199_08_211013.book Page 548 Tuesday, October 15, 2013 2:17 PM

Research

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

S

ince the first report of clinicaluse of testosterone in 1937,1 2
years after its Nobel Prizewinning
identification as the male
ANZAC Research Institute,
Concord Hospital,
testicular steroid,2,3 the sole unequivUniversity of Sydney,ocal therapeutic indication for testoSydney, NSW.
sterone is in replacement therapy fordjh@anzac.edu.au
pathological androgen deficiency(AD). This includes disorders of the
MJA 2013; 199: 548–551
testis, where damaged Leydig cells
doi: 10.5694/mja13.10111
cannot produce sufficient testosterone, and of the hypothalamus and/or
pituitary, where impaired pituitaryluteinising hormone (LH) secretion
reduces testosterone production by
Leydig cells. Pharmacological androgen therapy — the use of testosterone (or its synthetic androgenanalogues) beyond replacement
therapy — exploits androgenic
effects on muscle, bone, liver or brain
in men.4 It can also be used to treat
various functional AD states wherea n in tact reprodu ctive sy ste m
responds adaptively to acute or
chronic illness (eg, ageing, obesity,
diabetes, cardiovascular disease,chronic infections or organ failure
syndromes) by reducing testosterone
secretion. These uses require highquality clinical evidence of efficacy,
safety and cost-effectiveness fromtrials featuring randomisation andplacebo controls; however, few suchtrials are available.5
Nevertheless, despite the absenceof any new approved indications,
there have been major and progressive increases in testosterone prescribing in Australia over the past
two decades, with striking differences between states, increasing useof costlier newer products and partially effective regulatory curbs on
unproven
testosteroneprescribing.6,7
The Medical Journalof Australia
ISSN: 0025729X 21 October
2013 199 8 548-551
Anecdotally,
similar increases have
©The Medicalb een
Journalof ib
Australia
descr
ed in 2013th e Un ite dwww.mja.com.au
States, 8,9 Switzerland 10 and the
Research
United Kingdom, 11 but there has
been no systematic study of multinational temporal trends in testosterone prescribing.
David J Handelsman
MB BS, FRACP, PhD,
Director

548

MJA 199 (8) · 21 October 2013

Abstract
Objective: To provide the first multinational survey of temporal trends intestosterone prescribing, given that anecdotal evidence indicates that it isincreasing in some countries, including Australia.
Design: 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.
Main outcome measures: National testosterone prescribing rate overall and per
product type on a per capita basis.
Results: For every region and 37 of 41 countries, there was a major andprogressive 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 ofthe survey period. The proportion of testosterone prescribing represented bytransdermal testosterone products, a surrogate measure of prescribing for oldermen, increased even more than did the total usage of testosterone products.
Conclusions: In the absence of any new indications, off-label testosteroneprescribing has increased in most countries in 2000–2011, especially over thelast 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 dramaticincreases in prescription of testosterone products.

Methods
Data for sales of all testosterone products for each year from 2000 to 2011
inclusive were obtained from IMS
Health for 41 countries. Countries
were divided descriptively into six
groups: the Anglosphere (Australia,
Canada, Ireland, UK, US); Eastern
Europe (Bulgaria, Croatia, Czechoslovakia, Estonia, Hungary, Latvia,
Lithuania, Poland, Romania, Russia,
Slovakia, Slovenia); Middle Europe(Austria, Belgium, France, Germany,
Luxembourg, the Netherlands, Switzerland); Northern Europe (Denmark,Finland, Norway, Sweden); Southern
Europe (Greece, Italy, Spain); andAsia (Hong Kong, China, Japan,
Indonesia, Malaysia, the Philippines,
Singapore, Thailand, Vietnam). Data
were also obtained for Mexico.
Using the World Health Organization definition of standardised dosing(WHO Collaborating Centre for Drug
Statistics M ethodolog y, h ttp: //www.whocc.no; described in detailelsewhere 6,7) the defined monthly
dosage of testosterone was calculated
for each product category, country
and year. Testosterone products weregrouped into four categories as injectable, implantable, oral or transdermal
and, using a standard dosage regimen, sales of units were converted
into monthly dose equivalents. For
each country and region, total testosterone units were calculated for eachproduct category per year. These total
use estimates were adjusted to a population basis using annual national
population estimates obtained fromthe US Census Bureau based on
annual estimates for national population. This method uses commercial(wholesale) sales of testosterone
products as a surrogate for testosterone prescribing and assumes (i) aconstant proportion of adult males ineach country’s population over timeand between countries, and (ii) a
steady state existing between pur-

199_08_211013.book Page 549 Tuesday, October 15, 2013 2:17 PM

Research
1 Testosterone use, 2000–2011, by country or region
Defined monthly doses (% transdermal)*Country/region

2000

2001

2002

2003

2004

2005

2006

2007

2008

2009

2010

2011

Australia

9.6
(1%)

11.5
(10%)

12.5
(13%)

12.2
(13%)

12.2
(12%)

13.1
(13%)

13.1
(23%)

13.6
(23%)

15.1
(22%)

16.5
(22%)

17.4
(22%)

17.9
(23%)

Canada

10.0
(0)

11.3
(3%)

40.4
(7%)

82.1
(86%)

102.3
(89%)

108.5
(90%)

115.4
(91%)

122.3
(91%)

135.7
(91%)

220.0
(95%)

333.5
(96%)

385.5
(97%)

Ireland

1.2
(45%)

1.9
(41%)

1.7
(4%)

1.6
(54%)

1.9
(67%)

2.3
(72%)

2.5
(72%)

2.9
(74%)

3.6
(69%)

4.6
(64%)

5.0
(60%)

5.4
(58%)

United Kingdom

3.9
(15%)

4.1
(16%)

3.3
(21%)

3.6
(24%)

3.8
(37%)

4.2
(43%)

4.6
(45%)

5.4
(49%)

6.2
(51%)

7.9
(47%)

8.9
(48%)

9.8
(50%)

United States

10.3
(31%)

15.3
(53%)

19.4
(67%)

19.0
(61%)

19.3
(57%)

24.2
(66%)

26.0
(67%)

32.6
(71%)

39.7
(72%)

46.5
(69%)

52.9
(68%)

98.5
(78%)

Mexico

3.7
(0)

3.0
(0)

2.4
(0)

2.0
(0)

1.6
(0)

1.5
(0)

1.6
(0)

1.7
(2%)

1.9
(6%)

2.3
(7%)

2.0
(8%)

1.9
(11%)

Eastern Europe†

1.9
(0)

1.6
(0)

1.8
(0)

1.3
(0)

1.4
(0)

1.4
(1%)

1.7
(4%)

1.6
(6%)

1.8
(7%)

2.0
(9%)

1.8
(9%)

2.7
(7%)

Middle Europe‡

4.3
(7%)

4.8
(6%)

5.1
(6%)

5.0
(17%)

4.3
(27%)

4.8
(23%)

5.5
(24%)

6.0
(26%)

6.5
(27%)

7.1
(28%)

7.8
(29%)

8.5
(28%)

Northern Europe§

4.5
(14%)

4.8
(14%)

5.1
(14%)

5.2
(14%)

5.5
(26%)

6.4
(32%)

10.5
(47%)

12.6
(52%)

14.8
(56%)

16.6
(57%)

19.3
(60%)

22.1
(62%)

Denmark

1.6
(7%)

1.7
(3%)

1.7
(0)

1.8
(0)

2.0
(7%)

2.6
(9%)

4.9
(9%)

5.2
(10%)

5.4
(13%)

5.8
(15%)

6.3
(20%)

6.9
(21%)

Finland

5.4
(9%)

5.5
(7%)

6.0
(7%)

6.3
(10%)

6.8
(24%)

7.9
(28%)

9.2
(28%)

10.1
(29%)

11.6
(31%)

13.5
(31%)

14.4
(32%)

15.1
(34%)

Norway

5.1
(10%)

5.6
(9%)

6.1
(10%)

5.9
(10%)

6.7
(20%)

6.9
(24%)

8.3
(2%)

9.1
(23%)

9.5
(23%)

10.6
(23%)

11.5
(24%)

12.6
(25%)

Sweden

5.5
(20%)

5.8
(21%)

6.0
(22%)

6.2
(21%)

6.3
(34%)

7.5
(44%)

15.8
(67%)

20.4
(72%)

25.0
(75%)

28.2
(76%)

34.1
(77%)

40.2
(78%)

Southern Europe¶

5.6
(2%)

5.5
(6%)

5.3
(6%)

4.7
(7%)

4.5
(11%)

4.7
(15%)

5.1
(15%)

5.8
(17%)

6.3
(19%)

6.7
(21%)

6.9
(21%)

7.2
(21%)

Asia**

0.4
(0)

0.4
(0)

0.4
(0)

0.3
(0)

0.3
(0)

0.3
(0)

0.3
(0)

0.3
(0)

0.4
(0)

0.4
(0)

0.4
(0)

0.5
(0)

* Per year per 1000 population; proportion given via transdermal products (gel, patch). † Bulgaria, Croatia, Czechoslovakia, Estonia, Hungary, Latvia,
Lithuania, Poland, Romania, Russia, Slovakia, Slovenia. ‡ Austria, Belgium, France, Germany, Luxembourg, the Netherlands, Switzerland. § Denmark, Finland,
Norway, Sweden. ¶ Greece, Italy, Spain. ** China (hospitals), Hong Kong, Indonesia, Japan, Malaysia, the Philippines, Singapore, Thailand, Vietnam.
◆

chase, prescribing and clinical use of
testosterone products according totheir approved regimens.

Results
Over 11 years, total testosterone sales
increased 12-fold globally, rising from$150 million in 2000 to $1.8 billion in
2011. For all regions and 37 of 41
countries, there was a progressive andincreasingly steep increase in per capita use over that period (Box 1). This
rise was markedly steeper from the
middle of the decade, consistently inalmost all countries (Box 2). In parallel, the proportion of testosterone
sales as transdermal products also
increased overall as well as in eachregion, especially in the second half ofthe decade for most countries (Box 1).

Discussion
This study shows a large and progressive increase in testosterone prescrib-

ing across a wide range of countries
over more than a decade. This is notdue to any new indications for testosterone, and the rising trend accelerated over the last half decade of thesurvey period. The most dramaticincreases in per capita testosteroneprescribing were observed in Canada,
which displayed an almost fourfold
higher rate than the next country, its
southern neighbour the US (however,a similar pattern did not occur
between the US and its southernneighbour Mexico). This increase ismost probably due to internet pharmacies physically based in Canada,
which appear not to be subject tonational prohibitions of import andexport controls of androgens as
restricted drugs and are beyond the
US Food and Drug Administration’s
regulatory reach. In contrast, othernational data are likely to reflect use
only within a country. These findings
closely resemble, and widen, thespectrum of prescription drug misuse,
which has been described as a mod-ern epidemic12 involving the misuseof psychoactive drugs such as opioids,
sedatives and stimulants, as well as
non-psychoactive drugs such as antibiotics.13,14 Notably, testosterone haslong been known to have mood-elevating effects,15 reflected in its modest
efficacy as an adjuvant antidepressant,16,17 and hypomania as an overdosage side effect.18
Testosteron e prescribing was
already increasing before 2000 when
this survey commenced.6,8 The reasons for this coordinated global
increase in testosterone prescribing
are speculative. The dramatic differences between even neighbouring
countries is an indication that differences in local or regional marketingare responsible as shown previously
for Australian states.6,8 The impact of
direct-to-consumer advertising in the
US, materially unchanged during theperiod of survey, would be largely
confined to North America. Morelikely, a major contributor, especiallyin the second half of the decade,

MJA 199 (8) · 21 October 2013549

199_08_211013.book Page 550 Tuesday, October 15, 2013 2:17 PM

Research
2 Increasing testosterone use, 2000–2011, in selected countries

Monthly doses/year/1000 population (log scale)

1000

Australia

IrelandUnited States

CanadaUnited Kingdom

Sweden

100

10

11
20

10
20

0
9
20

0
7

0
8
20

20

0
6
20

20

0
5

0
4
20

0
3
20

0
1

0
2
20

20

20

0
0

1

Year

appears to be the permissive US19 andEuropean-based20 guidelines for testosterone prescribing, first publishedin 2005–2006 and republished virtually unchanged 4 years later.21,22 The
European-based guidelines appearedin seven different peer-reviewed journals, and both guidelines have beenfrequently cited (> 1300 times; Thomson Reuters Web of Knowledge, 20
June 2013, http://wok.mimas.ac.uk/
news/2013/20130620.html). These
guidelines are widely understood todefine and endorse testosterone prescription for age-related functional
AD (also known as andropause orlate-onset hypogonadism).23 In eliminating the distinction between pathological and functional AD, theseguidelines promote unproven offlabel testosterone prescribing, particularly for older men, bypassing theneed for high-quality evidence fromrandomised placebo-controlled clinical trials.5
The rising proportion of transdermal products may reflect that theincreased testosterone prescribing
was primarily for older men, although
the age and indications for treatment
were not available for this analysis.
Daily-use testosterone products are aconvenient surrogate metric for testosterone prescribing for older men, as
short-acting products allow for rapid
cessation with a new diagnosis of
prostate cancer. In contrast, younger

550

MJA 199 (8) · 21 October 2013

men, facing a lifetime of treatment,
prefer long-acting injections, whichfacilitate the continuity and convenience of long-term treatment.24
The known prevalence of pathological AD (about 0.5% of men 24)
equates to about 15 defined monthly
doses per year per 1000 population.
Population-linkage registry data fromthe UK25 and Denmark26 indicate
severe underdiagnosis of Klinefelter
syndrome (KS), the most frequentcause of pathological AD. Nevertheless, it is highly unlikely that recent
steep increases in testosterone prescribing can be attributed to rectifying
underdiagnosis of KS. Not only does
total testosterone prescribing in somecountries exceed the maximum
amount that could be attributed topathological AD, there is no evidence
that the diagnosis of KS has increased
in recent years.6,27 In contrast, theestimated population prevalence of
age-related functional AD amongolder men is up to 40%,28 more usually 10%–25%,29-31 with even thelowest estimates of 2%–3% 32 representing major (five- to 100-fold)increases in potential market size overpathological AD.
The potential harm of testosterone
overuse in older men is highlighted byadverse cardiovascular effects of testosterone in frail, older men.33 Nevertheless, previous longer and higher
dose studies produced no similar

exces s cardiovascular ha rms, 3 4although the bias in underreportingof cardiovascular harm in industrysponsored studies may lead to underestimating the risk.35 Such testosterone-induced cardiovascular harm
predicts that the substantial increases
in testosterone prescribing for older
men may lead to increased incidenceof cardiovascular disease among oldermen, warranting ongoing populationlevel surveillance. In the interim, testosterone prescribing for functionalAD, notably among older men without pathological hypogonadism,
should be confined to well controlled
and adequately powered clinical trials
that aim to determine the efficacy andsafety of testosterone prescribing for
andropause.
Limitations of this study include
that no information on patient age orthe indications for prescribing wasavailable. However, it is most likelythat the increased prescribing was forolder men with functional AD. The
study also did not include testosterone sold by compounding pharma c ie s . A n d ro g e n s (i n c lud in gtestosterone) obtained illicitly via theinternet or other non-medical sources
are at least partly included, to theextent that virtually all testosterone
originates from commercial production facilities that supply wholesalers.
This study provides the first multinational view of testosterone prescribing. It shows coordinated, global
increases in off-label testosteroneprescribing, apparently mainly for
older men, driven by permissive
guidelines promoting evidence-freeprescribing for functional AD including andropause. This overuse of testosterone shares many features of, andexpands the spectrum of, prescription
drug misuse.
Acknowledgements: I thank Lam Ly for his help withdata management and Nicole Sweetman of IMS Healthfor providing the data.
Competing interests: No relevant disclosures.

Received 23 Jan 2013, accepted 4 Aug 2013.
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underdevelopment with synthetic male hormone
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MJA 199 (8) · 21 October 2013551