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\begin{document}

\title{Effect of bariatric surgery on endometrial cancer regression as part of
fertility sparing treatment: A case series and literature review}



\author[1]{Jinlin Lin}%
\author[2]{Weng Yan Ho}%
\author[1]{Qi Xuan Lim}%
\author[2]{Hui Xian Felicia Chin}%
\affil[1]{Changi General Hospital Department of General Surgery}%
\affil[2]{KK Women's and Children's Hospital}%


\vspace{-1em}



  
  \date{May 23, 2024}


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





\selectlanguage{english}
\begin{abstract}
\textbf{Introduction:} Obesity is a major risk factor in the development
of endometrial cancer (EC) in young patients of reproductive age.
Fertility sparing treatment is a viable option for a select group of
patients with early EC, and involves systemic and intra-uterine hormonal
therapy. Weight loss has been associated with improved outcomes in this
group. Bariatric surgery (BS) has been shown to be the most efficient
and durable method of weight loss in obese patients. However, there is a
paucity of data studying the benefit of BS as part of fertility sparing
treatment. \textbf{Methods:} We present a retrospective case series of
five patients who are undergoing fertility sparing treatment for early
EC, who also underwent BS for treatment of obesity and related
comorbidities. We aim to show early regression of EC for all the
patients and also report on the other health benefits of BS.
\textbf{Results:} All five patients in the series achieved regression of
EC within six months of undergoing BS. They also achieved significant
weight loss consistent with previous studies, and three patients who had
comorbidities related to obesity had remission of these conditions. One
of the patients with EC regression also managed to conceive with IVF.
\textbf{Conclusion:} Patients on fertility sparing treatment for early
EC who underwent BS was associated with early regression within 6
months, significant weight loss and resolution of comorbidities. BS
could be a promising component of fertility sparing treatment. Long
term, prospective studies are required to confirm the benefits reported
in this case series.%
\end{abstract}%



\sloppy


\textbf{Effect of bariatric surgery on endometrial cancer regression as
part of fertility sparing treatment: A case series and literature
review}

Jinlin \emph{Lin} FRCS(Surg)\textsuperscript{1}, Weng Yan \emph{Ho}MRCOG
(UK)\textsuperscript{2}, Qi Xuan \emph{Lim}MBBS\textsuperscript{3}, Hui
Xian Felicia \emph{Chin} MRCOG (UK)\textsuperscript{4}

\begin{enumerate}
\tightlist
\item
  Consultant, Department of Surgery, Changi General Hospital, Singapore.
  Associate Program Director. Singhealth General Surgery Residency.
\item
  Consultant, Department of Gynaecological Oncology, Division of O\&G,
  KK Women's and Children Hospital, Singapore.
\item
  Medical Officer, Department of Surgery, Changi General Hospital,
  Singapore.
\item
  Consultant, Department of Gynaecological Oncology, Division of O\&G,
  KK Women's and Children Hospital, Singapore.
\end{enumerate}

\textbf{Correspondence to:}

Dr Jinlin Lin

Changi General Hospital

2 Simei Street 3, Singapore 529889

Department of Surgery

Lin.jinlin@singhealth.com.sg

(+65)98206249

The authors report no conflict of interests. Data available on request
from the authors

\emph{Effect of bariatric surgery on endometrial cancer regression as
part of fertility sparing treatment: A case series and literature
review}

\emph{Abstract and Keywords}

\textbf{Introduction:} Obesity is a major risk factor in the development
of endometrial cancer (EC) in young patients of reproductive age.
Fertility sparing treatment is a viable option for a select group of
patients with early EC, and involves systemic and intra-uterine hormonal
therapy. Weight loss has been associated with improved outcomes in this
group. Bariatric surgery (BS) has been shown to be the most efficient
and durable method of weight loss in obese patients. However, there is a
paucity of data studying the benefit of BS as part of fertility sparing
treatment.

\textbf{Methods:} We present a retrospective case series of five
patients who are undergoing fertility sparing treatment for early EC,
who also underwent BS for treatment of obesity and related
comorbidities. We aim to show early regression of EC for all the
patients and also report on the other health benefits of BS.

\textbf{Results:} All five patients in the series achieved regression of
EC within six months of undergoing BS. They also achieved significant
weight loss consistent with previous studies, and three patients who had
comorbidities related to obesity had remission of these conditions. One
of the patients with EC regression also managed to conceive with IVF.

\textbf{Conclusion:} Patients on fertility sparing treatment for early
EC who underwent BS was associated with early regression within 6
months, significant weight loss and resolution of comorbidities. BS
could be a promising component of fertility sparing treatment. Long
term, prospective studies are required to confirm the benefits reported
in this case series.

\textbf{Keywords: Endometrial cancer, fertility sparing, bariatric
surgery.}

\emph{Introduction}

Endometrial cancer (EC) is the second most common gynaecological cancer
worldwide with 417,367 cases diagnosed globally in
2020\textsuperscript{(1)}. Global estimates showing rising incidence
rates in both developed and developing countries \textsuperscript{(2)}.
EC can be divided into 2 subtypes: type 1, the oestrogen-dependent
endometrioid type associated with obesity that accounts for up to 85\%
of ECs, and type 2, the non-endometrioid subtypes that include serous,
clear-cell, undifferentiated carcinomas and malignant mixed Mullerian
tumours and are typically not associated with obesity
\textsuperscript{(3, 4)}. Although the majority of patients with EC are
diagnosed when they are postmenopausal, about 20\% of patients are
diagnosed when they are still of reproductive age. The majority of these
patients tend to present with low-grade early stage tumours of the
endometrioid subtype that are confined to the endometrium
\textsuperscript{(5)}.

The standard treatment for early EC is total hysterectomy, bilateral
salpingo-oopherectomy (THBSO) with or without
lymphadenectomy\textsuperscript{(6, 7)}. Following current standard
surgical treatment, the 5-year survival for EC is good, ranging from
74\% to 91\%, particularly for women diagnosed with low-grade
endometrioid tumours without lymph node involvement
\textsuperscript{(8)}. However, given the current trends of women of
reproductive age delaying childbearing\textsuperscript{(9)} and the
rising incidence of EC amongst nulliparous women, an alternative
treatment is necessary for patients who desire preservation of
childbearing potential. Fertility sparing treatment for EC can be
considered for a select group of patients who have FIGO grade 1 tumour
of the endometrioid subtype, without myometrial invasion, lymph node
involvement or distant metastasis. This treatment approach mainly
involves endocrine therapy with oral progestins, gonadotropin-releasing
hormone (GnRH) agonists or levonorgestrel-releasing intra-uterine
devices. Patients on this treatment protocol require regular
surveillance with endometrial biopsy until tumour
regression\textsuperscript{(10)}. However, medical treatment alone for
EC has the problems of long response time, unpredictable response and
high recurrence rates.

Obesity is an established risk factor for EC, mainly due to the
endogenous hyper-estrogenic state it creates in a patient's body. The
worldwide epidemic of obesity is likely to be a key factor in the
increasing incidence of EC \textsuperscript{(11)}. Despite this clear
link between obesity and EC, there is a paucity of data studying the
effect of weight loss induced by bariatric surgery (BS) as part of the
fertility sparing treatment. BS has been shown to be an effective
treatment of obesity, producing sustained and significant weight loss,
along with improvement in multiple obesity-related
co-morbidities\textsuperscript{(12)}. At the tissue level, BS is
associated with downregulation of pro-proliferative signalling pathways,
reduced endometrial growth, and spontaneous clearance of both latent and
precursor endometrial neoplastic lesions \textsuperscript{(13)}. BS is
also associated with reducing the odds of developing EC in obese
women\textsuperscript{(14)}. Based on these factors, there is a strong
biological rationale that weight loss induced from BS is an important
factor that could contribute to successful regression of EC in patients
on fertility sparing treatment. Additional benefits of BS for this group
of patients include improvement in overall health from weight loss and
improvement in fertility rates (from both natural conception and
assisted reproduction) after fertility sparing treatment. In the event
that these patients require surgical resection for EC in the future,
weight loss also reduces peri-operative risks and improves success rates
for minimally invasive techniques.

The aim of this study is to provide a case series of patients on
fertility sparing treatment who underwent BS for the treatment of morbid
obesity. The primary outcome of the study is to report on the early
regression of EC (within six months) with successful weight loss after
BS. The secondary outcome of the study is to report outcomes from BS
including weight loss and improvement in related medical co-morbidities.
In addition, we aim to review the literature on the relationship between
morbid obesity and EC, as well as the role of BS in the fertility
sparing treatment of obese patients with early EC.

\emph{Methods}

All patients undergoing BS in Changi General Hospital (CGH) have their
data collected prospectively in the hospital database for audit
purposes. The patients who undergo BS are selected based on national
healthcare guidelines (BMI greater than 37.5 kg/m\textsuperscript{2} or
BMI greater than 32.5 kg/m\textsuperscript{2}, with co-morbidities
related to obesity) and are treated by a multidisciplinary team
(comprising medical, nursing and allied health professionals) under a
standard pathway. The study was approved by the Institutional Review
Board (CIRB no: 2022/2195). Starting from January 2021 to December 2022,
from the database, we identified a group of five patients who have early
EC on fertility sparing treatment who also underwent BS for treatment of
morbid obesity. The patients who are on fertility sparing treatment for
EC are treated in a specialist gynecological oncology unit in KK Women's
and Children's Hospital (KKWCH) by a multidisciplinary team under a
standard pathway.

This is a retrospective case series. After consent was taken from
patients, we collected data from electronic medical records (EMR). The
data consisted of baseline patient characteristics, EC disease
characteristics, fertility sparing treatment details, BS details and
treatment outcome (in terms of EC regression, weight loss and
improvement in metabolic conditions) after BS. The descriptive analysis
of the data is show in the section below.

\emph{Results}

Five patients with confirmed EC were included in this case series. All
of them were females at reproductive age who opted for fertility sparing
treatment. Their age ranged between 27 and 37; the median patient age
was 32. Three patients (60\%) had co-morbidities which were related to
obesity. The mean pre-op weight was 109.54kg and the mean pre-op BMI was
40.73 kg/m\textsuperscript{2}. Table 1 summarizes the patient
characteristics.

Table 1: Patient Characteristics\selectlanguage{english}
\begin{longtable}[]{@{}lllll@{}}
\toprule
\begin{minipage}[b]{0.19\columnwidth}\raggedright\strut
Patient\strut
\end{minipage} & \begin{minipage}[b]{0.19\columnwidth}\raggedright\strut
Age\strut
\end{minipage} & \begin{minipage}[b]{0.19\columnwidth}\raggedright\strut
Co-morbidities\strut
\end{minipage} & \begin{minipage}[b]{0.19\columnwidth}\raggedright\strut
Pre-op Weight (kg)\strut
\end{minipage} & \begin{minipage}[b]{0.19\columnwidth}\raggedright\strut
Pre-op BMI (kg/M\textsuperscript{2})\strut
\end{minipage}\tabularnewline
\midrule
\endhead
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
1\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
32\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Asthma, DM\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
106.5\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
40.65\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
2\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
37\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Hypertension, Hyperlipidemia, DM\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
113.1\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
40.10\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
3\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
27\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
None\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
89.8\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
38.80\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
4\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
35\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Hyperlipidemia\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
106.4\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
40.00\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
5\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
29\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
None\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
131.9\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
44.10\strut
\end{minipage}\tabularnewline
\bottomrule
\end{longtable}

DM = Diabetes Mellitus.

The patients included in the study were diagnosed between 2020 and 2022.
Notably, there were two cases (Patients 4 and 5), where the endometrial
cancer had previously regressed with hormonal treatment but subsequently
recurred. In addition, Patient 1 had been treated with hormonal therapy
for twelve months without regression. This could be because the
underlying primary risk factor of obesity had not been addressed. Four
patients (80\%) were diagnosed with hysteroscopy, dilatation and
endometrial curettage (HDC), and one (20\%) was diagnosed using with
endometrial sampling with the Explora Device. All patients had low
grade, early-stage cancer, with endometroid as the tumor subtype. All
patients had standard staging investigations after diagnosis with CT
scan of the thorax and abdomen, as well as MRI scan of the pelvis. No
evidence of myometrial invasion, lymph node or distant metastases were
found after staging scans were performed for all patients. Patients 4
and 5 had repeat staging investigations before they were considered for
fertility sparing treatment again, after EC recurrence. Before fertility
sparing treatment was offered to all the patients, the cases were
discussed in a multidisciplinary tumor board meeting, with concurrence
from all treating specialists. All patients underwent hormonal therapy
with oral Megestrol, gonadotropin-releasing hormone agonists
(Triptorelin and Leuprolide) as well as levonorgestrel-releasing
intra-uterine device (Mirena), in accordance to the standard treatment
pathway. After starting on treatment, patients underwent HDC on three
monthly interval for surveillance. Table 2 summarizes EC disease
characteristics and hormonal therapy received.

Table 2: EC disease characteristics and hormonal therapy received.\selectlanguage{english}
\begin{longtable}[]{@{}lllllll@{}}
\toprule
Patient & Date of EC Diagnosis & Method of Diagnosis & Tumor Grade &
Tumor Subtype & Systemic Hormonal Therapy & Intra-Uterine Hormonal
Therapy\tabularnewline
\midrule
\endhead
1 & June 2020 & HDC & G1-G2 & Endometroid & Megestrol, Triptorelin &
Mirena\tabularnewline
2 & December 2020 & HDC & G1 & Endometroid & Megestrol, Triptorelin &
Mirena\tabularnewline
3 & August 2021 & Explora & G1 & Endometroid & Megestrol, Triptorelin &
Mirena\tabularnewline
4 & March 2016 (regressed July 2018, recurred October 2021) & HDC & G1 &
Endometroid & Megestrol, Triptorelin, Leuoprolide &
Mirena\tabularnewline
5 & March 2019 (regressed May 2020, recurred March 2022) & HDC & G1 &
Endometroid & Megestrol, Triptorelin, Leuoprolide &
Mirena\tabularnewline
\bottomrule
\end{longtable}

HDC = Hysteroscopy, dilatation and endometrial curettage.

All the patients were referred to undergo BS as their BMI fulfilled
criteria based on national healthcare guidelines. Pre-operative
preparation was done for all patients based on a standard pathway,
including review by members of a multidisciplinary team, blood tests,
upper gastro-intestinal endoscopy and two weeks of meal replacement with
a very low-calorie diet (VLCD). All patients underwent laparoscopic
sleeve gastrectomy (LSG) and there were no complications from BS. After
BS, all patients had EC regression within six months based on histology
on HDC (Table 3). After BS, the mean time taken for EC regression was
3.2 months. For three patients (1, 3 and 4), there was normalization of
endometrial cells. The other two patients (2 and 5) had regression to
complex hyperplasia. Patient 2 still had simple endometrial hyperplasia
10 months after BS, while follow-up duration for patient 5 is still very
short. Patients are instructed about contraception and to avoid
conceiving for at least twelve months after BS. Two patients (1 and 3)
underwent IVF 12 months after BS, with patient 1 successfully
conceiving. There are no maternal or fetal complications during the
gestation period up to the end of the follow-up period.

Table 3: EC regression after BS.\selectlanguage{english}
\begin{longtable}[]{@{}lllllll@{}}
\toprule
Patient & Type of BS & Date of BS & Length of follow-up (months) & Time
to EC regression (months) & Histology at time at EC regression &
Remarks\tabularnewline
\midrule
\endhead
1 & LSG & July 2021 & 19 & 1 & Progesterone effect. & Maintained EC
regression. Conceived via IVF 12 months after BS.\tabularnewline
2 & LSG & July 2021 & 19 & 2 & Complex hyperplasia without atypia. &
Regressed to simple hyperplasia 10 months after BS.\tabularnewline
3 & LSG & December 2021 & 14 & 6 & Progesterone effect with
endometritis. & Maintained EC regression. Started IVF 14 months after
BS.\tabularnewline
4 & LSG & April 2022 & 10 & 5 & Progesterone effect. & Maintained EC
regression.\tabularnewline
5 & LSG & November 2022 & 3 & 2 & Complex hyperplasia without atypia. &
Maintained EC regression.\tabularnewline
\bottomrule
\end{longtable}

IVF = in-vitro fertilization.

After BS, all patients were followed-up at three monthly intervals for
the first twelve months, with regular blood tests to check for
resolution of obesity-related comorbidities and nutritional deficiency.
All the patients were placed on vitamin, calcium and iron supplement as
part of the standard treatment pathway. The weight loss and comorbidity
resolution outcome are reported in Table 4. The mean total weight loss
was 27.24kg and mean percentage total weight loss was 25.28\%. Patient 5
had lower weight loss compared to the rest of the patients due to the
short follow-up, and patients undergoing BS usually achieve maximal
weight loss about 9 to 12 months post-op. We expect her weight loss to
continue. Besides the regression of endometrial cancer after BS,
patients' (1, 2 and 4) comorbidities related to obesity went into
remission, and they did not have to take medications to control these
conditions anymore.

Table 4: Weight loss and comorbidity resolution results after BS.\selectlanguage{english}
\begin{longtable}[]{@{}llllllll@{}}
\toprule
Patient & Type of BS & Date of BS & Pre-op Weight (kg) & Length of
follow-up (months) & Weight loss at end of follow-up (kg) & Total body
weight loss (\%) & Resolution of Comorbidities\tabularnewline
\midrule
\endhead
1 & LSG & July 2021 & 106.5 & 19 & 28.4 & 26.7 & DM\tabularnewline
2 & LSG & July 2021 & 113.1 & 19 & 30.4 & 26.8 & DM, Hypertension,
Hyperlipidemia\tabularnewline
3 & LSG & December 2021 & 89.8 & 14 & 23.8 & 26.5 & NA\tabularnewline
4 & LSG & April 2022 & 106.4 & 10 & 32.2 & 30.2 &
Hyperlipidemia\tabularnewline
5 & LSG & November 2022 & 131.9 & 3 & 21.4 & 16.2 & NA\tabularnewline
\bottomrule
\end{longtable}

BS = bariatric surgery. DM = diabetes Mellitus. LSG = Laparoscopic
Sleeve Gastrectomy.

\emph{Literature Review}

Effect of obesity on EC tumorigenesis

With advances in tissue molecular research, we are now becoming
increasingly aware that visceral fat functions as a complex endocrine
organ. It is made up of adipocytes, macrophages, stromal, nerve and stem
cells. The array of adipokines they secrete exerts a wide range of
effects on endometrial cells, leading to increased proliferation,
genetic mutations and eventually carcinogenesis \textsuperscript{(11,
15, 16)}.

Adipocytes, preadipocytes and mesenchymal stem cells within visceral fat
are the main source of endogenous aromatase, which converts androgens to
estrogen \textsuperscript{(17)}. In addition, sex hormone-binding
globulin levels decrease with increasing adiposity, leading to an
increase in the pool of bioactive estrogen \textsuperscript{(18)}. These
factors contributes to estrogen-induced proliferation of endometrial
cells, via the activation of the various signaling pathways. Estrogen
metabolites are also thought to be mutagenic, causing DNA breaks and
contributing to genetic instability, increasing the chance of
carcinogenesis \textsuperscript{(19)}.

EC is strongly associated with metabolic syndrome and hyperinsulinemia,
which in turn are strongly associated with obesity \textsuperscript{(20,
21)}. There is increased expression of insulin and IGF1 receptors
observed in endometrial cells when there is endometrial hyperplasia,
which increases the responsiveness of the cells to elevated levels of
insulin and insulin-like growth factor 1 (IGF1) \textsuperscript{(22)}.
This in turn leads to hyperactivity of MAPK and AKT signaling frequently
seen in endometrial hyperplasia and EC. Hyperglycemia also serves to
fuel the growth of metabolically tissues, including endometrial
hyperplastic and cancer cells \textsuperscript{(23)}.

It is an increasingly well-established fact that obesity and metabolic
syndrome is associated with a chronic inflammatory state. This is
modulated by pro-inflammatory adipokines, such as leptin, tumor necrosis
factor \selectlanguage{greek}α \selectlanguage{english}and interleukin-6. Together with worsening insulin resistance
and hyperinsulinemia, these inflammatory mediators increase the release
of IGF1, leading to endometrial cellular
proliferation\textsuperscript{(24)}. Because of the chronic inflammatory
state, there is also increased cellular stress, leading to genetic
instability and DNA damage. When endometrial cells with DNA mismatch
repair defects accumulate deleterious genetic mutations, this leads to
endometrial hyperplasia, atypia and eventually EC.

The interplay and synergistic effect of a hyper-estrogenic state,
hyperinsulinemia and chronic inflammatory state predisposes obese women
to an increased risk of developing EC much earlier, when they are of
reproductive age.

Bariatric Surgery and Endometrial Cancer

BS has been shown to be the most durable and effective treatment for
obesity \textsuperscript{(12)} while improving the life expectancy and
quality of life of obese patients \textsuperscript{(25)}. In addition,
BS has also been shown to improve multiple aspects of metabolic health
of obese patients, including diabetes control (decreased glycated
hemoglobin levels, better glycemic control, decreased requirement for
glucose-lowering medications), lipid control (decreased triglyceride
levels, increased HDL levels) and microvascular complications (decreased
urine albumin to creatinine ratio) \textsuperscript{(26, 27)}.

Patients who undergo BS have reduced overall cancer risk compared with
controls \textsuperscript{(14, 28 -- 30)}. There is also good evidence
that obese patients who had BS have a reduced risk of developing
endometrial cancer \textsuperscript{(14, 31 -- 33)}. This is most likely
from the improvement in the metabolic and insulin-resistance state from
weight loss and other beneficial effects of BS. These common factors and
pathways are also involved in the development of EC. Weight loss is
associated with spontaneous clearance of serum and endometrial tissue
biomarkers of endometrial cancer risks \textsuperscript{(34)}.

There is a paucity of data for using BS as part of the fertility sparing
treatment. A prospective nonrandomized study conducted by Barr et. al.
observed that weight loss improves the response rates in women with
obesity and atypical hyperplasia or early EC undergoing fertility
sparing treatment with intrauterine progestin. Patients who lost more
than 10\% of total body weight were nearly 4 times more likely to
respond to intrauterine progestin than those who did not (OR 3.95
p=0.02). In this study, BS was offered as a treatment for obese patients
and resulted in a greater and more sustainable weight loss compared to
nonsurgical treatment \textsuperscript{(35)}.

Reproductive outcomes in patients undergoing fertility sparing treatment
are promising, especially when Assisted Reproductive Techniques (ART)
are used \textsuperscript{(36)}. However, obesity negatively affects
fertility rates and lowers the chances of achieving a successful
pregnancy, one of the long-term goals of fertility sparing
treatment\textsuperscript{(37)}. Studies have indicated that BS improves
fertility rates in obese female patients \textsuperscript{(38)}.
Pregnancy is safe after BS and evidence shows lower risk of maternal
complications like gestational diabetes and pre-eclampsia, compared to
patients who are morbidly obese. There is mixed evidence regarding
perinatal outcomes in patients who had undergone BS, with some studies
showing possible association with reduced birth weight that may be due
to nutritional growth restriction \textsuperscript{(39)}. As such,
patients who have undergone BS should be advised to avoid conceiving for
at least 12 months post-op, with adequate contraception during this
period. When patients who have undergone BS conceive, they should have
nutritional surveillance and be screened for macro- and micro-nutrient
deficiencies regularly. They should also be instructed on strict
compliance with nutritional supplementation during
pregnancy\textsuperscript{(40)}.

\emph{Discussion}

This study describes BS as a promising component in the fertility
sparing treatment for patients who have early EC. This is the first
study discussing this topic in the local setting, and one of the few
studies worldwide describing using BS in this context.

Morbid obesity is the underlying biological factor that drives the
development of endometroid EC in young patients in the reproductive age
group. Addressing this underlying factor with BS is a logical treatment
strategy that can potentially improve the regression rates and reduce
recurrence rates of EC. Indeed, we see two patients who had EC
previously and had cancer regression with hormonal therapy. They had
recurrence a few years after treatment. Another patient had a long
treatment period with hormonal therapy, without regression of EC. This
could possibly be because obesity, as the underlying driving factor for
cellular proliferation and carcinogenesis, had not been addressed. Long
term follow-up and data is necessary to demonstrate if weight loss
induced by BS results in reduced EC recurrence and survival benefit.

In addition, weight loss induced by BS improves the chances of
fertility, both via natural conception or via ART, reduces maternal and
fetal complications antenatally and reduces risks in the peri-partum
period. We see that one of the patients had successfully conceived with
IVF and had no maternal or fetal complications during the antenatal
follow up period. Once the other patients pass the first 12 months after
BS, where weight loss is rapid and extensive, they would be counselled
to undergo ART to aid in conception.

The improvement in physical and psychological health after BS provides
additional benefit to this group of patients. Total weight loss is
between 25 to 30\%, which is consistent with other large-scale studies.
We also saw resolution of obesity related comorbidities, which could
lead to improved health outcomes and reduced complications from
cardiovascular diseases in the long term \textsuperscript{(12, 27)}.

The limitations of this case series include the retrospective nature of
the study design, the lack of a control group, the short follow-up time
and the small number of patients in the study group. The retrospective
nature of the study design makes it prone to selection and measurement
bias. The patients included in this study are only those that are
treated in the centers in which the authors are based. In addition, the
early cancer regression in this group of patient who chose to undergo BS
may be due to other factors like higher compliance to the fertility
sparing treatment or increased health seeking behavior. Measurement bias
can also result from incomplete or heterogeneous data from a lack of
standard study protocol. This is partially mitigated by the fact that
all the treatment received by the patient (both fertility sparing
treatment for EC and BS) were according to a standard pathway, and all
data collected were from the same comprehensive EMR system used in both
public healthcare institutions. The outcomes measured were also
objective in nature e.g. histology proving that EC has regressed and
weight loss measured in the outpatient clinic during follow-up
appointments. The lack of a control group prevents us from inferring a
causal relationship between EC regression and BS. We are also unable to
draw any conclusions about the longevity of the cancer regression due to
the short follow-up period.

\emph{Conclusion}

In this retrospective case series, patients on fertility sparing
treatment for early EC who underwent BS were associated with early
cancer regression within six months. In addition, patients had
significant weight loss and resolution of comorbidities. BS could be a
promising component of fertility sparing treatment for early EC. The
overall and metabolic health benefits from weight loss induced by BS in
this study is consistent with current literature. Larger scale,
prospective case controlled studies with longer follow-up period is
required to confirm the oncological benefit of BS for this purpose. This
study could add to the body of evidence and raise awareness for this
promising treatment strategy, while forming the background data for
future prospective studies.

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