Enhanced estrogen-induced proliferation in obese rat endometrium

Abstract

Objective-We tested the hypothesis that the proliferative estrogen effect on the endometrium is enhanced in obese versus lean animals. Study design-UsingZucker fa/fa obese rats and lean control, we examined endometrial cell proliferation and the expression patterns of certain estrogen-regulated pro-proliferative and antiproliferative genes after short-term treatment with estradiol.Results-No significant morphological/histological difference were seen between the obese rats and the lean rats. Estrogen-induced pro-proliferative genes cyclin A and c-Myc mRNA expression were significantly higher in the endometrium of obese rats compared with that of the lean control. Expression of the anti-proliferative gene p27Kip1 was suppressed by estrogen treatment in both obese and lean rats, however, the decrease was more pronounced in obese rats. Estrogen more strongly induced the anti-proliferative genes RALDH2 and sFRP4 in lean rats, but had little or no effect in obese rats.Conclusion-Enhancement of estrogen-induced endometrial pro-proliferative gene expression and suppression of anti-proliferative gene expression was seen in the endometrium of obese versus lean animals. KeywordsObesity; estrogen; endometrial; proliferation Obesity affects over 25% of adult women in the United States and continues to increase in prevalence. Numerous epidemiologic studies have demonstrated that obesity is a major risk * Corresponding Author: Karen H. Lu, MD, Department of Gynecologic Oncology, University of Texas, MD Anderson Cancer Center, P.O. Box 301439, Houston, TX 77230-1439, Telephone: (713) Fax: (713) 792-7586, khlu@mdanderson.org. Condensation: As compared to the endometrium of lean rats, obese rat endometrium shows an increase in cell proliferation markers with estrogen treatment.Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. NIH Public Access NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript factor for endometrial cancer. 1 While an average woman has a 3% lifetime risk of endometrial cancer, obese women have a 9-10% lifetime risk of endometrial cancer. 2 The increased peripheral conversion in adipose tissue of adrenal steroids to estrone and the increased bioavailability of free estrogens due to decreased sex hormone binding globulin contribute to a "hyperestrogenic state" in obese women, which results in increased endometrial cell proliferation, leading to endometrial hyperplasia and cancer. Clinical studies have shown that patients with endometrial cancer exhibit higher plasma levels of estrogens versus controls. 3 However, in a large study by Potisch...

Chemopreventive effects of metformin on obesity-associated endometrial proliferation

“…Specifically, we showed that the expression of the pro-proliferative genes was increased while the expression of anti-proliferative genes were inhibited in the endometrium of estrogen-treated obese, insulin-resistant rats as compared to lean controls 5 . These data suggested that insulin potentiates estrogen-regulated endometrial proliferation in the context of obesity.…”

Understanding obesity and endometrial cancer risk: opportunities for prevention

“…Our group has demonstrated that the proliferative effect of estrogen on the endometrium is enhanced in obese versus lean animals 35 . Using the Zucker rat model of hyperinsulinemia, estrogen induced significantly higher expression of the proproliferative genes, cyclin A and c-myc and in endometrium of obese rats, as compared that observed in lean control animals.…”

Prospective evaluation of insulin resistance among endometrial cancer patients

“…Preclinical studies conducted by our group suggest that hyperinsulinemia and insulin resistance associated with obesity may contribute to endometrial proliferation. 13 In addition, we have found that correction of hyperinsulinemia with insulin-sensitizing agents reverses the proliferative drive (unpublished data). Given the high prevalence of insulin resistance in our population of patients and potential contribution of IR to the carcinogenesis of endometrial cancer, insulin-sensitizing agents may have a role in treatment and prevention of this disease.…”

“…9–12 Additionally, preclinical studies have shown that insulin resistance accompanied by high circulating levels of insulin potentiates the effect of estrogen on endometrial proliferation. 13 Thus, insulin resistance may further clarify the link between obesity and endometrial cancer. We hypothesized that the risk of endometrial cancer associated with diabetes alone results in an underestimation of the true relationship between IR and endometrial cancer.…”