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 (11,
15, 16).
Adipocytes, preadipocytes and mesenchymal stem cells within visceral fat
are the main source of endogenous aromatase, which converts androgens to
estrogen (17). In addition, sex hormone-binding
globulin levels decrease with increasing adiposity, leading to an
increase in the pool of bioactive estrogen (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 (19).
EC is strongly associated with metabolic syndrome and hyperinsulinemia,
which in turn are strongly associated with obesity (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) (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 (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 α and interleukin-6. Together with worsening insulin resistance
and hyperinsulinemia, these inflammatory mediators increase the release
of IGF1, leading to endometrial cellular proliferation(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 (12) while improving the life expectancy and
quality of life of obese patients (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) (26, 27).
Patients who undergo BS have reduced overall cancer risk compared with
controls (14, 28 – 30). There is also good evidence
that obese patients who had BS have a reduced risk of developing
endometrial cancer (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 (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 (35).
Reproductive outcomes in patients undergoing fertility sparing treatment
are promising, especially when Assisted Reproductive Techniques (ART)
are used (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(37). Studies have indicated that BS improves
fertility rates in obese female patients (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 (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(40).