Letter to the Editor: “Long-Term Testosterone Administration on Insulin Sensitivity in Older Men With Low or Low-Normal Testosterone Levels”

Letter to the Editor: “Long-Term Testosterone Administration on Insulin Sensitivity in Older... A recent report in the Journal of Clinical Endocrinology & Metabolism demonstrated that testosterone therapy for 3 years does not affect insulin sensitivity in men >60 years of age with low or low-normal testosterone concentrations (1). Two limitations of the study need attention. First, most of men in the study did not have low free testosterone. The mean free testosterone concentration in men randomized to the testosterone group was 68 ± 13 pg/mL. The lower limit of normal for calculated free testosterone as per the authors is 50 pg/mL. Hence, at least 66% of study subjects had normal total free testosterone concentrations and would not have been candidates for testosterone replacement therapy. Furthermore, only 7% of men had total testosterone concentrations below the lower limit of normal (239 ng/dL) for the assay used in the study. The men were adequately treated with dose adjustments and achieved mid-normal testosterone concentrations in the study. However, the mean increase in testosterone concentrations after treatment was only ∼40% because the baseline concentration was quite normal for most men. This contrasts with a 200% to 300% increase in testosterone concentrations achieved after testosterone replacement therapy in hypogonadal men (2, 3). Hence, the lack of effect of testosterone replacement therapy in the study is not entirely surprising. Second, the majority of subjects in the study by Huang et al. (1) were nonobese men. The effect of testosterone replacement on insulin sensitivity (as measured by the gold standard technique of hyperinsulinemic euglycemic clamps) in hypogonadal men with insulin resistance is quite robust. Almost 2 decades ago, Mårin et al. (4) demonstrated an improvement in insulin sensitivity with oral and transdermal testosterone treatment in obese men. We have shown that men with type 2 diabetes and hypogonadism are less insulin sensitive (by 36%) than those without hypogonadism and that testosterone replacement increases insulin sensitivity by 32% in men with hypogonadism (2). In parallel with an increase in glucose uptake during clamps, we found a substantial increase in the expression of insulin receptor β, insulin receptor substrate-1, AkT-2, and glucose transporter-4 in adipose tissue. This provides a mechanistic explanation for the increase in insulin sensitivity. Testosterone administration also induced a reduction in free fatty acid concentrations, probably through the suppression of lipolysis. There was a reduction in fat mass by 3 kg and a similar increase in lean mass. The improvement in insulin sensitivity was also associated with suppression of inflammatory mediators that interfere with insulin signaling. Clearly, testosterone enhances insulin sensitivity in men who are (1) hypogonadal and (2) insulin resistant. The results of Huang et al. (1) are similar to another study in elderly men with normal average testosterone concentrations. Testosterone replacement for 2 years did not alter insulin sensitivity in that trial (5). In contrast, the largest trial of testosterone replacement conducted so far in elderly hypogonadal men showed a small reduction in homeostatic model assessment–insulin resistance after 1 year of transdermal testosterone therapy (6). It thus appears that the “inconsistency” in the effect of testosterone replacement on insulin sensitivity arises from studying testosterone replacement in men who are neither hypogonadal nor insulin resistant. Acknowledgments Disclosure Summary: P.D. has received research support from the National Institutes of Health, Juvenile Diabetes Research Foundation, American Diabetes Association, Novo Nordisk, Bristol Meyer Squibb, AbbVie Pharmaceuticals, Astra Zeneca, and Boehringer Ingelheim Pharmaceuticals and honoraria from Eli Lilly, Novartis, GlaxoSmithKline, Merck, Novo Nordisk, Takeda, and Sanofi-Aventis. The remaining authors have nothing to disclose. References 1. Huang G, Pencina KM, Li Z, Basaria S, Bhasin S, Travison TG, Storer TW, Harman SM, Tsitouras P. Long-term testosterone administration on insulin sensitivity in older men with low or low-normal testosterone levels [published online ahead of print January 24, 2018]. J Clin Endocrinol Metab . doi: 10.1210/jc.2017-02545. 2. Dhindsa S, Ghanim H, Batra M, Kuhadiya ND, Abuaysheh S, Sandhu S, Green K, Makdissi A, Hejna J, Chaudhuri A, Punyanitya M, Dandona P. Insulin resistance and inflammation in hypogonadotropic hypogonadism and their reduction after testosterone replacement in men with type 2 diabetes. Diabetes Care . 2016; 39( 1): 82– 91. Google Scholar CrossRef Search ADS PubMed  3. Snyder PJ, Bhasin S, 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 III, Parsons JK, Wenger NK, Zeldow B, Landis JR, Ellenberg SS; Testosterone Trials Investigators. Effects of testosterone treatment in older men. N Engl J Med . 2016; 374( 7): 611– 624. Google Scholar CrossRef Search ADS PubMed  4. Mårin P, Holmäng S, Gustafsson C, Jönsson L, Kvist H, Elander A, Eldh J, Sjöström L, Holm G, Björntorp P. Androgen treatment of abdominally obese men. Obes Res . 1993; 1( 4): 245– 251. Google Scholar CrossRef Search ADS PubMed  5. Nair KS, Rizza RA, O’Brien P, Dhatariya K, Short KR, Nehra A, Vittone JL, Klee GG, Basu A, Basu R, Cobelli C, Toffolo G, Dalla Man C, Tindall DJ, Melton LJ III, Smith GE, Khosla S, Jensen MD. DHEA in elderly women and DHEA or testosterone in elderly men. N Engl J Med . 2006; 355( 16): 1647– 1659. Google Scholar CrossRef Search ADS PubMed  6. Mohler ER III, Ellenberg SS, Lewis CE, Wenger NK, Budoff MJ, Lewis MR, Mohler ER III, Ellenberg SS, Lewis CE, Wenger NK, Budoff MJ, Lewis MR, Barrett-Connor E, Swerdloff RS, Stephens-Shields A, Bhasin S, Cauley JA, Crandall JP, Cunningham GR, Ensrud KE, Gill TM, Matsumoto AM, Molitch ME, Pahor M, Preston PE, Hou X, Cifelli D, Snyder PJ. The effect of testosterone on cardiovascular biomarkers in the testosterone trials. J Clin Endocrinol Metab . 2018; 103( 2): 681– 688. Google Scholar CrossRef Search ADS PubMed  Copyright © 2018 Endocrine Society http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Journal of Clinical Endocrinology and Metabolism Oxford University Press

Letter to the Editor: “Long-Term Testosterone Administration on Insulin Sensitivity in Older Men With Low or Low-Normal Testosterone Levels”

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Publisher
Endocrine Society
Copyright
Copyright © 2018 Endocrine Society
ISSN
0021-972X
eISSN
1945-7197
D.O.I.
10.1210/jc.2018-00265
Publisher site
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Abstract

A recent report in the Journal of Clinical Endocrinology & Metabolism demonstrated that testosterone therapy for 3 years does not affect insulin sensitivity in men >60 years of age with low or low-normal testosterone concentrations (1). Two limitations of the study need attention. First, most of men in the study did not have low free testosterone. The mean free testosterone concentration in men randomized to the testosterone group was 68 ± 13 pg/mL. The lower limit of normal for calculated free testosterone as per the authors is 50 pg/mL. Hence, at least 66% of study subjects had normal total free testosterone concentrations and would not have been candidates for testosterone replacement therapy. Furthermore, only 7% of men had total testosterone concentrations below the lower limit of normal (239 ng/dL) for the assay used in the study. The men were adequately treated with dose adjustments and achieved mid-normal testosterone concentrations in the study. However, the mean increase in testosterone concentrations after treatment was only ∼40% because the baseline concentration was quite normal for most men. This contrasts with a 200% to 300% increase in testosterone concentrations achieved after testosterone replacement therapy in hypogonadal men (2, 3). Hence, the lack of effect of testosterone replacement therapy in the study is not entirely surprising. Second, the majority of subjects in the study by Huang et al. (1) were nonobese men. The effect of testosterone replacement on insulin sensitivity (as measured by the gold standard technique of hyperinsulinemic euglycemic clamps) in hypogonadal men with insulin resistance is quite robust. Almost 2 decades ago, Mårin et al. (4) demonstrated an improvement in insulin sensitivity with oral and transdermal testosterone treatment in obese men. We have shown that men with type 2 diabetes and hypogonadism are less insulin sensitive (by 36%) than those without hypogonadism and that testosterone replacement increases insulin sensitivity by 32% in men with hypogonadism (2). In parallel with an increase in glucose uptake during clamps, we found a substantial increase in the expression of insulin receptor β, insulin receptor substrate-1, AkT-2, and glucose transporter-4 in adipose tissue. This provides a mechanistic explanation for the increase in insulin sensitivity. Testosterone administration also induced a reduction in free fatty acid concentrations, probably through the suppression of lipolysis. There was a reduction in fat mass by 3 kg and a similar increase in lean mass. The improvement in insulin sensitivity was also associated with suppression of inflammatory mediators that interfere with insulin signaling. Clearly, testosterone enhances insulin sensitivity in men who are (1) hypogonadal and (2) insulin resistant. The results of Huang et al. (1) are similar to another study in elderly men with normal average testosterone concentrations. Testosterone replacement for 2 years did not alter insulin sensitivity in that trial (5). In contrast, the largest trial of testosterone replacement conducted so far in elderly hypogonadal men showed a small reduction in homeostatic model assessment–insulin resistance after 1 year of transdermal testosterone therapy (6). It thus appears that the “inconsistency” in the effect of testosterone replacement on insulin sensitivity arises from studying testosterone replacement in men who are neither hypogonadal nor insulin resistant. Acknowledgments Disclosure Summary: P.D. has received research support from the National Institutes of Health, Juvenile Diabetes Research Foundation, American Diabetes Association, Novo Nordisk, Bristol Meyer Squibb, AbbVie Pharmaceuticals, Astra Zeneca, and Boehringer Ingelheim Pharmaceuticals and honoraria from Eli Lilly, Novartis, GlaxoSmithKline, Merck, Novo Nordisk, Takeda, and Sanofi-Aventis. The remaining authors have nothing to disclose. References 1. Huang G, Pencina KM, Li Z, Basaria S, Bhasin S, Travison TG, Storer TW, Harman SM, Tsitouras P. Long-term testosterone administration on insulin sensitivity in older men with low or low-normal testosterone levels [published online ahead of print January 24, 2018]. J Clin Endocrinol Metab . doi: 10.1210/jc.2017-02545. 2. Dhindsa S, Ghanim H, Batra M, Kuhadiya ND, Abuaysheh S, Sandhu S, Green K, Makdissi A, Hejna J, Chaudhuri A, Punyanitya M, Dandona P. Insulin resistance and inflammation in hypogonadotropic hypogonadism and their reduction after testosterone replacement in men with type 2 diabetes. Diabetes Care . 2016; 39( 1): 82– 91. Google Scholar CrossRef Search ADS PubMed  3. Snyder PJ, Bhasin S, 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 III, Parsons JK, Wenger NK, Zeldow B, Landis JR, Ellenberg SS; Testosterone Trials Investigators. Effects of testosterone treatment in older men. N Engl J Med . 2016; 374( 7): 611– 624. Google Scholar CrossRef Search ADS PubMed  4. Mårin P, Holmäng S, Gustafsson C, Jönsson L, Kvist H, Elander A, Eldh J, Sjöström L, Holm G, Björntorp P. Androgen treatment of abdominally obese men. Obes Res . 1993; 1( 4): 245– 251. Google Scholar CrossRef Search ADS PubMed  5. Nair KS, Rizza RA, O’Brien P, Dhatariya K, Short KR, Nehra A, Vittone JL, Klee GG, Basu A, Basu R, Cobelli C, Toffolo G, Dalla Man C, Tindall DJ, Melton LJ III, Smith GE, Khosla S, Jensen MD. DHEA in elderly women and DHEA or testosterone in elderly men. N Engl J Med . 2006; 355( 16): 1647– 1659. Google Scholar CrossRef Search ADS PubMed  6. Mohler ER III, Ellenberg SS, Lewis CE, Wenger NK, Budoff MJ, Lewis MR, Mohler ER III, Ellenberg SS, Lewis CE, Wenger NK, Budoff MJ, Lewis MR, Barrett-Connor E, Swerdloff RS, Stephens-Shields A, Bhasin S, Cauley JA, Crandall JP, Cunningham GR, Ensrud KE, Gill TM, Matsumoto AM, Molitch ME, Pahor M, Preston PE, Hou X, Cifelli D, Snyder PJ. The effect of testosterone on cardiovascular biomarkers in the testosterone trials. J Clin Endocrinol Metab . 2018; 103( 2): 681– 688. Google Scholar CrossRef Search ADS PubMed  Copyright © 2018 Endocrine Society

Journal

Journal of Clinical Endocrinology and MetabolismOxford University Press

Published: Mar 12, 2018

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