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Original Articles

Testosterone Replacement Therapy: Who to Evaluate, What to Use, How to Follow, and Who is at Risk?

, MD & , MD (Professor of Urology)

References

  • Bhasin S, Cunningham GR, Hayes FJ, et al. Testosterone therapy in men with androgen deficiency syndromes: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2010; 95(6):2536–2559.
  • Basaria S. Testosterone therapy in older men with late-onset hypogonadism: a counter-rationale. Endocr Pract. 2013; 19(5):1–40.
  • Delamothe T. Monkey business: reflections on testosterone. BMJ. 2012; 345:e4967.
  • Gorricho J, Gavilan E, Gervas J. Marketing, not evidence based arguments, has probably increased testosterone prescribing. BMJ. 2012; 345:e6905.
  • Hackett G, Kirby M, Jackson G, Wylie K. Evidence based medicine inevitably increases testosterone prescribing. BMJ. 2012; 345:e6167.
  • Layton JB, Li D, Meier CR, et al. Testosterone lab testing and initiation in the United Kingdom and the United States, 2000–2011. J Clin Endocrinol Metab. 2014; 99(3):835–842.
  • Baillargeon J, Urban RJ, Ottenbacher KJ, Pierson KS, Goodwin JS. Trends in androgen prescribing in the United States, 2001 to 2011. JAMA Intern Med. 2013; 173(15):1465–1466.
  • Gan EH, Pattman S, Pearce HS, Quinton R. A UK epidemic oftestosterone prescribing, 2001–2010. Clin Endocrinol. 2013; 79(4):564–570.
  • Handelsman DJ. Pharmacoepidemiology of testosterone prescribing in Australia, 1992–2010. Med J Aust. 2012; 196(10):642–645.
  • Handelsman DJ. Global trends in testosterone prescribing, 2000–2011: expanding the spectrum or prescription misuse. Med J Aust. 2013; 199(8):548–551.
  • Wang C, Nieschlag E, Swerdloff R, et al. ISA, ISSAM, EAU, EAA and ASA recommendations: Investigation, treatment and monitoring of late-onset hypogonadism in males. Eur J Endocrinol. 2008; 159(5):507–514.
  • Lazarou S, Reyes-Vallejo L, Morgentaler A. Wide variability in laboratory reference values for serum testosterone. J Sex Med. 2006; 3(6):1085–1089.
  • Finkelstein JS, Lee H, Burnett-Bowie SA, et al. Gonadal steroids and body composition, strength, and sexual function in men. N Engl J Med. 2013; 369(25):1011–1022.
  • Harman SM, Metter EJ, Tobin JD, Pearson J. Longitudinal effects of aging on serum total and free testosterone levels in healthy men. Baltimore Longitudinal Study of Aging. J Clin Endocrinol Metab. 2001; 86(2):724–731.
  • Mulligan T, Frick MF, Zuraw QC, Stemhagen A, Mcwhirter C. Prevalence of hypogonadism in males aged at least 45 years: the HIM study. Intl J Clin Pract. 2006; 60(7):762–769.
  • Araujo AB, O'Donnell AB, Brambilla DJ, et al. Prevalence and incidence of androgen deficiency in middle-aged and older men: estimates from the Massachusetts Male Aging Study. J Clin Endocrinol Metab. 2004; 89(12):5920–5926.
  • Surampadi PN, Wang C, Swerdloff R. Hypogonadism in the aging Male diagnosis, potential benefits, and risks of testosterone replacement therapy. Int J Endocrinol. 2012; 625434. doi:10.1155/2012/625434.
  • Miner M, Canty DJ, Shabsigh R. Testosterone Replacement therapy in hypogonadal men: assessing benefits, risks and best practices. Postgrad Med. 2008; 120(3):130–148.
  • Vermeulen A, Verdonck L, Kaufman JM. A critical evaluation of simple methods for estimation of free testosterone in serum. J Clin Endocrinol Metab. 1999; 84(10):3666–3672.
  • Gooren LJ. Late-onset hypogonadism. Front Horm Res. 2009; 37: 62–73.
  • Morales A, Tenover JL. Androgen deficiency in the aging male: when, who and how to investigate and treat. Urol Clin North Am. 2002; 29(4):974–982.
  • Matsumoto AM. Andropause: clinical implications of the decline in serum testosterone levels with aging in men. J Gerontol A Biol Sci Med Sci. 2002; 57(2):M76–M99.
  • Wu FC, Tajar A, Beynon M, et al. Identification of late-onset hypogonadism in middle-aged and elderly men. N Engl J Med. 2010; 363(2):123–135.
  • Goncharov N, Katsya G, Dobracheva A, et al. Serum testosterone measurement in men: evaluation of modern immunoassay technologies. Aging Male. 2005; 8(3–4):194–202.
  • Morley JE, Kaiser FE, Sih R, Hajjar R, Perry HM III. Testosterone and frailty. Clin Geriatr Med. 1997; 13(4):685–695.
  • Miwa Y, Kaneda T, Yokoyana O. Correlation between the aging males' symptoms scale and sex steroids, gonadotropins, dehydroepiandrosterone sulfate and growth hormone levels in ambulatory men. J Sex Med. 2006; 3(4):723–726.
  • Chen W, Liu ZY, Wang LH, Zeng QS, Wang HO, Sien YH. Are the Aging Male's Symptoms (AMS) scale and the Androgen Deficiency in the Aging Male (ADAM) questionnaires suitable for the screening of late onset hypogonadism in aging Chinese men? Aging Male. 2013; 16(3):926.
  • Cabral RD, Busin L, Rosito TE, Koff WJ. Performance of Massachusetts Male Aging Study (MMAS) and Androgen Deficiency in the Aging Male (ADAM) questionnaires in the prediction of free testosterone in patients aged 40 years or older treated in an outpatient regimen [published online ahead of print April 16, 2014]. Aging. No doi available.
  • Kang J II, Ham BK, Oh MM, Kim JJ, Moon DG. Correlation between serum total testosterone and the AMS and IIEF questionnaires in patients with erectile dysfunction with testosterone deficiency syndrome. Korean J Urol. 2011; 52(6):416–420.
  • Coward RM, Rajanahally S, Kovac JR, Smith RP, Pastuszak AW, Lipshultz LI. Anabolic steroid induced hypogonadism in young men. J Urol. 2013; 190(6):2200–2205.
  • Petak SM, Nankin HR, Spark RF, Swewrdloff RS, Rodriguez-Rigau LJ; American Association of Clinical Endocrinologists. American Association of Clinical Endocrinologists Medical Guidelines for Clinical Practice for the Evaluation and Treatment of Hypogonadism in Adult Male Patients–2002 Update. Endocr Pract. 2002; 8(6): 440–456.
  • Endocrine Today. February 2008. New testosterone assays may become gold standard. www.healio.com/endocrinology/reproduction-androgen-disorders/news/print/endocrin. Accessed June 5, 2014.
  • Lai Ming L, SangAeh P, Myong-Jin K, Chongwoo Yu, Li L. Baseline correction in testosterone bioequivalence study. Moderated Poster 32-10, Annual Meeting of the American Urologic Association, May 18, 2014, Orlando, FL.
  • Bremner WJ, Vitiello MV, Prinz PN. Loss of circadian rhythmicity in blood testosterone levels with aging in normal men. J Clin Endocrinol Metab. 1983; 56(6):1278–1281.
  • Brambilla DJ, O'Donnell AB, Matsumoto AM, McKinlay JB. Intra-individual variation in levels of serum testosterone and other reproductive and adrenal hormones in men. Clin Endocrinol (Oxf). 2007; 67(6):853–862.
  • Smith RP, Coward RM, Kovac JR, Lipshultz LI. The evidence for seasonal variations of testosterone in men. Maturitas. 2013; 74(3):208–212.
  • Vermeulen A, Verdonck L, Kaufman JM. A critical evaluation of simple methods for the estimation of free testosterone in serum. J Clin Endocrinol Metab. 1999; 84(10):3666–3672.
  • Coward R, Carson CC III. Prostate disease: testosterone replacement therapy after prostate cancer. Trends Urol Men's Health. 2011; 2(1):22–26.
  • Khera M, Grober ED, Najari B, et al. Testosterone replacement therapy following radical prostatectomy. J Sex Med. 2009; 6(4):1165–1170.
  • Kaufman JM, Graydon RJ. Androgen replacement after curative radical prostatectomy for prostate cancer in hypogonadal men. J Urol. 2004; 172(3):920–922.
  • Agarwal PK, Oefelein MG. Testosterone replacement therapy after primary treatment for prostate cancer. J Urol. 2005; 173(2):533–536.
  • Davila HH, Arison CN, Hall MK, et al. Analysis of the PSA response after testosterone supplementation in patients who have previously received management for their localized prostate cancer. J Urol. 2008; 179(Suppl):428. Abstract 1247.
  • Sarosdy MF. Testosterone replacement for hypogonadism after treatment of early prostate cancer with brachytherapy. Cancer. 2007; 109(3):536–541.
  • Pastuszak AW, Pearlman AM, Lai WS, et al. Testosterone replacement therapy in patients with prostate cancer after radical prostatectomy. J Urol. 2013; 190(2):639–644.
  • Hsieh TC, Pastuszak AW, Lipshultz LI. Concomitant intramuscular human chorionic gonadotropin preserves spermatogenesis in men undergoing testosterone replacement therapy. J Urol. 2013; 189(2):647–650.
  • de Ronde W, de Jong JH. Aromatase inhibitors in men: effects and therapeutic options. Reprod Biol Endocrinol. 2011; 9:93.
  • Ramasamy R, Scovell JM, Kovac JR, Lipshultz LI. Elevated serum estradiol is associated with higher libido in men on testosterone supplementation therapy. Letter to the editor. Eur Urol. 2014; 65(6):1224–1225.
  • Miner MM, Sadovsky R. Evolving issues in male hypogonadism: Evaluation, management and related co-morbidities. Cleve Clin J Med. 2007; 74(3):838–844.
  • Black AM, Day AG, Morales A. The reliability of clinical and biochemical assessment in symptomatic late-onset hypogonadism—can a case be made for a 3 month therapeutic trial? BJU Int. 2004; 94(7):1066–1070.
  • Saad F, Aversa A, Isidori A, Zitzmann M, Gooren L. Onset of effects of testosterone treatment and time span until maximum effects are achieved. Eur J Endocrinol. 2011; 165(5):675–685.
  • Zitmann M, Mattern A, Hanisch J, Gooren L, Jones H, Maggi M. IPASS: A study on the tolerability and effectiveness of injectable testosterone undecanoate for the treatment of male hypogonadism in a worldwide sample of 1,438 men. J Sex Med. 2013; 10(2):579–588.
  • Yassin DJ, Doros G, Hammerer PG, Yassin AA. Long-term testosterone treatment in elderly men with hypogonadism and erectile dysfunction reduces obesity parameters and improves metabolic syndrome and health-related quality of life. J Sex Med. 2014; 11(6):1567–1576.
  • Traish AM, Haider A, Doros G, Saad F. Long-term testosterone therapy in hypogonadal men ameliorates elements of the metabolic syndrome: an observational, long-term registry study. Int J Clin Pract. 2014; 68(3):314–329.
  • Hackett G, Cole B, Bhartia M, Kennedy D, Raju J, Wilkinson P. Testosterone replacement therapy with long-acting testosterone undecanoate improves sexual function and quality of life parameters vs placebo in a population of men with type 2 diabetes. J Sex Med. 2013; 10(6):1612–1627.
  • Hackett G, Cole N, Bhartia M, et al; for the BLAST study group. The response to testosterone undecanoate in men with type 2 diabetes is dependent on achieving threshold serum levels (the BLAST study). Int J Clin Pract. 2014; 68(2):203–215.
  • Snyder PJ, Lawrence DA. Treatment of male hypogonadism with testosterone enanthate. J Clin Endocrinol Metab. 1980; 51(6): 1335–1339.
  • Snyder PJ. Clinical use of androgens. Annu Rev Med. 1984; 35: 207–217.
  • Nieschlag E, Behre MM, Bouchard P, et al. Testosterone replacement therapy: current trends and future directions. Hum Reprod Update. 2004; 10(5):409–419.
  • Yassin AA, Haffejee M. Testosterone depot injection in male hypogonadism: a critical appraisal. Clin Interv Aging. 2007; 2(4):577–590.
  • Basaria S, Coviello A, Travison T, et al. Adverse events associated with testosterone administration. N Engl J Med. 2010; 363(2):109–122.
  • Rhoden EL, Morgentaler A. Risks of testosterone-replacement therapy and recommendations for monitoring. N Engl J Med. 2004; 350(5):482–492.
  • Calorf OM, Singh AB, Lee ML, et al. Adverse events associated with testosterone replacement in middle-aged and older men: a meta-analysis of randomized, placebo-controlled trials. J Gerontol A Biol Sci Med Sci. 2005; 60 A(11):1451–1457.
  • Dobs AS, Meikle AW, Arger S, et al. 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 Endocrinol Metab. 1999; 84(10):3469–3478.
  • Ip FF, de Pierro I, Brown R, Cunningham I, Handelsman DJ, Liu PY. Trough serum testosterone predicts the development of polycythemia in hypogonadal men treated for up to 21 years with subcutaneous testosterone pellets. Eur J Endocrinol. 2010; 162(2):385–390.
  • Knapp PE, Storer TW, Herbst KL, et al. Effects of a supraphysiological dose of testosterone on physical function, muscle performance, mood, and fatigue in men with HIV-associated weight loss. Am J Physiol Metab. 2008; 294(6):E1135–1143. http://ajpendo.physiology.org/content/294/6/E1135.long. Accessed May 16, 2014.
  • Fernandez-Balsells MM, Murad MH, Lane M, et al. Clinical reviews 1: adverse effects of testosterone therapy in adult men: a systemic review and meta-analysis. J Clin Endocrinol Metab. 2010; 95(6):2560–2575.
  • www.drugs.com/cdi/testosterone-cyprionate.html. Accessed May 16, 2014.
  • Corona G, Rastrelli G, Monami M, et al. Hypogonadism as a risk factor for cardiovascular mortality in men: a meta-analytic study. Eur J Endocrinol. 2011; 165(5):687–701.
  • Stellato RK, Feldman HA, Hamdy O, Horton ES, McKinlay JB. Testosterone, sex hormone-binding globulin, and the development of type 2 diabetes in middle-aged men: prospective results from the Massachusetts Male Aging Study. Diabetes Care. 2000; 23(4): 490–494.
  • Khaw KT, Dowsett M, Folkerd E, et al. Endogenous testosterone and mortality due to all causes, cardiovascular disease, and cancer in men: European Prospective Investigation into Cancer in Norfolk (EPIC-Norfolk) prospective population study. Circulation. 2007; 116(23):2694–2671.
  • Oh JY, Barrett-Connor E, Wedick NM, Wingard DL. Endogenous sex hormones and the development of type 2 diabetes in older men and women: the Rancho Bernardo study. Diabet Care. 2002; 25(1):55–60.
  • Shores MM, Matsumoto AM, Sloan KL, Kivlahan DR. Low serum testosterone and mortality in male veterans. Arch Intern Med. 2006; 166(15):1660–1665.
  • Hak AE, Witteman JCM, De Jong FH, Geerlings MI, Hofman A, Pols HA. Low levels of endogenous androgens increase the risk of atherosclerosis in elderly men: The Rotterdam Study. J Clin Endocrinol Metab. 2002; 87(8):3632–3639.
  • Tivesten A, Vandenput L, Labrie F, et al. Low serum testosterone and estradiol predict mortality in elderly men. J Endocrinol Metab. 2009; 94(7):2482–2488.
  • Vikan T, Schirmer H, Njolstad I, Svartber J. Endogenous sex hormones and the prospective association with cardiovascular disease and mortality in men: The Tromso Study. Eur J Endocrinol. 2009; 161(3):435–442.
  • Corona G, Monami M, Boddi V, et al. Low testosterone is associated with increased risk of MACE lethality in subjects with erectile dysfunction. J Sex Med. 2010; 7(4 pt 1):1557–1564.
  • Hyde Z, Norman P, Flicker L, et al. Low free testosterone predicts mortality from cardiovascular disease but not other causes: the Health in Men Study. J Clin Endocrinol Metab. 2012; 97(1):179–189.
  • Maggio M, Lauretani F, Ceda GP, et al. Relationship between low levels of anabolic hormones and 6-year mortality in older men: the aging in the Chianti Area (CHIANTI) study. Arch Intern Med. 2007; 167(20):2249–2254.
  • Pye SR, Huhtaniemi IT, Finn JD, et al; EMAS Study Group. Late-onset hypogonadism and mortality in aging men. J Clin Endocrinol Metab. 2014; 99(4):1357–1366.
  • Kalinchenko S, Tishova Y, Mskhalaya G, Gooren L, Giltay E, Saad F. Effects of testosterone supplementation on markers of the metabolic syndrome and inflammation in hypogonadal men with the metabolic syndrome: the double-blinded placebo-controlled Moscow study. Clin Endocrinol. 2010; 73(5):602–612.
  • Zgliczynski S, Ossowski M, Slowinska-Srzednicka J, et al. Effect of testosterone replacement therapy on lipids and lipoproteins in hypogonadal and elderly men. Atherosclerosis. 1996; 121(1):35–43.
  • Jones T. A placebo controlled study on the effects of transdermal testosterone gel in hypogonadal men with type II diabetes or metabolic syndrome in diabetic control and insulin sensitivity: the TIMES 2 study. Diabet Care. 2011; 34(4):828–837.
  • Boyanov MA, Boneva Z, Christov VG. Testosterone supplementation in men with type 2 diabetes, visceral obesity and partial androgen deficiency. Aging Male. 2003; 6(1):1–7.
  • Heufelder AE, Saad F, Bunck MC, Gooren L. Fifty-two-week treatment with diet and exercise plus transdermal testosterone reverses the metabolic syndrome and improves glycemic control in men with newly diagnosed type 2 diabetes and subnormal plasma testosterone. J Androl. 2009; 30(6):726–733.
  • Maggio M, Basaria S, Ble A, et al. Correlation between testosterone and the inflammatory marker soluble interleukin-6 receptor in older men. J Clin Endocrinol Metab. 2006; 91(1):345–347.
  • Haffner SM, Shaten J, Stern MP, Smith GD, Kuller L. Low levels of sex hormone-binding globulin and testosterone predict the development of non-insulin-dependent diabetes mellitus in men. MRFIT Research Group. Multiple Risk Factor Intervention Trial. Am J Epidemiol. 1996; 143(9):889–897.
  • Singh AB, Hsia S, Alaupovic P, et al. The effects of varying doses of T on insulin sensitivity, plasma lipids, apolipoproteins, and C-reactive protein in healthy young men. J Clin Endocrinol Metab. 2002; 87(1):136–143.
  • English KM, Steeds RP, Jones TH, Diver MJ, Channer MK, Channer KS. Low-dose transdermal testosterone therapy improves angina threshold in men with chronic stable angina: a randomized, double-blind, placebo-controlled study. Circulation. 2000; 102(16):1906–1911.
  • Mathur A, Malkin C, Saleem B, Muthusammy R, Jones CH, Channer K. The long-term benefits of testosterone on angina threshold and atheroma in men. Eur J Endocrinol. 2009; 161(3):443–449.
  • Finkle QD, Greenland S, Ridgeway GK, et al. Increased risk of nonfatal myocardial infarction following testosterone therapy prescription in men. PLOS One. 2014; 9(1). http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0085805. Accessed May 16, 2014.
  • Vigen R, O'Donnell CI, Baron AE, et al. Association of testosterone therapy with mortality, myocardial infarction, and stroke in men with low testosterone levels. JAMA. 2013; 310(7):1829–1836.
  • Xu L, freeman G, Cowling BJ, Schooling CM. Testosterone therapy and cardiovascular events among men: a systematic review and meta-analysis of placebo-controlled randomized trials. BMC Med. 2013; 11:108.
  • Haddad RM, Kennedy CC, Caples SM, et al. Testosterone and cardiovascular risk in men: a systematic review and meta-analysis of randomized-placebo-controlled trials. Mayo Clin Proc. 2007; 82(1): 29–39.
  • Shores MM, Smith NL, Forsberg CW, Anawalt BD, Matsumoto AM. Testosterone treatment and mortality in men with low testosterone levels. J Clin Endocrinol Metab. 2012; 97(6):2050–2058.
  • Muraleedaran V, Marsh H, Kapoor D, Channers KS, Jones TH. Testosterone deficiency is associated with increased risk of mortality and testosterone replacement therapy improves survival in men with type 2 diabetes mellitus. Eur J Endocrinol. 2013; 169(6):725–733.
  • Korenman SG, Morley JE, Mooradian AD, et al. Secondary hypogonadism in older men: its relation to impotence. J Clin Endocrinol Metab. 1990; 71(4):963–969.
  • Spark RF, White RA, Connolly PB. Impotence is not always psychogenic. Newer insights into hypothalamic-pituitary-gonadal dysfunction. JAMA. 1980; 243(8):750–755.
  • Slag MF, Morley JE, Elson MK, et al. Impotence in medical clinic outpatients. JAMA. 1983; 249(13):1736–1740.
  • Nickel JC, Morales A, Condra M, Fenemore J, Surridge DH. Endocrine dysfunction in impotence: incidence, significance and cost-effective screening. J Urol. 1984; 132(1):40–43.
  • . Guay AT, Bansal S, Heatley GJ. Effect of raising endogenous testosterone levels in impotent men with secondary hypogonadism: double blind placebo-controlled trial with clomiphene citrate. J Clin Endocrinol Metab. 1995; 80(12):3546–3552.
  • . Lugg JA, Rajfer J, Gonzalez-Cadavid NE. Dihydrotestosterone is the active androgen in the maintenance of nitric-oxide mediated penile erection in the rat. Endocrinology. 1995; 136(4):1495–1501.
  • . Mills TM, Reill CM, Lewis RW. Androgens and penile erection: a review. J Androl. 1996; 17(6):633–638.
  • . Morelli A, Filippi S, Mancina R, et al. Androgens regulate phosphodiesterase type 5 expression and functional activity in corpora cavernosa. Endocrinology. 2004; 145(5):2253–2263.
  • . Isidori AM, Giannetta E, Gianfrilli D, et al. Effects of testosterone on sexual function in men: results of a meta-analysis. Clin Endocrinol. 2005; 63(4):381–394.
  • . Bolona ER, Uraga MV, Haddad RM, et al. Testosterone use in men with sexual dysfunction: a systematic review and Meta-analysis of randomized placebo-controlled trials. Mayo Clin Proc. 2007; 82(1):20–28.
  • . Alhathal N, Elshal AM, Carrier S. Synergetic effect of testosterone and phosphodiesterase-5 inhibitors in hypogonadal men with erectile dysfunction: a systematic review. Can Urol Assoc J. 2012; 6(4):269–273.

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