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\begin{document}

\title{Polycystic ovary syndrom(PCOS) and the association of subsequent risk of
Graves' Diseases: a population-based cohort study}



\author[1]{Ming-Li Chen}%
\author[1]{Jia-Ying Lin}%
\author[2]{Kun-Hong Li}%
\author[3]{Hei-Tung  Yip}%
\author[2]{James Cheng-Chung Wei}%
\affil[1]{Chung Shan Medical University College of Medicine}%
\affil[2]{Chung Shan Medical University}%
\affil[3]{China Medical University Hospital}%


\vspace{-1em}



  
  \date{May 16, 2024}


\begingroup
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\selectlanguage{english}
\begin{abstract}
Objective: This study aimed to investigate the risk of Graves' disease
in Polycystic ovary syndrome (PCOS) patients. Design: Population-based
retrospective cohort study. Setting: We utilized the medical records
randomly selected from the Taiwan National Health Insurance Research
Database (NHIRD) during period between 2000 and 2013. Population: We
included women aged between 20 and 50 who have no previous Graves'
disease diagnosis records. Methods: We matched the baseline
characteristics and the index date of the PCOS-free cohort to the PCOS
cohort at a ratio of 4:1 by propensity score matching method. Cox
proportional hazards model was used to estimate hazard ratios (HRs) and
95\% confidence intervals (CIs). Main outcome measure: To analyze the
cumulative incidence and the hazard ratio of Graves' disease events in
both PCOS group and PCOS-free cohort. Results: We identified 5927
patients as the PCOS cohort, and included 23708 patients as the
PCOS-free cohort. The PCOS group had a significant increased risk of
Graves' disease with an adjusted hazard ratio (aHR) of 1.34 (95\% CI=
1.00-1.81). The p-value was 0.03 in log-rank test. PCOS patients without
anxiety, chronic obstructive pulmonary disease, hypertension or
hyperlipidemia had a higher risk of Graves' disease in the
stratification analysis. Conclusions: This study revealed a significant
association between PCOS and subsequent risk of developing Graves'
disease. Funding: Nil. Tweetable abstract: PCOS increase the risk of
Graves' disease. Keywords: Polycystic ovary syndrome, PCOS, Graves'
disease, GD, hyperthyroidism, autoimmune thyroiditis, cohort, hazard
ratio, epidemiology, Taiwan National Health Insurance Research Database%
\end{abstract}%



\sloppy


\textbf{Introduction}

Polycystic ovary syndrome (PCOS) is recognized as one of the most common
endocrine disorders in women, causing ovulatory and menstrual
irregularity, infertility, hyperandrogenism, and metabolic dysfunction.
The association of PCOS and autoimmune diseases, especially autoimmune
thyroiditis, is increasingly being recognized. Graves' disease is an
autoimmune thyroiditis affecting mostly young women, and causes symptoms
such as hyperthyroidism, sweating, heat intolerance, weight loss,
increased appetite, and tremor.(1, 2) Characterized by lymphocytic
infiltration of the thyroid parenchyma, Graves' disease is found to be
regulated by T helper 1 (Th1) lymphocytes, several cytokines, and
chemokines.(3) Thyrotropin receptor autoantibodies (TRAb) act as the
important indicator of the development of Graves' disease, which is
often used in clinical assessment.(4, 5) Although the exact pathogenic
mechanism is not fully clear to date, an individual's genetic
predisposition, interactions between endogenous and environmental
factors, and immune system dysregulation greatly contribute to the onset
of Graves' disease.(6, 7)

Previous studies showed that patients with PCOS run an elevated risk of
autoimmune thyroiditis compared with those without PCOS.(8, 9) A
previous clinical trial proved a positive relationship between ovary
function, thyroid function, and insulin resistance in women.(10) A
previous systematic review also revealed a higher prevalence of
autoimmune thyroid diseases in patients with PCOS compared with those
without.(11) A Danish cohort study further indicated that patients with
PCOS had a higher risk to develop thyroid diseases.(12) However, only
few pieces of research exclusively explored the association between PCOS
and Graves's disease. A previous case series of 6 patients indicated a
positive relationship of PCOS and Graves' disease.(13) A higher
prevalence of serological indicator of Graves' disease has also been
found in PCOS patients.(14) Since the epidemiology of the relationship
of PCOS and new-onset Graves' disease hasn't been well disclosed, we
conducted this original longitudinal nationwide cohort study to explore
this issue.

\textbf{Methods}

\emph{Data source}

The data form the Taiwan National Health Insurance Research Database
(NHIRD) was analyzed in this study. The Taiwan National Health Insurance
(NHI) program launched in 1995 and covered 99\% of Taiwan residents. The
comprehensive claims data form NHI program was collected into NHIRD. We
utilized the outpatients and in-patient records of one million
beneficiaries, the Longitudinal Health Insurance Database (LHID). The
database used the International Classification of Diseases, Ninth
Revision, Clinical Modification (ICD-9-CM) codes to define the
corresponding diseases. Due to safety and privacy concerns, the
identification information was encrypted. This study was approved by the
International Review Board (IRB) of China Medical University and
Hospital (IRB permit number: CMUH-104-REC2--115).

\emph{Study population}

This cohort study was conducted retrospectively from 2000 to 2013.
Female with newly diagnosed with polycystic ovary syndrome (PCOS), with
at least two outpatient visits or once admission record, were enrolled
as PCOS cohort. The inclusion criteria were female aged from 20 to 50
years old, and have never been diagnosed with Graves' disease before. We
exclude patients with a history of thyroid diseases or comorbidities
that might have caused Graves' disease: congenital hypothyroidism
(ICD-9-CM code 243), postsurgical hypothyroidism (ICD-9-CM code 244.0),
other postablative hypothyroidism (ICD-9-CM code 244.1), iodine
hypothyroidism (ICD-9-CM code 244.2), other iatrogenic hypothyroidism
(ICD-9-CM code 244.3), iatrogenic thyroiditis (ICD-9-CM code 245.4), and
thyroid dysfunction (ICD-9-CM code 648.1). The PCOS-free female was
recruited as the PCOS-free cohort. We matched one PCOS patient to four
PCOS-free patients according to age and index year. The index date was
designed to be the first date of PCOS diagnosis for PCOS cohort, and a
random date between 2000 and 2012 for the PCOS-free cohort. We observed
the participant until they started a Graves' disease event, loss of
follow-up, or the end of the study, whichever came first.

\emph{Main outcome and comorbidities}

Graves' disease was the primary end point in this study. We defined
Graves' disease patients as patients with two or more outpatient visit,
or one in-patient records of ICD code 242.0. The following comorbidities
developed before the index date were considered as confounders: anxiety
(ICD-9-CM 309.2-309.4), asthma (ICD-9-CM 493), coronary artery disease
(CAD) (ICD-9-CM 410--413, 414.01--414.05, 414.8, and 414.9), cancer
(ICD-9-CM 140-208), chronic obstructive pulmonary disease (COPD)
(ICD-9-CM 490-496), congestive heart failure (CHF) (ICD-9-CM 398.91,
402.01, 402.11, 402.91, and 428), chronic liver diseases (CLD) (ICD-9-CM
571.4), diabetes mellitus (DM) (ICD-9-CM 250), depression (ICD-9-CM
296.2, 296.3, 296.5, 296.82, 300.4, 309.0-309.1 and 311), hypertension
(ICD-9-CM 401-405), hyperlipidemia (ICD-9-CM 272), stroke (ICD-9-CM
430-438) and sleep apnea (ICD-9-CM 327.2, 780.51, 780.53, 780.57).

\emph{Statistical analysis}

The variables were presented as percentages for categorical variables,
and as mean for continuous variables. We examined the baseline variables
of the PCOS cohort and non-PCOS cohort by chi-square tests and student's
t-tests. The Kaplan-Meier method was used to acquire the cumulative
incidence curve for the two cohorts. Log-rank test was also performed.
The univariate Cox proportional hazard (PH) model was applied to
estimate the hazard ratio and then adjusted the hazard ratio by
multivariate Cox PH model. All statistical analyses were conducted with
SAS 9.4 software (SAS Institute, Cary, NC, USA). P-value of less than
0.05 was regarded as significant.



\textbf{Results}

As shown in Table 1, we included 5927 patients with PCOS from 2000 to
2012 and 23708 patients without PCOS. The mean follow-up time of the
case cohort was 6.80 (\selectlanguage{ngerman}±3.56) years. The participants in our study were
mainly aged from 20-30 years old (60\%). The mean age was about 29 years
old. The proportion of patients with comorbidities was similar in both
cohorts.

The incidence rate of Graves' diseases for PCOS patients was 1.46 per
1000 person-years and that of non-PCOS patients was 1.06 per 1000
person-years (Table 2.). Figure 1 presented the cumulative incidence
curve of Graves' diseases in patients with PCOS was significantly higher
than that in the patient without PCOS (Log-rank test: p-value=0.03). The
adjusted hazard ratio (aHR) of Graves' disease for the PCOS cohort
relative to the non-PCOS cohort was 1.34 (95\% CI=1.00-1.81). Patients
with CAD and DM increased the risk of Graves' disease by 2.66 (95\% CI =
1.08-6.56) and 2.17 (95\% CI = 1.06, 4.44) folds, respectively.

Table 3 presents the stratification analysis of the association of PCOS
and Graves' disease in each age group and comorbidities. PCOS patients
aged 31-40 had a higher risk of Graves' disease (aHR=2.31,
95\%CI=1.48-3.61). The independent association of PCOS with Graves'
disease was significant in patients without anxiety, COPD, or
hypertension. For patients with hyperlipidemia, PCOS raises the risk of
Graves' disease by 10.2 (95\% CI=1.21, 85.1) times.

\textbf{Structured Discussion}

\emph{Principal Findings}

This 13-year retrospective cohort study revealed an increased incidence
of Graves' diseases in PCOS patients with an aHR of 1.34 (95\%C.I.
1.00-1.81) after adjusting for age and confounders listed in table 1. In
stratification analysis, the independent association of PCOS with
Graves' disease was especially significant in group aged 31 to 40
(aHR=2.31, 95\%C.I. 1.48-3.61). The cluster of PCOS and Graves' disease
at this age may due to the nature of PCOS, a common endocrinopathy of
reproductive age-group women. Several comorbidities were found
influential in our Cox regression model, such as CAD (aHR=2.66, 95\%C.I.
1.08-6.56) and DM (aHR=2.17, 95\%C.I. 1.06-4.44). In our stratification
study investigating into the association of PCOS and Graves' diseases in
different subgroups, we found that in patients with hypertension, the
independent association of PCOS with Graves' disease became
insignificant, which may be explainable due to probable effect of other
coexisting comorbidities and relatively small numbers of events.
However, in patients with hyperlipidemia, PCOS increases the risk of
Graves' diseases by 10 folds, higher than PCOS acting alone. In general,
after adjusting for confounders in our study, the overall independent
association of PCOS with Graves' disease remains strong, which may
supports the hypothesis of PCOS as a possible risk factor to the
development of Graves' diseases.

\emph{Results}

Previous studies highlight the association of Graves' diseases and PCOS
was presented, although comparably rare to hypothyroidism events.(12,
13, 15, 16) In previous case series, the clinical observation of
coexisting of definite PCOS and active form of Graves' disease
emphasized the role of autoimmunity in the development of PCOS,
suggesting a common pathogenic linkage between these two diseases.(13)
The risk of Graves' disease in PCOS was reported more than two times
higher than controls in a previous epidemiology study.(12) Higher
prevalence of TRAb, which is crucial in the evaluation of Graves'
disease,(17) has also been described in PCOS patients.(14)

\emph{Research Implications}

One theoretical mechanism is hyperestrogenic state in PCOS.
Hyperestrogenism increased autoimmune diseases by having a proliferative
action on B\selectlanguage{english}-lymphocytes, T\selectlanguage{english}-cell and macrophages.(18, 19) The positive
result of our study serves as a retrospective population-based evidence
to sustain previous observations of the interplay between the two
clinical conditions. The relationship between PCOS and Graves' diseases
might be more than a mere coincident finding in coexistence.

\emph{Clinical Implications}

Metabolic comorbidities are also note-worthy in interpreting the risk of
Graves' diseases in PCOS. In our study, patients with DM and CAD have
more risk to develop Graves' diseases. Adverse metabolic outcomes in
PCOS have been widely discussed in previous studies, such as impaired
glucose tolerance, insulin resistance, DM, cardiovascular disease, and
metabolic syndrome.(20) Obesity exacerbates many of these subsequent
outcomes such as DM.(21) Higher metabolic inflexibility was observed to
be associated with hyperandrogenemia and insulin resistance in PCOS
patients,(22) as a result of an inflammation status triggered by
saturated fat ingestion, may be a separate and distinct contributor
independent from obesity.(23) Obesity increases leptin and TRH level,
which further raise TSH and induce proliferation of adipocytes again via
TSH receptors. Leptin also lead to autoimmunity by up\selectlanguage{english}-regulating
effector T\selectlanguage{english}-cells and down\selectlanguage{english}-regulating regulator T\selectlanguage{english}-cells.(24)

Additionally, in our study, patients with depression were prone to
develop Graves' diseases with a subtle but insignificant aHR of 1.57
(95\%C.I. 0.92-2.67). Little but consistent evidence for psychological
issues in PCOS patients was presented in previous studies.(25-28)
Objective measurements such as obesity, insulin resistance, and elevated
serum androgens might partly contribute to the association of depression
and PCOS, but the conclusion remains controversial.(27, 28) Since
comorbidities sustained in our study were proven to reduce the quality
of life for patients with PCOS, physicians are suggested to closely
monitor the progression of high-risk comorbidities in PCOS patients.

\emph{Strengths and Limitations}

The main strength of the study was the sizable long-term
population-based patient group included in our study. The advantages of
using the NHIRD such as long-term comprehensive follow-up and universal
coverage has been described in a previous study.(29) We excluded
patients with previous thyroid diseases due to possible interplay of a
history of thyroid diseases that might have caused Graves' diseases. We
also qualified the definition of PCOS events in our study to more than
twice outpatient or one hospitalized record. Generally, our database
size ensures similar distributions due to well-balanced matching, and
reduces the heterogeneity and selection bias.

There are some limitations to our study. Since PCOS and autoimmune
thyroid diseases, including Graves' diseases, have a familial clustering
phenomenon, an alternative explanation may be suggested to a common
genetic pathway.(30) However, the genetic background of individuals was
not available in our NHIRD scheme. The development of Graves' diseases
may depend on different ethnic groups. Lab data such as hormone level
was also not available in NHIRD, posing limitations in further
addressing the association of the role of hormones in the association of
PCOS and Graves' diseases. Although the Bureau of NHI uses strict
auditing mechanisms to reimburse insurance claims, the ICD-9 codes
claimed from the NHIRD might be inaccurate due to diagnostic uncertainty
and misclassification in reality. The symptoms of PCOS and Graves'
diseases may sometimes be too mild to be recognized by patients. Thus,
the underrepresentation of the identified population may occur and
eclipse the accuracy of prevalence.

\emph{Conclusion}

Our study revealed a positive finding of the association between PCOS
and Graves' diseases. Beside from known importance of screening for
common comorbidities in PCOS patients, our findings stress the need for
monitoring for thyroid diseases during follow-up.

\textbf{Ethics statement}

This study was approved by the International Review Board (IRB) of China
Medical University and Hospital (IRB permit number: CMUH-104-REC2--115).
The need of informed consent was waived.

\textbf{Declaration of interest}

The authors report no conflict of interest.

\textbf{Contribution to authorship}

\textbf{Ming-Li Chen:} Conceptualization, Writing-Original draft
preparation, Writing-Review and editing \textbf{Jia-Ying
Lin:}Writing-Original draft preparation \textbf{Kun-Hong Li:}
Writing-Review and editing, Supervision \textbf{Hei-Tung Yip:}
Methodology, Software, Investigation, Data curation, Writing-Original
draft preparation, Visualization \textbf{James Cheng-Chung Wei:}
Writing-Review and editing, Supervision, Project administration

\textbf{Funding}

There is no funding in this research.

\textbf{Acknowledgment}

This study is supported in part by Taiwan Ministry of Health and Welfare
Clinical Trial Center (MOHW109-TDU-B-212-114004), MOST Clinical Trial
Consortium for Stroke (MOST 108-2321-B-039-003-), Tseng-Lien Lin
Foundation, Taichung, Taiwan.

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Figure 1. The cumulative incidence of Graves's diseases in patients with
and without PCOS.

Table 1. Baseline characteristics of non-PCOS cohort and PCOS cohort.\selectlanguage{english}
\begin{longtable}[]{@{}lllllll@{}}
\toprule
& Non-PCOS & Non-PCOS & & PCOS & PCOS &\tabularnewline
\midrule
\endhead
& (N=23708) & (N=23708) & & (N=5927) & (N=5927) &\tabularnewline
Variables & n & \% & & n & \% & p-value\tabularnewline
Age, year & & & & & & 1.00\tabularnewline
20-30 & 14160 & 60\% & & 3540 & 60\% &\tabularnewline
31-40 & 8165 & 34\% & & 2043 & 34\% &\tabularnewline
41-50 & 1383 & 6\% & & 344 & 6\% &\tabularnewline
mean, (SD) & 29.3 & (6.19) & & 29.1 & (6.01) & 0.06\tabularnewline
Comorbidities & & & & & &\tabularnewline
asthma & 1066 & 4\% & & 332 & 6\% & \textless{}0.001\tabularnewline
anxiety & 70 & 0.30\% & & 27 & 0.46\% & 0.07\tabularnewline
CAD & 179 & 1\% & & 58 & 1\% & 0.10\tabularnewline
cancer & 87 & 0.37\% & & 14 & 0.24\% & 0.16\tabularnewline
COPD & 2617 & 11\% & & 798 & 13\% & \textless{}0.001\tabularnewline
CHF & 41 & 0.17\% & & 19 & 0.32\% & 0.04\tabularnewline
CLD & 1309 & 6\% & & 492 & 8\% & \textless{}0.001\tabularnewline
diabetes & 314 & 1\% & & 170 & 3\% & \textless{}0.001\tabularnewline
depression & 1062 & 4\% & & 361 & 6\% & \textless{}0.001\tabularnewline
hypertension & 390 & 2\% & & 171 & 3\% & \textless{}0.001\tabularnewline
hyperlipidemia & 624 & 3\% & & 338 & 6\% &
\textless{}0.001\tabularnewline
stroke & 162 & 1\% & & 55 & 1\% & 0.06\tabularnewline
sleep apnea & 34 & 0.14\% & & 19 & 0.32\% & 0.01\tabularnewline
CAD: coronary artery disease; COPD: chronic obstructive pulmonary
disease; CHF: congestive heart failure; CLD: chronic liver diseases;
Follow-up time: Control: 6.76(3.56) Case: 6.80(3.56) & CAD: coronary
artery disease; COPD: chronic obstructive pulmonary disease; CHF:
congestive heart failure; CLD: chronic liver diseases; Follow-up time:
Control: 6.76(3.56) Case: 6.80(3.56) & CAD: coronary artery disease;
COPD: chronic obstructive pulmonary disease; CHF: congestive heart
failure; CLD: chronic liver diseases; Follow-up time: Control:
6.76(3.56) Case: 6.80(3.56) & CAD: coronary artery disease; COPD:
chronic obstructive pulmonary disease; CHF: congestive heart failure;
CLD: chronic liver diseases; Follow-up time: Control: 6.76(3.56) Case:
6.80(3.56) & CAD: coronary artery disease; COPD: chronic obstructive
pulmonary disease; CHF: congestive heart failure; CLD: chronic liver
diseases; Follow-up time: Control: 6.76(3.56) Case: 6.80(3.56) & CAD:
coronary artery disease; COPD: chronic obstructive pulmonary disease;
CHF: congestive heart failure; CLD: chronic liver diseases; Follow-up
time: Control: 6.76(3.56) Case: 6.80(3.56) & CAD: coronary artery
disease; COPD: chronic obstructive pulmonary disease; CHF: congestive
heart failure; CLD: chronic liver diseases; Follow-up time: Control:
6.76(3.56) Case: 6.80(3.56)\tabularnewline
\bottomrule
\end{longtable}

Table 2. Incidence rate and hazard ratio of Graves's diseases.\selectlanguage{english}
\begin{longtable}[]{@{}llllllll@{}}
\toprule
& Graves's diseases & Graves's diseases & Graves's diseases & & &
&\tabularnewline
\midrule
\endhead
Variables & n & PY & IR & cHR & (95\% CI) & aHR? & (95\%
CI)\tabularnewline
All & & & & & & &\tabularnewline
non-PCOS & 170 & 160255 & 1.06 & 1.00 & - & 1.00 & -\tabularnewline
PCOS & 59 & 40304 & 1.46 & 1.38 & (1.03,1.86)* & 1.34 &
(1.00,1.81)\tabularnewline
Age, year & & & & & & &\tabularnewline
14-20 & 135 & 123609 & 1.09 & 1.00 & - & 1.00 & -\tabularnewline
21-50 & 83 & 66141 & 1.25 & 1.15 & (0.87,1.51) & 1.11 &
(0.85,1.46)\tabularnewline
\textgreater{}50 & 11 & 10809 & 1.02 & 0.93 & (0.50,1.72) & 0.84 &
(0.45,1.57)\tabularnewline
Comorbidities & & & & & & &\tabularnewline
asthma & & & & & & &\tabularnewline
No & 219 & 192540 & 1.14 & 1.00 & - & &\tabularnewline
Yes & 10 & 8019 & 1.25 & 1.10 & (0.58,2.07) & &\tabularnewline
anxiety & & & & & & &\tabularnewline
No & 228 & 200085 & 1.14 & 1.00 & - & &\tabularnewline
Yes & 1 & 473 & 2.11 & 1.85 & (0.26,13.22) & &\tabularnewline
CAD & & & & & & &\tabularnewline
No & 224 & 199115 & 1.12 & 1.00 & - & 1.00 & -\tabularnewline
Yes & 5 & 1444 & 3.46 & 3.08 & (1.27,7.48)* & 2.66 &
(1.08,6.56)*\tabularnewline
cancer & & & & & & &\tabularnewline
No & 229 & 200002 & 1.14 & 1.00 & - & &\tabularnewline
Yes & 0 & 556 & 0.00 & 0.00 & (0,Inf) & &\tabularnewline
COPD & & & & & & &\tabularnewline
No & 201 & 180104 & 1.12 & 1.00 & - & &\tabularnewline
Yes & 28 & 20454 & 1.37 & 1.23 & (0.83,1.82) & &\tabularnewline
CHF & & & & & & &\tabularnewline
No & 229 & 200242 & 1.14 & 1.00 & - & &\tabularnewline
Yes & 0 & 317 & 0.00 & 0.00 & (0,Inf) & &\tabularnewline
CLD & & & & & & &\tabularnewline
No & 214 & 188949 & 1.13 & 1.00 & - & &\tabularnewline
Yes & 15 & 11610 & 1.29 & 1.14 & (0.68,1.92) & &\tabularnewline
diabetes & & & & & & &\tabularnewline
No & 221 & 197572 & 1.12 & 1.00 & - & 1.00 & -\tabularnewline
Yes & 8 & 2987 & 2.68 & 2.40 & (1.18,4.85)* & 2.17 &
(1.06,4.44)*\tabularnewline
depression & & & & & & &\tabularnewline
No & 214 & 192652 & 1.11 & 1.00 & - & 1.00 & -\tabularnewline
Yes & 15 & 7906 & 1.90 & 1.71 & (1.01,2.89)* & 1.57 &
(0.92,2.67)\tabularnewline
hypertension & & & & & & &\tabularnewline
No & 225 & 197060 & 1.14 & 1.00 & - & &\tabularnewline
Yes & 4 & 3499 & 1.14 & 1.00 & (0.37,2.69) & &\tabularnewline
hyperlipidemia & & & & & & &\tabularnewline
No & 222 & 194455 & 1.14 & 1.00 & - & &\tabularnewline
Yes & 7 & 6103 & 1.15 & 1.00 & (0.47,2.13) & &\tabularnewline
stroke & & & & & & &\tabularnewline
No & 227 & 199223 & 1.14 & 1.00 & - & &\tabularnewline
Yes & 2 & 1336 & 1.50 & 1.31 & (0.33,5.27) & &\tabularnewline
sleep apnea & & & & & & &\tabularnewline
No & 229 & 200297 & 1.14 & 1.00 & - & &\tabularnewline
Yes & 0 & 262 & 0.00 & 0.00 & (0,Inf) & &\tabularnewline
*: p-value\textless{}0.05; **: p-value\textless{}0.01; ***:
p-value\textless{}0.001; PY: person-years; IR: incidence rate (per 1000
person-years); cHR: crude hazard ratio; aHR: adjusted hazard ratio; CAD:
coronary artery disease; COPD: chronic obstructive pulmonary disease;
CHF: congestive heart failure; CLD: chronic liver diseases; ?: adjusted
for age, CAD, diabetes and depression & *: p-value\textless{}0.05; **:
p-value\textless{}0.01; ***: p-value\textless{}0.001; PY: person-years;
IR: incidence rate (per 1000 person-years); cHR: crude hazard ratio;
aHR: adjusted hazard ratio; CAD: coronary artery disease; COPD: chronic
obstructive pulmonary disease; CHF: congestive heart failure; CLD:
chronic liver diseases; ?: adjusted for age, CAD, diabetes and
depression & *: p-value\textless{}0.05; **: p-value\textless{}0.01; ***:
p-value\textless{}0.001; PY: person-years; IR: incidence rate (per 1000
person-years); cHR: crude hazard ratio; aHR: adjusted hazard ratio; CAD:
coronary artery disease; COPD: chronic obstructive pulmonary disease;
CHF: congestive heart failure; CLD: chronic liver diseases; ?: adjusted
for age, CAD, diabetes and depression & *: p-value\textless{}0.05; **:
p-value\textless{}0.01; ***: p-value\textless{}0.001; PY: person-years;
IR: incidence rate (per 1000 person-years); cHR: crude hazard ratio;
aHR: adjusted hazard ratio; CAD: coronary artery disease; COPD: chronic
obstructive pulmonary disease; CHF: congestive heart failure; CLD:
chronic liver diseases; ?: adjusted for age, CAD, diabetes and
depression & *: p-value\textless{}0.05; **: p-value\textless{}0.01; ***:
p-value\textless{}0.001; PY: person-years; IR: incidence rate (per 1000
person-years); cHR: crude hazard ratio; aHR: adjusted hazard ratio; CAD:
coronary artery disease; COPD: chronic obstructive pulmonary disease;
CHF: congestive heart failure; CLD: chronic liver diseases; ?: adjusted
for age, CAD, diabetes and depression & *: p-value\textless{}0.05; **:
p-value\textless{}0.01; ***: p-value\textless{}0.001; PY: person-years;
IR: incidence rate (per 1000 person-years); cHR: crude hazard ratio;
aHR: adjusted hazard ratio; CAD: coronary artery disease; COPD: chronic
obstructive pulmonary disease; CHF: congestive heart failure; CLD:
chronic liver diseases; ?: adjusted for age, CAD, diabetes and
depression & *: p-value\textless{}0.05; **: p-value\textless{}0.01; ***:
p-value\textless{}0.001; PY: person-years; IR: incidence rate (per 1000
person-years); cHR: crude hazard ratio; aHR: adjusted hazard ratio; CAD:
coronary artery disease; COPD: chronic obstructive pulmonary disease;
CHF: congestive heart failure; CLD: chronic liver diseases; ?: adjusted
for age, CAD, diabetes and depression & *: p-value\textless{}0.05; **:
p-value\textless{}0.01; ***: p-value\textless{}0.001; PY: person-years;
IR: incidence rate (per 1000 person-years); cHR: crude hazard ratio;
aHR: adjusted hazard ratio; CAD: coronary artery disease; COPD: chronic
obstructive pulmonary disease; CHF: congestive heart failure; CLD:
chronic liver diseases; ?: adjusted for age, CAD, diabetes and
depression\tabularnewline
\bottomrule
\end{longtable}

Table 3. Incidence rate and hazard ratio of Graves's diseases stratified
by age and comorbidities.\selectlanguage{english}
\begin{longtable}[]{@{}llllllllllll@{}}
\toprule
& Non-PCOS & Non-PCOS & Non-PCOS & & PCOS & PCOS & PCOS & & &
&\tabularnewline
\midrule
\endhead
Variables & n & PY & IR & & n & PY & IR & cHR & (95\% CI) & aHR? & (95\%
CI)\tabularnewline
Age, year & & & & & & & & & & &\tabularnewline
20-30 & 108 & 98651 & 1.09 & & 27 & 24958 & 1.08 & 0.99 & (0.65,1.51) &
0.96 & (0.63,1.47)\tabularnewline
31-40 & 52 & 52931 & 0.98 & & 31 & 13210 & 2.35 & 2.38 & (1.53,3.72)***
& 2.31 & (1.48,3.61)***\tabularnewline
41-50 & 10 & 8673 & 1.15 & & 1 & 2135 & 0.47 & 0.40 & (0.05,3.16) & 0.38
& (0.05,2.96)\tabularnewline
Comorbidities & & & & & & & & & & &\tabularnewline
asthma & & & & & & & & & & &\tabularnewline
No & 164 & 154157 & 1.06 & & 55 & 38383 & 1.43 & 1.35 & (0.99,1.83) &
1.31 & (0.97,1.79)\tabularnewline
Yes & 6 & 6098 & 0.98 & & 4 & 1921 & 2.08 & 2.16 & (0.61,7.66) & 1.99 &
(0.55,7.15)\tabularnewline
anxiety & & & & & & & & & & &\tabularnewline
No & 169 & 159918 & 1.06 & & 59 & 40167 & 1.47 & 1.39 & (1.03,1.87)* &
1.35 & (1.00 ,1.82)*\tabularnewline
Yes & 1 & 336 & 2.97 & & 0 & 137 & 0.00 & 0.00 & (0,Inf) & 0.00 &
(0,Inf)\tabularnewline
CAD & & & & & & & & & & &\tabularnewline
No & 167 & 159163 & 1.05 & & 57 & 39952 & 1.43 & 1.36 & (1.01,1.84)* &
1.33 & (0.98,1.80)\tabularnewline
Yes & 3 & 1092 & 2.75 & & 2 & 352 & 5.68 & 2.09 & (0.35,12.5) & 1.74 &
(0.29,10.6)\tabularnewline
cancer & & & & & & & & & & &\tabularnewline
No & 170 & 159791 & 1.06 & & 59 & 40211 & 1.47 & 1.38 & (1.03,1.85)* &
1.34 & (1.00,1.81)\tabularnewline
Yes & 0 & 463 & 0.00 & & 0 & 93 & 0.00 & & & &\tabularnewline
COPD & & & & & & & & & & &\tabularnewline
No & 149 & 144616 & 1.03 & & 52 & 35488 & 1.47 & 1.42 & (1.04,1.95)* &
1.38 & (1.00,1.89)*\tabularnewline
Yes & 21 & 15638 & 1.34 & & 7 & 4816 & 1.45 & 1.09 & (0.46,2.56) & 1.09
& (0.46,2.56)\tabularnewline
CHF & & & & & & & & & & &\tabularnewline
No & 170 & 160029 & 1.06 & & 59 & 40213 & 1.47 & 1.38 & (1.03,1.86)* &
1.34 & (1.00,1.81)\tabularnewline
Yes & 0 & 226 & 0.00 & & 0 & 91 & 0.00 & & & &\tabularnewline
CLD & & & & & & & & & & &\tabularnewline
No & 162 & 151992 & 1.07 & & 52 & 36957 & 1.41 & 1.32 & (0.97,1.80) &
1.28 & (0.94,1.76)\tabularnewline
Yes & 8 & 8262 & 0.97 & & 7 & 3347 & 2.09 & 2.26 & (0.82,6.23) & 2.28 &
(0.82,6.31)\tabularnewline
diabetes & & & & & & & & & & &\tabularnewline
No & 166 & 158371 & 1.05 & & 55 & 39200 & 1.40 & 1.34 & (0.99,1.82) &
1.32 & (0.98,1.80)\tabularnewline
Yes & 4 & 1883 & 2.12 & & 4 & 1104 & 3.62 & 1.71 & (0.43,6.86) & 1.74 &
(0.43,7.02)\tabularnewline
depression & & & & & & & & & & &\tabularnewline
No & 160 & 154306 & 1.04 & & 54 & 38347 & 1.41 & 1.36 & (1.00,1.85) &
1.32 & (0.97,1.80)\tabularnewline
Yes & 10 & 5949 & 1.68 & & 5 & 1957 & 2.55 & 1.48 & (0.51,4.34) & 1.52 &
(0.52,4.45)\tabularnewline
hypertension & & & & & & & & & & &\tabularnewline
No & 167 & 157821 & 1.06 & & 58 & 39239 & 1.48 & 1.40 & (1.04,1.88)* &
1.36 & (1.01,1.84)*\tabularnewline
Yes & 3 & 2434 & 1.23 & & 1 & 1065 & 0.94 & 0.74 & (0.08,7.12) & 0.69 &
(0.07,6.95)\tabularnewline
hyperlipidemia & & & & & & & & & & &\tabularnewline
No & 169 & 156266 & 1.08 & & 53 & 38189 & 1.39 & 1.28 & (0.94,1.75) &
1.25 & (0.92,1.71)\tabularnewline
Yes & 1 & 3989 & 0.25 & & 6 & 2115 & 2.84 & 11.4 & (1.37,94.5)* & 10.2 &
(1.21,85.1)*\tabularnewline
stroke & & & & & & & & & & &\tabularnewline
No & 169 & 159256 & 1.06 & & 58 & 39966 & 1.45 & 1.37 & (1.01,1.84)* &
1.34 & (0.99,1.80)\tabularnewline
Yes & 1 & 998 & 1.00 & & 1 & 338 & 2.96 & 2.81 & (0.18,45.0) & 2.83 &
(0,Inf)\tabularnewline
sleep apnea & & & & & & & & & & &\tabularnewline
No & 170 & 160081 & 1.06 & & 59 & 40215 & 1.47 & 1.38 & (1.03,1.86)* &
1.34 & (1.00,1.81)\tabularnewline
Yes & 0 & 173 & 0.00 & & 0 & 89 & 0.00 & & & &\tabularnewline
*: p-value\textless{}0.05; **: p-value\textless{}0.01; ***:
p-value\textless{}0.001; PY: person-years; IR: incidence rate (per 1000
person-years); cHR: crude hazard ratio; aHR: adjusted hazard ratio; CAD:
coronary artery disease; COPD: chronic obstructive pulmonary disease;
CHF: congestive heart failure; CLD: chronic liver diseases; ?: adjusted
for age, CAD, diabetes and depression. & *: p-value\textless{}0.05; **:
p-value\textless{}0.01; ***: p-value\textless{}0.001; PY: person-years;
IR: incidence rate (per 1000 person-years); cHR: crude hazard ratio;
aHR: adjusted hazard ratio; CAD: coronary artery disease; COPD: chronic
obstructive pulmonary disease; CHF: congestive heart failure; CLD:
chronic liver diseases; ?: adjusted for age, CAD, diabetes and
depression. & *: p-value\textless{}0.05; **: p-value\textless{}0.01;
***: p-value\textless{}0.001; PY: person-years; IR: incidence rate (per
1000 person-years); cHR: crude hazard ratio; aHR: adjusted hazard ratio;
CAD: coronary artery disease; COPD: chronic obstructive pulmonary
disease; CHF: congestive heart failure; CLD: chronic liver diseases; ?:
adjusted for age, CAD, diabetes and depression. & *:
p-value\textless{}0.05; **: p-value\textless{}0.01; ***:
p-value\textless{}0.001; PY: person-years; IR: incidence rate (per 1000
person-years); cHR: crude hazard ratio; aHR: adjusted hazard ratio; CAD:
coronary artery disease; COPD: chronic obstructive pulmonary disease;
CHF: congestive heart failure; CLD: chronic liver diseases; ?: adjusted
for age, CAD, diabetes and depression. & *: p-value\textless{}0.05; **:
p-value\textless{}0.01; ***: p-value\textless{}0.001; PY: person-years;
IR: incidence rate (per 1000 person-years); cHR: crude hazard ratio;
aHR: adjusted hazard ratio; CAD: coronary artery disease; COPD: chronic
obstructive pulmonary disease; CHF: congestive heart failure; CLD:
chronic liver diseases; ?: adjusted for age, CAD, diabetes and
depression. & *: p-value\textless{}0.05; **: p-value\textless{}0.01;
***: p-value\textless{}0.001; PY: person-years; IR: incidence rate (per
1000 person-years); cHR: crude hazard ratio; aHR: adjusted hazard ratio;
CAD: coronary artery disease; COPD: chronic obstructive pulmonary
disease; CHF: congestive heart failure; CLD: chronic liver diseases; ?:
adjusted for age, CAD, diabetes and depression. & *:
p-value\textless{}0.05; **: p-value\textless{}0.01; ***:
p-value\textless{}0.001; PY: person-years; IR: incidence rate (per 1000
person-years); cHR: crude hazard ratio; aHR: adjusted hazard ratio; CAD:
coronary artery disease; COPD: chronic obstructive pulmonary disease;
CHF: congestive heart failure; CLD: chronic liver diseases; ?: adjusted
for age, CAD, diabetes and depression. & *: p-value\textless{}0.05; **:
p-value\textless{}0.01; ***: p-value\textless{}0.001; PY: person-years;
IR: incidence rate (per 1000 person-years); cHR: crude hazard ratio;
aHR: adjusted hazard ratio; CAD: coronary artery disease; COPD: chronic
obstructive pulmonary disease; CHF: congestive heart failure; CLD:
chronic liver diseases; ?: adjusted for age, CAD, diabetes and
depression. & *: p-value\textless{}0.05; **: p-value\textless{}0.01;
***: p-value\textless{}0.001; PY: person-years; IR: incidence rate (per
1000 person-years); cHR: crude hazard ratio; aHR: adjusted hazard ratio;
CAD: coronary artery disease; COPD: chronic obstructive pulmonary
disease; CHF: congestive heart failure; CLD: chronic liver diseases; ?:
adjusted for age, CAD, diabetes and depression. & *:
p-value\textless{}0.05; **: p-value\textless{}0.01; ***:
p-value\textless{}0.001; PY: person-years; IR: incidence rate (per 1000
person-years); cHR: crude hazard ratio; aHR: adjusted hazard ratio; CAD:
coronary artery disease; COPD: chronic obstructive pulmonary disease;
CHF: congestive heart failure; CLD: chronic liver diseases; ?: adjusted
for age, CAD, diabetes and depression. & *: p-value\textless{}0.05; **:
p-value\textless{}0.01; ***: p-value\textless{}0.001; PY: person-years;
IR: incidence rate (per 1000 person-years); cHR: crude hazard ratio;
aHR: adjusted hazard ratio; CAD: coronary artery disease; COPD: chronic
obstructive pulmonary disease; CHF: congestive heart failure; CLD:
chronic liver diseases; ?: adjusted for age, CAD, diabetes and
depression. & *: p-value\textless{}0.05; **: p-value\textless{}0.01;
***: p-value\textless{}0.001; PY: person-years; IR: incidence rate (per
1000 person-years); cHR: crude hazard ratio; aHR: adjusted hazard ratio;
CAD: coronary artery disease; COPD: chronic obstructive pulmonary
disease; CHF: congestive heart failure; CLD: chronic liver diseases; ?:
adjusted for age, CAD, diabetes and depression.\tabularnewline
\bottomrule
\end{longtable}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/fig-1/fig-1}

\end{center}
\end{figure}

\selectlanguage{english}
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\end{document}

