Trial Information

Prevalence of Menstrual Irregularities and Endometrial Pathology in Women Who Are Candidates for Bariatric Surgery: Correlation With Perceived Risk, Biomarkers, and Weight Loss

Obesity is defined qualitatively by the World Health Organization, is "abnormal or excessive
fat accumulation that may impair health. Obesity is now estimated to lead to 280,000 deaths
each year in the U.S., making it the second most common cause of preventable death only
behind tobacco[1]. Obesity leads to an increased risk of several cancers, most notably
endometrial cancer which is the fourth most common U.S. cancer with 40,000 affected women
accounting for 6% of all estimated cancers in 2008 [2]. The recent increase in endometrial
cancer has paralleled the increase in obesity [3]. The relative risk for an obese woman to
develop endometrial cancer increases proportionally with increasing body mass index (BMI -
weight in kilograms divided by height in meters squared)[4]. The risk may be 2-3 times
[12,13] or up to 10-times greater for a woman more than 50 pounds overweight [5]. The most
recent cohort study from Norway demonstrated increased adjusted relative risk based on BMI
of 4.28 for a BMI of 35-39 and 6.36 for a BMI of 40 or over [6]. Morbidly obese women are
also 23 fold more likely to harbor a precancerous endometrial condition compared to normal
weight women [7]

The link of obesity with endometrial cancer has been well-established for over 20 years[5,
8]. For the most common histological subtype (endometrioid adenocarcinoma), the development
of endometrial cancer is stimulated by the presence of estrogen. In obese patients, adipose
tissue is responsible for elevating endogenous estrogen levels through its conversion of
androgens to estrogens[9]. This also results in a relative decrease in progesterone, which
normally 'protects' the uterine lining from over-stimulation by estrogen[8]. Obesity impacts
multiple other factors including adiponectin, leptin, insulin, insulin growth factor one
(IGF-1), tumor necrosis factor alpha (TNF-α), aromatase, and peroxisome proliferator
activated receptor γ (PPAR) and the potential link of these factors to carcinogenesis has
yet to be elucidated.

Propelled by increasing obesity, there is interest in identifying at risk populations who
might benefit from screening and/or prevention. Viola et al looked at the prevalence of
endometrial cancer and its precursors by biopsying 193 asymptomatic pre- and post-menopausal
obese women (average BMI of 35.5 and 37.6 respectively) and found the prevalence of
endometrial hyperplasia and cancer was 5.8% and 1% in premenopausal women and 12.1% and 3%
in postmenopausal women[10]. These rates may even be higher in symptomatic women. For
example, Schmeler et al evaluated 188 women diagnosed with endometrial cancer before age 50,
61% of the obese women had reported irregular menses, 14% a history of infertility, and 35%
had diabetes[11]. The advantage to diagnosing endometrial cancer as precursor lesion or an
early stage is due to a dramatic survival benefit; women with stage 1 disease have an
excellent 5 year survival rate ranging between 80-95% and survival drops dramatically as
stage increases. Women with earlier-stage disease generally need less-invasive and
less-morbid post-operative treatments.

Universal screening of all women for endometrial cancer is not currently recommended[12,
13]. However, with the trend of endometrial cancer being found in younger, obese women,
there is an increased likelihood that screening could decrease morbidity and mortality and
that preventative strategies could be implemented in the highest risk women. Kwon and Lu
conducted a cost-effectiveness analysis comparing no screening (standard of care), oral
contraceptive pills as prevention, and endometrial biopsy either yearly or every other year
after age 30. They concluded that the risk of endometrial cancer in a high risk population
needed to be 13 times that of the general population to even warrant the use of oral
contraceptives as a preventive measure [13]. Another cost analysis study confirmed that
endometrial cancer screening is not warranted in the general population but that in a high
risk population, annual serum screening might be efficacious and cost effective [12]. To
date, there are no serum screening markers available in endometrial cancer. Prior authors
have demonstrated that low adiponectin levels correlate with an increased rate of
endometrial cancer. Adiponectin activates the AMPK pathway and the PPAR alpha pathway
through two different receptors and functions to increase insulin sensitivity and decrease
inflammation. Further prospective evaluation of adiponectin and other potential biomarkers
is warranted in this population and to correlate with both obesity and weight loss[14-21].

Given that the prevalence of obesity continues to increase while the age at time of
diagnosis of endometrial cancer has also begun to decrease, the early identification of
cancer or pre-cancerous change of the uterus will become an important way to decrease
morbidity and mortality in this ever-growing population of obese women[22, 23]. A previous
retrospective study of women undergoing bariatric surgery at UVA demonstrated that
endometrial cancer was one of the most common cancers diagnosed in this morbidly obese
population, and that most women were diagnosed before their bariatric surgery at an average
age of 35 and had a BMI of 65 kg/m2 [24]. Yet currently, the pre-operative gynecologic
evaluation for bariatric surgery for weight loss includes only mammogram (to screen for
breast cancer) and Pap smear (for cervical cancer) and compliance with these recommendations
has not been well documented.

Given the profound impact of obesity on the genesis of endometrial cancer, this study
proposes to prospectively evaluate the baseline prevalence of menstrual irregularities and
endometrial pathology in morbidly obese women presenting for evaluation for bariatric weight
loss surgery. The bariatric surgery population is ideal to define baseline characteristics
of this population, to assess prevalence of endometrial abnormalities and to determine
differences in hormones and adipocyte derived markers in women with and without endometrial
abnormalities and to assess the impact of weight loss on these same markers. Ultimately,
this study may allow the identification risk stratification markers that can potentially
identify women who might benefit from targeted cancer prevention strategies in a future
clinical trial.