EURURO Vol. 72 No. 6

1001 1030

1. Introduction
The fact that symptoms of testosterone (T) deficiency in
adulthood, also termed late-onset hypogonadism, often
overlap with those characteristics of the aging process and
its associated comorbidities underlies the recent controversy
regarding the value of testosterone therapy (TTh)
) . In the case of T deficiency (TD), there is uniform
consensus among professional medical societies that the
diagnosis requires a combination of symptoms/signs to-
gether with low serum T concentrations: a reduction of
circulating T alone is not enough for diagnosing the
condition . Symptoms of T deficiency include psycho-
logical (ie, depression), physical (ie, fatigue), and sexual
concerns .
A quantitative review by Millar et al on the accuracy
and operating characteristics of signs and symptoms for
predicting low T in aging men indicates that all relationships
are relatively poor in terms of sensitivity and specificity. The
European Male Aging Study, a population-based survey
performed on more than 3400 men recruited from eight
European centers, clearly showed that sexual symptoms—
particularly erectile dysfunction (ED) and decreased fre-
quency of sexual thoughts and morning erections—are the
most sensitive and specific symptoms in identifying patients
with low T . The syndromic association of these sexual
symptoms resulted in improved identification of men with T
deficiency. Similar results were recently reported by us in a
large cohort (n = 4890) of patients consulting for ED at the
University of Florence In contrast, psychological and
physical symptoms were less informative
Recently, even the association between T deficiency and
sexual symptoms has been questioned, because it has been
speculated that it is derived from cross-sectional observa-
tions and it is conceivable that sexual inactivity drives a
reduced testicular function, and not the other way around
. However, a longitudinal analysis of the European
Male Aging Study cohort showed that the presence of
sexual symptoms at baseline is not associated with an
incipient high grade, whereas an incipient high grade at
follow-up is associated with the development of sexual
symptoms .
An opportunity to solve the dilemma is offered by the ex-
juvantibus criterion. If T deficiency is causing sexual
symptoms, these symptoms should be improved by T
therapy. In our previously published meta-analysis we
showed that TTh is superior to placebo in improving all
aspects of sexual function . The outcomes observed were
independent of age but negatively related to the levels of T
at enrolment. In addition, as expected, the effects of TTh
were lower in the presence of conditions known to produce
vascular damage, such as in the case of diabetes mellitus
. It should be recognized that human studies evaluating
the effect of T on sexual function are extremely heteroge-
neous in their assessment, because, quite often, different
self-reported measures have been used for the evaluation of
the final outcome. To overcome this problem, in our
previous meta-analysis we homogenized the effect size
by using the method of Hedges and Olkin However, even
this method presents important limitations
Although most studies, including meta-analyses and
systematic reviews, have provided supporting evidence that
T therapy does in fact improve sexual symptoms in men
with TD , a recent systematic qualitative review on
the effect of TTh on several outcomes in controlled trials
concluded that TTh did not show consistent benefits for
sexual function . That conclusion was based on a
subjective interpretation of study results, without consid-
ering overall patient population characteristics at baseline,
including T levels. Despite those limitations, the question as
to whether TTh provides sexual benefits has again
resurfaced. For this reason, we have undertaken to perform
a new meta-analysis in which we have restricted article
inclusion to only randomized controlled trials (RCTs) in T-
deficient men in which the same assessment instrument
was used, the International Index of Erectile Function (IIEF).
The IIEF is the most frequently used validated tool to
assess male sexual function . It has been recommended
both as a primary endpoint for clinical trials of ED and for
diagnostic evaluation of ED severity. The original version
included 15 items encompassing several sexual domains;
however, in order to improve its usefulness in clinical
practice an abridged 5-item version was developed and is
known as the IIEF-5 or Sexual Health Inventory for Men
. Another 6-item version of IIEF-15 (IIEF6: the erectile
function domain of IIEF-15 [IIEF-EFD]) was separately
developed and validated to diagnose the presence and
severity of ED.
To better clarify the role of TTh on sexual function, the
aim of the present study was to perform a meta-analysis of
available data evaluating the effect TTh on male sexual
function using IIEF, in its different versions, as the primary
outcome.
2. Evidence acquisition
This meta-analysis was performed according to the
Preferred Reporting Items for Systematic Reviews and
Meta-analyses checklist (Supplementary data;
).
2.1. Eligibility criteria
All placebo-controlled RCTs enrolling men investigating the
effect of TTh on sexual function were included in the
analysis.
2.2. Information source and search strategy
An extensive Medline, Embase, and Cochrane search was
performed including the following words (‘‘testosterone’’[-
MeSH Terms] OR ‘‘testosterone’’[All Fields]) AND (‘‘sexual
behavior’’[MeSH Terms] OR (‘‘sexual’’[All Fields] AND
‘‘behavior’’[All Fields]) OR ‘‘sexual behavior’’[All Fields] OR
‘‘sexual’’[All Fields]) AND (‘‘physiology’’[Subheading] OR
‘‘physiology’’[All Fields] OR ‘‘function’’[All Fields] OR ‘‘phy-
siology’’[MeSH Terms] OR ‘‘function’’[All Fields]) AND
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 1001