\documentclass[10pt]{article}

\usepackage{fullpage}
\usepackage{setspace}
\usepackage{parskip}
\usepackage{titlesec}
\usepackage[section]{placeins}
\usepackage{xcolor}
\usepackage{breakcites}
\usepackage{lineno}
\usepackage{hyphenat}





\PassOptionsToPackage{hyphens}{url}
\usepackage[colorlinks = true,
            linkcolor = blue,
            urlcolor  = blue,
            citecolor = blue,
            anchorcolor = blue]{hyperref}
\usepackage{etoolbox}
\makeatletter
\patchcmd\@combinedblfloats{\box\@outputbox}{\unvbox\@outputbox}{}{%
  \errmessage{\noexpand\@combinedblfloats could not be patched}%
}%
\makeatother


\usepackage{natbib}




\renewenvironment{abstract}
  {{\bfseries\noindent{\abstractname}\par\nobreak}\footnotesize}
  {\bigskip}

\titlespacing{\section}{0pt}{*3}{*1}
\titlespacing{\subsection}{0pt}{*2}{*0.5}
\titlespacing{\subsubsection}{0pt}{*1.5}{0pt}


\usepackage{authblk}


\usepackage{graphicx}
\usepackage[space]{grffile}
\usepackage{latexsym}
\usepackage{textcomp}
\usepackage{longtable}
\usepackage{tabulary}
\usepackage{booktabs,array,multirow}
\usepackage{amsfonts,amsmath,amssymb}
\providecommand\citet{\cite}
\providecommand\citep{\cite}
\providecommand\citealt{\cite}
% You can conditionalize code for latexml or normal latex using this.
\newif\iflatexml\latexmlfalse
\providecommand{\tightlist}{\setlength{\itemsep}{0pt}\setlength{\parskip}{0pt}}%

\AtBeginDocument{\DeclareGraphicsExtensions{.pdf,.PDF,.eps,.EPS,.png,.PNG,.tif,.TIF,.jpg,.JPG,.jpeg,.JPEG}}

\usepackage[utf8]{inputenc}
\usepackage[ngerman,greek,english]{babel}



\usepackage{float}








\begin{document}

\title{Association of uterine leiomyoma with type 2 diabetes mellitus in young
women: a population-based cohort study}



\author[1]{Cheol-Young Park}%
\author[2]{Ji-Hee Sung}%
\author[3]{Kyung-Soo Kim}%
\author[4]{Kyungdo Han}%
\affil[1]{Kangbuk Samsung Hospital Department of Internal Medicine Division of Endocrinology and Metabolism}%
\affil[2]{Samsung Medical Center}%
\affil[3]{CHA Bundang Medical Center}%
\affil[4]{Soongsil University Department of Statistics and Actuarial Science}%


\vspace{-1em}



  
  \date{May 25, 2024}


\begingroup
\let\center\flushleft
\let\endcenter\endflushleft
\maketitle
\endgroup





\selectlanguage{english}
\begin{abstract}
\textbf{Objective: T}o evaluate the association between uterine
leiomyoma (UL) and development of type 2 diabetes mellitus in young
women using a nationwide database. \textbf{Design:} Nationwide
population-based cohort study \textbf{Setting:} South Korea.
\textbf{Population or Sample:} Women aged between 20 and 40 years at
baseline who underwent at least one health checkup between 2009 and 2012
and followed until December 31, 2018 \textbf{Methods}: We excluded those
who were previously diagnosed with type 2 diabetes mellitus (n =
28,136), those diagnosed with type 2 diabetes mellitus within the first
year of entry (n = 1,607), those who had hysterectomy during the study
period (n = 18,485), and those with missing data (n = 166,012). Cox
proportional hazards models were used to analyze the risk of developing
type 2 diabetes according to the presence of UL. \textbf{Main outcome
Measures:} Incidence of the development of type 2 diabetes mellitus
according to the presence of UL \textbf{Results:} 2,755,790 women were
selected and he mean age of the enrolled population was 29.70 y, and
mean body mass index was 21.31 kg/m \textsuperscript{2}. Among 2,541,550
participants, 18,375 (0.72\%) women had UL. Over a median 7.45 years of
follow-up, 23,829 women (0.94\%) were diagnosed with type 2 diabetes.
The incidence of type 2 diabetes in women with UL (1.805/1,000
person-years) was higher than in those without UL (1.289/1000
person-years). In the multivariable-adjusted model, the hazard ratio for
type 2 diabetes in women with UL was 1.216 (95\% confidence interval
{[}CI{]} 1.071-1.382), as compared to those without UL. Compared to
women without UL, women with UL who did not undergo myomectomy had a
risk 1.328 times (95\% CI 1.143-1.542) higher for developing type 2
diabetes. Interestingly, women with UL who underwent myomectomy had no
increased risk for developing type 2 diabetes. \textbf{Conclusions:}
This study found that young women with UL are more likely to develop
type 2 diabetes than those without UL. In addition, myomectomy seemed to
attenuate the risk for developing type 2 diabetes in young women with
UL.%
\end{abstract}%



\sloppy


\textbf{Association of uterine leiomyoma with type 2 diabetes mellitus
in young women: a population-based cohort study}

\textbf{Ji-Hee Sung\textsuperscript{1,*} \textbar{} Kyung-Soo
Kim\textsuperscript{2,*} \textbar{} Kyungdo
Han\textsuperscript{3}\textbar{} Cheol-Young Park\textsuperscript{4}}

\textsuperscript{1}Department of Obstetrics and Gynecology, Samsung
Medical Center, Sungkyunkwan University School of Medicine, Seoul,
Republic of Korea. obgysung@gmail.com

\textsuperscript{2}Department of Internal Medicine, CHA Bundang Medical
Center, CHA University School of Medicine, Seongnam, Republic of Korea.
kks982@hanmail.net

\textsuperscript{3}Department of Statistics and Actuarial Science,
Soongsil University, Seoul, Republic of Korea. hkd917@naver.com

\textsuperscript{4}Department of Internal Medicine, Kangbuk Samsung
Hospital, Sungkyunkwan University School of Medicine, Seoul, Republic of
Korea, cydoctor@chol.com

Article Word Count: 2,930 words

Table/Figure Number: 4

\textsuperscript{*} Ji-Hee Sung and Kyung-Soo Kim contributed equally to
the work.

\textbf{Corresponding author:} Cheol-Young Park, MD, PhD

Department of Internal Medicine, Kangbuk Samsung Hospital, Sungkyunkwan
University School of Medicine, 29 Saemunan-ro, Jongno-gu, Seoul 03181,
Korea

Tel: +82-2-2001-1869, Fax: +82-2-2001-1588, E-mail: cydoctor@chol.com

\textbf{Short title:} Uterine leiomyoma and type 2 diabetes mellitus



\textbf{Abstract}

\textbf{Objective: T} o evaluate the association between uterine
leiomyoma (UL) and development of type 2 diabetes mellitus in young
women using a nationwide database.

\textbf{Design:} Nationwide population-based cohort study

\textbf{Setting:} South Korea.

\textbf{Population or Sample:} Women aged between 20 and 40 years at
baseline who underwent at least one health checkup between 2009 and 2012
and followed until December 31, 2018

\textbf{Methods} : We excluded those who were previously diagnosed with
type 2 diabetes mellitus (n = 28,136), those diagnosed with type 2
diabetes mellitus within the first year of entry (n = 1,607), those who
had hysterectomy during the study period (n = 18,485), and those with
missing data (n = 166,012). Cox proportional hazards models were used to
analyze the risk of developing type 2 diabetes according to the presence
of UL.

\textbf{Main outcome Measures:} Incidence of the development of type 2
diabetes mellitus according to the presence of UL

\textbf{Results:} 2,755,790 women were selected and he mean age of the
enrolled population was 29.70 y, and mean body mass index was 21.31
kg/m\textsuperscript{2}. Among 2,541,550 participants, 18,375 (0.72\%)
women had UL. Over a median 7.45 years of follow-up, 23,829 women
(0.94\%) were diagnosed with type 2 diabetes. The incidence of type 2
diabetes in women with UL (1.805/1,000 person-years) was higher than in
those without UL (1.289/1000 person-years). In the
multivariable-adjusted model, the hazard ratio for type 2 diabetes in
women with UL was 1.216 (95\% confidence interval {[}CI{]} 1.071-1.382),
as compared to those without UL. Compared to women without UL, women
with UL who did not undergo myomectomy had a risk 1.328 times (95\% CI
1.143-1.542) higher for developing type 2 diabetes. Interestingly, women
with UL who underwent myomectomy had no increased risk for developing
type 2 diabetes.

\textbf{Conclusions:} This study found that young women with UL are more
likely to develop type 2 diabetes than those without UL. In addition,
myomectomy seemed to attenuate the risk for developing type 2 diabetes
in young women with UL.

\textbf{Keywords:} Type 2 diabetes mellitus, uterine fibroids, surgery,
young women, incidence

\textbf{1 \textbar{} Introduction}

Uterine leiomyoma (UL) is one of the most common benign tumors of the
uterus; by menopause, the incidence of UL in the general female
population is 70\%.\textsuperscript{1,2} UL is often asymptomatic and
rarely becomes malignant; however, it may cause pelvic pain,
dysmenorrhea, excessive uterine bleeding, and infertility in women of
reproductive age. Old age, younger age at menarche, and premenopausal
state are risk factors for developing UL, as it is linked to longer
duration of exposure to ovarian hormones.\textsuperscript{3,4}

Insulin resistance was suggested as one of the possible
pathophysiological explanations for UL
development.\textsuperscript{5,6}Furthermore, hyperinsulinemia induced
by insulin resistance can upregulate serum insulin-like growth factor-1
and epidermal growth factor levels.\textsuperscript{7-9} This can affect
the development of UL by enhancing either ovarian hormone secretion or
myometrial smooth muscle cell proliferation, or both. A report that
supports this rationale stated that metabolic syndrome was associated
with UL.\textsuperscript{10} Another study reported that the risk of
development of UL was decreased with the use of metformin in women with
type 2 diabetes mellitus.\textsuperscript{11} Based on these reports, we
can assume that there is a possible association between type 2 diabetes
and UL. However, there is no large scale, population-based study that
has investigated the association between presence of UL and development
of type 2 diabetes. The aim of this study was to evaluate the
association between UL and development of type 2 diabetes in a large
population of young women using a nationwide database.

\textbf{2 \textbar{} methods}

\textbf{2.1 \textbar{} Data source}

We conducted a nationwide population-based cohort study using claims and
health checkup data from the National Health Insurance Service-National
Sample Cohort (NHIS-NSC). The NHIS is a single-payer health care system
for all Korean residents managed by the Korean government, covering more
than 98\% of the Korean population. The claims data encompasses
sociodemographic variables; diagnosis statements defined by the
International Classification of Diseases, 10th revision (ICD-10);
prescriptions; and hospital visits dates. Our study protocol was
approved by the NHIS review committee and Institutional Review Board of
Kangbuk Samsung hospital (IRB No. KBSMC-07-034). Informed consent was
waived by IRB as the data set provided from NHIS is deidentified to
protect privacy.

\textbf{2.2 \textbar{} Study design and participants}

We selected 2,755,790 women aged between 20 and 40 years at baseline who
underwent at least one health checkup between 2009 and 2012. The time
point at the first health checkup for each patient between 2009 and 2012
was considered the index date. We excluded those who were previously
diagnosed with type 2 diabetes mellitus (\emph{n} = 28,136), those
diagnosed with type 2 diabetes mellitus within the first year of entry
(\emph{n} = 1,607), those who had uterine myomectomy during the study
period (\emph{n} = 18,485), and those with missing data for least 1
variable (\emph{n} = 166,012). Finally, a total of 2,541,550 patients
were eligible for inclusion and were followed until December 31, 2018.

\textbf{2.3 \textbar{} Study outcomes and follow-up}

he end point of this study was the incidence of type 2 diabetes
mellitus. The study population was followed from the index date to the
date of incident type 2 diabetes mellitus, or until December 31, 2018.
The median follow-up duration was 7.45 years.

\textbf{2.4 \textbar{} Measurements}

Blood pressure (both systolic and diastolic values) was measured by a
trained clinician while the participants were seated. Blood samples were
obtained after at least 8 hours of fasting. The levels of glucose, total
cholesterol, triglycerides (TG), high-density lipoprotein (HDL)
cholesterol, low-density lipoprotein (LDL) cholesterol, and creatinine
were measured. Estimated glomerular filtration rate (eGFR) was
calculated using the equation from the Modification of Diet in Renal
Disease study: eGFR=186.3\selectlanguage{ngerman}×serum
creatinine\selectlanguage{english}\textsuperscript{-1.154}xage\selectlanguage{english}\textsuperscript{-0.203}x0.742
(for women).

Information about lifestyle factors, including smoking status, alcohol
intake status, exercise frequency, and past medical history (history of
hypertension, dyslipidemia, impaired fasting glucose {[}IFG{]}, and
chronic kidney disease {[}CKD{]}) was obtained using a standardized
self-assessment questionnaire. Drinking status was divided into three
categories: nondrinker, mild drinker, and heavy drinker; heavy alcohol
consumption was defined as drinking more than 30 g of alcohol per day.
Regular physical activity was defined as more than 30 minutes of
moderate physical activity performed at least five times per week, or
more than 20 minutes of strenuous physical activity performed at least
three times per week. Low income was defined as being within the lowest
20\% of the total population based on monthly income.

\textbf{2.5 \textbar{} Definitions}

Uterine leiomyoma was identified in case of female patient admittance
with ICD-10 code D25 at least once or diagnosis with ICD-10 codes D25
upon outpatient clinic visit at least twice within one year from the
index date. Myomectomy was defined as an ICD-10 code for myomectomy
(QZ961, R4120-4126, R4130, R4141, R4145, R4146, RZ564-566, HA636, HA621,
M6644) logged within one year of the index date. Type 2 diabetes
mellitus was defined as having fasting plasma glucose (FPG)
concentrations \selectlanguage{english}[?]126 mg/dL or having been prescribed anti-diabetic drugs
under ICD-10 codes E11--E14.

Hypertension was defined as blood pressure \selectlanguage{english}[?]140/90 mm Hg or having been
prescribed anti-hypertensive drugs under ICD-10 codes I10-13, I15.
Dyslipidemia was defined using ICD-10 codes E78 and at least one record
per year for a prescription for a lipid-lowering agent or by a total
cholesterol level \selectlanguage{english}[?]240 mg/dL. Impaired fasting glucose was defined as
FPG 100-125 mg/dL, and CKD was defined as eGFR \textless{}60 mL/min/1.73
m\textsuperscript{2}.

\textbf{2.6 \textbar{} Statistical analyses}

Continuous variables are presented as mean +- standard deviation or
median (interquartile range), while categorical variables are presented
as numbers (\%). Baseline clinical characteristics were compared between
groups using Student's t-test for continuous variables and
\selectlanguage{greek}χ\selectlanguage{english}\textsuperscript{2} test for categorical variables. Incidence rates are
presented as the number of events occurring per 1000 person-years. The
Cox proportional hazards model was used to estimate adjusted hazard
ratio with a 95\% confidence interval (CI) for type 2 diabetes mellitus.
The covariates were as follows: age, smoking status, alcohol
consumption, and regular exercise in model 1; and age, smoking status,
alcohol consumption, regular exercise, hypertension, dyslipidemia, and
body mass index (BMI) in model 2. The cumulative incidence of type 2
diabetes mellitus according to the presence of UL and myomectomy was
estimated using the Kaplan-Meier method. Subgroup analyses were
performed according to age, BMI, smoking status, alcohol consumption,
regular exercise, and having hypertension, dyslipidemia, and CKD. All
data analyses were performed using SAS version 9.4 (SAS Institute, Cary,
NC, USA). A P-value \textless{} 0.05 was considered significant.

\textbf{2.7 \textbar{} Data and resource availability statements}

Restrictions apply to the availability of these data. Data were obtained
from Korea NHIS and are available at
https://nhiss.nhis.or.kr/bd/ay/bdaya001iv.do (accessed on 1st April
2022) with the permission of Korea NHIS.

\textbf{3 \textbar{} Results}

Baseline characteristics of patients are presented in Table 1. A total
of 2,541,550 women were eligible, of whom 18,375 (0.72\%) were diagnosed
with UL. The mean age was 29.70 y, and mean BMI was 21.31
kg/m\textsuperscript{2}. Women with UL were older; had higher BMI, blood
pressure, FPG, total cholesterol, TG, and LDL cholesterol; and had
higher prevalence of hypertension, dyslipidemia, and IFG, as well as
lower HDL cholesterol, than those without UL. However, women with UL
were revealed to have a lower rate of current smoking and heavy drinking
status as compared to those without UL. There was no significant
difference in CKD prevalence or regular exercise frequency between women
with UL and those without UL.

Over a median 7.45 years of follow-up, 23,829 women (0.94\%) were
diagnosed with type 2 diabetes mellitus (Table 2). The incidence rate of
type 2 diabetes mellitus in women with UL (1.805/1,000 person-years) was
higher than that in those without UL (1.289/1000 person-years)
(\emph{P}\textless{} 0.0001). The cumulative incidence of type 2
diabetes mellitus in women with UL was higher than that in those without
UL (\emph{P} = 0.0026) (Fig. 1A). The unadjusted HR for type 2 diabetes
mellitus in women with UL was 1.403 (95\%CI 1.236-1.593) compared to
that in those without UL. Although the HR for type 2 diabetes mellitus
was slightly decreased after adjustment for age, smoking status, alcohol
consumption, and regular exercise (model 1), women with UL still showed
an elevated HR for type 2 diabetes mellitus(HR 1.195, 95\%CI
1.053-1.358). In multivariable-adjusted model (model 2), the HR for type
2 diabetes mellitus in women with UL was 1.216 (95\%CI 1.071-1.382).

Subgroup analyses stratified by age, BMI, smoking status, alcohol
consumption, regular exercise, and having hypertension, dyslipidemia,
and CKD were performed (Table 3). Women with UL showed a higher risk for
type 2 diabetes mellitus than women without UL in various subgroups,
except in those with BMI [?]25 kg/m\textsuperscript{2} and a history of
CKD.

Women with UL who underwent myomectomy were older and had higher BMI
than those with UL who did not undergo myomectomy (Supplementary Table
1). There was no significant difference in other baseline
characteristics between the two groups. Compared with women without UL,
women with UL who did not undergo myomectomy had a 1.505 times (95\%CI
1.297-1.748) higher risk for type 2 diabetes mellitus, as opposed to no
increased risk for type 2 diabetes mellitus in those with UL who
underwent myomectomy (Table 2). Women with UL who did not undergo
myomectomy still had an elevated HR for type 2 diabetes (HR 1.287,
95\%CI 1.108-1.495) after adjustment for age, smoking status, alcohol
consumption and regular exercise (model 1). In the
multivariable-adjusted model (model 2), the HR for type 2 diabetes in
women with UL who did not undergo myomectomy was 1.328 (95\% CI
1.143-1.542). However, risk for type 2 diabetes mellitus was not
increased in women with UL who underwent myomectomy in models 1 and 2.
The cumulative incidence of type 2 diabetes mellitus in women with UL
who did not undergo myomectomy was higher than that in those with UL who
underwent myomectomy (\emph{P} = 0.0357) (Fig. 1B).

\textbf{4 \textbar{} Discussion}

\textbf{4.1 \textbar{} Principal findings}

This population-based cohort study demonstrated that young women with UL
appear to be at a higher risk for type 2 diabetes mellitus than those
without UL. Incidence rate of type 2 diabetes mellitus in women with UL
was higher than that in women without UL. However, women with UL who
underwent myomectomy did not have an increased risk for developing type
2 diabetes mellitus as compared to those without UL. The risk for type 2
diabetes mellitus was higher in women with UL who did not undergo
myomectomy as compared to that in those without UL.

\textbf{4.2 \textbar{} Results in the context of what is known}

To our knowledge, there is no large-scale, population-based,
longitudinal study evaluating the association between presence of UL and
development of type 2 diabetes mellitus in young women. This study
revealed that UL was associated with an elevated risk for type 2
diabetes mellitus and that myomectomy seemed to attenuate the risk for
type 2 diabetes mellitus in young women with UL.

Several studies indicate an association between obesity and
UL.\textsuperscript{2,12,13} Ciavattni et al. performed an observational
case-control study including 71 women of childbearing age diagnosed with
UL and 145 women as control group.\textsuperscript{12} Women with UL had
higher BMI (\emph{P} = 0.0034), preperitoneal fat thickness
(\emph{P}\textless{} 0.0001), and subcutaneous fat thickness (\emph{P} =
0.0003); however, only preperitoneal fat thickness showed an independent
significant association with the presence of UL in multivariate analysis
(\emph{P} \textless{} 0.0001). Another study, including 89 patients with
UL and 81 healthy women without UL, showed that increased body fat
(especially abdominal visceral fat) is associated with an increased risk
of UL.\textsuperscript{13} Recently, a meta-analysis examining 24
studies found a positive association between obesity and the
risk/prevalence of UL (odds ratio {[}OR{]} 1.19, 95\% CI
1.09-1.29).\textsuperscript{2} Consistent with the result of previous
studies, women with UL had a BMI higher than that of women without UL in
our study, although both groups had relatively low BMI. However, in
subgroup analysis stratified by BMI, women with BMI [?]25
kg/m\textsuperscript{2} revealed no significant difference in the
incidence rate of type 2 diabetes mellitus between women with UL and
without UL. This might be due to well-known close association between
obesity and the development of type 2 diabetes mellitus. Relative high
incidence rate of women with or without UL with BMI [?]25
kg/m\textsuperscript{2} compared to women with BMI less than 25
kg/m\textsuperscript{2} support this hypothesis (Table 3). Similarly,
there was no difference in the incidence rate of type 2 diabetes
mellitus between women with UL and without UL in whom with CKD history.
These findings also might be due to the inseparable association between
CKD and development of type 2 diabetes mellitus.\textsuperscript{14}

Beyond obesity, several studies reported that various metabolic
components were associated with UL.\textsuperscript{10,15} Takeda et al
investigated whether UL is associated with any specific criteria of
metabolic syndrome.\textsuperscript{15} In their case-control study,
BMI, blood pressure, TG, and FPG were significantly higher in 213 women
with UL compared to those in 159 women without UL. Moreover, the risk of
UL was correlated with increased metabolic component levels; the OR of
three metabolic components for UL was 3.64 (95\%CI 2.28-5.82). Another
study that enrolled 1,230 parous premenopausal women reported that women
with UL had higher waist circumferences, body fat, blood pressure, and
LDL cholesterol than women without UL.\textsuperscript{10} Increasing
evidence suggests that UL seems to share pathogenic features with the
development of metabolic syndrome. In our study, women with UL had poor
metabolic profiles, such as higher blood pressure, FPG, total
cholesterol, TG, LDL cholesterol, and lower HDL cholesterol, when
compared with women without UL.

Although the two disease states are likely to be related, few studies
have evaluated the association between UL and type 2 diabetes mellitus.
A nested case-control study enrolling 3,789 participants reported a
protective association between UL and type 2 diabetes with a relatively
greater protective effect observed among European Americans than African
Americans.\textsuperscript{16} However, this study was limited by design
and population as it was a cross-sectional study that included
relatively old women (mean age: 47 y in UL group; 44 y in control
group). On the other hand, the previously mentioned study by Tak et al
revealed that hyperglycemia is significantly associated with an
increased risk of UL (OR: 1.45, 95\%CI
1.10-1.89).\textsuperscript{10}Furthermore, in a Taiwanese
population-based cohort study, metformin use was associated with a lower
risk of UL (HR: 0.467, 95\%CI 0.387-0.564) in 21,996 women with
new-onset type 2 diabetes mellitus.\textsuperscript{11} However, there
was no longitudinal study to evaluate the risk for type 2 diabetes
mellitus solely in connection with the presence of UL, especially in
young women.

\textbf{4.3 \textbar{} Clinical implications}

Over a median 7.45 years of follow-up, women with UL had 21.4\% higher
risk for type 2 diabetes mellitus compared to women without UL in our
study. Since the mean age of participants was 29.70 years, young women
with UL are advised to pay attention to the prevention and monitoring of
type 2 diabetes mellitus.

The pathophysiology of how UL affects the development of type 2 diabetes
mellitus is unclear. The development of UL is known to be dependent on
ovarian steroid hormones.\textsuperscript{4} Considering the hormonal
changes in obese women or women with metabolic syndrome, it is likely
that rather than UL itself, the uterus, endometrium, and ovaries might
affect the development of type 2 diabetes
mellitus.\textsuperscript{17-20} A retrospective population-based cohort
study found that the risk of diabetes was higher in women with
hysterectomy compared to that in those without hysterectomy (HR 1.37,
95\%CI 1.23-1.52) and that diabetes risk was not increased in women with
hysterectomy and oophorectomy (HR: 1.28, 95\%CI
0.93-1.76).\textsuperscript{21} Interestingly, myomectomy seemed to
attenuate the risk for type 2 diabetes mellitus in women with UL in our
study. Compared to women without UL, women with UL who did not undergo
myomectomy had a higher risk for type 2 diabetes (HR 1.328, 95\%CI
1.143-1.542), but women with UL who underwent myomectomy did not. These
findings suggest a possible effect of UL on the development of diabetes.
UL has increased responsiveness and hypersensitivity to gonadal steroids
through increased expression of steroid hormone
receptors.\textsuperscript{21-24} Along with estrogen, which is
considered a primary mitogenic factor for the uterus, progesterone and
progesterone receptors are reported to play a key role in the
development and growth of UL.\textsuperscript{23} In response to
estrogen and progesterone, uterine fibroids can increase in size by cell
proliferation, hypertrophy, and accumulation of extracellular
matrix.\textsuperscript{24} Increased progesterone level is associated
with reduced insulin sensitivity, which can lead to development of type
2 diabetes.\textsuperscript{25,26} An animal study showing improved
glucose homeostasis in progesterone receptor knockout mice supports the
adverse effect of progesterone on glucose tolerance and insulin
release.\textsuperscript{27} A reasonable explanation for the reduction
of type 2 diabetes risk associated with myomectomy may be the reduction
of progesterone receptor expression through the mechanical removal of
the UL.

\textbf{4.4 \textbar{} Research implications}

Further prospective study to determine the direct association between UL
and the development of type 2 diabetes mellitus is warranted. In
addition, investigating the effect of the size and numbers of the UL on
the development of type 2 diabetes mellitus is needed.

\textbf{4.5 \textbar{} Strength and limtations}

Several limitations should be considered when interpreting the results
of this study. First, the definition of UL was not based on imaging, but
instead, on ICD-10 codes and outpatient clinic visits. Since UL is
mostly asymptomatic in early stages, women who have asymptomatic UL may
have been undiagnosed, which may cause the prevalence of UL to be
underestimated. Second, information about the size and number of ULs was
not available due to the database characteristics. Third, gynecologic
information, including parity, presence of polycystic ovarian syndrome,
or hormonal status, were also inaccessible; these factors can affect the
development of type 2 diabetes mellitus, and their absence lowers the
generalizability of our results. Finally, because this study was
conducted using the Korean nationwide database, the results might not be
generalizable to other ethnicities. However, this study is valuable
because, to our knowledge, it is the first large-scale, longitudinal
study to evaluate the association between presence of UL and development
of type 2 diabetes mellitus in young women.

\textbf{5 \textbar{} Conclusions}

The study results suggest that UL was associated with a higher risk for
developing type 2 diabetes mellitus in young women. Furthermore,
myomectomy seemed to attenuate the risk for type 2 diabetes mellitus in
women with UL, suggesting the importance of type 2 diabetes mellitus
screening and prevention in young women with UL.

\textbf{Author contributions}

C.Y.P, K.H, J.H.S and K.S.K were involved in the conception, design, and
conduct of the study and the analysis and interpretation of the results.
J.H.S and K.S.K wrote the first draft of the manuscript, and all authors
edited, reviewed, and approved the final version of the manuscript.

C.Y.P is the guarantor of this work and, as such, 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.

\textbf{CONFLICT OF INTEREST}

The authors declare that they have no competing interests.

\textbf{FUNDING}

The authors received no financial support for the research, authorship,
and/or publication of this article.

\textbf{ETHICAL STATEMENT}

Our study protocol was approved by the NHIS review committee and
Institutional Review Board of Kangbuk Samsung hospital on July 2022 (IRB
No. KBSMC-07-034).

\textbf{References}

1. American College of Obstetricians, Gynecologists' Committee on
Practice Bulletins-Gynecology. Management of Symptomatic Uterine
Leiomyomas: ACOG Practice Bulletin, Number 228. Obstet Gynecol.
2021;137(6):e100-e15.

2. Qin H, Lin Z, Vasquez E, Luan X, Guo F, Xu L. Association between
obesity and the risk of uterine fibroids: a systematic review and
meta-analysis. J Epidemiol Community Health. 2021;75(2):197-204.

3. Giuliani E, As-Sanie S, Marsh EE. Epidemiology and management of
uterine fibroids. Int J Gynaecol Obstet. 2020;149(1):3-9.

4. Kim JJ, Kurita T, Bulun SE. Progesterone action in endometrial
cancer, endometriosis, uterine fibroids, and breast cancer. Endocr Rev.
2013;34(1):130-62.

5. Eckel RH, Grundy SM, Zimmet PZ. The metabolic syndrome. Lancet.
2005;365(9468):1415-28.

6. Hebbar S, Chaya V, Rai L, Ramachandran A. Factors influencing
endometrial thickness in postmenopausal women. Ann Med Health Sci Res.
2014;4(4):608-14.

7. Januzzi JL, Jr., Butler J, Sattar N, Xu J, Shaw W, Rosenthal N, et
al. Insulin-Like Growth Factor Binding Protein 7 Predicts Renal and
Cardiovascular Outcomes in the Canagliflozin Cardiovascular Assessment
Study. Diabetes Care. 2021;44(1):210-6.

8. Yang Y, Yao S, Ding JM, Chen W, Guo Y. Enhancer-Gene Interaction
Analyses Identified the Epidermal Growth Factor Receptor as a
Susceptibility Gene for Type 2 Diabetes Mellitus. Diabetes Metab J.
2021;45(2):241-50.

9. Jeong IK, Byun JK, Noh J, Kim SW, Chung YS, Park TS, et al. Reference
Ranges of Serum Insulin-Like Growth Factor-I and Insulin-Like Growth
Factor Binding Protein-3: Results from a Multicenter Study in Healthy
Korean Adults. Endocrinol Metab (Seoul). 2020;35(4):954-9.

10. Tak YJ, Lee SY, Park SK, Kim YJ, Lee JG, Jeong DW, et al.
Association between uterine leiomyoma and metabolic syndrome in parous
premenopausal women: A case-control study. Medicine (Baltimore).
2016;95(46):e5325.

11. Tseng CH. Metformin use is associated with a lower risk of uterine
leiomyoma in female type 2 diabetes patients. Ther Adv Endocrinol Metab.
2019;10:2042018819895159.

12. Ciavattini A, Delli Carpini G, Moriconi L, Clemente N, Orici F,
Boschi AC, et al. The association between ultrasound-estimated visceral
fat deposition and uterine fibroids: an observational study. Gynecol
Endocrinol. 2017;33(8):634-7.

13. Sun K, Xie Y, Zhao N, Li Z. A case-control study of the relationship
between visceral fat and development of uterine fibroids. Exp Ther Med.
2019;18(1):404-10.

14. Levey AS, Bilous R, Shlipak MG. CKD and Diabetes: What Can We Learn
From Their Similarities and Differences? Am J Kidney Dis.
2016;67(3):360-3.

15. Takeda T, Sakata M, Isobe A, Miyake A, Nishimoto F, Ota Y, et al.
Relationship between metabolic syndrome and uterine leiomyomas: a
case-control study. Gynecol Obstet Invest. 2008;66(1):14-7.

16. Chiang CH, Chen W, Tsai IJ, Hsu CY, Wang JH, Lin SZ, et al. Diabetes
mellitus risk after hysterectomy: A population-based retrospective
cohort study. Medicine (Baltimore). 2021;100(4):e24468.

17. Kang S, Park YM, Kwon DJ, Chung YJ, Namkung J, Han K, et al.
Reproductive Life Span and Severe Hypoglycemia Risk in Postmenopausal
Women with Type 2 Diabetes Mellitus. Diabetes Metab J.
2022;46(4):578-91.

18. Oguz SH, Yildiz BO. An Update on Contraception in Polycystic Ovary
Syndrome. Endocrinol Metab (Seoul). 2021;36(2):296-311.

19. Luo J, Manson JE, Urrutia RP, Hendryx M, LeBlanc ES, Margolis KL.
Risk of Diabetes After Hysterectomy With or Without Oophorectomy in
Postmenopausal Women. Am J Epidemiol. 2017;185(9):777-85.

20. Appiah D, Winters SJ, Hornung CA. Bilateral oophorectomy and the
risk of incident diabetes in postmenopausal women. Diabetes Care.
2014;37(3):725-33.

21. Cermik D, Arici A, Taylor HS. Coordinated regulation of HOX gene
expression in myometrium and uterine leiomyoma. Fertil Steril.
2002;78(5):979-84.

22. Harrison-Woolrych ML, Charnock-Jones DS, Smith SK. Quantification of
messenger ribonucleic acid for epidermal growth factor in human
myometrium and leiomyomata using reverse transcriptase polymerase chain
reaction. J Clin Endocrinol Metab. 1994;78(5):1179-84.

23. Brandon DD, Bethea CL, Strawn EY, Novy MJ, Burry KA, Harrington MS,
et al. Progesterone receptor messenger ribonucleic acid and protein are
overexpressed in human uterine leiomyomas. Am J Obstet Gynecol.
1993;169(1):78-85.

24. Williams AR, Critchley HO, Osei J, Ingamells S, Cameron IT, Han C,
et al. The effects of the selective progesterone receptor modulator
asoprisnil on the morphology of uterine tissues after 3 months treatment
in patients with symptomatic uterine leiomyomata. Hum Reprod.
2007;22(6):1696-704.

25. Padmanabhan S, Lee VW, McLean M, Athayde N, Lanzarone V, Khoshnow Q,
et al. The Association of Falling Insulin Requirements With Maternal
Biomarkers and Placental Dysfunction: A Prospective Study of Women With
Preexisting Diabetes in Pregnancy. Diabetes Care. 2017;40(10):1323-30.

26. Ryan AS, Nicklas BJ, Berman DM. Hormone replacement therapy, insulin
sensitivity, and abdominal obesity in postmenopausal women. Diabetes
Care. 2002;25(1):127-33.

27. Picard F, Wanatabe M, Schoonjans K, Lydon J, O'Malley BW, Auwerx J.
Progesterone receptor knockout mice have an improved glucose homeostasis
secondary to beta -cell proliferation. Proc Natl Acad Sci U S A.
2002;99(24):15644-8.

\textbf{Figure Legend}

\textbf{Figure 1} The cumulative incidence of type 2 diabetes mellitus.
A:stratified according to presence of uterine leiomyoma adjusted for
age, smoking status, alcohol consumption, regular exercise,
hypertension, dyslipidemia, and body mass index (\emph{P} = 0.0026).
B:stratified according to myomectomy adjusted for age, smoking status,
alcohol consumption, regular exercise, hypertension, dyslipidemia, and
body mass index (\emph{P} = 0.0357).\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/BJOG-Figure1/BJOG-Figure1}

\end{center}
\end{figure}

\textbf{Hosted file}

\verb`tables.docx`  available at \url{https://authorea.com/users/616749/articles/642576-association-of-uterine-leiomyoma-with-type-2-diabetes-mellitus-in-young-women-a-population-based-cohort-study}

\textbf{Hosted file}

\verb`BJOG_Uterine_myoma_DM_Supple Table.docx`  available at \url{https://authorea.com/users/616749/articles/642576-association-of-uterine-leiomyoma-with-type-2-diabetes-mellitus-in-young-women-a-population-based-cohort-study}

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

