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Articles

Recommendations on the diagnosis, treatment and monitoring of testosterone deficiency in men

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Pages 119-138 | Received 08 Jun 2021, Accepted 28 Jul 2021, Published online: 14 Aug 2021

References

  • Morales A, Lunenfeld B. International society for the study of the aging male. Aging male. Investigation, treatment and monitoring of late-onset hypogonadism in males. Official recommendations of ISSAM. Aging Male. 2002;5(2):74–86.
  • Nieschlag E, Swerdloff R, Behre HM, et al. Investigation, treatment and monitoring of late-onset hypogonadism in males. Aging Male. 2005;8(2):56–58.
  • Wang C, Nieschlag E, Swerdloff RS, et al. ISA, ISSAM, EAU, EAA and ASA recommendations: investigation, treatment and monitoring of late-onset hypogonadism in males. Aging Male. 2009;12(1):5–12.
  • Lunenfeld B, Mskhalaya G, Kalinchenko S, et al. Recommendations on the diagnosis, treatment and monitoring of late-onset hypogonadism in men – a suggested update. Aging Male. 2013;16(4):143–150.
  • Lunenfeld B, Mskhalaya G, Zitzmann M, et al. Recommendations on the diagnosis, treatment and monitoring of hypogonadism in men. Aging Male. 2015;18(1):5–15.
  • Snyder PJ, Bhasin S, Cunningham GR, et al. Lessons from the testosterone trials. Endocr Rev. 2018;39(3):369–386.
  • Al-Sharefi A, Quinton R. Current national and international guidelines for the management of male hypogonadism: helping clinicians to navigate variation in diagnostic criteria and treatment recommendations. Endocrinol Metab. 2020;35(3):526–540.
  • Trinick TR, Feneley MR, Welford H, et al. International web survey shows high prevalence of symptomatic testosterone deficiency in men. Aging Male. 2011;14(1):10–15.
  • Wu FC, Tajar A, Beynon JM, et al. Identification of late-onset hypogonadism in Middle-aged and elderly men. N Engl J Med. 2010;363(2):123–135.
  • Rastrelli G, Corona G, Tarocchi M, et al. How to define hypogonadism? Results from a population of men consulting for sexual dysfunction. J Endocrinol Invest. 2016;39(4):473–484.
  • Petak SM, Nankin HR ,Spark RF, et al. 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.
  • Lejeune H, Huyghe É, Droupy S. Diminution du désir sexuel et déficit en testostérone chez l'homme [hypoactive sexual desire and testosterone deficiency in men]. Prog Urol. 2013;23(9):621–628.
  • Lunenfeld B, Arver S, Moncada I, et al. How to help the aging male? Current approaches to hypogonadism in primary care. Aging Male. 2012;15(4):187–197.
  • Corona G, Mannucci E, Ricca V, et al. The age-related decline of testosterone is associated with different specific symptoms and signs in patients with sexual dysfunction. Int J Androl. 2009;32(6):720–728.
  • Salonia A, Rastrelli G, Hackett G, et al. Paediatric and adult-onset male hypogonadism. Nat Rev Dis Primers. 2019;5(1):38.
  • Grossmann M, Matsumoto AM. A perspective on middle-aged and older men with functional hypogonadism: focus on holistic management. J Clin Endocrinol Metab. 2017;102(3):1067–1075.
  • Millar AC, Lau ANC, Tomlinson G, et al. Predicting low testosterone in aging men: a systematic review. CMAJ. 2016;188(13):E321–E330.
  • Morley JE, Perry HM, Kevorkian RT, et al. Comparison of screening questionnaires for the diagnosis of hypogonadism. Maturitas. 2006;53(4):424–429.
  • Chen W, Liu ZY, Wang LH, et al. Are the aging male’s symptoms (AMS) scale and the androgen deficiency in the aging male (ADAM) questionnaire suitable for the screening of late-onset hypogonadism in aging Chinese men? Aging Male. 2013;16(3):92–96.
  • Rabah DM, Altaweel W, Arafa MA. Clinical assessment and validation of an Arabic aging male symptoms questionnaire in patients with androgen deficiency. Aging Male. 2011;14(1):33–36.
  • Behre HM, Tammela TL, Arver S, et al. A randomized, double-blind, placebo-controlled trial of testosterone gel on body composition and health-related quality-of-life in men with hypogonadal to low-normal levels of serum testosterone and symptoms of androgen deficiency over 6 months with 12 months open-label follow-up. Aging Male. 2012;15(4):198–207.
  • Zengerling F, Schrader AJ, Cronauer MV, et al. The “aging males’ symptoms” scale (AMS): predictive value for lowered circulating androgens. Aging Male. 2012;15(4):253–257.
  • Lee CP, Jiang JR, Chen Y, et al. The “aging males’ symptoms” (AMS) scale assesses depression and anxiety. Aging Male. 2013;16(3):97–101.
  • Moore C, Huebler D, Zimmermann T, et al. The aging males’ symptoms scale (AMS) as outcome measure for treatment of androgen deficiency. Eur Urol. 2004;46(1):80–87.
  • Nakamura M, Fujimura T, Nagata M, et al. Association between lower urinary tract symptoms and sexual dysfunction assessed using the core lower urinary tract symptom score and international index of erectile function-5 questionnaires. Aging Male. 2012;15(2):111–114.
  • Hermanns-Lê T, Scheen A, Piérard GE. Acanthosis nigricans associated with insulinresistance: pathophysiology and management. Am J Clin Dermatol. 2004;5(3):199–203.
  • Saad F, Aversa A, Isidori AM, et al. Testosterone as potential effective therapy in treatment of obesity in men with testosterone deficiency: a review. Curr Diabetes Rev. 2012;8(2):131–143.
  • Corona G, Rastrelli G, Vignozzi L, et al. Testosterone, cardiovascular disease and the metabolic syndrome. Best Pract Res Clin Endocrinol Metab. 2011;25(2):337–353.
  • Wu FC, Tajar A, Pye SR, et al. European male aging study group. Hypothalamic-pituitary-testicular axis disruptions in older men are differentially linked to age and modifiable risk factors: the European male aging study. J Clin Endocrinol Metab. 2008;93(7):2737–2745.
  • Araujo AB, Esche GR, Kupelian V, et al. Prevalence of symptomatic androgen deficiency in men. J Clin Endocrinol Metab. 2007;92(11):4241–4247.
  • Schneider G, Nienhaus K, Gromoll J, et al. Depressive symptoms in men aged 50 years and older and their relationship to genetic androgen receptor polymorphism and sex hormone levels in three different samples. Am J Geriatr Psychiatry. 2011;19(3):274–283.
  • Rastrelli G, Corona G, Maggi M. Both comorbidity burden and low testosterone can explain symptoms and signs of testosterone deficiency in men consulting for sexual dysfunction. Asian J Androl. 2020;22(3):265–273.
  • Zitzmann M, Faber S, Nieschlag E. Association of specific symptoms and metabolic risks with serum testosterone in older men. J Clin Endocrinol Metab. 2006;91(11):4335–4343.
  • Mulligan T, Frick MF, Zuraw QC, et al. Prevalence of hypogonadism in males aged at least 45 years: the HIM study. Int J Clin Pract. 2008;60(7):762–769.
  • Kaplan SA, O’Neill E, Lowe R, et al. Prevalence of low testosterone in aging men with benign prostatic hyperplasia: data from the proscar long-term efficacy and safety study (PLESS). Aging Male. 2013;16(2):48–51., Jun Epub 2013 Mar 12. PMID: 23480623.
  • Schatzl G, Brössner C, Schmid S, et al. Endocrine status in elderly men with lower urinary tract symptoms: correlation of age, hormonal status, and lower urinary tract function. The prostate study group of the Austrian society of urology. Urology. 2000;55(3):397–402.
  • Higano C. Androgen deprivation therapy: monitoring and managing the complications. Hematol Oncol Clin North Am. 2006;20(4):909–923.
  • Choong K, Basaria S. Emerging cardiometabolic complications of androgen deprivation therapy. Aging Male. 2010;13(1):1–9.
  • Sharifi N, Gulley JL, Dahut WL. Androgen deprivation therapy for prostate cancer. JAMA. 2005;294(2):238–244.
  • Joly F, Alibhai SM, Galica J, et al. Impact of androgen deprivation therapy on physical and cognitive function, as well as quality of life of patients with nonmetastatic prostate cancer. J Urol. 2006;176(6):2443–2447.
  • Mohile SG, Bylow K, Dale W, et al. A pilot study of the vulnerable elders survey-13 compared with the comprehensive geriatric assessment for identifying disability in older patients with prostate cancer who receive androgen ablation. Cancer. 2007;109(4):802–810.
  • Aaronson NK, Ahmedzai S, Bergman B, et al. The European Organization for Research and Treatment of Cancer QLQ-C30: a quality-of-life instrument for use in international clinical trials in oncology. J Natl Cancer Inst. 1993;85(5):365–376.
  • Lee JH, Lee SW. Testosterone and chronic prostatitis/chronic pelvic pain syndrome: a propensity score-matched analysis. J Sex Med. 2016;13(7):1047–1055.
  • Kato Y, Shigehara K, Kawaguchi S, et al. Efficacy of testosterone replacement therapy on pain in hypogonadal men with chronic pain syndrome: a subanalysis of a prospective randomised controlled study in Japan (EARTH study). Andrologia. 2020;52(9):e13768.
  • White HD, Brown LA, Gyurik RJ, et al. Treatment of pain in fibromyalgia patients with testosterone gel: pharmacokinetics and clinical response. Int Immunopharmacol. 2015;27(2):249–256.
  • Saad F, Gooren LJ. Late onset hypogonadism of men is not equivalent to the menopause. Maturitas. 2014;79(1):52–57.
  • Cattabiani C, Basaria S, Ceda GP, et al. Relationship between testosterone deficiency and cardiovascular risk and mortality in adult men. J Endocrinol Invest. 2012;35(1):104–120.
  • Lee DM, Tajar A, Pye SR, et al. Association of hypogonadism with vitamin D status: the European male ageing study. Eur J Endocrinol. 2012;166(1):77–85.
  • Pilz S, Frisch S, Koertke H, et al. Effect of vitamin D supplementation on testosterone levels in men. Horm Metab Res. 2011;43(03):223–225.
  • Wehr E, Pilz S, Boehm BO, et al. Association of vitamin D status with serum androgen levels in men. Clin Endocrinol. 2010;73(2):243–248. Epub 2009 Dec 29. PMID: 20050857.
  • Rafiq R, van Schoor NM, Sohl E, et al. Associations of vitamin D status and vitamin D-related polymorphisms with sex hormones in older men. J Steroid Biochem Mol Biol. 2016;164:11–17.
  • D’Andrea S, Martorella A, Coccia F, et al. Relationship of vitamin D status with testosterone levels: a systematic review and Meta-analysis. Endocrine. 2021;72(1):49–61.
  • Bremner AP, Feddema P, Leedman PJ, et al. Age-related changes in thyroid function: a longitudinal study of a community-based cohort. J Clin Endocrinol Metab. 2012;97(5):1554–1562.
  • Hollowell JG, Staehling NW, Flanders WD, et al. Serum TSH, T(4), and thyroid antibodies in the United States population (1988 to 1994): National Health and Nutrition Examination Survey (NHANES III). J Clin Endocrinol Metab. 2002;87(2):489–499.
  • Brochmann H, Bjøro T, Gaarder PI, et al. Prevalence of thyroid dysfunction in elderly subjects. A randomized study in a Norwegian rural community (Naerøy). Acta Endocrinol. 1988;117(1):7–12.
  • Boucai L, Hollowell JG, Surks MI. An approach for development of age-, gender-, and ethnicity-specific thyrotropin reference limits. Thyroid. 2011;21(1):5–11.
  • Fischer S, Ehlert U, Amiel Castro R. Hormones of the hypothalamic-pituitary-gonadal (HPG) axis in male depressive disorders - A systematic review and Meta-analysis. Front Neuroendocrinol. 2019;55:100792.
  • Dobs AS, Few WL, 3rd, Blackman MR, et al. Serum hormones in men with human immunodeficiency virus-associated wasting. J Clin Endocrinol Metab. 1996;81(11):4108–4112.
  • Balasubramanian A, Kohn TP, Santiago JE, et al. Increased risk of hypogonadal symptoms in shift workers with shift work sleep disorder. Urology. 2020;138:52–59.
  • Knegtering H, van der Moolen AE, Castelein S, et al. What are the effects of antipsychotics on sexual dysfunctions and endocrine functioning? Psychoneuroendocrinology. 2003;28 Suppl 2(Suppl 2):109–123.
  • Molitch ME. Drugs and prolactin. Pituitary. 2008;11(2):209–218.
  • Martens HF, Sheets PK, Tenover JS, et al. Decreased testosterone levels in men with rheumatoid arthritis: effect of low dose prednisone therapy. J Rheumatol. 1994;21(8):1427–1431. PMID: 7983641.
  • Schooling CM, Au Yeung SL, Freeman G, et al. The effect of statins on testosterone in men and women, a systematic review and meta-analysis of randomized controlled trials. BMC Med. 2013;11:57.
  • Aloisi AM, Aurilio C, Bachiocco V, et al. Endocrine consequences of opioid therapy. Psychoneuroendocrinology. 2009;34 Suppl 1:S162–S8.
  • Reddy RG, Aung T, Karavitaki N, et al. Opioid induced hypogonadism. BMJ. 2010;341:c4462.
  • Basaria S, Travison TG, Alford D, et al. Effects of testosterone replacement in men with opioid-induced androgen deficiency: a randomized controlled trial. Pain. 2015;156(2):280–288.
  • Coluzzi F, Billeci D, Maggi M, et al. Testosterone deficiency in non-cancer opioid-treated patients. J Endocrinol Invest. 2018;41(12):1377–1388.
  • Rosner W, Vesper H. Toward excellence in testosterone testing: a consensus statement. J Clin Endocrinol Metab. 2010;95(10):4542–4548.
  • Antonio L, Wu FC, O’Neill TW, et al. Low free testosterone is associated with hypogonadal signs and symptoms in men with normal total testosterone. J Clin Endocrinol Metab. 2016;101(7):2647–2657.
  • Rastrelli G, O’Neill TW, Ahern T, et al. Symptomatic androgen deficiency develops only when both total and free testosterone decline in obese men who may have incident biochemical secondary hypogonadism: prospective results from the EMAS. Clin Endocrinol. 2018;89(4):459–469.
  • Kacker R, Hornstein A, Morgentaler A. Free testosterone by direct and calculated measurement versus equilibrium dialysis in a clinical population. Aging Male. 2013;16(4):164–168.
  • Morgentaler A. Commentary: guideline for male testosterone therapy: a clinician’s perspective. J Clin Endocrinol Metab. 2007;92(2):416–417.
  • Giagulli VA, Castellana M, Lisco G, et al. Critical evaluation of different available guidelines for late-onset hypogonadism. Andrology. 2020;8(6):1628–1641.
  • 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.
  • Keevil BG, Adaway J. Assessment of free testosterone concentration. J Steroid Biochem Mol Biol. 2019;190:207–211.
  • Bhasin S, Pencina M, Jasuja GK, et al. Reference ranges for testosterone in men generated using liquid chromatography tandem mass spectrometry in a community-based sample of healthy nonobese young men in the Framingham Heart Study and applied to three geographically distinct cohorts. J Clin Endocrinol Metab. 2011;96(8):2430–2439.
  • Corona G, Isidori AM, Buvat J, et al. Testosterone supplementation and sexual function: a Meta-analysis study. J Sex Med. 2014;11(6):1577–1592.
  • Corona G, Rastrelli G, Morgentaler A, et al. Meta-analysis of results of testosterone therapy on sexual function based on international index of erectile function scores. Eur Urol. 2017;72(6):1000–1011.
  • Corona G, Giagulli VA, Maseroli E, et al. Testosterone supplementation and body composition: results from a meta-analysis of observational studies. J Endocrinol Invest. 2016;39(9):967–981.
  • Krakowsky Y, Conners W, Morgentaler A. Serum concentrations of sex hormone-binding globulin vary widely in younger and older men: clinical data from a men’s health practice. Eur Urol Focus. 2019;5(2):273–279.
  • Isidori AM, Lenzi A. Risk factors for androgen decline in older males: lifestyle, chronic diseases and drugs. J Endocrinol Invest. 2005;28(3 Suppl):14–22.
  • Morgentaler A, Khera M, Maggi M, et al. Commentary: who is a candidate for testosterone therapy? A synthesis of international expert opinions. J Sex Med. 2014;11(7):1636–1645.
  • Diver MJ, Imtiaz KE, Ahmad AM, et al. Diurnal rhythms of serum total, free and bioavailable testosterone and of SHBG in middle-aged men compared with those in young men. Clin Endocrinol. 2003;58(6):710–717.
  • Crawford ED, Barqawi AB, O’Donnell C, et al. The association of time of day and serum testosterone concentration in a large screening population. BJU Int. 2007;100(3):509–513.
  • Guay A, Miller MG, McWhirter CL. Does early morning versus late morning draw time influence apparent testosterone concentration in men aged ≥45 years? Data from the hypogonadism in males study. Int J Impot Res. 2008;20(2):162–167.
  • Caronia LM, Dwyer AA, Hayden D, et al. Abrupt decrease in serum testosterone levels after an oral glucose load in men: implications for screening for hypogonadism. Clin Endocrinol. 2013;78(2):291–296.
  • Gagliano-Jucá T, Li Z, Pencina KM, et al. Oral glucose load and mixed meal feeding lowers testosterone levels in healthy eugonadal men. Endocrine. 2019;63(1):149–156.
  • Chamberlain NL, Driver ED, Miesfeld RL. The length and location of CAG trinucleotide repeats in the androgen receptor N-terminal domain affect transactivation function. Nucleic Acids Res. 1994;22(15):3181–3186.
  • Rajender S, Singh L, Thangaraj K. Phenotypic heterogeneity of mutations in androgen receptor gene. Asian J Androl. 2007;9(2):147–179.
  • Zitzmann M. The role of the CAG repeat androgen receptor polymorphism in andrology. Front Horm Res. 2009;37:52–61.
  • Zitzmann M. Pharmacogenetics of testosterone replacement therapy. Pharmacogenomics. 2009;10(8):1341–1349.
  • Holm AC, Fredrikson MG, Theodorsson E, et al. Change in testosterone concentrations over time is a better predictor than the actual concentrations for symptoms of late onset hypogonadism. Aging Male. 2011;14(4):249–256.
  • Canale D, Caglieresi C, Moschini C, et al. Androgen receptor polymorphism (CAG repeats) and androgenicity. Clin Endocrinol. 2005;63(3):356–361.
  • Berglund LH, Prytz HS, Perski A, et al. Testosterone levels and psychological health status in men from a general population: the Tromsø study. Aging Male. 2011;14(1):37–41.
  • Scovell JM, Ramasamy R, Wilken N, et al. Hypogonadal symptoms in young men are associated with a serum total testosterone threshold of 400 ng/dL. BJU Int. 2015;116(1):142–146.
  • Tajar A, McBeth J, Lee DM, et al. Elevated levels of gonadotrophins but not sex steroids are associated with musculoskeletal pain in Middle-aged and older European men. Pain. 2011;152(7):1495–1501.
  • Corona G, Rastrelli G, Dicuio M, et al. Subclinical male hypogonadism. Minerva Endocrinol. 2020. doi:https://doi.org/10.23736/S0391-1977.20.03208-3
  • Citron JT, Ettinger B, Rubinoff H, et al. Prevalence of hypothalamic-pituitary imaging abnormalities in impotent men with secondary hypogonadism. J Urol. 1996;155(2):529–533.
  • Bunch TJ, Abraham D, Wang S, et al. Pituitary radiographic abnormalities and clinical correlates of hypogonadism in elderly males presenting with erectile dysfunction. DAGM. 2002;5(1):38–46.
  • Dalvi M, Walker BR, Strachan MW, et al. The prevalence of structural pituitary abnormalities by MRI scanning in men presenting with isolated hypogonadotrophic hypogonadism. Clin Endocrinol. 2016;84(6):858–861.
  • 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.
  • Vermeulen A. Hormonal cut-offs of partial androgen deficiency: a survey of androgen assays. J Endocrinol Invest. 2005;28(3 Suppl):28–31.
  • Al-Sharefi A, Mohammed A, Abdalaziz A, et al. Androgens and anemia: current trends and future prospects. Front Endocrinol (Lausanne)). 2019;10:754.
  • Saad F, Aversa A, Isidori AM, et al. Onset of effects of testosterone treatment and time span until maximum effects are achieved. Eur J Endocrinol. 2011;165(5):675–685.
  • Hackett G, Cole N, Bhartia M, et al. 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.
  • Saad F, Caliber M, Doros G, et al. Long-term treatment with testosterone undecanoate injections in men with hypogonadism alleviates erectile dysfunction and reduces risk of major adverse cardiovascular events, prostate cancer, and mortality. Aging Male. 2020;23(1):81–92.
  • Hackett G, Cole N, Mulay A, et al. Long-term testosterone therapy in type 2 diabetes is associated with decreasing waist circumference and improving erectile Function. World J Mens Health. 2020;38(1):68–77.
  • Snyder PJ, Peachey H, Berlin JA, et al. Of testosterone replacement in hypogonadal men. J Clin Endocrinol Metab. 2000;85(8):2670–2677.
  • Aversa A, Bruzziches R, Francomano D, et al. 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;15(2):96–102.
  • Haider A, Meergans U, Traish A, et al. Progressive improvement of T-Scores in men with osteoporosis and subnormal serum testosterone levels upon treatment with testosterone over six years. Int J Endocrinol. 2014;2014:1–9.
  • Isidori AM, Giannetta E, Greco EA, et al. Effects of testosterone on body composition, bone metabolism and serum lipid profile in Middle-aged men: a Meta-analysis. Clin Endocrinol. 2005;63(3):280–293.
  • Bhasin S, Calof OM, Storer TW, et al. Drug insight: testosterone and selective androgen receptor modulators as anabolic therapies for chronic illness and aging. Nat Clin Pract Endocrinol Metab. 2006;2(3):146–159.
  • Rodriguez-Tolrà J, Torremadé Barreda J, del Rio L, et al. Effects of testosterone treatment on body composition in males with testosterone deficiency syndrome. Aging Male. 2013;16(4):184–190.
  • Yassin A, Doros G. Testosterone therapy in hypogonadal men results in sustained and clinically meaningful weight loss. Clin Obes. 2013;3(3-4):73–83.
  • Francomano D, Ilacqua A, Bruzziches R, et al. Effects of 5-year treatment with testosterone undecanoate on lower urinary tract symptoms in obese men with hypogonadism and metabolic syndrome. Urology. 2014;83(1):167–173.
  • Saad F, Doros G, Haider KS, et al. Differential effects of 11 years of long-term injectable testosterone undecanoate therapy on anthropometric and metabolic parameters in hypogonadal men with normal weight, overweight and obesity in comparison with untreated controls: real-world data from a controlled registry study. Int J Obes. 2020;44(6):1264–1278.
  • Haider A, Yassin A, Doros G, et al. Effects of long-term testosterone therapy on patients with “diabesity”: results of observational studies of pooled analyses in obese hypogonadal men with type 2 diabetes. Int J Endocrinol. 2014;2014:1–15.
  • Corona G, Torres LO, Maggi M. Testosterone therapy: what We have learned from trials. J Sex Med. 2020;17(3):447–460.
  • Grossmann M, Ng Tang Fui M, Cheung AS. Late-onset hypogonadism: metabolic impact. Andrology. 2020;8(6):1519–1529.
  • 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. 2010;95(6):2790–2799.
  • Walsh JS, Marshall H, Smith IL, et al. Testosterone replacement in young male cancer survivors: a 6-month double-blind randomised placebo-controlled trial. PLOS Med. 2019;16(11):e1002960.
  • Kacker R, Conners W, Zade J, et al. Bone mineral density and response to treatment in men younger than 50 years with testosterone deficiency and sexual dysfunction or infertility. J Urol. 2014;191(4):1072–1076.
  • Drake MT, Murad MH, Mauck KF, et al. Clinical review. Risk factors for low bone mass-related fractures in men: a systematic review and meta-analysis. J Clin Endocrinol Metab. 2012;97(6):1861–1870.
  • Kanis JA, Oden A, Johansson H, et al. FRAX and its applications to clinical practice. Bone. 2009;44(5):734–743.
  • Watts NB, Adler RA, Bilezikian JP, et al. Osteoporosis in men: an endocrine society clinical practice guideline. J Clin Endocrinol Metab. 2012;97(6):1802–1822.
  • Snyder PJ, Kopperdahl DL, Stephens-Shields AJ, et al. Effect of testosterone treatment on volumetric bone density and strength in older men with low testosterone: a controlled clinical trial. JAMA Intern Med. 2017;177(4):471–479.
  • Aminorroaya A, Kelleher S, Conway AJ, et al. Adequacy of androgen replacement influences bone density response to testosterone in androgen-deficient men. Eur J Endocrinol. 2005;152(6):881–886.
  • Pizzocaro A, Vena W, Condorelli R, Testosterone treatment in male patients with Klinefelter syndrome: a systematic review and meta-analysis. J Endocrinol Invest. 2020;43(12):1675–1687.
  • Orwoll E, Lambert LC, Marshall LM, et al. Endogenous testosterone levels, physical performance, and fall risk in older men. Arch Intern Med. 2006;166(19):2124–2131.
  • Rosenberg EA, Bůžková P, Fink HA, et al. Testosterone, dihydrotestosterone, bone density, and hip fracture risk among older men: the cardiovascular health study. Metabolism. 2021;114:154399.
  • Nethander M, Vandenput L, Eriksson AL, et al. Evidence of a causal effect of estradiol on fracture risk in Men. J Clin Endocrinol Metab. 2019;104(2):433–442.
  • Algeffari M, Jayasena CN, MacKeith P, et al. Testosterone therapy for sexual dysfunction in men with type 2 diabetes: a systematic review and meta-analysis of randomized controlled trials. Diabet Med. 2018;35(2):195–202.
  • Haider KS, Haider A, Doros G, et al. Long-term testosterone therapy improves urinary and sexual function, and quality of life in men with hypogonadism: results from a propensity matched subgroup of a controlled registry study. J Urol. 2018;199(1):257–265.
  • Cunningham GR, Stephens-Shields AJ, Rosen RC, et al. Testosterone treatment and sexual function in older men with low testosterone levels. J Clin Endocrinol Metab. 2016;101(8):3096–3104.
  • Brock G, Heiselman D, Maggi M, et al. Effect of testosterone solution 2% on testosterone concentration, sex drive and energy in hypogonadal men: results of a placebo controlled study. J Urol. 2016;195(3):699–705.
  • Hackett G, Cole N, Saghir A, et al. Testosterone undecanoate improves sexual function in men with type 2 diabetes and severe hypogonadism: results from a 30-week randomized placebo-controlled study. BJU Int. 2016;118(5):804–813.
  • Kalinchenko SY, Kozlov GI, Gontcharov NP, et al. Oral testosterone undecanoate reverses erectile dysfunction associated with diabetes mellitus in patients failing on sildenafil citrate therapy alone. Aging Male. 2003;6(2):94–99.
  • Zitzmann M, Mattern A, Hanisch J, et al. 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.
  • Tan WS, Ng CJ, Khoo EM, et al. The triad of erectile dysfunction, testosterone deficiency syndrome and metabolic syndrome: findings from a multi-ethnic asian men study (the subang men's health study). Aging Male. 2011;14(4):231–236. Dec PMID: 22115177.
  • Kapoor D, Aldred H, Clark S, et al. Clinical and biochemical assessment of hypogonadism in men with type 2 diabetes: correlations with bioavailable testosterone and visceral adiposity. Diabetes Care. 2007;30(4):911–917.
  • Tajar A, Huhtaniemi IT, O’Neill TW, et al. Characteristics of androgen deficiency in late-onset hypogonadism: results from the european male aging study (EMAS). J Clin Endocrinol Metab. 2012;97(5):1508–1516.
  • Tsujimura A, Miyagawa Y, Takezawa K, et al. Is low testosterone concentration a risk factor for metabolic syndrome in healthy middle-aged men? Urology. 2013;82(4):814–819.
  • Corona G, Monami M, Rastrelli G, et al. Testosterone and metabolic syndrome: a meta-analysis study. J Sex Med. 2011;8(1):272–283.
  • Aversa A, Bruzziches R, Francomano D, et al. Effects of testosterone undecanoate on cardiovascular risk factors and atherosclerosis in Middle-aged men with late-onset hypogonadism and metabolic syndrome: results from a 24-month, randomized, double-blind, placebo-controlled study. J Sex Med. 2010;7(10):3495–3503.
  • Strollo F, Strollo G, Morè M, et al. Low-intermediate dose testosterone replacement therapy by different pharmaceutical preparations improves frailty score in elderly hypogonadal hyperglycaemic patients. Aging Male. 2013;16(2):33–37.
  • Heufelder AE, Saad F, Bunck MC, et al. 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.
  • Groti K, Žuran I, Antonič B, et al. The impact of testosterone replacement therapy on glycemic control, vascular function, and components of the metabolic syndrome in obese hypogonadal men with type 2 diabetes. Aging Male. 2018;21(3):158–169.
  • Li SY, Zhao YL, Yang YF, et al. Metabolic effects of testosterone replacement therapy in patients with type 2 diabetes mellitus or metabolic syndrome: a Meta-Analysis. Int J Endocrinol. 2020;2020:1–12.
  • Wittert G, Bracken K, Robledo KP, et al. Testosterone treatment to prevent or revert type 2 diabetes in men enrolled in a lifestyle programme (T4DM): a randomised, double-blind, placebo-controlled, 2-year, phase 3b trial. Lancet Diabetes Endocrinol. 2021;9(1):32–45.
  • Muller M, van den Beld AW, Bots ML, et al. Endogenous sex hormones and progression of carotid atherosclerosis in elderly men. Circulation. 2004;109(17):2074–2079.
  • Groti Antonič K, Antonič B, Žuran I, et al. Testosterone treatment longer than 1 year shows more effects on functional hypogonadism and related metabolic, vascular, diabetic and obesity parameters (results of the 2-year clinical trial). Aging Male. 2020;23(5):1442–1413.
  • Akishita M, Hashimoto M, Ohike Y, et al. Low testosterone level is an independent determinant of endothelial dysfunction in men. Hypertens Res. 2007;30(11):1029–1034.
  • Kang SM, Jang Y, Kim Ji Chung N, et al. Effect of oral administration of testosterone on brachial arterial vasoreactivity in men with coronary artery disease. Am J Cardiol. 2002;89(7):862–864.
  • Zitzmann M, Vorona E, Wenk M, et al. Testosterone administration decreases carotid artery intima media thickness as indicator of vascular damage in middle-aged overweight men. J Androl. 2008;29:54–55.
  • Nettleship JE, Pugh PJ, Channer KS, et al. Inverse relationship between serum levels of interleukin-1beta and testosterone in men with stable coronary artery disease. Horm Metab Res. 2007;39(5):366–371.
  • Kalinchenko SY, Tishova YA, Mskhalaya GJ, et al. 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.
  • Kelly DM, Jones TH. Testosterone: a metabolic hormone in health and disease. J Endocrinol. 2013;217(3):R25–45.
  • Vodo S, Bechi N, Petroni A, et al. Testosterone-induced effects on lipids and inflammation. Mediators Inflamm. 2013;2013:183041
  • Wallis CJ, Lo K, Lee Y, et al. Survival and cardiovascular events in men treated with testosterone replacement therapy: an intention-to-treat observational cohort study. Lancet Diabetes Endocrinol. 2016;4(6):498–506.
  • Tan RS, Cook KR, Reilly WG. Myocardial infarction and stroke risk in young healthy men treated with injectable testosterone. Int J Endocrinol. 2015;2015:1–8
  • Loo SY, Azoulay L, Nie R, et al. Cardiovascular and cerebrovascular safety of testosterone replacement therapy among aging men with low testosterone levels: a cohort Study. Am J Med. 2019;132(9):1069–1077.e4.
  • Sesti F, Pofi R, Minnetti M, et al. Late-onset hypogonadism: reductio ad absurdum of the cardiovascular risk-benefit of testosterone replacement therapy. Andrology. 2020;8(6):1614–1627.
  • Traish AM, Hackett G, Miner M, et al. Cardiovascular and cerebrovascular safety of testosterone therapy. Am J Med. 2019;132(10):e748.
  • Rastrelli G, Dicuio M, Reismann Y, et al. Cardiovascular impact of testosterone therapy for hypogonadism. Expert Rev Cardiovasc Ther. 2018;16(9):617–625.
  • Corona G, Rastrelli G, Di Pasquale G, et al. Endogenous testosterone levels and cardiovascular risk: meta-analysis of observational studies. J Sex Med. 2018;15(9):1260–1271.
  • Corona G, Rastrelli G, Di Pasquale G, et al. Testosterone and cardiovascular risk: meta-analysis of interventional Studies. J Sex Med. 2018;15(6):820–838.
  • Park S, Gale SE, Watson K. The role of testosterone in patients with heart failure: a systematic review. Cardiol Rev. 2021;29(3):156–161.
  • Oni OA, Dehkordi SHH, Jazayeri MA, et al. Relation of testosterone normalization to mortality and myocardial infarction in men with previous myocardial infarction. Am J Cardiol. 2019;124(8):1171–1178.
  • Baillargeon J, Urban RJ, Morgentaler A, et al. Risk of venous thromboembolism in men receiving testosterone therapy. Mayo Clin Proc. 2015;90(8):1038–1045.
  • Houghton DE, Alsawas M, Barrioneuvo P, et al. Testosterone therapy and venous thromboembolism: a systematic review and meta-analysis. Thromb Res. 2018;172:94–103.
  • Martinez C, Suissa S, Rietbrock S, et al. Testosterone treatment and risk of venous thromboembolism: population based case-control study. BMJ. 2016;355:i5968.
  • Corona G, Dicuio M, Rastrelli G, et al. Testosterone treatment and cardiovascular and venous thromboembolism risk: what is ‘new’? J Investig Med. 2017;65(6):964–973.
  • Araujo AB, Dixon JM, Suarez EA, et al. Clinical review: endogenous testosterone and mortality in men: a systematic review and meta-analysis. J Clin Endocrinol Metab. 2011;96(10):3007–3019.
  • Hyde Z, Norman PE, Flicker L, et al. Low free testosterone predicts mortality from cardiovascular disease but not other causes: the health in menstudy. J Clin Endocrinol Metab. 2012;97(1):179–189.
  • Shores MM, Smith NL, Forsberg CW, et al. Testosterone treatment and mortality in men with low testosterone levels. J Clin Endocrinol Metab. 2012;97(6):2050–2058.
  • Muraleedharan V, Marsh H, Kapoor D, et al. Testosterone deficiency is associated with increased risk of mortality and testosterone replacement improves survival in men with type 2 diabetes. Eur J Endocrinol. 2013;169(6):725–733.
  • Yeap BB. Testosterone therapy and mortality in US veterans. Asian J Androl. 2012;14(5):667–668.
  • Wu FC. Caveat emptor: does testosterone treatment reduce mortality in men? J Clin Endocrinol Metab. 2012;97(6):1884–1886.
  • Yeap BB, Marriott RJ, Antonio L, et al. Serum testosterone is inversely, and sex hormone-binding globulin directly, associated with all-cause mortality in men. J Clin Endocrinol Metab. 2021;106(2):e625–e637.
  • Zarrouf FA, Artz S, Griffith J, et al. Testosterone and depression: systematic review and meta-analysis. J Psychiatr Pract. 2009;15(4):289–305.
  • Walther A, Breidenstein J, Miller R. Association of testosterone treatment with alleviation of depressive symptoms in men: a systematic review and Meta-analysis. JAMA Psychiatry. 2019;76(1):31–40.
  • Giltay EJ, Tishova YA, Mskhalaya GJ, et al. Effects of testosterone supplementation on depressive symptoms and sexual dysfunction in hypogonadal men with the metabolic syndrome. J Sex Med. 2010;7(7):2572–2582.
  • 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;15(1):14–21.
  • Zitzmann M. Testosterone, mood, behaviour and quality of life. Andrology. 2020;8(6):1598–1605.
  • Morley JE, Kaiser F, Raum WJ, et al. Potentially predictive and manipulable blood serum correlates of aging in the healthy human male: progressive decreases in bioavailable testosterone, dehydroepiandrosterone sulfate, and the ratio of insulin-like growth factor 1 to growth hormone. Proc Natl Acad Sci U S A. 1997;94(14):7537–7542.
  • Maggio M, Dall’Aglio E, Lauretani F, et al. The hormonal pathway to cognitive impairment in older men. J Nutr Health Aging. 2012;16(1):40–54.
  • Tan S, Sohrabi HR, Weinborn M, et al. Effects of testosterone supplementation on separate cognitive domains in cognitively healthy older men: a meta-analysis of current randomized clinical trials. Am J Geriatr Psychiatry. 2019;27(11):1232–1246
  • Janowsky JS. Thinking with your gonads: testosterone and cognition. Trends Cogn Sci. 2006;10(2):77–82.
  • Etgen T, Sander D, Bickel H, et al. Mild cognitive impairment and dementia: the importance of modifiable risk factors. Dtsch Arztebl Int. 2011;108(44):743–750.
  • Lv W, Du N, Liu Y, et al. Low testosterone level and risk of alzheimer’s disease in the elderly men: a systematic review and meta-Analysis. Mol Neurobiol. 2016;53(4):2679–2684.
  • Corona G, Guaraldi F, Rastrelli G, et al. Testosterone deficiency and risk of cognitive disorders in aging males. World J Mens Health. 2021;39(1):9–18.
  • Kim JW, Oh MM, Yoon CY, et al. Nocturnal polyuria and decreased serum testosterone: is there an association in men with lower urinary tract symptoms? Int J Urol. 2014;21(5):518–523.
  • Pearl JA, Berhanu D, François N, et al. Testosterone supplementation does not worsen lower urinary tract symptoms. J Urol. 2013;190(5):1828–1833.
  • 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 randomised controlled study. Aging Male. 2011;14(1):53–58.
  • Yassin DJ, El Douaihy Y, Yassin AA, et al. Lower urinary tract symptoms improve with testosterone replacement therapy in men with late-onset hypogonadism: 5-year prospective, observational and longitudinal registry study. World J Urol. 2014;32(4):1049–1054.
  • Kalinchenko S, Vishnevskiy EL, Koval AN, et al. Beneficial effects of testosterone administration on symptoms of the lower urinary tract in men with late-onset hypogonadism: a pilot study. Aging Male. 2008;11(2):57–61.
  • Teeling F, Raison N, Shabbir M, et al. Testosterone therapy for high-risk prostate cancer survivors: a systematic review and meta-analysis. Urology. 2019;126:16–23.
  • Kardoust Parizi M, Abufaraj M, Fajkovic H, et al. Oncological safety of testosterone replacement therapy in prostate cancer survivors after definitive local therapy: a systematic literature review and meta-analysis. Urol Oncol. 2019;37(10):637–646.
  • Morgentaler A, Lipshultz LI, Bennett R, et al. Testosterone therapy in men with untreated prostate cancer. J Urol. 2011;185(4):1256–1260.
  • Giganti F, Moore CM. Magnetic resonance imaging in active surveillance-a modern approach. Transl Androl Urol. 2018;7(1):116–131.
  • Ory J, Flannigan R, Lundeen C, et al. Testosterone therapy in patients with treated and untreated prostate cancer: impact on oncologic outcomes. J Urol. 2016;196(4):1082–1089.
  • Kacker R, Hult M, San Francisco IF, et al. Can testosterone therapy be offered to men on active surveillance for prostate cancer? Preliminary results. Asian J Androl. 2016;18(1):16–20.
  • 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(2):310–320.
  • Morgentaler A, Benesh JA, Denes BS, et al. Factors influencing prostate-specific antigen response among men treated with testosterone therapy for 6 months. J Sex Med. 2014;11(11):2818–2825.
  • Rastrelli G, Corona G, Vignozzi L, et al. Serum PSA as a predictor of testosterone deficiency. J Sex Med. 2013;10(10):2518–2528.
  • Lopez DS, Advani S, Tsilidis KK, et al. Endogenous and exogenous testosterone and prostate cancer: decreased-, increased- or null-risk? Transl Androl Urol. 2017;6(3):566–579.
  • Roddam AW, Allen NE, Appleby P, et al. Endogenous sex hormones and prostate cancer: a collaborative analysis of 18 prospective studies. J Natl Cancer Inst. 2008;100(3):170–183.
  • Fernández-Balsells MM, Murad MH, Lane M, et al. Clinical review 1: adverse effects of testosterone therapy in adult men: a systematic review and meta-analysis. J Clin Endocrinol Metab. 2010;95(6):2560–2575.
  • Boyle P, Koechlin A, Bota M, et al. Endogenous and exogenous testosterone and the risk of prostate cancer and increased prostate-specific antigen (PSA) level: a meta-analysis. BJU Int. 2016;118(5):731–741.
  • Haider A, Zitzmann M, Doros G, et al. Incidence of prostate cancer in hypogonadal men receiving testosterone therapy: observations from 5-year median followup of 3 registries. J Urol. 2015;193(1):80–86.
  • Calof 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(11):1451–1457.
  • Cui Y, Zong H, Yan H, et al. The effect of testosterone replacement therapy on prostate cancer: a systematic review and meta-analysis. Prostate Cancer Prostatic Dis. 2014;17(2):132–143.
  • Rhoden EL, Morgentaler A. Risks of testosterone-replacement therapy and recommendations for monitoring. N Engl J Med. 2004;350(5):482–492.
  • Carter HB, Pearson JD, Metter EJ, et al. Longitudinal evaluation of prostate-specific antigen levels in men with and without prostate disease. JAMA. 1992;267(16):2215–2220.
  • Rastrelli G, Maggi M, Corona G. Pharmacological management of late-onset hypogonadism. Expert Rev Clin Pharmacol. 2018;11(4):439–458.
  • Chen YW, Niu YH, Xu H, et al. Testosterone undecanoate supplementation together with human chorionic gonadotropin does not impair spermatogenesis in males with isolated hypogonadotropic hypogonadism: a retrospective study. Asian J Androl. 2019;21(4):413–418.
  • Hsieh TC, Pastuszak AW, Hwang K, et al. Concomitant intramuscular human chorionic gonadotropin preserves spermatogenesis in men undergoing testosterone replacement therapy. J Urol. 2013;189(2):647–650.
  • Rastrelli G, Corona G, Mannucci E, et al. Factors affecting spermatogenesis upon gonadotropin-replacement therapy: a meta-analytic study. Andrology. 2014;2(6):794–808.
  • Rambhatla A, Mills JN, Rajfer J. The role of estrogen modulators in male hypogonadism and infertility. Rev Urol. 2016;18(2):66–72.
  • 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(11):1011–1022.
  • Finkelstein JS, Lee H, Leder BZ, et al. Gonadal steroid-dependent effects on bone turnover and bone mineral density in men. J Clin Invest. 2016;126(3):1114–1125.
  • Dobs AS, Meikle AW, Arver 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.
  • Jones TH, Saad F. The effects of testosterone on risk factors for, and the mediators of, the atherosclerotic process. Atherosclerosis. 2009;207(2):318–327.
  • Zitzmann M, Junker R, Kamischke A, et al. Contraceptive steroids influence the hemostatic activation state in healthy men. J Androl. 2002;23(4):503–511.