EURURO Vol. 72 No. 6

1003 1030

2.4. Outcome and quality assessment
The primary outcome of this analysis was the effect of TTh
on EF as compared with placebo. Several other sexual
related components were evaluated according to IIEF
subdomains . For each IIEF subdomain, the mean and
the 95% confidence interval were evaluated. In addition, the
overall erectile function component, evaluated by either
IIEF-5 or IIEF-EFD score, was also considered. In the latter
case, the treatment-effect size and its 95% confidence
interval was calculated using the method of Hedges and
Olkin . According to Cohen , a small treatment-effect
size is considered to be about 0.2, a medium effect size to be
about 0.5, and a large effect size to be about 0.8
2.5. Statistical analysis
Heterogeneity across studies of effect size of TTh versus
placebo in studies using IIEF-5 or IIEF-EFD, or when only IIEF-
EFD score was considered, was assessed using I2 statistics,
and, although the validity of tests of heterogeneity can be
limited due to the small number of component studies, both
fixed and random effect models were applied for analysis.
Sensitivity analyses or regression linear adjusted models
were performed, whenever appropriate. All analyses were
performed using Comprehensive Meta-analysis Version 2,
Biostat (Englewood, NJ, USA). Multivariate analyses were
performed on SPSS (SPSS Inc., Chicago, IL, USA) for Windows
22.1. Risk of bias was generated with Revman software
Version 5.3 (The Cochrane Collaboration, London, UK).
3. Evidence synthesis
3.1. Studies characteristics
Out of 284 retrieved articles, 14 were included in the study
. However, one study not adequately reporting
p values or mean differences was used only when
standardized effect size calculations (standardized differ-
ence in means [SDM]) were performed. In addition, in one
study only IIEF orgasmic domain was analyzed
).
Available RCTs enrolled 2298 patients, with a mean
follow-up of 40.1 wk. These trials differed in baseline total
T levels. In addition, TTh was administered in different
doses and formulations. In particular, all studies except two
evaluated the effect of TTh in hypogonadal patients
(7 with T below 12 nM and 5 with T < 8 nM). In addition,
one trial used oral T formulations, whereas four and eight
studies used intramuscular and transdermal T preparations,
respectively. Finally, in one RCT both intramuscular and
transdermal T formulations were used. The characteristics
of the trials included in the meta-analysis are summarized
in .
3.1.1. Risk of bias
Risk of bias in included studies is summarized in
.
Allocation (selection bias). All studies were RCTs and
precisely specified the methodology of randomization.
Blinding (performance bias and detection). All studies
expect one were double-blind. One double-blind study
was a double dummy with cross-over .
Incomplete outcome data (attrition bias). Only 12 trials
correctly reported the drop-out rate and the evaluation of
data after drop-out. The remaining studies included
in the meta-analysis neither reported the drop-out rate nor
gave information about the evaluation of patient drop-out.
Selective reporting (reporting bias). The primary endpoints
described in the aims were reported in the results section of
each study. Several studies included secondary endpoints,
which, however, were not always completely reported in
the results and discussion sections.
Other potential sources of bias. None.
Table 1 – Characteristics and outcomes of the randomized, placebo-controlled clinical studies included in the meta-analysis (all data are
reported as mean W SD)
Study (ref.) No. patients
(T/placebo)
Trial
duration
(wk)
Age (yr),
mean SD
or age range
T levels
(nM)
Diabetes
(%)
Dose
(daily)
Sexual
function tool used
Cavallini et al., 2004 40/45 24 60–72 <12 NR TU 160 mg/d IIEF-15
Svartberget al 2004 15/14 26 54–75 Eugonadal 0 TE 250mg/mo IIEF-5
Chiang at al 2007 20/18 12 20–75 <12 0 TG 50 mg/d IIEF-EFD
Allan et al., 2008 31/31 52 63.3 <15 0 T path 50 mg/d IIEF-15
Chiang at al 2009 20/20 12 20–75 <8 0 TG 50 mg/d IIEF-15
Giltay et al., 2010 113/71 30 35-69 <8 29 TU 1000 mg/12 wk IIEF-5
Aversa et al., 2010 42/10 48 68.8 6.5 TU 160 mg/d IIEF-5
<8 7.5 TU 1000 mg/12 wk
Jones et al., 2011 103/102 52 59.9 9.3 <12 62 TG 60 mg/d IIEF-15
Hackett et al., 2013 92/98 30 33–83 <12 100 TU 1000 mg/12 wk IIEF-15
Gianatti et al., 2014 44/41 40 62.0 <12 100 TU 1000 mg/12 wk IIEF-15
Basaria et al., 2015 104/94 156 67.6 <12 15.1 TG 75 mg/d IIEF-5
Padouch et al., 2015 36/40 16 50.7 <8 NR T solution IIEF-15 orgasmic domain
Brock et al., 2016 303/297 16 55.3 <8 30 T solution IIEF-15
Snyder et al., 2016 234/266 52 71.6 <8 NR TG 50 mg/d IIEF-15
EFD = Erectile Function Domain; IIEF = International Index of Erectile Function; NR = not reported; ref. = reference; SD = standard deviation; TE = testosterone
enanthate; TG = testosterone gel; TU = testosterone undecanoate.
E U R O P E A N U R O L O G Y 7 2 ( 2 0 1 7 ) 1 0 0 0 – 1 0 1 1 1003