8
2
2
8
1
4
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
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.
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