Research

JAMA Internal Medicine | Original Investigation

Association of Testosterone Therapy With Risk of Venous Thromboembolism

Among Men With and Without Hypogonadism
Rob F. Walker, MPH; Neil A. Zakai, MD, MSc; Richard F. MacLehose, PhD; Logan T. Cowan, PhD;
Terrence J. Adam, RPH, PhD, MD; Alvaro Alonso, MD, PhD; Pamela L. Lutsey, PhD

Supplemental content
IMPORTANCE Testosterone therapy is increasingly prescribed in patients without a diagnosis
of hypogonadism. This therapy may be associated with increased risk of venous
thromboembolism (VTE) through several mechanisms, including elevated hematocrit levels,
which increase blood viscosity.

OBJECTIVE To assess whether short-term testosterone therapy exposure is associated with

increased short-term risk of VTE in men with and without evidence of hypogonadism.

DESIGN, SETTING, AND PARTICIPANTS This case-crossover study analyzed data on 39 622 men
from the IBM MarketScan Commercial Claims and Encounter Database and the Medicare
Supplemental Database from January 1, 2011, to December 31, 2017, with 12 months of
follow-up. Men with VTE cases who were free of cancer at baseline and had 12 months of
continuous enrollment before the VTE event were identified by International Classification of
Diseases codes. Men in the case period were matched with themselves in the control period.
Case periods of 6 months, 3 months, and 1 month before the VTE events were defined, with
equivalent control periods (6 months, 3 months, and 1 month) in the 6 months before the
case period.

EXPOSURES National drug codes were used to identify billed testosterone therapy
prescriptions in the case period (0-6 months before the VTE) and the control period (6-12
months before the VTE).

MAIN OUTCOMES AND MEASURES The main outcome in this case-only experiment was first
VTE event stratified by the presence or absence of hypogonadism.

RESULTS A total of 39 622 men (mean [SD] age, 57.4 [14.2] years) were enrolled in the study,
and 3110 men (7.8%) had evidence of hypogonadism. In age-adjusted models, testosterone
therapy use in all case periods was associated with a higher risk of VTE in men with (odds
ratio [OR], 2.32; 95% CI, 1.97-2.74) and without (OR, 2.02; 95% CI, 1.47-2.77) hypogonadism.
Among men without hypogonadism, the point estimate for testosterone therapy and VTE risk
in the 3-month case period was higher for men younger than 65 years (OR, 2.99; 95% CI,
1.91-4.68) than for older men (OR, 1.68; 95% CI, 0.90-3.14), although this interaction was not
statistically significant (P = .14).

CONCLUSIONS AND RELEVANCE Testosterone therapy was associated with an increase in

short-term risk for VTE among men with and without hypogonadism, with some evidence
that the association was more pronounced among younger men. These findings suggest that
caution should be used when prescribing testosterone therapy.

Author Affiliations: Author

affiliations are listed at the end of this
article.
Corresponding Author: Rob F.
Walker, MPH, Division of
Epidemiology and Community
Health, School of Public Health,
University of Minnesota,
1300 S Second St, Ste 300,
JAMA Intern Med. doi:10.1001/jamainternmed.2019.5135 Minneapolis, MN 55413
Published online November 11, 2019. (walk0493@umn.edu).

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 Research Original Investigation Testosterone Therapy and Venous Thromboembolism Risk in Men With and Without Hypogonadism
T
he clinical indication for testosterone therapy is
primarily to treat hypogonadism, a condition
in which serum testosterone levels in men
decrease below a specific threshold, resulting in sexual
dysfunction, altered bone metabolism and body composi-
tion, and potential emotional dysregulation.1-4 Although
testosterone levels may decrease with age, external causes
of clinic al hypogonadism include genetic diseases
or complications from surgery, infection, and medications.4
Testosterone prescriptions among men increased more
than 300% from 2001 to 20135,6; the increase is thought
to be caused by testosterone therapy being prescribed
for common symptoms, such as low libido and f at
redistribution, associated with aging, obesity, and diabetes
and not necessarily with clinical hypogonadism. 7 This
increase in prescription rate was more pronounced among
men aged 18 to 45 years than among older men.5 In 2014,
the US Food and Drug Administration released a warning
about testosterone therapy and the potential risk of heart
attack and stroke; since then, testosterone therapy prescrip-
tions have decreased and eventually plateaued.8,9 Recent
trends estimate that, in the United States, 2.3 million
men older than 30 years (3.2%) were prescribed testoste-
rone therapy in 2013 and that this trend decreased to
approximately 1.15 million men (1.6%) in 2016.6,10 Evidence
suggests that testosterone therapy is still being prescribed
to men without hypogonadism.7
Ve n o u s t h ro m b o e m b o l i s m ( V T E ) , c o n s i s t i ng o f
deep vein thrombosis and pulmonary embolism, is a com-
mon condition in the United States, with more than 1 mil-
lion individuals experiencing a VTE annually. 11 Baseline
testosterone levels are not associated with increase in VTE
risk. 12 However, exogenous testosterone therapy may
increase endogenous hematocrit levels, which can increase
blood viscosity, platelet accumulation, and thromboxane
A2 concentrations for up to 6 months and could subse-
q u e nt l y i n c r e a s e r i s k o f b l o o d c l o t f o r m at i o n a n d
subsequent VTE events.13-15 Testosterone therapy is most
commonly administered via transdermal gels, patches, or
intramuscular routes, each having their own rate of absorp-
tion and prescription strengths that potentially affect
cardiovascular pathophysiologic factors.16 Pathophysiologic
research suggests that exogenous testosterone therapy
could increase VTE risk, but the 2 largest observational
studies17,18 evaluating this association reached conflicting
c o n c l u s i o n s . Fu r t h e r m o re , t h e s e s t u d i e s 1 7, 1 8 we re
underpowered to examine testosterone therapy use within
important clinical subgroups, such as by clinical hypogo-
nadism status, 1 9 age, route of testosterone therapy
exposure, and duration of testosterone therapy use.
Using a c ase-c rossover design, this study tested
our primary hypothesis that exposure to testosterone
therapy is associated with increased risk of incident VTE
among men stratified by clinical hypogonadism status.
Secondary analyses stratifying by age group (<65 years
vs ≥65 years), route of testosterone therapy exposure, and
different case periods were performed to assess various
risk profiles.
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Key Points
Question Is clinical prescription of testosterone therapy
associated with short-term risk of venous thromboembolism in
men with and without hypogonadism?
Findings In this case-crossover study comparing 6-month
testosterone use for 39 622 men who had a venous
thromboembolism with testosterone use 6 to 12 months before
the venous thromboembolism, use of testosterone therapy in the
6-month case period was associated with an increased risk of
venous thromboembolism among men with and without
hypogonadism.
Meaning The findings suggest that testosterone therapy is
associated with increased short-term risk of venous
thromboembolism among all men prescribed the therapy.
Methods
Data Source
This case-crossover study included data obtained using inpatient
and outpatient medical claims provided from the IBM Market-
Scan Commercial Claims and Encounter Database and the Medi-
care Supplemental Database (IBM Watson Health) from January
1, 2011, through December 31, 2017. The databases contain health
care claims information from US employers, health plans, hos-
pitals, and Medicare programs. Data on all enrollment records
and inpatient, outpatient, ancillary, and drug claims are collated
and linked via individual-level identifiers. The MarketScan da-
tabases are compliant with the Health Insurance Portability and
Accountability Act, and all data are deidentified. As such, per
MarketScan operational procedure, enrollee consent was not re-
quired or obtained. This study was deemed to be exempt accord-
ing to the institutional review board process for the University
of Minnesota.
Study Population and VTE Definition
The initial cohort included 93 205 men aged 18 to 99 years with
at least 1 inpatient or 2 outpatient claims for VTE 7 to 184 days
apart (International Classification of Diseases, Ninth Revision,
Clinical Modification [ICD-9-CM] and International Statistical
Classification of Diseases, Tenth Revision, Clinical Modifica-
tion [ICD-10-CM] codes provided in eTable 1 in the Supple-
ment), with 1 corresponding anticoagulant prescription within
31 days of the initial VTE date. The positive predictive value
was 91% in a validation study that used a similar definition,
incorporating both inpatient and outpatient ICD-9-CM codes
and requiring evidence of treatment.20-23
After restriction of the sample to men with at least 12
months of continuous enrollment before their VTE, 52 203 men
remained. A total of 12 581 men with prevalent cancer were ex-
cluded, and the final analytic sample included 39 622 men with
12 months of follow-up before their VTE. For all men, only the
incident VTE event was considered in these analyses.
The US Endocrine Society defines hypogonadism as “con-
sistently low serum total testosterone and/or free testosterone
concentrations”24(p 1716) with trademark symptoms (loss of body
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 Testosterone Therapy and Venous Thromboembolism Risk in Men With and Without Hypogonadism
hair, small testis size, and delayed sexual development). Market-
Scan data do not contain specific laboratory values of tests or de-
tailed information about patient symptoms. Therefore, hypogo-
nadism for the main analysis was defined by the ICD-9-CM codes
257.xx and the ICD-10-CM codes E29.x and E89.5, which capture
an array of hypogonadism diagnoses, including postirradiation
and postsurgical diagnoses. These codes were based on a previ-
ous study17 that used claims data that controlled for hypogonad-
ism status and a review of the diagnosis code descriptions. A sen-
sitivity analysis was performed defining hypogonadism using a
different set of ICD-9-CM and ICD-10-CM codes spanning vari-
ous testicular, pituitary, and hypothalamic disorders used in an
analysis performed by Jasuja et al.25
Study Design
A case-crossover study design was used in which each man
with VTE served as his own control. We defined exposure case
periods of 6 months, 3 months, and 1 month before the inci-
dent VTE event, with equivalent exposure control periods (6
months, 3 months, and 1 month) starting 6 months before the
incident VTE event (Figure, A). Various case period lengths
were selected to assess the time frame in which VTE events
could be triggered after testosterone prescription exposure. Be-
cause each case patient serves as his own control, the case-
crossover design mitigates confounders that are time invari-
ant during a patient’s observation period.
Identification of Testosterone Therapy Prescriptions
The main exposure of interest was a received drug claim for
testosterone therapy 1 month, 3 months, or 6 months before
an individual’s first VTE event. The case periods were
defined based on the time that testosterone therapy is thought
to affect the previously mentioned pathophysiologic factors
known to increase VTE risk. We defined 612 different formu-
lations for testosterone therapy, including a variety of pre-
scription brands, strengths, and routes using a therapeutic de-
tail code (6808010090) unique to MarketScan databases (RED
BOOK, IBM Watson Health). Route of exposure was classified
as transdermal (includes both gel and patch methods of ap-
plication) or intramuscular injection. A sensitivity analysis was
performed that defined testosterone therapy use as having
more than 1 testosterone therapy prescription fill within the
3-month and 6-month case periods.
Statistical Analysis
The presence of a testosterone prescription 1, 3, and 6 months
before the incident VTE date was compared with the equiva-
lent control periods that occurred 6 months before the VTE date.
Conditional logistic regression was used to estimate the odds ra-
tios (ORs) and corresponding 95% CIs for the risk of VTE asso-
ciated with testosterone use in the case period compared with
the control period. Hospitalization has been found to be asso-
ciated with VTE,26,27 and the number of medical encounters may
be an indicator of general health. As such, in multivariable mod-
els, we controlled for the number of inpatient hospitalizations,
outpatient visits, and emergency department hospitalizations
that occurred in the case and control periods.
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Original Investigation Research
Figure. Study Design
A Main analysis
Control period Case period
6 mo 6 mo
3 mo 3 mo
1 mo 1 mo
6-12 mo 0-6 mo Incident
VTE
B Exploratory analysis
Control period Case period
6-3 mo 3-1 mo 1 mo 6-3 mo 3-1 mo 1 mo
6-12 mo 0-6 mo Incident
VTE
Schematic of the main (A) and exploratory (B) case-crossover study designs.
VTE indicate venous thromboembolism.
To explore multiplicative interaction associations, we con-
ducted the same overall analyses stratified by age category
(<65 vs ≥65 years) and route of testosterone (transdermal vs
intramuscular). Multiplicative interactive associations were for-
mally tested by adding an interaction term in the original lo-
gistic regression models. An exploratory analysis was con-
ducted that classified testosterone therapy use differently to
look for lagged associations. Time windows of less than 1, 1 to
3, or 3 to 6 months before the first VTE event and the corre-
sponding time windows for the control period 6 months be-
fore the VTE were used for all analyses (Figure, B). Use of
testosterone therapy in the 3- to 6-month case period was used
as a reference category (instead of no testosterone therapy use)
to detect different risk profiles from the 1- to 3-month and
1-month case periods. All statistical analyses were performed
with SAS statistical software, version 9.4 (SAS Institute Inc).
A 2-sided test for P < .05 was used as the significance
threshold.
Results
A total of 39 622 men (mean [SD] age, 57.4 [14.2] years) were
enrolled in the study, with 3110 men (7.8%) diagnosed with hy-
pogonadism and 29 182 men (73.7%) younger than 65 years.
Among the 36 512 men without hypogonadism, 374 (1.0%) were
ever prescribed testosterone in the year before their VTE event.
Among the 3110 men with hypogonadism, 1330 (42.8%) were
prescribed testosterone in the 12 months before their VTE
event. Compared with men without evidence of hypogonad-
ism, men with hypogonadism had more outpatient encoun-
ters in the year before their VTE (Table 1). All analyses were
stratified by hypogonadism status; primary results for men
without hypogonadism are provided in Table 2 and for men
with hypogonadism in Table 3.
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 Research Original Investigation Testosterone Therapy and Venous Thromboembolism Risk in Men With and Without Hypogonadism

sitivity analysis that required men to have more than 1 testos-

Table 1. Characteristics of Men With and Without Hypogonadism,
MarketScan Database, 2011-2017a terone prescription fill (eTable 4 in the Supplement), with ORs
of 2.46 (95% CI, 1.38-4.39) for the 6-month case period and 3.75
No
Hypogonadism Hypogonadism (95% CI, 1.95-7.22) for the 3-month case period.
Characteristic (n = 36 512) (n = 3110) In exploratory analyses, we considered exposure periods
Age, mean (SD), y 57.4 (14.4) 57.5 (10.9) of less than 1 month, 1 to 3 months, and 3 to 6 months. Use of
Age <65 y 53 512 (73.3) 4852 (78.0) testosterone therapy in the less than 1-month and 1- to 3-month
Ever used testosterone therapy 374 (1.0) 1330 (42.8) case periods was associated with approximately a doubling in
Testosterone therapy routeb the risk of VTE (<1-month OR, 1.96; 95% CI, 1.24-3.10; 1- to
Intramuscular 139/573 (24.3) 809/2189 (37.0) 3-month OR, 2.24; 95% CI, 1.42-3.54); however, no associa-
Transdermal 432/573 (75.4) 1371/2189 (62.7) tion was found in the 3- to 6-month period (OR, 0.99; 95% CI,
Other 2/573 (0.3) 9/2189 (0.3) 0.65-1.53). Risk in the less than 1-month and 1- to 3-month case
No. of inpatient hospitalizations, 0.2 (0.5) 0.2 (0.6) periods (OR, 1.87; 95% CI, 1.01-3.46) was statistically signifi-
mean (SD)c
cantly different from that in the 3- to 6-month case period (OR,
No. of outpatient encounters, 3.5 (13.4) 5.7 (4.8)
mean (SD)c 2.08; 95% CI, 1.17-3.70).
No. of emergency department 0.3 (0.6) 0.4 (0.8)
encounters, mean (SD)c Testosterone Therapy and VTE
a
Data are presented as number (percentage) unless otherwise indicated. Among Men With Hypogonadism
b
Denominators of 573 and 2189 are the amount of unique testosterone Among men with hypogonadism, testosterone therapy use was
prescriptions in the case and control periods during the 12-month also higher in the total 6-month case period (n = 1069) com-
study period.
pared with the control period (n = 697) (Table 3). Testoste-
c
Numbers for inpatient hospitalizations, outpatient encounters, and
rone prescriptions in the 1-month (OR, 1.66; 95% CI,
emergency department visits correspond to the 12-month period before the
initial venous thromboembolism date. 1.34-2.04), 3-month (OR, 2.28; 95% CI, 1.91-2.72), and 6-month
(OR, 2.32; 95% CI, 1.97-2.74) case periods were also associ-
ated with approximately double the risk of VTE compared with
Testosterone Therapy and VTE the control periods 6 months earlier after adjusting for con-
Among Men Without Hypogonadism founders. There was no evidence of interactive associations
Among the men without hypogonadism, testosterone pre- by age group or route of testosterone therapy exposure
scription was more common in the 6 months immediately be- (Table 4).
fore the VTE event (case period; n = 294) than in the control Sensitivity analyses yielded higher adjusted estimates
period (n = 177) (Table 2). Use of testosterone therapy in the when an alternate definition of hypogonadism was used
case period was associated with a doubling of VTE risk when (eTable 3 in the Supplement). In the other sensitivity analysis
using the 1-month case period (OR, 1.96; 95% CI, 1.24-3.10), with testosterone therapy use defined as having filled more
3-month case period (OR, 2.46; 95% CI, 1.71-3.53), and 6-month than 1 prescription, magnitudes of association were larger
case period (OR, 2.02; 95% CI, 1.47-2.77) compared with tes- (eTable 4 in the Supplement). This sensitivity analysis yielded
tosterone therapy use in the equivalent control periods after ORs of 2.95 (95% CI, 2.34-3.71) for the 6-month case period and
adjusting for the number of inpatient hospitalizations, outpa- 3.34 (95% CI, 2.42-4.60) for the 3-month case period.
tient encounters, and emergency department encounters. In the exploratory analyses, we also analyzed the expo-
eTable 2 in the Supplement provides additional information sure periods of 1 to 3 months and 3 to 6 months. Among men
on the cross-classification of testosterone therapy use in the with hypogonadism, the adjusted ORs were 1.96 (95% CI, 1.60-
case and control periods for all period lengths. 2.41) for the 1- to 3-month case period and 1.33 (95% CI, 1.06-
Stratified analyses were also conducted to explore poten- 1.66) for the 3- to 6-month case period. Risk in the 1- to 3-month
tial interactive associations by age category and route of tes- case period was statistically significantly different from that
tosterone therapy exposure (Table 4). Although the interac- in the 3- to 6-month case period (OR, 1.49; 95% CI, 1.12, 1.97),
tions were not statistically significant, men younger than 65 whereas risks in the less than 1-month vs 3- to 6-month case
years without hypogonadism using testosterone therapy in the periods were not statistically significant (OR, 1.31; 95% CI, 0.98-
6-month (OR, 2.33; 95% CI, 1.60-3.40) and 3-month case pe- 1.76). Exploratory analysis results stratified by age category and
riods (OR, 2.99; 95% CI, 1.91-4.68) had greater VTE risk com- testosterone therapy route are provided in eTable 5 in the
pared with men 65 years and older using testosterone therapy Supplement.
in the 6-month (OR, 1.41; 95% CI, 0.77-2.56) and 3-month case
periods (OR, 1.68; 95% CI, 0.90-3.14). Estimates were similar
when comparing the 1-month testosterone therapy use with
the control period for both age groups. No significant interac-
Discussion
tions were apparent when analyses were stratified by route of Using a large medical claims database and a case-crossover ap-
testosterone therapy (transdermal vs intramuscular). proach, this study found that men without cancer prescribed
Sensitivity analyses using the alternative hypogonadism testosterone therapy had approximately twice the risk of VTE
definition yielded similar association estimates (eTable 3 in the within the 1-, 3-, and 6-month case periods compared with the
Supplement). Magnitudes of association were larger in the sen- equivalent control periods 6 months earlier. The association

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 Testosterone Therapy and Venous Thromboembolism Risk in Men With and Without Hypogonadism Original Investigation Research

Table 2. Overall Association of Testosterone Therapy Prescription With Risk of Venous Thromboembolism
Among Men Without Hypogonadism, Main and Exploratory Analyses, MarketScan Database, 2011-2017

Testosterone Therapy Prescription, No. (%) Odds Ratio (95% CI)

Testosterone Therapy Case
Period Case Period Control Perioda Crudeb Adjustedc
Main Analysis (n = 36 512)
6 mo 294 (0.8) 177 (0.5) 2.46 (1.90-3.19) 2.02 (1.47-2.77)
3 mo 220 (0.6) 119 (0.3) 2.53 (1.90-3.37) 2.46 (1.71-3.53)
1 mo 96 (0.3) 59 (0.2) 1.82 (1.27-2.62) 1.96 (1.24-3.10)
Exploratory Analysis (n = 36 512)
3-6 mo 74 (0.2) 58 (0.2) 1.29 (0.91-1.84) 0.99 (0.65-1.53)
1-3 mo 124 (0.3) 60 (0.2) 2.64 (1.83-3.82) 2.24 (1.42-3.54)
1 mo 96 (0.3) 59 (0.2) 1.82 (1.27-1.62) 1.96 (1.24-3.10)
a
Control period for the main analysis is the equivalent-length period (6, 3, or 1 analyses, men were matched on identification numbers (ie, they served as
month[s]) exactly 6 months before the first venous thromboembolism their own controls).
diagnosis. Control period for the exploratory analysis is the equivalent-length c
Analyses adjusted for total number of hospitalizations, outpatient encounters,
period (3-6, 1-3, or 1 month[s]) exactly 6 months before the first venous and emergency department encounters in the case and control periods.
thromboembolism diagnosis.
b
Crude analyses were conditioned on matching factors. In the case-crossover

Table 3. Overall Association of Testosterone Therapy Prescription With Risk of Venous Thromboembolism
Among Men With Hypogonadism, Main and Exploratory Analyses, MarketScan Database, 2011-2017

Testosterone Therapy Prescription, No. (%) Odds Ratio (95% CI)

Testosterone Therapy Case
Period Case Period Control Perioda Crudeb Adjustedc
Main Analysis (n = 3110)
6 mo 1069 (34) 697 (22) 2.43 (2.10-2.80) 2.32 (1.97-2.74)
3 mo 802 (26) 494 (16) 2.36 (2.02-2.75) 2.28 (1.91-2.72)
1 mo 342 (11) 229 (7) 1.62 (1.35-1.96) 1.66 (1.34-2.04)
Exploratory Analysis (n = 3110)
3-6 mo 267 (9) 203 (7) 1.36 (1.12-1.65) 1.33 (1.06-1.66)
1-3 mo 460 (15) 265 (9) 2.11 (1.77-2.53) 1.96 (1.60-2.41)
1 mo 342 (11) 229 (7) 1.62 (1.35-1.96) 1.66 (1.34-2.04)
a
Control period for the main analysis was the equivalent-length period (6, 3, or 1 analyses, men were matched on identification numbers (ie, they serve as their
month[s]) exactly 6 months before the first venous thromboembolism own controls).
diagnosis. Control period for the exploratory analysis was the c
Analyses adjusted for total number of hospitalizations, outpatient encounters,
equivalent-length period (3-6, 1-3, or 1 month[s]) exactly 6 months before the and emergency department encounters in the case and control periods.
first venous thromboembolism diagnosis.
b
Crude analyses were conditioned on matching factors. In the case-crossover

Table 4. Covariate-Adjusted Associations of Testosterone Therapy Prescription With Risk of Venous Thromboembolism
Among Men With Differing Hypogonadism Status Stratified by Age and Route of Testosterone Exposure, MarketScan Database, 2011-2017

Odds Ratio (95% CI) by Age Inter- Odds Ratio (95% CI) by Route of Therapy
Testosterone action P Interaction
Therapy Case Period <65 Years ≥65 Years Value Transdermal Intramuscular P Value
Hypogonadism
6 mo 2.40 (1.99-2.88) 2.05 (1.44-2.93) .48 2.28 (1.86-2.80) 2.28 (1.72-3.03) .97
3 mo 2.28 (1.87-2.79) 2.26 (1.54-3.32) .97 2.21 (1.77-2.77) 2.30 (1.70-3.11) .83
1 mo 1.76 (1.38-2.23) 1.32 (0.83-2.09) .30 1.69 (1.29-2.22) 1.49 (1.05-2.12) .76
No Hypogonadism
6 mo 2.33 (1.60-3.40) 1.41 (0.77-2.56) .11 2.09 (1.46-2.99) 1.64 (0.82-3.30) .99
3 mo 2.99 (1.91-4.68) 1.68 (0.90-3.14) .14 2.52 (1.67-3.82) 1.96 (0.90-4.27) .82
1 mo 2.09 (1.18-3.69) 1.62 (0.74-3.51) .76 2.31 (1.35-3.97) 1.28 (0.50-3.22) .72

was stronger among men younger than 65 years compared with
men who were older; however, these differences were not sta-
tistically significant. Associations between testosterone
therapy and risk of VTE did not differ whether the route of tes-
tosterone therapy was transdermal or intramuscular. In addi-
tion, our study provides novel information about the time
frame of exposure most pertinent to risk, with risk being great-
est in the first 3 months after testosterone therapy initiation.
These findings complement prior work8,28,29 suggesting that
testosterone therapy use is associated with greater risk of stroke

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 Research Original Investigation Testosterone Therapy and Venous Thromboembolism Risk in Men With and Without Hypogonadism
and myocardial infarction and suggest that practitioners should
be cautious when prescribing testosterone therapy.
Prior observational studies about testosterone therapy and
VTE are scarce and have been inconclusive about whether tes-
tosterone therapy affects VTE risk. A prior case-control study
by Martinez et al18 also stratified by hypogonadism status and
compared 19 000 men with VTE with 900 000 controls. Only
21 men without hypogonadism were current testosterone
therapy users, and testosterone therapy use was associated
with a 1.69-fold (95% CI, 1.09-2.63) increased risk of VTE.
Among those with hypogonadism, 48 were receiving testos-
terone therapy, and current testosterone therapy use was as-
sociated with a relative risk of 1.08 (95% CI, 0.75-1.55). In ad-
dition, Baillargeon et al17 performed a case-control study of
30 000 men and 7500 VTE events identified from a large claims
database in the United States (OptumInsight). The investiga-
tors found no significant association in that analysis, in which
158 VTE events among testosterone therapy users occurred and
the focus was on testosterone use in the 15 to 60 days before
the VTE event. That study used a traditional matched case-
control design, and unmeasured time-invariant confound-
ers, such as smoking status and physical activity, could not be
directly addressed in the analyses. Our study corrects for this
unmeasured confounding with the case-crossover design and
appears to improve on the article by Baillargeon et al17 by hav-
ing a larger number of exposed cases (374 testosterone therapy
users without hypogonadism and 1330 testosterone therapy
users with hypogonadism) to analyze different case periods,
hypogonadism status, and age categories. Findings from
smaller observational studies and randomized clinical
trials15,30-33 have been inconsistent, with some reporting tes-
tosterone therapy to be a risk factor and others reporting no
association. Other studies6,17,31 recruited only hypogonadal
men or either controlled for or matched men by hypogonad-
ism status but did not investigate the association of testoste-
rone therapy on the large population of men without hypo-
gonadism who receive it.
Furthermore, our study provides novel information about
the time frame of exposure to testosterone therapy and risk
of VTE. Our exploratory analysis found evidence that risk es-
timates were higher in the 1- to 3-month and less than 1-month
case periods compared with the 3- to 6-month case periods.
This observation is analogous to patterns seen for oral contra-
ceptives and VTE risk, whereby women are at greatest risk
shortly after beginning oral contraceptive use, and provides
hypothesis-generating information for future research on tes-
tosterone therapy and VTE.34
Hypogonadism diagnosis, age, and route of testosterone
exposure were identified a priori as subgroups of particular in-
terest. Among men without hypogonadism, risk was greater
among men younger than 65 years compared with those who
were older, although the interaction was not statistically sig-
nificant. This finding is of potential public health importance
because of recent trends in increased testosterone therapy pre-
scriptions among men younger than 65 years.5 Men younger
than 65 years who begin testosterone therapy early to deter
common health symptoms potentially associated with aging
may be exposing themselves to greater risk of early-onset car-
E6 JAMA Internal Medicine Published online November 11, 2019 (Reprinted)
© 2019 American Medical Association. All rights reserved.
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diovascular disease outcomes, especially if there is no clini-
cal indication for starting therapy.
In the present analysis, VTE risk did not vary by route of
exposure. The article by Baillargeon et al,17 which reported no
overall association of testosterone therapy with VTE risk, also
did not find differences when transdermal and intramuscu-
lar testosterone therapy were evaluated separately. Likewise,
a meta-analysis of randomized clinical trials by Borst et al,33
with relatively small sample sizes and short follow-up times,
also reported no overall association of testosterone therapy
with cardiovascular risk and found no difference when trans-
dermal and intramuscular testosterone therapies were evalu-
ated. Venous thromboembolism was not specifically exam-
ined as an outcome. At present, there is no compelling evidence
that the association of the risk of VTE with testosterone therapy
varies according to route of exposure.
Strengths and Limitations
A strength of this study is the use of a large administrative
claims data. To our knowledge, we had the largest number of
cases included in a study evaluating testosterone therapy as
a potential VTE risk factor. One of the strengths of the case-
crossover design is its ability to account for time-invariant un-
measured confounding. With patients acting as their own con-
trols, relatively static or slowly varying factors (eg, obesity,
smoking status, and family history of VTE) are assumed to re-
main constant during the case and control periods.35 This de-
sign can be particularly useful in the context of administra-
tive data with information on important potential covariates
(eg, obesity or family history) not available in the data set. An
assumption of the case-crossover design is that exposures are
transient. Our exploratory analysis showed that the associa-
tion of testosterone therapy with VTE was transient because
the association was attenuated within the 3- to 6-month ex-
posure category compared with the 1-month and 1- to 3-month
categories.
Use of a large administrative claims database was also a
limitation of this study. Other common weaknesses, such as
misclassification and time-variant confounding found in claims
databases, were minimized as best as possible given the data
available. The VTE definition that we used had a good posi-
tive predictive value (91%) when validated in a different study
population.23 We are not aware of any validation studies of hy-
pogonadism diagnosis or testosterone therapy prescription
claims. Because there is no consensus regarding how to de-
fine hypogonadism in administrative data, we used 2 differ-
ent definitions: one similar to that used by Martinez et al18 and
Baillargeon et al17 and another similar to that used by Jasuja
et al.25 The estimates were similar regardless of which defini-
tion was used. Studies validating algorithms to define hypo-
gonadism in administrative data are needed. The testoste-
rone therapy codes used in this study were the same as those
used by another claims-based study17 and resulted in preva-
lence that matched current trend analysis numbers.5 Phar-
macy claims reflect whether patients fill their prescriptions;
however, whether the patient takes the prescription cannot be
assessed in administrative data. In addition, despite the large
data set, precision of some stratified analyses was not opti-
jamainternalmedicine.com
 Testosterone Therapy and Venous Thromboembolism Risk in Men With and Without Hypogonadism Original Investigation Research

mal because of the sparsity of men prescribed testosterone
therapy in subcategories.
Conclusions
Men without cancer who were prescribed testosterone therapy
in our study’s case period had an increased risk of incident VTE
compared with that in an equivalent control period 6 months
before the VTE. This risk of VTE was present for men with and
without hypogonadism who received a testosterone therapy
prescription. These data combined with prior data suggest that
future clinical trials of testosterone therapy, regardless of the
indication, should capture VTE events as part of safety end
points. Relative VTE risk may be exacerbated for men younger
than 65 years using testosterone therapy with and without
clinical indications. Men experiencing common symptoms that
result from natural aging have considered testosterone therapy
as a treatment; however, men without hypogonadism should
assess cardiovascular disease risk with their physicians
before prescription to minimize adverse cardiovascular
outcomes.

ARTICLE INFORMATION
Accepted for Publication: September 3, 2019.
Published Online: November 11, 2019.
doi:10.1001/jamainternmed.2019.5135
Author Affiliations: Division of Epidemiology and
Community Health, School of Public Health,
University of Minnesota, Minneapolis (Walker,
MacLehose, Lutsey); Department of Medicine, The
Robert Larner, M.D. College of Medicine, University
of Vermont, Burlington (Zakai); Department of
Pathology and Laboratory Medicine, The Robert
Larner, M.D. College of Medicine, University of
Vermont, Burlington (Zakai); Department of
Biostatistics, Epidemiology, and Environmental
Health Sciences, Jiann-Ping Hsu College of Public
Health, Georgia Southern University, Statesboro
(Cowan); Department of Pharmaceutical Care and
Health Systems, College of Pharmacy, University of
Minnesota, Minneapolis (Adam); Department of
Epidemiology, Rollins Emory University School of
Public Health, Atlanta, Georgia (Alonso).
Author Contributions: Mr Walker and Dr Lutsey
had full access to all the data in the study and take
responsibility for the integrity of the data and the
accuracy of the data analysis.
Concept and design: Walker, Zakai, MacLehose,
Cowan, Lutsey.
Acquisition, analysis, or interpretation of data:
Walker, Zakai, Cowan, Adam, Alonso, Lutsey.
Drafting of the manuscript: Walker, Cowan, Lutsey.
Critical revision of the manuscript for important
intellectual content: All authors.
Statistical analysis: Walker, MacLehose, Cowan.
Obtained funding: Lutsey.
Administrative, technical, or material support:
MacLehose, Cowan, Adam, Lutsey.
Supervision: Zakai, Lutsey.
Conflict of Interest Disclosures: Mr Walker and
Drs Adam and Lutsey reported receiving grants
from the National Heart, Lung, and Blood Institute,
National Institutes of Health during the conduct of
the study. Drs Zakai and Alonso reported receiving
grants from National Institutes of Health during the
conduct of the study. No other disclosures were
reported.
Funding/Support: This study was funded and
supported by grant R01-HL131579 (Mr Walker and
Drs Adam and Lutsey) from the National Heart,
Lung, and Blood Institute, National Institutes
of Health.
Role of the Funder/Sponsor: The funding source
had no role in the design and conduct of the study;
collection, management, analysis, and
interpretation of the data; preparation, review, or
approval of the manuscript; and decision to submit
the manuscript for publication.
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