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.



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Testosterone and Aging: Clinical Research Directions 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.

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Testosterone and Aging: Clinical Research Directions 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-

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Testosterone and Aging: Clinical Research Directions 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.

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Testosterone and Aging: Clinical Research Directions 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

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Testosterone and Aging: Clinical Research Directions 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

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Testosterone and Aging: Clinical Research Directions 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.

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Testosterone and Aging: Clinical Research Directions 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.

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Testosterone and Aging: Clinical Research Directions 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

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Testosterone and Aging: Clinical Research Directions 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-

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Testosterone and Aging: Clinical Research Directions tosterone therapy that were conducted in older or middle-aged men and were published from 1977 to 2003.2 Appendix B provides a table with the design characteristics of the placebo-controlled trials and includes information on the baseline testosterone levels in the study population and, where applicable, the entry criteria used for the trial regarding testosterone level. Placebo-controlled trials in older men have been conducted with small numbers of participants, ranging from 6 to 108 individuals, and most are of limited duration, ranging from 1 to 36 months. Of the 31 randomized trials, 18 administered testosterone intramuscularly, 5 used oral preparations, 5 used a testosterone patch, and 3 used testosterone gel. Many of the randomized trials have examined healthy, community-dwelling elderly men. There have been three trials of institutionalized populations: surgical patients, rehabilitation unit patients, and nursing home patients. The remainder of the trials studied men with chronic diseases. Many of the trials assessed multiple outcomes and are discussed in several of the health outcome sections. In subsequent tables in the chapter the results for the placebo-controlled clinical trials are sorted by the mean baseline total testosterone level of study participants and by testosterone preparation used in the trial. Because of the difficulty in assessing the physiologic effects of exogenous testosterone, the lack of definitions of normal ranges in older age groups, and differing variance around the mean testosterone levels in different clinical trials, the groupings are provisional and the borders between them are not sharp. Some of the trials did not report baseline testosterone levels. The rest of the trials were divided into three groups. These groups include trials that enrolled: Men with baseline testosterone levels that were frankly low, even for older males, usually with means less than 250 ng/dL; Men with baseline testosterone levels in the low to low-normal range, with means in the 250 to 400 ng/dL range; and Men with baseline testosterone levels in the normal range, with mean levels greater than 400 ng/dL. BONE Aging has major effects on bone strength. Men undergo a gradual reduction in bone mass in early to mid adulthood. Although they do not 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.

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Testosterone and Aging: Clinical Research Directions 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.

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Testosterone and Aging: Clinical Research Directions 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.

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Testosterone and Aging: Clinical Research Directions 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):1170–1173. 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):251–265. 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.

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