© The Canadian Journal of Urology™; 21(Supplement 2); June 2014
increased risk ofMI withmen over 65 years oldwithout
a prior history of heart disease, and for men less than
65 years old with a prior history of heart disease. The
authors concluded that the risk of MI is substantially
increased in older men and in younger men with pre-
existing known heart disease.
74
This study has received even greater media
attention, and appears to have led to the Food and
Drug Administration (FDA) decision to review CV
risks with testosterone. Neither the study by Vigen
et al
73
nor the more recent publication by Finkle et al
74
provide any credible evidence that testosterone use
is associated with increased CV risk. Both studies
were retrospective, highly statistical, and reported
only a minor effect size. These study characteristics
make it unlikely that these results are reproducible or
accurate.
75
Even if the results were exactly as described,
both studies could more plausibly be interpreted as
showing the CV benefits of T therapy and the risks
of untreated low T, as demonstrated repeatedly by a
wealth of studies over the past 30 years.
76
Although the authors of both studies cite a study
by Basaria et al as support for increased CV risk with
testosterone, that placebo-controlled study was not
designed to assess CV risk; it was to address mobility
in older men.
77
As a placebo controlled study of 1%
testosterone, it did utilize supraphysiologic (mean
100 mg) dosages in several elderly men of mean age
74 years. The study was terminated early due to the
fact that 23 of the 106 men in the testosterone group
had experienced adverse CV-related events including
myocardial infarction, arrhythmias, and hypertension
comparedwith 5 men of 103 men in the placebo group.
At the time the study was stopped the testosterone
group had significantly greater improvements in leg-
press and chest-press strength, and in stair climbing.
Though the study’s report of increased adverse
events in the T group compared with placebo was
based on a wide variety of events of questionable
significance, such as pedal edema, palpitations, and
premature ventricular contractions,
78
it did raise a
disturbing trend that needs to be answeredwith future
randomized controlled trials.
An unbiased examination of the literature reveals a
much different result. Awealth of evidence indicates
that low levels of testosterone are associated with CV
risks and known risk factors for CV disease, such as
obesity, diabetes, and the metabolic syndrome.
79
Nine
of eleven longitudinal studies have demonstrated
increased mortality rates in men with lower levels
of testosterone and improved survival in those
with higher testosterone.
51
The other two showed
no effect. In placebo-controlled trials men who
received testosterone demonstrated increased angina-
free exercise capacity,
80
and improved functional
capability in men with congestive heart failure.
81
Two retrospective studies demonstrated reduced
mortality, by half, in men with T < 300 ng/dL who
received testosterone prescriptions compared with
men who did not.
82,83
To date, there is not a single
study that provides any definitive evidence that T
therapy increases CV risk, and a wealth of information
suggesting testosterone may be beneficial for CV
health. We therefore await a randomized placebo
control effort of > 900 men placed on testosterone and
placebo examining CV safety for 1 year to conclusively
examine CV trends.
TRT formulations
Testosterone was isolated, purified, and introduced
to clinical medicine in the mid-20
th
century. Today’s
options for TRT include oral or buccal agents,
injections, transdermal systems (patches, gels, and
solutions), and subcutaneous pellets, Table 5. Some
formulations incorporate adaptations designed to
improve the bioavailability and pharmacokinetics of
the hormone, with the goal of slowing its metabolism
by the liver after oral or parenteral administration.
38
Others were developed for convenience and dosing
flexibility. Formulations are differentiated not only by
route of delivery but by side effects, ability to normalize
testosterone, expense, convenience, and tolerability.
TRT may be a lifetime therapy for hypogonadal men,
so initial and subsequent decisions about the best
formulation for therapy should be made carefully and
collaboratively between clinician and patient.
84
Factors in choosing TRT
Transdermal patches, gels, and solutions
The skin is a favorable route for delivery of stable
concentrations of testosterone. Transdermal patches
were the first technology to apply this principle using
skin in both genital and nongenital areas.
85
While
effective at mimicking physiologic testosterone levels,
skinpatches cause adverse skin reactions at the patch site
in about 30%of patients.
86
Testosterone gel formulations
were introduced in 2000 and have largely supplanted
patches as the most widely prescribed form of TRT.
Although testosterone gel formulations are convenient
(applied by hand to the shoulders, upper arms, or
abdomen) and associated with a lower risk of skin
irritation (approximately 6%), they leave unabsorbed
testosterone on the skin surface, which can then transfer
to the skin of intimate partners or children.
87
A goal
49
Testosterone deficiency: myth, facts, and controversy
