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.

DISCUSSION

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,

12–14

as well as the three prior studies

of TRT in a total of 74 men after RP.

9–11

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.

Two

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%.

21,22

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,

24,25

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

resection.

28,29

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.

31–34

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

after

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

months.

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