Download Prostate cancer and testosterone replacement therapy: what is the

TESTOSTERONE REPLACEMENT
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Prostate cancer and testosterone
replacement therapy: what is the risk?
CULLEY CARSON AND ROGER KIRBY
The use of testosterone
replacement therapy is
increasing in men with
hypogonadal symptoms.
In this article the authors
discuss the evidence that
supports the careful use of
testosterone replacement
in men with successfully
treated prostate cancer.
Prostate cancer growth
A
Near
castration range
B
Serum testosterone
Figure 1. Conventional wisdom was that prostate cancer growth increased in a linear way in
response to serum testosterone (line A). In the saturation model, prostate growth is sensitive
to testosterone at near-castration levels, but reaches a plateau as testosterone concentrations
rise (line B)
T
he last decade has seen a rise in
testosterone replacement therapy (TRT)
internationally.1 Controversy continues,
however, on the impact of TRT and its effect
on the prostate. While the effects of TRT on
benign prostatic hyperplasia (BPH) and lower
urinary tract symptoms (LUTS) are as yet
unsettled, the role of TRT in prostate cancer
appears to be clearer.
Culley Carson, Rhodes Distinguished
Professor, Chief of Urology, University of
North Carolina, USA; Roger Kirby, Medical
Director, The Prostate Centre, London
www.trendsinmenshealth.com
The effects of testosterone and castration
on the prostate and prostate cancer have a
long history, with the sentinel publication
of Charles Huggins and Clarence V. Hodges
in 1941 as the first clear demonstration of
the effects of withdrawing testosterone by
castration or oestrogen on the progression
of prostate cancer.2 In that publication, the
authors also showed that, in a single patient,
withdrawal of testosterone by castration
and subsequent replacement of testosterone
had the deleterious effect of causing the
prostate cancer to first involute then regrow.
This publication and subsequent reviews
and presentations led to the conventional
wisdom that testosterone could cause
prostate cancer, and that TRT could either
induce de novo prostate cancer or unearth
an occult prostate malignancy.3,4 Indeed,
an international survey published in 2007
showed that as many as 70% of healthcare
providers were concerned about the
association of TRT and prostate cancer.1
WISDOM CHALLENGED
This conventional wisdom is gradually being
challenged by newer studies. The Endogenous
Hormones and Prostate Cancer Collaborative
Group reviewed 18 prospective studies
and reported that there was no signal that
endogenous testosterone levels correlated
to prostate cancer, and that endogenous
levels were not correlated to prostate cancer
aggressiveness if identified.5
TRENDS IN UROLOGY & MEN’S HEALTH
JANUARY/FEBRUARY 2017
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Similarly, many studies have shown that TRT
does little to change PSA when hypogonadal
men are treated to normalise testosterone
levels. Morgentaler has proposed the
‘saturation model’ theory for testosterone
and the prostate, stating that while prostate
cancer is exquisitely testosterone-sensitive
at very low testosterone levels, once the
androgen receptors are fully occupied,
further testosterone levels do little to change
prostate or prostate cancer dynamics.6
This concept is supported by PSA studies
in men taking TRT showing only modest
PSA rises, usually in those men with the
lowest initial testosterone.
It has been suggested that high-grade
prostate cancer is associated with lower
levels of endogenous testosterone. In a recent
study of 681 men undergoing a 12-core
prostate biopsy, low testosterone level was
found to be an independent risk factor for
high-grade prostate cancer.7 Similarly,
Garcia-Cruz et al found that low pretreatment testosterone levels were
significantly related to poor prognostic
factors.8 While the aetiology of low
testosterone in high-grade prostate cancer
patients remains uncertain, the body of
evidence for this relationship continues
to grow, leading some to suggest that
monitoring testosterone levels prior to biopsy
may provide prognostic information.9
TRT AND PROSTATE CANCER HISTORY
Currently, there is rising interest in the
treatment of men with a history of prostate
cancer, both treated and under active
surveillance, with TRT. The first studies
documented the safety of TRT in men who
had undergone radical prostatectomy with
favourable pathology and undetectable
PSA. More than 250 men treated with TRT
that were reported in the literature show no
evidence for recurrence or progression of
prostate cancer.10
More recent studies have reviewed men
treated with external beam radiation
therapy or brachytherapy and TRT.11
These studies in highly selected patients
TRENDS IN UROLOGY & MEN’S HEALTH
have also shown safety and no signal to
recurrence, progression or significant PSA
rise. In another multicentre study of a small
number of highly selected patients with
active surveillance, hypogonadism and TRT,
the safety of TRT was again suggested.12
These studies are of small numbers and
limited follow-up, and need confirmation by
larger numbers and longer observation. The
message, however, is clear: TRT appears to
help men with hypogonadism, and is safe if
vigilant follow-up is maintained.
The SEER study by Baillargeon et al and a
very recent meta-analysis by Boyle et al add
further data to the safety discussion of TRT
in men with or at risk for prostate cancer.13,14
The SEER study has shown there is no clear
signal in this large population that TRT had
any negative effect on the frequency of
high-grade prostate cancer. While more
data are needed, healthcare providers can
begin to consider treating their hypogonadal
prostate cancer patients with TRT if they
are symptomatic, have documented
low testosterone levels and are properly
counselled and informed.13
REFERENCES
1. Gooren LJ, Behre HM, Saad F, et al. Diagnosing
and treating testosterone deficiency in different
parts of the world. Results from global market
research. Aging Male 2007;10:173–81.
2. Huggins C, Hodges CV. Studies on prostatic
cancer. The effect of castration, estrogen and
androgen injection on serum phosphatases
in metastatic carcinoma. Cancer Res
1941;1:293–7.
3. Fowler JR Jr, Whitmore WF Jr. The response of
metastatic adenocarcinoma of the prostate to
exogenous testosterone. J Urol 1981;126:372–5.
4. Prout GR Jr, Brewer WR. Response of men with
advanced prostatic carcinoma to exogenous
administration of testosterone. Cancer
1967;20:1871–8.
5. Endogenous Hormones and Prostate Cancer
Collaborative Group, Roddam AW, Allen NE,
Appleby P, Key TJ. Endogenous sex hormones
and prostate cancer: a collaborative analysis
of 18 prospective studies. J Natl Cancer Inst
2008;100:170–83.
JANUARY/FEBRUARY 2017
KEY POINTS
• Testosterone is important in the
development of the prostate
• No data support testosterone replacement
as a cause of prostate cancer
• Men with successfully treated prostate
cancer can be safely treated with
testosterone replacement
• Men on testosterone replacement should
have their prostate monitored with PSA
and DRE
6. Morgentaler A, Traish AM. Shifting the
paradigm of testosterone and prostate
cancer: the saturation model and the limits
of androgen-dependent growth. Eur Urol
2009;55:310–20.
7. Park J, Cho SY, Jeong SH, et al. Low testosterone
level is an independent risk factor for highgrade prostate cancer detection at biopsy. BJU
Int 2015;118:203–5.
8. Garcia-Cruz E, Piqueras M, Huguet J, et al.
Low testosterone levels are related to poor
prognosis factors in men with prostate cancer
prior to treatment. BJU Int 2012;110:E541–6.
9. Botto H, Neuzillet Y, Lebret T. High incidence
of predominant Gleason pattern 4 localized
prostate cancer is associated with low serum
testosterone. J Urol 2011;186:1400–5.
10. Khera M, Grober ED, Najari B, et al. Testosterone
replacement therapy following radical
prostatectomy. J Sex Med 2009;6:1165–70.
11. Pastuszak AW, Pearlman AM, Godoy G, et al.
Testosterone replacement therapy in the setting
of prostate cancer treated with radiation. Int J
Impot Res 2013;25:24–8.
12. Morgentaler A, Lipshultz LI, Bennett R, et al.
Testosterone therapy in men with untreated
prostate cancer. J Urol 2011;185:1256–60.
13. Baillargeon J, Kuo YF, Fang X, Shahinian VB.
Long-term exposure to testosterone therapy
and the risk of high-grade prostate cancer.
J Urol 2015:194:1612–6.
14. Boyle P, Koechlin A, Bota M, et al. Endogenous
and exogenous testosterone and the risk
of prostate cancer and increased prostatespecific antigen (PSA) levels: a meta-analysis.
BJU Int 2016;118:731–41.
www.trendsinmenshealth.com