Endometrial biomarkers in premenopausal women with obesity: an at-risk cohort

Abstract

Background: Obesity is a well-known risk factor for endometrial cancer, but the mechanisms of obesity-related carcinogenesis are not well defined, particularly for premenopausal women. With the continuing obesity epidemic, increases in the incidence of endometrial cancer and a younger age of diagnosis are often attributed to a hyperestrogenic state created by hormone production in adipose tissue, but significant knowledge gaps remain. The balance of estrogen-responsive signals has not been defined in the endometrium of premenopausal women with obesity, where obesity may not create hyperestrogenism in the context of ovaries being the primary source of estrogen production. Obesity is associated with a state of low-grade, chronic inflammation that can promote tumorigenesis, and it is also known that hormonal changes alter the immune microenvironment of the endometrium. However, limited research has been conducted on endometrial immune-response changes in women who have an increased risk for cancer due to obesity.

Objective: Endometrial estrogen-regulated biomarkers, previously shown to be dysregulated in endometrial cancer, were evaluated in a cohort of premenopausal women to determine if obesity is associated with differences in the biomarker expression levels, which might reflect an altered risk of developing cancer. The expression of a multiplexed panel of immune-related genes was also evaluated for expression differences related to obesity.

Study design: Premenopausal women with a body mass index of ≥30 kg/m2 (n=97) or a body mass index of ≤25 kg/m2 (n=33) were prospectively enrolled in this cross-sectional study, which included the assessment of serum metabolic markers and a timed endometrial biopsy for pathologic evaluation, hormone-regulated biomarker analysis, and immune response gene expression analysis. Medical and gynecologic histories were obtained. Endometrial gene expression markers were also compared across the body mass index groups in a previous cohort of premenopausal women with an inherited cancer risk (Lynch syndrome).

Results: In addition to known systemic metabolic differences, histologically normal endometria from women with obesity showed a decrease in gene expression of progesterone receptor (P=.0027) and the estrogen-induced genes retinaldehyde dehydrogenase 2 (P=.008), insulin-like growth factor 1 (P=.016), and survivin (P=.042) when compared with women without obesity. The endometrial biomarkers insulin-like growth factor 1, survivin, and progesterone receptor remained statistically significant in multivariate linear regression models. In contrast, women with obesity and Lynch syndrome had an increased expression of insulin-like growth factor 1 (P=.017). There were no differences in endometrial proliferation, and limited endometrial immune differences were observed.

Conclusion: When comparing premenopausal women with and without obesity in the absence of endometrial pathology or an inherited cancer risk, the expression of the endometrial biomarkers does not reflect a local hyperestrogenic environment, but it instead reflects a decreased cancer risk profile that may be indicative of a compensated state. In describing premenopausal endometrial cancer risk, it may be insufficient to attribute a high-risk state to obesity alone; further studies are warranted to evaluate individualized biomarker profiles for differences in the hormone-responsive signals or immune response. In patients with Lynch syndrome, the endometrial biomarker profile suggests that obesity further increases the risk of developing cancer.

Trial registration: ClinicalTrials.gov NCT00500591.

Keywords: Lynch syndrome; endometrial cancer; obesity; premenopausal; prevention.

Copyright © 2020 Elsevier Inc. All rights reserved.

Figures

Figure 1.

Obesity-related differences in estrogen-regulated gene expression levels in endometrial biopsy specimens. Non-obese women with BMI ≤25 kg/m2 (n=33) and obese women with BMI≥30 kg/m2 (n=96) were included. Box plots extend to 25th and 75th percentile with whiskers indicate 10th and 90th percentiles. All transcripts were normalized to “gNORM”, calculated as the geometric mean of the normalizer transcripts.

Figure 2.

Endometrial progesterone receptor (PR) gene expression and protein analyses. PR gene expression in endometrial biopsies from non-obese versus obese premenopausal women in women without inherited cancer risk (A) and women with Lynch syndrome (B) were measured by quantitative real-time PCR. Protein levels were assessed by immunohistochemistry (IHC) in women without inherited risk and quantitated for endometrial glands or stroma (C-D). Box plots extend to 25th and 75th percentile with whiskers indicate 10th and 90th percentiles.

Figure 3.

Endometrial proliferation in obese and non-obese cohorts. Proliferation rates evaluated using immunohistochemistry for Ki67 in non-obese and obese women without inherited cancer risk (A) and in women with Lynch syndrome (B).

Figure 4.

Obesity-related differences in estrogen-regulated gene expression levels in endometrial biopsy specimens in women with inherited cancer risk associated with Lynch syndrome. Non-obese women with BMI ≤25 kg/m2 (n=22) and obese women with BMI≥30 kg/m2 (n=13) were included. Box plots extend to 25th and 75th percentile with whiskers indicate 10th and 90th percentiles.