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Menopause Live - IMS Updates
InFocus

Date of release: 09 September, 2013

Endometrial cancer and adipokines

Endometrial cancer is the most prevalent type of female genital tract malignancy in the developed countries. It represents nearly 50% of all new genital cancers in the Western world, surpassing the incidence of cervical cancer. Endometrial cancer is a disease of postmenopausal women (median age 63 years) and 90% of cases occur in patients over 50 years of age. Clinical risk factors include early onset of menstruation, obesity, sedentarism, nulliparity, infertility, late menopause, diabetes mellitus, hypertension, estrogen exposure and prolonged tamoxifen treatment. Some 5% of endometrial cancers are associated with hereditary non-polyposis colorectal carcinoma (Lynch syndrome type II). There are different subtypes of endometrial cancer but the most common is the endometrioid type (90% of cases). Other subtypes are papillary, serous, clear cell carcinoma and carcinosarcomas. Endometrioid cancer has a good prognosis, while the other subtypes are associated with a bad prognosis.
 
Abdominal obesity is a well-established risk factor for endometrial cancer, but mechanisms underlying the association are unclear. Luhn and colleagues [1] recently reported the influences of serum estradiol, adiponectin, leptin and visfatin on endometrial cancer risk in a nested case–control sample of postmenopausal women included in the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial. The studied population included 167 incident endometrial cancer cases and 327 matched controls with similar sociodemographic characteristics. Estradiol and adipokine (adiponectin, leptin and visfatin) levels were categorized into tertiles (T). Conditional logistic regression showed inverse association between adiponectin levels (T3 vs. T1) for the risk of endometrial cancer (odds ratio (OR) 0.48; 95% confidence interval (CI) 0.29–0.80), while high leptin levels had a positive association (OR 2.77; 95% CI 1.60–4.79). The associations were stronger when considering only women not using menopause hormone therapy. There were non-significant associations between serum visfatin levels and endometrial cancer risk.

Comment

Endometrial cancer is considered a hormone steroid-dependent tumor. High serum androstendione levels are associated with about three-fold increased risks in both pre- and postmenopausal women, while high sex hormone binding globulin levels are associated with lower cancer risk in postmenopausal women. Both high estrone levels and albumin-bound estradiol (the bioactive fraction) are also significant risk factors, even after adjustments for body mass index. On the contrary, high total, free, and albumin-bound estradiol do not increase endometrial cancer risk in premenopausal women [2]. These facts and the age peak of clinical presentation suggest that other metabolic and endocrine influences, aside of steroid hormones, may contribute to endometrial carcinogenesis. Different hormone steroid-dependent cancers have been related with obesity, including breast, colorectal and prostate cancers. In addition, there is increasing evidence that the adipokines adiponectin and leptin, which are directly produced in adipose tissue, impact several obesity-related cancers. 
 
The connection between obesity and cancer may be mediated by metabolic changes associated with insulin resistance and a state of chronic low-grade inflammation. Excessive body weight, abdominal obesity, hyperinsulinemia and increased secretion of insulin growth factor increase endometrial cancer risk [3,4]. The augmentation of fat mass involves a complex interaction of adipokines and cytokines. Cytokine production in obese adipose tissue creates a chronic inflammatory microenvironment that favors tumor cell motility, invasion, and epithelial–mesenchymal transition to enhance the metastatic potential of tumor cells [5].
 
Obesity, sedentarism and hyperinsulinemia are associated with low circulating levels of adiponectin – a protein hormone with insulin-sensitizing properties. Leptin and adiponectin respond to increasing adiposity in a reciprocal manner, and the plasma leptin : adiponectin ratio is a measure of insulin resistance. Adiponectin possesses strong anti-inflammatory, antiatherogenic, antiproliferative and insulin-sensitizing properties. A low adiponectin level is an independent predictor of incident type 2 diabetes, cardiovascular disease and cancer [6,7]. 
 
The data from Luhn and colleagues [1] concerning adiponectin and endometrial cancer confirm similar results from an European case–control study [8] including both pre- and postmenopausal women. The authors reported a stronger inverse association between adiponectin and endometrial cancer risk among obese women than among non-obese women, and also a stronger association  for post- or perimenopausal women than for premenopausal women. In this study, the association remained significant after separate adjustment for other biochemical markers such as C-peptide, sex hormone binding globulin, estrone or free testosterone.
 
Friedenreich and co-workers [4] published the results on blood leptin, adiponectin, and insulin from a large Canadian case–control study including 541 incident endometrial cancer cases and 961 frequency age-matched controls. The highest quartile of insulin and the homeostasis model assessment ratio were associated with 64% and 72% increased risks of endometrial cancer as compared with the lowest quartile, respectively. After adjustments, the highest quartile of adiponectin was associated with a 45% reduction in endometrial cancer risk. There were no associations between fasting glucose, leptin and leptin : adiponectin ratio and endometrial cancer risk.
 
Adiponectin actions are mediated by two distinct receptors which have different affinities for low and high molecular weight adiponectins. The scarce available information indicates that the expression of adiponectin receptors is similar in endometrial cancer as compared with normal endometrium [9]. If these findings are confirmed, it would suggest that the adiponectin changes contribute to endometrial carcinogenesis by insulin resistance and metabolic-related effects rather than by a direct action on their tumor cell receptors. It seems that weight and the adipose tissue endocrinology may have a relevant role in endometrial carcinogenesis and prognosis that requires further studies. In addition, obesity can make it difficult to detect abdominal tumors, to carry out appropriate tumor treatments (difficult surgery, chemotherapy dosing), and fat cells may affect tumor cell growth and spread. 
 
Caloric restriction stimulates mechanism of cell protection against aging and uncontrolled proliferation [10]. Theoretic interventions include prevention of weight gain and sedentarism in adolescence and adulthood, monitoring waist circumference to detect abdominal obesity and for risk of metabolic syndrome, and promoting moderate regular physical activity; these may be instruments to neutralize the obesity- and adipokine-related risk of endometrial cancer. Small changes in lifestyle (diet + exercise + social links) can translate to significant improvement in cancer risk and well-being. On the other hand, taking care of women in their forties and fifties, decades before the age of endometrial cancer diagnosis, to reduce obesity may be challenging and rewarding to prevent endometrial cancer (and cancer in other localizations); this has not been prospectively tested so far.
 
The identification and development of protective agents that mimic the effects of caloric restriction may be a future alternative for cancer prevention. The development of an adiponectin receptor agonist [7] may be a way to prevent and treat clinical conditions associated with hypoadinectinemia, including obesity, the metabolic syndrome and endometrial cancer.

Faustino R. Pérez-López


Professor of Obstetrics and Gynecology, University of Zaragoza Faculty of Medicine & Lozano Blesa University Hospital, Zaragoza, Spain



    References

  1. Luhn P, Dallal CM, Weiss JM, et al. Circulating adipokine levels and endometrial cancer risk in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. Cancer Epidemiol Biomarkers Prev 2013;22:1304-12.


    http://www.ncbi.nlm.nih.gov/pubmed/23696194

  2. Potischman N, Hoover RN, Brinton LA, et al. Case-control study of endogenous steroid hormones and endometrial cancer. J Natl Cancer Inst 1996;88:1127-35.


    http://www.ncbi.nlm.nih.gov/pubmed/8757192

  3. Gunter MJ, Hoover DR, Yu H, et al. A prospective evaluation of insulin and insulin-like growth factor-I as risk factors for endometrial cancer. Cancer Epidemiol Biomarkers Prev 2008;17:921-9.
    http://www.ncbi.nlm.nih.gov/pubmed/18398032

  4. Friedenreich CM, Langley AR, Speidel TP, et al. Casecontrol study of markers of insulin resistance and endometrial cancer risk. Endocrine-Related Cancer 2012;19:78592.


    http://www.ncbi.nlm.nih.gov/pubmed/23033315

  5. Ellies LG, Johnson A, Olefsky JM. Obesity, inflammation and insulin resistance. In Dannenberg AJ, Berger NA, eds. Obesity, Inflammation and Cancer. Berlin: Springer, 2013:1-24




  6. Yadav A, Kataria MA, Saini V, Yadav A. Role of leptin and adiponectin in insulin resistance. Clin Chim Acta 2013;417:80-4.


    http://www.ncbi.nlm.nih.gov/pubmed/23266767

  7. Dalamaga M, Diakopoulos KN, Mantzoros CS. The role of adiponectin in cancer: A review of current evidence. Endocr Rev 2012; 33:547-94.


    http://www.ncbi.nlm.nih.gov/pubmed/22547160

  8. Cust AE, Allen NE, Rinaldi S, et al. Serum levels of C-peptide, IGFBP-1 and IGFBP-2 and endometrial cancer risk; results from the European Prospective Investigation into Cancer and Nutrition. Int J Cancer 2007;120:2656-64.


    http://www.ncbi.nlm.nih.gov/pubmed/17285578

  9. Moon HS, Chamberland JP, Aronis K, Tseleni-Balafouta S, Mantzoros CS. Direct role of adiponectin and adiponectin receptors in endometrial cancer: in vitro and ex vivo studies in humans. Mol Cancer Ther 2011;10:2234-43.


    http://www.ncbi.nlm.nih.gov/pubmed/21980131

  10. Chedraui P, Pérez-López FR. Nutrition and health during mid-life: searching for solutions and meeting challenges for the aging population. Climacteric 2013; 16(Suppl 1):85-95.


    http://www.ncbi.nlm.nih.gov/pubmed/23651240