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Servizio di Epidemiologia e Biostatistica, Centro di Riferimento Oncologico (L.D.M., L.S.A.A., R.T.), Aviano 33081, Italy; Department of Nutritional Sciences, Faculty of Medicine, University of Toronto and the Clinical Nutrition and Risk Factor Modification Center, St. Michaels Hospital (L.S.A.A.), Toronto M5C 2T2, Canada; Human Nutrition Research Unit, Division of Endocrinology, Diabetes and Metabolism, Beth Israel Deaconess Medical Center, Harvard Medical School (A.K, C.S.M.), Boston, Massachusetts 02215; International Agency for Research on Cancer (S.F.), Lyon 69008, France; Department of Epidemiology, Harvard School of Public Health (D.T.), Boston, Massachusetts 02215; Istituto di Ricerche Farmacologiche Mario Negri (C.L.V.), Milan 20157, Italy; and Istituto di Statistica Medica e Biometria, Università degli Studi di Milano (C.L.V.), Milan 20133, Italy
Address all correspondence and requests for reprints to: Dr. Luigino Dal Maso, Servizio di Epidemiologia e Biostatistica, Centro di Riferimento Oncologico, Institute for Cancer Research and Treatment, Via Pedemontana Occidentale, 33081 Aviano (PN), Italy. E-mail: epidemiology{at}cro.it.
| Abstract |
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| Introduction |
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In a case-control study of 84 cases and 84 controls from Greece (12), an increase in adiponectin by 1 SD was associated with an odds ratio (OR) of endometrial cancer of 0.44 among women under 65 yr of age, after allowance for body mass index (BMI). To provide additional information on the issue, we have conducted a hospital-based case-control study of endometrial cancer in Pordenone (North-Eastern Italy). As limited evidence is available concerning the possible role of plasma and serum levels of adiponectin and their potential impact on chronic diseases such as endometrial cancer, we performed the adiponectin assay on both serum and plasma.
| Subjects and Methods |
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Trained interviewers in hospital wards collected information on sociodemographic and anthropometric characteristics, smoking habits, physical activity, height and weight, selected medical conditions, menstrual and reproductive factors, and use of hormone replacement therapy. To assess the diet, including total energy intake, a validated food frequency questionnaire was used, including 78 foods, food groups, or recipes (13).
Two controls (1.4%) and no cases refused the interview. All study participants signed written informed consent and donated a 15-ml blood sample [7.5-ml Vacutainer (SARSTED, Nümbrecht, Germany) tubes with EDTA and 7.5-ml Vacutainer tubes without EDTA] on the day the interview took place (generally the first day of the hospital stay). Blood samples were kept refrigerated and were processed, within 12 h from collection, at the National Cancer Institute of Aviano. They were centrifuged at 1500 rpm for 20 min, extracted, and distributed into different cryotubes of serum, plasma, buffy coat, and red blood cells. All samples were stored at -80 C. Serum and plasma samples were sent to the Human Nutritional Research Unit, Harvard Medical School (Boston, MA), for testing (12). Adiponectin analysis was blindly performed by RIA with a sensitivity of 2 ng/ml and an intraassay coefficient of variation of 8%.
ORs and the corresponding 95% confidence intervals (CI) for tertiles of plasma and serum adiponectin were computed using unconditional multiple logistic regression models, including terms for age, education, parity, smoking status, BMI (kilograms per meter squared) and hormone replacement therapy (14). To evaluate dose-response effects, tests for linear trend were assessed, by means of the
2 (
12 trend) on the variables considered categorical by computing the difference between the deviance of the model with and that without the variables of interest (14).
| Results |
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30 vs. BMI < 25), less frequently parous (OR, 0.49), tended to report later menopause (OR, 1.86), and more frequently had a family history of endometrial cancer (OR, 2.01) than controls. Plasma adiponectin was weakly correlated with age (Spearman r = 0.09), energy intake (r = -0.08), and BMI (r = -0.18). Plasma and serum levels of adiponectin showed a strong correlation (r = 0.61).
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2300 kcal) and low adiponectin levels led to an OR of 2.75 (95% CI, 1.166.52) for plasma and 3.19 (95% CI, 1.367.44) for serum adiponectin (data not shown in tables). The exclusion of patients diagnosed at stage III or IV (17 cases) did not materially change any of the results. Moreover, the additional adjustment for waist to hip ratio did not appreciably modify the results. | Discussion |
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As in a Greek study (12), the inverse association was apparently stronger in younger women, particularly in premenopausal ones. The inclusion of young women with anovulation or polycystic ovary syndrome (4, 16), a disease characterized by several factors directly associated with endometrial cancer (4, 11, 17), may at least in part explain this finding.
The observation that overweight and adiponectin have independent roles in endometrial cancer risk indicates that the two mechanisms, possibly reflecting excess estrogen levels and insulin resistance, have multiplicative effects in endometrial carcinogenesis. We also observed that diets with high glycemic index and load, which are related to high levels of blood glucose, insulin, and possibly IGFs, are directly related to endometrial cancer risk (18).
Insulin stimulates the growth of endometrial stromal cells through direct binding to insulin receptors on endometrial cell membranes (19). An association between adiponectin and leptin binding protein was recently demonstrated (20), even if the direction of the causal relationship between them and the possibility of regulation by another, as yet unidentified, common factor deserves further investigation. However, the limited information available on the potential interaction among adiponectin, leptin, insulin, and IGF components on the mechanism of endometrial carcinogenesis (12) suggests cautious conclusions. Furthermore, adiponectin levels, as recently shown, are negatively and independently associated with estradiol, whereas no association emerged between leptin, cortisol, or free testosterone and adiponectin (21).
Although our study was hospital-based, it is unlikely that bias or confounding substantially influenced the main findings, because the catchment areas of cases and controls were similar, participation was practically complete, major identified risk factors were consistent with our knowledge of endometrial carcinogenesis, and allowance was made for major potential confounding factors. Reproducibility of self-reported medical history, menstrual, and reproductive factors were satisfactory (22). Moreover, self-reported anthropometric measures were not biased between cases and controls (23). Interview and blood collection were made in the majority of study subjects on the first day of hospital admission and for cancer cases always before surgical or radiation treatment. Moreover, in the present study the distribution of endometrial cancer cases by stage was similar to that reported in a larger series from developed countries (24) with a predominance of localized (stage I) cancers.
In conclusion, analyses of adiponectin in serum and plasma samples yielded consistent results; thus, either plasma or serum measurements could be used in future studies.
| Acknowledgments |
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| Footnotes |
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Abbreviations: BMI, Body mass index; CI, confidence interval; IQR, interquartile range; OR, odds ratio.
Received October 6, 2003.
Accepted December 16, 2003.
| References |
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