Testosterone supplementation therapy (TST) has become increasingly popular since the turn of the century. Most prescriptions in the U.S. are written by primary care providers, endocrinologists, or urologists. The FDA has requests pharmaceutical companies provide more long term data on efficacy and safety of testosterone products. Results from these studies will help define the appropriate population for TST going forward. It is hoped that these data combined with physician and public education will minimize inappropriate prescribing and allow those likely to benefit from TST to receive it.
Key points
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Testosterone supplementation therapy has become increasingly popular since the turn of the century.
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In the U.S., most testosterone prescriptions are written by primary care providers, endocrinologists, or urologists.
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Due to conflicting results regarding the efficacy and safety of testosterone supplementation, the US Food and Drug Administration has asked manufacturers to clarify the labeling of these products and requested further research into the long term use of testosterone products.
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Results from these studies will help define the appropriate population for testosterone supplementation therapy going forward. It is hoped that these data combined with physician and public education will minimize inappropriate prescribing and allow those likely to benefit from testosterone supplementation therapy to receive it.
“It is important not to conclude that every old man who is tired is suffering from the male climacteric. This diagnosis should be made only after the most careful search has been carried out to discover some other cause for the symptoms.” This statement is from an article entitled Uses and Abuses of the Male Sex Hormone published in The Journal of the American Medical Association in 1946, when age-related hypogonadism was referred to as climacteric . The struggle to define what is appropriate use of testosterone supplementation therapy (TST) and what constitutes misuse of these drugs has been present since the hormone was first synthesized in 1935.
The intensity of public scrutiny has increased with the approval and marketing of various testosterone formulations since the turn of the century. In 2002, recognizing the public interest in testosterone products, the National Institute of Aging and the National Cancer Institute requested the Institute of Medicine conduct an assessment of clinical research on TST. The study concluded that uncertainties remain regarding the use of TST in older men. Further developments in both the popularity and risk profile of these medications have led to increasing public health concerns in recent years.
Trends in the prescription of testosterone
The continued research and development of a diverse range of testosterone formulations will continue to benefit men with hypogonadism. Much of the concern about the use of TST, however, has arisen because of the rapidly increasing number of men using TST in the United States ( Table 1 ) and worldwide. Many of these men are prescribed testosterone for age-related decreases in testosterone (subsequently referred to as late-onset hypogonadism [LOH]) rather than classic androgen deficiency caused by pathologic conditions such as Klinefelter’s syndrome, orchiectomy, and chemotherapy. The trend of increasing use of TST has been documented in a variety of ways ranging from commercial insurance claims data to integrated health care systems.
| Study | Database Type | Population | Number | Years Studied | % Increase |
|---|---|---|---|---|---|
| Baillargeon et al, 2013 | Commercial insurance | >40 y | 10,739,815 | 2001–2011 | 359 |
| Layton et al, 2014 | Commercial insurance | >18 y | 410,019 | 2000–2010 | 374 |
| Jasuja et al, 2015 | Veteran Affairs | >20 y | 111,631 | 2009–2012 | 78 |
| Nguyen et al, 2015 | Outpatient pharmacy | All ages | 7,246,013 | 2010–2013 | 183 |
Commercial Insurance Claims Data
Layton and colleagues used a commercial health insurance database, MarketScan Commercial Claims and Encounters, to evaluate trends in testosterone initiation in the United States from 2000 to 2011. The authors evaluated 410,000 men older than 18 years who initiated testosterone therapy each year. They calculated the population rates of testosterone initiation by using person-years of eligibility as the denominator (calculated by summing the continuously enrolled person-time for men in each year). The annual rate of testosterone initiation increased from 20.2 per 10,000 person-years in 2000 to 75.7 per 10,000 person-years in 2011—a nearly 4-fold increase—with an accelerating rate after 2008. Most men initiating testosterone therapy were relatively young (74% were between the ages of 40 and 64); however, commercial health insurance databases are limited by undersampling of men older than 65 who use Medicare as their primary source of health care coverage.
Baillargeon and colleagues used data from Clinformatics DataMart, one of the largest commercial health insurance populations, to examine testosterone-prescribing practice patterns from the years 2001 to 2011. The authors restricted the study to men age 40 years and older to focus on the issue of testosterone use in men with LOH. The database included more than 10 million men in this age group, with at least 1 million men covered by insurance every year of the decade studied. They found that testosterone use increased 3-fold between 2001 and 2011. In 2001, 0.81% of men older than 40 years were using TST compared with 2.91% in 2011. Use of topical gel formulations of testosterone had the largest increase with a 5-fold increase during the decade. Again, one limitation of this report is its reliance on commercial health insurance, which undersamples men older than 65 years.
Pharmacy Sales
Using data obtained from IMS Consulting, the 2002 Institute of Medicine study reported that although sales of testosterone products were steady at approximately $18 million per year until1988, the annual sales of these projects was $400 million by 2002. The number of testosterone prescriptions written increased from 648,000 in 1999 to 1.75 million in 2002, a 170% increase. The first gel preparation of testosterone was approved for use in the United States in 2000.
The US Food and Drug Administration (FDA) held a joint meeting between the Bone, Reproductive, and Urologic Drugs Advisory Committee and the Drug Safety and Risk Management Advisory Committee on September 17, 2014. During the meeting, Mohamed A. Mohamoud from the FDA’s Office of Surveillance and Epidemiology presented recent prescription sales data using the Symphony Healthcare Solutions Anonymous Patient Longitudinal Database. This database captured unique patients filling a prescription for testosterone at outpatient pharmacies throughout the nation. National projections from these data estimated that the number of men filling testosterone prescriptions increased from 1.2 million in 2010 to 2.2 million in 2013, a near doubling in just 4 years.
Veterans Administration Health Care System Data
The Veterans Administration (VA) Health Care System is the largest integrated health care system in United States and allows for analysis of practice patterns using medical records, laboratory tests, and prescription data. Jasuja and colleagues evaluated the testosterone-prescribing practices in the VA Health Care System from fiscal years 2009 to 2012. Evaluating records from more than 6 million men who received at least 1 outpatient medication from a participating pharmacy, they found that 1.7% of the men received a new prescription for testosterone during the period. The annual number of men with new testosterone prescriptions increased from 20,437 in 2009 to 36,394 in 2012, a 78% increase over 4 years. In keeping with other studies in which age at the time of testosterone initiation was evaluated, 81.9% of men starting treatment were older than 49 years.
International Trends
In one of the earliest reports of increased testosterone prescribing around world, Handelsman used the Australian Pharmaceutical Benefits Scheme (PBS) to evaluate trends in testosterone prescribing in Australia from 1991 to 2001. The PBS provides coverage for medically necessary medications and represents 80% of prescriptions written in Australia. Overall there was an increase in annual testosterone prescriptions from 14,000 in 1991 to 26,000 in 2001. The author found that regulatory changes affected prescribing trends. The number of testosterone prescriptions doubled from approximately 14,000 prescriptions written in 1991 to 32,000 in 1994. Beginning in 1994, PBS required telephone authorization for testosterone prescriptions, which resulted in a decline in testosterone prescriptions to 22,000 in 1996; however, a steady increase in prescriptions followed with annual prescriptions peaking at 31,000 by 1999. In 2000, PBS implemented further restrictions requiring conformation to Endocrine Society of Australia consensus guidelines, resulting in a decrease to 26,000 prescriptions in 2001. This study provides insight into how regulatory oversight of testosterone products can influence physician prescribing habits.
Handelsman also used a pharmaceutical sales database to write a brief report on global sales of testosterone products from 2000 to 2011. He converted testosterone sales data from 41 countries into number of monthly doses sold per year. He found that global testosterone sales increased from $150 million in 2000 to $1.8 billion in 2011, a 12-fold increase. The slope of increase was increasingly steep during the latter part of the decade. These trends were seen in all regions of the world and in 37 of the 41 countries examined. Although sales data are likely proportional to the number of men using these products, patient-level data were lacking.
Layton and colleagues used the Clinical Practice Research Datalink database, a registry of health record information from general practitioners, to evaluate trends of TST in the United Kingdom from 2000 to 2010. A total of 6833 men initiated treatment during this period. The TST initiation rate increased from 3.4 per 10,000 person-years in 2000 to 4.5 per 10,000 patient-years in 2010, which was much lower than that reported in the United States. Most (83.4%) of these men were older than 39 years. This study may have underestimated the number of men initiating TST; however, prescribing data from specialists were not included in the database.
Trends in the prescription of testosterone
The continued research and development of a diverse range of testosterone formulations will continue to benefit men with hypogonadism. Much of the concern about the use of TST, however, has arisen because of the rapidly increasing number of men using TST in the United States ( Table 1 ) and worldwide. Many of these men are prescribed testosterone for age-related decreases in testosterone (subsequently referred to as late-onset hypogonadism [LOH]) rather than classic androgen deficiency caused by pathologic conditions such as Klinefelter’s syndrome, orchiectomy, and chemotherapy. The trend of increasing use of TST has been documented in a variety of ways ranging from commercial insurance claims data to integrated health care systems.
| Study | Database Type | Population | Number | Years Studied | % Increase |
|---|---|---|---|---|---|
| Baillargeon et al, 2013 | Commercial insurance | >40 y | 10,739,815 | 2001–2011 | 359 |
| Layton et al, 2014 | Commercial insurance | >18 y | 410,019 | 2000–2010 | 374 |
| Jasuja et al, 2015 | Veteran Affairs | >20 y | 111,631 | 2009–2012 | 78 |
| Nguyen et al, 2015 | Outpatient pharmacy | All ages | 7,246,013 | 2010–2013 | 183 |
Commercial Insurance Claims Data
Layton and colleagues used a commercial health insurance database, MarketScan Commercial Claims and Encounters, to evaluate trends in testosterone initiation in the United States from 2000 to 2011. The authors evaluated 410,000 men older than 18 years who initiated testosterone therapy each year. They calculated the population rates of testosterone initiation by using person-years of eligibility as the denominator (calculated by summing the continuously enrolled person-time for men in each year). The annual rate of testosterone initiation increased from 20.2 per 10,000 person-years in 2000 to 75.7 per 10,000 person-years in 2011—a nearly 4-fold increase—with an accelerating rate after 2008. Most men initiating testosterone therapy were relatively young (74% were between the ages of 40 and 64); however, commercial health insurance databases are limited by undersampling of men older than 65 who use Medicare as their primary source of health care coverage.
Baillargeon and colleagues used data from Clinformatics DataMart, one of the largest commercial health insurance populations, to examine testosterone-prescribing practice patterns from the years 2001 to 2011. The authors restricted the study to men age 40 years and older to focus on the issue of testosterone use in men with LOH. The database included more than 10 million men in this age group, with at least 1 million men covered by insurance every year of the decade studied. They found that testosterone use increased 3-fold between 2001 and 2011. In 2001, 0.81% of men older than 40 years were using TST compared with 2.91% in 2011. Use of topical gel formulations of testosterone had the largest increase with a 5-fold increase during the decade. Again, one limitation of this report is its reliance on commercial health insurance, which undersamples men older than 65 years.
Pharmacy Sales
Using data obtained from IMS Consulting, the 2002 Institute of Medicine study reported that although sales of testosterone products were steady at approximately $18 million per year until1988, the annual sales of these projects was $400 million by 2002. The number of testosterone prescriptions written increased from 648,000 in 1999 to 1.75 million in 2002, a 170% increase. The first gel preparation of testosterone was approved for use in the United States in 2000.
The US Food and Drug Administration (FDA) held a joint meeting between the Bone, Reproductive, and Urologic Drugs Advisory Committee and the Drug Safety and Risk Management Advisory Committee on September 17, 2014. During the meeting, Mohamed A. Mohamoud from the FDA’s Office of Surveillance and Epidemiology presented recent prescription sales data using the Symphony Healthcare Solutions Anonymous Patient Longitudinal Database. This database captured unique patients filling a prescription for testosterone at outpatient pharmacies throughout the nation. National projections from these data estimated that the number of men filling testosterone prescriptions increased from 1.2 million in 2010 to 2.2 million in 2013, a near doubling in just 4 years.
Veterans Administration Health Care System Data
The Veterans Administration (VA) Health Care System is the largest integrated health care system in United States and allows for analysis of practice patterns using medical records, laboratory tests, and prescription data. Jasuja and colleagues evaluated the testosterone-prescribing practices in the VA Health Care System from fiscal years 2009 to 2012. Evaluating records from more than 6 million men who received at least 1 outpatient medication from a participating pharmacy, they found that 1.7% of the men received a new prescription for testosterone during the period. The annual number of men with new testosterone prescriptions increased from 20,437 in 2009 to 36,394 in 2012, a 78% increase over 4 years. In keeping with other studies in which age at the time of testosterone initiation was evaluated, 81.9% of men starting treatment were older than 49 years.
International Trends
In one of the earliest reports of increased testosterone prescribing around world, Handelsman used the Australian Pharmaceutical Benefits Scheme (PBS) to evaluate trends in testosterone prescribing in Australia from 1991 to 2001. The PBS provides coverage for medically necessary medications and represents 80% of prescriptions written in Australia. Overall there was an increase in annual testosterone prescriptions from 14,000 in 1991 to 26,000 in 2001. The author found that regulatory changes affected prescribing trends. The number of testosterone prescriptions doubled from approximately 14,000 prescriptions written in 1991 to 32,000 in 1994. Beginning in 1994, PBS required telephone authorization for testosterone prescriptions, which resulted in a decline in testosterone prescriptions to 22,000 in 1996; however, a steady increase in prescriptions followed with annual prescriptions peaking at 31,000 by 1999. In 2000, PBS implemented further restrictions requiring conformation to Endocrine Society of Australia consensus guidelines, resulting in a decrease to 26,000 prescriptions in 2001. This study provides insight into how regulatory oversight of testosterone products can influence physician prescribing habits.
Handelsman also used a pharmaceutical sales database to write a brief report on global sales of testosterone products from 2000 to 2011. He converted testosterone sales data from 41 countries into number of monthly doses sold per year. He found that global testosterone sales increased from $150 million in 2000 to $1.8 billion in 2011, a 12-fold increase. The slope of increase was increasingly steep during the latter part of the decade. These trends were seen in all regions of the world and in 37 of the 41 countries examined. Although sales data are likely proportional to the number of men using these products, patient-level data were lacking.
Layton and colleagues used the Clinical Practice Research Datalink database, a registry of health record information from general practitioners, to evaluate trends of TST in the United Kingdom from 2000 to 2010. A total of 6833 men initiated treatment during this period. The TST initiation rate increased from 3.4 per 10,000 person-years in 2000 to 4.5 per 10,000 patient-years in 2010, which was much lower than that reported in the United States. Most (83.4%) of these men were older than 39 years. This study may have underestimated the number of men initiating TST; however, prescribing data from specialists were not included in the database.
Preferences in prescribed testosterone formulations
Testosterone is available as short- and long-acting injectables, transdermals (ie, gels and patches), pellets, and oral formulations, although availability varies by country. Details regarding specific testosterone preparations, their uses and limitations have been detailed elsewhere in this issue (See Khera M: Testosterone therapies , in this issue).
The worldwide increase in testosterone sales has largely been attributed to the increasing use of topical formulations. According to FDA data, an estimated 59,000 kg of testosterone products were sold in the United States between 2009 and 2013, with 71% of those products being testosterone gels. In Ontario, Canada, expenditures on topical preparations increased 464% between 2007 and 2012. The increase in testosterone prescribing seems to be blunted where formulary restrictions limit coverage of topical formulations, such as the Veterans Administration Health Care System in the United States.
This increase in prescribing reflects prescriber preferences. Among specialists prescribing TST, 62% reported a preference for testosterone gel when initiating treatment; 55% preferred gels for long-term treatment. Analysis of the geographic distribution of respondents found that testosterone gels were the preferred formulation among North American clinicians, whereas long-lasting injections were preferred among non–North American clinicians. This finding is somewhat misleading, as the long-lasting injection was only recently approved by the FDA for use in the United States and, therefore, would not have been available to those prescribers at the time of the study. Thus, formulation preferences are likely to evolve as practitioners become more familiar with newer options. A separate survey limited to European testosterone prescribers (45% general practitioners, 31% urologists, and 24% endocrinologists) found that 26% preferred long-acting intramuscular injections, 24% gels, 21% matrix transdermal device, 15% short-acting injections, and 13% oral formulations.
Testosterone prescriber demographics
Although there is variation based on the population sampled, most testosterone prescribers in the United States and Canada are primary care providers. In a large US health care system, 73% of TST prescribers were found to be primary care providers, 16% were endocrinologists, and 5% were urologists. Analysis of the Truven Marketscan Database found 59% of prescribers were primary care providers and 18% were urologists. Similarly, the FDA reported that 60% of US prescribers were primary care providers. Interestingly, a survey of men with hypogonadism already diagnosed in the United States found they were actively seeking treatment most commonly from a urologist (30.5%) followed by a general practitioner (28%), but this may not reflect which provider initiated TST. In Canada, family physicians initiated 66% to 78% of new prescriptions.
Although multiple studies have evaluated the distribution of providers prescribing TST, only one study evaluated changes in providers’ prescribing patterns with time. A worldwide survey of members of the major endocrine and andrology societies (91% of respondents were endocrinologists) found wide variation in practice patterns. When queried about their inclination to treat borderline hypogonadal men with nonspecific symptoms, 46% reported being less inclined to do so now than they were 5 years ago, whereas 30% reported no change. This trend was stronger among participants from North America and Oceania than in other parts of the world.
A survey of TST prescribers in Europe found that 74% considered that both symptoms and low testosterone levels were required for the diagnosis of testosterone deficiency syndrome in men. Although data regarding reasons for prescribing TST have not been published, a survey of 353 frequent TST prescribers from 6 large, non-US countries evaluated reasons for physicians not prescribing TST. Physicians reported initiating TST in approximately two-thirds of hypogonadal patients. Prostate cancer concerns were the primary reasons for not initiating TST. Of note, although 68% of physicians associated TST with side effects, 32% expressed a belief that there were no side effects.
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