B
Randomized Placebo-Controlled Trials of Testosterone Therapy in Older Men
Searches of the medical literature (described in Appendix A) resulted in 39 journal articles that reported the results of the 31 placebo-controlled trials of testosterone therapy in middle-aged or older men published from 1977 to 2003 (Table B-1). The committee focused its literature review on double-blinded placebo-controlled trials as they provide the best opportunity for obtaining accurate comparison data particularly when looking at qualitative endpoints such as sexual function and quality of life. Placebo-controlled trials to date have been conducted with small numbers of subjects, ranging from 6 to 108 participants, and most are of limited duration of treatment, ranging from 1 to 36 months. Of the 31 randomized trials, 18 studies administered testosterone intramuscularly, 5 gave it orally, 5 used a testosterone patch, and 3 used testosterone gel. Clinical trials of acute effects of testosterone used intravenous testosterone and are discussed in Chapter 2. 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. Table B-1 provides an overview of the design features of the trials and includes information on the baseline testosterone levels of study participants as well as the testosterone levels used as entry criteria to the trial.
TABLE B-1 Randomized Placebo-Controlled Studies of Testosterone Therapy in Middle-Aged and Older Mena
Reference |
Study Description, Dosageb |
Amory et al., 2002 |
T before elective knee replacement surgery; 600 mg TE, IM 21, 14, 7, and 1 day(s) before surgeryd |
Bakhshi et al., 2000 |
T during rehab unit stay; 100 mg TE, IM weekly |
Benkert et al., 1979 |
Effect of T on erectile dysfunction; 120 mg TU, orally daily |
Bhasin et al., 1998 |
Effect of T in hypogonadal HIV-positive men; Two 2.5 mg patches daily |
Blackman et al., 2002; Christmas et al., 2002; Münzer et al., 2001 |
T in healthy older men (also had GH and GH + T arms); 100 mg TE, IM every 2 weeks |
Cherrier et al., 2001 |
Effect of T on spatial and verbal memory in healthy older men; 100 mg TE, IM weekly |
Clague et al., 1999 |
Effect of T on muscle function in healthy older men; 200 mg TE, IM every 2 weeks |
Davidson et al., 1979 |
Effect of T on sexual behavior in hypogonadal men; 100 mg or 400 mg TE IM every 4 weeks |
Drinka et al., 1995 |
Effect of T on hematocrit in men in nursing home; 150 mg/70kg Tf IM every 2 weeks |
English et al., 2000 |
Effect of T on elderly men with CAD and stable angina; Two 2.5 mg patches daily |
Ferrando et al., 2002, 2003 |
Effect of T on muscle metabolism and function in older men; IM TE weekly for 1 month, then biweekly, adjusted doses |
Holmäng et al., 1993 |
Effect of T in middle-aged men; 80 mg TU orally twice daily |
Jaffe, 1977 |
Effect of T on post-exercise ST-segment depression; 200 mg TC IM weeklyd |
Janowsky et al., 1994 |
Effect of T on spatial cognition in older men; 15 mg scrotal patch 16 hours per day |
Janowsky et al., 2000 |
Effect of T on working memory in older men; 150 mg TE, IM weekly |
Duration |
N |
Population; Baseline T Level (ng/dL): Entry Criteria (ng/dL)c |
4 weeks |
22 |
Age 58–86 (mean 70) generally healthy; mean TT = 360 (Rx) and 375 (placebo) |
up to 8 weeks |
15 |
Age 65–90, ill, admitted to rehab unit |
8 weeks |
29 |
Age 45–75, erectile dysfunction; mean TT = 579 (Rx) and 495 (placebo) |
12 weeks |
32 |
Age 18–60, HIV positive; mean TT = 258 (Rx) and 211 (placebo): TT<400 ng/dL |
26 weeks |
74g |
Age 65–88, healthy; mean TT = 409 (Rx) and 392 (placebo): TT ≤ 470 ng/dL |
6 weeks |
25 |
Age 50–80, healthy community-dwelling; mean TT = 576 (Rx) and 548 (placebo) |
12 weeks |
14 |
Age 60+, healthy, community-dwelling; mean TT = 325 (Rx) and 334 (placebo): TT <403 ng/dL (14 nmol/L) |
5 months |
6 |
Age 37–61 with secondary gonadal failure or primary hypogonadism; circulating T<150 ng/100 mL |
6 months |
18 |
Veterans age 60–90 in nursing home: TT<320 ng/dL, FT<12 pg/mL |
12 weeks |
46 |
Mean age 62; mean TT = 390 (Rx) and 357 (placebo) |
6 months |
12 |
Age 64–71; mean TT = 357 (Rx) and 282 (placebo): TT = 480 ng/dL or less |
8 months |
23 |
Age 40–65 (median 52), slightly to moderately obese; mean TT = 461 (Rx) and 484 (placebo) |
8 weeks |
50 |
Age 35–71 (mean 58) with heart disease, baseline T not reported |
3 months |
56 |
Age 60–75 (mean 67), healthy; baseline T within normal ranges |
1 month |
19h |
Age 61–75, healthy; mean FT = 12.2 (Rx) and 12.3 (placebo) pg/mL |
Reference |
Study Description, Dosageb |
Kenny et al., 2001, 2002a,b |
Effect of T on older men with low bioavailable T levels; two 2.5 mg patches daily |
Mårin et al., 1992 |
Effect of T on body composition in middle-aged obese men; 125 mg TU orally twice daily |
Mårin et al., 1993, 1995 |
Effect of T and DHT on body composition in middle-aged obese men; 5 g T gel dailyj |
Nankin et al., 1986 |
Effect of T on erectile dysfunctione; 200 mg TC, IM every 2 weeks |
Pope et al., 2003 |
Effect of T on refractory depression; 10 g 1% gel daily, then adjusted |
Rabkin et al., 1999 |
Effect of T on HIV positive men; 200 mg once, then 400 mg TC IM biweekly, adjusted as needed |
Rabkin et al., 2000 |
Effect of T on HIV positive men; 200 mg once, then 400 mg TC IM biweekly, adjusted as needed |
Reddy et al., 2000 |
Effect of T on quality of life in older men; 200 mg TE IM every 2 weeks |
Schiavi et al., 1997 |
Effect of T on sexual behavior and mood in men with erectile dysfunctione; 200 mg TE IM biweekly |
Seidman et al., 2001 |
Effect of T on major depression in hypogonadal men; 200 mg TE, IM weekly |
Sih et al., 1997 |
T in hypogonadal older men; 200 mg TC, IM every 14–17 days |
Simon et al., 2001 |
Effect of T on insulin sensitivity and leptins in healthy men; 125 mg gel at first, then adjusted |
Skakkebaek et al., 1981 |
Effect of T on sexual function in chronically hypogonadal mene; 80 mg TU orally twice daily |
Snyder et al., 1999a,b, 2001 |
T treatment in older men; 6 mg scrotal patch daily |
Duration |
N |
Population; Baseline T Level (ng/dL): Entry Criteria (ng/dL)c |
12 months |
44 |
Age 65–87 (mean 76), healthy; mean TT = 389 (Rx and placebo): bioavailable T<128 ng/dL |
8 months |
23 |
Age >45 (mean 52i), abdominally obese; baseline mean TT = 461 (Rx) and 484 (placebo) |
9 months |
27 |
Mean age 58, abdominally obese; baseline mean TT = 435 (Rx) and 447 (placebo): TT <576 ng/dL |
12 weeks |
10 |
Age 51–74, healthy, community-dwelling, erectile dysfunction; mean TT = 377 (Rx) and 320 (placebo) |
8 weeks |
19 |
Age 30–65 (mean 47) with treated but refractory depression; mean TT = 293 (Rx) and 267 (placebo): TT in 100–350 ng/dL range |
6 week discontinuation trial |
77 |
Mean age 41, HIV positive with sexual dysfunction; mean TT = 303: TT <500 ng/dL |
6 weeks |
70 |
Mean age 38i, HIV positive with sexual dysfunction; mean TT = 378 (Rx) and 380 (placebo): TT <500 ng/dL |
8 weeks |
22 |
Age 65+, healthy; mean TT = 408 (Rx) and 282 (placebo) |
6 weeks |
12 |
Age 46–67 (median 60); mean TT = 454 |
6 weeks |
29 |
Age 35–71 (mean 52) with depression; mean TT = 270 (Rx) and 264 (placebo): TT ≤ 350 ng/dL |
12 months |
22 |
Mean age 65i, healthy; mean TT = 294 (Rx) and 233 (placebo): bioavailable T ≤ 60 ng/dL |
3 months |
18 |
Mean age 53i; mean TT = 240 (Rx) and 270 (placebo): TT <400 ng/dgk |
4 months |
11 |
Age 22–50, chronic hypogonadal |
36 months |
108l |
Age >65 (mean age 73), healthy; mean TT = 367 (Rx) and 369 (placebo): “T ≥ 1 SD below mean for healthy young men (<475 ng/dL)” |
Reference |
Study Description, Dosageb |
Tenover, 1992 |
T therapy in older mene; 100 mg TE IM weekly |
Uyanik et al., 1997 |
Effects of T on lipids/lipoproteins in healthy elderly; 120 mg TU, orally daily |
NOTE: CAD = coronary artery disease; FT = free testosterone; GH = growth hormone; HIV = human immunodeficiency virus; IM = intramuscular; NR = not reported; Rx = indicates treatment group receiving testosterone; SD = standard deviation; T = testosterone; TC = testosterone cypionate; TE = testosterone enanthate; TT = total testosterone; TU = testosterone undecanoate. aRandomized trials that assessed acute effects of testosterone on the heart are not included in this list but are discussed in the section on cardiovascular outcomes in Chapter 2. bAll trials are randomized and double-blinded and use physiologic doses unless otherwise noted. cPopulation age is given in years. Testosterone levels are converted to ng/dL. Entry criteria refer to the testosterone levels required to participate in the study and are not available for all studies. |
REFERENCES
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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.
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Duration |
N |
Population; Baseline T Level (ng/dL): Entry Criteria (ng/dL)c |
3 months |
13 |
Age 57–76; mean TT = 334: TT ≤ 400 ng/dL |
2 months |
37 |
Ages 53–89 (mean 67), healthy; mean TT = 224 (Rx) and 323 (placebo) |
dSupraphysiologic dose. eCross-over study. fTestosterone compound not specified. gMünzer et al., 2001 study, N = 64; Christmas et al., 2002 study, N = 72. hNumber of older male participants. There were additional groups of women and/or younger male participants. iMean age for the testosterone-treated group. jAs stated in the study, this dose corresponds to 125 mg of testosterone. kFor one of the cohorts the inclusion criteria was TT ≤ 340 ng/dL. l96 men completed the entire 36 months of the study. |
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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.
Holmäng S, Marin 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.
Jaffe MD. 1977. Effect of testosterone cypionate on postexercise ST segment depression. British Heart Journal 39(11):1217–1222.
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