Testosterone Prescriptions Research Articles

Promotion of “Low T” and citation bias in testosterone studies

The “Low T” marketing campaign playing on older men's concerns about flagging masculinity has driven a dramatic increase in testosterone prescription in the last few years, particularly in North America. However, sales of testosterone are now falling again [1], as regulators, particularly Health Canada [2], have drawn attention to the cardiovascular risk of testosterone supplementation. Health Canada, the Food and Drug Administration and the European Medicines Agency have all advised that testosterone prescription should be restricted [2–4], consistent with the lack of established benefit and the possibility of putting millions of older men at risk of venous thromboembolism or heart attacks [2].

The role of testosterone therapy in cardiovascular mortality: culprit or innocent bystander?

Testosterone therapy is recommended for men with symptomatic androgen deficiency and unequivocally low testosterone levels. Although the prevalence of hypogonadism seems relatively constant, studies of prescribing patterns in both the United States and the United Kingdom show a dramatic increase in testosterone prescription in recent years, possibly due to increased marketing and inappropriate therapy. Concurrent with this, there has been growing concern regarding the potential adverse effects of testosterone therapy, particularly its cardiovascular risks. In this review, we present our current understanding of the implications of testosterone deficiency, as well as the conflicting evidence surrounding the cardiovascular effects of testosterone replacement therapy. Although there is a lack of adequate data, based on the current evidence, we conclude that testosterone therapy can be safely considered in men with appropriately diagnosed clinical androgen deficiency and increased cardiovascular risk after a thorough discussion of potential risks and with guideline recommended safety monitoring.

Effect of testosterone replacement treatment on constitutional and sexual symptoms in type 2 diabetic men: need for rules.

In a recent publication, Gianatti and colleagues investigated the effect of testosterone treatment in obese, aging men with type 2 diabetes (T2D) with mild to moderate symptoms, a modest reduction in testosterone levels, mild to moderate aging male symptoms, and erectile dysfunction.1 The authors could not show any significant improvement in constitutional or sexual symptoms in this group of men. This randomized double-blind, parallel, and placebo-controlled trial among other critically emphasizes the increased testosterone prescriptions worldwide and together with other corroborating or contradictory studies awakes the need for guidelines in the androgen replacement treatment.

Testosterone levels and type 2 diabetes in men: current knowledge and clinical implications.

The relationship between testosterone and diabetes is an important issue, given the fact that diabetes is becoming a fast-growing epidemic, the morbidity associated with which is more disabling than the disease itself. Various studies have demonstrated the increasing prevalence of hypogonadism in diabetic subjects, but whether this is a cause or effect is still an area of active research. The past couple of decades have witnessed an increasing rate of testosterone prescriptions, even though the relationship between testosterone therapy and cardiovascular effects is still not conclusive. The studies done in this regard have shown conflicting results, and there is still a dearth of long-term, follow-up studies in this field. This paper reviews in brief the postulated mechanisms, observational studies, and interventional data regarding the adverse effects of testosterone therapy in type 2 diabetes mellitus, stressing the cardiovascular risks.

The implications of low testosterone on mortality in men.

Testosterone levels in men slowly decline with aging and also decline more abruptly due to medical illness or medications. Prescriptions for testosterone have increased dramatically over the past decade, since a testosterone-gel formulation was approved and since numerous studies reported an association between low serum testosterone and increased mortality. However, recent observational studies of testosterone treatment have reported conflicting results with some studies reporting decreased risks for mortality while others reported increased mortality risks with testosterone treatment. This paper will summarize recent studies of low serum testosterone and mortality and testosterone treatment and mortality and what the potential implications of these studies are for the clinician.

AB19. Testosterone replacement therapy: how safe is it?

AB19. Testosterone replacement therapy: how safe is it?

The impact of drug reimbursement policy on rates of testosterone replacement therapy among older men.

BackgroundDespite a lack of data describing the long-term efficacy and safety of testosterone replacement therapy (TRT), prescribing of testosterone to older men has increased with the availability of topical formulations. The magnitude of this increase and the impact of formulary restrictions on testosterone prescribing are poorly characterized.MethodsWe conducted a time series analysis using the linked health administrative records of men aged 66 years or older in Ontario, Canada between January 1, 1997 and March 31, 2012. We used interventional autoregressive integrated moving average models to examine the impact of a restrictive drug reimbursement policy on testosterone prescribing and examined the demographic profile of men initiating testosterone in the final 2 years of the study period.ResultsA total of 28,477 men were dispensed testosterone over the study period. Overall testosterone prescribing declined 27.9% in the 6 months following the implementation of the restriction policy (9.5 to 6.9 men per 1000 eligible; p<0.01). However, the overall decrease was temporary and testosterone use exceeded pre-policy levels by the end of the study period (11.0 men per 1000 eligible), largely driven by prescriptions for topical testosterone (4.8 men per 1000 eligible). Only 6.3% of men who initiated testosterone had a documented diagnosis of hypogonadism, the main criteria for TRT reimbursement according to the new policy.ConclusionGovernment-imposed restrictions did not influence long-term prescribing of testosterone to older men. By 2012, approximately 1 in every 90 men aged 66 or older was being treated with TRT, most with topical formulations.

Testosterone, aging and survival: biomarker or deficiency.

The purpose of this study is to review recent studies that examined the association of endogenous and exogenous testosterone and mortality in older men. Over the past several years, there has been a steep rise in testosterone prescriptions. The increased use of testosterone occurred in the context of several studies that reported an association between low serum testosterone and increased cardiovascular events and mortality. In contrast, recent studies have reported an association between testosterone treatment and adverse events. A testosterone treatment trial of mobility-impaired elderly men with prevalent cardiovascular disease was stopped due to increased cardiovascular events in the T-treated men and a meta-analysis reported increased cardiovascular events in T-treated men. In two recent large observational studies, testosterone treatment was associated with an increased risk for serious adverse cardiovascular events. Low testosterone is associated with mortality in multiple cohort studies; however, it is unclear if this is a causal association or due to low testosterone being a biomarker of poor health. Given recent reports of adverse outcomes associated with testosterone treatment, a conservative use of testosterone is warranted in men with cardiovascular disease who may be at greater risk for adverse outcomes.

Testosterone and cardiovascular disease.

Use of testosterone among men is increasing rapidly. Low serum testosterone is positively associated with cardiovascular disease and its risk factors. No large randomized controlled trial (RCT) has assessed the effects of testosterone on cardiovascular outcomes. Here recent evidence accumulating from other sources - pharmacoepidemiology, Mendelian randomization studies and meta-analysis of small RCTs - is reviewed to inform current testosterone usage. In a large, well conducted pharmacoepidemiology study specifically testosterone prescription was associated with myocardial infarction. Two Mendelian randomization studies did not corroborate beneficial effects of higher endogenous testosterone on cardiovascular risk factors, but suggested higher endogenous testosterone raised LDL cholesterol and lowered HDL cholesterol. A comprehensive meta-analysis of RCTs summarizing 27 trials including 2994 men found increased risk of cardiovascular-related events on testosterone (odds ratio 1.54, 95% confidence interval 1.09-2.18). Contrary to expectations from observational studies, current indications suggest testosterone causes ischemic cardiovascular disease with corresponding implications for practice. A large RCT would undoubtedly settle the issue definitively. Given mounting evidence of harm and the urgency of the situation assembling all the evidence from completed RCTs of testosterone or androgen deprivation therapy and use of Mendelian randomization might generate a definitive answer most quickly.

Testosterone, cardiovascular disease, and mortality in men: living in the dark

Two recent observational studies1,2 and associated articles in the press3,4 have raised concerns about the potential risks associated with prescription of testosterone to older men. However, these concerns are not new and are reminiscent of the debate about hormone replacement therapy and heart disease in women that raged before the Women's Health Initiative. However, if one thing was learnt from the Women's Health Initiative, it is that cumulative observational data cannot replace well-designed and undertaken randomised clinical trials.

Acute testosterone infusion does not exacerbate arrhythmias in the rat model of ischemia/reperfusion (547.15)

Introduction: With increasing direct‐to‐consumer marketing, testosterone (T) prescriptions have tripled over the past decade. Clinical literature suggests that exogenous T use may increase various arrhythmias. Therefore, we examined the effect of exogenous T in an acute rat model of arrhythmias.Methods and Results: Anesthetized female Sprague Dawley rats (250g) were given T (2.5 mg/kg, n=9) or vehicle (n=10) intravenously 15 minutes before 5 minutes of coronary artery occlusion. Rats were then reperfused for 5 minutes and arrhythmias were examined. T levels were measured one minute before occlusion. T levels were different between groups (5.4 ± 1 ng/mL control; 206.9 ± 35 ng/mL T, P &lt; 0.001). The ischemic risk zone as a percentage of the left ventricle did not differ between groups (33 ± 2% control; 29 ± 3% T, P = 0.48). The number of episodes of ventricular tachycardia did not differ between groups (11.7 ± 3.2 control; 8.8 ± 3.0 T, P = 0.3). There was a non‐significant trend toward fewer ventricular premature beats with T (37.8 ± 10.3 control; 16.9 ± 8.9 T, P = 0.06) Conclusion: Despite large differences in T levels between groups, T had little effect on the incidence of arrhythmias, suggesting that T supplementation does not increase risk of arrhythmias.

Trends in Management of Testosterone in the U.K. and the U.S.

In a new study, researchers evaluated a U.S. insurance claims database and a U.K. general practice database to document trends in testosterone testing and prescribing in these two countries during the past decade. Findings include the following:

Global trends in testosterone prescribing, 2000–2011: expanding the spectrum of prescription drug misuse

To provide the first multinational survey of temporal trends in testosterone prescribing, given that anecdotal evidence indicates that it is increasing in some countries, including Australia. Sales data for all testosterone products were obtained for 41 countries for each year from 2000 to 2011. For each testosterone product type (injectable, implantable, oral, transdermal), units sold were converted into defined monthly doses per year, reflecting total testosterone prescribing per product. National testosterone prescribing rate overall and per product type on a per capita basis. For every region and 37 of 41 countries, there was a major and progressive increase in defined monthly doses per year per capita over the 11 years surveyed. In most countries, the increases were steeper for the last half of the survey period. The proportion of testosterone prescribing represented by transdermal testosterone products, a surrogate measure of prescribing for older men, increased even more than did the total usage of testosterone products. In the absence of any new indications, off-label testosterone prescribing has increased in most countries in 2000-2011, especially over the last half of the period. The increased testosterone prescribing appears to be primarily for older men and driven by clinical guidelines that endorse testosterone prescribing for age-related functional androgen deficiency (andropause). By eliminating the fundamental distinction between pathological and functional androgen deficiency, these guidelines tacitly promote increased testosterone prescribing, bypassing the requirement for high-quality clinical evidence of safety and efficacy and creating dramatic increases in prescription of testosterone products.

PS3-36: Testosterone Replacement Therapy Patterns for Aging Males in a Managed Care Setting

Clin Med Res 2013; 11: 141. Abstract available at http://jurology.com/ Editorial Comment: The purpose of this article was to describe the characteristics and treatment patterns of males receiving testosterone therapy. Included were members of Kaiser Permanente Southern California (KPSC) who received a testosterone prescription between January 1999 and December 2010. Of the 10,159 testosterone users mean SD age was 56.8 11.6 years, and 67.7% were white. From 1999 to 2010 the yearly treatment rate increased by 183%, and number of pre- scriptions per patient increased by 22%. The most frequently prescribed testosterone products were transdermal gels (55.7%), patches (26.2%) and intramuscular injections (14.4%). Average duration of exposure was close to 1 year (mean SD supply 320.0 504.2 days). Baseline testosterone levels were obtained in 91.0% of patients, and mean SD serum testosterone level was 259.7 179.5 ng/dl. Followup testosterone levels were drawn in 59.8% of patients within 1 year of the index date, and mean SD serum testosterone was 395.0 275.3 ng/dl. Mean increase from baseline was 151.9 ng/dl (95% CI 160.5, 143.3) for transdermal gels, 118.0 ng/dl (95% CI 129.5, 106.5) for patches and 200.7 ng/dl (95% CI 237.0, 164.3) for intramuscular injections. The most frequent diagnoses at baseline were hypertension (43.7%), hyperlipidemia (43.1%), erectile dysfunction (33.5%), testicular dysfunction (26.7%) and diabetes (20.3%). Testosterone prescriptions were most frequently written by primary care providers (family practice 36.0%, internal medicine 20.1%), followed by specialists (endocrinology 13.5%, urology 6.6%). These extraordinarily interesting data highlight the changing milieu in testosterone replacement therapy. It is noteworthy that primary care providers account for the largest increase in testosterone prescriptions written.

Medication Adherence and Treatment Patterns for Hypogonadal Patients Treated with Topical Testosterone Therapy: A Retrospective Medical Claims Analysis

There is limited information on adherence to topical testosterone replacement therapy (TRT) among hypogonadal men. To determine adherence rates among men treated with topical testosterone gels and to examine factors that may influence adherence, including age, presence of a specific diagnosis, and index dose. Included were 15,435 hypogonadal men, from the Thomson Reuters MarketScan Database, who had an initial topical testosterone prescription in 2009 and who were followed for 12 months. Adherence to testosterone was measured by medication possession ratio (MPR), with high adherence defined as ≥0.8. Persistence was defined as the duration of therapy from the index date to the earliest of the following events: end date of the last prescription, date of the first gap of >30 days between prescriptions, or end of the study period (12 months). Adherence to topical TRT was low. By 6 months, only 34.7% of patients had continued on medication; at 12 months, only 15.4%. Adherence rates were numerically similar among men who received AndroGel or Testim topical gels and did not differ among men of different age groups. Approximately 80% of patients initiated at the recommended dose of 50 mg/day. Over time, an increased proportion of men used a higher dose. This change was the result of dose escalation, rather than of greater adherence among men initiating therapy at a high dose. Dose escalation was seen as early as 1 month into therapy. Approximately 50% of men who discontinued treatment resumed therapy; most men used the same medication and dose. Discontinuation rates are high among hypogonadal men treated with testosterone gels, irrespective of their age, diagnosis, and index dose. Further study, evaluating other measurable factors associated with low adherence among patients receiving topical TRT, may lead to interventions designed to improve adherence with therapy.

A UK epidemic of testosterone prescribing, 2001–2010

Testosterone replacement therapy is the standard treatment for male hypogonadism. There has lately been increased marketing in the medical media promoting testosterone replacement for men with erectile dysfunction or for older men with low serum testosterone, despite the lack of long-term safety and efficacy data. Therefore, we aimed to examine trends in testosterone prescribing in UK primary care over the last 10years. Data about the use of testosterone preparations from the Departments of Health Prescription Cost Analysis for community pharmacies 2001-2010, for England, Scotland and Wales, were collated. Community requests for serum total testosterone assay in men to the Biochemistry Department at the Newcastle upon Tyne Hospitals Trust were also examined over the same time period. The number of prescriptions for testosterone preparations increased by nearly 90% from 157602 to 298134 dispensed items annually, over a 10-year period. However, due to a particularly significant (fivefold) increase in prescribing of (more expensive) transdermal preparations, the cost to the NHS showed a 267% escalation, from £3·2 to £11·7 million, annually over the same period. Local requests from primary care in the Newcastle and North Tyneside area for serum testosterone measurement in men also increased, from 347 requests in 2000 to 823 requests in 2010, a 137% increase. However, the number of men with likely unequivocal hypogonadism (testosterone less than 6·0nm) remained constant at 5·2% in 2000 and 6·3% in 2010. Many men in the UK might be receiving testosterone replacement therapy with neither clearly established indications nor robustly diagnosed hypogonadism. A national registry for men treated with testosterone and further evidence to improve current guidance (national and/or international) on the indications for testosterone replacement would be beneficial.

2291 TESTOSTERONE PRESCRIBING PATTERNS IN THE MALE INFERTILITY POPULATION

You have accessJournal of UrologyInfertility: Evaluation1 Apr 20132291 TESTOSTERONE PRESCRIBING PATTERNS IN THE MALE INFERTILITY POPULATION Mary Samplaski, Yasir Loai, Kirk Lo, Ethan Grober, and Keith Jarvi Mary SamplaskiMary Samplaski Toronto, Canada More articles by this author , Yasir LoaiYasir Loai Toronto, Canada More articles by this author , Kirk LoKirk Lo Toronto, Canada More articles by this author , Ethan GroberEthan Grober Toronto, Canada More articles by this author , and Keith JarviKeith Jarvi Toronto, Canada More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2013.02.2232AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Over the last decade there has been a gradual increase in testosterone (T) prescribing. We sought to analyze patterns of T prescribing in men presenting for infertility evaluation. METHODS Men presenting for fertility evaluation from 2008-2012 on T were identified via a prospective database. Data were analyzed for prevalence, prescriber, formulation, dosage and indication. RESULTS 4400 men were evaluated for male infertility, and 56 (1.3%) were on T at presentation. Prescribers included: Endocrinologists (10, 17.9%), General Practitioners (5, 8.9%), Urologists (3, 5.3%), and independently obtained (4, 7.1%). Formulations and dosages included: Gel (26, 46.4%): most commonly 5mg every other day (QOD), range: 5mg QOD to 10mg daily; Intramuscular injection (25, 44.6%), most commonly 200mg every 2 weeks, range: 50-300mg every 2 weeks; Oral (1, 1.8%), 80mg QOD; Pellet (1, 1.7%), dose unknown; and unknown formulation and dose (5, 8.9%). Indications for T included: symptoms of hypogonadism (27, 48.2%), symptoms + low serum T (21, 37.5%), low serum T (4, 7.1%), athletic purposes (3, 5.4%), and subfertility (1, 1.8%). Co-existing conditions included: Klinefelters syndrome (8, 14.3%), history of bilateral undescended testicles (7, 12.5%), Kallmans syndrome (5, 8.9%), Sertoli only syndrome (2, 3.6%), chemotherapy induced testicular failure (2, 3.6%), prolactinoma (2, 3.6%), anejaculation (1, 1.8%), and opioid induced testicular failure (1, 1.8%). CONCLUSIONS At our infertility center, T was not commonly used by men presenting for infertility investigation. Most men on T were being treated for appropriate conditions, with appropriate routes and dosages. Endocrinologists and General Practitioners were the most common prescribers, and educational efforts to emphasize the negative impacts of T on spermatogenesis should be focused on these groups. There are a group of men that obtain their T independently, and a group that uses T for athletic purposes. While this was a small fraction of the men in our population of infertile men, as the use of T increases, this fraction will undoubtedly grow. © 2013 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 189Issue 4SApril 2013Page: e939 Peer Review Report Advertisement Copyright & Permissions© 2013 by American Urological Association Education and Research, Inc.MetricsAuthor Information Mary Samplaski Toronto, Canada More articles by this author Yasir Loai Toronto, Canada More articles by this author Kirk Lo Toronto, Canada More articles by this author Ethan Grober Toronto, Canada More articles by this author Keith Jarvi Toronto, Canada More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Pharmacoepidemiology of testosterone prescribing in Australia, 1992–2010

To describe patterns of testosterone prescribing in Australia over the past two decades by state or territory and by product type. Observational analysis of testosterone prescribing data obtained from two independent data sources--the Pharmaceutical Benefits Scheme (PBS) and IMS, a source of commercial pharmaceutical sales data. Temporal trends in testosterone prescribing--measured as units prescribed (converted into monthly defined doses) and expenditure--to state or territory and product type (injectable, implantable, transdermal and oral). Over two decades, total annual expenditure on testosterone products increased ninefold to $12.7 million according to PBS data and fivefold to $16.3 million according to IMS data. When adjusted for inflation and population growth, expenditure increased 4.5-fold according to PBS data and 2.5-fold according to IMS data. The patterns of testosterone prescribing according to PBS and IMS data were highly congruent. When converted into monthly defined dose units, testosterone prescribing increased over the two decades with approximately twofold differences in total testosterone prescribed per capita between the states and territories with the highest and lowest rates of prescribing. When analysed by product type, the stable market patterns over the first 15 years were disrupted by sharp changes to create market dominance owing to introduction of two new testosterone products--a depot injectable testosterone and a transdermal testosterone gel. The progressive increase in PBS-subsidised testosterone prescribing without changes in proven medical indications or improvements in diagnosis of pathologically based androgen deficiency are likely to be due to promotion-driven non-compliance with PBS prescribing criteria, indicating that more effective implementation of the criteria is needed.

PIH79 Medication Adherence and Persistence for Hypogondal Patients Treated with Topical Testosterone Therapy: A Retrospective Claims Analysis

The diagnosis of hypogonadism is established in symptomatic men with consistently low levels of serum testosterone, whether due to specific diagnoses, such as Klinefelter syndrome, or non-specific diagnoses, which often occur with aging. Testosterone gels are the most common form of testosterone replacement therapy for hypogonadism in the United States, but little is known about patient adherence and persistence with therapy. This study seeks to examine testosterone gel adherence and persistence among hypogonadism patients. The type of hypogonadism (specific versus non-specific) was classified using either ICD-9-CM diagnostic codes or testosterone prescription codes in the Thomson Reuters MarketScan® Database in 2009. Medication persistence was defined as the length of therapy (LOT) from the index date to the earliest ending date of the last prescription, defined as either the date of the first gap of >30 days between prescriptions or the end of study period (12 months). Medication adherence was measured by medication possession ratio (MPR) in the 6 months follow-up period. Adherence rate was defined as percent of MPR ≥0.8. LOT, MPR and adherence rate were calculated by diagnostic code and age group and compared using t-test or chi-square test. 91,200 men met study criteria for hypogonadism: 11.1% with specific and 89.9% with non-specific diagnostic codes. The mean LOT was 196 days and 178 days, respectively (p< 0.0001). MPR and adherence rates were similar between men with specific (0.4 and 8.6%, respectively) and non-specific (0.4 and 9.0%, respectively) diagnoses. LOT, MPR and adherence rate were numerically similar across all age groups. Unexpectedly, diagnostic specificity and age were not found to be key etiologic factors in testosterone gel adherence and persistence for hypogonadal men. Unexplored factors that might provide more sensitivity include other testosterone application methods, hypogonadal symptom severity, and ascertainment of testosterone levels.

Reversible testosterone-induced azoospermia in a 45-year-old man attending an infertility outpatient clinic

A 45-year-old male with azoospermia was presented to us with primary infertility. We found that he had been taking testosterone due to erectile dysfunction. Upon its discontinuation, the normozoospermia was restored. This led to a pregnancy. In men aged 40-50, the diagnostic work up of testosterone deficiency should be in accordance with the current guidelines. Moreover, no testosterone prescription should be made without having inquired about parenthood desires. In men of the reproductive age with recent-onset azoospermia, consider the possibility of an iatrogenic cause, primarily due to the testosterone replacement therapy. The treatment is simple: to discontinue the therapy.