This Article Abstract Full Text (PDF) Services Download to citation manager Citing Articles Citing Articles via HighWire PubMed PubMed Citation

Effects of Transdermal Testosterone on Bone and Muscle in Older Men With Low Bioavailable Testosterone Levels

^a Center on Aging, University of Connecticut Health Center, Farmington
^b Lowell P. Weicker General Clinical Research Center, University of Connecticut Health Center, Farmington
^c Braceland Center for Mental Health and Aging, Institute of Living/Hartford Hospital, Hartford, Connecticut

Anne M. Kenny, Center on Aging, MC-5215 University of Connecticut Health Center, Farmington, CT 06030-5215 E-mail: kenny{at}nso1.uchc.edu.

Decision Editor: John E. Morley, MB, BCh

	Abstract

Top Abstract Methods Results Discussion References

 
Background. A large proportion of men over 65 years of age have bioavailable testosterone levels below the reference range of young adult men. The impact of this on musculoskeletal health and the potential for improvement in function in this group with testosterone supplementation require investigation.

Methods. Sixty-seven men (mean age 76 ± 4 years, range 65–87) with bioavailable testosterone levels below 4.44 nmol/l (lower limit for adult normal range) were randomized to receive transdermal testosterone (two 2.5-mg patches per day) or placebo patches for 1 year. All men received 500 mg supplemental calcium and 400 IU vitamin D. Outcome measures included sex hormones (testosterone, bioavailable testosterone, sex-hormone binding globulin [SHBG], estradiol, and estrone), bone mineral density (BMD; femoral neck, Ward's triangle, trochanter, lumbar spine, and total body), bone turnover markers, lower extremity muscle strength, percent body fat, lean body mass, hemoglobin, hematocrit, prostate symptoms, and prostate specific antigen (PSA) levels.

Results. Twenty-three men (34%) withdrew from the study; 44 men completed the trial. In these men, bioavailable testosterone levels increased from 3.2 ± 1.2 nmol/l (SD) to 5.6 ± 3.5 nmol/l (p < .002) at 12 months in the testosterone group, whereas no change occurred in the control group. Although there was no change in estradiol levels in either group, estrone levels increased in the testosterone group (103 ± 26 pmol/l to 117 ± 33 pmol/l; p < .017). The testosterone group had a 0.3% gain in femoral neck BMD, whereas the control group lost 1.6% over 12 months (p = .015). No significant changes were seen in markers of bone turnover in either group. Improvements in muscle strength were seen in both groups at 12 months compared with baseline scores. Strength increased 38% (p = .017) in the testosterone group and 27% in the control group (p = .06), with no statistical difference between the groups. In the testosterone group, body fat decreased from 26.3 ± 5.8% to 24.6 ± 6.5% (p = .001), and lean body mass increased from 56.2 ± 5.3 kg to 57.2 ± 5.1 kg (p = .001), whereas body mass did not change. Men receiving testosterone had an increase in PSA from 2.0 ± 1.4 µg/l to 2.6 ± 1.8 µg/l (p = .04), whereas men receiving placebo had an increase in PSA from 1.9 ± 1.0 µg/l to 2.2 ± 1.5 µg/l (p = .09). No significant differences between groups were seen in hemoglobin, hematocrit, symptoms or signs of benign prostate hyperplasia, or PSA levels.

Conclusions. Transdermal testosterone (5 mg/d) prevented bone loss at the femoral neck, decreased body fat, and increased lean body mass in a group of healthy men over age 65 with low bioavailable testosterone levels. In addition, both testosterone and placebo groups demonstrated gains in lower extremity muscle strength, possibly due to the beneficial effects of vitamin D. Testosterone did result in a modest increase in PSA levels but resulted in no change in signs or symptoms of prostate hyperplasia.

TESTOSTERONE levels decline with age ⁽¹⁾, and as many as 50% of men over age 65 have bioavailable testosterone levels below the reference range for young adult men ^{(2) (3) (4)}. The importance of the decline in testosterone levels to the health of older men is not established, but testosterone insufficiency may play a role in age-related bone loss and muscle weakness ^{(5) (6)}. We have previously observed that baseline testosterone levels account for 20% of the variability in femoral neck bone mineral density. We also found a direct correlation between baseline bioavailable testosterone levels and strength among older men selected for low bioavailable testosterone levels ⁽⁷⁾. Therefore, we undertook this placebo-controlled study to determine if testosterone supplementation using nonscrotal testosterone patches would affect sex hormone levels, bone mineral density (BMD), biochemical markers of bone turnover, lower extremity muscle strength, body composition, calcium (Ca)-regulating hormones, and prostate parameters in men with bioavailable testosterone levels at least 2 SD below the average for young adult men but without specific complaints of hypogonadism or osteoporosis.

	Methods

Top Abstract Methods Results Discussion References

 
Subjects
The Institutional Review Board at the University of Connecticut Health Center approved the study, and all men gave written informed consent prior to screening evaluation. Men were recruited using the following strategies: (i) letters were sent to men over age 65 (names were provided by the Department of Motor Vehicles for the area surrounding the University of Connecticut Health Center); (ii) community outreach lectures were provided to men's groups and senior centers; (iii) mailings were sent to men's groups; and (iv) flyers were distributed at senior centers and housing sites. The informative talks were about general health, and the flyers solicited men to be involved in a research proposal, not specifically to study bone or muscle health. We included men over age 65 with bioavailable testosterone levels below 4.44 nmol/l (normal range 4.44–14.91 nmol/l). Exclusion criteria were (i) systemic disease or unresolved endocrine disorder known to affect bone turnover, such as Paget's disease or hyperparathyroidism; (ii) use of androgens in the last 12 months; (iii) use of medication known to affect bone turnover in the last 12 months, such as glucocorticoids, alendronate, calcitonin, or anti-seizure medication; or (iv) serum creatinine (Cr) 1.5 mg/dl. A total of 194 men responded to the various recruitment strategies and were screened for eligibility by telephone survey. Of these, 121 were interested and eligible for laboratory screening. Laboratory screening identified 90 (74%) men who met bioavailable testosterone criterion for eligibility. Twelve men were excluded for prostate specific antigen (PSA) levels that were above the normal range, and eleven men refused further participation. A total of 67 men were randomly assigned to treatment or placebo for participation in the study.

Treatment
Men were randomized in a double-masked manner to receive either transdermal testosterone supplementation (two 2.5-mg Androderm, SmithKline Beecham, Collegeville, PA, patches per day; 5 mg/d total dose) or a matching placebo regimen. The active and placebo patches were void of any distinguishing characteristics. The randomization and labeling of the patches was performed by SmithKline Beecham (Collegeville, PA). Participants were instructed to apply patches each evening before going to bed. A randomization list was provided to the consulting pharmacist who had no direct contact with research participants. Investigators and subjects were unaware of the content of the patch. Both groups received 500 mg Ca and 400 IU of vitamin D supplementation. Follow-up examinations and repeat measurement of outcome variables were performed at 6 and 12 months.

Evaluations
Participants in the study underwent medical history, physical exam, and measurement of fasting serum Ca, Cr, alkaline phosphatase, thyroid function tests, total and bioavailable testosterone, sex-hormone–binding globulin, estrone, estradiol, PSA level, and urinary Ca and Cr. Baseline and follow-up evaluations of the outcome variables (sex- and Ca-regulating hormone levels, BMD, bone markers, strength, physical activity score, body composition, and safety parameters) were performed at 0, 6, and 12 months of treatment. Ca and vitamin D intake (including supplements) were estimated by a 3-day food record. Activity was estimated by the Physical Activity Scale for the Elderly questionnaire ⁽⁸⁾. Symptoms of benign prostate hyperplasia were assessed using the International Prostate Symptom Score (IPSS), and symptoms of urinary retention were recorded. Measurement of PSA levels was repeated when elevations were detected; decisions to discontinue treatment were made on the basis of participant and physician (primary physician, urologist, and principal investigator) discussion. Assessment of skin effects of the transdermal patch were made using a 5-point scale with 0 representing no rash and 4 representing erythema, induration, and bullae ⁽⁹⁾. We also assessed symptoms of itching on a 4-point scale with 1 representing no itching and 4 representing persistent itching ⁽⁹⁾. The BMD of the proximal femur, lumbar spine, and total body were obtained at baseline (Lunar DPX-L, Madison, WI). The coefficient of variation (CV) of BMD measurement at the proximal femur, spine, and total body was <1%, 1.5%, and 2%, respectively. Analysis of the lumbar spine was restricted to L1 for all men due to the osteophyte formation and deformity noted in the lower lumbar vertebrae in 75% of the men. Body fat and lean mass measurements were obtained from the DXA. Leg extension strength [1 repetition maximum ⁽¹⁰⁾; intra- and intertester variability <10%] was measured on the Keiser Sitting Leg Press.

Biochemical Measurements
Blood and urine samples were collected between 7 and 9 AM after a 10- to 12-hour fast. Urine and serum were divided into 0.5-ml aliquots and stored at -70°C. Ionized Ca was measured within 2 hours of collection. All bone marker assays were performed on batched serum or urine in the Core Laboratory of the General Clinical Research Center at the University of Connecticut Health Center.

Markers of bone formation included bone-specific alkaline phosphatase and N-terminal type I procollagen peptide measured by enzyme-linked immunosorbent assay (ELISA) (Metra Biosystems Inc., Palo Alto, CA). Average intra-assay variability was <5% for both measures of bone formation. Markers of bone resorption were crosslinked N-telopeptide (NTX) and C-telopeptide (CTX) of type I collagen measured by ELISA (Ostex International Inc., Seattle, WA; and Osteometer A/S, Copenhagen, Denmark, respectively). Intra-assay variability was <10% for measures of bone resorption.

Total and bioavailable testosterone and sex-hormone binding globulin (SHBG) measurements were performed at Endocrine Sciences Inc., Calabasas Hills, California. Testosterone levels were measured by radioimmunoassay SHBG by competitive binding assay, and bioavailable testosterone by competitive binding of the non-SHBG–bound portion of testosterone following ammonium sulfate precipitation of the SHBG-bound steroid as described by Nankin ⁽⁴⁾. Intra-assay variability of the testosterone assay is less than 7%, bioavailable testosterone less than 4%, and SHBG less than 10%. 25-hydroxyvitamin D was measured by competitive protein binding with an intra-assay CV of less than 10%. Samples for off-site assay were shipped on dry ice by overnight mail. Estradiol and estrone were performed in the GCRC core lab using radioimmunoassay (Diagnostic Systems Lab, Inc., Webster, TX); intra-assay variability was <10%. The detection limit of the estradiol assay is 2 pg/ml.

Statistical Analysis
Analysis was done on those individuals who completed the study. Baseline and clinical characteristics were reported using means and standard deviations stratified by treatment group. One-way analysis of variance (ANOVA) was used to test the difference in baseline characteristics between the treatment groups. For each participant we calculated the percent change in BMD, biochemical markers of bone turnover, hormone levels, and strength and compiled questionnaire results from baseline to 12 months. Paired t tests were used to assess change within the groups over time. We also compared the percent change of each variable of the groups using one-way ANOVA. We checked variables for normality of distribution and for the impact of outliers. All analyses were done using SPSS version 10.0 (SPSS, Inc, Chicago, IL).

	Results

Top Abstract Methods Results Discussion References

 
Subject Population and Disposition
Sixty-seven men were recruited for the study. Twenty-three men (33%) discontinued due to intercurrent illness, rash, elevation in PSA level, and personal reasons (Table 1 ). Forty-four men completed the study, with 24 men in the testosterone group and 20 men in the placebo group. Baseline characteristics of the 44 men who finished the study are presented in Table 2 ; no significant differences existed in baseline information between the treatment and control groups. None of the men were active smokers; 34% had never smoked, and 66% reported a prior history of smoking. Sixty-three percent (42/67) of the men reported the use of alcohol; mean alcohol consumption was 6 drinks/wk (range 1–21 drinks/wk), using the standard definition of 0.5 oz of ethanol per drink ⁽¹¹⁾. Medical conditions most commonly reported included coronary artery disease (n = 34), hypertension (n = 34), and osteoarthritis (n = 31). None of the men were receiving treatment for medical conditions that might produce hypogonadism such as liver disease, alcoholism, hemachromatosis, or Klinefelter's disease. Commonly used medications included antihypertensives (n = 31), cholesterol-lowering agents (n = 10), thiazide diuretics (n = 12), histamine blockers (n = 9), alpha-adrenergic antagonists (n = 11), and aspirin for cardioprotective reasons (n = 20). None of the men reported a history of long-term corticosteroid therapy.

View larger version (14K): [in this window] [in a new window]   Figure 1. Changes in bioavailable testosterone levels with therapy. Subjects on testosterone replacement had significant increases in levels at 6 and 12 months (p .001).

View larger version (8K): [in this window] [in a new window]   Figure 2. The effects of testosterone or placebo on percent change in femoral neck bone mineral density (FN BMD) following one year of therapy.

Muscle Strength, Physical Activity, and Body Composition
The baseline and 12-month data for lower extremity muscle strength, physical activity scores, body mass index (BMI), height, lean body mass, and body fat are shown in Table 5 . Both the testosterone and placebo groups had significant increases in lower extremity muscle strength. Body fat decreased and lean mass increased from baseline values in the testosterone group, and this was significantly different from the placebo group for body fat (p = .04), with a trend for lean mass (p = .07). No changes were detected in BMI, height, or physical activity in either group.

	Discussion

Top Abstract Methods Results Discussion References

 
Transdermal testosterone therapy prevented bone loss at the femoral neck in men over age 65 selected for low bioavailable testosterone levels. Few studies to date have evaluated the effects of testosterone supplementation on bone density in older men with modest testosterone insufficiency, which is common with aging. In a 3-year study in which men selected for testosterone levels below 2.1 nmol/l received transscrotal testosterone, Snyder and colleagues found no significant treatment effect on BMD; however, linear regression analysis indicated a stronger treatment effect on lumbar spine in men with low baseline testosterone levels ⁽¹²⁾. Other investigators have found testosterone replacement beneficial to bone density in younger men with long-standing severe testosterone deficiency ^{(13) (14)} as well as acquired testosterone deficiency associated with pituitary tumors and other causes ⁽¹⁵⁾. We found no significant changes in markers of bone turnover in our population receiving testosterone or Ca and vitamin D, but we did observe a nonsignificant 15% decline in markers of bone resorption consistent with our earlier pilot study ⁽¹⁶⁾ and with the work of Snyder and colleagues ⁽¹²⁾. In contrast, studies of older men receiving short-term testosterone therapy delivered by intramuscular injection or sublingual delivery have decreased bone resorption ^{(5) (17)} or increased bone formation ^{(6) (16)}. Differences in testosterone replacement regimens, the duration of treatment, and patient selection may account for some of the differences between the studies. No study to date has evaluated the effect of testosterone replacement on fracture risk.

It is noteworthy that the control subjects in our study who received Ca and vitamin D nevertheless lost 1.6% of bone at the femoral neck over 1 year. Snyder and colleagues found no bone loss in a similar population of older men selected for low testosterone levels ⁽¹²⁾, and Dawson-Hughes and colleagues demonstrated gains in BMD in eugonadal men receiving similar Ca and vitamin D supplementation ⁽¹⁸⁾ in studies over three years. The expected loss in bone density of community-dwelling, healthy older men is 0.5% to 1% per year ⁽¹⁹⁾, suggesting that men with the moderate testosterone insufficiency associated with aging and comorbidity may be at increased risk for bone loss. We have previously reported that 52% of older men selected for low testosterone levels (2 SD) have BMD at least 1 SD below the mean value for young adult men and that 15% of this group has bone density scores more than 2.5 SD below the mean value for young adult men, signifying osteoporosis and increased risk for fracture ⁽⁷⁾. Similarly, some investigators have found testosterone or estrogen to be predictors of low bone density in older men ^{(20) (21) (22)}, although other studies failed to find such an association ^{(23) (24) (25)}.

Lower extremity muscle strength, measured by a sitting leg press, increased in both the testosterone group (38%) and the control group (27%); both groups were supplemented with Ca and vitamin D. In other studies of testosterone replacement in older hypogonadal men, hand grip strength increased in men selected for testosterone below 60 ng/dl ^{(5) (26)}, whereas no changes were seen in other studies where baseline testosterone levels were higher ^{(6) (12)}. In an uncontrolled study, Urban and colleagues found improvement in lower extremity strength in men receiving testosterone ⁽²⁷⁾. Improvement in strength in the control group may have been due to familiarity with the leg press, but we do not expect improvements of more than 10%–15%. However, it is likely that some of the improvement in strength was due to the anabolic effects of vitamin D on muscle. Improvement in muscle strength ^{(28) (29)}, decreased body sway ⁽³⁰⁾, and improvement in physical performance ^{(31) (32) (33)} were reported following supplementation with vitamin D in subjects with low vitamin D levels, whereas no effect was seen on similar parameters in a controlled trial of vitamin D supplementation in a group in which vitamin D levels were not decreased at baseline ⁽³⁴⁾.

Testosterone supplementation resulted in a significant decrease in body fat and an increase in lean body mass in our study. Several investigators have found a decrease in body fat and an increase in lean mass in older men treated with testosterone ^{(12) (26) (27)}.

The men in the testosterone group did not have a worsening of symptoms of benign prostate hyperplasia (IPSS score), and there were no reports of urinary retention during the year of therapy. There was a significant increase in PSA levels in the men finishing testosterone therapy, but the PSA levels also increased in the controls, and the changes were not significantly different between the groups, suggesting that PSA levels were increasing irrespective of testosterone therapy. Small increases or no change in PSA levels have been described in other studies ^{(5) (6) (12) (16) (35)}, similar to our results. Our study was not long enough to establish the safety of testosterone on the prostate. Moreover, there are no data to address whether androgens enhance the progression of preclinical to clinical prostate cancer. Nested case control studies from two large population-based epidemiologic studies reveal both an association ⁽³⁶⁾ and a lack of association ⁽³⁷⁾ between baseline testosterone levels and the subsequent risk of developing prostate cancer.

Our study has several limitations. The drop-out rate was high in both groups, limiting the sample size for analysis of our primary outcome. Some men with elevation in PSA level on testosterone therapy remained in the study, which may have been responsible for the slightly greater increase in PSA levels in the testosterone group. In addition, whereas testosterone levels increased into the young adult normal range in a majority of the men on transdermal testosterone replacement, more robust outcomes might have been observed if higher serum levels had been attained. No increase in hematocrit was detected in this study, similar to previous published work using transdermal or scrotal testosterone ^{(12) (16) (38)}. Polycythemia has been found in studies using parenteral testosterone and has limited therapy ^{(5) (26)}.

Conclusions
Testosterone replacement therapy given to older men selected for bioavailable testosterone levels 2 SD below the mean value for young adult men maintained bone mineral density in the femoral neck, increased muscle strength, decreased body fat, and increased lean body mass. There were modest increases in PSA and no changes in hematologic parameters. In this study, testosterone replacement appeared to be safe and beneficial in older men with low testosterone levels, supporting the need for further clinical trials.

	Acknowledgments

 
This work was supported by the Patrick and Catherine Donaghue Research Foundation, General Clinical Research Center (MO1-RR06192), Claude Pepper Older Americans Independence Center (5P60-AG13631). Dr. Kenny was supported with fellowships from the Brookdale Foundation and the Paul Beeson Faculty Scholar Program. We thank Pamela Fall and Christine Abreu for assistance with running the biochemical assays, Julie Fenster for assistance with data management, and Helen-Mary Schwartz for manuscript preparation. Testosterone and placebo patches were provided by SmithKline Beecham at no charge to the study.

Received October 27, 2000

Accepted November 6, 2000

	References

Top Abstract Methods Results Discussion References

 

1. 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. Am J Epidemiol. 147:750-754. [Abstract/Free Full Text]
2. Nankin HR, Calkins JH, 1986. Decreased bioavailable testosterone in aging normal and impotent men. J Clin Endocrinol Metab. 63:1418-1420. [Abstract/Free Full Text]
3. Korenman SG, Morley JE, Mooradian AD, et al. 1990. Secondary hypogonadism in older men: its relationship to impotence. J Clin Endocrinol Metab. 71:963-969. [Abstract/Free Full Text]
4. Gray A, Berlin JA, McKinlay JB, Longcope C, 1991. An examination of research design effects on the association of testosterone and aging: results of a meta-analysis. J Clin Epidemiol. 44:671-684. [Medline]
5. Morley JE, Perry HM, III Kaiser FE, et al. 1993. Effects of testosterone replacement therapy in old hypogonadal males: a preliminary study. J Am Geriatr Soc. 41:149-152. [Medline]
6. Tenover JS, 1992. Effects of testosterone supplementation in the aging male. J Clin Endocrinol Metab. 75:1092-1098. [Abstract]
7. Kenny AM, Prestwood KM, Marcello KM, Raisz LG, 2000. Determinants of bone density in healthy older men with low testosterone levels. J Gerontol Med Sci. 55A:M1-M6.
8. Washburn RA, Smith KW, Jette AM, Janney CA, 1993. The physical activity scale for the elderly (PASE): development and evaluation. J Clin Epidemiol. 46:153-162. [Medline]
9. Meikle AW, Arver S, Dobs AS, Sanders SW, Rajaram L, Mazer NA, 1996. Pharmacokinetics and metabolism of a permeation-enhanced testosterone transdermal system in hypogonadal men: influence of application site: a clinical research center study. J Clin Endocrinol Metab. 81:1832-1840. [Abstract]
10. Fiatarone MA, O'Neill EF, Ryan ND, et al. 1994. Exercise training and nutritional supplementation for physical frailty in very elderly people. N Engl J Med. 330:1769-1775. [Abstract/Free Full Text]
11. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. (DSM –IV). Washington, DC: American Psychiatric Association; 1994.
12. Snyder PJ, Peachey H, Hannoush P, et al. 1999. Effect of testosterone treatment on bone mineral density in men over 65 years of age. J Clin Med Endocrinol. 84:1966-1972.
13. Finkelstein JS, Klibanski A, Neer RM, et al. 1989. Increases in bone density during treatment of men with idiopathic hypogonadotropic hypogonadism. J Clin Endocrinol Metab. 69:776-783. [Abstract/Free Full Text]
14. 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. 18:171-177. [Medline]
15. Katznelson L, Finkelstein JS, Schoenfeld DA, Rosenthal DI, Anderson EJ, Klibanski A, 1996. Increase in bone density and lean body mass during testosterone administration in men with acquired hypogonadism. J Clin Endocrinol Metab. 81:4358-4365. [Abstract]
16. Kenny AM, Prestwood KM, Marcello KD, Raisz LG, 2000. Effects of intramuscular and transdermal testosterone on bone turnover markers, prostate symptoms, and cholesterol in men over age 70 with low testosterone levels: a pilot study. Endocrine Res. 26:153-168. [Medline]
17. Wang C, Eyre DR, Clark R, et al. 1996. Sublingual testosterone replacement improves muscle mass and strength, decreases bone resorption, and increases bone formation markers in hypogonadal men: a clinical research center study. J Clin Endocrinol Metab. 81:3654-3662. [Abstract]
18. Dawson-Hughes B, Harris SS, Krall EA, Dallal GE, 1997. Effect of calcium and vitamin D supplementation on bone density in men and women 65 years of age or older. N Engl J Med. 337:670-676. [Abstract/Free Full Text]
19. Orwoll ES, Oviatt SK, McClung MR, et al. 1990. The rate of bone mineral loss in normal men and the effects of calcium and cholecalciferol supplementation. Ann Int Med. 112:29-34.
20. Khosla S, Melton LJ, III 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. J Clin Endocrinol Metab. 83:2266-2274. [Abstract/Free Full Text]
21. Center JR, Nguyen TV, White CP, Eisman JA, 1997. Male osteoporosis predictors: sex hormones and calcitropic hormones. J Bone Miner Res. 12:S368
22. Greendale GA, Edelstein S, Barrett-Connor E, 1997. Endogenous sex steroids and bone mineral density in older women and men: The Rancho Bernardo study. J Bone Miner Res. 12:1833-1843. [Medline]
23. Slemenda CW, Longcope C, Zhou L, Hui SL, Peacock M, Johnston C, 1997. Sex steroids and bone mass in older men: positive association with serum estrogens and negative associations with androgens. J Clin Invest. 100:1755-1759. [Medline]
24. Drinka PJ, Olson J, Bauwens S, Voeks SK, Carlson I, Wilson M, 1993. Lack of association between free testosterone and bone density separate from age in elderly males. Calcif Tiss Internat. 52:67-69. [Medline]
25. Meier DE, Orwoll ES, Keenan EJ, Fagerstrom RM, 1987. Marked decline in trabecular bone mineral content in healthy men with age: lack of association with sex steroid levels. J Am Geriatr Soc. 35:189-197. [Medline]
26. Sih R, Morley JE, Kaiser FE, Perry HM, III Patrick P, Ross C, 1997. Testosterone replacement in older hypogonadal men: a 12-month randomized controlled trial. J Clin Endocrinol Metab. 82:1661-1667. [Abstract/Free Full Text]
27. Urban RJ, Bodenburg YH, Gilkison C, et al. 1995. Testosterone administration to elderly men increases skeletal muscle strength and protein synthesis. Am J Physiol. 269:E820-E826. [Abstract/Free Full Text]
28. Young NR, Baker HWG, Liu G, Seeman E, 1993. Body composition and muscle strength in healthy men receiving testosterone enanthate for contraception. J Clin Endocrinol Metab. 77:1028-1032. [Abstract]
29. Glerup H, Mikkelsen K, Poulson L, et al. 2000. Hypovitaminosis D myopathy without biochemical signs of osteomalacic bone involvement. Calcif Tissue Internat. 66:419-424. [Medline]
30. Pfeifer M, Begerow B, Minne HW, Abrams C, Nachtigall D, Hansen C, 2000. Effects of a short-term vitamin D and calcium supplementation on body sway and secondary hyperparathyroidism in elderly women. J Bone Miner Res. 15:1113-1118. [Medline]
31. Gloth FM, Smith CE, Hollis BW, Tobin JD, 1995. Functional improvement with vitamin D replenishment in a cohort of frail, vitamin D-deficient older people. J Am Geriatr Soc. 43:1269-1271. [Medline]
32. Sorenson OH, Lund BI, Saltin B, et al. 1979. Myopathy in bone loss of aging: improvement by treatment with 1alpha-hydroxycholecalciferol and calcium. Clin Sci. 56:157-161. [Medline]
33. Corless D, Dawson E, Fraser F, et al. 1985. Do vitamin D supplements improve the physical capabilities of elderly hospital patients?. Age and Aging. 14:76-84.
34. Grady D, Halloran B, Cummings S, et al. 1991. 1,25-Dihydroxyvitamin D3 and muscle strength in the elderly: a randomized controlled trial. J Clin Endocrinol Metab. 73:1111-1117. [Abstract/Free Full Text]
35. Jackson JA, Waxman J, Spiekerman AM, 1989. Prostatic complications of testosterone replacement therapy. Arch Intern Med. 149:2365-2366. [Abstract/Free Full Text]
36. Gann PH, Hennekens CH, Ma J, Longcope C, Stampfer MJ, 1996. Prospective study of sex hormone levels and risk of prostate cancer. J Natl Cancer Inst. 88:1118-1126. [Abstract/Free Full Text]
37. Carter HB, Pearson JD, Metter EJ, et al. 1995. Longitudinal evaluation of serum androgen levels in men with and without prostate cancer. Prostate. 27:25-31. [Medline]
38. Dobson AS, Meikle AW, Arver S, Sanders SW, Caramelli KE, Mazer NM, 1999. Pharmacokinetics, efficacy, and safety of a permeation-enhanced testosterone transdermal system in comparison with bi-weekly injections of testosterone enanthate for the treatment of hypogonadal men. J Clin Endocrin Metabol. 84:3469-3478. [Abstract/Free Full Text]

This article has been cited by other articles:

				M. Wald, M. Miner, and A. D. Seftel State of the Art Reviews: Male Menopause: Fact or Fiction? American Journal of Lifestyle Medicine, April 1, 2008; 2(2): 132 - 141. [Abstract] [PDF]

				M. H. Emmelot-Vonk, H. J. J. Verhaar, H. R. Nakhai Pour, A. Aleman, T. M. T. W. Lock, J. L. H. R. Bosch, D. E. Grobbee, and Y. T. van der Schouw Effect of Testosterone Supplementation on Functional Mobility, Cognition, and Other Parameters in Older Men: A Randomized Controlled Trial JAMA, January 2, 2008; 299(1): 39 - 52. [Abstract] [Full Text] [PDF]

				C. A Clay, S. Perera, J. M Wagner, M. E Miller, J. B Nelson, and S. L Greenspan Physical Function in Men With Prostate Cancer on Androgen Deprivation Therapy Physical Therapy, October 1, 2007; 87(10): 1325 - 1333. [Abstract] [Full Text] [PDF]

				S. E. Borst, C. F. Conover, C. S. Carter, C. M. Gregory, E. Marzetti, C. Leeuwenburgh, K. Vandenborne, and T. J. Wronski Anabolic effects of testosterone are preserved during inhibition of 5{alpha}-reductase Am J Physiol Endocrinol Metab, August 1, 2007; 293(2): E507 - E514. [Abstract] [Full Text] [PDF]

				E. T. Schroeder, A. F. Vallejo, L. Zheng, Y. Stewart, C. Flores, S. Nakao, C. Martinez, and F. R. Sattler Six-Week Improvements in Muscle Mass and Strength During Androgen Therapy in Older Men J. Gerontol. A Biol. Sci. Med. Sci., December 1, 2005; 60(12): 1586 - 1592. [Abstract] [Full Text] [PDF]

				P. Szulc, F. Duboeuf, F. Marchand, and P. D Delmas Hormonal and lifestyle determinants of appendicular skeletal muscle mass in men: the MINOS study Am. J. Clinical Nutrition, August 1, 2004; 80(2): 496 - 503. [Abstract] [Full Text] [PDF]

				D. Vanderschueren, L. Vandenput, S. Boonen, M. K. Lindberg, R. Bouillon, and C. Ohlsson Androgens and Bone Endocr. Rev., June 1, 2004; 25(3): 389 - 425. [Abstract] [Full Text] [PDF]

				E. T. Schroeder, L. Zheng, K. E. Yarasheski, D. Qian, Y. Stewart, C. Flores, C. Martinez, M. Terk, and F. R. Sattler Treatment with oxandrolone and the durability of effects in older men J Appl Physiol, March 1, 2004; 96(3): 1055 - 1062. [Abstract] [Full Text] [PDF]

				E. L. Rhoden and A. Morgentaler Risks of Testosterone-Replacement Therapy and Recommendations for Monitoring N. Engl. J. Med., January 29, 2004; 350(5): 482 - 492. [Full Text] [PDF]

				S. Bhasin, W. E. Taylor, R. Singh, J. Artaza, I. Sinha-Hikim, R. Jasuja, H. Choi, and N. F. Gonzalez-Cadavid The Mechanisms of Androgen Effects on Body Composition: Mesenchymal Pluripotent Cell as the Target of Androgen Action J. Gerontol. A Biol. Sci. Med. Sci., December 1, 2003; 58(12): M1103 - 1110. [Abstract] [Full Text] [PDF]

				D. R. Thomas The Relationship Between Functional Status and Inflammatory Disease in Older Adults J. Gerontol. A Biol. Sci. Med. Sci., November 1, 2003; 58(11): M995 - 998. [Full Text] [PDF]

				S. Bhasin Testosterone Supplementation for Aging-Associated Sarcopenia J. Gerontol. A Biol. Sci. Med. Sci., November 1, 2003; 58(11): M1002 - 1008. [Abstract] [Full Text] [PDF]

				M.-M. G. Wilson and J. E. Morley Invited Review: Aging and energy balance J Appl Physiol, October 1, 2003; 95(4): 1728 - 1736. [Abstract] [Full Text] [PDF]

				J. E. Morley Editorial: Sarcopenia Revisited J. Gerontol. A Biol. Sci. Med. Sci., October 1, 2003; 58(10): M909 - 910. [Full Text] [PDF]

				J. E. Morley Editorial. Mobility Performance: A High-Tech Test for Geriatricians J. Gerontol. A Biol. Sci. Med. Sci., August 1, 2003; 58(8): M712 - 714. [Full Text] [PDF]

				J. E. Morley The Need for a Men's Health Initiative J. Gerontol. A Biol. Sci. Med. Sci., July 1, 2003; 58(7): M614 - 617. [Full Text] [PDF]

				G. A. Wittert, I. M. Chapman, M. T. Haren, S. Mackintosh, P. Coates, and J. E. Morley Oral Testosterone Supplementation Increases Muscle and Decreases Fat Mass in Healthy Elderly Males With Low-Normal Gonadal Status J. Gerontol. A Biol. Sci. Med. Sci., July 1, 2003; 58(7): M618 - 625. [Abstract] [Full Text] [PDF]

				I. Sinha-Hikim, S. M. Roth, M. I. Lee, and S. Bhasin Testosterone-induced muscle hypertrophy is associated with an increase in satellite cell number in healthy, young men Am J Physiol Endocrinol Metab, July 1, 2003; 285(1): E197 - E205. [Abstract] [Full Text] [PDF]

				S. Bhasin, A. B. Singh, R. P. Mac, B. Carter, M. I. Lee, and G. R. Cunningham Managing the Risks of Prostate Disease During Testosterone Replacement Therapy in Older Men: Recommendations for a Standardized Monitoring Plan J Androl, May 1, 2003; 24(3): 299 - 311. [Full Text] [PDF]

				L. J. Woodhouse, S. Reisz-Porszasz, M. Javanbakht, T. W. Storer, M. Lee, H. Zerounian, and S. Bhasin Development of models to predict anabolic response to testosterone administration in healthy young men Am J Physiol Endocrinol Metab, May 1, 2003; 284(5): E1009 - E1017. [Abstract] [Full Text] [PDF]

				S. H. Tariq MD KNOWLEDGE ABOUT LOW TESTOSTERONE IN OLDER MEN J. Gerontol. A Biol. Sci. Med. Sci., April 1, 2003; 58(4): M382 - 383. [Full Text] [PDF]

				J. E. Morley Anorexia and Weight Loss in Older Persons J. Gerontol. A Biol. Sci. Med. Sci., February 1, 2003; 58(2): M131 - 137. [Full Text] [PDF]

				H. T. Blumenthal The Aging-Disease Dichotomy: True or False? J. Gerontol. A Biol. Sci. Med. Sci., February 1, 2003; 58(2): M138 - 145. [Full Text] [PDF]

				J. E. Morley Editorial: Hot Topics in Geriatrics J. Gerontol. A Biol. Sci. Med. Sci., January 1, 2003; 58(1): M30 - 36. [Full Text] [PDF]

				E. T. Schroeder, A. Singh, S. Bhasin, T. W. Storer, C. Azen, T. Davidson, C. Martinez, I. Sinha-Hikim, S. V. Jaque, M. Terk, et al. Effects of an oral androgen on muscle and metabolism in older, community-dwelling men Am J Physiol Endocrinol Metab, January 1, 2003; 284(1): E120 - E128. [Abstract] [Full Text] [PDF]

				J. E. Morley Editorial: Citations, Impact Factor, and the Journal J. Gerontol. A Biol. Sci. Med. Sci., December 1, 2002; 57(12): M765 - 769. [Full Text] [PDF]

				M. Iannuzzi-Sucich, K. M. Prestwood, and A. M. Kenny Prevalence of Sarcopenia and Predictors of Skeletal Muscle Mass in Healthy, Older Men and Women J. Gerontol. A Biol. Sci. Med. Sci., December 1, 2002; 57(12): M772 - 777. [Abstract] [Full Text] [PDF]

				J. K. Anderson, S. Faulkner, C. Cranor, J. Briley, F. Gevirtz, and S. Roberts Andropause: Knowledge and Perceptions Among the General Public and Health Care Professionals J. Gerontol. A Biol. Sci. Med. Sci., December 1, 2002; 57(12): M793 - 796. [Abstract] [Full Text] [PDF]

				J. E. Morley, H. M. Perry III, and D. K. Miller Editorial: Something About Frailty J. Gerontol. A Biol. Sci. Med. Sci., November 1, 2002; 57(11): M698 - 704. [Full Text] [PDF]

				A. Fisher and J. E. Morley Editorial: Antiaging Medicine: The Good, the Bad, and the Ugly J. Gerontol. A Biol. Sci. Med. Sci., October 1, 2002; 57(10): M636 - 639. [Full Text] [PDF]

				J. E. Morley Editorial: A Fall Is a Major Event in the Life of an Older Person J. Gerontol. A Biol. Sci. Med. Sci., August 1, 2002; 57(8): M492 - 495. [Full Text] [PDF]

				A. M. Kenny, K. M. Prestwood, C. A. Gruman, G. Fabregas, B. Biskup, and G. Mansoor Effects of Transdermal Testosterone on Lipids and Vascular Reactivity in Older Men With Low Bioavailable Testosterone Levels J. Gerontol. A Biol. Sci. Med. Sci., July 1, 2002; 57(7): M460 - 465. [Abstract] [Full Text]

				J. E. Morley and J. H. Flaherty Editorial It's Never Too Late: Health Promotion and Illness Prevention in Older Persons J. Gerontol. A Biol. Sci. Med. Sci., June 1, 2002; 57(6): M338 - 342. [Full Text]

				F. Scopacasa, J.M. Wishart, A.G. Need, M. Horowitz, H.A. Morris, and B.E.C. Nordin Bone Density and Bone-Related Biochemical Variables in Normal Men: A Longitudinal Study J. Gerontol. A Biol. Sci. Med. Sci., June 1, 2002; 57(6): M385 - 391. [Abstract] [Full Text]

				A. M. Kenny, S. Bellantonio, C. A. Gruman, R. D. Acosta, and K. M. Prestwood Effects of Transdermal Testosterone on Cognitive Function and Health Perception in Older Men With Low Bioavailable Testosterone Levels J. Gerontol. A Biol. Sci. Med. Sci., May 1, 2002; 57(5): M321 - 325. [Abstract] [Full Text]

				A. M. Matsumoto Andropause: Clinical Implications of the Decline in Serum Testosterone Levels With Aging in Men J. Gerontol. A Biol. Sci. Med. Sci., February 1, 2002; 57(2): M76 - 99. [Full Text]

				J. E. Morley Editorial: Drugs, Aging, and the Future J. Gerontol. A Biol. Sci. Med. Sci., January 1, 2002; 57(1): M2 - 6. [Full Text] [PDF]

				J. E. Morley Editorial: Andropause: Is It Time for the Geriatrician to Treat It? J. Gerontol. A Biol. Sci. Med. Sci., May 1, 2001; 56(5): 263M - 265. [Full Text]

This Article Abstract Full Text (PDF) Services Download to citation manager Citing Articles Citing Articles via HighWire PubMed PubMed Citation