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SEPTEMBER 2014

VOLUME 11

www.nature.com/nrurol

TST and prostate cancer risk

In men without prostate cancer

If elevated testosterone levels are associ-

ated with an increased risk of prostate

cancer, analysis of data from clinical trials

performed to evaluate the efficacy of TST

should provide useful insight into the

relationship between TST and the incidence

of prostate cancer among men at histori-

cally average risk of this disease. With this

in mind, a meta-analysis of 19 placebo-

controlled TST studies in men with low

or low–normal serum testosterone levels

found no statistically significant difference

in prostate cancer incidence, PSA levels, or

urinary symptom scores in men treated with

TST, compared with placebo.

Pooled mean

testosterone levels for the men included in

these studies before therapy were 344 ng/dl

and 320 ng/dl for placebo and testosterone

treated groups, respectively;

after treat-

ment, mean testosterone levels were

339 ng/dl and 536 ng/dl, respectively.

both groups, the initial serum PSA level

was 1.3 ng/dl, and men in the TST cohorts

of the studies analysed had an increase in

PSA of only 0.3 ng/dl, on average, after

treatment.

This meta-analysis demon-

strated a pooled event rate for the diagno-

sis of prostate cancer of 8.3 and 9.2 events

per 1,000 patient-years for patients treated

with placebo and testosterone, respectively

(OR 1.09, 95% CI 0.48–2.49).

In addition,

events constituting either an increase in

serum PSA of ≥1.5 ng/ml or achievement

of a PSA level >4 ng/ml was identified at

a frequency of 41.6 and 57.1 events per

1,000 patient-years for the placebo-treated

and testosterone-treated patients, respec-

tively (OR 1.19, 95% CI 0.67–2.09). In

addition, a review of seven published trials

evaluating TST found the rate of prostate

cancer in testosterone-treated patients to be

similar to the rate observed in population-

screening trials.

Together, these findings

suggest that TST therapy has a limited, if

any, clinically relevant effect on prostate-

cancer risk in individuals with low–normal

baseline testosterone levels.

In men at risk of prostate cancer

Patients with HGPIN detected in a single

sextant prostate biopsy sample have a

25–30% chance of a prostate cancer diag-

nosis upon subsequent biopsies. García-

Cruz

et al.

prospectively analysed 82

men diagnosed with HGPIN, and found

a signifi cant positive correlation of both

low bioavailable—unbound or albumin-

bound (that is, testosterone not bound to

high-affinity testosterone-binding proteins

such as sex hormone-binding globulin)

—testosterone and low free serum testos-

terone levels in serum with a subsequent

prostate-cancer diagnosis (

0.04 for both

free and bioavailable testosterone). This

finding provides further evidence indicat-

ing that low serum testosterone, rather than

high testosterone levels, might be a risk

factor for prostate cancer.

Additionally, Rhoden

et al.

examined

75 hypogonadal men treated with TST for

12 months; all the men included underwent

a prostate biopsy before beginning TST, and

20 men had HGPIN based on this initial

biopsy.

After a 1-year follow-up period,

the investigators found no statistically

signifi cant change in PSA levels in men

with normal biopsy results versus men with

evidence of HGPIN in the initial biopsy

tissues.

One patient with HGPIN was

later found to have prostate cancer based

on an abnormal DRE.

The authors con-

cluded that hypogonadal men with HGPIN

on biopsy did not have an increased risk

of prostate cancer after TST compared to

men with a normal prostate biopsy.

These

data suggest that TST does not increase the

incidence of prostate cancer, even among

individuals with a high-risk of developing

the disease.

In men treated for prostate cancer

Much controversy regarding TST is focused

on concerns over the safety of testosterone

administration in men who have previ-

ously been treated for prostate cancer.

Considering the demographical similari-

ties between patients with prostate cancer

and hypogonadal men, that some men

have both conditions is not surprising.

Traditionally, patients with prostate cancer

have been considered ineligible for TST,

but studies published over the past decade

suggest that TST for hypogonadism can be

safe when given to carefully selected and

monitored patients.

Men can receive definitive treatment for

prostate cancer with radical prostatectomy,

or with brachytherapy or external beam

radiation therapy (EBRT). With regard to

patients treated with radical prostatectomy,

Pastuszak

et al.

retrospectively reviewed

103 hypogonadal patients who received

transdermal TST after surgical treatment

of prostate cancer between 2003 and 2011.

The authors also included 49 eugonadal

patients also treated with radical prosta-

tectomy, but not with TST, as a reference

group, and categorized all patients as being

at high risk or low risk of postoperative

prostate-cancer recurrence.

High risk

of recurrence was defined as postsurgical

pathology findings of one or more of the

following: Gleason score ≥8, positive sur-

gical margins, or positive lymph nodes.

Overall, the TST and eugonadal control

populations had similar proportions of

high-risk patients (25% versus 30%).

The

hypogonadal patients had an initial median

serum testosterone level of 261 ng/dl, which

increased to 460 ng/dl during the course of

TST.

After a median follow-up duration of

27.5 months, a small increase in serum PSA

of 0.003 ng/dl (

<0.001) was detected in the

hypogonadal patients as a whole, with no

increase in PSA levels in the eugonadal ref-

erence group.

In the hypogonadal cohort,

four cases of biochemical recurrence were

observed, compared with eight cases in the

reference group of eugonadal men.

TST in men who have previously received

definitive brachytherapy for prostate cancer

has been evaluated by Sarosdy.

This

author studied 31 men with serum testos-

terone levels of <300 ng/dl and symptoms

of hypogonadism, in whom TST was ini-

tiated at least 6 months after brachyther-

apy, with most patients receiving weekly

200 mg injections of testosterone cypio-

nate.

Patients were followed for a median

of 5 years (range 1.5–9.0 years), with serum

testosterone levels increasing from a median

of 188 ng/dl before TST to 498 ng/dl at

follow-up assessment.

One patient dem-

onstrated a single rise in serum PSA, which

was followed by a decline in PSA.

signs of cancer recurrence were observed

in this patient group and, therefore, no

patients stopped TST because of possible

or confirmed cancer recurrence.

In addition, Pastuszak

et al.

retrospec-

tively studied data from three men who

were treated with brachytherapy for pros-

tate cancer, as well as 10 men who were

treated with EBRT. All the men had symp-

toms of hypogonadism and serum testos-

terone levels of <300 ng/dl, and 12 were

sub sequently treated with transdermal

testosterone whereas the remaining patient

received testosterone pellets.

At a median

‘‘

These data suggest that TST

does not increase the incidence

of prostate cancer, even among

individuals with a high-risk of

developing the disease

’’

PERSPECTIVES