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Selective Use of Testosterone Replacement Therapy
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Selective Use of Testosterone Replacement Therapy IN a study on testosterone replacement (TRT) in this issue of The Journal (page 000), Brock et al examine the 2 important aspects of safety and symptom improvement.1 The safety profile in the open label study was consistent with the safety outcomes of the double-blind phase and other trials using testosterone solution that suggest that this form of testosterone replacement is safe. The efficacy outcomes are somewhat more uncertain. At the completion of the open label phase only 60% and 66% of the participants had total testosterone levels within the normal range for the former placebo and continuing active therapy groups, respectively. However, no baseline and exit testosterone levels are given and the results are not stratified by age. Why did such a large number of patients not respond to treatment? Was the response age related? The mean age of this study population was only 55 years old, but beyond that, further age stratification is not provided. The symptom instruments used to measure clinical response were developed in a group of 125 men with hypogonadism who were also relatively young (mean age 53 years, 85% adult onset).2 Again, it is hard to know if the clinical response reported in the current study correlates with testosterone levels achieved by replacement therapy and whether the age of the patients had any bearing on the clinical response. The interest in TRT continues to intensify. Androgen use among men 40 years or older increased more than threefold from 2001 to 2011.3 Among all new androgen users (2001 to 2011) only 74.72% had their testosterone level measured in the prior 12 months.3 However, despite this explosion in TRT, the prevalence of unequivocal hypogonadism remains unchanged. This finding led Spitzer et al to suggest that a sizable number of testosterone prescriptions are written for age related decline in testosterone levels, an indication for which testosterone therapy is not approved.4 It is well established that testosterone levels decrease in men as they age. Longitudinal studies in male aging show that serum testosterone levels decline with age, total testosterone levels fall at an
0022-5347/16/1965-0001/0 THE JOURNAL OF UROLOGY® Ó 2016 by AMERICAN UROLOGICAL ASSOCIATION EDUCATION
AND
RESEARCH, INC.
average of 1.6% per year and free bioavailable testosterone levels fall by 2% to 3% per year.5 The reduction in bioavailable testosterone is greater because aging is also associated with increases in sex hormone-binding globulin levels. The challenge of diagnosing and treating late onset hypogonadism (LOH) is compounded by the fact that there is considerable overlap of the symptoms of normal aging and those of hypogonadism. Nguyen et al have cautioned that serum testosterone appears to decrease as men age and, although this decline is usually modest, concentrations can fall below the normal range for healthy young men.6 In these cases it is unclear whether coexisting nonspecific signs and symptoms, such as decreases in energy and muscle mass, are a consequence of the age related decline in endogenous testosterone or whether they are a result of other factors, such as coexisting conditions, concomitant medications or perhaps aging itself. Wu et al further elaborated on this clinical dilemma of what truly defines LOH when they stated, “...symptoms in aging men are nonspecific and are mimicked by other prevalent disorders. The testosterone level below which symptoms of androgen deficiency emerge and adverse health outcomes occur in older men remains unclear, and the use of arbitrary thresholds is not appropriate.”7 In 2003 the Institute of Medicine assembled a committee to study the question of LOH. The committee found a paucity of randomized, placebo controlled clinical trials involving older men and noted a lack of definite evidence that testosterone therapy conferred benefits. The committee recommended that clinical trials be initiated. Snyder et al recently published the results of these trials.8 They assigned 790 men 65 years old or older with a serum testosterone concentration of less than 275 ng/dl and symptoms suggesting hypoandrogenism to receive testosterone gel or placebo for 1 year. Increasing the serum testosterone concentrations of men 65 years old or older from a moderately low to mid-normal range for men 19 to 40 years old had significant effects on all measures of sexual function and some benefit with
http://dx.doi.org/10.1016/j.juro.2016.08.075 Vol. 196, 1-2, November 2016 Printed in U.S.A.
www.jurology.com Dochead: Editorials
EDI 5.4.0 DTD JURO13954_proof 18 August 2016 7:39 am EO:
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SELECTIVE USE OF TESTOSTERONE REPLACEMENT THERAPY
respect to mood and depressive symptoms, but no benefit with respect to vitality or walking distance. The question was asked, why was there such a tepid improvement in symptoms when serum testosterone levels were corrected to levels that were considered “normal” in younger men? In an accompanying editorial Orwoll offered the perspective that testosterone therapy did yield certain benefits, but at this time their clinical importance is uncertain and the evidence might be insufficient to support initiation of TRT in older men.9 The unaddressed issue remains whether these men who were defined as “hypogonadal” using serum values considered normal in men decades younger, were truly hypogonadal or actually eugonadal for their age. If, in fact, these men were eugonadal for their age, it should not be unexpected that testosterone supplementation may not result in a significant clinical benefit. Many areas of medicine have already embraced the concept of consideration of age when
interpreting results.10,11 Many laboratory values including alkaline phosphatase, ANA, rheumatoid factor, creatinine, postprandial glucose and magnesium are age related. In our own specialty age adjusted prostate specific antigen levels have been used clinically for more than 20 years.12 The quantification of age adjusted testosterone levels is an obvious clinical need. It is not unreasonable to posit that some of the explosion in testosterone prescriptions is due to the fact that some older men are being diagnosed as “hypogonadal” based on serum levels that apply to men who are decades younger. A prospective trial to better define age adjusted testosterone levels is long overdue and should be near the top of our research agenda. Kevin R. Loughlin and Julia Klap Department of Urology Brigham and Women’s Hospital Boston, Massachusetts
REFERENCES 1. Brock G, Heiselman D, Knorr J et al: 9-Month efficacy and safety study of testosterone solution 2% for sex drive and energy in hypogonadal men: results of a 6-month open label extension of a 3-month double-blind study. J Urol 2016; 196: xxx.
5. Feldman HA, Longcope C, Derby CA et al: Age trends in the level of serum testosterone and other hormones in middle-aged men: longitudinal results from the Massachusetts male aging study. J Clin Endocrinol Metab 2002; 87: 589.
2. Hayes RP, Henne J and Kinchen KS: Establishing the content validity of the Sexual Arousal, Interest, and Drive Scale and the Hypogonadism Energy Diary. Int J Clin Pract 2015; 69: 454.
6. Nguyen CP, Hirsch MS, Moeny D et al: Testosterone and “age-related hypogonadism”dFDA concerns. N Engl J Med 2015; 373: 689.
3. Baillargeon J, Urban RJ, Ottenbacher KJ et al: Trends in androgen prescribing in the United States, 2001 to 2011. JAMA Intern Med 2013; 173: 1465.
7. Wu FC, Tajar A, Beynon JM et al: Identification of late-onset hypogonadism in middle-aged and elderly men. N Engl J Med 2010; 363: 123.
4. Spitzer M, Huang G, Basaria S et al: Risks and benefits of testosterone therapy in older men. Nat Rev Endocrinol 2013; 9: 414.
8. Snyder PJ, Bhasin S, Cunningham GR et al: Effects of testosterone treatment in older men. N Engl J Med 2016; 374: 611.
Dochead: Editorials
9. Orwoll ES: Establishing a frameworkddoes testosterone supplementation help older men? N Engl J Med 2016; 374: 682. 10. ClinLab Navigator: Aging effect on laboratory values. Available at http://www.clinlabnavigator. com/aging-effect-on-laboratory-values.html. Accessed June 6, 2016. 11. Bertoia ML, Waring ME, Gupta PS et al: Implications of new hypertension guidelines in the United States. Hypertension 2012; 60: 639. 12. Oesterling JE, Jacobsen SJ, Chute CG et al: Serum prostate-specific antigen in a communitybased population of healthy men. Establishment of age-specific reference ranges. JAMA 1993; 270: 860.
EDI 5.4.0 DTD JURO13954_proof 18 August 2016 7:39 am EO:
164 165 166 167 168 169 170 171 172 173 174 175 176 177 178 179 180 181 182 183 184 185 186 187 188 189 190 191 192 193 194 195 196 197 198 199 200 201 202 203 204 205 206 207 208 209 210 211 212
Selective Use of Testosterone Replacement Therapy IN a study on testosterone replacement (TRT) in this issue of The Journal (page 000), Brock et al examine the 2 important aspects of safety and symptom improvement.1 The safety profile in the open label study was consistent with the safety outcomes of the double-blind phase and other trials using testosterone solution that suggest that this form of testosterone replacement is safe. The efficacy outcomes are somewhat more uncertain. At the completion of the open label phase only 60% and 66% of the participants had total testosterone levels within the normal range for the former placebo and continuing active therapy groups, respectively. However, no baseline and exit testosterone levels are given and the results are not stratified by age. Why did such a large number of patients not respond to treatment? Was the response age related? The mean age of this study population was only 55 years old, but beyond that, further age stratification is not provided. The symptom instruments used to measure clinical response were developed in a group of 125 men with hypogonadism who were also relatively young (mean age 53 years, 85% adult onset).2 Again, it is hard to know if the clinical response reported in the current study correlates with testosterone levels achieved by replacement therapy and whether the age of the patients had any bearing on the clinical response. The interest in TRT continues to intensify. Androgen use among men 40 years or older increased more than threefold from 2001 to 2011.3 Among all new androgen users (2001 to 2011) only 74.72% had their testosterone level measured in the prior 12 months.3 However, despite this explosion in TRT, the prevalence of unequivocal hypogonadism remains unchanged. This finding led Spitzer et al to suggest that a sizable number of testosterone prescriptions are written for age related decline in testosterone levels, an indication for which testosterone therapy is not approved.4 It is well established that testosterone levels decrease in men as they age. Longitudinal studies in male aging show that serum testosterone levels decline with age, total testosterone levels fall at an
0022-5347/16/1965-0001/0 THE JOURNAL OF UROLOGY® Ó 2016 by AMERICAN UROLOGICAL ASSOCIATION EDUCATION
AND
RESEARCH, INC.
average of 1.6% per year and free bioavailable testosterone levels fall by 2% to 3% per year.5 The reduction in bioavailable testosterone is greater because aging is also associated with increases in sex hormone-binding globulin levels. The challenge of diagnosing and treating late onset hypogonadism (LOH) is compounded by the fact that there is considerable overlap of the symptoms of normal aging and those of hypogonadism. Nguyen et al have cautioned that serum testosterone appears to decrease as men age and, although this decline is usually modest, concentrations can fall below the normal range for healthy young men.6 In these cases it is unclear whether coexisting nonspecific signs and symptoms, such as decreases in energy and muscle mass, are a consequence of the age related decline in endogenous testosterone or whether they are a result of other factors, such as coexisting conditions, concomitant medications or perhaps aging itself. Wu et al further elaborated on this clinical dilemma of what truly defines LOH when they stated, “...symptoms in aging men are nonspecific and are mimicked by other prevalent disorders. The testosterone level below which symptoms of androgen deficiency emerge and adverse health outcomes occur in older men remains unclear, and the use of arbitrary thresholds is not appropriate.”7 In 2003 the Institute of Medicine assembled a committee to study the question of LOH. The committee found a paucity of randomized, placebo controlled clinical trials involving older men and noted a lack of definite evidence that testosterone therapy conferred benefits. The committee recommended that clinical trials be initiated. Snyder et al recently published the results of these trials.8 They assigned 790 men 65 years old or older with a serum testosterone concentration of less than 275 ng/dl and symptoms suggesting hypoandrogenism to receive testosterone gel or placebo for 1 year. Increasing the serum testosterone concentrations of men 65 years old or older from a moderately low to mid-normal range for men 19 to 40 years old had significant effects on all measures of sexual function and some benefit with
http://dx.doi.org/10.1016/j.juro.2016.08.075 Vol. 196, 1-2, November 2016 Printed in U.S.A.
www.jurology.com Dochead: Editorials
EDI 5.4.0 DTD JURO13954_proof 18 August 2016 7:39 am EO:
j
1
58 59 60 61 62 63 64 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100 101 102 103 104 105 106 107 108 109 110 111 112 113 114
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115 116 117 118 119 120 121 122 123 124 125 126 127 128 129 130 131 132 133 134 135 136 137 138 139 140 141 142 143 144 145 146 147 148 149 150 151 152 153 154 155 156 157 158 159 160 161 162 163
SELECTIVE USE OF TESTOSTERONE REPLACEMENT THERAPY
respect to mood and depressive symptoms, but no benefit with respect to vitality or walking distance. The question was asked, why was there such a tepid improvement in symptoms when serum testosterone levels were corrected to levels that were considered “normal” in younger men? In an accompanying editorial Orwoll offered the perspective that testosterone therapy did yield certain benefits, but at this time their clinical importance is uncertain and the evidence might be insufficient to support initiation of TRT in older men.9 The unaddressed issue remains whether these men who were defined as “hypogonadal” using serum values considered normal in men decades younger, were truly hypogonadal or actually eugonadal for their age. If, in fact, these men were eugonadal for their age, it should not be unexpected that testosterone supplementation may not result in a significant clinical benefit. Many areas of medicine have already embraced the concept of consideration of age when
interpreting results.10,11 Many laboratory values including alkaline phosphatase, ANA, rheumatoid factor, creatinine, postprandial glucose and magnesium are age related. In our own specialty age adjusted prostate specific antigen levels have been used clinically for more than 20 years.12 The quantification of age adjusted testosterone levels is an obvious clinical need. It is not unreasonable to posit that some of the explosion in testosterone prescriptions is due to the fact that some older men are being diagnosed as “hypogonadal” based on serum levels that apply to men who are decades younger. A prospective trial to better define age adjusted testosterone levels is long overdue and should be near the top of our research agenda. Kevin R. Loughlin and Julia Klap Department of Urology Brigham and Women’s Hospital Boston, Massachusetts
REFERENCES 1. Brock G, Heiselman D, Knorr J et al: 9-Month efficacy and safety study of testosterone solution 2% for sex drive and energy in hypogonadal men: results of a 6-month open label extension of a 3-month double-blind study. J Urol 2016; 196: xxx.
5. Feldman HA, Longcope C, Derby CA et al: Age trends in the level of serum testosterone and other hormones in middle-aged men: longitudinal results from the Massachusetts male aging study. J Clin Endocrinol Metab 2002; 87: 589.
2. Hayes RP, Henne J and Kinchen KS: Establishing the content validity of the Sexual Arousal, Interest, and Drive Scale and the Hypogonadism Energy Diary. Int J Clin Pract 2015; 69: 454.
6. Nguyen CP, Hirsch MS, Moeny D et al: Testosterone and “age-related hypogonadism”dFDA concerns. N Engl J Med 2015; 373: 689.
3. Baillargeon J, Urban RJ, Ottenbacher KJ et al: Trends in androgen prescribing in the United States, 2001 to 2011. JAMA Intern Med 2013; 173: 1465.
7. Wu FC, Tajar A, Beynon JM et al: Identification of late-onset hypogonadism in middle-aged and elderly men. N Engl J Med 2010; 363: 123.
4. Spitzer M, Huang G, Basaria S et al: Risks and benefits of testosterone therapy in older men. Nat Rev Endocrinol 2013; 9: 414.
8. Snyder PJ, Bhasin S, Cunningham GR et al: Effects of testosterone treatment in older men. N Engl J Med 2016; 374: 611.
Dochead: Editorials
9. Orwoll ES: Establishing a frameworkddoes testosterone supplementation help older men? N Engl J Med 2016; 374: 682. 10. ClinLab Navigator: Aging effect on laboratory values. Available at http://www.clinlabnavigator. com/aging-effect-on-laboratory-values.html. Accessed June 6, 2016. 11. Bertoia ML, Waring ME, Gupta PS et al: Implications of new hypertension guidelines in the United States. Hypertension 2012; 60: 639. 12. Oesterling JE, Jacobsen SJ, Chute CG et al: Serum prostate-specific antigen in a communitybased population of healthy men. Establishment of age-specific reference ranges. JAMA 1993; 270: 860.
EDI 5.4.0 DTD JURO13954_proof 18 August 2016 7:39 am EO:
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