Review Benign Prostatic Enlargement

The Effect of Androgen-replacement Therapy on Prostate Growth:

A Systematic Review and Meta-analysis
Yuanshan Cui, Yong Zhang *
Department of Urology, Beijing Tian-Tan Hospital, Capital Medical University, Beijing, China
1. Introduction
Androgen deficiency in the aging male has become a topic of
increasing interest and debate worldwide. Cross-sectional
and longitudinal data indicate that testosterone levels
are reduced progressively with age and that a significant
percentage of men aged >60 yr have serum testosterone
levels that are below the lower limits of young adult men
aged 2030 yr [13]. Late-onset hypogonadism (LOH) is a
clinical andbiochemical syndromeassociatedwithadvancing
ageandis characterizedbya deficiencyinserumtestosterone
levels, among other signs and symptoms [4,5]. LOH may
result in significant detriment to quality of life and may
adversely affect the function of multiple organ systems.
Androgen-replacement therapy (ART) is a widely ac-
cepted treatment to prevent or ameliorate many of the
E UR OP E AN UR OL OGY 6 4 ( 2 0 1 3 ) 8 1 1 8 2 2
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Article info
Article history:
Accepted March 24, 2013
Published online ahead of
print on April 3, 2013
Keywords:
Androgens
Prostate
Meta-analysis
Randomized controlled trial
Abstract
Context: Androgen-replacement therapy (ART) is a widely accepted form of treatment
worldwide for aging men with late-onset hypogonadism syndrome. Urologists have
been concerned about the possibility of ART causing prostate growth.
Objective: To assess the relationship between ART and prostate growth.
Evidence acquisition: A literature review was performed to identify all published
randomized controlled trials (RCTs) of androgen treatment for hypogonadism. The
search included the Medline, Embase, and Cochrane ControlledTrials Register databases.
The reference lists of the retrieved studies were also investigated. A systematic review
and meta-analysis were conducted.
Evidence synthesis: Results of 16 RCTs involving a total of 1030 patients were analyzed.
Seven RCTs were short-term (<12 mo) and nine were long-term (1236 mo)
comparisons of ART with a placebo; ART was administered transdermally, orally, or
by injection. Respective p values for injection, transdermal administration, and oral
administration of short-term ART were as follows: PSA level: 0.07, 0.01, and 0.95;
prostate volume: 0.70, 0.79, and 0.32; IPSS: 0.78, 0.98, and no oral; Q
max
: 0.92, no
transdermal, and 0.10. Respective p values for injection, transdermal administration,
and oral administration of long-term ART were as follows: PSA level: 0.42, 0.51, and
0.57; prostate volume: 0.35, 0.59, and 0.47; IPSS: 0.34, 0.32, and 0.97; Q
max
: 0.11, 0.63,
and no oral. Neither short-term nor long-term ART showed signicant changes in the
four determinants of prostate growth investigated compared with placebo.
Conclusions: This meta-analysis shows that regardless of the administration method,
neither short-term nor long-term ART increases the risk of prostate growth. Further
high-quality, prospective studies are required to conrm this observation.
#2013 European Association of Urology. Published by Elsevier B.V. All rights reserved.
* Corresponding author. Department of Urology, Beijing Tian-Tan Hospital afliated Capital Medical
University, No. 6 Tiantan Xi Li, Dong cheng District, Beijing 100050, China. Tel. +86 10 67098393/
67098394; Fax: +86 10 67096611.
E-mail address: doctorzhy@126.com (Y. Zhang).
0302-2838/$ see back matter # 2013 European Association of Urology. Published by Elsevier B.V. All rights reserved.
http://dx.doi.org/10.1016/j.eururo.2013.03.042
symptoms and conditions associated with LOH in aging
men. Studies over the past decade have reported evidence of
benefit of androgen treatment for multiple target organs
of hypogonadal men, including short-termbeneficial effects
of testosterone in older men that are similar to those seen in
younger men [6]. ART is most commonly administered by
injection, by transdermal application, or orally.
Sometimes a gradual increase in prostate volume
concomitant with the progressive decline in testosterone
level that occurs in middle age reflects the evolution of
benign prostatic hyperplasia (BPH) [7]. It is well known that
androgen plays an important role in the development of
BPH; therefore, it has been suggested that ART may
potentially promote prostate growth [811]. Many urolo-
gists are concerned that ART may accelerate prostate
growth not only in cancer but also in benign disease.
2. Evidence acquisition
2.1. Search strategy
The Medline (1966 to October 2012), Embase (1974 to
October 2012), and Cochrane Controlled Trials Register
databases were searched to identify randomized controlled
trials (RCTs) that referred to the impact of ART on the
prostate. We also searched the reference lists of the
retrieved studies. The following search terms were used:
androgen, prostate, and randomized controlled trials.
2.2. Inclusion criteria and trial selection
RCTs that met the following criteria were included: (1) The
study design included ART; (2) the study provided accurate
data that could be analyzed, including the total number of
subjects and the values of each determinant of prostate
growth, such as prostate-specific antigen (PSA) levels,
prostate volume, International Prostate Symptom Score
(IPSS), and maximum flow rate (Q
max
); and (3) the full text
of the study could be accessed. When the same study was
published in various journals or in different years, the most
recent publication was used for the meta-analysis. If the
same group of researchers studied a group of subjects with
multiple experiments, then each study was included. A flow
diagram of the study selection process is presented in
Figure 1.
2.3. Quality assessment
The quality of the retrieved RCTs was assessed using the
Jadad scale [12]. All the identified RCTs were included in the
meta-analysis, regardless of the quality score. The method-
ological quality of each study was assessed according to
how patients were allocated to the arms of the study, the
concealment of allocation procedures, blinding, and data
loss due to attrition. The studies were then classified
qualitatively according to the guidelines published in the
Cochrane Handbook for Systematic Reviews of Interven-
tions v.5.1.0 [13]. Based on the quality assessment criteria,
each study was rated and assigned to one of the three
following quality categories:
A: If all quality criteria were adequately met, the study was
deemed to have a low risk of bias.
B: If one quality criterion or more were only partially met
or were unclear, the study was deemed to have a
moderate risk of bias.
C: If one criterion or more were not met or not included, the
study was deemed to have a high risk of bias.
Differences were resolved by discussion among the
authors.
2.4. Data extraction
The following information was collected for each study:
(1) the name of the first author and the publication
year; (2) the study design and sample size; (3) the therapy
that the patients received; (4) the country in which
the study was conducted; (5) data on the four determi-
nants of prostate growth (ie, PSA levels, prostate volume,
IPSS, Q
max
); and (6) the ART administration method and
dosage.
2.5. Statistical analysis and meta-analysis
The meta-analysis of comparable data was carried out using
RevMan v.5.1.0 (Cochrane Collaboration, Oxford, UK) [13].
Changes in all four determinants of prostate growth were
determined as differences between baseline (study entry)
and study completion. We estimated the relative risk for
dichotomous outcomes and the standardized mean differ-
ence (SMD) for continuous outcomes pooled across studies
by using the DerSimonian and Laird random-effects model
[14]. We used a 95% confidence interval (CI). If the result
of analysis showed p > 0.05, we considered the studies

2 articles lacked useful data.

18 relevant articles were included.
16 RCTs were included in the analysis: 7 RCTs compared
androgen with a placebo over the short term (12 mo)
and 9 RCTs compared androgen with a placebo over the
long term (12-36 mo).
On the basis of titles and abstracts,
128 articles were excluded.
146 articles were identified including:
Medline: 96 articles
Embase: 50 articles
Cochrane Controlled Trials Register: 0
Fig. 1 A flow diagram of the study selection process. RCT = randomized
controlled trial.
E UR OP E AN UR OL OGY 6 4 ( 2 0 1 3 ) 8 1 1 8 2 2 812
homogeneous and so chose a fixed-effect model for meta-
analysis. Otherwise, a random-effect model was used. We
quantified inconsistency using the I
2
statistic, which
describes the proportion of heterogeneity across studies
that is not due to chance, thus describing the extent of true
inconsistency in results across trials [15]. I
2
<25% reflects a
small level of inconsistency and I
2
>50% reflects significant
inconsistency.
2.6. Subgroup and sensitivity analysis
To explore causes of inconsistency and subgroup treatment
interactions, subgroup analyses were specified a priori
according to the following factors:
Participants: aged <65 or 65 yr; total testosterone
level at baseline (testosterone level was considered low
if <350 ng/dl or 12 nmol/l); if total testosterone was not
available, then the lower limit of normal for bioavailable
or free testosterone levels was used; if neither total nor
free testosterone levels were available, then studies were
classified according to PSA levels
Interventions: testosterone formulation, route of admin-
istration
Outcome characteristic: duration of follow-up (<12 mo
vs 12 mo)
Study quality measure: proportion of patients lost to
follow-up (10% vs >10%), concealment of allocation,
and blinding of patients.
3. Evidence synthesis
3.1. Characteristics of the individual studies
The database search found 146 articles that could have been
included in our meta-analysis. Based on the inclusion and
exclusion criteria, 128 articles were excluded after reading
the titles and abstracts of the articles. Two articles lacked
useful data. In all, 16 articles [1631], reporting data from a
total of 16 RCTs, were included in the analysis: 7 RCTs
compared androgen with a placebo over the short term
(<12 mo), and 9 RCTs compared androgen with a placebo
over the long term (1236 mo). Three different administra-
tion methods were used: oral, transdermal, and injection
(Fig. 1). The baseline characteristics of the studies included
in our meta-analysis are listed in Table 1.
Only four of the included studies had as their end points
the same determinants of prostate growth measured in the
present analysis (ie, prostate volume, IPSS, PSA levels, and
Q
max
). All 16 RCTs included in our analysis involved rigorous,
periodic monitoring of patients, and treatment was with-
drawn when there were indications suspicious for prostate
cancer or other serious complications. Few patients suffered
serious complications, and all patients who withdrew from
treatment had returned to normal at long-term assessment.
Five of the 16 RCTs [18,21,23,25,26] reported that the
few patients with increased PSA levels on follow-up had
undergone prostate biopsy (Table 3), and pathologic
examination of biopsy specimens revealed benign histology.
All 16 RCTs provided baseline PSA levels, prostate volume,
IPSS, and Q
max
, and only one patient from the studies [29]
suffered from BPH symptoms (Table 3). In addition, for all
16 RCTs, no patient had prostate enlargement at baseline, all
patients had normal PSA levels at baseline (Table 3), and no
patient underwent prostate biopsy at study entry.
3.2. Quality of the individual studies
All 16 RCTs were double blinded, and all described the
randomization processes used. All except Kenny et al. [22]
included a power calculation to determine the optimal
sample size, and seven used intention-to-treat analysis
(Table 2). The level of quality of each identified study was A
(Table 2). The funnel plot provided a qualitative estimation
of publication bias of the studies, and no evidence of bias
was found (Fig. 4).
3.3. Short-term androgen replacement therapy versus placebo
3.3.1. Prostate-specific antigen levels
Six RCTs, representing 345 participants (170 in the
androgen group and 175 in the control group), included
PSA data [16,22,23,26,30,31] (Fig. 2). Three studies used
injection for administration [16,22,23]; two used transder-
mal application [26,30]; and in one, treatment was given
orally [31]. No heterogeneity was found among the trials
(Fig. 2). For the three RCTs using injected treatments, the
fixed-effects estimate of the SMDwas 0.50 (95% CI, 0.04 to
1.05; p = 0.07) (Fig. 2). For the RCTs using transdermal
application, the SMDwas 0.30 (95% CI, 0.070.54; p = 0.002)
(Fig. 2). For the study in which treatment was given orally,
the SMD was 0.02 (95% CI, 0.64 to 0.60; p = 0.95) (Fig. 2).
This result suggests that ART was more likely to result in
increased PSA levels than treatment with a placebo when
administered transdermally.
3.3.2. Prostate volume changes
Four RCTs [16,23,30,31], representing 103 participants
(50 in the androgen group and 53 in the control group),
included data on prostate volume changes (Fig. 2). Two
trials used injection for administration [16,23], one used
transdermal application [30], and one used oral delivery
[31]. No heterogeneity was found between the RCTs in
which treatment was given by injection (Fig. 2); the SMD
was 0.95 (95% CI, 3.82 to 5.72; p = 0.70) (Fig. 2). For the
study that used transdermal treatment application [30], the
SMD was 0.40 (95% CI, 2.61 to 3.41; p = 0.79) (Fig. 2). For
the study in which treatment was given orally [31], the
SMDwas 3.00 (95% CI, 2.96 to 8.96; p = 0.32) (Fig. 2). These
results suggests that regardless of administration method,
comparing androgen with a placebo revealed no apparent
differences in prostate volume changes.
3.3.3. International Prostate Symptom Score changes
Five RCTs [2224,26,30], representing 346 participants
(173 in the androgen group and 173 in the control group),
included the data for changes in IPSS between groups
(Fig. 2). Two trials used injection for administration of ART
E UR OP E AN UR OL OGY 6 4 ( 2 0 1 3 ) 8 1 1 8 2 2 813
Table 1 Study and patient characteristics
Study Therapy in
experimental
group
Therapy
in control
group
Country Sample size T cut-off
level for
study entry
Other inclusion
criteria
Exclusion of
PSA levels,
ng/ml
Short-term
or long-term
ART
Administration
method
Dosage
Experimental Control
Tenover, 1992 [16] T Placebo USA 6 7 TT
12.1 nmol/l
No history disease,
BMI 2229 kg/m
2
>4 Short-term I 100 mg/2 wk
Kenny et al., 2004 [22] T Placebo USA 6 5 BT
128 ng/dl
Folstein Mini-Mental State
Exam scores 1428
>4 Short-term I 200 mg/3 wk
Marks et al., 2006 [23] T Placebo USA 21 19 TT
300 ng/dl
Men with late-onset
hypogonadism symptoms
>10 Short-term I 150 mg/2 wk
Chiang et al., 2007 [24] T Placebo Taiwan 20 17 TT
300 ng/dl
T deciency, never took ART >4 Short-term Tr 50 mg/d
Srinivas-Shankar
et al., 2010 [26]
T Placebo New Zealand 114 117 TT
12 nmol/l
Men with late-onset
hypogonadism symptoms
>4 Short-term Tr 50 mg/d
Page et al., 2011 [30] DHT Placebo USA 12 15 TT normal IPSS <10 and a normal
prostate TRUS
>2 Short-term Tr 7 mg/d
Holmang et al., 1993 [31] T Placebo Sweden 11 12 TT normal Men without urinary
tract symptoms
>10 Short-term O 160 mg/d
Sih et al., 1997 [17] T Placebo USA 12 10 BT
60 ng/dl
Normal liver function tests,
PSA, and hematocrit
>4 Long-term I 200 mg/2 wk
Snyder et al., 1999 [18] T Placebo USA 45 51 TT
475 ng/dl
Men with BMD of the lumbar
spine below the mean for
healthy young men
>4 Long-term Tr 6 mg/d
Kenny et al., 2001 [19] T Placebo USA 24 20 BT
4.44 nmol/l
Men with late-onset
hypogonadism symptoms
>4 Long-term Tr 5 mg/d
Wittert et al., 2003 [20] T Placebo Australia 33 25 TT normal Men with late-onset
hypogonadism symptoms
>5 Long-term O 80 mg 2/d
Amory et al., 2004 [21] T Placebo USA 17 18 TT
12.1 nmol/l
Men with late-onset
hypogonadism symptoms
>4 Long-term I 200 mg/2 wk
Emmelot-Vonk
et al., 2008 [25]
T Placebo Netherlands 104 103 TT
13.7 nmol/l
Men with late-onset
hypogonadism symptoms
>4.5 Long-term O 80 mg 2/d
Idan et al., 2010 [28] DHT Placebo Australia 55 55 TT normal Men had no known prostate
disease (cancer, disease
requiring further treatment)
>4 Long-term Tr 70 mg/d
Aversa et al., 2010 [27] T Placebo Italy 40 10 TT
11 nmol/l
At least two symptoms
of hypogonadism
>4 Long-term Tr 1000 mg/12 wk
Shigehara et al., 2011 [29] T Placebo Japan 23 23 BT
11.8 pg/ml
IPSS >7 and total prostate
volume >20 ml
>2 Long-term I 250 mg/4 wk
ART = androgen replacement therapy; BMD = bone mineral density; BMI = body mass index;DHT = dihydrotestosterone; FTI = free testosterone index; I = injection; IPSS = International Prostate Symptom Score; O = oral;
PSA = prostate-specic antigen; RCT = randomized controlled trial; SHBG = sex hormone-binding globulin; TT = total testosterone; BT = bioavailable testosterone; T = testosterone; Tr = transdermal; TRUS = transrectal
ultrasound.
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or placebo [22,23], and three used a transdermal method
[24,26,30]. No heterogeneity was found between the trials
using the injection method [22,23] (Fig. 2); the SMD was
0.46 (95% CI, 3.74 to 2.82; p = 0.78) (Fig. 2). Nor was
there heterogeneity among the trials using transdermal
application [24,26,30] (Fig. 2); the SMD was 0.02 (95% CI,
1.01 to 1.04; p = 0.98) (Fig. 2). These results demonstrate
that ART and placebo were similar in terms of the IPSS
changes whether administered by injection or transder-
mally.
3.3.4. Maximum urine flow rate changes
Only two RCTs [23,31], involving a total of 63 participants
(32 in the androgen group and 31 in the control group),
included Q
max
data (Fig. 2). Treatment was given by
injection in one study [23] and orally in the other [31].
No heterogeneity was found between the trials (Fig. 2). The
SMD was 0.22 (95% CI, 4.35 to 4.79) for the study using
delivery by injection and 5.00 (95% CI, 0.96 to 10.96) for
the study using oral delivery ( p = 0.28) (Fig. 2). Therefore,
for either an injection or an oral administration method,
androgen did not decrease Q
max
compared with placebo.
3.4. Long-term androgen replacement therapy versus placebo
3.4.1. Prostate-specific antigen levels
Nine RCTs [1721,25,2729] included PSA data for a total
of 670 participants (255 in the androgen group and 315 in
the control group) (Fig. 3). Three used injection [17,21,29]
for administration, four used transdermal administration
[18,19,27,28], and two gave treatments orally [20,25].
According to our analysis, no heterogeneity was found
among the trials (Fig. 3). The SMDs were 0.15 (95% CI,
0.22 to 0.53; p = 0.42), 0.06 (95% CI, 0.23 to 0.12;
p = 0.51), and 0.08 (95% CI, 0.36 to 0.20; p = 0.57) for ART
administered by injection, transdermally, and orally,
respectively (Fig. 3). These results indicate no apparent
differences between ART and placebo in changes in PSA
levels regardless of how the treatments were administered.
3.4.2. Prostate volume changes
Four RCTs [21,25,27,28], representing a total of 402 partici-
pants (216 in the androgen group and 186 in the control
group), included data on changes in prostate volume
(Fig. 3). One study used injection [21] for administration,
two used transdermal administration [27,28], and one
administered treatment orally [25]. No heterogeneity was
found among the trials (Fig. 3). Our analysis revealed that
the SMDfor injectionwas 4 (95%CI, 4.32to 12.32; p = 0.35),
SMD for transdermal delivery was 0.42 (95% CI, 1.99
to 1.14; p = 0.59), and SMD for oral delivery was 1.20
(2.024.42; p = 0.47) (Fig. 3). The result clarified that there
was no difference between ART and a placebo in terms
of prostate volume changes for all three administration
methods.
3.4.3. International Prostate Symptom Score changes
Six RCTs [1820,25,28,29], representing 563 participants
(286 in the androgen group and 277 in the control group),
included data on IPSS changes (Fig. 3). One trial delivered
treatment by injection [29], three used transdermal
application [18,19,28], and two used oral delivery [20,25].
No heterogeneity was found among the trials (Fig. 3), and a
fixed-effects model was chosen for the analysis. The SMDs
were 2.70 (95% CI, 2.88 to 8.28; p = 0.34), 0.42 (95% CI,
0.41 to 1.24; p = 0.32), and 0.02 (95% CI, 1.11 to 1.15;
p = 0.97) for administration by injection, transdermally, and
orally, respectively (Fig. 3). Therefore, we concluded that
androgen and a placebo were nearly the same in terms of
the IPSS changes for all three methods of administration.
3.4.4. Maximum urine flow rate changes
Only two RCTs [18,29], representing a total of 142
participants (68 in the androgen group and 74 in the control
Table 2 Quality assessment of individual studies
Study Allocation
sequence
generation
Allocation
concealment
Blinding Loss to
follow-up
Calculation
of sample
size
Statistical
analysis
ITT
analysis
Level
of quality
Tenover, 1992 [16] B A A 0 Yes ANOVA No A
Kenny et al., 2004 [22] B A A 0 No ANOVA No A
Marks et al., 2006 [23] B A A 21 Yes Paired t tests No A
Chiang et al., 2007 [24] A A A 3 Yes ANOVA Yes A
Srinivas-Shankar et al., 2010 [26] A A A 31 Yes ANCOVA Yes A
Page et al., 2011 [30] A A A 4 Yes Wilcoxon rank-sum tests No A
Holmang et al., 1993 [31] B A A 2 Yes Student t test No A
Sih et al., 1997 [17] A A A 10 Yes Student t test No A
Snyder et al., 1999 [18] A A A 12 Yes ANOVA Yes A
Kenny et al., 2001 [19] A A A 24 Yes Paired t tests No A
Wittert et al., 2003 [20] A A A 18 Yes Fisher exact test Yes A
Amory et al., 2004 [21] A A A 13 Yes Student t test Yes A
Emmelot-Vonk et al., 2008 [25] A A A 16 Yes Unpaired t tests Yes A
Idan et al., 2010 [28] A A A 33 Yes Fisher exact test Yes A
Aversa et al., 2010 [27] A A A 0 Yes ANOVA No A
Shigehara et al., 2011 [29] B A A 6 Yes Student t test No A
A = all quality criteria met (adequate), low risk of bias; ANCOVA = analysis of covariance; ANOVA = analysis of variance; B = one quality criterion or more only
partly met (unclear), moderate risk of bias; C = one criterion or more not met (inadequate or not used), high risk of bias; ITT = intention-to-treat analysis.
E UR OP E AN UR OL OGY 6 4 ( 2 0 1 3 ) 8 1 1 8 2 2 815

Fig. 2 Forest plots showing changes in (a) prostate-specific antigen levels, (b) prostate volume, (c) International Prostate Symptom Score, and
(d) maximum urine flow rate in the short-term treatment studies. CI = confidence interval; IV = inverse; SD = standard deviation.
E UR OP E AN UR OL OGY 6 4 ( 2 0 1 3 ) 8 1 1 8 2 2 816

Fig. 3 Forest plots showing changes in (a) prostate-specific antigen levels, (b) prostate volume, (c) International Prostate Symptom Score, and
(d) maximum urine flow rate in the long-term treatment studies. CI = confidence interval; IV = inverse; SD = standard deviation.
E UR OP E AN UR OL OGY 6 4 ( 2 0 1 3 ) 8 1 1 8 2 2 817
group), includedQ
max
data (Fig. 3). One usedaninjection[29]
method, and one used a transdermal method [18] of
delivering treatment. No heterogeneity was found between
the trials (Fig. 3). The SMD for the study using delivery by
injection[29] was 3.70(95%CI, 0.85to8.25) and0.60(95%
CI, 3.04 to 1.84) for the study using transdermal application
[18] ( p = 0.74) (Fig. 3). Therefore, we concluded that for
either an injection or a transdermal administration method,
ART did not decrease the Q
max
compared with a placebo.
3.5. Subgroup analyses and sensitivity analysis
According to the baseline data of PSA levels and the
inclusion criteria for our studies, we divided the included
studies into three groups for preplanned subgroup analy-
ses: PSA 2 ng/ml, PSA 12 ng/ml, and PSA 1 ng/ml. There
were no differences between the ART and placebo groups
regarding the changes of the four determinants of prostate
growth (Table 4). Subgroup analyses shows that all the
results of determinants of prostate growth in the ART and
placebo groups matched our findings (Table 4) except that
ART using the transdermal administration method was
more likely to increase PSA levels than treatment with a
placebo ( p = 0.0005) in the group aged 65 yr (Table 4).
Sensitivity analysis was performed by removing the
studies for which generation of allocation sequence was
inadequate. Our analysis indicated that short-term ART
using the transdermal administration method was more
likely to increase PSA levels than treatment with placebo
( p = 0.01) (Table 4). No differences were found between the
ART and placebo groups in the long-term studies regarding
changes in PSA levels ( p = 0.57), prostate volume ( p = 1.00),
IPSS ( p = 0.41), or Q
max
( p = 0.63) (Table 4).
3.6. Discussion
Prostate growth is dependent on the presence of androgens;
conversely, antiandrogen and orchidectomy can decrease
prostate volume in patients with BPH [9]. It has been
suggested that ART may potentially increase prostate
volume. Urologists have been concerned about the use of
androgen supplementation due to the possibility of fueling
prostate growth not only in cancer but also in benign
disease. Resolving this question will inform methods of
treating LOH accompanied by prostatic problems.
In our analysis, short-termART delivered by transdermal
application was more likely to increase PSA levels than
treatment with a placebo; therefore, we can state that PSA
levels increased slightly over 12 mo in patients receiving
treatment transdermally. This is not in accord with clinical
manifestation, however. There are two possible reasons
for this discrepancy. One is that skin expresses high
5a-reductase activity; therefore, testosterone gel applied
to the skin achieves much higher dihydrotestosterone
levels than a comparable dose of testosterone enanthate
[3234], which may increase PSA levels. The other is that
PSA is sensitive to changes in the level of testosterone at low
concentrations, when unbound receptors are available to
respond to an increase in testosterone. With an increase in
testosterone to eugonadal levels in the clinical setting, the
receptors become saturated, and increasing the testoster-
one level further has no real effect on the level of PSA [35].
Some urologists think that testosterone has a linear
effect on prostate growth, and prostate dysfunction as an
adverse effect of this was the dominant theory in the past.
Now there is a new paradigm: the saturation model of
testosterone and the prostate [36]. This theory holds that
testosterones effect on the prostate reaches a saturation
point well below the physiologic testosterone levels
encountered in the clinical setting, beyond which additional
testosterone does not have an increased effect. This theory
is gaining traction in modern studies. In the study by Page
et al. [30], for example, the inclusion criteria for patients
receiving treatment transdermally included PSA level
<2 ng/ml, which was lower than in other short-term
studies (Table 1). Perhaps due to the relatively low level of
testosterone, unbound receptors are available to respond,
leading to increased PSA levels in the short term. Combined
with the long-term ART trial data, we recognized that the
PSA levels exhibited small increases associated with ART.
However, there was no significant difference between the
PSA levels of the two groups at baseline compared with the
end of the trial. Therefore, we hypothesize that the PSAlevel
increases slightly in the early stage of ART and then
decreases to a relatively low level that is still higher than
baseline and remains relatively stable for a long period
during ART.
Our study also evaluated the safety of long-term ART
(1236 mo) for prostate growth. All 16 RCTs included in our
analysis involved rigorous, periodic monitoring of patients,
and treatment was withdrawn when there were indications
suspicious for prostate cancer or other serious complica-
tions. In addition, for all 16 RCTs, no patient had prostate
enlargement at baseline, all patients had normal PSA levels
at baseline, and no patient underwent prostate biopsy at
study entry (Table 3). Consequently, long-term ART is safe
in terms of prostate growth, although rigorous monitoring
is indispensable. Our conclusion is based on the fact that

Fig. 4 Funnel plot of the studies represented in the meta-analysis.

Although 16 articles are included, 15 symbols are shown because of
overlap among the articles in reporting the determinants of prostate
growth. MD = mean difference; SE = standard error.
E UR OP E AN UR OL OGY 6 4 ( 2 0 1 3 ) 8 1 1 8 2 2 818
Table 3 Baseline data in our study
Age, yr,
median
PSA, ng/ml Prostate volume, ml IPSS Maximum ow
rate, ml/s
Prostate volume
determination
Prostate
biopsy at
study entry
Prostate
biopsy during
follow-up
TG PG TG PG TG PG TG PG
Tenover, 1992 [16] 66.7 2.1 (0.4) 2.1 (0.4) 33 (4) 33 (4) Transabdominal US No No
Kenny et al., 2004 [22] 79.5 0.88 (0.71) 1.30 (0.78) 6.6 (5.8) 8.8 (6.4) NA No No
Marks et al., 2006 [23] 69 1.55 (0.89) 0.97 (1.55) 43.8 (9.94) 36.8 (6.51) 13.0 (8.14) 11.0 (7.74) 14.0 (7.48) 10.6 (7.27) Transabdominal US No Yes
Chiang et al., 2007 [24] 52 8.6 (6.9) 8.8 (5.9) NA No No
Srinivas-Shankar
et al., 2010 [26]
73.8 1.5 (0.9) 1.5 (0.9) 7.0 (5.0) 5.9 (4.3) NA No Yes
Page et al., 2011 [30] 43 0.7 (0.4) 1.1 (0.6) 20.3 (4.6) 21.5 (4.2) 2.3 (1.7) 2.5 (2.8) TRUS No No
Holmang et al., 1993 [31] 52 1.28 (1.22) 0.72 (1.06) 24.6 (5.97) 22.1 (6.79) 15 (8.73) 17 (7.91) TRUS No No
Sih et al., 1997 [17] 65 1.0 (0.82) 1.5 (1.16) NA No No
Snyder et al., 1999 [18] 73 1.7 (1.1) 1.6 (1.0) 3.9 (2.5) 4.0 (2.3) 25.7 (5.4) 24.7 (6.1) NA No Yes
Kenny et al., 2001 [19] 75.5 2.0 (1.3) 2.0 (1.2) 9.3 (6.5) 9.0 (5.2) NA No No
Wittert et al., 2003 [20] 68.5 2.5 (0.8) 2.5 (1.2) 6.0 (4.0) 5.6 (5.1) NA No No
Amory et al., 2004 [21] 71 0.9 (0.8) 1.4 (1.1) 29 (11) 32 (14) TRUS No Yes
Emmelot-Vonk
et al., 2008 [25]
67 1.6 (1.1) 1.7 (1.1) 28.3 (12.6) 28.0 (9.9) 6.3 (5.1) 6.7 (4.9) TRUS No Yes
Idan et al., 2010 [28] 60.5 1.6 (1.1) 1.5 (1.1) 28.6 (10.4) 29.3 (16.2) 5.4 (4.2) 6.2 (5.0) TRUS No No
Aversa et al., 2010 [27] 57 1.07 (0.4) 1.1 (0.5) 26 (3) 26.5 (2) TRUS No No
Shigehara et al., 2011 [29] 70.5 1.06 (0.53) 1.06 (0.53) 15.7 (8.7) 14.0 (10.1) 12.9 (5.6) 11.4 (4.9) TRUS No No
IPSS = International Prostate Symptom Score; NA = not available; PG = placebo group; PSA = prostate-specic antigen; TG = androgen group; TRUS = transrectal ultrasound; US = ultrasound.
Baseline data are expressed as mean (standard deviation). Yes indicates that few patients with increased PSA levels on follow-up had undergone prostate biopsy.
E
U
R
O
P
E
A
N
U
R
O
L
O
G
Y
6
4
(
2
0
1
3
)
8
1
1

8
2
2
8
1
9
ART has no adverse effect on prostate growth in patients
without prostatic hyperplasia. Whether or not ART will
increase the risk for prostate growth in patients with BPH
needs further investigation in larger, high-quality studies.
Current laboratory protocol to support a diagnosis of
LOH is for a serum sample for total testosterone determi-
nation to be obtained between 7:00 AM and 11:00 AM [37].
It is generally agreed that a total testosterone level
>12 nmol/l (350 ng/dl) does not require substitution [5],
and that a free testosterone level <225 pmol/l (65 pg/ml)
can provide supportive evidence for testosterone treatment
[38]. The cohorts of 11 of the 16 studies in our meta-analysis
were evaluated in accordance with the diagnosis standard
(Table 1). Combined with our study, ART following this
diagnosis standard dose not increase the risk of prostate
growth. Inadequate data are available to determine the
optimal serum testosterone level for efficiency and safety.
For the present time, moderate to lower serumtestosterone
levels seemappropriate in young adult males and should be
the therapeutic goal. Although different methods and
dosages were used in the selected RCTs, supraphysiologic
levels were avoided.
This meta-analysis included findings from 16 double-
blinded RCTs. According to the quality-assessment scale
that we developed, the quality of the individual studies in
the meta-analysis was high. The results of this analysis are
important from a scientific standpoint, and they apply to
everyday clinical practice, particularly because data were
analyzed by method of ART delivery. The results of the
subgroup and sensitivity analyses are in accordance with
our findings, indicating that our results are robust and
reliable.
Nevertheless, there are some limitations to our analysis.
Data on prostate volume after short-term ART and on Q
max
were derived from a relatively small sample because cohort
sizes of a few of the studies [16,17,22,31] were not large.
Major limitations include heterogeneity in the populations
examined (Table 1), androgen dosage used (Table 1), and
baseline prostate status (with the exception of PSA levels)
(Table 3). LOH is a clinical and biochemical syndrome that
adversely affects the function of multiple organ systems.
The presence of symptoms associated with LOH was not
consistent across the included studies, and this may have
contributed to the heterogeneous population. Although we
Table 4 The results of subgroup, sensitivity, and preplanned subgroup analysis
PSA Prostate volume IPSS Maximum ow rate
SMD
(95% CI)
p value SMD
(95% CI)
p value SMD
(95% CI)
p value SMD
(95% CI)
p value
Age
<65 yr 0.08
(0.24 to 0.08)
0.31 0.08
(1.43 to 1.27)
0.91 0.32
(0.59 to 1.23)
0.49
65 yr 0.23
(0.060.39)
0.007 1.39 (1.15 to 3.93) 0.28 0.14
(0.54 to 0.83)
0.68 0.34
(1.61 to 2.28)
0.73
Testosterone level
Lower 0.15
(0.010.29)
0.03 0.76
(1.21 to 2.73)
0.45 0.31
(0.28 to 0.9)
0.30 0.34
(1.61 to 2.28)
0.73
Normal 0.10
(0.30 to 0.10)
0.32 0.05
(1.55 to 1.44)
0.94 0.41
(1.84 to 1.03)
0.58
Testosterone assay types
Gold standard
*
0.05
(0.25 to 0.15)
0.64 0.26
(1.74 to 2.26)
0.80 0.34
(0.59 to 1.27)
0.47
Not gold standard
*
0.13
(0.01 to 0.27)
0.08 0.23
(1.26 to 1.72)
0.76 0.14
(0.54 to 0.81)
0.69 0.90
(1.13 to 2.92)
0.38
Study quality (A level)
**
Short-term 0.30
(0.070.54)
0.01 0.40
(2.61 to 3.41)
0.79 0.02
(1.01 to 1.04)
0.98
Long-term 0.04
(0.18 to 0.10)
0.57 0.00
(1.39 to 1.39)
1 0.28
(0.39 to 0.95)
0.41 0.60
(3.04 to 1.84)
0.63
Serum PSA level
PSA 2 ng/ml 0.41
(0.36 to 1.18)
0.29 0.00
(12.55 to 12.55)
1 1.50
(4.30 to 1.30)
0.29
PSA 12 ng/ml 0.06
(0.07 to 0.20)
0.38 0.11
(1.52 to 1.29)
0.87 0.44
(0.19 to 1.07)
0.17 0.36
(1.79 to 2.52)
0.74
PSA 1 ng/ml 0.14
(0.11 to 0.39)
0.28 1.2
(1.09 to 3.49)
0.31 0.34
(1.90 to 1.23)
0.67 1.99
(1.64 to 5.62)
0.28
Duration of ART
Short-term 0.30
(0.090.50)
0.005 0.93
(1.41 to 3.27)
0.43 0.03
(1.00 to 0.95)
0.96 1.99
(1.64 to 5.62)
0.28
Long-term 0.04
(0.17 to 0.10)
0.62 0.00
(1.39 to 1.39)
1.00 0.31
(0.35 to 0.98)
0.35 0.36
(1.79 to 2.52)
0.74
ART = androgen-replacement therapy; CI = condence interval; IPSS = International Prostate Symptom Score; PSA = prostate-specic antigen;
SMD = standardized mean difference.
*
Gold standard was tandem mass spectrometry and liquid chromatography.
**
A level: all quality criteria were met (adequate), low risk of bias.
E UR OP E AN UR OL OGY 6 4 ( 2 0 1 3 ) 8 1 1 8 2 2 820
conducted subgroup and sensitivity analyses to assess the
quality of the studies, the problem of heterogeneity still
could not be completely avoided. Only four of the included
studies had as their end points the same determinants of
prostate growth measured in the present analysis (ie,
prostate volume, IPSS, PSA levels, and Q
max
). Although 15 of
the 16 RCTs drew morning blood samples to measure
testosterone levels, 11 of the 15 studies reported 6
measurement assay methods included tandem mass
spectrometry-liquid chromatography, mass spectroscopy,
chemiluminescent immunoassay, radioimmunoassay,
fluoroimmunoassay, and electrochemiluminescence. It is
generally known that the first method is the gold standard.
Although the results of subgroup analysis by testosterone
assay types (gold standard and not gold standard) matched
our findings, this made inclusion of studies using different
testosterone assays problematic and potentially influenced
the results of the meta-analysis.
4. Conclusions
This meta-analysis shows that regardless of the adminis-
tration method, neither short-term nor long-term ART
increases the risk of prostate growth. Further high-
quality, prospective studies are required to confirm this
observation.
Author contributions: Yong Zhang had full access to all the data in the
study and takes responsibility for the integrity of the data and the
accuracy of the data analysis.
Study concept and design: Zhang.
Acquisition of data: Zhang, Cui.
Analysis and interpretation of data: Zhang, Cui.
Drafting of the manuscript: Zhang, Cui.
Critical revision of the manuscript for important intellectual content: Zhang,
Cui.
Statistical analysis: Zhang, Cui.
Obtaining funding: None.
Administrative, technical, or material support: Zhang.
Supervision: Zhang.
Other (specify): None.
Financial disclosures: Yong Zhang certies that all conicts of interest,
including specic nancial interests and relationships and afliations
relevant to the subject matter or materials discussed in the manuscript
(eg, employment/afliation, grants or funding, consultancies, honoraria,
stock ownership or options, expert testimony, royalties, or patents led,
received, or pending), are the following: None.
Funding/Support and role of the sponsor: None.
Acknowledgment statement: The authors thank Dragony Editorial for
assisting in the preparation of this manuscript.
References
[1] Araujo AB, Esche GR, Kupelian V, et al. Prevalence of symptomatic
androgen deciency in men. J Clin Endocrinol Metab 2007;92:
42417.
[2] Harman SM, Metter EJ, Tobin JD, Pearson J, Blackman MR. Longitu-
dinal effects of aging on serum total and free testosterone levels in
healthy men. Baltimore Longitudinal Study of Aging. J Clin Endo-
crinol Metab 2001;86:72431.
[3] Wu FC, Tajar A, Pye SR, et al. Hypothalamic-pituitary-testicular axis
disruptions in older men are differentially linked to age and modi-
able risk factors. J Clin Endocrinol Metab 2008;93:273745.
[4] Wang C, Nieschlag E, Swerdloff R, et al. Investigation, treatment,
and monitoring of late-onset hypogonadism in males: ISA, ISSAM,
EAU, EAA, and ASA recommendations. Eur Urol 2009;55:12130.
[5] Morales A, Schulman CC, Tostain J, Wu FCW. Testosterone decien-
cy syndrome (TDS) needs to be named appropriatelythe impor-
tance of accurate terminology. Eur Urol 2006;50:4079.
[6] Kaufman JM, Vermeulen A. The decline of androgen levels in elderly
men and its clinical and therapeutic implications. Endocr Rev
2005;26:83376.
[7] Meigs JB, Mohr B, Barry MJ, Collins MM, McKinlay JB. Risk factors for
clinical benign prostatic hyperplasia in a community-based popu-
lation of healthy aging men. J Clin Epidemiol 2001;54:93544.
[8] Roehrborn CG, Boyle P, Nickel JC, Hoefner K, Andriole G. Efcacy and
safety of a dual inhibitor of 5-alpha-reductase types 1 and 2
(dutasteride) in men with benign prostatic hyperplasia. Urology
2002;60:43441.
[9] Roehrborn CG, Siami P, Barkin J, et al. The effects of combination
therapy with dutasteride and tamsulosin on clinical outcomes in
men with symptomatic benign prostatic hyperplasia: 4-year results
from the CombAT Study. Eur Urol 2010;57:12331.
[10] Fowler Jr JE, Whitmore Jr WF. Considerations for the use of testos-
terone with systemic chemotherapy in prostatic cancer. Cancer
1982;49:13737.
[11] McConnell JD. Prostatic growth: new insights into hormonal regu-
lation. Br J Urol 1995;76(Suppl 1):510.
[12] Jadad AR. Randomised controlled trials. London, UK: BMJ Publish-
ing Group; 1998.
[13] Higgins JPT, Green S, editors. Cochrane handbook for systematic
reviews of interventions, v.5.1. Cochrane Collaboration Web site.
http://www.cochrane-handbook.org/. Updated March 2011.
[14] DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin
Trials 1986;7:17788.
[15] Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring incon-
sistency in meta-analyses. BMJ 2003;327:55760.
[16] Tenover JS. Effects of testosterone supplementation in the aging
male. J Clin Endocrinol Metab 1992;75:10928.
[17] Sih R, Morlet JE, Kaiser FE, Perry III HM, Patrick P, Ross C. Testos-
terone replacement in older hypogonadal men: a 12-month ran-
domized controlled trial. J Clin Endocrinol Metab 1997;82:
16617.
[18] Snyder PJ, Peachey H, Hannoush P, et al. Effect of testosterone
treatment on bone mineral density in men over 65 years of age.
J Clin Endocrinol Metab 1999;84:196672.
[19] Kenny AM, Prestwood KM, Gruman CA, Marcello KM, Raisz LG.
Effects of transdermal testosterone on bone and muscle in older
men with low bioavailable testosterone levels. J Gerontol A Biol Sci
Med Sci 2001;565:26672.
[20] Wittert GA, Chapman IM, Haren MT, Mackintosh, Coates P, Morley
JE. Oral testosterone supplementation increases muscle and
decreases fat mass in healthy elderly males with lownormal
gonadal status. J Gerontol A Biol Sci Med Sci 2003;587:61825.
[21] Amory JK, Watts NB, Easley KA, et al. Exogenous testosterone or
testosterone with nasteride increases bone mineral density in
older men with low serum testosterone. J Clin Endocrinol Metab
2004;89:50310.
[22] Kenny AM, Fabregas G, Song C, Biskup B, Bellantonio S. Effects of
testosterone on behavior, depression, and cognitive function in
older men with mild cognitive loss. J Gerontol A Biol Sci Med Sci
2004;591:758.
E UR OP E AN UR OL OGY 6 4 ( 2 0 1 3 ) 8 1 1 8 2 2 821
[23] Marks LS, Mazer NA, Mostaghel E, et al. Effect of testosterone
replacement therapy on prostate tissue in men with late-onset
hypogonadism. JAMA 2006;296:235161.
[24] Chiang HS, Hwang TIS, Hsui YS, et al. Transdermal testosterone gel
increases serum testosterone levels in hypogonadal men in Taiwan
with improvements in sexual function. Int J Impot Res 2007;19:
4117.
[25] Emmelot-Vonk MH, Verhaar HJJ, Pour HRN, et al. Effect of testos-
terone supplementation on functional mobility, cognition, and
other parameters in older men. JAMA 2008;299:3952.
[26] Srinivas-Shankar U, Roberts SA, Connolly MJ, et al. Effects of tes-
tosterone on muscle strength, physical function, body composition,
and quality of life in intermediate-frail and frail elderly men: a
randomized, double-blind, placebo-controlled study. J Clin Endo-
crinol Metab 2010;95:63950.
[27] Aversa A, Bruzziches R, Francomano D, et al. Effects of testosterone
undecanoate on cardiovascular risk factors and atherosclerosis in
middle-aged men with late-onset hypogonadism and metabolic
syndrome: results from a 24-month, randomized, double-blind,
placebo-controlled study. J Sex Med 2010;7:3495503.
[28] Idan A, Grifths KA, Harwood DT, et al. Long-termeffects of dihydro-
testosterone treatment on prostate growth in healthy, middle-aged
men without prostate disease. Ann Intern Med 2010;153:62132.
[29] Shigehara K, Sugimoto K, Konaka H, et al. Androgen replacement
therapy contributes to improving lower urinary tract symptoms in
patients with hypogonadism and benign prostate hypertrophy: a
randomised controlled study. Aging Male 2011;14:538.
[30] Page ST, Lin DW, Mostaghel EA, et al. Dihydrotestosterone admin-
istration does not increase intraprostatic androgen concentrations
or alter prostate androgen action in healthy men: a randomized-
controlled trial. J Clin Endocrinol Metab 2011;96:4307.
[31] Holmang S, Marin P, Lindstedt G, Hedelin H. Effect of long-termoral
testosterone undecanoate treatment on prostate volume and se-
rum prostate-specic antigen concentration in eugonadal middle-
aged men. Prostate 1993;23:99106.
[32] Wang C, Berman N, Longstreth JA, et al. Pharmacokinetics of
transdermal testosterone gel in hypogonadal men: application of
gel at one site versus four sites: a General Clinical Research Center
Study. J Clin Endocrinol Metab 2000;85:9649.
[33] Swerdloff RS, Wang C, Cunningham G, et al. Long-term pharmaco-
kinetics of transdermal testosterone gel in hypogonadal men. J Clin
Endocrinol Metab 2000;85:450010.
[34] Bhasin S, Travison TG, Storer TW, et al. Effect of testosterone
supplementation with and without a dual 5a-reductase inhibitor
on fat-free mass in men with suppressed testosterone production:
a randomized controlled trial. JAMA 2012;307:9319.
[35] Polackwich AS, Ostrowski KA, Hedges JC. Testosterone replacement
therapy and prostate health. Curr Urol Rep 2012;13:4416.
[36] 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;55:31021.
[37] Diver MJ, Imtiaz KE, Ahmad AM, Vora JP, Fraser WD. Diurnal
rhythms of serum total, free and bioavailable testosterone and of
SHBGin middle-aged men compared with those in young men. Clin
Endocrinol 2003;58:7107.
[38] Rosner W, Auchus RJ, Azziz R, Sluss PM, Raff H. Utility, limitations,
and pitfalls in measuring testosterone: an Endocrine Society Posi-
tion Statement. J Clin Endocrinol Metab 2007;92:40513.
E UR OP E AN UR OL OGY 6 4 ( 2 0 1 3 ) 8 1 1 8 2 2 822