Hormone receptor expression patterns in the endometrium of asymptomatic morbidly obese women before and after bariatric surgery
Introduction
Increasing obesity in women is associated with a progressively worsening estrogen/progesterone imbalance [1]. The causal effect of unopposed estrogen on the induction of endometrial cancer is singularly well established through historical study of early hormone replacement efforts [2]; but there is increasing epidemiologic evidence indicating that obesity increases the risk of adenocarcinoma in other endocrine sensitive organs such as the breast, ovary, and prostate [3], [4], [5]. Simple estrogen imbalance, however, does not account for all of the increased risk attributable to obesity. Obese patients also have an increased risk for adenocarcinomas of the pancreas and colon which are not traditionally considered endocrine-sensitive, suggesting that alternate or multiple molecular pathways may be involved [6].
Despite a rising incidence and relative mortality of endometrial cancer, coinciding with a national epidemic of obesity, no prevention or screening strategy has proven cost-effective to date [7]. This is largely owing to a relatively low prevalence of endometrial pathology in the asymptomatic general population and a tendency for detection at early stages because of symptomatic bleeding. Recently however, our group has completed a natural history study of the effect of bariatric surgery-induced weight loss, in which we observed that the rate of occult hyperplasia in untreated, asymptomatic, morbidly obese women is up to 10% and that weight loss reduced but did not eliminate this risk [8]. This level of premalignant disease suggests that in morbidly obese women screening or proactive intervention may be cost effective.
Ultimately, effective screening efforts will require the treating clinicians to be able to stratify risk based on objective and reproducible measures, while prevention efforts will require an understanding of the natural history of disease progression and the range of potential treatment options. Multiple studies have demonstrated that the risk of coincident or subsequent endometrial cancer rises along a continuum of endometrial architectural complexity and cytologic atypia [9]. Despite these findings, traditional pathologic assessments have high inter-observer variability, and are increasingly unreliable at the lower end of the risk spectrum. Efforts to simplify the grading system using endometrial intraepithelial neoplasia (EIN) nomenclature have encouraging initial results, but have been slow to be adopted, and still rely heavily on microscopic, as opposed to molecular features [10].
The expression patterns of both the estrogen receptor (ER) and the progesterone receptor (PR) in normal endometria and to a lesser extent in malignant and premalignant endometria are well characterized [11]. However, the significance of the expression patterns in obese women, the implications of androgen receptor (AR) expression, and the effect of weight loss on hormone expression patterns remain unknown. The present study was undertaken to determine if morbidly obese patients with premalignant changes had detectably different expression profiles of markers known or suspected to be involved in the development of endometrial cancer; and to determine if weight loss affected these profiles.
Section snippets
Tissue acquisition
After obtaining institutional review board approval, 59 patients were enrolled in a prospective non-interventional trial to assess the effect of Roux-en-Y gastric bypass surgery on the prevalence of endometrial pathology. The details of this study are reported elsewhere; but briefly, all morbidly obese women who were asymptomatic by self report (no abnormal vaginal bleeding in the previous 6 months), had a negative pregnancy test or prior sterilization, and gave consent were eligible. We
Clinical results
59 morbidly obese women underwent initial sampling. Patient demographics are listed in Table 1, most patients were Caucasian, less than 50 years old, had good access to health care and relatively few medical co-morbidities. All patients underwent Roux-en-Y bypass and endometrial biopsy without overt complication, though in five pre-operative (8.5%) and one post-operative (2.2%) specimens there was insufficient tissue for diagnosis. Twelve months post-operatively the median (range) weight loss
Discussion
Our data indicate that obese women with hyperplasia have a different profile of hormone receptor expression from women without endometrial pathology. The differential expression pattern appears to resolve with weight loss, even in the absence of histological change; and in this sample, preceded the resolution of histological abnormalities in half of the four cases that ultimately resolved. The intricate balance of the hormonal influences, regulated through their respective receptors, is crucial
Conclusion
Morbidly obese women have a relatively high risk for harboring endometrial pathology even when asymptomatic. In some patients, both the histologic abnormalities and the high expression of ER and PR appear to normalize over one year in the absence of other medical interventions suggesting that the effects of bariatric surgery-induced weight loss may favorably influence a patient's risk of developing endometrial neoplasia. The high prevalence of occult disease in this population and the absence
Conflict of interest statement
The authors declare no conflicts of interest with regard to the results or interpretation of this data.
Acknowledgments
This research was supported by an American Cancer Society Mentored Research Award (#MRSG-10-079-01-CPPB) and by a grant from the Scaife Foundation, for which the authors are grateful.
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2019, Surgery for Obesity and Related DiseasesCitation Excerpt :In their case report, Bentio et al. [22] described a grade I endometrioid adenocarcinoma of the endometrium that failed treatment with a levonorgestrol intrauterine device and was found to regress at 18 months postsurgery. Estrogen and progesterone receptors in the endometrium also have been demonstrated to normalize postoperatively [23], while tumor suppressor gene expression has not demonstrated significant differences [24]. Metabolic profiles have also demonstrated favorable changes toward a decreased risk in endometrial cancer, demonstrating improved insulin response, decreased inflammation, and normalization of steroid hormones [20,25].