Age-related androgen deficiency: at the peak of controversy
A.Yu. Babenko
Almazov National Medical Research Centre, St. Petersburg
Androgen deficiency associated with ageing or metabolic disorders (i.e., obesity, metabolic syndrome, type 2 diabetes etc.) is addressed in many guidelines and papers. However, it is still controversial whether or not testosterone deficiency should be treated in these patients. Leading endocrinological societies disagree in several important points. This paper discusses disputable issues on the treatment and maintenance of optimal testosterone levels in men.
The maintenance of optimal and safe (considering age) testosterone levels in male patients with clinically relevant testosterone deficiency is beneficial in terms of improving the quality of life and metabolic health by reducing the risks of cardiovascular events and death. Regular (i.e., every 3 months) measurements of testosterone levels and safety tests (i.e., PSA levels, hematocrit, prostate volume) are required to provide safe treatment. Testosteron e transdermal gel is characterized by good cardiovascular safety profile resulting from optimal (without drastic fluctuations) testosterone levels when using this medication.
Keywords: optimal testosterone levels, male hypogonadism, testosterone deficiency, testosterone replacement therapy, transdermal gel.
For citation: Babenko A.Yu. Age-related androgen deficiency: at the peak of controversy. RMJ. Medical Review. 2019;10(II):92–95.
References
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16. Isidori A.M., Giannetta E., Greco E.A. et al. Effects of testosterone on body composition, bone metabolism and serum lipid profile in middle-aged men: a metaanalysis. Clin Endocrinol. 2005;63:280–293.
17. Zitzmann М., 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.
18. Zitzmann M., Brune M., Vieth V. et al. Monitoring bone density in hypogonadal men with phalangeal ultrasound. Bone. 2002;31:422–429.
19. Snyder P.J., Bhasin S., Cunningham G.R. et al. Effects of testosterone treatment in older men. N Engl J Med. 2016;374:611–624.
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21. Mulligan T., Frick M.F., Zuraw Q.C. et al. Prevalence of hypogonadism in males aged at least 45 years: the HIM study. Int J Clin Pract. 2006;60:762–769.
22. Corona G. 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. DOI: 10.1111/j.1365-2605.2009.00952.x.
23. Аметов А.С. и др. Взаимосвязь ожирения и сахарного диабета 2 в свете доказательной медицины. Эндокринология. 2016;3:83–93. [Ametov A.S. and others. The relationship of obesity and diabetes mellitus 2 in the light of evidence-based medicine. Endocrinology. 2016; 3: 83–93 (in Russ.)].
24. Pugh P.J. Acute haemodynamic effects of testosterone in men with chronic heart failure. Eur Heart J. 2003;24(10):909–915. DOI: 10.1016/s0195-668x(03)00083-6.
25. Pugh P.J. Testosterone treatment for men with chronic heart failure. Heart. 2004;90(4):446–447. DOI: 10.1136/hrt.2003.014639.
26. Beilin J., Ball E.M.A., Favaloro J.M. et al. Effect of the androgen receptor CAG repeat polymorphism on transcriptional activity: specificity in prostate and non-prostate cell lines. J Mol Endocrinol. 2000;25:85–96.
27. 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. American Journal of Geriatric Psychiatry. 2011;19(3):274–283. DOI: 10.1097/JGP.0b013e3181e70c22.
28. Zitzman M., Brune M., Kornmann G. et al. The CAG repeat polymorphism androgen receptor gene affects bone density and bone metabolism in healthy males. Clin Endocrinol (Oxf). 2001;55:649–657.
29. Zitzman M., Depenbusch M., Gromoll J., Nieschlag E. Prostate volume and growth in testosterone-substituted hypogonadal men are dependent on the CAG repeat polymorphism of the androgen receptor gene: a longitudinal pharmacogenetic study. J Clin Endocrinol Metab. 2003;88(5):2049–2054.
30. Zitzmann М. and Nieschlag Е. Androgen Receptor Gene CAG Repeat Length and Body Mass Index Modulate the Safety of Long-Term Intramuscular Testosterone Undecanoate Therapy in Hypogonadal Men. J Clin Endocrinol Metab. 2007;92(10):3844–3853. DOI: 10.1210/jc.2007-0620.
31. Wang C., Swerdloff R.S., Iranmanesh A. et al Transdermal testosterone gel improves sexual function, mood, muscle strength, and body composition parameters in hypogonadal men. J Clin Endocrinol Metab. 2000;85(8):2839–2853.
32. Brock G., Heiselman D., Maqqi M. Effect of T solution 2% on T concentration, sex drive and Energy in Hypogonadal men: results of a placebo controlled study. J Urol. 2016;195(3):699–705.
33. Dobs A.S., McGettigan J., Norwood P. et al. A novel testosterone 2% gel for the treatment of hypogonadal males. J Androl. 2012;33:601–607. DOI: 10.2164/jandrol.111.014308.
34. Davidiuk A.J. and Broderick G.A. Adult-onset hypogonadism: evaluation and role of testosterone replacement therapy. Transl Androl Urol. 2016;5(6):824–833.
35. Kaufman J.M., Miller M.G., Garwin J.L. et al. Efficacy and safety study of 1.62% testosterone gel for the treatment of hypogonadal men. J Sex Med. 2011;8:2079–2089. DOI: 10.1111/j.1743-6109.2011.02265.
36. Dean J.D., McMahon C.G., Guay A.T. et al. The International Society for Sexual Medicine’s process of care for the assessment and management of testosterone deficiency in adult men. J Sex Med. 2015;12:1660–1686. DOI: 10.1111/jsm.12952.
37. Bradley L.J. et al. Comparative Safety of Testosterone Dosage Form. JAMA Intern Med. 2015;175(7):1187–1196.
38. Corona G., Sforza A., Maggi M. Testosterone replacement therapy: Long-term safety and efficacy. World J Mens Health. 2017;35:65–76.
39. Dobs A.S., Meikle A.W., 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;84:3469–3478.
40. Abdulmaged M. Traish Testosterone and weight loss: the evidence. Curr Opin Endocrinol Diabetes Obes. 2014;21(5):313–322. DOI: 10.1097/MED.0000000000000086.
41. Behre Н.М., Tammela T.L., 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. The Aging Male. 2012;15(4):198–207. DOI: 10.3109/13685538.2012.699562.
42. Jones T.H., Arver S., Behre H.M. et al. Testosterone replacement in hypogonadal men with type 2 diabetes and/or metabolic syndrome (the TIMES2 study). Diabetes Care. 2011;34(4):828–837. DOI: 10.2337/dc10-1233.
43. Wang C., Cunningham G., Dobs A. Long-term testosterone gel (AndroGel) treatment maintains beneficial effects on sexual function and mood, lean and fat mass, and bone mineral density in hypogonadal men et al. J Clin Endocrinol Metab. 2004;89:2085–2098.
44. Srinivas-Shankar U., Roberts S.A., Connolly M.J. 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. J Clin Endocrinol Metab. 2010;95:639–650.
45. Vigen R., O’Donnell C.I., Barón A.E. et al. Association of testosterone therapy with mortality, myocardial infarction, and stroke in men with low testosterone levels. JAMA. 2013;310(17):1829–1836. DOI: 10.1001/jama.2013.280386.
46. Chrysant S.G., Chrysant G.S. Cardiovascular benefits and risks of testosterone replacement therapy in older men with low testosterone. Hosp Pract (1995). 2018;46(2):47–55. DOI: 10.1080/21548331.2018.1445405.
47. Hackett G.I. Testosterone Replacement Therapy and Mortality in Older Men. Drug Saf. 2016;39(2):117–130.
2. Bhasin S., Brito J.P., Cunningham G.R. et al. Testosterone therapy in men with hypogonadism: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2018;103:1715–1744.
3. Дедов И.И., Мельниченко Г.А., Шестакова М.В. и др. Рекомендации по диагностике и лечению дефицита тестостерона (гипогонадизма) у мужчин. Сахарный диабет. 2017;20(2):151–160. [Dedov I.I., Melnichenko G.A., Shestakova M.V. et al. Recommendations for the diagnosis and treatment of testosterone deficiency (hypogonadism) in men. Diabetes. 2017;20(2):151–160 (in Russ.)].
4. Lunenfeld B., Mskhalaya G. et al. Recommendations on the diagnosis, treatment and monitoring of hypogonadism in men. Aging Male. 2015;18(1):5–15.
5. Davidiuk A.J. and Broderick G.A. Adult-onset hypogonadism: evaluation and role of testosterone replacement therapy. Transl Androl Urol. 2016;5(6):824–833.
6. Bhasin S., Pencina M., Jasuja G.K. 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;2430–2439.
7. Sartorius G., Spasevska S., Idan A. et al. Serum testosterone, dihydrotestosterone and estradiol concentrations in older men self-reporting very good health: the Healthy Man Study. Clin Endocrinol (Oxf). 2012;77:755–763.
8. Harman S.M., Metter E.J., Tobin J.D. et al. Longitudinal effects of aging on serum total and free testosterone levels in healthy men. Baltimore Longitudinal Study of Aging. J Clin Endocrinol Metab. 2001;86(2):724–731.
9. Sikaris K., McLachlan R.I., Kazlauskas R. et al. Reproductive hormone reference intervals for healthy fertile young men: evaluation of automated platform assays. J Clin Endocrinol Metab. 2005;90:5928–5936.
10. Yeap B.B., Alfonso H., Chubb S.A. et al. Reference ranges and determinants of testosterone, dihydrotestosterone, and estradiol levels measured using liquid chromatography-tandem mass spectrometry in a population-based cohort of older men. J Clin Endocrinol Metab. 2012;97:4030–4039.
11. Yeap B.B., Alfonso H., Chubb S.A. et al. In older men an optimal plasma testosterone is associated with reduced all-cause mortality and higher dihydrotestosterone with reduced ischemic heart disease mortality, while estradiol levels do not predict mortality. J Clin Endocrinol Metab. 2014;99:E9–E18.
12. Corona G., Rastrelli G., Morelli A. et al. Hypogonadism and metabolic syndrome. J Endocrinol Invest. 2011;34:557–567.
13. Saad F., Aversa A., Isidori A.M. et al. Testosterone as potential effective therapy in treatment of obesity in men with testosterone deficiency: a review. Curr Diabetes Rev. 2012;8:131–143.
14. 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;30:911–917.
15. 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;82:814–819.
16. Isidori A.M., Giannetta E., Greco E.A. et al. Effects of testosterone on body composition, bone metabolism and serum lipid profile in middle-aged men: a metaanalysis. Clin Endocrinol. 2005;63:280–293.
17. Zitzmann М., 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.
18. Zitzmann M., Brune M., Vieth V. et al. Monitoring bone density in hypogonadal men with phalangeal ultrasound. Bone. 2002;31:422–429.
19. Snyder P.J., Bhasin S., Cunningham G.R. et al. Effects of testosterone treatment in older men. N Engl J Med. 2016;374:611–624.
20. Snyder P.J., Bhasin S., Cunningham G.R. et al. Lessons from the Testosterone Trials. Endocr Rev. 2018;39:369–386.
21. Mulligan T., Frick M.F., Zuraw Q.C. et al. Prevalence of hypogonadism in males aged at least 45 years: the HIM study. Int J Clin Pract. 2006;60:762–769.
22. Corona G. 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. DOI: 10.1111/j.1365-2605.2009.00952.x.
23. Аметов А.С. и др. Взаимосвязь ожирения и сахарного диабета 2 в свете доказательной медицины. Эндокринология. 2016;3:83–93. [Ametov A.S. and others. The relationship of obesity and diabetes mellitus 2 in the light of evidence-based medicine. Endocrinology. 2016; 3: 83–93 (in Russ.)].
24. Pugh P.J. Acute haemodynamic effects of testosterone in men with chronic heart failure. Eur Heart J. 2003;24(10):909–915. DOI: 10.1016/s0195-668x(03)00083-6.
25. Pugh P.J. Testosterone treatment for men with chronic heart failure. Heart. 2004;90(4):446–447. DOI: 10.1136/hrt.2003.014639.
26. Beilin J., Ball E.M.A., Favaloro J.M. et al. Effect of the androgen receptor CAG repeat polymorphism on transcriptional activity: specificity in prostate and non-prostate cell lines. J Mol Endocrinol. 2000;25:85–96.
27. 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. American Journal of Geriatric Psychiatry. 2011;19(3):274–283. DOI: 10.1097/JGP.0b013e3181e70c22.
28. Zitzman M., Brune M., Kornmann G. et al. The CAG repeat polymorphism androgen receptor gene affects bone density and bone metabolism in healthy males. Clin Endocrinol (Oxf). 2001;55:649–657.
29. Zitzman M., Depenbusch M., Gromoll J., Nieschlag E. Prostate volume and growth in testosterone-substituted hypogonadal men are dependent on the CAG repeat polymorphism of the androgen receptor gene: a longitudinal pharmacogenetic study. J Clin Endocrinol Metab. 2003;88(5):2049–2054.
30. Zitzmann М. and Nieschlag Е. Androgen Receptor Gene CAG Repeat Length and Body Mass Index Modulate the Safety of Long-Term Intramuscular Testosterone Undecanoate Therapy in Hypogonadal Men. J Clin Endocrinol Metab. 2007;92(10):3844–3853. DOI: 10.1210/jc.2007-0620.
31. Wang C., Swerdloff R.S., Iranmanesh A. et al Transdermal testosterone gel improves sexual function, mood, muscle strength, and body composition parameters in hypogonadal men. J Clin Endocrinol Metab. 2000;85(8):2839–2853.
32. Brock G., Heiselman D., Maqqi M. Effect of T solution 2% on T concentration, sex drive and Energy in Hypogonadal men: results of a placebo controlled study. J Urol. 2016;195(3):699–705.
33. Dobs A.S., McGettigan J., Norwood P. et al. A novel testosterone 2% gel for the treatment of hypogonadal males. J Androl. 2012;33:601–607. DOI: 10.2164/jandrol.111.014308.
34. Davidiuk A.J. and Broderick G.A. Adult-onset hypogonadism: evaluation and role of testosterone replacement therapy. Transl Androl Urol. 2016;5(6):824–833.
35. Kaufman J.M., Miller M.G., Garwin J.L. et al. Efficacy and safety study of 1.62% testosterone gel for the treatment of hypogonadal men. J Sex Med. 2011;8:2079–2089. DOI: 10.1111/j.1743-6109.2011.02265.
36. Dean J.D., McMahon C.G., Guay A.T. et al. The International Society for Sexual Medicine’s process of care for the assessment and management of testosterone deficiency in adult men. J Sex Med. 2015;12:1660–1686. DOI: 10.1111/jsm.12952.
37. Bradley L.J. et al. Comparative Safety of Testosterone Dosage Form. JAMA Intern Med. 2015;175(7):1187–1196.
38. Corona G., Sforza A., Maggi M. Testosterone replacement therapy: Long-term safety and efficacy. World J Mens Health. 2017;35:65–76.
39. Dobs A.S., Meikle A.W., 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;84:3469–3478.
40. Abdulmaged M. Traish Testosterone and weight loss: the evidence. Curr Opin Endocrinol Diabetes Obes. 2014;21(5):313–322. DOI: 10.1097/MED.0000000000000086.
41. Behre Н.М., Tammela T.L., 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. The Aging Male. 2012;15(4):198–207. DOI: 10.3109/13685538.2012.699562.
42. Jones T.H., Arver S., Behre H.M. et al. Testosterone replacement in hypogonadal men with type 2 diabetes and/or metabolic syndrome (the TIMES2 study). Diabetes Care. 2011;34(4):828–837. DOI: 10.2337/dc10-1233.
43. Wang C., Cunningham G., Dobs A. Long-term testosterone gel (AndroGel) treatment maintains beneficial effects on sexual function and mood, lean and fat mass, and bone mineral density in hypogonadal men et al. J Clin Endocrinol Metab. 2004;89:2085–2098.
44. Srinivas-Shankar U., Roberts S.A., Connolly M.J. 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. J Clin Endocrinol Metab. 2010;95:639–650.
45. Vigen R., O’Donnell C.I., Barón A.E. et al. Association of testosterone therapy with mortality, myocardial infarction, and stroke in men with low testosterone levels. JAMA. 2013;310(17):1829–1836. DOI: 10.1001/jama.2013.280386.
46. Chrysant S.G., Chrysant G.S. Cardiovascular benefits and risks of testosterone replacement therapy in older men with low testosterone. Hosp Pract (1995). 2018;46(2):47–55. DOI: 10.1080/21548331.2018.1445405.
47. Hackett G.I. Testosterone Replacement Therapy and Mortality in Older Men. Drug Saf. 2016;39(2):117–130.
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