patient during follow-up were 17.9 g dl
and 52.3%, respectively,
and no men required phlebotomy for erythrocytosis treatment.
Improvement in hypogonadal symptoms was assessed through
direct patient questioning and subjective improvements in
energy, libido and erections were each reported by 85%, 85%
and 54% of men, respectively.
The use of TRT in the setting of CaP remains controversial, in large
part owing to the androgen responsiveness of CaP and the
concern that TRT will stimulate the growth of latent CaP cells.
However, mounting evidence supports the safety of TRT in the
setting of CaP, though data from randomized controlled trials are
currently not available to corroborate these Fndings. This study
assesses the effects of TRT in hypogonadal men having under-
gone radiation treatment for CaP, and our results suggest that the
use of TRT in men with a history of CaP does not increase the risk
of CaP recurrence or progression for up to 5.5 years after TRT
initiation. These results are consistent with the three prior
uncontrolled studies assessing the effects of TRT in a total of 43
men after radiation therapy,
as well as the three prior studies
of TRT in a total of 74 men after RP.
RP and radiation therapy, even in the absence of ADT, have
been associated with changes in serum T levels over time, though
the underlying mechanism is unknown. One study found that men
treated with radiation therapy were more likely to become
hypogonadal than men who underwent RP, with a 27.3% lower T
and 31.6% lower ±T in the radiation therapy group.
additional studies reported T levels that did not recover to
pretreatment levels in 40% of men after EBRT, with median
decreases in T of 17–19%.
The increased risk of hypogonadism
in the setting of radiation therapy is linked to radiation scatter
during treatment and resulting testicular damage.
Other studies
have reported no signiFcant changes in serum T levels after
radiation therapy,
and several studies have reported drops in T
levels after radiation therapy, with subsequent normalization to
pretreatment levels.
In the setting of CaP treated with RP, one
study reported increased T levels, though the mechanism behind
this rise is unclear,
and other studies have reported no changes
in serum T levels after prostatectomy or prostatic adenoma
Given the variable effects of CaP treatment on
serum T levels, particularly the decline seen in most studies of
men treated with radiation, evaluation for hypogonadism in this
cohort is clearly important.
All 13 men in our cohort received at least 2 months of TRT, with
a median follow-up of 2.5 years after TRT initiation and a
maximum follow-up of approximately 5.5 years. It is important to
note that several patients were treated with subcutaneous
T pellets at some point during therapy and hormone levels were
at times drawn several months after pellet insertion towards the
end of the efFcacy period.
Thus, peak serum T levels may have
been missed in several patients at several time points. Neverthe-
less, we observed a signiFcant increase in mean T levels during
follow-up. ±urthermore, we observed a signiFcant rise in SHBG
levels in our cohort, but only at 18–24 months of TRT. While
this may be consistent with an increase in serum T, it may also
be a statistical artifact considering the time period required
for a signiFcant increase. Notably, no signiFcant change in serum E
levels was observed, suggesting a low rate of T aromatization
within our cohort.
While on TRT, no men in our cohort were found to have
recurrence or progression of their cancer. In contrast, the rate of
biochemical and/or clinical recurrence in the setting of CaP
treated with radiation therapy without TRT is 13–53% and varies
according to the deFnition of recurrence used.
Although one
patient in our cohort had a suspected biochemical recurrence,
subsequent workup demonstrated no evidence of disease.
Notably, this same patient had a baseline T of 40 ng dl
ADT. This patient’s baseline PSA was 0.009 ng ml
and rose to a
high of 1.82 ng ml
during TRT, prompting evaluation for CaP
recurrence. However, the observed rise in this patient’s PSA in the
setting of an abnormally low T is consistent with the Prostate
Saturation Theory, which posits that prostatic androgen receptors
may saturate at a serum T level in the castrate range, and that
serum PSA is more likely to rise in the setting of lower serum
T levels.
Thus, the above patient’s prostatic androgen receptors
may not have been saturated at the time of TRT initiation in the
setting of castrate T levels, resulting in an initial rise in PSA.
However, once the patient was eugonadal and his prostate
androgen receptors were saturated, there was no further increase
in his PSA.
Though numerous deFnitions of biochemical recurrence exist
for men with CaP treated with radiation therapy, the three with
the highest sensitivities and speciFcities after EBRT are: (1) PSA
greater than absolute nadir plus 2 ng ml
; (2) PSA greater than
current nadir plus 3 ng ml
; and (3) two consecutive PSA
increases of
0.5 ng ml
Even though the absolute nadirs
for most men in our cohort were unavailable, the maximum PSA
after TRT initiation for men treated with EBRT was 1.75 ng ml
and no patients experienced two consecutive increases of
0.5 ng ml
, precluding biochemical recurrences according to
the above deFnitions and further supporting the safe use of TRT in
this cohort of men.
±our patients received ADT in addition to radiation therapy, the
combination of which has been shown to improve overall survival
compared with radiation therapy alone.
Given the intermediate-
to high-risk nature of cancer in these four men, and in the absence
of conFrmed biochemical recurrences, our data support the
efFcacious use of TRT without overt clinical consequences, even in
men with more serious CaP with continued close follow-up.
One of the most common side effects of TRT is erythrocytosis,
which may be caused by suppression of hepcidin by exogenous
Though rates of erythrocytosis vary depending on the
T formulation, transdermal formulations have an approximately
18% rate of associated erythrocytosis
and injectable formu-
lations up to 40%. Data are less readily available for rates of
erythrocytosis after treatment with subcutaneous T pellets,
although a recent prospective study of 30 subjects treated with
T pellets resulted in no signiFcant increases in Hct over 6
Our results overall corroborate the published Fndings,
as no patients developed erythrocytosis over the course of 5.5
years of follow-up. We acknowledge that the small size of our
cohort, as well as limited data, preclude a true assessment of the
effects of TRT on Hgb and Hct parameters.
Our study is limited by several factors. ±irst, as indicated above,
our study was small, comprising only 13 men, and without a
control group. Thus, while several individuals were found to have
rising PSA without recurrence of their CaP, extrapolation to a
population level based on such a small cohort is not possible.
Second, the retrospective nature of the study resulted in limited
data, speciFcally with respect to baseline Hgb and Hct values as
well as T levels for men treated with T pellets. Third, the median
follow-up of 2.5 years after TRT initiation may be of insufFcient
duration to detect biochemical recurrence, as recurrences can
occur much longer than 2 years after therapy.
±inally, assess-
ment of symptomatic improvement on TRT was limited, as
symptoms were not assessed using a validated questionnaire,
though the recent incorporation of a set of validated online
questionnaires in our clinic will remedy this in future work.
In summary, our results are consistent with published data on
CaP patients who receive TRT after RP, radiation therapy and while
on active surveillance. This study also adds to the body of
evidence challenging the androgen-dependent model of CaP
growth while supporting the Prostate Saturation Theory, and
ultimately supporting the use of TRT to treat hypogonadism
Testosterone replacement after radiation treatment for prostate cancer
AW Pastuszak
et al
2013 Macmillan Publishers Limited
International Journal of Impotence Research (2013), 24 – 28