Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Testosterone deficiency and the aging male

Abstract

Testosterone deficiency (TD), also known as male hypogonadism, is a complex syndrome encompassing physical, biochemical, and social aspects that increasingly affects the aging population. TD has been analyzed over recent decades, with an enhanced focus on etiologies relating to aging males. There is debate whether testosterone decline leading to hypogonadism is directly and primarily related to age-specific processes or if it is the subsequent result of accumulating comorbidities throughout a lifetime. Several studies have been done to further characterize this distinction. Chronic comorbidities that have commonly been associated with TD include hypertension (HTN), cardiovascular disease (CVD), diabetes mellitus (DM), obesity, metabolic syndrome (MetS), chronic kidney disease (CKD), and tobacco use. Although clear associations between hypogonadism and aging have been biochemically demonstrated, many large studies have illustrated the concomitant effects of highly prevalent chronic diseases and social behaviors in aging men. Given the significant impact of hypogonadism on the physical and mental health of men, this paper aims to delve into these studies and further define the complex relationship of testosterone deficiency in the aging male.

This is a preview of subscription content, access via your institution

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

References

  1. Chodick G, Epstein S, Shalev V. Secular trends in testosterone- findings from a large state-mandate care provider. Reprod Biol Endocrinol. 2020;18:19.

    Article  PubMed  PubMed Central  Google Scholar 

  2. Mulhall JP, Trost LW, Brannigan RE, Kurtz EG, Redmon JB, Chiles KA, et al. Evaluation and Management of Testosterone Deficiency: AUA Guideline. J Urol. 2018;200:423–32.

    Article  PubMed  Google Scholar 

  3. Goldman AL, Bhasin S, Wu FCW, Krishna M, Matsumoto AM, Jasuja R. A Reappraisal of Testosterone’s Binding in Circulation: Physiological and Clinical Implications. Endocr Rev. 2017;38:302–24.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Wu FC, Tajar A, Beynon JM, Pye SR, Silman AJ, Finn JD, et al. Identification of late-onset hypogonadism in middle-aged and elderly men. N. Engl J Med. 2010;363:123–35.

    Article  CAS  PubMed  Google Scholar 

  5. Mulligan T, Frick MF, Zuraw QC, Stemhagen A, McWhirter C. Prevalence of hypogonadism in males aged at least 45 years: the HIM study. Int J Clin Pr. 2006;60:762–9.

    Article  CAS  Google Scholar 

  6. Krakowsky Y, Grober ED. Testosterone Deficiency—Establishing A Biochemical Diagnosis. EJIFCC 2015;26:105–13.

    PubMed  PubMed Central  Google Scholar 

  7. Erenpreiss J, Fodina V, Pozarska R, Zubkova K, Dudorova A, Pozarskis A. Prevalence of testosterone deficiency among aging men with and without morbidities. Aging Male. 2020;23:901–5.

    Article  PubMed  Google Scholar 

  8. Wu FC, Tajar A, Pye SR, Silman AJ, Finn JD, O’Neill TW, et al. 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;93:2737–45.

    Article  CAS  PubMed  Google Scholar 

  9. McBride JA, Carson CC, Coward RM. Testosterone deficiency in the aging male. Ther Adv Urol. 2016;8:47–60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Huhtaniemi I. Late-onset hypogonadism: current concepts and controversies of pathogenesis, diagnosis and treatment. Asian J Androl. 2014;16:192–202.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Yang Q, Li Z, Li W, Lu L, Wu H, Zhuang Y, et al. Association of total testosterone, free testosterone, bioavailable testosterone, sex hormone-binding globulin, and hypertension. Med (Baltim). 2019;98:e15628.

    Article  CAS  Google Scholar 

  12. Svartberg J, von Mühlen D, Schirmer H, Barrett-Connor E, Sundfjord J, Jorde R. Association of endogenous testosterone with blood pressure and left ventricular mass in men. The Tromsø Study. Eur J Endocrinol. 2004;150:65–71.

    Article  CAS  PubMed  Google Scholar 

  13. Traish AM, Abdou R, Kypreos KE. Androgen deficiency and atherosclerosis: The lipid link. Vasc Pharm. 2009;51:303–13.

    Article  CAS  Google Scholar 

  14. Fahed AC, Gholmieh JM, Azar ST. Connecting the Lines between Hypogonadism and Atherosclerosis. Int J Endocrinol. 2012;2012:793953.

    Article  PubMed  PubMed Central  Google Scholar 

  15. Hughes GS, Mathur RS, Margolius HS. Sex steroid hormones are altered in essential hypertension. J Hypertens. 1989;7:181–7.

    Article  CAS  PubMed  Google Scholar 

  16. Khaw KT, Barrett-Connor E. Blood pressure and endogenous testosterone in men: an inverse relationship. J Hypertens. 1988;6:329–32.

    Article  CAS  PubMed  Google Scholar 

  17. Prévost G, Eas F, Kuhn JM. [Plasma testosterone, obesity, metabolic syndrome and diabetes]. Presse Med. 2014;43:186–95.

    Article  PubMed  Google Scholar 

  18. Escobar-Morreale HF, Santacruz E, Luque-Ramírez M, Botella, Carretero JI. Prevalence of ‘obesity-associated gonadal dysfunction’ in severely obese men and women and its resolution after bariatric surgery: a systematic review and meta-analysis. Hum Reprod Update. 2017;23:390–408.

    Article  CAS  PubMed  Google Scholar 

  19. Corona G, Vignozzi L, Sforza A, Mannucci E, Maggi M. Obesity and late-onset hypogonadism. Mol Cell Endocrinol. 2015;418:120–33.

    Article  CAS  PubMed  Google Scholar 

  20. Derby CA, Zilber S, Brambilla D, Morales KH, McKinlay JB. Body mass index, waist circumference and waist to hip ratio and change in sex steroid hormones: the Massachusetts Male Ageing Study. Clin Endocrinol. 2006;65:125–31.

    Article  CAS  Google Scholar 

  21. Kaplan SA, Meehan AG, Shah A. The age related decrease in testosterone is significantly exacerbated in obese men with the metabolic syndrome. What are the implications for the relatively high incidence of erectile dysfunction observed in these men. J Urol. 2006;176:1524–7.

    Article  CAS  PubMed  Google Scholar 

  22. Eriksson J, Haring R, Grarup N, Vandenput L, Wallaschofski H, Lorentzen E, et al. Causal relationship between obesity and serum testosterone status in men: A bi-directional mendelian randomization analysis. PLoS One. 2017;12:e0176277.

    Article  PubMed  PubMed Central  Google Scholar 

  23. Salam R, Kshetrimayum AS, Keisam R. Testosterone and metabolic syndrome: The link. Indian J Endocrinol Metab. 2012;16:S12–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Muraleedharan V, Jones TH. Testosterone and the metabolic syndrome. Ther Adv Endocrinol Metab. 2010;1:207–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Gianatti EJ, Grossmann M. Testosterone deficiency in men with Type 2 diabetes: pathophysiology and treatment. Diabet Med. 2020;37:174–86.

    Article  CAS  PubMed  Google Scholar 

  26. Kupelian V, Page ST, Araujo AB, Travison TG, Bremner WJ, McKinlay JB. Low sex hormone-binding globulin, total testosterone, and symptomatic androgen deficiency are associated with development of the metabolic syndrome in nonobese men. J Clin Endocrinol Metab. 2006;91:843–50.

    Article  CAS  PubMed  Google Scholar 

  27. Dhindsa S, Prabhakar S, Sethi M, Bandyopadhyay A, Chaudhuri A, Dandona P. Frequent occurrence of hypogonadotropic hypogonadism in type 2 diabetes. J Clin Endocrinol Metab. 2004;89:5462–8.

    Article  CAS  PubMed  Google Scholar 

  28. Vermeulen A, Kaufman JM, Deslypere JP, Thomas G. Attenuated luteinizing hormone (LH) pulse amplitude but normal LH pulse frequency, and its relation to plasma androgens in hypogonadism of obese men. J Clin Endocrinol Metab. 1993;76:1140–6.

    CAS  PubMed  Google Scholar 

  29. Giagulli VA, Kaufman JM, Vermeulen A. Pathogenesis of the decreased androgen levels in obese men. J Clin Endocrinol Metab. 1994;79:997–1000.

    CAS  PubMed  Google Scholar 

  30. Costanzo PR, Suárez SM, Scaglia HE, Zylbersztein C, Litwak LE, Knoblovits P. Evaluation of the hypothalamic-pituitary-gonadal axis in eugonadal men with type 2 diabetes mellitus. Andrology. 2014;2:117–24.

    Article  CAS  PubMed  Google Scholar 

  31. Pitteloud N, Hardin M, Dwyer AA, Valassi E, Yialamas M, Elahi D, et al. Increasing insulin resistance is associated with a decrease in Leydig cell testosterone secretion in men. J Clin Endocrinol Metab. 2005;90:2636–41.

    Article  CAS  PubMed  Google Scholar 

  32. Di Lorenzo C, Dell’agli M, Colombo E, Sangiovanni E, Restani P. Metabolic syndrome and inflammation: a critical review of in vitro and clinical approaches for benefit assessment of plant food supplements. Evid Based Complement Altern Med. 2013;2013:782461.

    Article  Google Scholar 

  33. Barabás K, Szabó-Meleg E, Ábrahám IM. Effect of Inflammation on Female Gonadotropin-Releasing Hormone (GnRH) Neurons: Mechanisms and Consequences. Int J Mol Sci. 2020;21:E529.

    Article  PubMed  Google Scholar 

  34. Fui MN, Dupuis P, Grossmann M. Lowered testosterone in male obesity: mechanisms, morbidity and management. Asian J Androl. 2014;16:223–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Webster AC, Nagler EV, Morton RL, Masson P. Chronic Kidney Disease. Lancet 2017;389:1238–52.

    Article  PubMed  Google Scholar 

  36. Carrero JJ, Qureshi AR, Nakashima A, Arver S, Parini P, Lindholm B, et al. Prevalence and clinical implications of testosterone deficiency in men with end-stage renal disease. Nephrol Dial Transpl. 2011;26:184–90.

    Article  CAS  Google Scholar 

  37. Zhao JV, Schooling CM. The role of testosterone in chronic kidney disease and kidney function in men and women: a bi-directional Mendelian randomization study in the UK Biobank. BMC Med. 2020;18:122.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Khurana KK, Navaneethan SD, Arrigain S, Schold JD, Nally JV, Shoskes DA. Serum testosterone levels and mortality in men with CKD stages 3-4. Am J Kidney Dis. 2014;64:367–74.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Schmidt A, Luger A, Hörl WH. Sexual hormone abnormalities in male patients with renal failure. Nephrol Dial Transpl. 2002;17:368–71.

    Article  CAS  Google Scholar 

  40. Veldhuis JD, Wilkowski MJ, Zwart AD, Urban RJ, Lizarralde G, Iranmanesh A, et al. Evidence for attenuation of hypothalamic gonadotropin-releasing hormone (GnRH) impulse strength with preservation of GnRH pulse frequency in men with chronic renal failure. J Clin Endocrinol Metab. 1993;76:648–54.

    CAS  PubMed  Google Scholar 

  41. Dunkel L, Raivio T, Laine J, Holmberg C. Circulating luteinizing hormone receptor inhibitor(s) in boys with chronic renal failure. Kidney Int. 1997;51:777–84.

    Article  CAS  PubMed  Google Scholar 

  42. Edey MM. Male Sexual Dysfunction and Chronic Kidney Disease. Front Med. 2017;4:32.

    Article  Google Scholar 

  43. Park MG, Koo HS, Lee B. Characteristics of testosterone deficiency syndrome in men with chronic kidney disease and male renal transplant recipients: a cross-sectional study. Transpl Proc. 2013;45:2970–4.

    Article  CAS  Google Scholar 

  44. Halmenschlager G, Rossetto S, Lara GM, Rhoden EL. Evaluation of the effects of cigarette smoking on testosterone levels in adult men. J Sex Med. 2009;6:1763–72.

    Article  CAS  PubMed  Google Scholar 

  45. Wang W, Yang X, Liang J, Liao M, Zhang H, Qin X, et al. Cigarette smoking has a positive and independent effect on testosterone levels. Hormones. 2013;12:567–77.

    Article  PubMed  Google Scholar 

  46. Svartberg J, Jorde R. Endogenous testosterone levels and smoking in men. The fifth Tromsø study. Int J Androl. 2007;30:137–43.

    Article  CAS  PubMed  Google Scholar 

  47. Trummer H, Habermann H, Haas J, Pummer K. The impact of cigarette smoking on human semen parameters and hormones. Hum Reprod. 2002;17:1554–9.

    Article  PubMed  Google Scholar 

  48. Field AE, Colditz GA, Willett WC, Longcope C, McKinlay JB. The relation of smoking, age, relative weight, and dietary intake to serum adrenal steroids, sex hormones, and sex hormone-binding globulin in middle-aged men. J Clin Endocrinol Metab. 1994;79:1310–6.

    CAS  PubMed  Google Scholar 

  49. Blanco-Muñoz J, Lacasaña M, Aguilar-Garduño C. Effect of current tobacco consumption on the male reproductive hormone profile. Sci Total Environ. 2012;426:100–5.

    Article  PubMed  Google Scholar 

  50. English KM, Pugh PJ, Parry H, Scutt NE, Channer KS, Jones TH. Effect of cigarette smoking on levels of bioavailable testosterone in healthy men. Clin Sci. 2001;100:661–5.

    Article  CAS  Google Scholar 

  51. Mitra A, Chakraborty B, Mukhopadhay D, Pal M, Mukherjee S, Banerjee S, et al. Effect of smoking on semen quality, FSH, testosterone level, and CAG repeat length in androgen receptor gene of infertile men in an Indian city. Syst Biol Reprod Med. 2012;58:255–62.

    Article  CAS  PubMed  Google Scholar 

  52. Liu Q, Peng X, Gu Y, Shang X, Zhou Y, Zhang H, et al. Associations between smoking, sex hormone levels and late-onset hypogonadism in men differ depending on age. Aging. 2021;13:5226–37.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Funabashi T, Sano A, Mitsushima D, Kimura F. Nicotine inhibits pulsatile luteinizing hormone secretion in human males but not in human females, and tolerance to this nicotine effect is lost within one week of quitting smoking. J Clin Endocrinol Metab. 2005;90:3908–13.

    Article  CAS  PubMed  Google Scholar 

  54. Ochedalski T, Lachowicz-Ochedalska A, Dec W, Czechowski B. [Examining the effects of tobacco smoking on levels of certain hormones in serum of young men]. Ginekol Pol. 1994;65:87–93.

    CAS  PubMed  Google Scholar 

  55. Coleman DT, Bancroft C. Nicotine acts directly on pituitary GH3 cells to inhibit prolactin promoter activity. J Neuroendocrinol. 1995;7:785–9.

    Article  CAS  PubMed  Google Scholar 

  56. Zeitlin SI, Rajfer J. Hyperprolactinemia and erectile dysfunction. Rev Urol. 2000;2:39–42.

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Attia AM, el-Dakhly MR, Halawa FA, Ragab NF, Mossa MM. Cigarette smoking and male reproduction. Arch Androl. 1989;23:45–9.

    Article  CAS  PubMed  Google Scholar 

  58. Ohlsson C, Barrett-Connor E, Bhasin S, Orwoll E, Labrie F, Karlsson MK, et al. High serum testosterone is associated with reduced risk of cardiovascular events in elderly men. The MrOS (Osteoporotic Fractures in Men) study in Sweden. J Am Coll Cardiol. 2011;58:1674–81.

    Article  CAS  PubMed  Google Scholar 

  59. Tivesten A, Vandenput L, Labrie F, Karlsson MK, Ljunggren O, Mellström D, et al. Low serum testosterone and estradiol predict mortality in elderly men. J Clin Endocrinol Metab. 2009;94:2482–8.

    Article  CAS  PubMed  Google Scholar 

  60. Yeap BB, Hyde Z, Almeida OP, Norman PE, Chubb SA, Jamrozik K, et al. Lower testosterone levels predict incident stroke and transient ischemic attack in older men. J Clin Endocrinol Metab. 2009;94:2353–9.

    Article  CAS  PubMed  Google Scholar 

  61. Laughlin GA, Barrett-Connor E, Bergstrom J. Low serum testosterone and mortality in older men. J Clin Endocrinol Metab. 2008;93:68–75.

    Article  CAS  PubMed  Google Scholar 

  62. Keating NL, O’Malley AJ, Smith MR. Diabetes and cardiovascular disease during androgen deprivation therapy for prostate cancer. J Clin Oncol. 2006;24:4448–56.

    Article  CAS  PubMed  Google Scholar 

  63. Conteduca V, Di Lorenzo G, Tartarone A, Aieta M. The cardiovascular risk of gonadotropin releasing hormone agonists in men with prostate cancer: an unresolved controversy. Crit Rev Oncol Hematol. 2013;86:42–51.

    Article  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Contributions

All aspects of writing, drafting, final editing/revising, and submission were completed by HLB and GMG.

Corresponding author

Correspondence to Helen L. Bernie.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Gryzinski, G.M., Bernie, H.L. Testosterone deficiency and the aging male. Int J Impot Res 34, 630–634 (2022). https://doi.org/10.1038/s41443-022-00555-7

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41443-022-00555-7

Search

Quick links