Male hypogonadism and testosterone therapy: current clinical evidence and controversies

Hipogonadismo masculino y terapia con testosterona: evidencia clínica actual y controversias

Male hypogonadism, also referred to as testosterone deficiency (TD) in several clinical guidelines, is a common but frequently underdiagnosed condition that affects multiple domains of male health. This narrative review summarizes current evidence on the diagnosis and management of male hypogonadism, with emphasis on testosterone replacement therapy (TRT). Advances in the understanding of testosterone physiology, particularly the saturation model, have reshaped clinical perspectives. We review the effects of TRT on sexual function, metabolic health, bone density, mood, and physical function. Its relationship with cardiovascular risk, prostate safety, and lower urinary tract symptoms is also examined, highlighting the reassuring findings of the landmark TRAVERSE trial (Testosterone Replacement Therapy for Assessment of Long-term Vascular Events and Efficacy trial). Evidence also supports cautious use in men with comorbidities such as obstructive sleep apnea and previously treated prostate cancer. A guideline-based, individualized approach, prioritizing symptomatic men with confirmed biochemical deficiency, remains essential to optimize outcomes while minimizing risks.

Resumen

El hipogonadismo masculino, también denominado déficit de testosterona (DT) en diversas guías clínicas, es una condición frecuente pero a menudo infradiagnosticada que afecta múltiples dominios de la salud del varón. Esta revisión narrativa sintetiza la evidencia actual sobre el diagnóstico y manejo del hipogonadismo masculino, con especial énfasis en la terapia de reemplazo con testosterona (TRT). Los avances en la comprensión de la fisiología androgénica, en particular el modelo de saturación, han modificado la perspectiva clínica contemporánea. Se revisan los efectos de la TRT sobre la función sexual, la salud metabólica, la densidad mineral ósea, el estado de ánimo y la función física. Asimismo, se examina su relación con el riesgo cardiovascular, la seguridad prostática y los síntomas del tracto urinario inferior, destacando los resultados tranquilizadores del ensayo TRAVERSE (Ensayo sobre la terapia de reemplazo de testosterona para la evaluación de eventos vasculares a largo plazo y su eficacia). La evidencia también respalda un uso cauteloso en pacientes con comorbilidades como apnea obstructiva del sueño o cáncer de próstata tratado. Mantener un enfoque individualizado, basado en guías y centrado en varones sintomáticos con confirmación bioquímica del déficit androgénico, sigue siendo esencial para optimizar los beneficios y minimizar los riesgos.

Testosterone replacement therapy; Controversies; Hypogonadism; Cardiovascular risk; Prostate cancer; Male sexual health; Hormone therapy safety; Aging male; Andrology

Palabras Clave

Terapia de reemplazo con testosterona; Controversias; Hipogonadismo; Riesgo cardiovascular; Cáncer de próstata; Salud sexual masculina; Seguridad de la terapia hormonal; Varón envejecido; Andrología

[1] Khera M, Torres LO, Grober ED, Morgentaler A, Miner M, Jones TH, et al. Male hypogonadism: recommendations from the Fifth International Consultation on Sexual Medicine (ICSM 2024). Sexual Medicine Reviews. 2025; 13: 548–573.

[2] Wu FC, Tajar A, Beynon JM, Pye SR, Silman AJ, Finn JD, et al.; EMAS Group. Identification of late-onset hypogonadism in middle-aged and elderly men. The New England Journal of Medicine. 2010; 363: 123–135.

[3] Mulhall JP, Maggi M, Trost L. Controversies in testosterone deficiency. 1st edn. Springer: Cham. 2021.

[4] Nieschlag E, Behre HM, Bouchard P, Corrales JJ, Jones TH, Stalla GK, et al. Testosterone replacement therapy: current trends and future directions. Human Reproduction Update. 2004; 10: 409–419.

[5] Bhasin S, Brito JP, Cunningham GR, Hayes FJ, Hodis HN, Matsumoto AM, et al. Testosterone therapy in men with hypogonadism: an endocrine society clinical practice guideline. The Journal of Clinical Endocrinology and Metabolism. 2018; 103: 1715–1744.

[6] Vartolomei MD, Kimura S, Vartolomei L, Shariat SF. Systematic review of the impact of testosterone replacement therapy on depression in patients with late-onset testosterone deficiency. European Urology Focus. 2020; 6: 170–177.

[7] Debruyne FM, Behre HM, Roehrborn CG, Maggi M, Wu FC, Schröder FH, et al.; RHYME Investigators. Testosterone treatment is not associated with increased risk of prostate cancer or worsening of lower urinary tract symptoms: prostate health outcomes in the registry of hypogonadism in men. BJU International. 2017; 119: 216–224.

[8] Wallis CJ, Lo K, Lee Y, Krakowsky Y, Garbens A, Satkunasivam R, et al. Survival and cardiovascular events in men treated with testosterone replacement therapy: an intention-to-treat observational cohort study. The Lancet Diabetes & Endocrinology. 2016; 4: 498–506.

[9] Snyder PJ, Bhasin S, Cunningham GR, Matsumoto AM, Stephens-Shields AJ, Cauley JA, et al.; Testosterone Trials Investigators. Effects of testosterone treatment in older men. The New England Journal of Medicine. 2016; 374: 611–624.

[10] Barbonetti A, D’Andrea S, Francavilla S. Testosterone replacement therapy. Andrology. 2020; 8: 1551–1556.

[11] Mulhall JP, Trost LW, Brannigan RE, Kurtz EG, Redmon JB, Chiles KA, et al. Evaluation and management of testosterone deficiency: AUA guideline. Journal of Urology. 2018; 200: 423–432.

[12] Snyder JP. Testosterone treatment of male hypogonadism. 2024. Available at: https://www.uptodate.com/contents/testosterone-treatment-of-male-hypogonadism (Accessed: 19 November 2025).

[13] Isidori AM, Aversa A, Calogero A, Ferlin A, Francavilla S, Lanfranco F, et al. Adult- and late-onset male hypogonadism: the clinical practice guidelines of the Italian Society of Andrology and Sexual Medicine (SIAMS) and the Italian Society of Endocrinology (SIE). Journal of Endocrinological Investigation. 2022; 45: 2385–2403.

[14] Corona G, Goulis DG, Huhtaniemi I, Zitzmann M, Toppari J, Forti G, et al. European Academy of Andrology (EAA) guidelines on investigation, treatment and monitoring of functional hypogonadism in males: endorsing organization: European Society of Endocrinology. Andrology. 2020; 8: 970–987.

[15] Salonia A, Boeri L, Capogrosso P, Corona G, Dinkelman-Smith M, Falcone M, et al. EAU Guidelines on sexual and reproductive health. 1st edn. EAU Guidelines Office: Arnhem, The Netherlands. 2025.

[16] Dean JD, McMahon CG, Guay AT, Morgentaler A, Althof SE, Becher EF, et al. The international society for sexual medicine’s process of care for the assessment and management of testosterone deficiency in adult men. The Journal of Sexual Medicine. 2015; 12: 1660–1686.

[17] Jayasena CN, Anderson RA, Llahana S, Barth JH, MacKenzie F, Wilkes S, et al. Society for Endocrinology guidelines for testosterone replacement therapy in male hypogonadism. Clinical Endocrinology. 2022; 96: 200–219.

[18] Yeap BB, Grossmann M, McLachlan RI, Handelsman DJ, Wittert GA, Conway AJ, et al. Endocrine Society of Australia position statement on male hypogonadism (part 1): assessment and indications for testosterone therapy. The Medical Journal of Australia. 2016; 205: 173–178.

[19] Miller C, Madden-Doyle L, Jayasena C, McIlroy M, Sherlock M, O’Reilly MW. Mechanisms in endocrinology: hypogonadism and metabolic health in men—novel insights into pathophysiology. European Journal of Endocrinology. 2024; 191: R1–R17.

[20] Gianatti EJ, Dupuis P, Hoermann R, Strauss BJ, Wentworth JM, Zajac JD, et al. Effect of testosterone treatment on glucose metabolism in men with type 2 diabetes: a randomized controlled trial. Diabetes Care. 2014; 37: 2098–2107.

[21] Wittert G, Bracken K, Robledo KP, Grossmann M, Yeap BB, Handelsman DJ, 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. The Lancet Diabetes & Endocrinology. 2021; 9: 32–45.

[22] Shende P, Vadivel S, Sanghani D, Khamkar K. Association of obesity, inflammation, and hypogonadism: a cross-sectional study in males under 60 years of age. Cureus. 2024; 16: e70439.

[23] Grahnemo L, Marriott RJ, Murray K, Tyack LT, Nethander M, Matsumoto AM, et al. Associations of serum testosterone and SHBG with incident fractures in middle-aged to older men. The Journal of Clinical Endocrinology and Metabolism. 2025; 110: 1964–1973.

[24] Snyder PJ, Bauer DC, Ellenberg SS, Cauley JA, Buhr KA, Bhasin S, et al. Testosterone treatment and fractures in men with hypogonadism. The New England Journal of Medicine. 2024; 390: 203–211.

[25] Lincoff AM, Bhasin S, Flevaris P, Mitchell LM, Basaria S, Boden WE, et al.; TRAVERSE Study Investigators. Cardiovascular safety of testosterone-replacement therapy. The New England Journal of Medicine. 2023; 389: 1151–1161.

[26] Basaria S, Coviello AD, Travison TG, Storer TW, Farwell WR, Jette AM, et al. Adverse events associated with testosterone administration. The New England Journal of Medicine. 2010; 363: 109–122.

[27] Vigen R, O’Donnell CI, Barón AE, Grunwald GK, Maddox TM, Bradley SM, et al. Association of testosterone therapy with mortality, myocardial infarction, and stroke in men with low testosterone levels. JAMA. 2013; 310: 1829–1836.

[28] Finkle WD, Greenland S, Ridgeway GK, Adams JL, Frasco MA, Cook MB, et al. Increased risk of non-fatal myocardial infarction following testosterone therapy prescription in men. PLOS ONE. 2014; 9: e85805.

[29] 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 Medicine. 2013; 11: 108.

[30] Corona G, Maseroli E, Rastrelli G, Isidori AM, Sforza A, Mannucci E, et al. Cardiovascular risk associated with testosterone-boosting medications: a systematic review and meta-analysis. Expert Opinion on Drug Safety. 2014; 13: 1327–1351.

[31] Yassin A, Alwani M, Al-Zoubi RM, Aboumarzouk OM, Talib R, Nettleship J, et al. Voiding function improves under long-term testosterone treatment (TTh) in hypogonadal men, independent of prostate size. International Urology and Nephrology. 2023; 55: 1649–1658.

[32] Kohn TP, Mata DA, Ramasamy R, Lipshultz LI. Effects of testosterone replacement therapy on lower urinary tract symptoms: a systematic review and meta-analysis. European Urology. 2016; 69: 1083–1090.

[33] Morgentaler A, Traish AM. Shifting the paradigm of testosterone and prostate cancer: the saturation model and the limits of androgen-dependent growth. European Urology. 2009; 55: 310–320.

[34] Huggins C, Hodges CV. Studies on prostatic cancer: the effect of castration, of estrogen and of androgen injection on serum phosphatases in metastatic carcinoma of the prostate. Cancer Research. 1941; 1: 293–297.

[35] Boyle P, Koechlin A, Bota M, d’Onofrio A, Zaridze DG, Perrin P, et al. Endogenous and exogenous testosterone and the risk of prostate cancer and increased prostate-specific antigen (PSA) level: a meta-analysis. BJU International. 2016; 118: 731–741.

[36] Porcaro AB, Serafin E, Brusa D, Costantino S, Brancelli C, Cerruto MA, et al. The role of endogenous testosterone in relationship with low- and intermediate-risk prostate cancer: a systematic review. Asian Journal of Andrology. 2024; 26: 569–574.

[37] Morales A, Black AM, Emerson LE. Testosterone administration to men with testosterone deficiency syndrome after external beam radiotherapy for localized prostate cancer: preliminary observations. BJU International. 2009; 103: 62–64.

[38] Handelsman DJ. Testosterone and male aging: faltering hope for rejuvenation. JAMA. 2017; 317: 699–701.

[39] Muir CA, Wittert GA, Handelsman DJ. Approach to the patient: low testosterone concentrations in men with obesity. The Journal of Clinical Endocrinology and Metabolism. 2025; 110: e3125–e3130.

[40] Hackett GI. Long term cardiovascular safety of testosterone therapy: a review of the TRAVERSE study. The World Journal of Men's Health. 2025; 43: 282–290.

[41] Lundy SD, Parekh NV, Shoskes DA. Obstructive sleep apnea is associated with polycythemia in hypogonadal men on testosterone replacement therapy. The Journal of Sexual Medicine. 2020; 17: 1297–1303.

[42] Zakharov MN, Bhasin S, Travison TG, Xue R, Ulloor J, Vasan RS, et al. A multi-step, dynamic allosteric model of testosterone's binding to sex hormone binding globulin. Molecular and Cellular Endocrinology. 2015; 399: 190–200.

[43] Yao QM, Wang B, An XF, Zhang JA, Ding L. Testosterone level and risk of type 2 diabetes in men: a systematic review and meta-analysis. Endocrine Connections. 2018; 7: 220–231.

[44] Lee H, Hwang EC, Oh CK, Lee S, Yu HS, Lim JS, et al. Testosterone replacement in men with sexual dysfunction. Cochrane Database of Systematic Reviews. 2024; 1: CD013071.

[45] Sizar O, Leslie SW, Schwartz J. Male hypogonadism. 1st edn. StatPearls Publishing: Treasure Island (FL). 2024.

[46] Ohlander SJ, Varghese B, Pastuszak AW. Erythrocytosis following testosterone therapy. Sexual Medicine Reviews. 2018; 6: 77–85.

[47] Tenuta M, Hasenmajer V, Gianfrilli D, Isidori AM. Testosterone and male bone health: a puzzle of interactions. The Journal of Clinical Endocrinology and Metabolism. 2025; 110: e2121–e2135.

[48] Janowsky JS. The role of androgens in cognition and brain aging in men. Neuroscience. 2006; 138: 1015–1020.

[49] Mann A, Strange RC, Hackett G, König C, Ramachandran S. Adult-onset testosterone deficiency: the usefulness of hormone replacement in reducing mortality in men with this common age-related condition. Exploration of Endocrine and Metabolic Diseases. 2024; 1: 83–100.

[50] Indirli R, Lanzi V, Arosio M, Mantovani G, Ferrante E. The association of hypogonadism with depression and its treatments. Frontiers in Endocrinology. 2023; 14: 1198437.

[51] Green HJ, Pakenham KI, Headley BC, Yaxley J, Nicol DL, Mactaggart PN, et al. Altered cognitive function in men treated for prostate cancer with luteinizing hormone-releasing hormone analogues and cyproterone acetate: a randomized controlled trial. BJU International. 2002; 90: 427–432.

[52] Srinivas-Shankar U, Roberts SA, Connolly MJ, O’Connell MD, Adams JE, Oldham JA, 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. The Journal of Clinical Endocrinology and Metabolism. 2010; 95: 639–650.

[53] Resnick SM, Matsumoto AM, Stephens-Shields AJ, Ellenberg SS, Gill TM, Shumaker SA, et al. Testosterone treatment and cognitive function in older men with low testosterone and age-associated memory impairment. JAMA. 2017; 317: 717–727.

[54] Bhasin S, Woodhouse L, Casaburi R, Singh AB, Bhasin D, Berman N, et al. Testosterone dose-response relationships in healthy young men. American Journal of Physiology. Endocrinology and Metabolism. 2001; 281: E1172–E1181.

[55] Gurbuz N, Mammadov E, Usta MF. Hypogonadism and erectile dysfunction: an overview. Asian Journal of Andrology. 2008; 10: 36–43.

[56] Xu Z, Chen X, Zhou H, Ren C, Wang Q, Pan Y, et al. An updated systematic review and meta-analysis of the effects of testosterone replacement therapy on erectile function and prostate. Frontiers in Endocrinology. 2024; 15: 1335146.

[57] Tajar A, Forti G, O’Neill TW, Lee DM, Silman AJ, Finn JD, et al.; EMAS Group. Characteristics of secondary, primary, and compensated hypogonadism in aging men: evidence from the European Male Ageing Study. The Journal of Clinical Endocrinology and Metabolism. 2010; 95: 1810–1818.

[58] Huo S, Scialli AR, McGarvey S, Hill E, Tügertimur B, Hogenmiller A, et al. Treatment of men for “low testosterone”: a systematic review. PLOS ONE. 2016; 11: e0162480.

[59] Yassin DJ, Yassin AA, Hammerer PG. Combined testosterone and vardenafil treatment for restoring erectile function in hypogonadal patients who failed to respond to testosterone therapy alone. The Journal of Sexual Medicine. 2014; 11: 543–552.

[60] Buvat J, Maggi M, Gooren L, Guay AT, Kaufman J, Morgentaler A, et al. Endocrine aspects of male sexual dysfunctions. The Journal of Sexual Medicine. 2010; 7: 1627–1656.

[61] Podlasek CA, Mulhall J, Davies K, Wingard CJ, Hannan JL, Bivalacqua TJ, et al. Translational perspective on the role of testosterone in sexual function and dysfunction. The Journal of Sexual Medicine. 2016; 13: 1183–1198.

[62] Baggish AL, Weiner RB, Kanayama G, Hudson JI, Lu MT, Hoffmann U, et al. Cardiovascular toxicity of illicit anabolic-androgenic steroid use. Circulation. 2017; 135: 1991–2002.

[63] Liu PY, Yee B, Wishart SM, Jimenez M, Jung DG, Grunstein RR, et al. The short-term effects of high-dose testosterone on sleep, breathing, and function in older men. The Journal of Clinical Endocrinology and Metabolism. 2003; 88: 3605–3613.

[64] Cignarelli A, Castellana M, Castellana G, Perrini S, Brescia F, Natalicchio A, et al. Effects of CPAP on testosterone levels in patients with obstructive sleep apnea: a meta-analysis study. Frontiers in Endocrinology. 2019; 10: 551.

[65] Roehrborn CG. Benign prostatic hyperplasia: an overview. Reviews in Urology. 2005; 7: S3–S14.

[66] Applewhite J, McCarter J, Saffati G, Kronstedt S, Hinojosa-Gonzalez D, La T, et al. Testosterone replacement therapy in men on active surveillance for prostate cancer. The Journal of Sexual Medicine. 2025; 22: 432–438.

[67] Pichon A, Neuzillet Y, Botto H, Raynaud JP, Radulescu C, Molinié V, et al. Preoperative low serum testosterone is associated with high-grade prostate cancer and an increased Gleason score upgrading. Prostate Cancer and Prostatic Diseases. 2015; 18: 382–387.