Obesity and endometrial hyperplasia and cancer in premenopausal women: A systematic review

Wise, Michelle; Jordan, Vanessa; Lagas, Alice Kitty; Showell, Marian; Wong, Nicole; Lensen, Sarah; Farquhar, Cindy

doi:10.1016/j.ajog.2016.01.175

Cited by 115 publications

(76 citation statements)

References 30 publications

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“…Body mass index (BMI) is a consistent and leading risk factor for EH in premenopausal women. [4] Adipose tissue is not only an organ for fat storage but also an active participant in the regulation of energy homeostasis and secreting a large number of biologically active adipokines. [5] Adiponectin is a hormone originally identified in adipocytes and is recently shown to modulate a wide range of physiological processes including carbohydrate and lipid metabolism, atherosclerosis, blood pressure regulation, and insulin sensitivity, and even influence immunity and inflammation.…”

Section: Introductionmentioning

confidence: 99%

Effect of High-fat Diet-induced Disorders on Rat with Endometrial Hyperplasia and Adiponectin System in Circulation and Uterus

Shang

Liu

Wang

et al. 2017

Chinese Medical Journal

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Background:Epidemiologic and genetic studies suggest a link between insulin resistance (IR) and endometrial cancer, and endometrial hyperplasia (EH) is a precancerous stage of endometrial cancer. Adiponectin is an adipokine which previously shown to be a risk factor for endometrial cancer. The aim of the study was to develop a rat model of IR and EH and evaluate adiponectin system in circulation and uterus.Methods:This study was a 46-week animal trial from February 2014 to January 2015. Female Sprague-Dawley rats were fed with high-fat diet (HFD) for 40 weeks to induce IR. Followed by ovariectomization, rats were orally administrated to 17β-estradiol (E2) for 4 weeks to induce EH and then sacrificed. A total of 36 rats were divided into four groups: E2, HFD, HFD + E2, and control groups. Data were analyzed with Student's t-test, one-way analysis of variance (ANOVA), and Mann-Whitney U-tests. Chi-square was used to evaluate the score of immunohistochemistry.Results:The thickness of endometrial, glandular epithelium, and myometrium in the HFD-E2 group were higher than the E2 group (F = 59.02, F = 23.51 and F = 12.53, respectively, all P < 0.001). Plasma adiponectin levels in the E2 group were lower than those in the control group, and the levels in the HFD-E2 group were lower than those in the HFD group (F = 13.15, P < 0.05). However, after normalized to visceral adipose tissue, compared to the control group, plasma adiponectin levels were decreased in rat with HFD in the absence or presence of E2, respectively (F = 6.72, P < 0.05). Adiponectin gene (F = 10.48, P < 0.05) and protein (P < 0.05) levels in uterus in the HFD-E2 group were higher than those in the HFD group.Conclusions:This study manifests that IR can effectively modulate EH, which suggests the involvement of energetic metabolism in uterine alternation. The combination effects of IR and EH modulate circulating adiponectin levels. However, adiponectin gene and protein levels in uterus are mainly response to estradiol.

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Section: Introductionmentioning

confidence: 99%

Effect of High-fat Diet-induced Disorders on Rat with Endometrial Hyperplasia and Adiponectin System in Circulation and Uterus

Shang

Liu

Wang

et al. 2017

Chinese Medical Journal

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“…More than 47,000 women are diagnosed with endometrial carcinoma in the United States each year23, Numerous epidemiological studies have confirmed that metabolic factors are closely associated with various cancers, particularly EC456. Hyperinsulinemia has been considered as an EC risk factor independent of estradiol7, and metformin, an insulin-sensitizer, is found to diminish EC proliferation and has positive effects on cancer clinical evolution89.…”

mentioning

confidence: 99%

Cholesterol Synthetase DHCR24 Induced by Insulin Aggravates Cancer Invasion and Progesterone Resistance in Endometrial Carcinoma

Dai

Zhu

Liu

et al. 2017

Sci Rep

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3β-Hydroxysteroid-Δ24 reductase (DHCR24), the final enzyme of the cholesterol biosynthetic pathway, has been associated with urogenital neoplasms. However, the function of DHCR24 in endometrial cancer (EC) remains largely elusive. Here, we analyzed the expression profile of DHCR24 and the progesterone receptor (PGR) in our tissue microarray of EC (n = 258), the existing EC database in GEO (Gene Expression Omnibus), and TCGA (The Cancer Genome Atlas). We found that DHCR24 was significantly elevated in patients with EC, and that the up-regulation of DHCR24 was associated with advanced clinical stage, histological grading, vascular invasion, lymphatic metastasis, and reduced overall survival. In addition, DHCR24 expression could be induced by insulin though STAT3, which directly binds to the promoter elements of DHCR24, as demonstrated by ChIP-PCR and luciferase assays. Furthermore, genetically silencing DHCR24 inhibited the metastatic ability of endometrial cancer cells and up-regulated PGR expression, which made cells more sensitive to progestin. Taken together, we have demonstrated for the first time the crucial role of the insulin/STAT3/DHCR24/PGR axis in the progression of EC by modulating the metastasis and progesterone response, which could serve as potential therapeutic targets for the treatment of EC with progesterone receptor loss.

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“…In particular, obesity has been noted to be strongly associated with risk of endometrial cancer in several case-control studies and meta-analyses (21–25, 27, 28). Multiple measures of adiposity, including BMI, waist circumference, waist-to-hip-ratio, and hip circumference, have been found to be directly associated with endometrial cancer incidence.…”

Section: Associations With Metabolic Syndrome Obesity and Metabolismmentioning

confidence: 99%

Metformin as a Therapeutic Target in Endometrial Cancers

et al. 2018

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Endometrial cancer is the most common gynecologic malignancy in developed countries. Its increasing incidence is thought to be related in part to the rise of metabolic syndrome, which has been shown to be a risk factor for the development of hyperestrogenic and hyperinsulinemic states. This has consequently lead to an increase in other hormone-responsive cancers as well e.g., breast and ovarian cancer. The correlation between obesity, hyperglycemia, and endometrial cancer has highlighted the important role of metabolism in cancer establishment and persistence. Tumor-mediated reprogramming of the microenvironment and macroenvironment can range from induction of cytokines and growth factors to stimulation of surrounding stromal cells to produce energy-rich catabolites, fueling the growth, and survival of cancer cells. Such mechanisms raise the prospect of the metabolic microenvironment itself as a viable target for treatment of malignancies. Metformin is a biguanide drug that is a first-line treatment for type 2 diabetes that has beneficial effects on various markers of the metabolic syndrome. Many studies suggest that metformin shows potential as an adjuvant treatment for uterine and other cancers. Here, we review the evidence for metformin as a treatment for cancers of the endometrium. We discuss the available clinical data and the molecular mechanisms by which it may exert its effects, with a focus on how it may alter the tumor microenvironment. The pleiotropic effects of metformin on cellular energy production and usage as well as intercellular and hormone-based interactions make it a promising candidate for reprogramming of the cancer ecosystem. This, along with other treatments aimed at targeting tumor metabolic pathways, may lead to novel treatment strategies for endometrial cancer.

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Obesity and endometrial hyperplasia and cancer in premenopausal women: A systematic review

Cited by 115 publications

References 30 publications

Effect of High-fat Diet-induced Disorders on Rat with Endometrial Hyperplasia and Adiponectin System in Circulation and Uterus

Effect of High-fat Diet-induced Disorders on Rat with Endometrial Hyperplasia and Adiponectin System in Circulation and Uterus

Cholesterol Synthetase DHCR24 Induced by Insulin Aggravates Cancer Invasion and Progesterone Resistance in Endometrial Carcinoma

Metformin as a Therapeutic Target in Endometrial Cancers

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