Skip to main content

Efficacy of testosterone replacement therapy for treating metabolic disturbances in late-onset hypogonadism: a systematic review and meta-analysis

Abstract

Purpose

Late onset hypogonadism (LOH) is an age-dependent reduction of testosterone associated with alterations of metabolic profile, including glucose control, insulin sensitivity, and lipid profile. The purpose of this study was to investigate the efficacy of testosterone replacement therapy (TRT) for treating metabolic disturbances through a meta-analysis of randomized clinical trials (RCTs).

Methods

A systematic review of literature published from 1964 to November, 2019 was performed using the PubMed/Medline, Embase, and Cochrane databases. Among the 1562 articles screened, 17 articles were selected for qualitative analysis and 16 articles (n = 1373) were included for data synthesis following the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA). Criteria for final inclusion were RCTs.

Results

Sixteen studies were finally included (TRT group, n = 709; placebo group, n = 664). Among the metabolic markers, HbA1C [Mean difference (MD) = − 0.172, 95% CI − 0.329, − 0.015], HOMA IR (MD = − 0.514, 95% CI − 0.863, − 0.165), serum insulin (MD = − 12.622, 95% CI − 19.660, − 5.585), and leptin (MD = − 2.381, 95% CI − 2.952, − 1.810) showed significant improvement after TRT versus placebo. Among the lipid profiles, total cholesterol showed significant improvement (MD = − 0.433, 95% CI − 0.761, − 0.105) after TRT. However, HDL showed a decrease (MD = − 0.069, 95% CI − 0.121, − 0.018) after TRT. Among anthropometric markers, waist circumference showed significant improvement (MD = − 0.1640, 95% CI − 2.857, − 0.423).

Conclusion

This study demonstrated greater improvement in metabolic profiles for patients given TRT versus placebo. Further well-designed trials are needed to verify our findings and further elucidate effects of TRT on lipid profiles. This systematic review demonstrates that TRT can exert a net beneficial effect on metabolic profiles.

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

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

References

  1. 1.

    Wu FC, Tajar A, Beynon JM, Pye SR, Silman AJ, Finn JD, O’Neill TW, Bartfai G, Casanueva FF, Forti G, Giwercman A, Han TS, Kula K, Lean ME, Pendleton N, Punab M, Boonen S, Vanderschueren D, Labrie F, Huhtaniemi IT, EMAS Group (2010) Identification of late-onset hypogonadism in middle-aged and elderly men. N Engl J Med 363(2):123–135. https://doi.org/10.1056/NEJMoa0911101

    CAS  Article  PubMed  Google Scholar 

  2. 2.

    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 

  3. 3.

    Corona G, Goulis DG, Huhtaniemi I, Zitzmann M, Toppari J, Forti G, Vanderschueren D, Wu FC (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. https://doi.org/10.1111/andr.12770

    Article  PubMed  Google Scholar 

  4. 4.

    Ponce OJ, Spencer-Bonilla G, Alvarez-Villalobos N, Serrano V, Singh-Ospina N, Rodriguez-Gutierrez R, Salcido-Montenegro A, Benkhadra R, Prokop LJ, Bhasin S, Brito JP (2018) The efficacy and adverse events of testosterone replacement therapy in hypogonadal men: a systematic review and meta-analysis of randomized, placebo-controlled trials. J Clin Endocrinol Metab 103(5):1745–1754

    Article  Google Scholar 

  5. 5.

    Corona GG, Rastrelli G, Maseroli E, Sforza A, Maggi M (2015) Testosterone replacement therapy and cardiovascular risk: a review. World J Mens Health 33(3):130–142. https://doi.org/10.5534/wjmh.2015.33.3.130

    Article  Google Scholar 

  6. 6.

    Goodman N, Guay A, Dandona P, Dhindsa S, Faiman C, Cunningham GR, ARES Committee (2015) American Association of Clinical Endocrinologists and American College of Endocrinology position statement on the association of testosterone and cardiovascular risk. Endocr Pract 21(9):1066–1073. https://doi.org/10.4158/EP14434.PS

    Article  PubMed  Google Scholar 

  7. 7.

    Chang Y, Kim JH, Noh JW, Cho YS, Park HJ, Joo KJ, Ryu S (2019) Prostate-specific antigen within the reference range, subclinical coronary atherosclerosis, and cardiovascular mortality. Circ Res 124(10):1492–1504. https://doi.org/10.1161/circresaha.118.313413

    CAS  Article  PubMed  Google Scholar 

  8. 8.

    Corona G, Isidori AM, Buvat J, Aversa A, Rastrelli G, Hackett G, Rochira V, Sforza A, Lenzi A, Mannucci E, Maggi M (2014) Testosterone supplementation and sexual function: a meta-analysis study. J Sex Med 11(6):1577–1592. https://doi.org/10.1111/jsm.12536

    CAS  Article  PubMed  Google Scholar 

  9. 9.

    Moher D, Liberati A, Tetzlaff J, Altman DG, PRISMA Group (2009) Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLoS Med 6(7):e1000097. https://doi.org/10.1371/journal.pmed.1000097

    Article  PubMed  PubMed Central  Google Scholar 

  10. 10.

    Hozo SP, Djulbegovic B, Hozo I (2005) Estimating the mean and variance from the median, range, and the size of a sample. BMC Med Res Methodol 5:13. https://doi.org/10.1186/1471-2288-5-13

    Article  PubMed  PubMed Central  Google Scholar 

  11. 11.

    DerSimonian R, Laird N (1986) Meta-analysis in clinical trials. Control Clin Trials 7(3):177–188. https://doi.org/10.1016/0197-2456(86)90046-2

    CAS  Article  PubMed  Google Scholar 

  12. 12.

    Shim SR, Kim S-J (2019) Intervention meta-analysis: application and practice using R software. Epidemiol Health 41:e2019008

    Article  Google Scholar 

  13. 13.

    Basu R, Dalla Man C, Campioni M, Basu A, Nair KS, Jensen MD, Khosla S, Klee G, Toffolo G, Cobelli C, Rizza RA (2007) Effect of 2 years of testosterone replacement on insulin secretion, insulin action, glucose effectiveness, hepatic insulin clearance, and postprandial glucose turnover in elderly men. Diabetes Care 30(8):1972–1978. https://doi.org/10.2337/dc07-0359

    CAS  Article  PubMed  Google Scholar 

  14. 14.

    Magnussen LV, Hvid LG, Hermann AP, Hougaard DM, Gram B, Caserotti P, Andersen MS (2017) Testosterone therapy preserves muscle strength and power in aging men with type 2 diabetes-a randomized controlled trial. Andrology 5(5):946–953. https://doi.org/10.1111/andr.12396

    CAS  Article  PubMed  Google Scholar 

  15. 15.

    Hackett G, Cole N, Saghir A, Jones P, Strange RC, Ramachandran S (2017) Testosterone replacement therapy: improved sexual desire and erectile function in men with type 2 diabetes following a 30-week randomized placebo-controlled study. Andrology 5(5):905–913. https://doi.org/10.1111/andr.12399

    CAS  Article  PubMed  Google Scholar 

  16. 16.

    Hackett G, Cole N, Bhartia M, Kennedy D, Raju J, Wilkinson P, Saghir A (2014) 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 68(2):203–215. https://doi.org/10.1111/ijcp.12235

    CAS  Article  PubMed  Google Scholar 

  17. 17.

    Magnussen LV, Glintborg D, Hermann P, Hougaard DM, Hojlund K, Andersen M (2016) Effect of testosterone on insulin sensitivity, oxidative metabolism and body composition in aging men with type 2 diabetes on metformin monotherapy. Diabetes Obes Metab 18(10):980–989. https://doi.org/10.1111/dom.12701

    CAS  Article  PubMed  Google Scholar 

  18. 18.

    Aversa A, Bruzziches R, Francomano D, Spera G, Lenzi A (2010) Efficacy and safety of two different testosterone undecanoate formulations in hypogonadal men with metabolic syndrome. J Endocrinol Invest 33(11):776–783. https://doi.org/10.1007/bf03350341

    CAS  Article  PubMed  Google Scholar 

  19. 19.

    Fui MNT, Prendergast LA, Dupuis P, Raval M, Strauss BJ, Zajac JD, Grossmann M (2016) Effects of testosterone treatment on body fat and lean mass in obese men on a hypocaloric diet: a randomised controlled trial. BMC Med. https://doi.org/10.1186/s12916-016-0700-9

    Article  Google Scholar 

  20. 20.

    Groti K, Zuran I, Antonic B, Forsnaric L, Pfeifer M (2018) 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 21(3):158–169. https://doi.org/10.1080/13685538.2018.1468429

    CAS  Article  PubMed  Google Scholar 

  21. 21.

    Shigehara K, Konaka H, Nohara T, Izumi K, Kitagawa Y, Kadono Y, Iwamoto T, Koh E, Mizokami A, Namiki M (2018) Effects of testosterone replacement therapy on metabolic syndrome among Japanese hypogonadal men: a subanalysis of a prospective randomised controlled trial (EARTH study). Andrologia. https://doi.org/10.1111/and.12815

    Article  PubMed  Google Scholar 

  22. 22.

    Jones TH, Arver S, Behre HM, Buvat J, Meuleman E, Moncada I, Morales AM, Volterrani M, Yellowlees A, Howell JD, Channer KS (2011) Testosterone replacement in hypogonadal men with type 2 diabetes and/or metabolic syndrome (the TIMES2 study). Diabetes Care 34(4):828–837. https://doi.org/10.2337/dc10-1233

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  23. 23.

    Simon D, Charles MA, Lahlou N, Nahoul K, Oppert JM, Gouault-Heilmann M, Lemort N, Thibult N, Joubert E, Balkau B, Eschwege E (2001) Androgen therapy improves insulin sensitivity and decreases leptin level in healthy adult men with low plasma total testosterone: a 3-month randomized placebo-controlled trial. Diabetes Care 24(12):2149–2151

    CAS  Article  Google Scholar 

  24. 24.

    Heufelder AE, Saad F, Bunck MC, Gooren L (2009) 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 30(6):726–733. https://doi.org/10.2164/jandrol.108.007005

    CAS  Article  PubMed  Google Scholar 

  25. 25.

    Fui MNT, Hoermann R, Grossmann M (2017) Effect of testosterone treatment on adipokines and gut hormones in obese men on a hypocaloric diet. J Endocr Soc 1(4):302–312. https://doi.org/10.1210/js.2017-00062

    CAS  Article  Google Scholar 

  26. 26.

    Hackett G, Cole N, Bhartia M, Kennedy D, Raju J, Wilkinson P (2014) Testosterone replacement therapy improves metabolic parameters in hypogonadal men with type 2 diabetes but not in men with coexisting depression: the BLAST study. J Sex Med 11(3):840–856. https://doi.org/10.1111/jsm.12404

    CAS  Article  PubMed  Google Scholar 

  27. 27.

    Jensen RC, Christensen LL, Nielsen J, Schrøder HD, Kvorning T, Gejl K, Højlund K, Glintborg D, Andersen M (2018) Mitochondria, glycogen, and lipid droplets in skeletal muscle during testosterone treatment and strength training: a randomized, double-blinded, placebo-controlled trial. Andrology 6(4):547–555. https://doi.org/10.1111/andr.12492

    CAS  Article  PubMed  Google Scholar 

  28. 28.

    Janjgava S, Zerekidze T, Uchava L, Giorgadze E, Asatiani K (2014) Influence of testosterone replacement therapy on metabolic disorders in male patients with type 2 diabetes mellitus and androgen deficiency. Eur J Med Res 19:56. https://doi.org/10.1186/s40001-014-0056-6

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  29. 29.

    Wittert G, Bracken K, Robledo KP, Grossmann M, Yeap BB, Handelsman DJ, Stuckey B, Conway A, Inder W, McLachlan R, Allan C, Jesudason D, Fui MNT, Hague W, Jenkins A, Daniel M, Gebski V, Keech A (2021) 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 9(1):32–45. https://doi.org/10.1016/s2213-8587(20)30367-3

    CAS  Article  PubMed  Google Scholar 

  30. 30.

    Rydén L, Grant PJ, Anker SD, Berne C, Cosentino F, Danchin N, Deaton C, Escaned J, Hammes HP, Huikuri H, Marre M, Marx N, Mellbin L, Ostergren J, Patrono C, Seferovic P, Uva MS, Taskinen MR, Tendera M, Tuomilehto J, Valensi P, Zamorano JL, Zamorano JL, Achenbach S, Baumgartner H, Bax JJ, Bueno H, Dean V, Deaton C, Erol C, Fagard R, Ferrari R, Hasdai D, Hoes AW, Kirchhof P, Knuuti J, Kolh P, Lancellotti P, Linhart A, Nihoyannopoulos P, Piepoli MF, Ponikowski P, Sirnes PA, Tamargo JL, Tendera M, Torbicki A, Wijns W, Windecker S, De Backer G, Sirnes PA, Ezquerra EA, Avogaro A, Badimon L, Baranova E, Baumgartner H, Betteridge J, Ceriello A, Fagard R, Funck-Brentano C, Gulba DC, Hasdai D, Hoes AW, Kjekshus JK, Knuuti J, Kolh P, Lev E, Mueller C, Neyses L, Nilsson PM, Perk J, Ponikowski P, Reiner Z, Sattar N, Schächinger V, Scheen A, Schirmer H, Strömberg A, Sudzhaeva S, Tamargo JL, Viigimaa M, Vlachopoulos C, Xuereb RG (2013) ESC guidelines on diabetes, pre-diabetes, and cardiovascular diseases developed in collaboration with the EASD: the task force on diabetes, pre-diabetes, and cardiovascular diseases of the European Society of Cardiology (ESC) and developed in collaboration with the European Association for the Study of Diabetes (EASD). Eur Heart J 34(39):3035–3087. https://doi.org/10.1093/eurheartj/eht108

    Article  PubMed  Google Scholar 

  31. 31.

    Corona G, Giagulli VA, Maseroli E, Vignozzi L, Aversa A, Zitzmann M, Saad F, Mannucci E, Maggi M (2016) THERAPY OF ENDOCRINE DISEASE: testosterone supplementation and body composition: results from a meta-analysis study. Eur J Endocrinol 174(3):R99-116. https://doi.org/10.1530/EJE-15-0262

    CAS  Article  PubMed  Google Scholar 

  32. 32.

    Corona G, Maseroli E, Maggi M (2014) Injectable testosterone undecanoate for the treatment of hypogonadism. Expert Opin Pharmacother 15(13):1903–1926. https://doi.org/10.1517/14656566.2014.944896

    CAS  Article  PubMed  Google Scholar 

  33. 33.

    Keating NL, O’Malley AJ, Smith MR (2006) Diabetes and cardiovascular disease during androgen deprivation therapy for prostate cancer. J Clin Oncol 24(27):4448–4456. https://doi.org/10.1200/JCO.2006.06.2497

    CAS  Article  PubMed  Google Scholar 

  34. 34.

    Harada N (2018) Role of androgens in energy metabolism affecting on body composition, metabolic syndrome, type 2 diabetes, cardiovascular disease, and longevity: lessons from a meta-analysis and rodent studies. Biosci Biotechnol Biochem 82(10):1667–1682. https://doi.org/10.1080/09168451.2018.1490172

    CAS  Article  PubMed  Google Scholar 

  35. 35.

    Hackett G, Cole N, Mulay A, Strange RC, Ramachandran S (2019) Long-term testosterone therapy in type 2 diabetes is associated with reduced mortality without improvement in conventional cardiovascular risk factors. BJU Int 123(3):519–529

    CAS  Article  Google Scholar 

  36. 36.

    Magnussen LV, Andersen PE, Diaz A, Ostojic J, Hojlund K, Hougaard DM, Christensen AN, Nielsen TL, Andersen M (2017) MR spectroscopy of hepatic fat and adiponectin and leptin levels during testosterone therapy in type 2 diabetes: a randomized, double-blinded, placebo-controlled trial. Eur J Endocrinol 177(2):157–168. https://doi.org/10.1530/EJE-17-0071

    CAS  Article  PubMed  Google Scholar 

  37. 37.

    Feingold KR, Brinton EA, Grunfeld C (2000) The effect of endocrine disorders on lipids and lipoproteins. In: Feingold KR, Anawalt B, Boyce A et al (eds) Endotext. MDText.com, Inc, South Dartmouth

    Google Scholar 

  38. 38.

    Finkle WD, Greenland S, Ridgeway GK, Adams JL, Frasco MA, Cook MB, Fraumeni JF Jr, Hoover RN (2014) Increased risk of non-fatal myocardial infarction following testosterone therapy prescription in men. PLoS ONE 9(1):e85805. https://doi.org/10.1371/journal.pone.0085805

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  39. 39.

    Lunenfeld B, Mskhalaya G, Zitzmann M, Arver S, Kalinchenko S, Tishova Y, Morgentaler A (2015) Recommendations on the diagnosis, treatment and monitoring of hypogonadism in men. Aging Male 18(1):5–15. https://doi.org/10.3109/13685538.2015.1004049

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  40. 40.

    Morgentaler A, Miner MM, Caliber M, Guay AT, Khera M, Traish AM (2015) Testosterone therapy and cardiovascular risk: advances and controversies. Mayo Clin Proc 90(2):224–251. https://doi.org/10.1016/j.mayocp.2014.10.011

    CAS  Article  PubMed  Google Scholar 

  41. 41.

    Kim DK, Noh JW, Chang Y, Lee HY, Park JJ, Ryu S, Kim JHJA (2020) Association between prostate-specific antigen and serum testosterone: a systematic review and meta-analysis. Andrology 8:1194–1213

    CAS  Article  Google Scholar 

Download references

Acknowledgements

This study was supported by “Soonchunhyang University Research Fund”.

Author information

Affiliations

Authors

Corresponding authors

Correspondence to Sung Ryul Shim or Jae Heon Kim.

Ethics declarations

Conflict of interest

The authors declare that they have no conflicts of interest.

Additional information

Publisher's Note

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

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 Basic biological characteristics (JPG 386 KB)

11255_2021_2876_MOESM2_ESM.jpg

Supplementary file2 Changes of metabolic markers after testosterone replacement therapy: A, Adiponectin; B, hsCRP (JPG 273 KB)

11255_2021_2876_MOESM3_ESM.jpg

Supplementary file3 Changes of anthropometric markers after testosterone replacement therapy: A, Total lean body mass; B, Total fat mass (JPG 130 KB)

Supplementary file4 Summary for risk of bias of randomized controlled trials (JPG 163 KB)

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Kim, S., Park, J., Kim, . et al. Efficacy of testosterone replacement therapy for treating metabolic disturbances in late-onset hypogonadism: a systematic review and meta-analysis. Int Urol Nephrol 53, 1733–1746 (2021). https://doi.org/10.1007/s11255-021-02876-w

Download citation

Keywords

  • Hypogonadism
  • Hormone replacement therapy
  • Meta-analysis
  • Metabolic syndrome
  • Testosterone