ANDROLOGY
ISSN: 2047-2919
ORIGINAL ARTICLE
Correspondence: Thomas J. Walsh, Department of Urology, University of Washington, 1959 NE Pacific St., Seattle, WA 98195, USA. E-mail: [email protected]
Keywords: testosterone, trends, Veterans Received: 6-Oct-2014 Revised: 9-Feb-2014 Accepted: 6-Jan-2015 doi: 10.1111/andr.12014
Recent trends in testosterone testing, low testosterone levels, and testosterone treatment among Veterans 1
T. J. Walsh, 2M. M. Shores, 2A. E. Fox, 2K. P. Moore, 2 C. W. Forsberg, 2C. E. Kinsey, 1S. R. Heckbert, 2S. Zeliadt, 2,3M. L. Thompson, 2N. L. Smith and 2,4,5A. M. Matsumoto 1
University of Washington, 2VA Puget Sound Health Care System, 3Department of Biostatistics, University of Washington, 4Geriatric Research, Education and Clinical Center, VA Puget Sound Health Care System, and 5Division of Gerontology and Geriatric Medicine, Department of Medicine, University of Washington School of Medicine, Seattle, WA, USA
SUMMARY Low serum testosterone (T) is common and increasingly prevalent with increased age. Recent studies report an ‘epidemic’ of T prescribing and concern about unnecessary T treatment. We investigated the number of men tested for T, the prevalence of low serum T levels, and initiation of T treatment among those with low T levels in men treated at Veterans Affairs (VA) facilities in the Northwest US (VISN 20). We identified male Veterans aged 40–89 years and examined yearly proportions of men tested for T, found to have low T levels (total T < 280 ng/dL, free T < 34 pg/mL, or bioavailable T < 84 ng/dL), and subsequently treated with T from 2002 to 2011. We excluded men who had T treatment in the year prior and men with diagnoses of prostate or breast cancer. Treatment initiation was defined as the first prescription for T within a year following a low T test. From 2002 to 2011, the yearly population of eligible men in VISN 20 increased from 129 247 to 163 572. The proportion of men who had serum T tests increased from 3.2% in 2002 to 5.8% in 2011. Among the tested men, the percentage of men with low T levels increased from 35.0 to 47.3%. However, the proportion of men with low T levels who were given T treatment within a year decreased from 31.0 to 28.0%. Despite large increases in T testing, and detection of men with low T levels, there was a slight decrease in the proportion of men with low T levels who were treated with T. The decrease in T treatment during this time period contrasts with other studies and may be related to higher comorbidity in Veterans and/or VA formulary restrictions on the use of transdermal T formulations.
INTRODUCTION Low serum testosterone (T) levels in men are common and are increasingly prevalent with increased age (Harman et al., 2001; Araujo et al., 2004, 2007; Wang et al., 2009). Low T levels are associated with a number of comorbid conditions, for example chronic illness, obesity, and diabetes mellitus (DM). Furthermore, T levels may be transiently low with acute illness, malnutrition, and use of certain medications (Bhasin et al., 2010). Multiple studies suggest a significant increase in the prevalence of men with low T levels over the last decade, although the prevalence of true hypogonadism – defined as low T levels plus signs and symptoms – is much lower (Wu et al., 2010). Because the signs and symptoms of hypogonadism lack specificity, there is greater reliance on low T levels and increased likelihood of overdiagnosis of hypogonadism and subsequent T treatment in middle-aged and older men who may have comorbid medical conditions that mimic the © 2015 American Society of Andrology and European Academy of Andrology
symptoms of hypogonadism (Wu et al., 2010; Anawalt et al., 2012). One study has reported increasing prescription rates of T in community-based populations throughout the world over the last decade (Layton et al., 2014). These increases have occurred in association with the introduction of transdermal T formulations (patches and gels), numerous studies suggesting that low T levels are associated with elevated risk of cardiovascular mortality (Shores et al., 2006; Khaw et al., 2007; Vikan et al., 2009; Corona et al., 2010; Malkin et al., 2010; Ponikowska et al., 2010; Haring et al., 2011, 2012; Kyriazis et al., 2011; Hyde et al., 2012; Schneider et al., 2012), and increases in direct-to-consumer advertising for T treatment in the US emphasizing ‘low T’ as a medical problem requiring treatment (Handelsman, 2013). Prior reports of increasing T prescription rates were derived from pharmacy claims of commercially insured individuals (Baillargeon et al., 2013; Handelsman, 2013; Layton et al., 2014). Andrology, 1–6
1
ANDROLOGY
T. J. Walsh et al.
However, it remains unclear whether the increased prescriptions for T are the result of increased T testing and identification of men with previously unmeasured low serum T levels, or reflect increased use of T among men without documented low T levels. The aim of this study was to characterize the prevalence of T testing, identification of men with low T levels, and subsequent T treatment in an integrated Veterans Affairs (VA) health care system in which there were formulary restrictions on the use of transdermal T formulations. We examined yearly proportions of men tested for T, found to have low T levels, and subsequently treated with T in male Veterans from 2002 to 2011.
MATERIALS AND METHODS Setting The VA Health Care System provides longitudinal health care to a large population of older men and maintains a well-developed and comprehensive electronic health record database. In addition to extensive data on T prescriptions and pharmacy dispensation, the VA database contains comprehensive clinical information on all enrolled patients, including demographic data, outpatient and inpatient clinical care, and laboratory testing, including laboratory test results. This study was approved by the VA Puget Sound Health Care System Institutional Review Board. Cohort identification We identified all men aged 40–89 years who used any VA health care in a single Veterans Integrated Service Network (VISN) in the Pacific Northwest (VISN 20) from January 2002 to December 2011. VISN 20 encompasses all VA health care facilities in Washington, Idaho, Alaska, and Oregon. For men to be included in the study group of men who were ‘T-tested’, they needed to demonstrate utilization of the VA VISN 20 health care system by presenting for care at a VA clinic on at least one occasion in the year prior to their first T test in the study period. We excluded men with a history of prostate or breast cancer identified by International Classification of Diseases–9th Edition coding in the VA medical record, or T treatment in the VA in the year prior to the T test. Men with prostate or breast cancer were excluded from the study as these conditions are a contraindication to T treatment. The number of men aged 40–89 years who utilized the VA VISN 20 health care system in each year was used as the denominator for the proportion of men who were tested for T in VISN 20. Laboratory evaluation For each subject who had a T test between 2002 and 2011, we identified if and when they first had a low T level, where low T was defined as a serum total T < 280 ng/dL, free T < 34 pg/mL, and bioavailable T < 84 ng/dL. All samples in the VISN 20 were measured in the clinical laboratory at the VA Puget Sound Health Care System, and reference ranges provided by the laboratory were used by ordering providers for usual day-to-day clinical decision making. This is in line with the testing guidelines of The Endocrine Society (Bhasin et al., 2010). Total T concentrations were measured using an Elecsys platform-based immunoassay (F. Hoffman-La Roche AG, Basel, Switzerland). The total T 2
Andrology, 1–6
assay range was 2.0–1500 ng/dL and the normal reference range was 280–800 ng/dL (9.7–27.7 nmol/L). Free T concentrations were calculated from total T, sex-hormone-binding globulin, and albumin levels using the Vermeulen formula (Vermeulen et al., 1999). Among all men who underwent T testing and were determined to have low T levels, 95.3% had a low total T level, while 3.4% had a low free T level, 1.0% had a low free T/total T ratio level, and 0.3% had a low bioavailable T level. A previous study examining T testing in the VISN 20 found that 60.2% of the physicians ordering T tests were in primary care, followed by urology (10.3%), endocrinology (8.6%), geriatrics (7.3%), oncology, rheumatology, or neurology (6.5%), and psychiatry (0.3%) (Shores et al., 2004). Because of the observational study design, blood sampling was not standardized for the time of day. The average time of sampling was 11:12 a.m. A prior study drawing on the same database found that most serum T laboratory draws in the VISN 20 occur in the morning (Shores et al., 2012). The testosterone tests were identified in subjects’ electronic medical records using the Logical Observation Identifiers Names and Codes for total, free, free/total ratio, and bioavailable testosterone tests (Appendix A). Testosterone treatment T treatment initiation was defined as a prescription for T occurring within 12 months after the first low T test based on the VA National Drug Internal Entry Numbers for testosterone formulations (Appendix A). Treatment included intramuscular (IM) testosterone injections, transdermal testosterone patches, or topical testosterone gel formulations, dispensed from the VA pharmacy between January 1, 2002 and September 1, 2012. The electronic data contain all prescription drugs dispensed either at a VA facility, via mail, or through the outpatient shot clinic (an outpatient clinic where Veterans can receive injections), including dispensing date and drug formulation. Analysis We determined the absolute number and proportion of men who were tested for T, had low T levels, were treated with T, and the T formulations used in each year. The results presented are descriptive only. Given the observational study design, we elected to use the term ‘low T level’ rather than ‘hypogonadism’. The signs and symptoms associated with hypogonadism were not assessed as part of this study because they were not available in the database. Men were characterized by 10-year age categories, by calendar year of T testing, and by body mass index (BMI) and DM diagnosis (see Appendix A, for variable definitions). We chose to assess BMI and DM due to the strong association of these factors with low T levels.
RESULTS Serum testosterone testing The number of eligible men receiving care within VISN 20 increased each year, from 129 247 in 2002 to 163 572 in 2011 (Table 1). During this time, the number of men per year who had serum T tested more than doubled from 4078 in 2002 to 9452 in 2011 (Fig. 1). The proportion of men tested annually increased from 3.2 to 5.8% of all men (Fig. 2). The observed increase in testing primarily occurred between 2007 and 2011, © 2015 American Society of Andrology and European Academy of Andrology
ANDROLOGY
RECENT TRENDS IN TESTOSTERONE TESTING
who were tested, the proportion with DM varied with age and was lowest among men aged 40–49 (9.2%) and highest among men aged 60–69 (16.1%) (data not shown). The proportion of men who underwent serum T testing and were obese (BMI ≥ 30 kg/m2) was 41.8%. The average BMI among tested men was 29 kg/m2. The average BMI among tested men was similar over the period of study and demonstrated little variation among different age groups.
Table 1 VISN 20 men aged 40–89 who underwent testosterone testing, who have low T levels, and who were treated with T, 2002–2011 Year
Total VISN 20 men (age 40–89)
Total tested for T (% of total men)
Total low T (% of total tests)
Total given TRTa (% of low T)
2002 2003 2004 2005 2006 2007 2008 2009 2010 2011
129 135 146 143 144 144 147 152 157 163
4078 (3.2) 4646 (3.4) 5044 (3.4) 4841 (3.4) 4894 (3.4) 5124 (3.5) 5919 (4.0) 6527 (4.3) 8143 (5.2) 9452 (5.8)
1428 (35.0) 1813 (39.0) 1761 (34.9) 1928 (39.8) 2093 (42.8) 2121 (41.4) 2635 (44.5) 3084 (47.2) 3949 (48.5) 4472 (47.3)
443 (31.0) 548 (30.2) 451 (25.6) 459 (23.8) 521 (24.9) 536 (25.3) 668 (25.4) 805 (26.1) 1110 (28.1) 1251 (28.0)
247 325 250 657 912 552 266 398 454 572
Men with low testosterone There was a 35% increase in the proportion of tested men who had low T levels (Table 1 & Fig. 1), from 35.0% of men tested in 2002 to 47.3% in 2011 (Fig. 2). While a rise in the proportion of men with low T levels annually was seen in all age groups, it was greatest in the youngest men and least in the oldest men, with 65, 58, 25, and 9% increases in the proportion of men with low T levels in the 40–49, 50–59, 60–69, and 70–89 age groups, respectively. The average BMI of men with low T levels was 32 kg/m2 and 56.5% of men with low T levels were obese (Table 2). The average BMI in each year was stable over the period of study, and was similar among different age groups. Twenty-two percent of men of all ages with low T levels had DM (Table 2). Among men with low T levels, the proportion with DM increased with increasing age group, where 16, 23, 28, and 30% of men with low T levels had DM in the 40–49, 50–59, 60–69, and 70–89 age groups, respectively.
VISN 20, Veterans Integrated Service Network 20 in the Pacific Northwest. a Within 1 year of low T measurement.
where the proportion tested yearly increased from 3.5 to 5.8%. In men aged 40–49 years, the increase in annual T testing was more substantial over the period of study compared to other decade-age groups. Among this age group, annual testing increased from 2.6% in 2002 to 6.6% in 2011 (Table S1). Similar to men of all ages, the observed increase in annual testing occurred primarily between 2007 and 2011, during which time the proportion tested increased from 3.5 to 6.6%. In men aged 70–89 years, annual T testing was proportionately less and increased minimally during the study period compared to other age groups. The proportion of men tested annually in this age group was 0.7% between 2002 and 2006 and rose to 0.9% in 2011 (Table S1). Among all men who underwent serum T testing, the proportion with a diagnosis of DM was 13.9% (Table 2). Among men Figure 1 Total number of Veterans Integrated Service Network 20 in the Pacific Northwest men aged 40–89 years who: underwent testosterone testing, had low T, and were treated with T*, 2002–2011. *Treated within 1 year of first test showing low T.
Testosterone treatment Throughout the period of study, approximately 30% of men with low T levels were treated with T within 1 year, with the exception of men aged 70–89, in which 20% were treated with T. Most men were treated with injectable T (81.4%), as compared
10 000 Tested for T, not low 9000 Low T Test, not treated 8000 Low T Test, treated 7000
No. of men
6000
5000
4000
3000
2000
1000
0 2002
2003
© 2015 American Society of Andrology and European Academy of Andrology
2004
2005
2006
2007
2008
2009
2010
2011
Andrology, 1–6
3
ANDROLOGY
T. J. Walsh et al. 60%
50%
Figure 2 Percentages of Veterans Integrated Service Network 20 in the Pacific Northwest men aged 40–89 who underwent testosterone testing, who have low T, and who were treated with T, 2002–2011.
Percent of total men tested with low T Percent of total low T men treated with T Percent of total men tested for T
40%
30%
20%
10%
0% 2002
2003
2004
2005
2006
2007
2008
Table 2 Diabetes, BMI and obesity among VISN 20 men aged 40–89 who underwent testosterone testing, who have low T levels, and who were treated with T, 2002–2011 Men tested for T Total VISN 20 men: 351 421 Total 44 762 (12.7% of total men) No. with diabetes 6213 (13.9) ICD-9 code (%) 29.3 (5.4)a Mean BMI, kg/m2 (SD) Obese (BMI ≥ 18 725 (41.8) 30 kg/m2) (%)
Men with low T
Men treated with T
17 546 (39.2% of men tested) 3858 (22.0)
6792 (38.7% of low T men) 2801 (41.2)
31.9 (6.9)b
32.8 (6.6)c
9920 (56.5)
4172 (61.4)
Missing BMI: a2343; b1417; c360. BMI, body mass index; Veterans Integrated Service Network 20 in the Pacific Northwest; ICD-9, International Classification of Diseases–9th Edition.
to T patches (13.2%) and T gels (5.4%). The use of all treatment modalities increased over the period of study. The proportion of men with low T levels who were T treated decreased slightly over time, with 31% of men with low T levels treated in 2002 and 28% treated in 2011 (Fig. 2). The decline in T treatment occurred in every age group. The proportion of obese men among those who had low T levels and were subsequently treated with T was 61.4%. The average BMI of men treated with T was 33 kg/m2, was unchanged over the period of study, demonstrated little variation among different age groups, and was only slightly higher than that of all men with low T levels. Among treated men, 41% had DM (Table 2) and the proportion was 30, 40, 47, and 41% in the 40–49, 50–59, 60–69, and 70–89 age groups, respectively (data not shown).
DISCUSSION We found that the proportion of men undergoing serum T testing yearly in the Pacific Northwest VA health care system from 2002 to 2011 increased by 82% with most of this increase 4
Andrology, 1–6
2009
2010
2011
occurring over the last 3–4 years of the study period. The increase in T testing is consistent with an observed worldwide trend in increased T prescriptions (Layton et al., 2014), which has been attributed to the introduction of transdermal formulations and an increase in direct-to-consumer marketing of T in the US (Handelsman, 2013). In addition, it may reflect provider awareness of a number of recent studies associating low serum T levels with increased risk of mortality (Shores et al., 2006; Khaw et al., 2007; Vikan et al., 2009; Corona et al., 2010; Malkin et al., 2010; Ponikowska et al., 2010; Haring et al., 2011, 2012; Kyriazis et al., 2011; Hyde et al., 2012; Schneider et al., 2012). With this increase in T testing in the VA system, there was also an increase in the proportion of men found to have low T levels in each year, particularly among men aged 40–49 and 50–59 years. Because declining serum T levels are associated with aging (Harman et al., 2001; Araujo et al., 2004, 2007), substantial increases in the proportion of younger (40–59 year old) men with low T levels among those tested may indicate that VA providers are employing more targeted testing, based on patient symptoms and comorbid conditions. Although the absolute number of men treated annually with T doubled over the course of the study, the proportion of men with low T levels who were treated with T yearly decreased by 9.7% from 2002 to 2011. This contrasts to several other studies that reported a substantial increase in T prescriptions over the past several years, which have been associated with large increases in prescriptions for T gels. The lack of an increase in T prescriptions within the VA may be related to VA formulary restrictions for transdermal T formulations and/or higher comorbidity in Veterans. The VA has a restricted drug formulary that requires initial use of T injections prior to transdermal T preparations. There was minimal increase in the use of T gels within the VA system during this time period, which is in marked contrast to studies indicating a significant increase in gel formulations. Our data differ from recent work by Layton et al. (2014), who reported testosterone prescribing patterns in the US from the © 2015 American Society of Andrology and European Academy of Andrology
ANDROLOGY
RECENT TRENDS IN TESTOSTERONE TESTING
MarketScan Commercial Claims database and in the UK from the Clinical Practice Research Datalink. This study found an increase in T prescriptions over 10 years, despite a decline in the proportion of men with low T levels. Authors concluded that testosterone testing in the US population may be less targeted to symptoms, and more driven by direct-to-consumer marketing of testosterone replacement pharmaceuticals. Layton et al. noted that the percentage of men tested who had low T levels remained near 20% from 2007 to 2011 in the US, while the percentage of tested men with low T levels rose from less than 10% to nearly 30% among men tested in the UK. Tests for serum T levels within our cohort appeared to be more focused on symptom presentation as the percentage of men with low T levels ranged from 35 to 49%, which is a greater prevalence of men with low T levels than in either of the prior studies. Baillargeon et al. (2013) described increased testosterone utilization from 2001 to 2011 using data from the Clinformatics DataMart, one of the largest US commercial health insurance populations. The authors noted that the percentage of T-treated men aged 40 years and over rose from 0.54% in 2001 to 2.29% in 2011. While suggesting a significant and more than 4-fold rise in T utilization in this population, the interpretation of these data is limited by the lack of concomitant information on T testing and the proportion of men with low T levels. Among male subscribers in the Northwest VA population, rise in T utilization as a proportion of the total number of eligible men was far more modest, with 0.34% of the total receiving T in 2002 and 0.76% of the total receiving T in 2011. Handelsman (2013) described global testosterone prescribing from 2000 to 2011 for 41 different countries. Data from IMS Health were used to calculate number of T doses per month per 1000 of the eligible population, and suggests that T prescribing in the US rose by more than 10-fold over the period of study. However, given that T utilization overall rose just over 2-fold from 2002 to 2011 in the VISN 20 population, it seems that the trends described by Handelsman are not reflected in Veterans in the VISN 20 Health Network. Hall et al. (2014) described changes in T utilization in the province of Saskatchewan, Canada from 1976 to 2008. Similar to our results, these authors reported much more modest T utilization and change over the entire period of study, with 0.15% of men in 1976 rising to a peak of ~0.45% of men in 2000 receiving T. Unlike others, but similar to ours, this report found a decline in T utilization from 2000 onward, with only ~0.25% of men receiving T in 2008. Given greater prescribing constraints that may accompany a nationalized healthcare system, comparison of these data to ours is intriguing as both of these health care systems involve formulary constraints. However, such a comparison is limited given that Hall et al. considered eligible men to be 18 and older and, like others, they do not provide information on men who are tested and found to have low T levels. Other factors that may explain why annual T treatment did not increase as markedly in the VA setting as in other practice settings is that there may be greater adherence to clinical guidelines, which may be related to local practice patterns. Clinical guidelines (Wang et al., 2009; Bhasin et al., 2010) generally advocate careful assessment prior to prescribing T, emphasizing that special attention should be paid to clinically significant symptoms related to low T levels and to comorbidities. In addition, the limited availability of transdermal T because of formulary © 2015 American Society of Andrology and European Academy of Andrology
restrictions is also likely to impact decisions for T treatment. Between 2002 and 2011, 81.4% of T-treated men in the VISN 20 received injectable T, while only 13.2% received patches and just 5.4% received gels. Finally, the VA patient population has a high degree of medical comorbidity that may affect the patient and provider’s decision to initiate T treatment. A recent report (Kramarow & Pastor, 2012) found that male Veterans who use VA health care have poorer reported physical and mental health and have more chronic health conditions when compared with nonVeteran men. While providing novel information on a unique population, our data have limitations, as we were unable to ascertain if treated men had signs and symptoms of hypogonadism. Thus, despite detailed laboratory data prior to treatment, we are unable to determine which men are treated in accordance with The Endocrine Society guidelines. Despite guideline recommendations, many practitioners measure only one testosterone level before treating. In addition, our data are limited to T tests, T levels, and T treatment obtained within the VA system. Treatment and testing that Veterans received outside the VA system may not have been recorded in their VA record. However, it is important to note that most Veterans who utilize VA care qualify because of low income or lack of private insurance. Many of the Veterans served by the VA system have no co-pays for the medications they receive through the VA, while purchasing the medications outside the VA would require them to pay for the entire cost of the medication. In summary, this is the first report to describe T treatment in the context of men having T levels tested, and of men found to have low T levels. Our results suggest that the number of men aged 40–89 years who are undergoing T testing yearly in the VA system has increased substantially, particularly over the last three to 4 years of the study period, while the proportion of those with low T levels has increased more modestly. However, the proportion of men with low T levels who are treated annually has decreased slightly over this time period. This may reflect specific local clinical practice patterns, patient preferences, higher comorbidity, and/or the impact of a more restricted pharmacy formulary that limits initial T treatment to IM T.
FUNDING This study was supported by an R01 Grant, National Institutes of Health-National Institute on Aging.
DISCLOSURE No conflicts of interest.
REFERENCES Anawalt BD, Hotaling JM, Walsh TJ & Matsumoto AM. (2012) Performance of total testosterone measurement to predict free testosterone for the biochemical evaluation of male hypogonadism. J Urol 187, 1369–1373. Araujo AB, O’Donnell AB, Brambilla DJ, Simpson WB, Longcope C, Matsumoto AM & McKinlay JB. (2004) Prevalence and incidence of androgen deficiency in middle-aged and older men: estimates from the Massachusetts Male Aging Study. J Clin Endocrinol Metab 89, 5920–5926. Araujo AB, Esche GR, Kupelian V, O’Donnell AB, Travison TG, Williams RE, Clark RV & McKinlay JB. (2007) Prevalence of symptomatic androgen deficiency in men. J Clin Endocrinol Metab 92, 4241–4247. Andrology, 1–6
5
ANDROLOGY
T. J. Walsh et al. Baillargeon J, Urban RJ, Ottenbacher KJ, Pierson KS & Goodwin JS. (2013) Trends in androgen prescribing in the United States, 2001 to 2011. JAMA Intern Med 173, 1465–1466. Bhasin S, Cunningham GR, Hayes FJ, Matsumoto AM, Snyder PJ, Swerdloff RS & Montori VM & Endocrine Society Task Force. (2010) Testosterone therapy in men with androgen deficiency syndromes: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab 95, 2536–2559. Corona G, Monami M, Boddi V, Cameron-Smith M, Fisher AD, de Vita G, Melani C, Balzi D, Sforza A, Forti G, Mannucci E & Maggi M. (2010) Low testosterone is associated with an increased risk of MACE lethality in subjects with erectile dysfunction. J Sex Med 7, 1557–1564. Hall SA, Ranganathan G, Tinsley LJ, Lund JL, Kupelian V, Wittert GA, Kantoff PW, Morales A & Araujo AB. (2014) Population-based patterns of prescription androgen use, 1976–2008. Pharmacoepidemiol Drug Saf 23, 498–506. Handelsman DJ. (2013) Global trends in testosterone prescribing, 2000– 2011: expanding the spectrum of prescription drug misuse. Med J Aust 199, 548–551. Haring R, Nauck M, Volzke H, Endlich K, Lendeckel U, Friedrich N, Dorr M, Rettig R, Kroemer HK & Wallaschofski H. (2011) Low serum testosterone is associated with increased mortality in men with stage 3 or greater nephropathy. Am J Nephrol 33, 209–217. Haring R, John U, Volzke H, Nauck M, Dorr M, Felix SB & Wallaschofski H. (2012) Low testosterone concentrations in men contribute to the gender gap in cardiovascular morbidity and mortality. Gend Med 9, 557–568. Harman SM, Metter EJ, Tobin JD, Pearson J & Blackman MR & Baltimore Longitudinal Study of Aging. (2001) Longitudinal effects of aging on serum total and free testosterone levels in healthy men. Baltimore Longitudinal Study of Aging. J Clin Endocrinol Metab 86, 724–731. Hyde Z, Norman PE, Flicker L, Hankey GJ, Almeida OP, McCaul KA, Chubb SA & Yeap BB. (2012) Low free testosterone predicts mortality from cardiovascular disease but not other causes: the Health in Men Study. J Clin Endocrinol Metab 97, 179–189. Khaw KT, Dowsett M, Folkerd E, Bingham S, Wareham N, Luben R, Welch A & Day N. (2007) 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 116, 2694–2701. Kramarow EA & Pastor PN. (2012) The health of male Veterans and nonVeterans aged 25–64: United States, 2007–2010. NCHS Data Brief 101, 1–7. Kyriazis J, Tzanakis I, Stylianou K, Katsipi I, Moisiadis D, Papadaki A, Mavroeidi V, Kagia S, Karkavitsas N & Daphnis E. (2011) Low serum testosterone, arterial stiffness and mortality in male haemodialysis patients. Nephrol Dial Transplant 26, 2971–2977. Layton JB, Li D, Meier CR, Sharpless J, Sturmer T, Jick SS & Brookhart MA. (2014) Testosterone lab testing and initiation in the United Kingdom and the United States, 2000–2011. J Clin Endocrinol Metab 99, 835–842. Malkin CJ, Pugh PJ, Morris PD, Asif S, Jones TH & Channer KS. (2010) Low serum testosterone and increased mortality in men with coronary heart disease. Heart 96, 1821–1825. Ponikowska B, Jankowska EA, Maj J, Wegrzynowska-Teodorczyk K, Biel B, Reczuch K, Borodulin-Nadzieja L, Banasiak W & Ponikowski P. (2010) Gonadal and adrenal androgen deficiencies as independent predictors of increased cardiovascular mortality in men with type II diabetes mellitus and stable coronary artery disease. Int J Cardiol 143, 343–348. Schneider HJ, Wallaschofski H, Volzke H, Markus MR, Doerr M, Felix SB, Nauck M & Friedrich N. (2012) Incremental effects of endocrine and metabolic biomarkers and abdominal obesity on cardiovascular mortality prediction. PLoS ONE 7, e33084.
6
Andrology, 1–6
Shores MM, Sloan KL, Matsumoto AM, Moceri VM, Felker B & Kivlahan DR. (2004) Increased incidence of diagnosed depressive illness in hypogonadal older men. Arch Gen Psychiatry 61, 162–167. Shores MM, Matsumoto AM, Sloan KL & Kivlahan DR. (2006) Low serum testosterone and mortality in male veterans. Arch Intern Med 166, 1660–1665. Shores MM, Smith NL, Forsberg CW, Anawalt BD & Matsumoto AM. (2012) Testosterone treatment and mortality in men with low testosterone levels. J Clin Endocrinol Metab 97, 2050–2058. Vermeulen A, Verdonck L & Kaufman JM. (1999) A critical evaluation of simple methods for the estimation of free testosterone in serum. J Clin Endocrinol Metab 84, 3666–3672. Vikan T, Schirmer H, Njolstad I & Svartberg J. (2009) Endogenous sex hormones and the prospective association with cardiovascular disease and mortality in men: the Tromsø Study. Eur J Endocrinol 161, 435–442. Wang C, Nieschlag E, Swerdloff R, Behre HM, Hellstrom WJ, Gooren LJ, Kaufman JM, Legros JJ, Lunenfeld B, Morales A, Morley JE, Schulman C, Thompson IM, Weidner W & Wu FCW. (2009) Investigation, treatment and monitoring of late-onset hypogonadism in males. J Androl 30, 1–9. Wu FC, Tajar A, Beynon JM, Pye SR, Silman AJ, Finn JD, O’Neill TW, Bartfai G, Casanueva FF, Forti G, Giwercman A, Han TS, Kula K, Lean ME, Pendleton N, Punab M, Boonen S, Vanderschueren D, Labrie F & Huhtaniemi IT & EMAS Study Group. (2010) Identification of lateonset hypogonadism in middle-aged and elderly men. N Engl J Med 363, 123–135.
SUPPORTING INFORMATION Additional Supporting Information may be found in the online version of this article: Table S1. VISN 20 men aged 40–89 who underwent testosterone testing, who have low T levels, and who were treated with T, 2002–2011.
APPENDIX A VARIABLE DEFINITIONS Characteristic
Based on
Age BMI (kg/m2)
Age at time of cohort entry BMI (body mass index) recorded closest to cohort entry date, with preference for prior to cohort entry
Diabetes
ICD-9 codes (International Classification of Diseases– 9th Edition) in subject’s medical record LOINC laboratory codes (Logical Observation Identifiers Names and Codes) in subject’s medical record
Testosterone level
Treatment formulation
Drug IENs (Internal Entry Numbers)
Codes/details
BMI data missing for: 2343 men (5.2%) of men Tested for T 1417 men (8.1%) of men with Low T 360 men (5.3%) of men Treated with T Total rate of missing BMI is 6.7% ICD-9 code: 250.xx (diabetes mellitus)
LOINC codes: 2990-0 (testosterone bioavailable) 2991-8 (testosterone free) 2986-8 (testosterone total) 15432-8 (testosterone free/ testosterone total) IENs: 513, 514, 515, 516, 518, 524, 525, 526, 527, 530, 531, 532, 533, 534, 14379, 14380, 14775, 15507, 15508, 16064, 17475, 17503, 17901, 21468, 21470, 21471
© 2015 American Society of Andrology and European Academy of Andrology
ISSN: 2047-2919
ORIGINAL ARTICLE
Correspondence: Thomas J. Walsh, Department of Urology, University of Washington, 1959 NE Pacific St., Seattle, WA 98195, USA. E-mail: [email protected]
Keywords: testosterone, trends, Veterans Received: 6-Oct-2014 Revised: 9-Feb-2014 Accepted: 6-Jan-2015 doi: 10.1111/andr.12014
Recent trends in testosterone testing, low testosterone levels, and testosterone treatment among Veterans 1
T. J. Walsh, 2M. M. Shores, 2A. E. Fox, 2K. P. Moore, 2 C. W. Forsberg, 2C. E. Kinsey, 1S. R. Heckbert, 2S. Zeliadt, 2,3M. L. Thompson, 2N. L. Smith and 2,4,5A. M. Matsumoto 1
University of Washington, 2VA Puget Sound Health Care System, 3Department of Biostatistics, University of Washington, 4Geriatric Research, Education and Clinical Center, VA Puget Sound Health Care System, and 5Division of Gerontology and Geriatric Medicine, Department of Medicine, University of Washington School of Medicine, Seattle, WA, USA
SUMMARY Low serum testosterone (T) is common and increasingly prevalent with increased age. Recent studies report an ‘epidemic’ of T prescribing and concern about unnecessary T treatment. We investigated the number of men tested for T, the prevalence of low serum T levels, and initiation of T treatment among those with low T levels in men treated at Veterans Affairs (VA) facilities in the Northwest US (VISN 20). We identified male Veterans aged 40–89 years and examined yearly proportions of men tested for T, found to have low T levels (total T < 280 ng/dL, free T < 34 pg/mL, or bioavailable T < 84 ng/dL), and subsequently treated with T from 2002 to 2011. We excluded men who had T treatment in the year prior and men with diagnoses of prostate or breast cancer. Treatment initiation was defined as the first prescription for T within a year following a low T test. From 2002 to 2011, the yearly population of eligible men in VISN 20 increased from 129 247 to 163 572. The proportion of men who had serum T tests increased from 3.2% in 2002 to 5.8% in 2011. Among the tested men, the percentage of men with low T levels increased from 35.0 to 47.3%. However, the proportion of men with low T levels who were given T treatment within a year decreased from 31.0 to 28.0%. Despite large increases in T testing, and detection of men with low T levels, there was a slight decrease in the proportion of men with low T levels who were treated with T. The decrease in T treatment during this time period contrasts with other studies and may be related to higher comorbidity in Veterans and/or VA formulary restrictions on the use of transdermal T formulations.
INTRODUCTION Low serum testosterone (T) levels in men are common and are increasingly prevalent with increased age (Harman et al., 2001; Araujo et al., 2004, 2007; Wang et al., 2009). Low T levels are associated with a number of comorbid conditions, for example chronic illness, obesity, and diabetes mellitus (DM). Furthermore, T levels may be transiently low with acute illness, malnutrition, and use of certain medications (Bhasin et al., 2010). Multiple studies suggest a significant increase in the prevalence of men with low T levels over the last decade, although the prevalence of true hypogonadism – defined as low T levels plus signs and symptoms – is much lower (Wu et al., 2010). Because the signs and symptoms of hypogonadism lack specificity, there is greater reliance on low T levels and increased likelihood of overdiagnosis of hypogonadism and subsequent T treatment in middle-aged and older men who may have comorbid medical conditions that mimic the © 2015 American Society of Andrology and European Academy of Andrology
symptoms of hypogonadism (Wu et al., 2010; Anawalt et al., 2012). One study has reported increasing prescription rates of T in community-based populations throughout the world over the last decade (Layton et al., 2014). These increases have occurred in association with the introduction of transdermal T formulations (patches and gels), numerous studies suggesting that low T levels are associated with elevated risk of cardiovascular mortality (Shores et al., 2006; Khaw et al., 2007; Vikan et al., 2009; Corona et al., 2010; Malkin et al., 2010; Ponikowska et al., 2010; Haring et al., 2011, 2012; Kyriazis et al., 2011; Hyde et al., 2012; Schneider et al., 2012), and increases in direct-to-consumer advertising for T treatment in the US emphasizing ‘low T’ as a medical problem requiring treatment (Handelsman, 2013). Prior reports of increasing T prescription rates were derived from pharmacy claims of commercially insured individuals (Baillargeon et al., 2013; Handelsman, 2013; Layton et al., 2014). Andrology, 1–6
1
ANDROLOGY
T. J. Walsh et al.
However, it remains unclear whether the increased prescriptions for T are the result of increased T testing and identification of men with previously unmeasured low serum T levels, or reflect increased use of T among men without documented low T levels. The aim of this study was to characterize the prevalence of T testing, identification of men with low T levels, and subsequent T treatment in an integrated Veterans Affairs (VA) health care system in which there were formulary restrictions on the use of transdermal T formulations. We examined yearly proportions of men tested for T, found to have low T levels, and subsequently treated with T in male Veterans from 2002 to 2011.
MATERIALS AND METHODS Setting The VA Health Care System provides longitudinal health care to a large population of older men and maintains a well-developed and comprehensive electronic health record database. In addition to extensive data on T prescriptions and pharmacy dispensation, the VA database contains comprehensive clinical information on all enrolled patients, including demographic data, outpatient and inpatient clinical care, and laboratory testing, including laboratory test results. This study was approved by the VA Puget Sound Health Care System Institutional Review Board. Cohort identification We identified all men aged 40–89 years who used any VA health care in a single Veterans Integrated Service Network (VISN) in the Pacific Northwest (VISN 20) from January 2002 to December 2011. VISN 20 encompasses all VA health care facilities in Washington, Idaho, Alaska, and Oregon. For men to be included in the study group of men who were ‘T-tested’, they needed to demonstrate utilization of the VA VISN 20 health care system by presenting for care at a VA clinic on at least one occasion in the year prior to their first T test in the study period. We excluded men with a history of prostate or breast cancer identified by International Classification of Diseases–9th Edition coding in the VA medical record, or T treatment in the VA in the year prior to the T test. Men with prostate or breast cancer were excluded from the study as these conditions are a contraindication to T treatment. The number of men aged 40–89 years who utilized the VA VISN 20 health care system in each year was used as the denominator for the proportion of men who were tested for T in VISN 20. Laboratory evaluation For each subject who had a T test between 2002 and 2011, we identified if and when they first had a low T level, where low T was defined as a serum total T < 280 ng/dL, free T < 34 pg/mL, and bioavailable T < 84 ng/dL. All samples in the VISN 20 were measured in the clinical laboratory at the VA Puget Sound Health Care System, and reference ranges provided by the laboratory were used by ordering providers for usual day-to-day clinical decision making. This is in line with the testing guidelines of The Endocrine Society (Bhasin et al., 2010). Total T concentrations were measured using an Elecsys platform-based immunoassay (F. Hoffman-La Roche AG, Basel, Switzerland). The total T 2
Andrology, 1–6
assay range was 2.0–1500 ng/dL and the normal reference range was 280–800 ng/dL (9.7–27.7 nmol/L). Free T concentrations were calculated from total T, sex-hormone-binding globulin, and albumin levels using the Vermeulen formula (Vermeulen et al., 1999). Among all men who underwent T testing and were determined to have low T levels, 95.3% had a low total T level, while 3.4% had a low free T level, 1.0% had a low free T/total T ratio level, and 0.3% had a low bioavailable T level. A previous study examining T testing in the VISN 20 found that 60.2% of the physicians ordering T tests were in primary care, followed by urology (10.3%), endocrinology (8.6%), geriatrics (7.3%), oncology, rheumatology, or neurology (6.5%), and psychiatry (0.3%) (Shores et al., 2004). Because of the observational study design, blood sampling was not standardized for the time of day. The average time of sampling was 11:12 a.m. A prior study drawing on the same database found that most serum T laboratory draws in the VISN 20 occur in the morning (Shores et al., 2012). The testosterone tests were identified in subjects’ electronic medical records using the Logical Observation Identifiers Names and Codes for total, free, free/total ratio, and bioavailable testosterone tests (Appendix A). Testosterone treatment T treatment initiation was defined as a prescription for T occurring within 12 months after the first low T test based on the VA National Drug Internal Entry Numbers for testosterone formulations (Appendix A). Treatment included intramuscular (IM) testosterone injections, transdermal testosterone patches, or topical testosterone gel formulations, dispensed from the VA pharmacy between January 1, 2002 and September 1, 2012. The electronic data contain all prescription drugs dispensed either at a VA facility, via mail, or through the outpatient shot clinic (an outpatient clinic where Veterans can receive injections), including dispensing date and drug formulation. Analysis We determined the absolute number and proportion of men who were tested for T, had low T levels, were treated with T, and the T formulations used in each year. The results presented are descriptive only. Given the observational study design, we elected to use the term ‘low T level’ rather than ‘hypogonadism’. The signs and symptoms associated with hypogonadism were not assessed as part of this study because they were not available in the database. Men were characterized by 10-year age categories, by calendar year of T testing, and by body mass index (BMI) and DM diagnosis (see Appendix A, for variable definitions). We chose to assess BMI and DM due to the strong association of these factors with low T levels.
RESULTS Serum testosterone testing The number of eligible men receiving care within VISN 20 increased each year, from 129 247 in 2002 to 163 572 in 2011 (Table 1). During this time, the number of men per year who had serum T tested more than doubled from 4078 in 2002 to 9452 in 2011 (Fig. 1). The proportion of men tested annually increased from 3.2 to 5.8% of all men (Fig. 2). The observed increase in testing primarily occurred between 2007 and 2011, © 2015 American Society of Andrology and European Academy of Andrology
ANDROLOGY
RECENT TRENDS IN TESTOSTERONE TESTING
who were tested, the proportion with DM varied with age and was lowest among men aged 40–49 (9.2%) and highest among men aged 60–69 (16.1%) (data not shown). The proportion of men who underwent serum T testing and were obese (BMI ≥ 30 kg/m2) was 41.8%. The average BMI among tested men was 29 kg/m2. The average BMI among tested men was similar over the period of study and demonstrated little variation among different age groups.
Table 1 VISN 20 men aged 40–89 who underwent testosterone testing, who have low T levels, and who were treated with T, 2002–2011 Year
Total VISN 20 men (age 40–89)
Total tested for T (% of total men)
Total low T (% of total tests)
Total given TRTa (% of low T)
2002 2003 2004 2005 2006 2007 2008 2009 2010 2011
129 135 146 143 144 144 147 152 157 163
4078 (3.2) 4646 (3.4) 5044 (3.4) 4841 (3.4) 4894 (3.4) 5124 (3.5) 5919 (4.0) 6527 (4.3) 8143 (5.2) 9452 (5.8)
1428 (35.0) 1813 (39.0) 1761 (34.9) 1928 (39.8) 2093 (42.8) 2121 (41.4) 2635 (44.5) 3084 (47.2) 3949 (48.5) 4472 (47.3)
443 (31.0) 548 (30.2) 451 (25.6) 459 (23.8) 521 (24.9) 536 (25.3) 668 (25.4) 805 (26.1) 1110 (28.1) 1251 (28.0)
247 325 250 657 912 552 266 398 454 572
Men with low testosterone There was a 35% increase in the proportion of tested men who had low T levels (Table 1 & Fig. 1), from 35.0% of men tested in 2002 to 47.3% in 2011 (Fig. 2). While a rise in the proportion of men with low T levels annually was seen in all age groups, it was greatest in the youngest men and least in the oldest men, with 65, 58, 25, and 9% increases in the proportion of men with low T levels in the 40–49, 50–59, 60–69, and 70–89 age groups, respectively. The average BMI of men with low T levels was 32 kg/m2 and 56.5% of men with low T levels were obese (Table 2). The average BMI in each year was stable over the period of study, and was similar among different age groups. Twenty-two percent of men of all ages with low T levels had DM (Table 2). Among men with low T levels, the proportion with DM increased with increasing age group, where 16, 23, 28, and 30% of men with low T levels had DM in the 40–49, 50–59, 60–69, and 70–89 age groups, respectively.
VISN 20, Veterans Integrated Service Network 20 in the Pacific Northwest. a Within 1 year of low T measurement.
where the proportion tested yearly increased from 3.5 to 5.8%. In men aged 40–49 years, the increase in annual T testing was more substantial over the period of study compared to other decade-age groups. Among this age group, annual testing increased from 2.6% in 2002 to 6.6% in 2011 (Table S1). Similar to men of all ages, the observed increase in annual testing occurred primarily between 2007 and 2011, during which time the proportion tested increased from 3.5 to 6.6%. In men aged 70–89 years, annual T testing was proportionately less and increased minimally during the study period compared to other age groups. The proportion of men tested annually in this age group was 0.7% between 2002 and 2006 and rose to 0.9% in 2011 (Table S1). Among all men who underwent serum T testing, the proportion with a diagnosis of DM was 13.9% (Table 2). Among men Figure 1 Total number of Veterans Integrated Service Network 20 in the Pacific Northwest men aged 40–89 years who: underwent testosterone testing, had low T, and were treated with T*, 2002–2011. *Treated within 1 year of first test showing low T.
Testosterone treatment Throughout the period of study, approximately 30% of men with low T levels were treated with T within 1 year, with the exception of men aged 70–89, in which 20% were treated with T. Most men were treated with injectable T (81.4%), as compared
10 000 Tested for T, not low 9000 Low T Test, not treated 8000 Low T Test, treated 7000
No. of men
6000
5000
4000
3000
2000
1000
0 2002
2003
© 2015 American Society of Andrology and European Academy of Andrology
2004
2005
2006
2007
2008
2009
2010
2011
Andrology, 1–6
3
ANDROLOGY
T. J. Walsh et al. 60%
50%
Figure 2 Percentages of Veterans Integrated Service Network 20 in the Pacific Northwest men aged 40–89 who underwent testosterone testing, who have low T, and who were treated with T, 2002–2011.
Percent of total men tested with low T Percent of total low T men treated with T Percent of total men tested for T
40%
30%
20%
10%
0% 2002
2003
2004
2005
2006
2007
2008
Table 2 Diabetes, BMI and obesity among VISN 20 men aged 40–89 who underwent testosterone testing, who have low T levels, and who were treated with T, 2002–2011 Men tested for T Total VISN 20 men: 351 421 Total 44 762 (12.7% of total men) No. with diabetes 6213 (13.9) ICD-9 code (%) 29.3 (5.4)a Mean BMI, kg/m2 (SD) Obese (BMI ≥ 18 725 (41.8) 30 kg/m2) (%)
Men with low T
Men treated with T
17 546 (39.2% of men tested) 3858 (22.0)
6792 (38.7% of low T men) 2801 (41.2)
31.9 (6.9)b
32.8 (6.6)c
9920 (56.5)
4172 (61.4)
Missing BMI: a2343; b1417; c360. BMI, body mass index; Veterans Integrated Service Network 20 in the Pacific Northwest; ICD-9, International Classification of Diseases–9th Edition.
to T patches (13.2%) and T gels (5.4%). The use of all treatment modalities increased over the period of study. The proportion of men with low T levels who were T treated decreased slightly over time, with 31% of men with low T levels treated in 2002 and 28% treated in 2011 (Fig. 2). The decline in T treatment occurred in every age group. The proportion of obese men among those who had low T levels and were subsequently treated with T was 61.4%. The average BMI of men treated with T was 33 kg/m2, was unchanged over the period of study, demonstrated little variation among different age groups, and was only slightly higher than that of all men with low T levels. Among treated men, 41% had DM (Table 2) and the proportion was 30, 40, 47, and 41% in the 40–49, 50–59, 60–69, and 70–89 age groups, respectively (data not shown).
DISCUSSION We found that the proportion of men undergoing serum T testing yearly in the Pacific Northwest VA health care system from 2002 to 2011 increased by 82% with most of this increase 4
Andrology, 1–6
2009
2010
2011
occurring over the last 3–4 years of the study period. The increase in T testing is consistent with an observed worldwide trend in increased T prescriptions (Layton et al., 2014), which has been attributed to the introduction of transdermal formulations and an increase in direct-to-consumer marketing of T in the US (Handelsman, 2013). In addition, it may reflect provider awareness of a number of recent studies associating low serum T levels with increased risk of mortality (Shores et al., 2006; Khaw et al., 2007; Vikan et al., 2009; Corona et al., 2010; Malkin et al., 2010; Ponikowska et al., 2010; Haring et al., 2011, 2012; Kyriazis et al., 2011; Hyde et al., 2012; Schneider et al., 2012). With this increase in T testing in the VA system, there was also an increase in the proportion of men found to have low T levels in each year, particularly among men aged 40–49 and 50–59 years. Because declining serum T levels are associated with aging (Harman et al., 2001; Araujo et al., 2004, 2007), substantial increases in the proportion of younger (40–59 year old) men with low T levels among those tested may indicate that VA providers are employing more targeted testing, based on patient symptoms and comorbid conditions. Although the absolute number of men treated annually with T doubled over the course of the study, the proportion of men with low T levels who were treated with T yearly decreased by 9.7% from 2002 to 2011. This contrasts to several other studies that reported a substantial increase in T prescriptions over the past several years, which have been associated with large increases in prescriptions for T gels. The lack of an increase in T prescriptions within the VA may be related to VA formulary restrictions for transdermal T formulations and/or higher comorbidity in Veterans. The VA has a restricted drug formulary that requires initial use of T injections prior to transdermal T preparations. There was minimal increase in the use of T gels within the VA system during this time period, which is in marked contrast to studies indicating a significant increase in gel formulations. Our data differ from recent work by Layton et al. (2014), who reported testosterone prescribing patterns in the US from the © 2015 American Society of Andrology and European Academy of Andrology
ANDROLOGY
RECENT TRENDS IN TESTOSTERONE TESTING
MarketScan Commercial Claims database and in the UK from the Clinical Practice Research Datalink. This study found an increase in T prescriptions over 10 years, despite a decline in the proportion of men with low T levels. Authors concluded that testosterone testing in the US population may be less targeted to symptoms, and more driven by direct-to-consumer marketing of testosterone replacement pharmaceuticals. Layton et al. noted that the percentage of men tested who had low T levels remained near 20% from 2007 to 2011 in the US, while the percentage of tested men with low T levels rose from less than 10% to nearly 30% among men tested in the UK. Tests for serum T levels within our cohort appeared to be more focused on symptom presentation as the percentage of men with low T levels ranged from 35 to 49%, which is a greater prevalence of men with low T levels than in either of the prior studies. Baillargeon et al. (2013) described increased testosterone utilization from 2001 to 2011 using data from the Clinformatics DataMart, one of the largest US commercial health insurance populations. The authors noted that the percentage of T-treated men aged 40 years and over rose from 0.54% in 2001 to 2.29% in 2011. While suggesting a significant and more than 4-fold rise in T utilization in this population, the interpretation of these data is limited by the lack of concomitant information on T testing and the proportion of men with low T levels. Among male subscribers in the Northwest VA population, rise in T utilization as a proportion of the total number of eligible men was far more modest, with 0.34% of the total receiving T in 2002 and 0.76% of the total receiving T in 2011. Handelsman (2013) described global testosterone prescribing from 2000 to 2011 for 41 different countries. Data from IMS Health were used to calculate number of T doses per month per 1000 of the eligible population, and suggests that T prescribing in the US rose by more than 10-fold over the period of study. However, given that T utilization overall rose just over 2-fold from 2002 to 2011 in the VISN 20 population, it seems that the trends described by Handelsman are not reflected in Veterans in the VISN 20 Health Network. Hall et al. (2014) described changes in T utilization in the province of Saskatchewan, Canada from 1976 to 2008. Similar to our results, these authors reported much more modest T utilization and change over the entire period of study, with 0.15% of men in 1976 rising to a peak of ~0.45% of men in 2000 receiving T. Unlike others, but similar to ours, this report found a decline in T utilization from 2000 onward, with only ~0.25% of men receiving T in 2008. Given greater prescribing constraints that may accompany a nationalized healthcare system, comparison of these data to ours is intriguing as both of these health care systems involve formulary constraints. However, such a comparison is limited given that Hall et al. considered eligible men to be 18 and older and, like others, they do not provide information on men who are tested and found to have low T levels. Other factors that may explain why annual T treatment did not increase as markedly in the VA setting as in other practice settings is that there may be greater adherence to clinical guidelines, which may be related to local practice patterns. Clinical guidelines (Wang et al., 2009; Bhasin et al., 2010) generally advocate careful assessment prior to prescribing T, emphasizing that special attention should be paid to clinically significant symptoms related to low T levels and to comorbidities. In addition, the limited availability of transdermal T because of formulary © 2015 American Society of Andrology and European Academy of Andrology
restrictions is also likely to impact decisions for T treatment. Between 2002 and 2011, 81.4% of T-treated men in the VISN 20 received injectable T, while only 13.2% received patches and just 5.4% received gels. Finally, the VA patient population has a high degree of medical comorbidity that may affect the patient and provider’s decision to initiate T treatment. A recent report (Kramarow & Pastor, 2012) found that male Veterans who use VA health care have poorer reported physical and mental health and have more chronic health conditions when compared with nonVeteran men. While providing novel information on a unique population, our data have limitations, as we were unable to ascertain if treated men had signs and symptoms of hypogonadism. Thus, despite detailed laboratory data prior to treatment, we are unable to determine which men are treated in accordance with The Endocrine Society guidelines. Despite guideline recommendations, many practitioners measure only one testosterone level before treating. In addition, our data are limited to T tests, T levels, and T treatment obtained within the VA system. Treatment and testing that Veterans received outside the VA system may not have been recorded in their VA record. However, it is important to note that most Veterans who utilize VA care qualify because of low income or lack of private insurance. Many of the Veterans served by the VA system have no co-pays for the medications they receive through the VA, while purchasing the medications outside the VA would require them to pay for the entire cost of the medication. In summary, this is the first report to describe T treatment in the context of men having T levels tested, and of men found to have low T levels. Our results suggest that the number of men aged 40–89 years who are undergoing T testing yearly in the VA system has increased substantially, particularly over the last three to 4 years of the study period, while the proportion of those with low T levels has increased more modestly. However, the proportion of men with low T levels who are treated annually has decreased slightly over this time period. This may reflect specific local clinical practice patterns, patient preferences, higher comorbidity, and/or the impact of a more restricted pharmacy formulary that limits initial T treatment to IM T.
FUNDING This study was supported by an R01 Grant, National Institutes of Health-National Institute on Aging.
DISCLOSURE No conflicts of interest.
REFERENCES Anawalt BD, Hotaling JM, Walsh TJ & Matsumoto AM. (2012) Performance of total testosterone measurement to predict free testosterone for the biochemical evaluation of male hypogonadism. J Urol 187, 1369–1373. Araujo AB, O’Donnell AB, Brambilla DJ, Simpson WB, Longcope C, Matsumoto AM & McKinlay JB. (2004) Prevalence and incidence of androgen deficiency in middle-aged and older men: estimates from the Massachusetts Male Aging Study. J Clin Endocrinol Metab 89, 5920–5926. Araujo AB, Esche GR, Kupelian V, O’Donnell AB, Travison TG, Williams RE, Clark RV & McKinlay JB. (2007) Prevalence of symptomatic androgen deficiency in men. J Clin Endocrinol Metab 92, 4241–4247. Andrology, 1–6
5
ANDROLOGY
T. J. Walsh et al. Baillargeon J, Urban RJ, Ottenbacher KJ, Pierson KS & Goodwin JS. (2013) Trends in androgen prescribing in the United States, 2001 to 2011. JAMA Intern Med 173, 1465–1466. Bhasin S, Cunningham GR, Hayes FJ, Matsumoto AM, Snyder PJ, Swerdloff RS & Montori VM & Endocrine Society Task Force. (2010) Testosterone therapy in men with androgen deficiency syndromes: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab 95, 2536–2559. Corona G, Monami M, Boddi V, Cameron-Smith M, Fisher AD, de Vita G, Melani C, Balzi D, Sforza A, Forti G, Mannucci E & Maggi M. (2010) Low testosterone is associated with an increased risk of MACE lethality in subjects with erectile dysfunction. J Sex Med 7, 1557–1564. Hall SA, Ranganathan G, Tinsley LJ, Lund JL, Kupelian V, Wittert GA, Kantoff PW, Morales A & Araujo AB. (2014) Population-based patterns of prescription androgen use, 1976–2008. Pharmacoepidemiol Drug Saf 23, 498–506. Handelsman DJ. (2013) Global trends in testosterone prescribing, 2000– 2011: expanding the spectrum of prescription drug misuse. Med J Aust 199, 548–551. Haring R, Nauck M, Volzke H, Endlich K, Lendeckel U, Friedrich N, Dorr M, Rettig R, Kroemer HK & Wallaschofski H. (2011) Low serum testosterone is associated with increased mortality in men with stage 3 or greater nephropathy. Am J Nephrol 33, 209–217. Haring R, John U, Volzke H, Nauck M, Dorr M, Felix SB & Wallaschofski H. (2012) Low testosterone concentrations in men contribute to the gender gap in cardiovascular morbidity and mortality. Gend Med 9, 557–568. Harman SM, Metter EJ, Tobin JD, Pearson J & Blackman MR & Baltimore Longitudinal Study of Aging. (2001) Longitudinal effects of aging on serum total and free testosterone levels in healthy men. Baltimore Longitudinal Study of Aging. J Clin Endocrinol Metab 86, 724–731. Hyde Z, Norman PE, Flicker L, Hankey GJ, Almeida OP, McCaul KA, Chubb SA & Yeap BB. (2012) Low free testosterone predicts mortality from cardiovascular disease but not other causes: the Health in Men Study. J Clin Endocrinol Metab 97, 179–189. Khaw KT, Dowsett M, Folkerd E, Bingham S, Wareham N, Luben R, Welch A & Day N. (2007) 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 116, 2694–2701. Kramarow EA & Pastor PN. (2012) The health of male Veterans and nonVeterans aged 25–64: United States, 2007–2010. NCHS Data Brief 101, 1–7. Kyriazis J, Tzanakis I, Stylianou K, Katsipi I, Moisiadis D, Papadaki A, Mavroeidi V, Kagia S, Karkavitsas N & Daphnis E. (2011) Low serum testosterone, arterial stiffness and mortality in male haemodialysis patients. Nephrol Dial Transplant 26, 2971–2977. Layton JB, Li D, Meier CR, Sharpless J, Sturmer T, Jick SS & Brookhart MA. (2014) Testosterone lab testing and initiation in the United Kingdom and the United States, 2000–2011. J Clin Endocrinol Metab 99, 835–842. Malkin CJ, Pugh PJ, Morris PD, Asif S, Jones TH & Channer KS. (2010) Low serum testosterone and increased mortality in men with coronary heart disease. Heart 96, 1821–1825. Ponikowska B, Jankowska EA, Maj J, Wegrzynowska-Teodorczyk K, Biel B, Reczuch K, Borodulin-Nadzieja L, Banasiak W & Ponikowski P. (2010) Gonadal and adrenal androgen deficiencies as independent predictors of increased cardiovascular mortality in men with type II diabetes mellitus and stable coronary artery disease. Int J Cardiol 143, 343–348. Schneider HJ, Wallaschofski H, Volzke H, Markus MR, Doerr M, Felix SB, Nauck M & Friedrich N. (2012) Incremental effects of endocrine and metabolic biomarkers and abdominal obesity on cardiovascular mortality prediction. PLoS ONE 7, e33084.
6
Andrology, 1–6
Shores MM, Sloan KL, Matsumoto AM, Moceri VM, Felker B & Kivlahan DR. (2004) Increased incidence of diagnosed depressive illness in hypogonadal older men. Arch Gen Psychiatry 61, 162–167. Shores MM, Matsumoto AM, Sloan KL & Kivlahan DR. (2006) Low serum testosterone and mortality in male veterans. Arch Intern Med 166, 1660–1665. Shores MM, Smith NL, Forsberg CW, Anawalt BD & Matsumoto AM. (2012) Testosterone treatment and mortality in men with low testosterone levels. J Clin Endocrinol Metab 97, 2050–2058. Vermeulen A, Verdonck L & Kaufman JM. (1999) A critical evaluation of simple methods for the estimation of free testosterone in serum. J Clin Endocrinol Metab 84, 3666–3672. Vikan T, Schirmer H, Njolstad I & Svartberg J. (2009) Endogenous sex hormones and the prospective association with cardiovascular disease and mortality in men: the Tromsø Study. Eur J Endocrinol 161, 435–442. Wang C, Nieschlag E, Swerdloff R, Behre HM, Hellstrom WJ, Gooren LJ, Kaufman JM, Legros JJ, Lunenfeld B, Morales A, Morley JE, Schulman C, Thompson IM, Weidner W & Wu FCW. (2009) Investigation, treatment and monitoring of late-onset hypogonadism in males. J Androl 30, 1–9. Wu FC, Tajar A, Beynon JM, Pye SR, Silman AJ, Finn JD, O’Neill TW, Bartfai G, Casanueva FF, Forti G, Giwercman A, Han TS, Kula K, Lean ME, Pendleton N, Punab M, Boonen S, Vanderschueren D, Labrie F & Huhtaniemi IT & EMAS Study Group. (2010) Identification of lateonset hypogonadism in middle-aged and elderly men. N Engl J Med 363, 123–135.
SUPPORTING INFORMATION Additional Supporting Information may be found in the online version of this article: Table S1. VISN 20 men aged 40–89 who underwent testosterone testing, who have low T levels, and who were treated with T, 2002–2011.
APPENDIX A VARIABLE DEFINITIONS Characteristic
Based on
Age BMI (kg/m2)
Age at time of cohort entry BMI (body mass index) recorded closest to cohort entry date, with preference for prior to cohort entry
Diabetes
ICD-9 codes (International Classification of Diseases– 9th Edition) in subject’s medical record LOINC laboratory codes (Logical Observation Identifiers Names and Codes) in subject’s medical record
Testosterone level
Treatment formulation
Drug IENs (Internal Entry Numbers)
Codes/details
BMI data missing for: 2343 men (5.2%) of men Tested for T 1417 men (8.1%) of men with Low T 360 men (5.3%) of men Treated with T Total rate of missing BMI is 6.7% ICD-9 code: 250.xx (diabetes mellitus)
LOINC codes: 2990-0 (testosterone bioavailable) 2991-8 (testosterone free) 2986-8 (testosterone total) 15432-8 (testosterone free/ testosterone total) IENs: 513, 514, 515, 516, 518, 524, 525, 526, 527, 530, 531, 532, 533, 534, 14379, 14380, 14775, 15507, 15508, 16064, 17475, 17503, 17901, 21468, 21470, 21471
© 2015 American Society of Andrology and European Academy of Andrology
