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The comment by McCarthy [1] is consistent with a recent position statement from the Endocrine Society of Australia recommending testosterone replacement therapy for men with the clinical syndrome of androgen deficiency due to underlying hypothalamic, pituitary or testicular disease, but not for older men with comorbidities, obesity or diabetes who may exhibit “low testosterone” in the absence of pathological hypogonadism [2]. However the conclusion by Huo et al [3] that further trials of testosterone are not necessary might be premature.
The US Testosterone Trials showed a moderate benefit of testosterone supplementation to improve sexual function in older men [4], proving causality for prior observational data [5]. Additional outcome measures from that trial have yet to be reported. Epidemiological studies in middle-aged and older men implicate low testosterone with increased risk of metabolic syndrome [6] and diabetes [7]. The ongoing Australia-wide study Testosterone for the Prevention of Diabetes Mellitus (T4DM, ACTRN12612000287831) in overweight men with impaired glucose tolerance will discover whether causality applies to diabetes risk. In older men low testosterone concentrations are independently associated with increased incidence of stroke [8] and with mortality [9]. Testosterone’s bioactive metabolites dihydrotestosterone and estradiol may influence biological ageing favourably in men [10].
Thus the next challenge will be to design and conduct adequately powered randomised controlled trials to determine the effect of testosterone on cardiovascular and mortality risk. The systematic review by Huo et al [3] defines the limits of available evidence, illuminating by extension the scope of our current ignorance. Additional clinical studies, particularly randomised controlled trials, are vital to inform health care for the increasing demographic of men at risk of ill-health who wish to age well.
References
1. McCarthy M. Testosterone supplementation for "low T" is not supported by evidence, review concludes. BMJ 2016; 354: i5166.
2. Yeap BB, Grossmann M, McLachlan RI, Handelsman DJ, Wittert GA, Conway AJ, Stuckey BGA, Lording DW, Allan CA, Zajac JD, Burger HG. Endocrine Society of Australia position statement on male hypogonadism (part 1): assessment and indications for testosterone therapy. Med J Aust 2016: 205: 173-178.
3. Huo S, Scialli AR, McGarvey S, Hill E, Tugertimur B, Hogenmiller A, Hirsch AI, Fugh-Berman A. Treatment of men for “low testosterone”: a systematic review. PLoS One 2016; 11: e0162480.
4. Snyder PJ, Bhasin B, Cunningham GR, Matsumoto AM, Stephens-Shields AJ, Cauley JA, Gill TM, Barrett-Connor E, Swerdloff RS, Wang C, Ensrud KE, Lewis CE, Farrar JT, Cella D, Rosen RC, Pahor M, Crandall JP, Molitch ME, Cifelli D, Dougar D, Fluharty L, Resnick SM, Storer TW, Anton S, Basaria S, Diem SJ, Hou X, Mohler ER, Parsons JK, Wenger NK, Zeldow B, Landis JR, Ellenberg SS. Effects of testosterone treatment in older men. New Engl J Med 2016; 374: 611-624.
5. Hyde Z, Flicker L, Hankey GJ, Almeida OP, McCaul KA, Chubb SAP, Yeap BB. Prevalence of sexual activity and associated factors in men aged 75-95 years: A cohort study. Ann Intern Med 2010; 153: 693-702.
6. Brand JS, Rovers MM, Yeap BB, Schneider HJ, Tuomainen T-P, Haring R, Corona G, Onat A, Maggio M, Bouchard C, Tong PCY, Chen RYT, Akishita M, Gietema JA, Gannage-Yared M-H, Unden A-L, Hautanen A, Goncharov NP, Kumanov P, Chubb SAP, Almeida OP, Wittchen H-U, Klotsche J, Wallaschofski H, Volzke H, Kauhanen J, Salonen JT, Ferrucci L, van der Schouw YT. Testosterone, sex hormone-binding globulin and the metabolic syndrome in men: An individual participant data meta-analysis of observational studies. PLoS One 2014; 9: e100409.
7. Ding EL, Song Y, Malik VS, Liu S. Sex differences of endogenous sex hormones and risk of Type 2 diabetes. JAMA 2006; 295: 1288-1299.
8. Yeap BB, Alfonso H, Chubb SAP, Handelsman DJ, Hankey GJ, Almeida OP, Golledge J, Norman PE, Flicker L. In older men, higher plasma testosterone or dihydrotestosterone are independent predictors for reduced incidence of stroke but not myocardial infarction. J Clin Endocrinol Metab 2014; 99: 4565-4573.
9. Yeap BB, Alfonso H, Chubb SAP, Handelsman DJ, Hankey GJ, Almeida OP, Golledge J, Norman PE, Flicker L. In older men an optimal plasma testosterone is associated with reduced all-cause mortality, and higher dihydrotestosterone with reduced ischaemic heart disease mortality, while estradiol levels do not predict mortality. J Clin Endocrinol Metab 2014; 99: E9-E18.
10. Yeap BB, Knuiman MW, Divitini ML, Hui J, Arscott GM, Handelsman DJ, McLennan SV, Twigg SM, McQuillan B, Hung J, Beilby JP. Epidemiological and Mendelian randomisation studies of dihydrotestosterone and estradiol, and leucocyte telomere length in men. J Clin Endocrinol Metab 2016; 101: 1299-1306.
Competing interests:
I have received speaker honoraria and conference support from Bayer, Eli Lilly and Besins, research support from Bayer, Eli Lilly and Lawley Pharmaceuticals, and participated in Advisory Boards for Eli Lilly and Besins.
03 October 2016
Bu B. Yeap
Endocrinologist
University of Western Australia, and Fiona Stanley Hospital, Perth, Western Australia
Harry Perkins Institute of Medical Research, Fiona Stanley Hospital, Murdoch 6150, Western Australia, Australia
Testosterone supplementation for men in the absence of pathological hypogonadism: more research needs to be done.
The comment by McCarthy [1] is consistent with a recent position statement from the Endocrine Society of Australia recommending testosterone replacement therapy for men with the clinical syndrome of androgen deficiency due to underlying hypothalamic, pituitary or testicular disease, but not for older men with comorbidities, obesity or diabetes who may exhibit “low testosterone” in the absence of pathological hypogonadism [2]. However the conclusion by Huo et al [3] that further trials of testosterone are not necessary might be premature.
The US Testosterone Trials showed a moderate benefit of testosterone supplementation to improve sexual function in older men [4], proving causality for prior observational data [5]. Additional outcome measures from that trial have yet to be reported. Epidemiological studies in middle-aged and older men implicate low testosterone with increased risk of metabolic syndrome [6] and diabetes [7]. The ongoing Australia-wide study Testosterone for the Prevention of Diabetes Mellitus (T4DM, ACTRN12612000287831) in overweight men with impaired glucose tolerance will discover whether causality applies to diabetes risk. In older men low testosterone concentrations are independently associated with increased incidence of stroke [8] and with mortality [9]. Testosterone’s bioactive metabolites dihydrotestosterone and estradiol may influence biological ageing favourably in men [10].
Thus the next challenge will be to design and conduct adequately powered randomised controlled trials to determine the effect of testosterone on cardiovascular and mortality risk. The systematic review by Huo et al [3] defines the limits of available evidence, illuminating by extension the scope of our current ignorance. Additional clinical studies, particularly randomised controlled trials, are vital to inform health care for the increasing demographic of men at risk of ill-health who wish to age well.
References
1. McCarthy M. Testosterone supplementation for "low T" is not supported by evidence, review concludes. BMJ 2016; 354: i5166.
2. Yeap BB, Grossmann M, McLachlan RI, Handelsman DJ, Wittert GA, Conway AJ, Stuckey BGA, Lording DW, Allan CA, Zajac JD, Burger HG. Endocrine Society of Australia position statement on male hypogonadism (part 1): assessment and indications for testosterone therapy. Med J Aust 2016: 205: 173-178.
3. Huo S, Scialli AR, McGarvey S, Hill E, Tugertimur B, Hogenmiller A, Hirsch AI, Fugh-Berman A. Treatment of men for “low testosterone”: a systematic review. PLoS One 2016; 11: e0162480.
4. Snyder PJ, Bhasin B, Cunningham GR, Matsumoto AM, Stephens-Shields AJ, Cauley JA, Gill TM, Barrett-Connor E, Swerdloff RS, Wang C, Ensrud KE, Lewis CE, Farrar JT, Cella D, Rosen RC, Pahor M, Crandall JP, Molitch ME, Cifelli D, Dougar D, Fluharty L, Resnick SM, Storer TW, Anton S, Basaria S, Diem SJ, Hou X, Mohler ER, Parsons JK, Wenger NK, Zeldow B, Landis JR, Ellenberg SS. Effects of testosterone treatment in older men. New Engl J Med 2016; 374: 611-624.
5. Hyde Z, Flicker L, Hankey GJ, Almeida OP, McCaul KA, Chubb SAP, Yeap BB. Prevalence of sexual activity and associated factors in men aged 75-95 years: A cohort study. Ann Intern Med 2010; 153: 693-702.
6. Brand JS, Rovers MM, Yeap BB, Schneider HJ, Tuomainen T-P, Haring R, Corona G, Onat A, Maggio M, Bouchard C, Tong PCY, Chen RYT, Akishita M, Gietema JA, Gannage-Yared M-H, Unden A-L, Hautanen A, Goncharov NP, Kumanov P, Chubb SAP, Almeida OP, Wittchen H-U, Klotsche J, Wallaschofski H, Volzke H, Kauhanen J, Salonen JT, Ferrucci L, van der Schouw YT. Testosterone, sex hormone-binding globulin and the metabolic syndrome in men: An individual participant data meta-analysis of observational studies. PLoS One 2014; 9: e100409.
7. Ding EL, Song Y, Malik VS, Liu S. Sex differences of endogenous sex hormones and risk of Type 2 diabetes. JAMA 2006; 295: 1288-1299.
8. Yeap BB, Alfonso H, Chubb SAP, Handelsman DJ, Hankey GJ, Almeida OP, Golledge J, Norman PE, Flicker L. In older men, higher plasma testosterone or dihydrotestosterone are independent predictors for reduced incidence of stroke but not myocardial infarction. J Clin Endocrinol Metab 2014; 99: 4565-4573.
9. Yeap BB, Alfonso H, Chubb SAP, Handelsman DJ, Hankey GJ, Almeida OP, Golledge J, Norman PE, Flicker L. In older men an optimal plasma testosterone is associated with reduced all-cause mortality, and higher dihydrotestosterone with reduced ischaemic heart disease mortality, while estradiol levels do not predict mortality. J Clin Endocrinol Metab 2014; 99: E9-E18.
10. Yeap BB, Knuiman MW, Divitini ML, Hui J, Arscott GM, Handelsman DJ, McLennan SV, Twigg SM, McQuillan B, Hung J, Beilby JP. Epidemiological and Mendelian randomisation studies of dihydrotestosterone and estradiol, and leucocyte telomere length in men. J Clin Endocrinol Metab 2016; 101: 1299-1306.
Competing interests: I have received speaker honoraria and conference support from Bayer, Eli Lilly and Besins, research support from Bayer, Eli Lilly and Lawley Pharmaceuticals, and participated in Advisory Boards for Eli Lilly and Besins.