submit to the journals

Benefits and Consequences of Testosterone Replacement Therapy: A Review

European Endocrinology, 2013;9(1):59-64 DOI: http://doi.org/10.17925/EE.2013.09.01.59

Abstract:

late onset hypogonadism (loh) is an issue of increasing concern. Studies have shown the importance of testosterone in the maintenance of homeostasis,especially with respect to bone health, sexual function, diabetes, cardiovascular risk, mental health and cognition. Much of the dysfunction in hypogonadism can be reversed or improved with testosterone replacement therapy (TRT). Physicians worry about the possible consequences of TRT, especially regarding the prostate. By reviewing the literature, we have found there are significant benefits to TRT, and fears of adverse effects on the prostate are largely unfounded, though there is a great need for larger studies with longer periods of follow-up, especially to evaluate adverse events.
Keywords: late onset hypogonadism (loh), testosterone replacement, hormone replacement, testosterone, aging
Disclosure: The authors have no conflicts of interest to declare.
Received: December 25, 2012 Accepted: January 21, 2013
Correspondence: aScott Polackwich Jr., Md, department of urology, oregon health & Science university, 3303 SW Bond ave, ch10u,Portland, oR 97223, uS. E: polackwi@ohsu.edu

Introduction In our increasingly aged population, late-onset hypogonadism (LOH) is an important public health issue with an incidence estimated at 12.3 cases per 1000 person years.1 There is an increased public knowledge of this condition and more patients are approaching their physicians about diagnosis and treatment. Late-onset hypogonadism is an important clinical entity that should not be ignored by practitioners. it is associated with osteoporosis,2 frailty, 3 loss of libido and erectile dysfunction,4 depression,5 cognitive dysfunction,6 even cardiovascular disease7 and metabolic syndrome.8 Many patients and practitioners have lingering questions about the risks and benefits of this therapy as well as its use in certain populations, such as patients who have had prostate cancer or voiding dysfunction. While the use of testosterone in patients with a history of prostate cancer is currently contraindicated and considered off label use, many studies have started to evaluate it. here we provide a review of testosterone replacement therapy (TRT); the benefits of this treatment and the risks it may pose. Testosterone and Erectile Dysfunction The incidence of erectile dysfunction (ED) is increasing9 along with the incidence of hypogonadism.10 links between the two have been found on epidemiologic and basic science levels. after controlling for cofounders such as diabetes and vascular disease that typically occur in this population, the Massachusetts Male aging Study found an increase in ED with decreasing testosterone among 625 patients, especially with luteinizing hormone (LH) levels >8 iu/l.11 overall sexual dysfunction,especially ED has been associated with testosterone levels up to 8 nmol/lin a study of 2838 men.12 The effect of testosterone on ED is even more important in those with metabolic syndrome.13 Endothelial dysfunction appears to be the main mechanism by which testosterone deficiency increases the incidence of ED.14 Studies in rats have shown decreased cavernosal tissue apoptosis in diabetic rats when treated with testosterone.15 Similar effects are seen in humans and studies have found testosterone is important in tissue remodeling and maintenance of smooth muscle in erectile tissue. lateonset hypogonadism alters this hormonal support and may increase progenitor cell differentiation into adipocytes.16 This translates into an increase in arterial stiffness and arteriogenic ED in patients with lateonset hypogonadism.17,18 In addition to lohbeing a risk factor for development of ED,multiple studies have found improvement in ED with TRT. animal studies have found improvement in nitric oxide (No) synthase and erections after TRT therapy.19 in human studies, improvement in iiEF scores can be seen after as little as 3–6 months of testosterone replacement therapy (TRT) alone.20,21 This improvement in erectile function, along with multiple other indices of sexual function (libido, ejaculatory function and bother), have been found to improve quickly with TRT, and continue to improve for 12 months in an evaluation of 849 patients in a large multicenter registry.4 One study that evaluated patients’ response to TRT after maximal titration of phosphodiesterase type 5 inhibitors (PDE5I) found no additional improvement, though patients were not significantly hypogonadal, and these patients had good initial response to PDE5Is.22 in patients with lohwho have previously failed oral PDE5I therapy however, TRT has been found to improve responsiveness to PDE5Is.23 Penile doppler studies have shown this is likely by improvement of vasodilatory response to PDE5Is.24 This may save patients from being advanced to more invasive ED management such as intracavernosal injections and penile prosthesis placement. Evidence also suggests that early TRT may help in post prostatectomy ED25 (use in this population is currently contraindicated). With this evidence, patients with refractory ED should be evaluated for hypogonadism as evidence suggests there is a clinical benefit to concurrent treatment.
References:
  1. Araujo aB, o’donnell aB, Brambilla dJ, Simpson WB, et al., prevalence and incidence of androgen deficiency in Middleaged and older Men: Estimates from the Massachusetts Male aging Study, J Clin Endocrinol Metabol, 2004;89:5920–6.
  2. Cawthon pM. Ensrud KE, laughlin ga, cauley Ja, dam TT, Sex hormones and frailty in older men: the osteoporotic fractures in men (MroS) study,J Clin Endocrinol Metabol, 2009 oct;94(10):3806–15.
  3. Krasnoff JB, Basaria S, pencina MJ, et al., Free Testosterone levels are associated with Mobility limitation and physical performance in community-dwelling Men: The Framingham offspring Study, J Clin Endocrinol Metab,June 2010;95(6):2790–9
  4. Khera M, Bhattacharya rK, Blick g,et al., improved Sexual Function with Testosterone replacement Therapy in Hypogonadal Men: real-World data from the Testim registry in the united States (TriuS), J Sex Med, 2011 nov;8(11):3204–13.
  5. yesavage Ja, davidson J, Widrow l, Berger pa, plasma Testosterone levels, depression, Sexuality and age, Biol Psychiatry,1985;20:199–228.
  6. Christiansen K, Knussmann r, Sex Hormones and cognitive Functioning in Men, Neuropsychobiology,1987;18(1):27–36.
  7. Stellato rK, Feldman Ha, Hamdy o,et al., Testosterone, Sex Hormone-Binding globulin, and the development of Type 2 diabetes in Middle-aged Men: prospective results From the Massachusetts Male aging Study, Diabet Care,2000;23:490–4.
  8. Saad F, gooren lJ, The role of Testosterone in the Etiology and Treatment of obesity, the Metabolic Syndrome, and diabetes Mellitus Type 2, J Obes, 2011;(2011). article id: 471584.
  9. Johannes cB, araujo aB, Feldman Ha, et al., incidence of Erectile dysfunction in Men 40 to 69 years old: longitudinal results from the Massachusetts Male aging Study, J Urol, 2000;163:460.
  10. Feldman Ha, longcope c, derby ca, et al., age Trends in the level of Serum Testosterone and other Hormones in Middleaged Men: longitudinal results from the Massachusetts Male aging Study, J Clin Endocrinol Metab, 2002;87:589.
  11. Kupelian V, Shabsigh r, Travison Tg,et al., is There a relationship Between Sex Hormones and Erectile dysfunction? results from the Massachusetts Male aging Study, J Urol, 2006 dec;176(6 pt 1):2584–8.
  12. O’connor dB, lee dM, corona g,et al. The relationships Between Sex Hormones and Sexual Function in Middleaged and older European Men, J Clin Endocrinol Metab, october 2011, 96(10):E1577–E1587.
  13. yeh Hc,Wang cJ, lee yc,et al., association among Metabolic Syndrome, Testosterone level and Severity of Erectile dysfunction, Kaohsiung J Med Sci, 2008 May;24(5):240–7.
  14. Aversa a, Bruzziches r, Francomano d,et al., Endothelial dysfunction and Erectile dysfunction in the aging Man, International Journal of Urology, 2010;17:38–47.
  15. Mostafa T, rashed laand Kotb K, Testosterone and chronic Sildenafil/Tadalafil anti-apoptotic role in aged diabetic rats, International Journal of Impotence Research, 2010;22:255–61.
  16. Traish aM, Kim n.,Weapons of penile Smooth Muscle destruction: androgen deficiency promotes accumulation of adipocytes in the corpus cavernosum, Aging Male, 2005 Sep-dec;8(3-4):141–6.
  17. Corona g,Mannucci E, lotti F, et al., pulse pressure, an index of arterial Stiffness, is associated with androgen deficiency and impaired penile Blood Flow in Men with Ed, J Sex Med, 2009 Jan;6(1):285–93.
  18. Aversa a, isidori aM, de Martino Mu,et al., androgens and penile Erection: Evidence For a direct relationship Between Free Testosterone and cavernous Vasodilation in Men with Erectile dysfunction, Clinical Endocrinology, 2000;53:517–522.
  19. Baba K,M. yajima M, carrier S, et al., delayed Testosterone replacement restores nitric oxide Synthase-containing nerve Fibres and the Erectile response in rat penis, BJU International,2000;85:953–8.
  20. Chiang HS, cho Sl, lin yc,Hwang Ti. Testosterone gel Monotherapy improves Sexual Function of Hypogonadal Men Mainly Through restoring Erection: Evaluation by iiEF Score, J Urology. 2009 apr;73(4):762–6.
  21. Corona g, petrone l, Fisher ad,et al., Six-month administration of 1% testosterone gel is able to restore erectile function in hypogonadal patients with erectile dysfunction, Arch Ital Urol Androl, 2008 Sep;80(3):103–8.
  22. Spitzer M,Basaria S, Travison Tg, davda Mn,Effect of Testosterone replacement on response to Sildenafil citrate in Men With Erectile dysfunction: a parallel, randomized Trial, Ann Intern Med, 2012 nov 20;157(10):681–91.
  23. Garcia Ja, Sanchez pE, Fraile c,Escovar p,Testosterone undecanoate improves erectile dysfunction in hypogonadal metabolism in the prostate, specifically, the saturation model of testosterone’s effect on the prostate. While no recent study has found an association between TrT and prostate cancer incidence, recurrence, or progression, these studies have relatively low patient numbers and short follow-up for prostate cancer studies. Thus, TrT is still contraindicated in this population. What are needed now are large rcTs to definitively answer these questions for patients and providers. 102n men with the metabolic syndrome refractory to treatment with phosphodiesterase type 5 inhibitors alone, Andrologia, 2011 oct;43(5):293–6.
  24. Aversa a, isidori aM, Spera g, lenzi a, Fabbri a, androgens improve cavernous vasodilation and response to sildenafil in patients with erectile dysfunction, Clinical Endocrinology, 2003;58:632–8.
  25. Khera M, androgens and erectile function: a case for early androgen use in postprostatectomy hypogonadal men, J Sex Med, 2009 Mar;6 Suppl 3:234–8.
  26. Katznelson l, rosenthal di, rosol MS, et al., using quantitative cT to assess adipose distribution in adult men with acquired hypogonadism, AJR Am J Roentgenol, 1998 Feb;170(2):423–7.
  27. Yeap BB, chubb Sa, Hyde Z, et al., lower serum testosterone is independently associated with insulin resistance in non-diabetic older men: the Health in Men Study, Eur J Endocrinol. 2009 oct;161(4):591-8
  28. Garcia-cruz E, piqueras M, Huguet J, et al. Hypertension, dyslipidemia and overweight are related to lower testosterone levels in a cohort of men undergoing prostate biopsy, Int J Impot Res, 2012 May-Jun;24(3):110–3.
  29. Tamler r, deveney T, Hypogonadism, erectile dysfunction, and type 2 diabetes mellitus: what the clinician needs to know, Postgrad Med, 2010 nov;122(6):165–75.
  30. Aftab SS, Kumar S, Barber T, The role of obesity and Type 2 diabetes Mellitus in the development of Male obesityassociated Secondary Hypogonadism, Clin Endocrinol (oxf), 2012 nov 3 (epub).
  31. Lapauw B, ouwens M, Hart lM, et al., Sex steroids affect triglyceride handling, glucose-dependent insulinotropic polypeptide, and insulin sensitivity: a 1-week randomized clinical trial in healthy young men, Diabetes Care, 2010 aug;33(8):1831–3.
  32. Kapoor d, goodwin E, channer KS, Jones TH, Testosterone replacement therapy improves insulin resistance, glycaemic control, visceral adiposity and hypercholesterolaemia in hypogonadal men with type 2 diabetes, Eur J Endocrinol, June 1, 2006;154:899–906
  33. Frederiksen l, Højlund K, Hougaard dM, et al., Testosterone therapy decreases subcutaneous fat and adiponectin in aging men, Eur J Endocrinol, 2012 Mar;166(3):469–76.
  34. Agledahl i, Hansen JB, Svartberg J, impact of testosterone treatment on postprandial triglyceride metabolism in elderly men with subnormal testosterone levels, Scand J Clin Lab Invest, 2008;68(7):641–8.
  35. Mcgill JJ, Shoskes da, Sabanegh ES, androgen deficiency in older men: indications, advantages, and pitfalls of testosterone replacement therapy, Cleve Clin J Med, 2012 nov;79(11):797–806.
  36. Volzke Hr, Steveling a, Krebs a, et al., low serum testosterone levels are associated with increased risk of mortality in a population-based cohort of men aged 20-79, European Heart Journal, 2010 Jun;31(12):1494–501.
  37. Hyde Z, norman pE, Flicker l, et al., low free testosterone predicts mortality from cardiovascular disease but not other causes: the Health in Men Study, Journal of Clinical Endocrinology & Metabolism, 2012 Jan;97(1):179–89.
  38. Firtser S. Juonala M, Magnussen cg,et al., relation of total and free testosterone and sex hormone-binding globulin with cardiovascular risk factors in men aged 24-45 years, The cardiovascular risk in young Finns Study, Atherosclerosis, 2012 May;222(1):257–62.
  39. Araujo aB, dixon JM, Suarez Ea, et al., clinical review: Endogenous testosterone and mortality in men: a systematic review and meta-analysis, Journal of Clinical Endocrinology & Metabolism. 96(10):3007-19, 2011 oct.
  40. Haring r, Volzke H, Steveling aet al. low serum testosterone levels are associated with increased risk of mortality in a population-based cohort of men aged 20-79, Eur Heart J, 2010;31:1494–501.
  41. Hackett g,Testosterone and the heart, The international Journal of clinical practice, July 2012;66,7,648–55.
  42. Shores MM, Smith nl, Forsberg cW, et al., Testosterone treatment and mortality in men with low testosterone, J Clin Endocrinol Metab, 2012 Jun;97(6)2050–8.
  43. Basaria S, coviello ad,Travison Tg,Storer TW, adverse events associated with testosterone administration, N Engl J Med, 2010 Jul 8;363(2):109–22.
  44. Hyde Z,Flicker l, almeida op,et al., low Free Testosterone predicts Frailty in older Men: The Health in Men Study, J Clin Endocrinol Metab,95:3165–72, 2010.
  45. Storer TW, Woodhouse l, Magliano l, et al., changes in Muscle Mass, Muscle Strength, and power but not physical Function are related to Testosterone dose in Healthy older Men, J Am Geriatr Soc, 2008 nov;56(11):1991–9.
  46. Frederiksen l, Højlund K, Hougaard dM, et al., Testosterone therapy increased muscle mass and lipid oxidation in aging men, Age,2012 Feb;34(1):145–56.
  47. Srinivas-Shankar u, roberts Sa, et al., Effects of testosterone on muscle strength, physical function, body composition, and quality of life in intermediate-frail and frail elderly men: a randomized, double-blind, placebo-controlled study, J Clin Endocrinol Metab, 2010 Feb;95(2):639–50.
  48. Travison Tg,Basaria S, Storer TW, et al., clinical meaningfulness of the changes in muscle performance and physical function associated with testosterone administration in older men with mobility limitation, J Gerontol A Biol Sci Med Sci, 2011 oct;66(10):1090–9.
  49. risto o,Hammar E, Hammar K, et al., Elderly men with a history of distal radius fracture have significantly lower calcaneal bone density and free androgen index than agematched controls, Aging Male, 2012 Mar;15(1):59–62.
  50. Szulc p,Hawa g,Boutroy S, et al., cortical bone status is associated with serum osteoprotegerin concentration in men: the STraMBostudy, Journal of Clinical Endocrinology & Metabolism, 2011 Jul;96(7):2216–26.
  51. Rariy cM, ratcliffe SJ, Weinstein r, et al., Higher serum free testosterone concentration in older women is associated with greater bone mineral density, lean body mass, and total fat mass: the cardiovascular health study, Journal of Clinical Endocrinology & Metabolism, 2011;96(4):989–96.
  52. Kuchuk no,van Schoor nM, pluijm SM, et al., The association of sex hormone levels with quantitative ultrasound, bone mineral density, bone turnover and osteoporotic fractures in older men and women, Clinical Endocrinology, 2007 aug;67(2):295–303.
  53. Merza Z,Blumsohn a, Mah pM, et al., double-blind placebo-controlled study of testosterone patch therapy on bone turnover in men with borderline hypogonadism, International Journal of Andrology, 2006 Jun;29(3):381-91.
  54. Emmelot-Vonk MH, Verhaar HJ, nakhai pour Hr, et al., van der Schouw yT. Effect of testosterone supplementation on functional mobility, cognition, and other parameters in older men: a randomized controlled trial, JAMA, 2008 Jan;299(1):39–52.
  55. Kenny aM, Kleppinger a, annis K, et al., Effects of transdermal testosterone on bone and muscle in older men with low bioavailable testosterone levels, low bone mass, and physical frailty, Journal of the American Geriatrics Society, 2010 Jun;58(6):1134–43.
  56. Aversa a, Bruzziches r, Francomano d,et al., Migliaccio S. Effects of long-acting testosterone undecanoate on bone mineral density in middle-aged men with late-onset hypogonadism and metabolic syndrome: results from a 36 months controlled study, Aging Male, 2012 Jun;15(2):96–102.
  57. Wang c, cunningham g, dobs a, et al., long-term testosterone gel (androgel) treatment maintains beneficial effects on sexual function and mood, lean and fat mass, and bone mineral density in hypogonadal men, Journal of Clinical Endocrinology & Metabolism, 89(5):2085-98, .
  58. Berglund lH. prytz HS. perski a. Svartberg J. Testosterone levels and psychological health status in men from a general population: the Tromsø study, Aging Male, 2004 May 14(1):37–41.
  59. Pope HgJr, cohane gH, Kanayama g,et al., Testosterone gel supplementation for men with refractory depression: arandomized, placebo-controlled trial, Am J Psychiatry, 2003;160:105–11.
  60. Rabkin Jg,Wagner gJ, rabkin r, adouble-blind, placebocontrolled trial of testosterone therapy for HiV-positive men with hypogonadal symptoms, Arch Gen Psychiatry, 2000;57:141–7.
  61. Shores MM, Matsumoto aM, Sadak Ti, et al., Testosterone replacement decreases depressive symptoms in older hypogonadal men with subsyndromal depression. presentation at the american association of geriatric psychiatry, new orleans, la, March 4, 2007.
  62. Rabkin Jg,Wagner gJ, McElhiney Mc,et al., Testosterone versus fluoxetine for depression and fatigue in HiV/ aidS: aplacebo-controlled trial, J Clin Psychopharmacol, 2004;24:379–85.
  63. Seidman Sn,Miyazaki M, roose Sp, intramuscular testosterone supplementation to selective serotonin reuptake inhibitor in treatment-resistant depressed men: randomized placebo-controlled clinical trial, J Clin Psychopharmacol, 2005;25:584–8.
  64. Khera M, Bhattacharya rK, Blick g.et al., The effect of testosterone supplementation on depression symptoms in hypogonadal men from the Testim registry in the uS (TriuS), Aging Male, 2012 Mar;15(1):14–21.
  65. Driscoll i, Hamilton da, yeo ra, et al. Virtual navigation in humans:the impact of age, sex, and hormones on place learning, Horm Behav,2005;47(3):326–35.
  66. Thilers pp,Macdonald SW, Herlitz a, The association between endogenous free testosterone and cognitive performance: a population-based study in 35 to 90 year-old men and women, Psychoneuroendocrinology, 2006;31(5):565–76.
  67. Moffat Sd,Zonderman aB, Metter EJ, et al., longitudinal assessment of serum free testosterone concentration predicts memory performance and cognitive status in elderly men, J Clin Endo Metab,2002;87(11):5001–7.
  68. Tadros nn, garzotto M, androgen deprivation therapy for prostate cancer: not so simple, Asian J Androl, 2011 Mar;13(2):187–8.
  69. Alibhai SM, Breunis H, Timilshina n,et al., impact of androgen-deprivation therapy on cognitive function in men with nonmetastatic prostate cancer, J Clin Oncol, 2010;28:5030–7.
  70. Emmelot-Vonk MH, Verhaar HJ, nakhai pour Hr, et al., Effect of testosterone supplementation on functional mobility, cognition, and other parameters in older men: a randomized controlled trial, JAMA, 2008 Jan 2;299(1):39-52.
  71. Kenny aM, Bellantonio S, gruman ca, et al., 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, 2002 May;57(5):M321–5.
  72. Huggins c,Hodges cV, Studies on prostatic cancer, i: the effect of castration, of estrogen and of androgen injection on serum phosphatases in metastatic carcinoma of the prostate, Cancer Res, 1941;1:293–297.
  73. Fowler JE, Whitmore WF, The response of metastatic adenocarcinoma of the prostate to exogenous testosterone, J Urol, 1981;126:372–5.
  74. Morgentaler a, Testosterone and prostate cancer: an Historical perspective on a Modern Myth, European Urology, nov 2006;50(5):935–9.
  75. Morgentaler a, Traish aM, Shifting the paradigm of testosterone and prostate cancer: the saturation model and the limits of androgen-dependent growth, Eur Urol, 2009;55:310–320.
  76. Page ST, lin dW, Mostaghel Ea, et al., dihydrotestosterone administration does not increase intraprostatic androgen concentrations or alter prostate androgen action in Healthy Men: a randomized-controlled Trial, J Clin Endocrinol Metab,February 2011;96(2):430–7.
  77. Marks lS, Mazer na, Mostaghel E, et al., Effect of testosterone replacement therapy on prostate tissue in men with late-onset hypogonadism: a randomized controlled trial, JAMA, 2006 nov 15;296(19):2351–61.
  78. El-Sakka ai, Hassoba HM, Elbakry aM, Hassan Ha, prostatic specific antigen in patients with hypogonadism: effect of testosterone replacement, J Sex Med, 2005 Mar;2(2):235–40.
  79. Khera M, Miner M, Bhattacharya r, et al., pSalevels significantly rise after 3 months of testosterone replacement therapy in severely hypogonadal men in the Testim registry in the uS (TriuS) cohort, J Urol, 2010;183(Suppl):e533.
  80. Khera M, Bhattacharya rK, Blick g,et al., changes in prostate specific antigen in hypogonadal men after 12 months of testosterone replacement therapy: support for the prostate saturation theory, J Urol, 2011;186(3):1005–11.
  81. Morgentaler a, rhoden El, prevalence of prostate cancer among Hypogonadal Men With prostate-Specific antigen levels of 4 ng/ml or less, J Urology,2006;68:1263–7.
  82. Coward rM, Simhan J, carson cc, prostate-specific antigen changes and prostate cancer in hypogonadal men treated with testosterone replacement therapy, BJU International, 2008;103:1179–83.
  83. Shabsigh r, crawford Ed, nehra a, Slawin KM, Testosterone therapy in hypogonadal men and potential prostate cancer risk: a systematic review, Int J Impot Res,2009;21:9–23.
  84. Rhoden El, Morgentaler a, Testosterone replacement Therapy in Hypogonadal Men at High risk for prostate cancer: results of 1 year of Treatment in Men with prostatic intraepithelial neoplasia, J Urology,2003;170:2348–51.
  85. Agarwal pK, oefelein Mg.Testosterone replacement Therapy after primary Treatment for prostate cancer, J Urology, Feb 2005;173:533–6.
  86. Kaufman JM, graydon rJ, androgen replacement after curative radical prostatectomy for prostate cancer in Hypogonadal Men, J Urology,Sept 2004;172:920–2.
  87. Khera M, grober Ed, najari B, et al., Testosterone replacement therapy following radical prostatectomy, J Sex Med, 2009 apr;6(4):1165–70.
  88. Morales M, Black aM, Emerson lE, Testosterone administration to men with testosterone deficiency syndrome after external beam radiotherapy for localized prostate cancer: preliminary observations, BJU International,2008;103:62–4.
  89. Sarosdy MF, Testosterone replacement for Hypogonadism after Treatment of Early prostate cancer With Brachytherapy, Cancer,February 1 2007:109(3):536–41.
  90. Pastuszak aW, pearlman aM, godoy g,et al., Testosterone replacement therapy in the setting of prostate cancer treated with radiation, International Journal of Impotence Research, [epub. 13 September 2012].
  91. Morgentaler a, Two years of testosterone therapy associated with decline in prostate-specific antigen in a man with untreated prostate cancer, J Sex Med, 2009 Feb;6(2):574–7.
  92. Morales a, Effect of testosterone administration to men with prostate cancer is unpredictable: a word of caution and suggestions for a registry, BJU International, 2011;107:1369–73.
  93. Kirby r, gould d,Testosterone replacement Therapy in Hypogonadal men and prostate cancer risk, BJU International,2005;96:471–6.
  94. Polackwich aS, ostrowski Ka, Hedges Jc,Testosterone replacement Therapy and prostate Health, Curr Urol Rep, 2012;13:441–6.
  95. Trifiro Md, parsons JK, palazzi-churas K, et al., Serum sex hormones and the 20-year risk of lower urinary tract symptoms in community-dwelling older men, BJU Int, 2010;105(11):1554–9.
  96. Takao T, Tsujimura a, nakayama J, et al., lower urinary Tract Symptoms after Hormone replacement Therapy in Japanese patients with late-onset Hypogonadism: a preliminary report, Int J Urol, 2009;16:212–4.
  97. Haider H, gooren lJ, padungtod p,Saad F, concurrent improvement of the metabolic syndrome and lower urinary tract symptoms upon normalisation of plasma testosterone levels in hypogonadal elderly men, Andrologia, 2009;41(1):7–13.
  98. Amano T, imao T, Takemae K, et al., Testosterone replacement Therapy by Testosterone ointment relieves lower urinary Tract Symptoms in late onset Hypogonadism patients, Aging Male, 2010;13(4):242–6.
  99. Shigehara K, Sugimoto K, Konaka H, et al., androgen replacement Therapy contributes to improving lower urinary Tract Symptoms in patients with Hypogonadism and Benign prostate Hypertrophy: a randomized controlled study, Aging Male, 2011;14(1):53–8.
  100. Marberger M, roehrborn cg,Marks lS, et al., relationship among Serum Testosterone, Sexual Function, and the response to Treatment in Men receiving dutasteride for Benign prostatic Hyperplasia, J Clin Endocrinol Metab, 2006;91(4):1323–8.
  101. Page ST, Hirano l, gilchriest J, et al., dutasteride reduces prostate Size and prostate Specific antigen in older Hypogonadal Men With Benign prostatic Hyperplasia undergoing Testosterone replacement Therapy, J Urol, 2011;186:191–7.
  102. Bremner WJ, Testosterone deficiency and replacement in older Men, N Engl J Med, 2010;363:189–91.
Keywords: late onset hypogonadism (loh), testosterone replacement, hormone replacement, testosterone, aging