Characteristics of Men Undergoing Testosterone Replacement Therapy and Adherence to Follow-up Recommendations in Metropolitan Multicenter Health Care System

Characteristics of Men Undergoing Testosterone Replacement Therapy and Adherence to Follow-up Recommendations in Metropolitan Multicenter Health Care System

Male Sexual Dysfunction Characteristics of Men Undergoing Testosterone Replacement Therapy and Adherence to Follow-up Recommendations in Metropolitan ...

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Male Sexual Dysfunction Characteristics of Men Undergoing Testosterone Replacement Therapy and Adherence to Follow-up Recommendations in Metropolitan Multicenter Health Care System Rena D. Malik, Chihsiung E. Wang, Brittany Lapin, Justin C. Lakeman, and Brian T. Helfand OBJECTIVE METHODS

RESULTS

CONCLUSION

To identify the frequencies of treatment and recommended laboratory follow-up for men with low serum testosterone levels. The Electronic Data Warehouse was queried to identify men of ages 18-85 years, who obtained a testing for serum total testosterone level from 2009 to 2012. The frequency of testosterone replacement therapy (TRT), patient demographics, and clinical characteristics were collected. The frequency of follow-up with serum total testosterone and complete blood count levels was documented. Among 9176 men who underwent testing for low testosterone levels, 3320 (36%) of them were hypogonadal with a mean serum total testosterone level of 194.3  64.9 ng/dL. Of them, 17.7% men were treated with TRTs. The treatment frequency significantly increased from 8.3% in 2009 to 24% in 2012. A total of 4.8% of men of reproductive ages (age, 18-35 years) were placed on TRTs. Within 180 days of initial testing, only 40% of treated men received follow-up with liver function tests and/or complete blood count, and only 49% had a follow-up serum testosterone level. Although the frequency of TRT is increasing, only a small percentage of hypogonadal men are actively undergoing treatment. A significant proportion of men of reproductive age are being treated with significant impacts on potential fertility. Less than half of the patients treated are being monitored appropriately after testosterone replacement. This highlights the importance of further education for providers prescribing testosterone replacement. UROLOGY 85: 1382e1388, 2015.  2015 Elsevier Inc.

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ypogonadism in adult men is often manifested by a constellation of symptoms including sexual dysfunction, fatigue, mood disturbances, decline in bone mineral density, increased adipose tissue, decreased muscle mass, anemia, impaired cognition, and decline in feeling of general well-being.1-3 Furthermore, hypogonadism has been linked to several comorbid conditions such as obesity, type 2 diabetes, hypertension, Financial Disclosure: The authors declare that they have no relevant financial interests. Funding Support: This work received philanthropic support from the Division of Urology and the John and Carol Walter Center for Urological Health, NorthShore University HealthSystem. From the Department of Surgery, Section of Urology, University of Chicago Medical Center, Chicago, IL; and the Department of Surgery, Division of Urology, NorthShore University HealthSystem, Evanston, IL Address correspondence to: Rena D. Malik, M.D., The Department of Surgery, Section of Urology, University of Chicago Medicine and Biological Sciences, 5841 S. Maryland Ave., Rm. J-653, MC6038, Chicago, IL 60637. E-mail: [email protected] uchospitals.edu; [email protected] Submitted: October 17, 2014, accepted (with revisions): January 23, 2015

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ª 2015 Elsevier Inc. All Rights Reserved

osteoporosis, cardiovascular disease, metabolic syndrome, frailty, and Alzheimer disease.1,4-11 It has been approximated that there are 2.4 million 40- to 69-year-old US men with hypogonadism defined by the presence of both signs and symptoms and specific biochemical parameters (total testosterone level <200 ng/dL or total testosterone level 200-400 ng/dL þ free testosterone level <8.91 ng/dL). The prevalence of hypogonadism is estimated to range between 6% and 12%.12 However, it has been projected that only 5%-35% of hypogonadal men actually receive treatment for their condition.13 Testing for hypogonadism should be directed toward identifying hypogonadal symptoms and confirmation with a low serum total testosterone level.3,14,15 Those with confirmed hypogonadism should subsequently receive testosterone replacement therapy (TRT) with goals to raise serum testosterone levels to the normal physiological range, improve hypogonadal symptoms, and potentially http://dx.doi.org/10.1016/j.urology.2015.01.027 0090-4295/15

benefit associated comorbidities such as decreased bone mineral density and insulin resistance.7,16 Several professional societies including the International Society of Andrology, International Society for the Study of the Aging Male, European Association of Urology, European Academy of Andrology, American Society of Andrology,14 the Endocrine Society,3 and the American Association of Clinical Endocrinologists15 have published clinical guidelines for the treatment and monitoring of hypogonadism. Generally, they recommend a confirmatory early morning repeat total testosterone or in patients with equivocal levels or patients with comorbidities altering levels of sex hormoneebinding globulin, a measured or calculated free or bioavailable testosterone level for men with suspected hypogonadism. Additionally, they recommend serum luteinizing hormone (LH), follicle-stimulating hormone (FSH), and prolactin levels to evaluate for secondary causes of hypogonadism. Because of the diurnal variation of testosterone levels, early morning levels are recommended when serum levels are at their peak. If TRT is initiated, a clinical follow-up evaluation at 3-6 months after treatment initiation, a hematocrit at the baseline, at 3-6 months, and then annually to evaluate for polycythemia. In recent years, advertising costs for TRT for hypogonadism have significantly increased. Pharmaceutical companies spent almost $3.5 billion on direct-toconsumer advertising in 2012.17 Similarly, sales of TRT have soared to nearly $2 billion, with experts estimating an increase to $5 billion in 2017.18 This increase in advertising along with the ease and widespread availability of TRT has resulted in an increased awareness of testosterone deficiency and treatment options. Although guidelines are readily available, there is a paucity of data on the behaviors of clinicians with regard to the initiation and follow-up of TRT. We sought to determine the frequency of TRT in men who underwent testing for low testosterone levels, compare patient characteristics between men treated and those not treated, and assess clinician adherence to follow-up guidelines for men receiving TRT.

METHODS The NorthShore University HealthSystem electronic data warehouse was used to identify men, of ages 18-85 years, who visited a physician within our medical group between 2009 and 2012. The NorthShore University HealthSystem is composed of 4 inpatient hospitals as well as a large multispecialty group practice encompassing >100 offices throughout the Chicago region. Patients were included in the analysis, if they received a testing for serum total testosterone level during the study period. Institutional laboratory codes were used to identify the presence of serum total testosterone assay and corresponding serum values. Patients who received multiple testing serum levels were counted only once, and their first-ever serum level was used for analysis. All patients were required to have no evidence of a previous serum total testosterone assay from January 1, 2008, to the date of their first serum level. Men were excluded, if they UROLOGY 85 (6), 2015

had a history of prostate cancer. The demographic characteristics of men meeting inclusion criteria were collected, including age, race, and body mass index (BMI). Clinical characteristics were documented using institutional and International Classification of Diseases, Ninth Revision, codes including smoking history, family history of prostate cancer, comorbid benign prostatic hyperplasia, chronic obstructive pulmonary disease, decreased libido, diabetes mellitus, erectile dysfunction hypertension, male infertility, myocardial infarction, osteoporosis, and peripheral vascular disease (Appendix 1). The practitioner specialty ordering the serum level, as well as the time the serum level was drawn, was collected. Additionally, institutional codes were used to see if patients had any of the following serum laboratory tests collected within 90 days of their original serum total testosterone level: prolactin, LH, or FSH. For the purposes of this study, hypogonadal men were defined as men with a serum total testosterone level of <300 ng/dL, as this is the lower limit of normal in the reference range established in our institutional laboratory. For some analyses, tested men were further subdivided into men who received treatment with testosterone supplementation or those who were not treated. Men were defined as treated, if they were prescribed a formulation of testosterone supplementation. Institutional codes for various testosterone formulations including transdermal gel, intramuscular injections, and buccal formulations were used. Follow-up laboratory data including complete blood count (CBC) and total testosterone level were collected for men undergoing TRT.

Statistical Analysis Patient characteristics were compared between treated and untreated patients, as well as between hypogonadal men and eugonadal men, at the baseline and at follow-up. Categorical variables were analyzed using chi-square and Fisher exact tests. Continuous variables were analyzed using t tests or WilcoxonMann-Whitney (nonparametric) tests. All statistical analyses were performed using SAS 9.3 statistical software (SAS Inc, Cary, NC).

RESULTS A total of 9176 men underwent testing for serum total testosterone during the study period, and 3320 (36%) of them were hypogonadal with a mean serum total testosterone level of 194.3  64.9 ng/dL. Nine percent (827) of all tested men subsequently underwent TRT; 29% (238) of men treated had serum total testosterone levels >300 ng/dL, whereas 71% (589) were considered hypogonadal. Between 2009 and 2012, the frequency of treatment significantly increased from 4.3% to 12.4%. This increase was more dramatic in the subset of hypogonadal men where treatment rates rose from 8.3% to 24% in 2012 (Supplementary Fig. 1). When subcategorized by age, frequency of treatment increased in all groups, however, most markedly in men of ages 18-35 years and between ages of 40 and 69 years (P <.01 for all). A total of 5.8% of the total men treated were in the reproductive age group of 18-35 years, and frequency of treatment in these men increased from 1.7% in 2009 to 8.1% in 2012 (Table 1). 1383

Table 1. Rate of treatment by age group over time Age (y) 18-35 36-39 40-49 50-59 60-69 70

Overall 48 26 188 257 186 122

(5.1) (6.3) (9.1) (9.8) (9.0) (11.4)

2009 3 7 13 12 8 14

(1.7) (8.1) (4.6) (3.4) (2.9) (10.3)

2010 3 1 13 23 12 6

2011

(1.6) (1.2) (3.1) (4.7) (3.0) (3.2)

17 6 61 90 54 43

2012

(6.5) (5.3) (10.5) (12.7) (9.6) (13.9)

25 12 101 132 112 59

(8.1) (9.2) (12.9) (12.5) (13.5) (13.6)

P Value .001 .11 <.001 <.001 <.001 .01

Table 2. Patient characteristics by treatment status Characteristic

Treated, N (%)

Not Treated, N (%)

P Value

Total no. of patients Mean age (y)  SD Mean body mass index (kg/m2)  SD Early morning testing (7 AM-12 PM) Concomitant serum levels* Race White Black Hispanic Asian Other Authorizing providers Endocrinology Family medicine Internal medicine Urology Other Unknown Comorbidities COPD Osteoporosis Peripheral vascular disease BPH Male infertility Erectile dysfunction Decreased libido/hypoactive sexual desire Diabetes Myocardial infarction Depression Hypertension

827 (9.0) 55.5  12.9 32.1  6.8 63 (7.6) 195 (23.6)

8349 (91.0) 53.4  13.6 29.7  5.9 723 (8.7) 1191 (14.3)

<.001 <.001 .307 <.001

609 36 17 14 151

(73.6) (4.4) (2.1) (1.7) (18.3)

5936 356 243 188 1626

(71.1) (4.3) (2.9) (2.3) (19.5)

.370

134 177 427 45 36 8

(16.2) (21.4) (51.6) (5.4) (4.4) (1.0)

857 1822 4631 443 405 191

(10.3) (21.8) (55.5) (5.3) (4.8) (2.3)

<.001

13 29 20 118 4 209 30 184 14 186 189

(1.6) (3.5) (2.4) (14.3) (0.5) (25.3) (3.6) (22.3) (1.7) (22.5) (22.9)

155 180 140 1311 51 2040 218 1374 150 1128 1472

(1.9) (2.2) (1.7) (15.7) (0.6) (24.4) (2.6) (16.5) (1.8) (13.5) (17.6)

.560 .013 .120 .278 .816 .593 .086 <.001 .830 <.001 <.001

BPH, benign prostatic hyperplasia; COPD, chronic obstructive pulmonary disease; SD, standard deviation. * Prolactin, luteinizing hormone, or follicle-stimulating hormone drawn within 90 days of initial serum total testosterone.

The majority of men who received TRT were prescribed a form of testosterone gel (70.7%) for treatment, followed by transdermal patch (14.5%) and intramuscular injection (14%; data not shown). Small minorities of men were prescribed alternate formulations including buccal and testosterone suspension. TRT was prescribed primarily by internal and family medicine practitioners (52% and 21%, respectively), followed by endocrinologists (16%) and urologists (5%; Table 2). Since 2009, the use of testosterone gel has increased, whereas the use of transdermal patch and intramuscular preparations has decreased (Supplementary Table 1). Proportion of TRT formulations used by specialists was similar except that family medicine practitioners used more transdermal patch and less intramuscular formulations in comparison with other clinicians (Supplementary Table 2). 1384

Treated vs Not Treated: Patient Characteristics The clinical characteristics were compared between treated and untreated groups of men (Table 2). Treated men had a significantly higher BMI and were significantly more likely to have diabetes, hypertension, depression, and osteoporosis. Treated men also had a higher frequency of having comorbid low libido. Eugonadal vs Hypogonadal Treated Men: Patient Characteristics In the cohort of men who received treatment, hypogonadal men were significantly more likely to have an increased BMI and have a serum FSH, LH, or prolactin level assessed within 90 days of testing (Table 3). Eugonadal men were more likely to have hypogonadal symptoms and comorbid conditions including osteoporosis, benign prostatic hyperplasia, and decreased libido. UROLOGY 85 (6), 2015

Table 3. Hypogonadal vs eugonadal treated men Characteristic

Hypogonadal, N (%)

Eugonadal, N (%)

P Value

589 (71.2) 55.5  12.5 32.9  7.1 39 (6.6) 161 (27.3)

238 (28.8) 55.5  14.0 30.0  5.5 24 (10.1) 34 (14.3)

.939 <.001 .089 <.001

Total no. of patients Mean age (y)  SD Mean body mass index (kg/m2)  SD Testing between 7 AM and 12 PM Concomitant serum levels* Race White Black Hispanic Asian Other Authorizing providers Endocrinology Family medicine Internal medicine Urology Other Unknown Comorbidities COPD Osteoporosis Peripheral vascular disease BPH Male infertility Erectile dysfunction Decreased libido/hypoactive sexual desire Diabetes Myocardial infarction Depression Hypertension

430 28 11 10 110

(73.0) (4.8) (1.9) (1.7) (18.7)

179 8 6 4 41

(75.2) (3.4) (2.5) (1.7) (17.2)

.842

86 126 304 38 29 6

(14.6) (21.4) (51.6) (6.5) (4.9) (1.0)

48 51 123 7 7 2

(20.2) (21.4) (51.7) (2.9) (2.9) (0.8)

.123

10 14 13 75 4 148 16 140 10 130 136

(1.7) (2.4) (2.2) (12.7) (0.7) (25.1) (2.7) (23.8) (1.7) (22.1) (23.1)

3 15 7 43 0 61 14 44 4 56 53

(1.3) (6.3) (2.9) (18.1) (0.0) (25.6) (5.9) (18.5) (1.7) (23.5) (22.3)

.767 .006 .534 .047 .583 .880 .028 .098 .999 .649 .799

Abbreviations as in Table 2. * Prolactin, luteinizing hormone, or follicle-stimulating hormone drawn within 90 days of initial serum total testosterone.

Table 4. Follow-up of hypogonadal vs eugonadal treated men Characteristic Number treated Follow-up CBC (%) Initial mean serum total testosterone (ng/dL)  SD Follow-up serum total testosterone (%) Mean follow-up serum total testosterone (ng/dL)  SD Men who remained hypogonadal on follow-up

Hypogonadal, N (%)

Eugonadal, N (%)

P Value

589 (71.2) 234 (39.7) 194.3  64.9 291 (49.4) 370.3  285.9 153/291 (52.6)

238 (28.8) 101 (42.4) 509.1  287.0 98 (41.2) 531.4  286.4 23/98 (23.5)

<.001 .473 <.001 .032 <.001 <.001

CBC, complete blood count; other abbreviation as in Table 1.

Treated eugonadal men were more often tested in the early morning between 7 AM and 12 PM. Eugonadal men with a serum total testosterone value >500 ng/dL (32.8%) were significantly more likely to receive treatment by an endocrinologist in comparison with other medical specialties (data not shown). Follow-up Assessment of Treated Men After initial testing, only 23.6% (195) of all men treated had a prolactin, FSH, or LH level assessed within 90 days. Only 40.5% of men received a CBC, and only 47% (398) of men received a follow-up serum total testosterone level within 6 months of initial testing (Table 4). Hypogonadal men who underwent treatment were significantly more likely to obtain a follow-up serum total testosterone within 6 months of the initial testing level. Mean serum UROLOGY 85 (6), 2015

total testosterone level after treatment was significantly lower in hypogonadal men, and a larger proportion of men remained hypogonadal on follow-up. Treatment and Follow-up Based on Provider Type Endocrinologists were significantly more likely to treat men with TRT in comparison with all other provider types (P <.001), were more likely to obtain a follow-up CBC after treating eugonadal men in comparison with internal medicine and family medicine practitioners (P ¼ .011), and tended to more often obtain a follow-up CBC in comparison with family medicine practitioners when treating hypogonadal men (47.7% vs 31.8%; P ¼ .062). However, urologists tended to more often treat hypogonadal men in comparison with endocrinologists (84.4% vs 64.2%; P ¼ .074). Mean follow-up serum total 1385

testosterone levels and the proportion of men who remained hypogonadal on follow-up were similar for all providers (Supplementary Table 3).

COMMENT In our population, the frequency of TRT has increased 3-fold since 2009, with an even greater increase in the treatment among the subset of hypogonadal men. This is consistent with previous studies evaluating trends of TRT. For example, Baillargeon et al19 found that rates of androgen prescription in the United States increased >3fold, from 0.81% in 2000 to 2.91% in 2011. Layton et al20 recently published data revealing an increase in the rate of treatment for hypogonadal men from 36% to 43% between 2007 and 2011 and 4%-9% of men with normal or high levels. This rise is likely attributed to the increase in pharmaceutical company advertising, growing attention in medical literature, and exposure to TRT in training and Continuing Medical Education programs. Although nationwide interest is difficult to assess, rudimentary data from Google Trends on search terms “low testosterone” reveal that in the United States, Internet searches for low testosterone have increased 4.7 fold.21 Previous studies have documented the benefits of testosterone supplementation. These improvements are often first manifested by improvements in sexual function, libido, mood, and energy levels. This is followed by a reduction in body fat and increase in muscle and lean body mass, as well as improved bone mineral density.16,22,23 Men with type 2 diabetes and metabolic syndrome have witnessed improvements in insulin resistance, visceral adiposity, and total cholesterol.7,24 Some have argued that TRT when used appropriately can be a means to provide cost-effective preventative medical care in select populations.25 Treated men in our cohort were significantly more likely to have symptoms and comorbidities associated with hypogonadism, specifically elevated BMI, comorbid diabetes, hypertension, depression, decreased libido, and osteoporosis. These men are potentially more apt to receive long-term benefits from TRT. Specifically, these men may see improvement in insulin resistance or bone mineral density, which has significant implications for their overall health and longevity. These data are encouraging as one can infer that practitioners are effectively identifying patients most likely to have hypogonadism and benefit from treatment with TRT. Despite its benefits and safety when used appropriately, TRT requires appropriate patient selection and follow-up. The present study suggests that only half of men receive appropriate follow-up after initiation of TRT. About onefourth of treated hypogonadal men in our cohort had a concomitant serum LH, FSH, or prolactin level assessed within 90 days of initial serum testing. Only 41% received a CBC, and 47% received a follow-up serum total testosterone level within 6 months of initial laboratory testing. Physician adherence to guideline recommendations is 1386

historically low. Commonly cited reasons include lack of awareness or familiarity with guidelines, patient noncompliance, or a combination of factors.26 Education of practitioners on follow-up recommendations remains vitally important for those prescribing TRT. Computerized reminders have been shown in other arenas such as inpatient venous thrombophylaxis to allow for statistically significant improvements in use of prophylaxis27 and could potentially be useful in alerting physicians to guideline recommendations for patients on TRT. Furthermore, we were unable to determine patient compliance with TRT usage and therefore are unable to quantify noncompliant patients who did not require follow-up laboratory assessment. Interestingly, 29% of men in our treated cohort had serum total testosterone levels >300 ng/dL, and one-third of this population had values >500 ng/dL. The threshold value of serum total testosterone for treatment initiation is not agreed on by expert groups, and the point below which adverse events occur is unknown.3,14,15 Cutoff values remain a point of contention in the management of hypogonadism. Opponents argue that assays for testosterone testing have a wide range of interlaboratory and reference range variation combined with inconsistencies in sampling procedures making it difficult to validate a single threshold value. Additionally, some believe there may be a component of androgen resistance in men with clinical hypogonadism irrespective of androgen production, which may potentially worsen with age, lifestyle, specific medical conditions, and medications.28 This combined with the nonspecific nature of hypogonadal symptoms and lack of a widely used easy-toadminister validated questionnaire makes it difficult for clinicians to test and treat men appropriately. Although we are unable to quantify patient request for TRT, advertising demonstrating improvements in libido, fatigue, and muscle mass may make it enticing for young men to desire TRT. In an online blog focusing on masculinity, the author advocates TRT for all men with promises of “more energy, more focus, more strength, more power, more dominance, better sex, more drive, less anxiety, better mood, more muscle, and less fat.”29 However, exogenous testosterone results in feedback inhibition of the hypothalamic-pituitary-gonadal axis causing impaired spermatogenesis, testicular atrophy, and infertility. A total of 5.3% of men in our study were of ages 18-35 years, which are commonly, viewed as peak reproductive years. Although it is plausible that these men did not desire fertility, it is unclear if they understood the absolute risk of infertility associated with TRT. With this potential for misuse of TRT in young men, it remains important to counsel in regard to the certain side effect of infertility in young men desiring TRT. The prevalence of hypogonadism far outweighs the treatment rate in ours and other studies as previously mentioned. Potential reasons for this may include physician discomfort with the prescription of TRT, controversy surrounding threshold values of serum testosterone UROLOGY 85 (6), 2015

levels for clinical hypogonadism, lack of large scale randomized studies attesting to the safety of TRT, or lack of familiarity with the literature regarding benefits of TRT. Additionally, many men do not exhibit symptoms associated with low testosterone levels and may not desire treatment. Previous negative literature surrounding estrogen and estrogen-progestin use in women associated with increased heart disease, thromboembolic disease, and breast cancer serves as a cautionary tale for some practitioners when considering TRT in men.30 This combined with fears of inducing prostate cancer, despite clear evidence-based literature refuting the possibility of worsening subclinical prostate cancer and inducing new prostate cancer, likely contributes to the proportion of untreated hypogonadal men. This study should be interpreted in light of its limitations. Our data are analyzed from a patient population, which is largely Caucasian and privately insured, which may not be generalizable to the US population at large. Serum total testosterone levels were the sole test we used to identify men tested for hypogonadism. Hence, we may have missed patients who were tested with free or bioavailable testosterone, specifically those where total testosterone is nondiagnostic, that is, men with chronic illness, obesity, or alcoholism, which alter the concentration of sex hormoneebinding globulin. Additionally, within the confines of our database, we are unable to verify the timing of treatment related to the testing of serum total testosterone level. For our analysis, we assumed that treatment occurred after the initial testing and therefore eliminated patients who did not have a testosterone drawn before January 1, 2008; we hope that we were able to isolate patients starting newly on TRT. However, it is possible that some patients were not treatment naïve. Also, we are unable to attribute the purpose of the follow-up CBC specifically for TRT follow-up, as the reason for ordering cannot be extracted from our database. We do not know whether those treated or untreated with testosterone were symptomatic. Finally, we cannot verify if patients who were prescribed TRT were actually taking the prescribed medication.

CONCLUSION The rate of TRT is increasing as awareness of symptomatology and benefits of treatment become widespread. Despite this rise, several patients remain untreated despite serum total testosterone values in the hypogonadal range. Furthermore, adherence to guidelines regarding timing of testosterone testing and follow-up is poor. Further education of providers is needed to identify patients requiring TRT and continue appropriate follow-up. References 1. Dandona P, Rosenberg MT. A practical guide to male hypogonadism in the primary care setting. Int J Clin Pract. 2010;64: 682-696.

UROLOGY 85 (6), 2015

2. Margo K, Winn R. Testosterone treatments: why, when, and how? Am Fam Physician. 2006;73:1591-1598. 3. Bhasin S, Cunningham GR, Hayes FJ, et al. Testosterone therapy in adult men with androgen deficiency syndromes: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2006;91: 1995-2010. 4. Traish AM, Guay A, Feeley R, Saad F. The dark side of testosterone deficiency: I. Metabolic syndrome and erectile dysfunction. J Androl. 2009;30:10-22. 5. Jones RD, Malkin CJ, Channer KS, Jones TH. Low levels of endogenous androgens increase the risk of atherosclerosis in elderly men: further supportive data. J Clin Endocrinol Metab. 2003;88: 1403-1404; author reply 1404. 6. Khaw KT, Dowsett M, Folkerd E, et al. Endogenous testosterone and mortality due to all causes, cardiovascular disease, and cancer in men: European prospective investigation into cancer in Norfolk (EPIC-Norfolk) prospective population study. Circulation. 2007; 116:2694-2701. 7. Kapoor D, Goodwin E, Channer KS, Jones TH. Testosterone replacement therapy improves insulin resistance, glycaemic control, visceral adiposity and hypercholesterolaemia in hypogonadal men with type 2 diabetes. Eur J Endocrinol. 2006;154:899-906. 8. Grossmann M, Thomas MC, Panagiotopoulos S, et al. Low testosterone levels are common and associated with insulin resistance in men with diabetes. J Clin Endocrinol Metab. 2008;93: 1834-1840. 9. Meier C, Nguyen TV, Handelsman DJ, et al. Endogenous sex hormones and incident fracture risk in older men: the Dubbo Osteoporosis Epidemiology Study. Arch Intern Med. 2008;168:47-54. 10. Mohr BA, Bhasin S, Kupelian V, et al. Testosterone, sex hormonebinding globulin, and frailty in older men. J Am Geriatr Soc. 2007; 55:548-555. 11. Bates KA, Harvey AR, Carruthers M, Martins RN. Androgens, andropause and neurodegeneration: exploring the link between steroidogenesis, androgens and Alzheimer’s disease. Cell Mol Life Sci. 2005;62:281-292. 12. Araujo AB, O’Donnell AB, Brambilla DJ, et al. Prevalence and incidence of androgen deficiency in middle-aged and older men: estimates from the Massachusetts Male Aging Study. J Clin Endocrinol Metab. 2004;89:5920-5926. 13. Gooren LJ, Behre HM, Saad F, et al. Diagnosing and treating testosterone deficiency in different parts of the world. Results from global market research. Aging Male. 2007;10:173-181. 14. Wang C, Nieschlag E, Swerdloff RS, et al. ISA, ISSAM, EAU, EAA and ASA recommendations: investigation, treatment and monitoring of late-onset hypogonadism in males. Aging Male. 2009; 12:5-12. 15. Petak SM, Nankin HR, Spark RF, et al. American Association of Clinical Endocrinologists Medical Guidelines for the clinical practice for evaluation and treatment of hypogonadism in adult male patients—2002 update. Endocr Pract. 2002;8:439-456. 16. Wang C, Swerdloff RS, Iranmanesh A, et al. Effects of transdermal testosterone gel on bone turnover markers and bone mineral density in hypogonadal men. Clin Endocrinol (Oxf). 2001;54:739-750. 17. E Rosenthal. A Push to Sell Testosterone Gels Troubles Doctors NYTimes.com. N Y Times. Available at: http://www.nytimes.com/ 2013/10/16/us/a-push-to-sell-testosterone-gels-troubles-doctors.html?_ r¼2&. Accessed December 16, 2013. 18. Global Industry Analysts, Inc. Testosterone Replacement Therapy (TRT): A Global Strategic Business Report; Available at: http://www. strategyr.com/MCP-6770.asp, 2013; Accessed October 1, 2013. 19. Baillargeon J, Urban RJ, Ottenbacher KJ, et al. Trends in androgen prescribing in the United States, 2001 to 2011. JAMA Intern Med. 2013;173:1465-1466. 20. Layton JB, Li D, Meier CR, et al. Testosterone lab testing and initiation in the United Kingdom and the United States, 20002011. J Clin Endocrinol Metab. 2014;99:835-842; Available at: http://press.endocrine.org/doi/abs/10.1210/jc.2013-3570; Accessed January 20, 2014.

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surgical patients at risk for venous thromboembolism. Cochrane Database Syst Rev. 2013;7:CD008201. 28. Carruthers M, Trinick TR, Wheeler MJ. The validity of androgen assays. Aging Male Off J Int Soc Study Aging Male. 2007;10: 165-172. 29. Frost J. Testosterone Replacement Therapy for Young Men. Thumotic Community Men Fight Spirit; 2013; Available at: http://www. thumotic.com/testosterone-therapy-for-young-men/, 2013; Accessed February 19, 2014. 30. Rossouw JE, Anderson GL, Prentice RL, et al. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women’s Health Initiative randomized controlled trial. JAMA. 2002;288:321-333.

APPENDIX SUPPLEMENTARY DATA

Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.urology. 2015.01.027.

Appendix 1. ICD-9 codes used for comorbidities used in data analysis Benign prostatic hypertrophy 600.90, 600.00, 600.01, V13.89 Chronic obstructive SNOMED codes pulmonary disease Diabetes 250, 250.0, 250.00, 250.01, 250.02, 250.03, 250.1, 250.10, 250.11, 250.12, 250.13, 250.2, 250.20, 250.21, 250.22, 250.23, 250.3, 250.30, 250.31, 250.32, 250.33, 250.4, 250.40, 250.41, 250.42, 250.43, 250.5, 250.50, 250.51, 250.52, 250.53, 250.6, 250.60, 250.61, 250.62, 250.63, 250.7, 250.70, 250.71, 250.72, 250.73, 250.8, 250.80, 250.81, 250.82, 250.83, 250.9, 250.90, 250.91, 250.92, 250.93 Decreased libido 799.81 Depression SNOMED codes Erectile dysfunction 607.84, 302.72, 250.80, 250.81, V13.89, 250.6, 250.70, 250.62, 250.73, 250.63, 250.72, 250.71, 250.61 Hypertension 403.1, 404.13, 404.91, 403.00, 404.93, 404.02, 404.11, 401.9, 404.10, 404.12, 402.00, 405, 403.90, 402.90, 405.01, 405.09, 404.01, 402.01, 405.0, 405.19, 404.90, 403.11, 402.1, 402.91, 403.10, 402.11, 404.92, 404.00, 402, 402.10, 405.11, 403.91, 403.01, 401.1, 403.0, 404.03, 404.9, 403, 403.9, 404.0, 404.1, 405.1, 404, 402.9, 402.0, 405.9 Male infertility V13.29, 606.9, 606.8, 606.0, 606.1 Myocardial infarction 410.00, 410.01, 410.02, 410.10, 410.11, 410.12, 410.2, 410.20, 410.21, 410.22, 410.30, 410.31, 410.32, 410.40, 410.41, 410.42, 410.50, 410.51, 410.6, 410.60, 410.61, 410.62, 410.7, 410.70, 410.71, 410.72, 410.8, 410.80, 410.81, 410.82, 410.9, 410.90, 410.91, 410.92, 411.89, 412 Osteoporosis 733.00, 733.02, 733.01 Peripheral vascular 443.9, 443.81, 249.7, 250.7, 250.71, 440.2, 440.24, 440.22, 440.23, V12.59, 443.89 disease ICD-9, International Classification of Diseases, Ninth Revision; SNOMED, Systematized Nomenclature of Medicine.

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