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\begin{document}

\title{Systematic review and meta-analysis for the value of thyroid disorder
screening in men with ejaculatory dysfunction}



\author[1]{Ahmet Cihan}%
\author[2]{Ahmet Adil Esen}%
\affil[1]{Affiliation not available}%
\affil[2]{Dokuz Eylül University}%


\vspace{-1em}



  
  \date{June 15, 2024}


\begingroup
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\selectlanguage{english}
\begin{abstract}
Abstract Objective: To demonstrate evidence from available clinical
studies to clarify the scientific points that have been achieved in
relation to thyroid disorders and ejaculatory dysfunction. Data sources:
Clinical trial articles published in English on Medline. Eligibility
criteria: Clinical studies that investigated the association of thyroid
disorders with the ejaculatory function of subjects and the trials
evaluating the effect of thyroid dysfunction treatment on the
ejaculatory function of the subjects were eligible. Synthesis methods:
We searched Medline with ``ejaculation'' and different combinations of
``thyroid,'' ``serum TSH,'' ``serum T3,'' ``serum T4'' keywords in
PubMed. Results: Standardized mean serum thyroid-stimulating hormone
(TSH) levels in premature ejaculation (PE) sufferers differed from
non-PE control subjects (p=.05). Hyperthyroidism was associated with
increased odds among PE subjects (OR=2.0, p=.03). Delayed ejaculation
was seen with increased odds in hypothyroid patients compared with
hyperthyroidism patients (OR=57, p=.0001). Serum TSH and mean
intra-vaginal ejaculation latency time (IELT) of the subjects showed a
correlation both before and after treatment for thyroid disorder.
Treatment of thyroid disorders improved the mean IELT measures of the
subjects. The overall estimate of the effect of hyperthyroidism
treatment on mean IELT was .64 (p=.0001) in the random-effects model.
Limitations: The low quality and quantity of evidence from available
studies limited the interpretation of our study findings. Conclusions:
The causal relationship between ejaculatory dysfunction and thyroid
disorders remains to be clarified. Sufferers of delayed ejaculation
acquired PE subjects, and PE sufferers who have accompanying erectile
dysfunction and/or anxiety may benefit from thyroid disorder
investigation.%
\end{abstract}%



\sloppy


\textbf{Introduction}

A higher prevalence of hyperthyroidism in patients with premature
ejaculation (PE) has been reported; treatment of hyperthyroidism in a
small group of patients resulted in improved outcomes by means of
patient-reported outcome (PRO) measures related to PE and the mean
intra-vaginal ejaculation latency time (IELT) of the subjects (Carani et
al., 2005; Cihan, Demir, et al., 2009; G. Corona et al., 2004). On the
other hand, delayed ejaculation (DE) has been observed in a large
proportion of hypothyroidism patients; the mean IELT is also improved
with the treatment of the thyroid disorder itself (Carani et al., 2005).
In the same decade, it has also been clarified that there is no
association with very low prevalence rates between thyroid dysfunction
and lifelong PE in patients with normal erectile function (Waldinger,
Zwinderman, Olivier, \& Schweitzer, 2005). The aforementioned findings
led to recommendations such as ``thyroid hormone disorders should be
suspected in ejaculatory disorders'' with low certainty (Buvat et al.,
2010). However, evidence from animal studies supports the presence of at
least modulatory effects of thyroid hormones on the ejaculatory reflex
operated from the central nervous system (Cahangirov et al., 2011;
Cihan, Murat, et al., 2009; Cinar et al., 2018). We aimed to clarify the
clinical evidence supporting the possible causality between thyroid
dysfunction and EjD and the scientific background that supports the
investigation of thyroid function in patients suffering from EjD.

\textbf{Methods}

Protocol and registration: The study protocol was established and
recorded in the International Prospective Register of Systematic Reviews
(Prospero: CRD42020198387).

Eligibility criteria: Studies investigating the proportion of human
subjects with accompanying thyroid disorders among PE or DE sufferers or
vice versa, correlation studies evaluating serum TSH with IELT and/or
PRO measures of the EjD sufferers and measuring treatment effects that
aim to establish a euthyroid state on the IELT and/or PRO measures of
thyroid dysfunction sufferers were considered for this review. Both
studies performed in the population and hospital settings were eligible
in the case of appropriate ethical review board approval.

Information sources and search: An electronic data search was performed
on Medline (via PubMed) without any time limit. A query by the different
combinations of the following keywords: ``ejaculation'' and ``thyroid,''
``serum TSH,'' ``serum T3,'' and ``serum T4''was performed on July 3rd
2020 and updated on November 3rd 2020.

Study selection: Initial screening via review keywords on PubMed was
performed by the first author and title and abstract of the journal
articles were evaluated for eligibility. Randomized and non-randomized
studies on human subjects that declare ethical approval and clearly
report all of the components of the population, interventions,
comparators, and outcome measures of the trial were eligible for our
review. Reviews and meta-analyses of existing data were not included in
the current study. Irrelevant reports were removed, and candidate
studies for the scope of the current review were finally evaluated for
eligibility with their full-text files. Finally, the relevance of the
studies was assessed with both review authors not blinded to the names
and institutions of the study authors. The study flow diagram is shown
in Figure 1 and characteristics of the included studies are shown in
Table 1.

Risk of bias in individual studies: We established the risk of bias
assessment tool for eligible studies specific to the current review and
classified all of the included studies according to their grade and type
of bias according to GRADE recommendations for evaluation of certainty
of the evidence (Table 2) (Guyatt et al., 2008).

Summary measures: We rendered the presence of EjD, either PE or DE, as a
dichotomous qualitative outcome measure. The mean PRO measures of the
subjects and the mean of the IELT measurements in the reviewed studies
were quantitative outcome measures.

Primary outcomes

We defined three primary outcomes for the current review:

I. Relative risk or odds ratio of EjD diagnosis among the studied
subjects according to the presence of accompanying thyroid dysfunction.

II. Correlation measure and direction between serum TSH and IELT with or
without PRO measures related to ejaculation in the subjects.

III. Proportional improvement in the IELT and/or PRO measures related to
ejaculation of the subjects in studies investigating the quantitative
effects of treatment for accompanying thyroid dysfunction.

Secondary outcomes ~

The time interval between the achievement of euthyroid status and
observed effects on ejaculatory function among subjects in the studies,
presence of need for further treatment except intervention aimed at
euthyroidism for related EjD, treatment-related sexual side effects (de
novo ED or loss of libido, etc.), and economic aspects of treatment to
achieve changes in ejaculatory function were the secondary outcomes if
reported in eligible studies.

Synthesis of results: Data of eligible articles were extracted into
Excel sheets and analyzed for quality, the quantity of the measured
effect, the direction of the effect, and rated according to the possible
risk of bias.

Additional analysis: The random effects model was used for all measures
obtained from eligible studies. Measures of intervention effect on
outcomes with change over time or differences between groups were the
main aim of the current meta-analysis. We initially evaluated the
consistency of standardized correlation coefficients between the IELT
and serum TSH measurements of the subjects across studies. Observed
effect measures (p values) with 95\% confidence intervals, measured
effects of thyroid dysfunction treatment with odds ratios, and PRO and
IELT measurements were analyzed. While different methods were
anticipated to be used in the measurement of IELT and PRO measures of
the heterogeneous group of subjects across the eligible studies, a
standardized mean difference was used to estimate the overall size of
the effect on the measured variable. We have used ``Review Manager
(RevMan)'' computer program Version 5.4 for windows from ``Cochrane
Collaboration, 2020'' and Open Meta program
(http://www.cebm.brown.edu/open\_meta) during our study conduction. Both
of these programs have already been launched for the use of external
reviewers.

\textbf{Results}

The odds ratio of hyperthyroidism among PE patients compared with
control subjects was 2.0 (0.6-6.9 at 95\% CI, p=.03). The odds ratio of
PE among hyperthyroid patients compared with euthyroid subjects was 2.2
(1.1-4.5 at 95\% CI, p=.0001). The odds ratio of PE among hyperthyroid
patients compared with hypothyroid subjects was 13.2 (5.6-31.4 at 95\%
CI, p=.006). The odds ratio of DE among hypothyroid patients compared
with hyperthyroid subjects was 57.4 (16.9-194.5 at 95\% CI, p=.0001).
Table-3 summarizes the findings from interventional studies.

The standardized mean serum TSH difference between PE and non-PE
subjects in the random-effects model had an estimate of effect of -0.45
(lower and upper bound: -0.91 and 0.006; SE: 0.23; p=0.05) (Figure 2.A).
The effect of treatment of hyperthyroidism on mean IELT in the
random-effects model was as an overall estimate of effect of 0.64 (lower
and upper bound: 0.27 and 1.02; SE: 0.19; p\textless{}0.001) (Figure
2.B). The effect of treatment of hyperthyroidism on the prevalence of PE
in the binary random-effects model was as an overall estimate of effect
of 0.13 (lower and upper bound: 0.05 and 0.33; p\textless{}0.001)
(Figure 2.C).

\textbf{Discussion}

Summary of evidence

Despite the limitations of the available studies, we clarified that
patients with hyperthyroidism have at least two-fold increased odds for
PE. Patients with hypothyroidism had more increased odds for DE compared
to hyperthyroidism subjects. Hyperthyroidism is much more common in
patients with PE; however, the latter association is not true for
lifelong PE sufferers who have normal erectile function. Current
evidence indicates that serum TSH levels in men are correlated with
their ejaculation latency control ability by means of time in both
hypothyroid and hyperthyroid subjects. From the treatment aspect,
relieving the thyroid disorder by itself improves both IELT control and
subjective PRO measures related to ejaculation at least 2 months after
the achievement of euthyroidism in men. Several aspects of erectile
function and the accompanying anxiety of the subjects also improved with
the treatment of thyroid disorders only.

With respect to the memory of Waldinger, who emphasized the necessity of
large cohorts (for example, to identify at least 55 lifelong PE
patients, you need at least 100,000 screened subjects) to demonstrate
the natural distribution of serum TSH among lifelong PE and non-PE
subjects, we are still far from clarifying the contribution of thyroid
hormone axis distortions to the ejaculatory reflex machinery with
currently available clinical studies (Waldinger et al., 2005). For
instance, if a case-control study aimed to reveal the proportions of
thyroid disorders among EjD sufferers, at least 833 subjects for each
group are needed to achieve 80\% power with 95\% CIs according to power
analysis for sample size with a known prevalence. Therefore, the lack of
large population-based comparative studies, excessive heterogeneity
across available studies, absence of standardization in the evaluation
of both objective (IELT) and subjective measures related to ejaculation,
erectile function, anxiety, etc., has led to a deficiency in the overall
completeness of our study evidence. The absence of placebo effect
elaboration and results of long-term follow-up studies with the presence
of selection bias also lowered the quantity of evidence for
interventional studies available in the current review.

The association of hyperthyroidism and PE with increased odds for each
other has been confirmed in our study, which is in agreement with
previous reports (Giovanni Corona, Jannini, Vignozzi, Rastrelli, \&
Maggi, 2012a; Gabrielson et al., 2019). Considering that only one study
by Waldinger is available, the absence of this association among a
subgroup of patients who have lifelong PE has also been confirmed in our
study (Giovanni Corona, Jannini, Vignozzi, Rastrelli, \& Maggi, 2012b;
Waldinger et al., 2005). On the other end of the ejaculatory axis, DE
has been shown to be strongly associated with hypothyroidism, which has
been reported in previous reviews, as evidenced by one available study
(Carani et al., 2005; Di Sante et al., 2016; Gabrielson et al., 2019).
Finally, the median age of the available studies that demonstrate the
aforementioned associations is in the forties, which agrees with the
previous argument that thyroid disorders may be a relevant risk factor
for sexual problems in young adults (Gabrielson et al., 2019).

The higher prevalence of anxiety among acquired PE patients and
hyperthyroid patients has been demonstrated with currently available
data (Cihan, Demir, et al., 2009; Culha, Tuken, Gonultas, Cakir, \&
Serefoglu, 2020). However, the exact role of anxiety (direct or indirect
role) on the ejaculatory disturbance due to underlying thyroid
dysfunction is another issue that still remains to be clarified.

Treatment of thyroid dysfunction by itself has led to significant
improvements in the majority of patients with respect to ejaculatory
latency control, PRO measures related to ejaculation and accompanying
erectile function domains, and anxiety levels, which is demonstrated in
the available studies in our study and has already been reported in
previous reviews (Bates, Kohn, \& Pastuszak, 2020; Sansone, Romanelli,
Jannini, \& Lenzi, 2015). Surgically treated hyperthyroid patients
demonstrated much more improvement in their ejaculatory control outcomes
compared with other treatment groups, which should also be emphasized
again for planning future trials (Cihan, Demir, et al., 2009). However,
as shown by Bates et al., although there are statistically significant
and desired improvements in the IELT of subjects suffering from a
thyroid disorder, a small but perhaps clinically significant proportion
of patients still complain of EjD (Bates et al., 2020). Therefore, we
concluded that the relevance and different dimensions of treatment
effects with targeting euthyroidism alone on the EjD in patients with
thyroid disorder should be validated with large, longitudinal studies
with longer follow-up evaluations.

Limitations

The lack of blinding of the authors during data extraction and synthesis
in the current review may have contributed to the potential bias.
However, heterogeneity of the available studies was the major limitation
during the meta-analysis process of our study.

Conclusions

\emph{Implications for practice:} Acquired PE subjects and PE sufferers
who have accompanying erectile dysfunction and/or anxiety may benefit
from thyroid disorder investigation. Screening men for thyroid disease
may also be useful in patients with DE.

\emph{Implications for research:} With current knowledge of available
studies, we are still far from establishing any conclusion on a causal
relationship between EjD and thyroid disorders. Available evidence
suggests Dopaminergic pathways in the central nervous system that
mediates the emission phase of the ejaculation might be a good research
area for experimental studies that aimed to clarify the interrelation
between thyroid disorder and ejaculatory dysfunction in men. Further
longitudinal studies with a good sample size estimation based on the
population-based prevalence rates of thyroid disorders, using
standardized diagnostic tools (PRO related to ejaculation, measured
IELT, etc.) and an appropriate length of follow--up evaluations may
enhance the quality of scientific evidence on this emerging topic.

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\textbf{Table 1. Characteristics of the included studies}\selectlanguage{english}
\begin{longtable}[]{@{}lllllllll@{}}
\toprule
\begin{minipage}[b]{0.08\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[b]{0.08\columnwidth}\raggedright\strut
\emph{Country}\strut
\end{minipage} & \begin{minipage}[b]{0.08\columnwidth}\raggedright\strut
\emph{Design}\strut
\end{minipage} & \begin{minipage}[b]{0.08\columnwidth}\raggedright\strut
\emph{Setting}\strut
\end{minipage} & \begin{minipage}[b]{0.08\columnwidth}\raggedright\strut
\emph{Participants}\strut
\end{minipage} & \begin{minipage}[b]{0.08\columnwidth}\raggedright\strut
\emph{Diagnosis of EjD}\strut
\end{minipage} & \begin{minipage}[b]{0.08\columnwidth}\raggedright\strut
\emph{Cut-offs for serum TSH measurement}\strut
\end{minipage} & \begin{minipage}[b]{0.08\columnwidth}\raggedright\strut
\emph{Intervention}\strut
\end{minipage} & \begin{minipage}[b]{0.08\columnwidth}\raggedright\strut
\emph{Funding}\strut
\end{minipage}\tabularnewline
\midrule
\endhead
\begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
\emph{Culha MG} (Culha et al., 2020)\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Turkey\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Case series (prospective)\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Hospital\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Acquired PE sufferers\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
ISSM definition\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Not stated\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
no\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
none\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
\emph{Khan HL}(Khan et al., 2018)\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Pakistan\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Case-control study\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Hospital\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
PE with Diabetes mellitus vs. non-PE (control)\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
DSM-4TR definition and estimated IELT ( with 3 min cut-off)\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
0.4-4.5 mcIU/ml\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
no\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
none\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
\emph{Canat L} (Canat, Erbin, Canat, Dinek, \& \selectlanguage{ngerman}Ça\selectlanguage{polish}ş\selectlanguage{english}kurlu, 2017)\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Turkey\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Case-control study\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Hospital\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
PE sufferers without ED vs. non-PE (control)\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
PEDT\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Not stated\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
no\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
none\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
\selectlanguage{ngerman}\emph{Öztürk MI} (Öztürk et al., 2012)\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Turkey\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Case-control study\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Hospital\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
PE patients vs. non-PE (control)\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Measured IELT\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
0.4-4 mIU/L\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
no\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
none\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
\emph{Corona G} (G Corona et al., 2011)\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Italy\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Retrospective cohort\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Hospital\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
PE or DE sufferers following admission to sexual health unit\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Study specific PRO for EjD and estimated IELT\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
TSH \textless{} 0.2 mIU/L for hyperthyroidism\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
no\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
none\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
\emph{Cihan A} (Cihan, Demir, et al., 2009)\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Turkey\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Prospective cohort\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Hospital\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Hyperthyroid male patients who admitted to Endocrinology outpatient
clinic\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
DSM-4TR and measured IELT\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
0.4mcIU/ml cut-off for Hyperthyroid-ism\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Specific treatment of hyperthyroidism with medication, surgery or
RAI\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
none\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
\emph{Carani C} (Carani et al., 2005)\strut
\end{minipage} & \begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
Italy\strut
\end{minipage} & \begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
Prospective cohort\strut
\end{minipage} & \begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
Hospital\strut
\end{minipage} & \begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
Hyperthyroid and Hypothyroid male patients who admitted to Endocrinology
clinic\strut
\end{minipage} & \begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
DSM-4TR and measured IELT\strut
\end{minipage} & \begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
0.3-5.0 mcIU/ml\strut
\end{minipage} & \begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
Medical tx of thyroid dysfunction (Metimazole, L-Thyroxine plus
Propanolol and Benzodiazepine's in some cases)\strut
\end{minipage} & \begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
yes\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
\emph{Waldinger MD} (Waldinger et al., 2005)\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Netherlands\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Case series (prospective)\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Hospital\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Patients who admitted to Andrology Unit recruited according to presence
of lifelong PE and absence ED\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Estimated IELT\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
0.3 -4.0 mcIU/ml\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
no\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
none\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
\emph{Corona G} (G. Corona et al., 2004)\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Italy\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Cross-sectional\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Hospital\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Patients who admitted to sexual health unit\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Study specific PRO for PE\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
TSH \textless{} 0.2 mIU/L for hyperthyroid-ism\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
no\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
yes\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
\emph{Abbreviations}\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
\emph{Abbreviations}\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
\emph{Abbreviations}\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
\emph{Abbreviations}\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
\emph{Abbreviations}\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
\emph{Abbreviations}\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
\emph{Abbreviations}\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
\emph{Abbreviations}\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
\emph{Abbreviations}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
DE:\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
DE:\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
DE:\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Delayed ejaculation\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Delayed ejaculation\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Delayed ejaculation\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Delayed ejaculation\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Delayed ejaculation\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Delayed ejaculation\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
ED:\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
ED:\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
ED:\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Erectile dysfunction\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Erectile dysfunction\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Erectile dysfunction\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Erectile dysfunction\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Erectile dysfunction\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Erectile dysfunction\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
EjD:\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
EjD:\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
EjD:\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Ejaculatory dysfunction\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Ejaculatory dysfunction\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Ejaculatory dysfunction\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Ejaculatory dysfunction\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Ejaculatory dysfunction\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Ejaculatory dysfunction\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
IELT:\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
IELT:\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
IELT:\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Intra-vaginal ejaculation latency time\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Intra-vaginal ejaculation latency time\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Intra-vaginal ejaculation latency time\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Intra-vaginal ejaculation latency time\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Intra-vaginal ejaculation latency time\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Intra-vaginal ejaculation latency time\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
PE:\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
PE:\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
PE:\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Premature ejaculation\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Premature ejaculation\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Premature ejaculation\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Premature ejaculation\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Premature ejaculation\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Premature ejaculation\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
PRO:\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
PRO:\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
PRO:\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Patient reported outcome\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Patient reported outcome\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Patient reported outcome\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Patient reported outcome\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Patient reported outcome\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Patient reported outcome\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
PEDT:\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
PEDT:\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
PEDT:\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Premature ejaculation diagnostic tool\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Premature ejaculation diagnostic tool\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Premature ejaculation diagnostic tool\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Premature ejaculation diagnostic tool\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Premature ejaculation diagnostic tool\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Premature ejaculation diagnostic tool\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
RAI:\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
RAI:\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
RAI:\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Radioactive Iodine\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Radioactive Iodine\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Radioactive Iodine\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Radioactive Iodine\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Radioactive Iodine\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Radioactive Iodine\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
TSH:\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
TSH:\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
TSH:\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Thyroid stimulating hormone\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Thyroid stimulating hormone\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Thyroid stimulating hormone\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Thyroid stimulating hormone\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Thyroid stimulating hormone\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Thyroid stimulating hormone\strut
\end{minipage}\tabularnewline
\bottomrule
\end{longtable}

\textbf{Table.2 Risk of bias assessment}\selectlanguage{english}
\begin{longtable}[]{@{}lllllllll@{}}
\toprule
& \emph{Confounding} & \emph{Selection of participants} &
\emph{Classification of interventions} & \emph{Deviations from intended
interventions} & \emph{Missing data} & \emph{Measurement of the outcome}
& \emph{Selection of the reported result} & \emph{Overall
assessment}\tabularnewline
\midrule
\endhead
\emph{Culha MG,2020} & MR & MR & NI & NI & NI & MR & LR &
Moderate\tabularnewline
\emph{Khan HL,2018} & SR & MR & NI & NI & NI & MR & LR &
Serious\tabularnewline
\emph{Canat L,2017} & MR & SR & NI & NI & NI & MR & LR &
Serious\tabularnewline
\selectlanguage{ngerman}\emph{Öztürk MI, 2012} & LR & MR & NI & NI & NI & LR & LR &
Moderate\tabularnewline
\emph{Corona G,2010} & MR & MR & NI & NI & NI & MR & LR &
Moderate\tabularnewline
\emph{Cihan A,2009} & LR & LR & LR & LR & MR & LR & LR &
Moderate\tabularnewline
\emph{Carani C, 2005} & LR & LR & MR & MR & NI & LR & LR &
Moderate\tabularnewline
\emph{Waldinger MD, 2005} & SR & SR & NI & NI & NI & LR & MR &
Serious\tabularnewline
\emph{Corona G,2004} & MR & MR & NI & NI & NI & MR & LR &
Moderate\tabularnewline
Abbreviations: & LR: low Risk, MR: Moderate risk, SR: Serious risk, NI:
No information & LR: low Risk, MR: Moderate risk, SR: Serious risk, NI:
No information & LR: low Risk, MR: Moderate risk, SR: Serious risk, NI:
No information & LR: low Risk, MR: Moderate risk, SR: Serious risk, NI:
No information & LR: low Risk, MR: Moderate risk, SR: Serious risk, NI:
No information & LR: low Risk, MR: Moderate risk, SR: Serious risk, NI:
No information & LR: low Risk, MR: Moderate risk, SR: Serious risk, NI:
No information & LR: low Risk, MR: Moderate risk, SR: Serious risk, NI:
No information\tabularnewline
\bottomrule
\end{longtable}

\textbf{Table 3. Summary of findings of interventional studies}

Patients and population: Men with thyroid disorder\selectlanguage{english}
\begin{longtable}[]{@{}lll@{}}
\toprule
Patients and population: Men with thyroid disorder Patients and
population: Men with thyroid disorder Patients and population: Men with
thyroid disorder Setting: Hospital \emph{Intervention:} Thyroid disorder
treatment only. \emph{Intervention:} Thyroid disorder treatment only. &
&\tabularnewline
\bottomrule
\end{longtable}

\&

Patients and population: Men with thyroid disorder\selectlanguage{english}
\begin{longtable}[]{@{}lll@{}}
\toprule
Setting: Hospital & &\tabularnewline
\emph{Intervention:} Thyroid disorder treatment only. &
\emph{Intervention:} Thyroid disorder treatment only. &\tabularnewline
\bottomrule
\end{longtable}

\&

Patients and population: Men with thyroid disorder\selectlanguage{english}
\begin{longtable}[]{@{}lll@{}}
\toprule
Setting: Hospital & &\tabularnewline
\emph{Intervention:} Thyroid disorder treatment only. &
\emph{Intervention:} Thyroid disorder treatment only. &\tabularnewline
\bottomrule
\end{longtable}

\&

Patients and population: Men with thyroid disorder\selectlanguage{english}
\begin{longtable}[]{@{}lll@{}}
\toprule
Setting: Hospital & &\tabularnewline
\emph{Intervention:} Thyroid disorder treatment only. &
\emph{Intervention:} Thyroid disorder treatment only. &\tabularnewline
\bottomrule
\end{longtable}

\&

Patients and population: Men with thyroid disorder\selectlanguage{english}
\begin{longtable}[]{@{}lll@{}}
\toprule
Setting: Hospital & &\tabularnewline
\emph{Intervention:} Thyroid disorder treatment only. &
\emph{Intervention:} Thyroid disorder treatment only. &\tabularnewline
\bottomrule
\end{longtable}

\&

Patients and population: Men with thyroid disorder\selectlanguage{english}
\begin{longtable}[]{@{}lll@{}}
\toprule
Setting: Hospital & &\tabularnewline
\emph{Intervention:} Thyroid disorder treatment only. &
\emph{Intervention:} Thyroid disorder treatment only. &\tabularnewline
\bottomrule
\end{longtable}

\&

Patients and population: Men with thyroid disorder\selectlanguage{english}
\begin{longtable}[]{@{}lll@{}}
\toprule
Setting: Hospital & &\tabularnewline
\emph{Intervention:} Thyroid disorder treatment only. &
\emph{Intervention:} Thyroid disorder treatment only. &\tabularnewline
\bottomrule
\end{longtable}

\&

Patients and population: Men with thyroid disorder\selectlanguage{english}
\begin{longtable}[]{@{}lll@{}}
\toprule
Setting: Hospital & &\tabularnewline
\emph{Intervention:} Thyroid disorder treatment only. &
\emph{Intervention:} Thyroid disorder treatment only. &\tabularnewline
\bottomrule
\end{longtable}



\textbf{Figure legends.}

Figure 1. Study flow diagram

Figure 2-A. The forest plot of mean difference for serum TSH among PE
and non-PE subjects in available studies

Figure 2-B. The forest plot of the treatment effect of Hyperthyroidism
on mean IELT

Figure 2-C. The forest plot of the treatment effect of Hyperthyroidism
on the prevalence of PE\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Figure-1/Figure-1}

\end{center}
\end{figure}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Figure-2A/Figure-2A}

\end{center}
\end{figure}

\selectlanguage{english}
\FloatBarrier
\end{document}

