum adrenal steroids, sex hormones, and sex hormone-binding globulin in middle-aged men. Journal of Clinical Endocrinology and Metabolism 79(5):1310–1316.

Finkelstein JS. 1998. Androgens and bone metabolism. In: Nieschlag E, Behre HM, eds. Testosterone: Action, Deficiency, Substitution. Berlin: Springer. Pp. 187–207.

Fried LP, Walston J. 2003. Frailty and failure to thrive. In: Hazzard WR, Blass JP, Ettinger WH Jr, Halter JB, Ouslander J, eds. Principles of Geriatric Medicine and Gerontology. New York: McGraw-Hill. Pp. 1487–1502.

Suggested Citation:"2 Testosterone and Health Outcomes." Institute of Medicine. 2004. Testosterone and Aging: Clinical Research Directions. Washington, DC: The National Academies Press. doi: 10.17226/10852.
×

Fried LP, Tangen CM, Walston J, Newman AB, Hirsch C, Gottdiener J, Seeman T, Tracy R, Kop WJ, Burke G, McBurnie MA. 2001. Frailty in older adults: evidence for a phenotype. Journals of Gerontology. Series A, Biological Sciences & Medical Sciences 56(3):M146– M156.

Frontera WR, Hughes VA, Fielding RA, Fiatarone MA, Evans WJ, Roubenoff R. 2000. Aging of skeletal muscle: a 12-year longitudinal study. Journal of Applied Physiology 88(4):1321–1326.

Frye CA, Seliga AM. 2001. Testosterone increases analgesia, anxiolysis, and cognitive performance of male rats. Cognitive, Affective and Behavioral Neuroscience 1(4):371–381.


Gann PH, Hennekens CH, Ma J, Longcope C, Stampfer MJ. 1996. Prospective study of sex hormone levels and risk of prostate cancer. Journal of the National Cancer Institute 88(16):1118–1126.

Gray A, Feldman HA, McKinlay JB, Longcope C. 1991a. Age, disease, and changing sex hormone levels in middle-aged men: results of the Massachusetts Male Aging Study. Journal of Clinical Endocrinology and Metabolism 73(5):1016–1025.

Gray A, Jackson DN, McKinlay JB. 1991b. The relation between dominance, anger, and hormones in normally aging men: results from the Massachusetts Male Aging Study. Psychosomatic Medicine 53(4):375–385.

Greendale GA, Edelstein S, Barrett-Connor E. 1997. Endogenous sex steroids and bone mineral density in older women and men: the Rancho Bernardo Study. Journal of Bone and Mineral Research 12(11):1833–1843.

Griggs RC, Kingston W, Jozefowicz RF, Herr BE, Forbes G, Halliday D. 1989. Effect of testosterone on muscle mass and muscle protein synthesis. Journal of Applied Physiology 66(1):498–503.


Hakkinen K, Pakarinen A. 1993. Muscle strength and serum testosterone, cortisol, and SHBG concentrations in middle-aged and elderly men and women. Acta Physiologica Scandinavica 148(2):199–207.

Han G, Foster BA, Mistry S, Buchanan G, Harris JM, Tilley WD, Greenberg NM. 2001. Hormone status selects for spontaneous somatic androgen receptor variants that demonstrate specific ligand and cofactor dependent activities in autochthonous prostate cancer. Journal of Biological Chemistry 276(14):1120411213.

Harkonen K, Huhtaniemi I, Makinen J, Hubler D, Irjala K, Koskenvuo M, Oettel M, Raitakari O, Saad F, Pollanen P. 2003. The polymorphic androgen receptor gene CAG repeat, pituitary-testicular function, and andropausal symptoms in ageing men. International Journal of Andrology 26(3):187–194.

Harman SM, Metter EJ, Tobin JD, Pearson J, Blackman MR. 2001. Longitudinal effects of aging on serum total and free testosterone levels in healthy men. Baltimore Longitudinal Study of Aging. Journal of Clinical Endocrinology and Metabolism 86(2):724–731.

Heikkila R, Aho K, Heliovaara M, Hakama M, Marniemi J, Reunanen A, Knekt P. 1999. Serum testosterone and sex hormone-binding globulin concentrations and the risk of prostate carcinoma: a longitudinal study. Cancer 86(2):312–315.

Hobbs FB, Damon BL. 1999. 65+ in the United States. Bethesda, MD: National Institutes of Health.

Hoffman MA, DeWolf WC, Morgentaler A. 2000. Is low serum-free testosterone a marker for high grade prostate cancer? Journal of Urology 163(3):824827.

Holmäng S, Mårin P, Lindstedt G, Hedelin H. 1993. Effect of long-term oral testosterone undecanoate treatment on prostate volume and serum prostate-specific antigen concentration in eugonadal middle-aged men. Prostate 23(2):99–106.

Holund B. 1980. Latent prostatic cancer in a consecutive autopsy series. Scandinavian Journal of Urology and Nephrology 14(1):29–35.

Suggested Citation:"2 Testosterone and Health Outcomes." Institute of Medicine. 2004. Testosterone and Aging: Clinical Research Directions. Washington, DC: The National Academies Press. doi: 10.17226/10852.
×

Hsing AW, Comstock GW. 1993. Serological precursors of cancer: serum hormones and risk of subsequent prostate cancer. Cancer Epidemiology, Biomarkers and Prevention 2(1):27–32.


IOM (Institute of Medicine). 2001. Exploring the Biological Contributions to Human Health: Does Sex Matter? Washington, DC: National Academies Press.

Isaacs JT. 1996. Role of androgens in normal and malignant growth of the prostate. In: Bhasin S, Gabelnick HL, Spieler JM, Swerdloff RS, Wang C, Kelly C., eds. Pharmacology, Biology, and Clinical Applications of Androgens: Current Status and Future Prospects. New York: Wiley-Liss. Pp. 95–101.


Jaffe MD. 1977. Effect of testosterone cypionate on postexercise ST segment depression. British Heart Journal 39(11):1217–1222.

JAMA (Journal of the American Medical Association). 2001. Système International (SI) Conversion Factors for Selected Laboratory Components. [Online]. Available: http://jama.amaassn.org/content/vol290/issue1/images/data/125/DC6/auinst_si.dtl [accessed July 2003].

Jannini EA, Screponi E, Carosa E, Pepe M, Lo Guiddice F, Trimarchi F, Benavenga S. 1999. Lack of sexual activity from erectile dysfunction is associated with a reversible reduction in serum testosterone. International Journal of Andrology 22(6):385–392.

Janowsky JS, Oviatt SK, Orwoll ES. 1994. Testosterone influences spatial cognition in older men. Behavioral Neuroscience 108(2):325–332.

Janowsky JS, Chavez B, Orwoll E. 2000. Sex steroids modify working memory. Journal of Cognitive Neuroscience 12(3):407–414.


Kaufman JM, Vermeulen A. 1997. Declining gonadal function in elderly men. Bailliere’s Clinical Endocrinology and Metabolism 11(2):289–309.

Kaufman JM, Vermeulen A. 1998. Androgens in male senescence. In: Nieschlag E, Behre HM, eds. Testosterone: Action, Deficiency, Substitution. Berlin: Springer. Pp. 437–471.

Kenny AM, Prestwood KM, Gruman CA, Marcello KM, Raisz LG. 2001. Effects of transdermal testosterone on bone and muscle in older men with low bioavailable testosterone levels. Journals of Gerontology. Series A, Biological Sciences & Medical Sciences 56(5):M266–M272.

Kenny AM, Bellantonio S, Gruman CA, Acosta RD, Prestwood KM. 2002a. Effects of transdermal testosterone on cognitive function and health perception in older men with low bioavailable testosterone levels. Journals of Gerontology. Series A, Biological Sciences & Medical Sciences 57(5):M321–M325.

Kenny AM, Prestwood KM, Gruman CA, Fabregas G, Biskup B, Mansoor G. 2002b. Effects of transdermal testosterone on lipids and vascular reactivity in older men with low bioavailable testosterone levels. Journals of Gerontology. Series A, Biological Sciences & Medical Sciences 57(7):M460–M465.

Khaw K, Barrett-Connor E. 1988. Blood pressure and exogenous testosterone in men: an inverse relationship. Journal of Hypertension 6:329–332.

Khosla S, Melton LJ 3rd, Atkinson EJ, O’Fallon WM, Klee GG, Riggs BL. 1998. Relationship of serum sex steroid levels and bone turnover markers with bone mineral density in men and women: a key role for bioavailable estrogen. Journal of Clinical Endocrinology and Metabolism 83(7):2266–2274.

Khosla S, Melton LJ 3rd, Atkinson EJ, O’Fallon WM. 2001. Relationship of serum sex steroid levels to longitudinal changes in bone density in young versus elderly men. Journal of Clinical Endocrinology and Metabolism 86(8):3555–3561.

Khosla S, Melton LJ 3rd, Riggs BL. 2002. Clinical review 144: estrogen and the male skeleton. Journal of Clinical Endocrinology and Metabolism 87(4):1443–1450.

Suggested Citation:"2 Testosterone and Health Outcomes." Institute of Medicine. 2004. Testosterone and Aging: Clinical Research Directions. Washington, DC: The National Academies Press. doi: 10.17226/10852.
×

Kokontis JM, Hay N, Liao S. 1998. Progression of LNCaP prostate tumor cells during androgen deprivation: hormone-independent growth, repression of proliferation by androgen, and role for p27Kip1 in androgen-induced cell cycle arrest. Molecular Endocrinology 12(7):941953.

Kouri EM, Pope HG Jr, Oliva PS. 1996. Changes in lipoprotein-lipid levels in normal men following administration of increasing doses of testosterone cypionate. Clinical Journal of Sport Medicine 6(3):152–157.


Laumann EO, Paik A, Rosen RC. 1999. Sexual dysfunction in the United States: prevalence and predictors. Journal of the American Medical Association 281(6):537–544.

Leav I, Merk FB, Kwan PW, Ho SM. 1989. Androgen-supported estrogen-enhanced epithelial proliferation in the prostates of intact Noble rats. Prostate 15(1):2340.

Levere RD, Gidari AS. 1974. Steroid metabolites and the control of hemoglobin synthesis. Bulletin of the New York Academy of Medicine 50(5):563–575.

Luboshitzky R, Aviv A, Hefetz A, Herer P, Shen-Orr Z, Lavie L, Lavie P. 2002. Decreased pituitary-gonadal secretion in men with obstructive sleep apnea. Journal of Clinical Endocrinology and Metabolism 87(7):3394–3398.


Maas D, Jochen A, Lalande B. 1997. Age-related changes in male gonadal function: implications for therapy. Drugs and Aging 11(1):45–60.

Mårin P. 2002. Testosterone, aging, and body composition. In: Lunenfeld B, Gooren L, eds. Textbook of Men’s Health. Boca Raton, FL: Parthenon Publishing. Pp. 227–240.

Mårin P, Holmäng S, Jonsson L, Sjostrom L, Kvist H, Holm G, Lindstedt G, Bjorntorp P. 1992. The effects of testosterone treatment on body composition and metabolism in middle-aged obese men. International Journal of Obesity & Related Metabolic Disorders 16(12):991–997.

Mårin P, Holmäng S, Gustafsson C, Jönsson L, Kvist H, Elander A, Eldh J, Sjöström L, Holm G, Björntorp P. 1993. Androgen treatment of abdominally obese men. Obesity Research 1(4):245–251.

Mårin P, Oden B, Bjorntorp P. 1995. Assimilation and mobilization of triglycerides in subcutaneous abdominal and femoral adipose tissue in vivo in men: effects of androgens. Journal of Clinical Endocrinology and Metabolism 80(1):239–243.

Massengill JC, Sun L, Moul JW, Wu H, McLeaod DG, Amling C, Lance R, Foley J, Sexton W, Kusuda L, Chung A, Soderhal D, Donahue T. 2003. Pretreatment total testosterone level predicts pathological stage in patients with localized prostate cancer treated with radical prostatectomy. Journal of Urology 169(5):16701675.

Matsumoto AM. 2002. Andropause: clinical implications of the decline in serum testosterone levels with aging in men. Journals of Gerontology. Series A, Biological Sciences & Medical Sciences 57(2):M76–M99.

Meigs JB, Mohr B, Barry MJ, Collins MM, McKinlay JB. 2001. Risk factors for clinical benign prostatic hyperplasia in a community-based population of healthy aging men. Journal of Clinical Epidemiology 54(9):935–944.

Meriggiola MC, Marcovina S, Paulsen CA, Bremner WJ. 1995. Testosterone enanthate at a dose of 200 mg/week decreases HDL-cholesterol levels in healthy men. International Journal of Andrology. 18(5):237–242.

Mohr BA, Feldman HA, Kalish LA, Longcope C, McKinlay JB. 2001. Are serum hormones associated with the risk of prostate cancer? Prospective results from the Massachusetts Male Aging Study. Urology 57(5): 930–935.

Münzer T, Harman SM, Hees P, Shapiro E, Christmas C, Bellantoni MF, Stevens TE, O’Connor KG, Pabst KM, St. Clair C, Sorkin JD, Blackman MR. 2001. Effects of GH and/or sex steroid administration on abdominal subcutaneous and visceral fat in healthy aged women and men. Journal of Clinical Endocrinology and Metabolism 86(8):3604–3610.

Suggested Citation:"2 Testosterone and Health Outcomes." Institute of Medicine. 2004. Testosterone and Aging: Clinical Research Directions. Washington, DC: The National Academies Press. doi: 10.17226/10852.
×

Nankin HR, Lin T, Osterman J. 1986. Chronic testosterone cypionate therapy in men with secondary impotence. Fertility & Sterility 46(2):300–307.

NCHS (National Center for Health Statistics). 1999. Health, United States, 1999 with Health and Aging Chartbook. [Online]. Available: http://www.cdc.gov/nchs/data/hus/hus99.pdf [accessed July 2003].

NCHS. 2003. Health, United States, 2002 with Chartbook on Trends in the Health of Americans. [Online]. Available: www.cdc.gov/nchs [accessed May 2003].

NCI (National Cancer Institute). 2003. Prevention of Prostate Cancer. [Online]. Available: http://www.nci.nih.gov/cancerinfo/pdq/prevention/prostate/health-professional/ [accessed April 2003].

Nelson WG, De Marzo AM, Isaacs WB. 2003. Prostate cancer: mechanisms of disease. New England Journal of Medicine 349:366–381.

NHLBI (National Heart, Lung, and Blood Institute). 2003. Sleep Apnea. [Online]. Available: http://www.nhlbi.nih.gov/health/public/sleep/sleepapn.pdf [accessed May 2003].

NIAMS (National Institute of Arthritis and Musculoskeletal and Skin Diseases). 2003. Osteoporosis: Progress and Promise. [Online]. Available: http://www.niams.nih.gov/hi/topics/osteoporosis/opbkgr.htm [accessed July 2003].

NIDDK (National Institute of Diabetes and Digestive and Kidney Diseases). 2003a. Erectile Dysfunction. [Online]. Available: http://www.niddk.nih.gov/health/orolog/pubs/impotnce/impotnce.htm [accessed April 2003].

NIDDK 2003b. Prostate Enlargement: Benign Prostatic Hyperplasia. [Online]. Available: http://www.niddk.nih.gov/health/urolog/pubs/prostate/#symptoms [accessed April 2003].

NIH (National Institutes of Health) Osteoporosis and Related Bone Diseases National Resource Center. 2003. Fast Facts on Osteoporosis. [Online]. Available: http://www.osteo.org [accessed May 2003].

NIMH (National Institute of Mental Health) 2003a. Men and Depression [Online] Available: http://menanddepression.nimh.nih.gov/infopage.asp?id=10#men [accessed July 2003].

NIMH (National Institute of Mental Health) 2003b. Older Adults: Depression and Suicide Facts. [Online]. Available: http://www.nimh.nih.gov/publicat/elderlydepsuicide.pdf [accessed July 2003].

NINDS (National Institute of Neurological Disorders and Stroke). 2001. NINDS Sleep Apnea Information Page. [Online]. Available: http://www.ninds.nih.gov/health_and_medical/disorders/sleep_apnea.htm [accessed May 2003].

Noble RL. 1977. The development of prostatic adenocarcinoma in Nb rats following prolonged sex hormone administration. Cancer Research 37(6):19291933.

Nomura A, Heilbrun LK, Stemmermann GN, Judd HL. 1988. Prediagnostic serum hormones and the risk of prostate cancer. Cancer Research 48(12):3515–3517.


Oh JY, Barrett-Connor E, Wedick NM, Wingard DL. 2002. Endogenous sex hormones and the development of type 2 diabetes in older men and women: The Rancho Bernardo study. Diabetes Care 25(1):55–60.

Ong PJ, Patrizi G, Chong WC, Webb CM, Hayward CS, Collins P. 2000. Testosterone enhances flow-mediated brachial artery reactivity in men with coronary artery disease. American Journal of Cardiology 85(2):269–272.


Patrick DL, Erickson P. 1993. Health Status and Health Policy: Quality of Life in Health Care Evaluation and Resource Allocation. New York: Oxford University Press.

Pope HG Jr, Cohane GH, Kanayama G, Siegel AJ, Hudson JI. 2003. Testosterone gel supplementation for men with refractory depression: a randomized, placebo-controlled trial. American Journal of Psychiatry 160(1):105–111.

Suggested Citation:"2 Testosterone and Health Outcomes." Institute of Medicine. 2004. Testosterone and Aging: Clinical Research Directions. Washington, DC: The National Academies Press. doi: 10.17226/10852.
×

Prehn RT. 1999. On the prevention and therapy of prostate cancer by androgen administration. Cancer Research 59(17):4161–4164.


Rabkin JG, Wagner GJ, Rabkin R. 1999. Testosterone therapy for human immunodeficiency virus-positive men with and without hypogonadism. Journal of Clinical Psychopharmacology 19(1):19–27.

Rabkin JG, Wagner GJ, Rabkin R. 2000. A double-blind, placebo-controlled trial of testosterone therapy for HIV-positive men with hypogonadal symptoms. Archives of General Psychiatry 57(2):141–147.

Reddy P, White CM, Dunn AB, Moyna NM, Thompson PD. 2000. The effect of testosterone on health-related quality of life in elderly males—a pilot study. Journal of Clinical Pharmacy & Therapeutics 25(6):421–426.

Reiter RE, deKernion JB. 2002. Epidemiology, etiology, and prevention of prostate cancer. In: Walsh PC, Retick, AB, Vaughan ED, Wein AJ, eds. Campbell’s Urology. Philadelphia: W. B. Saunders. Pp. 3003–3024.

Rosano GM, Leonardo F, Pagnotta P, Pelliccia F, Panina G, Cerquetani E, della Monica PL, Bonfigli B, Volpe M, Chierchia SL. 1999. Acute anti-ischemic effect of testosterone in men with coronary artery disease. Circulation 99(13):1666–1670.

Roubenoff R, Hughes VA. 2000. Sarcopenia: current concepts. Journals of Gerontology. Series A, Biological Sciences & Medical Sciences 55(12):M716–M724.

Roubenoff R, Grinspoon S, Skolnik PR, Tchetgen E, Abad L, Spiegelman D, Knox T, Gorbach S. 2002. Role of cytokines and testosterone in regulating lean body mass and resting energy expenditure in HIV-infected men. American Journal of Physiology—Endocrinology and Metabolism 283(1):E138–E145.

Rowland DL, Heiman JR, Gladue BA, Hatch JP, Doering CH, Weiler SJ. 1987. Endocrine, psychological, and genital response to sexual arousal in men. Psychoneuroendocrinology 12(2):149–158.

Rowland DL, Greenleaf WJ, Dorfman J, Davidson JM. 1993. Aging and sexual function in men. Archives of Sexual Behavior 22(6):545–557.


Sakr WA, Haas GP, Cassin BF, Pontes JE, Crissman JD. 1993. The frequency of carcinoma and intraepithelial neoplasia of the prostate in young male patients. Journal of Urology 150(2 Pt 1):379–385.

Sato N, Gleave ME, Bruchovsky N, Rennie PS, Goldenberg, SL. Lange PH, Sullivan LD. 1996. Intermittent androgen suppression delays progression to androgen-independent regulation of prostate-specific antigen gene in the LNCaP prostate tumour model. Journal of Steroid Biochemistry and Molecular Biology 58:139–146.

Scardino PT. 2003. The prevention of prostate cancer—the dilemma continues. New England Journal of Medicine 349(3):297299.

Schatzl G, Madersbacher S, Thurridl T, Waldmuller J, Kramer G, Haitel A, Marberger M. 2001. High-grade prostate cancer is associated with low serum testosterone levels. Prostate 47(1):5258.

Schiavi RC, White D, Mandeli J, Schreiner-Engel P. 1993. Hormones and nocturnal penile tumescence in healthy aging men. Archives of Sexual Behavior 22(3):207–215.

Schiavi RC, White D, Mandeli J, Levine AC. 1997. Effect of testosterone administration on sexual behavior and mood in men with erectile dysfunction. Archives of Sexual Behavior 26(3):231–241.

Seidman SN, Araujo AB, Roose SP, McKinlay JB. 2001a. Testosterone level, androgen receptor polymorphism, and depressive symptoms in middle-aged men. Biological Psychiatry 50(5):371–376.

Seidman SN, Spatz E, Rizzo C, Roose SP. 2001b. Testosterone replacement therapy for hypogonadal men with major depressive disorder: a randomized, placebo-controlled clinical trial. Journal of Clinical Psychiatry 62(6):406–412.

Suggested Citation:"2 Testosterone and Health Outcomes." Institute of Medicine. 2004. Testosterone and Aging: Clinical Research Directions. Washington, DC: The National Academies Press. doi: 10.17226/10852.
×

Shaneyfelt T, Husein R, Bubley G, Mantzoros CS. 2000. Hormonal predictors of prostate cancer: a meta-analysis. Journal of Clinical Oncology 18(4):847–853.

Sih R, Morley JE, Kaiser FE, Perry HM 3rd, Patrick P, Ross C. 1997. Testosterone replacement in older hypogonadal men: a 12-month randomized controlled trial. Journal of Clinical Endocrinology and Metabolism 82(6):1661–1667.

Simon D, Charles MA, Lahlou N, Nahoul K, Oppert JM, Gouault-Heilmann M, Lemort N, Thibult N, Joubert E, Balkau B, Eschwege E. 2001. Androgen therapy improves insulin sensitivity and decreases leptin level in healthy adult men with low plasma total testosterone: a 3-month randomized placebo-controlled trial. Diabetes Care 24(12):2149–2151.

Skakkebaek NE, Bancroft J, Davidson DW, Warner P. 1981. Androgen replacement with oral testosterone undecanoate in hypogonadal men: a double blind controlled study. Clinical Endocrinology 14(1):49–61.

Smith MR. 2003. Diagnosis and management of treatment-related osteoporosis in men with prostate carcinoma. Cancer 97(3 Suppl):789–795.

Snyder PJ, Peachey H, Hannoush P, Berlin JA, Loh L, Holmes JH, Dlewati A, Staley J, Santanna J, Kapoor SC, Attie MF, Haddad JG Jr, Strom BL. 1999a. Effect of testosterone treatment on bone mineral density in men over 65 years of age. Journal of Clinical Endocrinology and Metabolism 84(6):1966–1972.

Snyder PJ, Peachey H, Hannoush P, Berlin JA, Loh L, Lenrow DA, Holmes JH, Dlewati A, Santanna J, Rosen CJ, Strom BL. 1999b. Effect of testosterone treatment on body composition and muscle strength in men over 65 years of age. Journal of Clinical Endocrinology and Metabolism 84(8):2647–2653.

Snyder PJ, Peachey H, Berlin JA, Hannoush P, Haddad G, Dlewati A, Santanna J, Loh L, Lenrow DA, Holmes JH, Kapoor SC, Atkinson LE, Strom BL. 2000. Effects of testosterone replacement in hypogonadal men. Journal of Clinical Endocrinology and Metabolism 85(8):2670–2677.

Snyder PJ, Peachey H, Berlin JA, Rader D, Usher D, Loh L, Hannoush P, Dlewati A, Holmes JH, Santanna J, Strom BL. 2001. Effect of transdermal testosterone treatment on serum lipid and apolipoprotein levels in men more than 65 years of age. American Journal of Medicine 111(4):255–260.

Stanbrough M, Leav I, Kwan PW, Bubley GJ, Balk SP. 2001. Prostatic intraepithelial neoplasia in mice expressing an androgen receptor transgene inprostate epithelium. Proceedings of the National Academy of Sciences (USA) 98(19):10823–10828.

Stanley HL, Schmitt BP, Poses RM, Deiss WP. 1991. Does hypogonadism contribute to the occurrence of a minimal trauma hip fracture in elderly men? Journal of the American Geriatrics Society 39(8):766–771.

Stellato RK, Feldman HA, Hamdy O, Horton ES, McKinlay JB. 2000. Testosterone, sex hormone-binding globulin, and the development of type 2 diabetes in middle-aged men: prospective results from the Massachusetts Male Aging Study. Diabetes Care 23(4):490–494.


Tenover JS. 1992. Effects of testosterone supplementation in the aging male. Journal of Clinical Endocrinology and Metabolism 75(4):1092–1098.

Tenover JS. 1994. Androgen administration to aging men. Endocrinology and Metabolism Clinics of North America 23(4):877–892.

Thompson IM, Goodman PJ, Tangen CM, Lucia MS, Miller GJ, Ford LG, Lieber MM, Cespedes RD, Atkins JN, Lippman SM, Carlin SM, Ryan A, Szczepanek CM, Crowley JJ, Coltman CA Jr. 2003. The influence of finasteride on the development of prostate cancer. New England Journal of Medicine 349(3):215–224.

Suggested Citation:"2 Testosterone and Health Outcomes." Institute of Medicine. 2004. Testosterone and Aging: Clinical Research Directions. Washington, DC: The National Academies Press. doi: 10.17226/10852.
×

Thompson PD, Ahlberg AW, Moyna NM, Duncan B, Ferraro-Borgida M, White CM, McGill CC, Heller GV. 2002. Effect of intravenous testosterone on myocardial ischemia in men with coronary artery disease. American Heart Journal 143(2):249–256.


Urban RJ, Bodenburg YH, Gilkison C, Foxworth J, Coggan AR, Wolfe RR, Ferrando A. 1995. Testosterone administration to elderly men increases skeletal muscle strength and protein synthesis. American Journal of Physiology 269(5 Pt 1):E820–E826.

Uyanik BS, Ari Z, Gumus B, Yigitoglu MR, Arslan T. 1997. Beneficial effects of testosterone undecanoate on the lipoprotein profiles in healthy elderly men: a placebo controlled study. Japanese Heart Journal 38(1):73–82.


van den Beld AW, Bots ML, Janssen JA, Pols HA, Lamberts SW, Grobbee DE. 2003. Endogenous hormones and carotid atherosclerosis in elderly men. American Journal of Epidemiology 157(1):25–31.

Vatten LJ, Ursin G, Ross RK, Stanczyk FZ, Lobo RA, Harvei S, Jellum E. 1997. Androgens in serum and the risk of prostate cancer: a nested case-control study from the Janus serum bank in Norway. Cancer Epidemiology, Biomarkers, and Prevention 6(11):967–969.

Vermeulen A. 2001. Androgen replacement therapy in the aging male—a critical evaluation. Journal of Clinical Endocrinology and Metabolism 86(6):2380–2390.


Wagner EH, LaCroix AZ, Buchner DM, Larson EB. 1992. Effects of physical activity on health status in older adults. I: Observational studies. Annual Review of Public Health 13:451–468.

Walston J, McBurnie MA, Newman A, Tracy RP, Kop WJ, Hirsch CH, Gottdiener J, Fried LP; Cardiovascular Health Study. 2002. Frailty and activation of the inflammation and coagulation systems with and without clinical comorbidities: results from the Cardiovascular Health Study. Archives of Internal Medicine 162(20):2333–2341.

Wang C, Alexander G, Berman N, Salehian B, Davidson T, McDonald V, Steiner B, Hull L, Callegari C, Swerdloff RS. 1996. Testosterone replacement therapy improves mood in hypogonadal men: a clinical research center study. Journal of Clinical Endocrinology and Metabolism 81(10):3578–3583.

Webb CM, Adamson DL, de Zeigler D, Collins P. 1999a. Effect of acute testosterone on myocardial ischemia in men with coronary artery disease. American Journal of Cardiology 83(3):437–439.

Webb CM, McNeill JG, Hayward CS, de Zeigler D, Collins P. 1999b. Effects of testosterone on coronary vasomotor regulation in men with coronary heart disease. Circulation 100(16):1690–1696.

Wergdal JE, Baylink DJ. 1996. Mechanism of action of androgens on bone cells. In: Bhasin S, Gabelnick HL, Spieler JM, Swerdloff RS, Wang C, Kelly C, eds. Pharmacology, Biology, and Clinical Applications of Androgens: Current Status and Future Prospects. New York:Wiley-Liss. Pp. 259–264.

White CM, Ferraro-Borgida MJ, Moyna NM, McGill CC, Ahlberg AW, Thompson PD, Heller GV. 1999. The effect of pharmacokinetically guided acute intravenous testosterone administration on electrocardiographic and blood pressure variables. Journal of Clinical Pharmacology 39(10):1038–1043.

Wolf OT, Preut R, Hellhammer DH, Kudielka BM, Schurmeyer TH, Kirschbaum C. 2000. Testosterone and cognition in elderly men: a single testosterone injection blocks the practice effect in verbal fluency, but has no effect on spatial or verbal memory. Biological Psychiatry 47(7):650–654.


Yarnell JW, Beswick AD, Sweetnam PM, Riad-Fahmy D. 1993. Endogenous sex hormones and ischemic heart disease in men. The Caerphilly prospective study. Arteriosclerosis and Thrombosis 13(4):517–520.

Suggested Citation:"2 Testosterone and Health Outcomes." Institute of Medicine. 2004. Testosterone and Aging: Clinical Research Directions. Washington, DC: The National Academies Press. doi: 10.17226/10852.
×

Yuan S, Trachtenberg J, Mills GB, Brown TJ, Xu F, Keating A. 1993. Androgen-induced inhibition of cell proliferation in an androgen-insensitive prostate cancer cell line (PC-3) transfected with a human androgen receptor complementary DNA. Cancer Research 53(6):1304–1311.


Zmuda JM, Cauley JA, Kriska A, Glynn NW, Gutai JP, Kuller LH. 1997. Longitudinal relation between endogenous testosterone and cardiovascular disease risk factors in middle-aged men. A 13-year follow-up of former Multiple Risk Factor Intervention Trial participants. American Journal of Epidemiology 146(8):609–617.

Suggested Citation:"2 Testosterone and Health Outcomes." Institute of Medicine. 2004. Testosterone and Aging: Clinical Research Directions. Washington, DC: The National Academies Press. doi: 10.17226/10852.
×
Page 32
Suggested Citation:"2 Testosterone and Health Outcomes." Institute of Medicine. 2004. Testosterone and Aging: Clinical Research Directions. Washington, DC: The National Academies Press. doi: 10.17226/10852.
×
Page 33
Suggested Citation:"2 Testosterone and Health Outcomes." Institute of Medicine. 2004. Testosterone and Aging: Clinical Research Directions. Washington, DC: The National Academies Press. doi: 10.17226/10852.
×
Page 34
Suggested Citation:"2 Testosterone and Health Outcomes." Institute of Medicine. 2004. Testosterone and Aging: Clinical Research Directions. Washington, DC: The National Academies Press. doi: 10.17226/10852.
×
Page 35
Suggested Citation:"2 Testosterone and Health Outcomes." Institute of Medicine. 2004. Testosterone and Aging: Clinical Research Directions. Washington, DC: The National Academies Press. doi: 10.17226/10852.
×
Page 36
Suggested Citation:"2 Testosterone and Health Outcomes." Institute of Medicine. 2004. Testosterone and Aging: Clinical Research Directions. Washington, DC: The National Academies Press. doi: 10.17226/10852.
×
Page 37
Suggested Citation:"2 Testosterone and Health Outcomes." Institute of Medicine. 2004. Testosterone and Aging: Clinical Research Directions. Washington, DC: The National Academies Press. doi: 10.17226/10852.
×
Page 38
Suggested Citation:"2 Testosterone and Health Outcomes." Institute of Medicine. 2004. Testosterone and Aging: Clinical Research Directions. Washington, DC: The National Academies Press. doi: 10.17226/10852.
×
Page 39
Suggested Citation:"2 Testosterone and Health Outcomes." Institute of Medicine. 2004. Testosterone and Aging: Clinical Research Directions. Washington, DC: The National Academies Press. doi: 10.17226/10852.
×
Page 40
Suggested Citation:"2 Testosterone and Health Outcomes." Institute of Medicine. 2004. Testosterone and Aging: Clinical Research Directions. Washington, DC: The National Academies Press. doi: 10.17226/10852.
×
Page 41
Suggested Citation:"2 Testosterone and Health Outcomes." Institute of Medicine. 2004. Testosterone and Aging: Clinical Research Directions. Washington, DC: The National Academies Press. doi: 10.17226/10852.
×
Page 42
Suggested Citation:"2 Testosterone and Health Outcomes." Institute of Medicine. 2004. Testosterone and Aging: Clinical Research Directions. Washington, DC: The National Academies Press. doi: 10.17226/10852.
×
Page 43
Suggested Citation:"2 Testosterone and Health Outcomes." Institute of Medicine. 2004. Testosterone and Aging: Clinical Research Directions. Washington, DC: The National Academies Press. doi: 10.17226/10852.
×
Page 44
Suggested Citation:"2 Testosterone and Health Outcomes." Institute of Medicine. 2004. Testosterone and Aging: Clinical Research Directions. Washington, DC: The National Academies Press. doi: 10.17226/10852.
×
Page 45
Suggested Citation:"2 Testosterone and Health Outcomes." Institute of Medicine. 2004. Testosterone and Aging: Clinical Research Directions. Washington, DC: The National Academies Press. doi: 10.17226/10852.
×
Page 46
Suggested Citation:"2 Testosterone and Health Outcomes." Institute of Medicine. 2004. Testosterone and Aging: Clinical Research Directions. Washington, DC: The National Academies Press. doi: 10.17226/10852.
×
Page 47
Suggested Citation:"2 Testosterone and Health Outcomes." Institute of Medicine. 2004. Testosterone and Aging: Clinical Research Directions. Washington, DC: The National Academies Press. doi: 10.17226/10852.
×
Page 48
Suggested Citation:"2 Testosterone and Health Outcomes." Institute of Medicine. 2004. Testosterone and Aging: Clinical Research Directions. Washington, DC: The National Academies Press. doi: 10.17226/10852.
×
Page 49
Suggested Citation:"2 Testosterone and Health Outcomes." Institute of Medicine. 2004. Testosterone and Aging: Clinical Research Directions. Washington, DC: The National Academies Press. doi: 10.17226/10852.
×
Page 50
Suggested Citation:"2 Testosterone and Health Outcomes." Institute of Medicine. 2004. Testosterone and Aging: Clinical Research Directions. Washington, DC: The National Academies Press. doi: 10.17226/10852.
×
Page 51
Suggested Citation:"2 Testosterone and Health Outcomes." Institute of Medicine. 2004. Testosterone and Aging: Clinical Research Directions. Washington, DC: The National Academies Press. doi: 10.17226/10852.
×
Page 52
Suggested Citation:"2 Testosterone and Health Outcomes." Institute of Medicine. 2004. Testosterone and Aging: Clinical Research Directions. Washington, DC: The National Academies Press. doi: 10.17226/10852.
×
Page 53
Suggested Citation:"2 Testosterone and Health Outcomes." Institute of Medicine. 2004. Testosterone and Aging: Clinical Research Directions. Washington, DC: The National Academies Press. doi: 10.17226/10852.
×
Page 54
Suggested Citation:"2 Testosterone and Health Outcomes." Institute of Medicine. 2004. Testosterone and Aging: Clinical Research Directions. Washington, DC: The National Academies Press. doi: 10.17226/10852.
×
Page 55
Suggested Citation:"2 Testosterone and Health Outcomes." Institute of Medicine. 2004. Testosterone and Aging: Clinical Research Directions. Washington, DC: The National Academies Press. doi: 10.17226/10852.
×
Page 56
Suggested Citation:"2 Testosterone and Health Outcomes." Institute of Medicine. 2004. Testosterone and Aging: Clinical Research Directions. Washington, DC: The National Academies Press. doi: 10.17226/10852.
×
Page 57
Suggested Citation:"2 Testosterone and Health Outcomes." Institute of Medicine. 2004. Testosterone and Aging: Clinical Research Directions. Washington, DC: The National Academies Press. doi: 10.17226/10852.
×
Page 58
Suggested Citation:"2 Testosterone and Health Outcomes." Institute of Medicine. 2004. Testosterone and Aging: Clinical Research Directions. Washington, DC: The National Academies Press. doi: 10.17226/10852.
×
Page 59
Suggested Citation:"2 Testosterone and Health Outcomes." Institute of Medicine. 2004. Testosterone and Aging: Clinical Research Directions. Washington, DC: The National Academies Press. doi: 10.17226/10852.
×
Page 60
Suggested Citation:"2 Testosterone and Health Outcomes." Institute of Medicine. 2004. Testosterone and Aging: Clinical Research Directions. Washington, DC: The National Academies Press. doi: 10.17226/10852.
×
Page 61
Suggested Citation:"2 Testosterone and Health Outcomes." Institute of Medicine. 2004. Testosterone and Aging: Clinical Research Directions. Washington, DC: The National Academies Press. doi: 10.17226/10852.
×
Page 62
Suggested Citation:"2 Testosterone and Health Outcomes." Institute of Medicine. 2004. Testosterone and Aging: Clinical Research Directions. Washington, DC: The National Academies Press. doi: 10.17226/10852.
×
Page 63
Suggested Citation:"2 Testosterone and Health Outcomes." Institute of Medicine. 2004. Testosterone and Aging: Clinical Research Directions. Washington, DC: The National Academies Press. doi: 10.17226/10852.
×
Page 64
Suggested Citation:"2 Testosterone and Health Outcomes." Institute of Medicine. 2004. Testosterone and Aging: Clinical Research Directions. Washington, DC: The National Academies Press. doi: 10.17226/10852.
×
Page 65
Suggested Citation:"2 Testosterone and Health Outcomes." Institute of Medicine. 2004. Testosterone and Aging: Clinical Research Directions. Washington, DC: The National Academies Press. doi: 10.17226/10852.
×
Page 66
Suggested Citation:"2 Testosterone and Health Outcomes." Institute of Medicine. 2004. Testosterone and Aging: Clinical Research Directions. Washington, DC: The National Academies Press. doi: 10.17226/10852.
×
Page 67
Suggested Citation:"2 Testosterone and Health Outcomes." Institute of Medicine. 2004. Testosterone and Aging: Clinical Research Directions. Washington, DC: The National Academies Press. doi: 10.17226/10852.
×
Page 68
Suggested Citation:"2 Testosterone and Health Outcomes." Institute of Medicine. 2004. Testosterone and Aging: Clinical Research Directions. Washington, DC: The National Academies Press. doi: 10.17226/10852.
×
Page 69
Suggested Citation:"2 Testosterone and Health Outcomes." Institute of Medicine. 2004. Testosterone and Aging: Clinical Research Directions. Washington, DC: The National Academies Press. doi: 10.17226/10852.
×
Page 70
Suggested Citation:"2 Testosterone and Health Outcomes." Institute of Medicine. 2004. Testosterone and Aging: Clinical Research Directions. Washington, DC: The National Academies Press. doi: 10.17226/10852.
×
Page 71
Suggested Citation:"2 Testosterone and Health Outcomes." Institute of Medicine. 2004. Testosterone and Aging: Clinical Research Directions. Washington, DC: The National Academies Press. doi: 10.17226/10852.
×
Page 72
Suggested Citation:"2 Testosterone and Health Outcomes." Institute of Medicine. 2004. Testosterone and Aging: Clinical Research Directions. Washington, DC: The National Academies Press. doi: 10.17226/10852.
×
Page 73
Suggested Citation:"2 Testosterone and Health Outcomes." Institute of Medicine. 2004. Testosterone and Aging: Clinical Research Directions. Washington, DC: The National Academies Press. doi: 10.17226/10852.
×
Page 74
Suggested Citation:"2 Testosterone and Health Outcomes." Institute of Medicine. 2004. Testosterone and Aging: Clinical Research Directions. Washington, DC: The National Academies Press. doi: 10.17226/10852.
×
Page 75
Suggested Citation:"2 Testosterone and Health Outcomes." Institute of Medicine. 2004. Testosterone and Aging: Clinical Research Directions. Washington, DC: The National Academies Press. doi: 10.17226/10852.
×
Page 76
Suggested Citation:"2 Testosterone and Health Outcomes." Institute of Medicine. 2004. Testosterone and Aging: Clinical Research Directions. Washington, DC: The National Academies Press. doi: 10.17226/10852.
×
Page 77
Suggested Citation:"2 Testosterone and Health Outcomes." Institute of Medicine. 2004. Testosterone and Aging: Clinical Research Directions. Washington, DC: The National Academies Press. doi: 10.17226/10852.
×
Page 78
Suggested Citation:"2 Testosterone and Health Outcomes." Institute of Medicine. 2004. Testosterone and Aging: Clinical Research Directions. Washington, DC: The National Academies Press. doi: 10.17226/10852.
×
Page 79
Suggested Citation:"2 Testosterone and Health Outcomes." Institute of Medicine. 2004. Testosterone and Aging: Clinical Research Directions. Washington, DC: The National Academies Press. doi: 10.17226/10852.
×
Page 80
Suggested Citation:"2 Testosterone and Health Outcomes." Institute of Medicine. 2004. Testosterone and Aging: Clinical Research Directions. Washington, DC: The National Academies Press. doi: 10.17226/10852.
×
Page 81
Suggested Citation:"2 Testosterone and Health Outcomes." Institute of Medicine. 2004. Testosterone and Aging: Clinical Research Directions. Washington, DC: The National Academies Press. doi: 10.17226/10852.
×
Page 82
Suggested Citation:"2 Testosterone and Health Outcomes." Institute of Medicine. 2004. Testosterone and Aging: Clinical Research Directions. Washington, DC: The National Academies Press. doi: 10.17226/10852.
×
Page 83
Suggested Citation:"2 Testosterone and Health Outcomes." Institute of Medicine. 2004. Testosterone and Aging: Clinical Research Directions. Washington, DC: The National Academies Press. doi: 10.17226/10852.
×
Page 84
Suggested Citation:"2 Testosterone and Health Outcomes." Institute of Medicine. 2004. Testosterone and Aging: Clinical Research Directions. Washington, DC: The National Academies Press. doi: 10.17226/10852.
×
Page 85
Suggested Citation:"2 Testosterone and Health Outcomes." Institute of Medicine. 2004. Testosterone and Aging: Clinical Research Directions. Washington, DC: The National Academies Press. doi: 10.17226/10852.
×
Page 86
Suggested Citation:"2 Testosterone and Health Outcomes." Institute of Medicine. 2004. Testosterone and Aging: Clinical Research Directions. Washington, DC: The National Academies Press. doi: 10.17226/10852.
×
Page 87
Suggested Citation:"2 Testosterone and Health Outcomes." Institute of Medicine. 2004. Testosterone and Aging: Clinical Research Directions. Washington, DC: The National Academies Press. doi: 10.17226/10852.
×
Page 88
Suggested Citation:"2 Testosterone and Health Outcomes." Institute of Medicine. 2004. Testosterone and Aging: Clinical Research Directions. Washington, DC: The National Academies Press. doi: 10.17226/10852.
×
Page 89
Suggested Citation:"2 Testosterone and Health Outcomes." Institute of Medicine. 2004. Testosterone and Aging: Clinical Research Directions. Washington, DC: The National Academies Press. doi: 10.17226/10852.
×
Page 90
Suggested Citation:"2 Testosterone and Health Outcomes." Institute of Medicine. 2004. Testosterone and Aging: Clinical Research Directions. Washington, DC: The National Academies Press. doi: 10.17226/10852.
×
Page 91
Suggested Citation:"2 Testosterone and Health Outcomes." Institute of Medicine. 2004. Testosterone and Aging: Clinical Research Directions. Washington, DC: The National Academies Press. doi: 10.17226/10852.
×
Page 92
Suggested Citation:"2 Testosterone and Health Outcomes." Institute of Medicine. 2004. Testosterone and Aging: Clinical Research Directions. Washington, DC: The National Academies Press. doi: 10.17226/10852.
×
Page 93
Suggested Citation:"2 Testosterone and Health Outcomes." Institute of Medicine. 2004. Testosterone and Aging: Clinical Research Directions. Washington, DC: The National Academies Press. doi: 10.17226/10852.
×
Page 94
Suggested Citation:"2 Testosterone and Health Outcomes." Institute of Medicine. 2004. Testosterone and Aging: Clinical Research Directions. Washington, DC: The National Academies Press. doi: 10.17226/10852.
×
Page 95
Suggested Citation:"2 Testosterone and Health Outcomes." Institute of Medicine. 2004. Testosterone and Aging: Clinical Research Directions. Washington, DC: The National Academies Press. doi: 10.17226/10852.
×
Page 96
Suggested Citation:"2 Testosterone and Health Outcomes." Institute of Medicine. 2004. Testosterone and Aging: Clinical Research Directions. Washington, DC: The National Academies Press. doi: 10.17226/10852.
×
Page 97
Suggested Citation:"2 Testosterone and Health Outcomes." Institute of Medicine. 2004. Testosterone and Aging: Clinical Research Directions. Washington, DC: The National Academies Press. doi: 10.17226/10852.
×
Page 98
Suggested Citation:"2 Testosterone and Health Outcomes." Institute of Medicine. 2004. Testosterone and Aging: Clinical Research Directions. Washington, DC: The National Academies Press. doi: 10.17226/10852.
×
Page 99
Suggested Citation:"2 Testosterone and Health Outcomes." Institute of Medicine. 2004. Testosterone and Aging: Clinical Research Directions. Washington, DC: The National Academies Press. doi: 10.17226/10852.
×
Page 100
Suggested Citation:"2 Testosterone and Health Outcomes." Institute of Medicine. 2004. Testosterone and Aging: Clinical Research Directions. Washington, DC: The National Academies Press. doi: 10.17226/10852.
×
Page 101
Suggested Citation:"2 Testosterone and Health Outcomes." Institute of Medicine. 2004. Testosterone and Aging: Clinical Research Directions. Washington, DC: The National Academies Press. doi: 10.17226/10852.
×
Page 102
Suggested Citation:"2 Testosterone and Health Outcomes." Institute of Medicine. 2004. Testosterone and Aging: Clinical Research Directions. Washington, DC: The National Academies Press. doi: 10.17226/10852.
×
Page 103
Suggested Citation:"2 Testosterone and Health Outcomes." Institute of Medicine. 2004. Testosterone and Aging: Clinical Research Directions. Washington, DC: The National Academies Press. doi: 10.17226/10852.
×
Page 104
Suggested Citation:"2 Testosterone and Health Outcomes." Institute of Medicine. 2004. Testosterone and Aging: Clinical Research Directions. Washington, DC: The National Academies Press. doi: 10.17226/10852.
×
Page 105
Suggested Citation:"2 Testosterone and Health Outcomes." Institute of Medicine. 2004. Testosterone and Aging: Clinical Research Directions. Washington, DC: The National Academies Press. doi: 10.17226/10852.
×
Page 106
Suggested Citation:"2 Testosterone and Health Outcomes." Institute of Medicine. 2004. Testosterone and Aging: Clinical Research Directions. Washington, DC: The National Academies Press. doi: 10.17226/10852.
×
Page 107
Suggested Citation:"2 Testosterone and Health Outcomes." Institute of Medicine. 2004. Testosterone and Aging: Clinical Research Directions. Washington, DC: The National Academies Press. doi: 10.17226/10852.
×
Page 108
Suggested Citation:"2 Testosterone and Health Outcomes." Institute of Medicine. 2004. Testosterone and Aging: Clinical Research Directions. Washington, DC: The National Academies Press. doi: 10.17226/10852.
×
Page 109
Suggested Citation:"2 Testosterone and Health Outcomes." Institute of Medicine. 2004. Testosterone and Aging: Clinical Research Directions. Washington, DC: The National Academies Press. doi: 10.17226/10852.
×
Page 110
Suggested Citation:"2 Testosterone and Health Outcomes." Institute of Medicine. 2004. Testosterone and Aging: Clinical Research Directions. Washington, DC: The National Academies Press. doi: 10.17226/10852.
×
Page 111
Next: 3 Future Research Directions »
Testosterone and Aging: Clinical Research Directions Get This Book
×
Buy Paperback | $53.00 Buy Ebook | $42.99
MyNAP members save 10% online.
Login or Register to save!
Download Free PDF

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

  1. ×

    Welcome to OpenBook!

    You're looking at OpenBook, NAP.edu's online reading room since 1999. Based on feedback from you, our users, we've made some improvements that make it easier than ever to read thousands of publications on our website.

    Do you want to take a quick tour of the OpenBook's features?

    No Thanks Take a Tour »
  2. ×

    Show this book's table of contents, where you can jump to any chapter by name.

    « Back Next »
  3. ×

    ...or use these buttons to go back to the previous chapter or skip to the next one.

    « Back Next »
  4. ×

    Jump up to the previous page or down to the next one. Also, you can type in a page number and press Enter to go directly to that page in the book.

    « Back Next »
  5. ×

    Switch between the Original Pages, where you can read the report as it appeared in print, and Text Pages for the web version, where you can highlight and search the text.

    « Back Next »
  6. ×

    To search the entire text of this book, type in your search term here and press Enter.

    « Back Next »
  7. ×

    Share a link to this book page on your preferred social network or via email.

    « Back Next »
  8. ×

    View our suggested citation for this chapter.

    « Back Next »
  9. ×

    Ready to take your reading offline? Click here to buy this book in print or download it as a free PDF, if available.

    « Back Next »
Stay Connected!