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The role of testosterone in men’s health: is it time for a new approach?

  • Urology - Review
  • Published:
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Abstract

Purpose

Because of many unanswered questions regarding men’s health, a literature review was performed to better understand the role of testosterone and testosterone replacement therapy (TRT) in the management of hypogonadism and aging related prostate gland diseases (ARPGD) including prostate cancer (PCa) and benign prostatic hyperplasia (BPH) with lower urinary tract symptoms (LUTS).

Methods

The PubMed database was screened for pertinent peer reviewed articles published during the last four decades that culminated in the positions and recommendations in this paper.

Results

Hypogonadism seriously impacts men’s health, and the diagnosis remains controversial. The incidence of ARPGD is projected to increase worldwide and treatment still has significant limitations. There is compelling evidence that lower, not higher, testosterone levels trigger the development of PCa and BPH through androgen receptor over-expression. TRT was found to be safe and effective in treating hypogonadism including in PCa survivors and those harboring PCa. There is also evidence that TRT might reduce the incidence and prevalence of ARPGD.

Conclusions and recommendations

This review synthesizes a wide-ranging compendium of basic science and clinical research that strongly encourages altering the present approach to diagnosing and treating men with hypogonadism and ARPGD. These findings underscore the importance of avoiding significant testosterone decline and support the use of TRT. Ten recommendations are offered as a framework for the way forward. It is now time for clinicians, payers, researchers, funding agencies, professional associations, and patient advocacy groups to embrace this new paradigm to increase longevity and improve the quality of life.

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References

  1. Huggins C, Hodges CV (1941) Studies on prostatic cancer: I. effect of castration, of oestrogen and of androgen injections on serum phosphatases in metastatic carcinoma of the prostate. Cancer Res 1:293–297

    CAS  Google Scholar 

  2. Araujo AB, O’Donnell AB, Brambilla DJ, Simpson WB, Longcope C, Matsumoto AM, McKinley JB (2004) Prevalence and incidence of androgen deficiency in middle-aged and older men: estimates from the Massachusetts Male Aging Study. J Clin Endocrino Metab 89(12):5920–5926. https://doi.org/10.1210/jc.2003-031719

    Article  CAS  Google Scholar 

  3. Pemar CH, Ebot EM, Wilson K, Mucci L (2018) The epidemiology of prostate cancer. Cold Spring Harb Perspect Med 8(12):a030361. https://doi.org/10.1101/cshperspect.a030361

    Article  Google Scholar 

  4. Launer BM, McVary KT, Ricke WA, Lloyd G (2021) The rising worldwide impact of benign prostatic hyperplasia. BJU Int 127(6):722–728. https://doi.org/10.1111/bju.15286

    Article  PubMed  Google Scholar 

  5. Yeo S, Holl K, Penaherrera N, Wissinger U, Anstee K, Wyn R (2021) Burden of male hypogonadism and major comorbidities and the clinical economic and humanistic benefits of testosterone therapy: a narrative review. Clinicoecon Outcomes Res 13:32–38. https://doi.org/10.2147/CEOR.S285434

    Article  Google Scholar 

  6. Haider KS, Haider A, Doros G et al (2018) 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 199(1):257–265. https://doi.org/10.1016/j.juro.2017.07.039

    Article  CAS  PubMed  Google Scholar 

  7. Almehmadi Y, Yassin AA, Nettleship JE et al (2016) Testosterone replacement therapy improves the health-related quality of life of men diagnosed with late-onset hypogonadism. Arab J Urol 14(1):31–36. https://doi.org/10.1016/j.aju.2015.10.002

    Article  PubMed  Google Scholar 

  8. Decaroli MC, Rochira V (2017) Aging and sex hormones in males. Virulence 8(5):545–570

    Article  CAS  PubMed  Google Scholar 

  9. Morley JE, Perry HM 3rd, Kevorkian RT, Patrick P (2006) Comparison of screening questionnaires for the diagnosis of hypogonadism. Maturitas 53(4):424–429. https://doi.org/10.1016/j.maturitas.2005.07.004

    Article  PubMed  Google Scholar 

  10. Matsumoto AM (2002) Andropause: clinical implications of the decline in serum testosterone levels with aging in men. J Gerontol 57(2):M76–M99

    Article  Google Scholar 

  11. Corona G, Goulis DG, Huhtaniemi I, Zitzmann M, Toppari J, Forti G et al (2020) European Academy of Andrology (EAA) guidelines on investigation, treatment and monitoring of functional hypogonadism in males: endorsing organization: European Society of endocrinology. Andrology 8(5):970–987

    Article  PubMed  Google Scholar 

  12. Spetz Holm AE, Fredrikson MG, Theodorsson E, Palmefors LG, Karlsson PS, Joborn C et al (2011) Change in testosterone concentrations over time is a better predictor than the actual concentrations for symptoms of late onset hypogonadism. Aging Male 14(4):249–256

    Article  CAS  Google Scholar 

  13. Travison TG, Vesper HW, Orwoll E, Wu F, Kaufman JM, Wang Y (2017) Harmonized reference ranges for circulating testosterone levels in men of four cohort studies in the United States and Europe. J Clin Endocrinol Metab 102(4):1161–1173

    Article  PubMed  PubMed Central  Google Scholar 

  14. Diver M (2009) Laboratory measurement of testosterone. Front Horm Res 37:21–31. https://doi.org/10.1159/0001758441

    Article  CAS  PubMed  Google Scholar 

  15. Defeudis G, Mazzilli R, Gianfrilli D et al (2018) The CATCH checklist to investigate adult-onset hypogonadism. Andrology 6(5):665–679

    Article  CAS  PubMed  Google Scholar 

  16. Bhasin S, Cunningham GR, Hayes FJ, Matsumoto AM, Snyder PJ, Swerdloff RS et al (2010) Testosterone therapy in men with androgen deficiency syndromes: an endocrine society clinical practice guideline. J Clin Endocrinol Metab 96(6):2536–2559

    Article  Google Scholar 

  17. Harman SM, Metter EJ, Tobin JD, Pearson J, Blackman MR (2001) Longitudinal effects of aging on serum total and free testosterone levels in healthy men Baltimore longitudinal study of aging. J Clin Endocrinol Metab 86:724–731

    Article  CAS  PubMed  Google Scholar 

  18. Zmuda JM, Cauley JA, Kriska A, Glynn NW, Gutai JP, Kuller LH (1997) Longitudinal relation between endogenous testosterone and cardiovascular disease risk factors in middle-aged men a 13-year follow-up of former multiple risk factor intervention trial participants. Am J Epidemiol 146:609–617

    Article  CAS  PubMed  Google Scholar 

  19. Kaufman JM, Vermeulen A (2005) The decline of androgen levels in elderly men and its clinical and therapeutic implications. Endocr Rev 26:833–876

    Article  CAS  PubMed  Google Scholar 

  20. Corona G, Sforza A, Maggi M (2017) Testosterone replacement therapy: long-term safety and efficacy. World J Mens Health 35(2):65–76. https://doi.org/10.5534/wjmh.2017.35.2.65

    Article  PubMed  PubMed Central  Google Scholar 

  21. Snyder PJ, Bhasin S, Cunningham GR, Matsumoto AM, Stephens-Shields AJ, Cauley JA et al (2018) Lessons from the testosterone trials. Endocr Rev 39(3):389–486. https://doi.org/10.1210/er.2017-00234

    Article  Google Scholar 

  22. Corona G, Maseroli E, Rastrelli G et al (2014) Cardiovascular risk associated with testosterone-boosting medications: a systematic review and meta-analysis. Expert Opin Drug Saf 13(10):1327–1351

    Article  CAS  PubMed  Google Scholar 

  23. Traish AM, Haider A, Haider KS, Doros G, Saad F (2017) Long-term testosterone therapy improves cardiometabolic function and reduces risk of cardiovascular disease in men with hypogonadism: a real-life observational registry study setting comparing treated and untreated (control) groups. J Cardiovasc Pharmacol Ther 22(5):414–433

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Tong S-F, Ng C-J, Lee B-C et al (2012) Effect of long-acting testosterone undecanoate treatment on quality of life in men with testosterone deficiency syndrome: a double blind randomized controlled trial. Asian J Androl 14(4):604. https://doi.org/10.1038/aja.2011.178

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Mearini L, Zucchi A, Nunzi E, Villirillo T, Bini V, Porena M (2013) Low serum testosterone levels are predictive of prostate cancer. World J Urol 31(2):247–252

    Article  CAS  PubMed  Google Scholar 

  26. Porcaro AB, Cerrato C, Tafuri A, Bianchi A, Gallina S, Orlando R et al (2021) Low endogenous testosterone levels are associated with the extend of lymphnodal invasion at radical prostatectomy and extended pelvic lymph node dissection. Int Urol Nephrol 53(10):2027–2039

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Hsing AW, Tsao L, Devesa SS (2000) International trends and patterns of prostate cancer incidence and mortality. Int J Cancer 85(1):60–67

    Article  CAS  PubMed  Google Scholar 

  28. Shim JS, Kim JH, Yoon YS et al (2018) Serum testosterone levels are negatively correlated with international prostate symptom score and transitional prostate volume. Low Urin Tract Symptoms 10(2):143–147. https://doi.org/10.1111/luts.12150

    Article  CAS  PubMed  Google Scholar 

  29. Saad F, Caliber M, Doros G et al (2020) 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 23(1):81–92. https://doi.org/10.1080/13685538.2019

    Article  CAS  PubMed  Google Scholar 

  30. Okada K, Miyake H, Ishida T, Sumii K, Enatsu N, Chiba K et al (2018) Improved lower urinary tract symptoms associated with testosterone replacement therapy in Japanese men with late-onset hypogonadism. Am J Mens Health 12(5):1403–1408

    Article  PubMed  Google Scholar 

  31. Haider A, Zitzmann M, Doros G, Isbarn H, Hammerer P, Yassin A (2015) Incidence of prostate cancer in hypogonadal men receiving testosterone therapy: observations from 5-year median follow-up of 3 registries. J Urol 193(1):80–86

    Article  PubMed  Google Scholar 

  32. Cook MB, Beachler DC, Parlett LE, Cochetti PT, Finkle WD, Lanes S et al (2020) Testosterone therapy in relation to prostate cancer in a U.S. commercial insurance claims database. Cancer Epidemiol Biomarkers Prev 29(1):236–246

    Article  CAS  PubMed  Google Scholar 

  33. Shoskes DA, Barazani Y, Fareed K, Sabanegh E Jr (2015) Outcome of prostate biopsy in men with hypogonadism prior or during testosterone replacement therapy. Int Braz J Urol 41(6):1167–1171

    Article  PubMed  PubMed Central  Google Scholar 

  34. Walburton D, Hobaugh C, Wang G, Lin H, Wang R (2015) Testosterone replacement therapy and the risk of prostate cancer. Asian J Androl 17(6):878–881

    Article  Google Scholar 

  35. Morgentaler A, Lipshultz LI, Bennett R, Sweeney M, Avila D Jr, Khera M (2011) Testosterone therapy in men with untreated prostate cancer. J Urol 185(4):1256–1260

    Article  CAS  PubMed  Google Scholar 

  36. Szmulewitz R, Mohile S, Posadas E, Kunnavakkam R, Karrison T, Manchen E, Stadler WM (2009) A randomized phase 1 study of testosterone replacement for patients with low-risk castration-resistant prostate cancer. Eur Urol 56:97–103

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Morris MJ, Huang D, Kelly WK, Slovin SF, Stephenson RD, Eicher C, Delacruz A, Curley T, Schwartz LH, Scher HI (2009) Phase 1 trial of high-dose exogenous testosterone in patients with castration-resistant metastatic prostate cancer. Eur Urol 56:237–244

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Prout GR Jr, Brewer WR (1967) Response of men with advanced prostatic carcinoma to exogenous administration of testosterone. Cancer 20:1871–1878

    Article  PubMed  Google Scholar 

  39. Schweizer MT, Antonarakis ES, Wan H, Ajiboye AS, Spitz A, Cao H et al (2015) Effect of bipolar therapy for asymptomatic men with castration-resistant prostate cancer: results from a pilot clinical study. Sci Transl Med 7(269):269ra2

    Article  PubMed  PubMed Central  Google Scholar 

  40. Sartor AO, Tangen CM, Hussain MHA, Eisenberger MA, Parab M, Fontana JA et al (2008) Antiandrogen withdrawal in castrate-refractory prostate cancer: a Southwest Oncology Group trial (SWOG 9426). Cancer 112(11):2393–2400

    Article  CAS  PubMed  Google Scholar 

  41. Nam W, Choi SY, Yoo SJ, Ryu J, Lee J, Kyung YS et al (2018) Factors associated with testosterone recovery after androgen deprivation therapy in patients with prostate cancer. Investig Clin Urol 59(1):18–24

    Article  PubMed  Google Scholar 

  42. Hunter I, Hay CW, Esswein B, Watt K, Mcewan IJ (2018) Tissue control of androgen action: the ups and downs of androgen receptor expression. Mol Cell Endocrinol 15(465):27–35

    Article  Google Scholar 

  43. Brinkmann AO, Jenster G, Ris-Stalpers C, van der Korput JA, Brüggenwirth HT, Boehmer AL et al (1995) Androgen receptor mutations. J Steroid Biochem Mol Biol 53:443–448

    Article  CAS  PubMed  Google Scholar 

  44. Claessens F, Denayer S, Van Tilborgh N, Kerkhofs S, Helsen C, Haelens A (2008) Diverse roles of androgen receptor (AR) domains in AR-mediated signaling. Nucl Recept Signal 6:e06008

    Article  Google Scholar 

  45. Feng Q, He B (2019) Androgen receptor signaling in the development of castration-resistant prostate cancer. Front Oncol 4(9):859

    Google Scholar 

  46. Urbanucci A, Sahu B, Seppala J, Larjo A, Latonen LM, Waltering KK et al (2012) Overerxpression of androgen receptor enhances the binding of the receptor to the chromatin in prostate cancer. Oncogene 31(17):2153–2163

    Article  CAS  PubMed  Google Scholar 

  47. Weischenfeldt J, Simon R, Feurbach L, Schlangen K, Weichenhan D, Minner S et al (2013) Integrative genomic analysis reveals an androgen-driven somatic alteration landscape in early-onset prostate cancer. Cancer Cell 23(2):159–170

    Article  CAS  PubMed  Google Scholar 

  48. Graham MK, Meeker A (2017) Telomeres and telomerase in prostate cancer development and therapy. Nat Rev Urol 14(10):607–619

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Costello LC, Franklin RB (2016) A comprehensive review of the role of zinc in the normal prostate function and metabolism; and its implications in prostate cancer. Arch Biochem Biophys 1(611):100–112

    Article  Google Scholar 

  50. Beilin J, Ball EM, Favaloro JM, Zajac JD (2000) Effect of the androgen receptor CAG repeat polymorphism on transcriptional activity: specificity in prostate and non-prostate cell lines. J Mol Endocrinol 25(1):85–96

    Article  CAS  PubMed  Google Scholar 

  51. Meng J, Mostaghel EA, Vakar-Lopez F, Montgomery B, True L, Nelson PS (2011) Testosterone regulates tight junction proteins and influences prostatic autoimmune responses. Horm Cancer 2(3):145–156

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Song W, Khera M (2014) Physiological normal levels of androgen inhibit proliferation of prostate cancer cells in vitro. Asian J Androl 16(6):864–868

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Li H, Pham T, McWhinney BC, Ungerer JP, Pretorius CJ, Richard DJ et al (2016) Sex hormones binding globulin modifies testosterone action and metabolism in prostate cancer cells. Int J Endocrinol 2016:6437585

    Article  PubMed  PubMed Central  Google Scholar 

  54. Zhou Y, Otto-Duessel M, He M, Markel S, Synold T, Jones JO (2013) Low systemic testosterone levels induce androgen maintenance in benign rat prostate tissue. J Mol Endocrinol 51(1):143–153

    Article  CAS  PubMed  Google Scholar 

  55. Morgentaler A, Traish AM (2009) Shifting the paradigm of testosterone and prostate cancer: the saturation model and the limits of androgen-dependent growth. Eur Urol 55(2):310–320

    Article  PubMed  Google Scholar 

  56. Banach-Petroskey W, Jessen WJ, Ouyang X, Gao H, Rao J, Quinn J et al (2007) Prolonged exposure to reduced levels of androgen accelerates prostate cancer progression in Nkx3.1 Pten mutant mice. Mol Cancer Res 67(19):9089–9096

    Article  Google Scholar 

  57. Goldenberg SL, Koupparis A, Robinson ME (2011) Differing levels of testosterone and the prostate: a physiological interplay. Nat Rev Urol 8(7):365–377

    Article  CAS  PubMed  Google Scholar 

  58. Robinson D, Garmo H, Bill-Axelson A, Mucci L, Holmberg L, Stattin P (2013) Use of 5 alpha-reductase inhibitors for lower urinary tract symptoms and risk of prostate cancer in Swedish men: nationwide, population-based case-control study. BMJ 346:f3406

    Article  PubMed  PubMed Central  Google Scholar 

  59. Roehrborn CG, Lee M, Meehan A et al (2003) Effects of finasteride on serum testosterone and body mass index in men with benign prostatic hyperplasia. Urology 62(5):894–899

    Article  PubMed  Google Scholar 

  60. Clark RV, Hermann DJ, Cunningham GR, Wilson TH, Morrill BB, Hobbs S (2004) Marked suppression of dihydrotestosterone in men with benign prostatic hyperplasia by dutasteride, a dual 5alpha-reductase inhibitor. J Clin Endocrinol Metab 89(5):2179–2184. https://doi.org/10.1210/jc.2003-030330

    Article  CAS  PubMed  Google Scholar 

  61. Watts EL, Goldacre R, Key TJ, Allen NE, Travis RC, Perez-Comago A (2020) Hormone-related diseases and prostate cancer: an English national record linkage study. Int J Cancer 147(3):803–810. https://doi.org/10.1002/ijc.32808

    Article  CAS  PubMed  Google Scholar 

  62. English HF, Kyprianou N, Isaacs JT (1989) Relationships between DNA fragmentation and apoptosis in the programmed cell death in the rat prostate following castration. Prostate 15(3):233–250

    Article  CAS  PubMed  Google Scholar 

  63. Karthaus WR, Hofree M, Choi D, Linton EL, Turkeku M, Bejnood A et al (2020) Regenerative potential of prostate luminal cells revealed by single-cell analysis. Science 368(6490):497–505

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Attar RM, Takimoto CH, Goffardis MM (2009) Castration-resistant prostate cancer: locking up the molecular escape routes. Clin Cancer Res 15:3251–3255

    Article  CAS  PubMed  Google Scholar 

  65. Miyahira AK, Lang JM, Den RB, Garraway IP, Lotan TL, Ross AE et al (2016) Multidisciplinary intervention in early, lethal metastatic prostatic cancer: report from the 2015 Coffey-Holden Prostate Cancer Academy Meeting. Prostate 76(2):125–139

    Article  PubMed  Google Scholar 

  66. Sun Y, Wang B, Leong KG, Yue P, Li L, Jhunjhunwala S et al (2012) Androgen deprivation causes epithelial-mesenchymal transition in the prostate: implication for androgen-deprivation therapy. Cancer Res 72(2):527–536

    Article  CAS  PubMed  Google Scholar 

  67. Wang K, Chen X, Bird VY, Gerke TA, Manini TM, Prosperi M (2017) Association between age-related reduction in testosterone and risk of prostate cancer—an analysis of patients’ data with prostatic diseases. Int J Cancer 141(9):1783–1793

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Xu X, Chen X, Hu H, Dailey AB, Taylor BD (2015) Current opinion on the role of testosterone in the development of prostate cancer: a dynamic model. BMC Cancer 26(15):806

    Article  Google Scholar 

  69. Hu H, Odedina FT, Reams RR, Lissaker CTK, Xu X (2015) Racial differences in age-related variations of testosterone levels among us males: potential implications for prostate cancer and personalized medication. J Racial Ethn Health Disparities 2:69–76

    Article  PubMed  Google Scholar 

  70. Ross R, Bernstein L, Judd H, Hanisch R, Pike M, Henderson B (1986) Serum testosterone levels in healthy young black and white men. J Natl Cancer Inst 76(1):45–48

    CAS  PubMed  Google Scholar 

  71. Khodamoradi K, Khosravizadeh Z, Parmar M, Kuchakulla M, Ramasamy R, Arora H (2021) Exogenous testosterone replacement therapy versus raising endogenous testosterone levels: current and future prospects. FS Rev 2(1):32–42

    Google Scholar 

  72. Smith SJ, Lopresti AL, Teo SYM, Fairchild TJ (2021) Examining the effects of herbs on testosterone concentration in men: a systematic review. Adv Nutr 12(3):744–765

    Article  PubMed  Google Scholar 

  73. Ory J, Flannigan R, Lundeen C, Huang JG, Pommerville P, Goldenberg L (2016) Testosterone therapy in patients with treated and untreated prostate cancer: impact on oncologic outcomes. J Urol 196(4):1082–1089

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Nguyen TM, Pastuszak AW (2016) Testosterone therapy among prostate cancer survivors. Sex Med Rev 4(4):376–388

    Article  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

Thanks to David H. Forst, MD, FACC, FASE, FSCCT, Professor of Internal Medicine, Oakland University William Beaumont School of Medicine for his sage advice and excellent manuscript editing. His alacrity during this process is a testament to the memory of his father and my friend, Sid Forst, whose sapient, selfless, unwavering commitment to the health of the community remains a guiding light. My gratitude to Michael Chancellor MD & Bernadette Zwaans, PhD, Director & Administrator respectively of the Beaumont Royal Oak, MI Urologic Research for their advice and guidance throughout the preparation of this review.

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  1. Department of Urology, Oakland University William Beaumont School of Medicine, Rochester, MI, USA

    Ananias C. Diokno

  2. Department of Clinical Sciences, University of Central Florida College of Medicine, Orlando, FL, USA

    Ananias C. Diokno

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Diokno, A.C. The role of testosterone in men’s health: is it time for a new approach?. Int Urol Nephrol 54, 2767–2774 (2022). https://doi.org/10.1007/s11255-022-03292-4

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