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.



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Testosterone and Aging: Clinical Research Directions 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.

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Testosterone and Aging: Clinical Research Directions 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

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Testosterone and Aging: Clinical Research Directions 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

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Testosterone and Aging: Clinical Research Directions 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

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Testosterone and Aging: Clinical Research Directions 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)”

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Testosterone and Aging: Clinical Research Directions 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 Amory JK, Chansky HA, Chansky KL, Camuso MR, Hoey CT, Anawalt BD, Matsumoto AM, Bremner WJ. 2002. Preoperative supraphysiological testosterone in older men undergoing knee replacement surgery. Journal of the American Geriatrics Society 50(10):1698–1701. 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. 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, Storer TW, Asbel-Sethi N, Kilbourne A, Hays R, Sinha-Hikim I, Shen R, Arver S, Beall G. 1998. 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. 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. 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.

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Testosterone and Aging: Clinical Research Directions 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. 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. Journal 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. 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. 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. 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. 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. 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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Testosterone and Aging: Clinical Research Directions 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. 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. Mårin P, Holmäng S, Jönsson L, Sjöström L, Kvist H, Holm G, Lindstedt G, Björntorp P. 1992. The effects of testosterone treatment on body composition and metabolism in middle-aged obese men. International Journal of Obesity and 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, Björntorp 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. Münzer T, Harman SM, Hees P, Shapiro E, Christmas C, Bellantoni MF, Stevens TE, O’Connor KG, Pabst KM, St Clai 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. Nankin HR, Lin T, Osterman J. 1986. Chronic testosterone cypionate therapy in men with secondary impotence. Fertility & Sterility 46(2):300–307. 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. 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 and Therapeutics 25(6):421–426. 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, Spatz E, Rizzo C, Roose SP. 2001. Testosterone replacement therapy for hypogonadal men with major depressive disorder: a randomized, placebo-controlled clinical trial. Journal of Clinical Psychiatry 62(6):406–412.

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