© The Canadian Journal of Urology™; 21(Supplement 2); June 2014
Testosterone therapy is associated with reduced
body fat mass, improved muscle mass and strength,
and a possible positive effect on lipid levels and
glucose control.
11,43,58,64,65
Therefore, one does not
often note a change in body mass index, as fat mass is
replaced by leanmuscle mass. Functionally important
changes in strength have been reported particularly for
older, frail hypogonadal men
64
and those withmobility
limitations.
66
Mood, cognition, energy, and quality-of-
life have also been credited to TRT.
49,58,64
Its effect on
mood extends to improving depression.
49
Risks and contraindications
Testosterone therapy that restores the hormone to
physiologic levels is generally well tolerated. Even the
most common adverse effects associated with therapy
are usually mild and infrequent if testosterone is kept
in the normal range. However, the clinician should be
alert to increased hemoglobin and hematocrit, a small
decrease in high-density lipoprotein (HDL) cholesterol,
fluid retention, gynecomastia, acne, and exacerbation
of sleep apnea.
11,47,67,68
Most effects are more common
(though still infrequent) in older men. Infertility, on
the other hand, is common in younger men and usually
reversible. Some adverse effects are associated with
themode of TRT delivery. Erythrocytosis, for example,
occurs in as many as 44% of men receiving injected
TRT but only 3%-18% of those using testosterone gels
or patches.
68
Hepatotoxicity is associated only with
certain oral testosterone formulations, which are not
approved for use in the United States and Canada.
68
TRT and prostate cancer
Growth of prostate cancer is one of the more serious
potential adverse effects of TRT. Continuing research
on TRT and prostate cancer has been helping to
allay general concerns about a causal association,
especially if cancer is confined to the prostate gland.
69
Nevertheless, treatment guidelines list untreated
prostate cancer (and breast cancer) as a definite
contraindication to therapy; and high risk of prostate
cancer (unevaluated prostate nodule or induration,
or PSA > 4 ng/mL) as a relative contraindication.
Hematocrit > 50% and uncontrolled congestive heart
failure are additional relative contraindications.
11,13
Although TRT has been available and in use for
decades, uncertainties about its links to prostate
cancer have never been fully resolved because trials of
sufficient size and duration are unavailable. However,
analyses of existing clinical data suggest that TRT
has no specific effect on PSA levels in hypogonadal
men and does not increase their risk of prostate
cancer.
69,70
This finding may perhaps be explained by
the “saturation model,” which holds that androgen
receptors in prostate tissue are sensitive to testosterone
increases onlywhen levels are low and the testosterone
receptors are unfilled; once filled, the tissue is no longer
sensitive to testosterone levels.
71
Whether this model
applies in hypogonadal men receiving TRT is unclear,
but data from small studies suggest that it does, and
that evenmenwith untreated prostate cancer may thus
be safely treated with TRT.
72
TRT and cardiovascular risk
The first of the two recent studies reporting risks
with testosterone prescriptions, published in the
Journal of the American Medical Association by
Vigen et al, was a retrospective analysis of a dataset
of 8709 men in the VA health system who had
undergone coronary angiography.
73
Among men
with testosterone concentrations less than 300 ng/dL,
the authors reported an increased rate of heart attacks,
strokes, and deaths inmenwho received a testosterone
prescription compared with men who did not. No
significant differences in event rates were noted for
any year of follow up; however, the overall event
curves demonstrated a significant increase in events
for testosterone-treated men of 29%. Strangely, the
percentage of men who suffered an event was actually
lower by one half for the testosterone group compared
with the no-testosterone group (10.1% versus 21.2%)
compiled by the raw data.
73
The authors came to an
opposite conclusion resulting from complex statistical
modeling based on more than 50 variables. This
modeling failed to include substantially lower baseline
testosterone levels in the T group, despite evidence
that lower T values are associated with increased
cardiovascular (CV) risk andmortality. In addition, the
authors improperly excluded 1132 men who suffered
stroke or heart attack prior to receiving a testosterone
prescription. Without that exclusion, the rate of events
in the no-testosterone groupwould have been increased
by 71%, reversing the results. It is impossible to
conclude from this study that testosterone prescriptions
increase rates of cardiovascular events.
The second study published in PLoS One by Finkle
et al was a retrospective analysis of insurance claims
data in 55,593 men in which the only information
available were diagnosis codes, procedure codes, and
prescription data.
74
The primary reported result was an
increased rate of non-fatal myocardial infarction (MI)
within 90 days after filling a testosterone prescription
compared with the prior 12 months. The authors also
compared these rates with pre- and post-prescription
rates for PDE5i, reporting no increase in MI following
PDE5i prescription. Subgroups by age revealed
48
Miner ET AL.
