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Journal of Clinical Endocrinology & Metabolism, doi:10.1210/jc.2006-1371
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The Journal of Clinical Endocrinology & Metabolism Vol. 92, No. 1 255-263
Copyright © 2007 by The Endocrine Society

Plasma Adiponectin Levels and Endometrial Cancer Risk in Pre- and Postmenopausal Women

Anne E. Cust, Rudolf Kaaks, Christine Friedenreich, Fabrice Bonnet, Martine Laville, Annekatrin Lukanova, Sabina Rinaldi, Laure Dossus, Nadia Slimani, Eva Lundin, Anne Tjønneland, Anja Olsen, Kim Overvad, Françoise Clavel-Chapelon, Sylvie Mesrine, Virginie Joulin, Jakob Linseisen, Sabine Rohrmann, Tobias Pischon, Heiner Boeing, Dimitrios Trichopoulos, Antonia Trichopoulou, Vassiliki Benetou, Domenico Palli, Franco Berrino, Rosario Tumino, Carlotta Sacerdote, Amalia Mattiello, J. Ramón Quirós, Michelle A. Mendez, María-José Sánchez, Nerea Larrañaga, M. J. Tormo, Eva Ardanaz, H. Bas Bueno-de-Mesquita, Petra H. M. Peeters, Carla H. van Gils, Kay-Tee Khaw, Sheila Bingham, Naomi Allen, Tim Key, Mazda Jenab and Elio Riboli

Nutrition and Hormones Unit (A.E.C., R.K., S.Ri., L.D., N.S., M.J.), International Agency for Research on Cancer, 69372 Lyon, France; School of Public Health (A.E.C.), University of Sydney, Sydney 2006, Australia; Université Claude Bernard Lyon 1 (A.E.C.), 69622 Lyon, France; Division of Population Health and Information (C.F.), Alberta Cancer Board, Calgary, Alberta, Canada T2N 4N2; Center for Research in Human Nutrition Rhône-Alpes (F.Bo., M.L.), University of Lyon 1, 69622 Lyon, France; Unité Mixte de Recherche, Institut National de la Santé et de la Recherche Médicale U449/Institut National de la Recherche Agronomique 1235 (F.Bo., M.L.), Lyon, France; Department of Obstetrics and Gynecology (A.L.), New York University School of Medicine, New York, New York 10016; Department of Pathology (E.L.), Umeå University, SE-901 87 Umeå, Sweden; Institute of Cancer Epidemiology (A.Tj., A.O.), Danish Cancer Society, DK-2100 Copenhagen, Denmark; Department of Clinical Epidemiology (K.O.), Aarhus University Hospital, DK-8000 C Aalborg, Denmark; Institut National de la Santé et de la Recherche Médicale (F.C.-C., S.M., V.J.), Institut Gustave Roussy, 94805 Villejuif, France; German Cancer Research Center (R.K., J.L., S.Ro.), 69120 Heidelberg, Germany; German Institute of Human Nutrition (T.P., H.B.), Potsdam-Rehbrücke, 14558 Nuthetal, Germany; University of Athens Medical School (D.T., A.Tr., V.B.), Athens 11527, Greece; Department of Molecular and Nutritional Epidemiology (D.P.), CSPO-Scientific Institute of Tuscany, 50135 Florence, Italy; Epidemiology Unit (F.Be.), Istituto Nazionale Tumori, 20133 Milan, Italy; Cancer Registry (R.T.), Azienda Ospedaliera "Civile M.P. Arezzo," 98158 Ragusa, Italy; CPO-Piemonte (C.S.), 10126 Torino, Italy; Dipartimento di Medicina Clinica e Sperimentale (A.M.), Federico II University of Naples, 80131 Naples, Italy; Public Health and Health Planning Directorate (J.R.Q.), Asturias, Spain; Institut d’Investigació Biomèdica de Bellvitge (M.A.M.), Catalan Institute of Oncology, 08907 Barcelona, Spain; Andalusian School of Public Health (M.-J.S.), Granada, Spain; Public Health Department of Gipuzkoa (N.L.), Basque Government; Epidemiology Department (M.J.T.), Health Council of Murcia, 30008 Murcia, Spain; Public Health Institute of Navarra (E.A.), Pamplona, Spain; National Institute of Public Health and the Environment (H.B.B.-d.M.), 3720 BA Bilthoven, The Netherlands; Julius Center for Health Sciences and Primary Care (P.H.M.P., C.H.v.G.), University Medical Center, 3508 CX Utrecht, The Netherlands; Clinical Gerontology (K.-T.K.), Medical Research Council Centre for Nutritional Epidemiology in Cancer Prevention and Survival (S.B.), Department of Public Health and Primary Care, University of Cambridge, Cambridge CB2 1TN, United Kingdom; Medical Research Council Dunn Human Nutrition Unit (S.B.), Cambridge CB2 2XY, United Kingdom; Cancer Research U.K. Epidemiology Unit (N.A., T.K.), University of Oxford, Oxford OX3 7LF, United Kingdom; and Department of Epidemiology and Public Health (E.R.), Imperial College London, London SW7 2AZ, United Kingdom

Address all correspondence and requests for reprints to: Professor Rudolf Kaaks, German National Cancer Center (DKFZ), Division of Cancer Epidemiology, 69120 Heidelberg, Germany. E-mail: r.kaaks{at}dkfz.de.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Background: Adiponectin, an adipocytokine secreted by adipose tissue, is decreased in obesity, insulin resistance, type 2 diabetes, and polycystic ovary syndrome, all of which are well-established risk factors for endometrial cancer.

Methods: We conducted a case-control study nested within the European Prospective Investigation into Cancer and Nutrition to examine the relation between prediagnostic plasma adiponectin levels and endometrial cancer risk. Among pre- and postmenopausal women who were not currently using exogenous hormones, 284 women developed incident endometrial cancer during an average of 5.1 yr of follow-up. Using risk set sampling, 548 control subjects were selected, matched on center, age, menopausal status, phase of menstrual cycle, time of blood draw, and fasting status. Conditional logistic regression models were used to estimate relative risks and 95% confidence intervals.

Results: Adiponectin levels were inversely associated with endometrial cancer risk [body mass index-adjusted relative risk for the top vs. bottom quartile = 0.56 (95% confidence interval 0.36–0.86), Ptrend = 0.006]. There was evidence of a stronger inverse association among obese women than among nonobese women (Pheterogeneity = 0.03). The inverse association also appeared stronger for women who were postmenopausal or perimenopausal than premenopausal at baseline, but this was not statistically significantly heterogeneous (Pheterogeneity = 0.51). The association remained statistically significant after separate adjustment for other obesity-related physiological risk factors such as C-peptide, IGF binding protein-1, IGF binding protein-2, SHBG, estrone, or free testosterone but only marginally statistically significant after simultaneous adjustment for these factors.

Conclusions: High circulating adiponectin levels are associated with reduced endometrial cancer risk, largely independent of other obesity-related risk factors.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
ADIPOSE TISSUE IS an active endocrine organ that releases a number of cytokines and hormones, collectively termed adipocytokines, including adiponectin, leptin, resistin, and TNF-{alpha} (1). Adiponectin is the most abundant circulating adipocytokine and is decreased in obesity, insulin resistance, type 2 diabetes, and polycystic ovary syndrome, all of which are independent and well-established risk factors for endometrial cancer (2). Polymorphisms in the gene encoding adiponectin have also been associated with these risk factors (1, 3, 4). Thus, adiponectin may have a role in endometrial carcinogenesis.

A major metabolic pathway through which adiponectin could influence risk is by decreasing blood insulin and glucose levels, through increased fatty acid oxidation, inhibition of hepatic glucose production, improved insulin signal transduction, and increased peripheral tissue sensitivity to insulin (1, 5, 6, 7). Animal models and human studies suggest that adiponectin may have strong antiinflammatory properties that could counteract the proinflammatory and neoplastic effects of TNF-{alpha}, IL-6, and C-reactive protein (7, 8, 9, 10, 11, 12, 13). These cytokines are implicated in endometrial cancer development through their effects on nuclear factor-{kappa}B activity (10, 14), estrogen (14, 15), and insulin levels (7, 9, 16).

Initial, more direct evidence linking adiponectin with endometrial cancer comes from the results of three relatively small (<120 cases) hospital-based case-control studies (17, 18, 19). High adiponectin levels were associated with a 20–90% reduction in risk of endometrial cancer, independently of body mass index (BMI), and particularly strongly among younger or premenopausal women.

To address the hypothesis that prediagnostic adiponectin levels are inversely associated with risk of endometrial cancer, we designed a case-control study among 284 incident cases of endometrial cancer in pre- and postmenopausal women and 548 matched controls, nested within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort study. Furthermore, to investigate whether other obesity-related biological markers may mediate this association, we also examined the relations between plasma adiponectin concentrations, measures of adiposity, and circulating levels of C-peptide (a marker of pancreatic insulin production), IGF binding proteins (IGFBP)-1 and IGFBP-2 and endogenous sex steroid hormones.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Study population

EPIC recruitment and follow-up procedures and collection of questionnaire data, anthropometric measurements, and blood samples have been described in detail elsewhere (20). Briefly, approximately 366,500 women and 153,500 men in 10 western European countries joined the study between 1992 and 1998, and of these, about 386,000 also provided a blood sample. The present study includes subjects from eight of the 10 participating countries: Denmark, France, Germany, Greece, Italy, The Netherlands, Spain, and the United Kingdom. Norway was not included in the present study because blood samples had been collected only recently, and very few cases of endometrial cancer had been diagnosed when the present study was initiated. Sweden was not included because a separate study within their cohort had already been planned.

Methods for the collection of data and blood samples and ascertainment of follow-up

Data on nondietary lifestyle and health factors were collected via standardized questionnaires that included menstrual and reproductive history, current and previous use of oral contraceptives (OCs) and postmenopausal hormone replacement therapy (HRT), health history, smoking and alcohol consumption, past-year physical activity, level of education, and brief occupational history. Height, weight, and waist and hip circumferences were measured according to standardized protocols, in light dressing, except for part of the Oxford cohort, in which height and weight were self-reported (21). A summary measure of physical activity, combining recreational and household activity in metabolic equivalent (MET)-hours/week, and the definition of menopausal status have been previously described (22, 23). All baseline questionnaire and follow-up data were entered into a central database at the International Agency for Research on Cancer (IARC) in Lyon, France. Blood samples were collected and stored according to standardized protocols (20, 23). Methods for the follow-up for cancer incidence and vital status in each EPIC country are described elsewhere (20). Vital status was known for 98.4% of all EPIC participants as of April 2004. For each EPIC study center, closure dates of the study period were defined as the date of the last complete follow-up for both cancer incidence and vital status (between June 1999 and December 2003, depending on the center). The average duration of follow-up for this analysis was 5.1 yr.

Selection of case and control subjects

Case subjects were women who were diagnosed with endometrial cancer after the initial blood donation and before the end of the study follow-up period in each study center. Women were excluded from being a case or control for this study if, at the time of blood donation, they had a previous diagnosis of cancer (except nonmelanoma skin cancer), had had a hysterectomy, or were presently using exogenous hormones (OCs or HRT) because these can alter circulating hormone levels (24). We further excluded endometrial tumors of known nonepithelial or nonmalignant morphology (25). A total of 135,953 women from the eight participating countries met these eligibility criteria, of whom 300 women were diagnosed with endometrial cancer during the follow-up period. After further exclusion of 16 cases with insufficient blood sample volume, there were 284 cases included in this study, comprising 67 cases in Denmark, 61 in Italy, 41 in Spain, 36 in The Netherlands, 34 in the United Kingdom, 19 in Germany, 17 in France, and nine in Greece. The cancer diagnosis was confirmed by histology (92%), clinical examination (7%), self-report, tomography scan, surgery, or autopsy (1%). Detailed tumor morphology was specified for 142 cases (50%), of which 133 cases (94%) were classified as type I (generally estrogen dependent endometrioid adenocarcinomas) and nine cases (6%) as type II (mostly nonestrogen dependent, serous papillary, clear cell, or squamous adenocarcinomas) (25, 26).

Control subjects were chosen at random among risk sets consisting of all eligible cohort members alive and free of cancer (except nonmelanoma skin cancer) at the time of diagnosis of the index case. An incidence density sampling protocol for control selection was used, such that controls could include subjects who became a case later in time, whereas each control could also be sampled more than once. Matching criteria included: study center, menopausal status (premenopausal, postmenopausal, perimenopausal/unknown), age at blood collection (±6 months), time of the day of blood collection (±1 h), time between blood draw and last consumption of foods or drinks (<3, 3–6, >6 h, unknown), and for premenopausal women phase of menstrual cycle [estimated from the reported start date of the menses preceding or subsequent to the blood donation, reported in detail elsewhere (27)]. Two matched controls were identified for 264 cases, and one matched control for 20 cases (total of 548 controls).

All participants gave written consent for future analyses of their blood samples, and the study was approved by the local ethics committees in the participating countries and the Internal Review Board of the IARC.

Hormone assays

All hormone assays were performed at the IARC, France, by laboratory staff blinded to the case-control status of the study subjects. The plasma samples of each matched case-control set were analyzed with sets from the same center, within the same batch (i.e. using the same assay kit) on the same day. Adiponectin concentrations were measured by ELISA (R&D Systems Europe, Abingdon, UK). Three additional samples were inserted randomly in each batch as a quality control measure. The intrabatch coefficients of variation were 8.2, 5.6, and 5.1%, and the interbatch coefficients of variation were 7.7, 7.9, and 7.6% for adiponectin concentrations of 4.3, 4.9, and 14.7 µg/ml, respectively.

Serum levels of C-peptide, IGFBP-1, IGFBP-2, and endogenous sex steroid hormones (testosterone, androstenedione, dehydroepiandrosterone sulfate, estrone, SHBG, free testosterone, and, in postmenopausal women, total and free estradiol) had been previously analyzed and will be examined in separate papers.

Statistical analyses

Circulating levels of adiponectin and other hormones were log transformed to normalize their distributions. Differences in baseline characteristics and the geometric mean adiponectin levels between cases and controls (using the average of the two matched controls) were compared using paired t tests for continuous variables and {chi}2 tests for categorical variables. Analysis of covariance, adjusting for age and laboratory batch, was used to examine the contribution of different factors on the between-subject variation in adiponectin levels. Pearson’s partial correlation coefficients, adjusted for age at blood collection, laboratory batch, and case-control status, were estimated to assess the correlations between adiponectin levels, anthropometric measures, physical activity, and levels of circulating hormones.

Conditional logistic regression models were used to estimate relative risks (RRs) and 95% confidence intervals (CIs) for the associations between plasma adiponectin levels and endometrial cancer risk. For stratification by BMI categories, we used unconditional logistic regression adjusted for laboratory batch and all matching factors, to retain all subjects in the model. The prospective design and use of incidence density sampling for selecting controls in this study permitted the direct estimation of the relative risk rather than the odds ratio (28). Quartile cut-points (or tertile cut-points for subgroup analyses) were based on the distribution of adiponectin concentration in control subjects in the full study group; these same cut-points were also used for the subgroup analyses. Likelihood ratio tests using medians for each quantile category were used to assess linear trends in RRs.

Multivariate logistic regression was used to examine the effects of potential confounders other than those controlled for by matching, including BMI (kilograms per square meter; continuous), waist circumference (centimeters; continuous), waist-hip ratio (continuous), age at menarche (<12, 12, 13, 14 yr, ≥15, missing), age at menopause (<44, 44–47, 48–50, 51–52, 53–54, ≥55 yr, missing), parity (nulliparous, one or more, missing), age at birth of last child (nulliparous, <25, 25–29, 30–34, ≥35 yr, missing), OC use (never, past, missing), HRT use (never, past, missing), smoking (never, past, current, missing), physical activity level (MET-hours/week in quartiles: <61.5, 61.5–96.9, 97.0–141.9, ≥142.0), and education level (completed secondary school: yes, no, missing). Other than BMI and waist circumference, none of these variables changed the beta coefficients for the association between adiponectin (as a log continuous variable) and endometrial cancer risk by more than 10%; therefore, we present only the crude (adjustment for matching variables only) and adiposity-adjusted values in this paper.

In addition, we examined whether circulating levels of C-peptide, IGFBP-1, IGFBP-2, SHBG, estrone, free estradiol, and free testosterone mediated the association between adiponectin and endometrial cancer risk by including these variables as continuous variables in the regression models.

{chi}2 tests were used to examine heterogeneity of endometrial cancer risk estimates associated with a doubling of adiponectin levels among the following subgroups: country, menopausal status, age at cancer diagnosis (<55, ≥55 yr), BMI (<25, 25–29.9, ≥30 kg/m2), fasting status (≤6 h, >6 h since last food or drink), physical activity level (above and below the median MET-hours/week), and lag time between blood donation and diagnosis (<2, ≥2 yr). All statistical tests were two tailed, and P < 0.05 was considered statistically significant. All statistical analyses were performed using the SAS software package, version 9.1 (SAS Institute, Cary, NC).


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Baseline characteristics and geometric mean plasma adiponectin levels of the study participants are shown in Table 1Go. Overall, the mean prediagnostic plasma adiponectin concentration was 15% lower for cases, compared with control subjects. The mean adiponectin concentration remained consistently lower among cases, compared with controls, when stratified by menopausal status, BMI, or fasting status, although the differences were not always statistically significant.


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  		TABLE 1. Baseline characteristics and geometric mean prediagnostic plasma adiponectin levels for women who developed endometrial cancer during follow-up (cases) and control subjects

 
Differences in adiponectin levels according to baseline characteristics were evaluated after adjustment for age at blood collection, case-control status, and laboratory batch (data not shown). Increasing BMI, waist circumference, and waist to hip ratio were associated with lower adiponectin levels (Ptrend < 0.0001). Adiponectin levels were also lower in women who reported having diabetes (P = 0.03), never using OCs (P = 0.05), or having less education (P = 0.03). There were no significant differences in adiponectin levels according to fasting status, menopausal status, previous HRT use, reproductive factors, phase of menstrual cycle, or level of physical activity. Similarly, analysis of covariance showed that menopausal status, fasting status, physical activity level, and country of recruitment each predicted less than 1% of the between-subject variation in levels.

Pearson partial correlation coefficients, adjusted for age, case-control status, and laboratory batch, showed that plasma adiponectin levels were negatively correlated with measures of adiposity (Table 2Go). In addition, adiponectin levels were negatively correlated with levels of C-peptide and estrogens and positively correlated with SHBG, IGFBP-1, and IGFBP-2 levels. Adiponectin levels were negatively correlated with free testosterone but not other serum androgen levels or physical activity. The correlations were somewhat weakened but remained statistically significant after additional adjustment for BMI (Table 2Go).


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  		TABLE 2. Pearson partial correlation coefficients and 95% CIs of baseline plasma adiponectin levels with anthropometric measures, C-peptide, sex steroid hormones, and physical activity

 
Conditional logistic regression analyses showed a strong inverse association between adiponectin concentration and risk [RR for the top vs. bottom quartile = 0.47 (95% CI 0.31–0.72), Ptrend = 0.0002] (Table 3Go).


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  		TABLE 3. RR estimates for the association between plasma adiponectin levels and endometrial cancer risk among all women

 
When stratified by menopausal status at the time of blood donation, there was a strong inverse association between adiponectin levels and risk among postmenopausal women [RR for the top vs. the bottom tertile = 0.44 (95% CI 0.28–0.69), Ptrend = 0.0003] and perimenopausal/unknown women [RR for the top vs. the bottom tertile = 0.41 (95% CI 0.16–1.01), Ptrend = 0.03] but not among premenopausal women [RR for the top vs. the bottom tertile = 1.05 (95% CI 0.49–2.25), Ptrend =0.84] (Table 4GoGo). Formal tests for heterogeneity of the effect of menopausal status on the association between adiponectin and endometrial cancer risk were not statistically significant (Pheterogeneity = 0.51). There was some evidence of a stronger inverse association between adiponectin levels and endometrial cancer risk among obese women than among nonobese women (Table 4GoGo) (Pheterogeneity = 0.03), even after additional adjustment for BMI and other obesity-related biological factors within each BMI category. A similar effect was observed when postmenopausal women were analyzed separately (Table 4GoGo). There was no evidence that the associations between adiponectin and endometrial cancer risk significantly differed by age at cancer diagnosis (Table 4GoGo), time to diagnosis, fasting status, physical activity, or country (Pheterogeneity all > 0.10).


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  		TABLE 4. RR estimates for the association between plasma adiponectin levels and endometrial cancer risk, stratified by baseline menopausal status, age at cancer diagnosis, and BMI

 

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  		TABLE 4A. Continued

 
Adjustment for BMI, or both BMI and waist circumference, mildly attenuated the RRs for the association between adiponectin and endometrial cancer risk, but the associations remained statistically significant both overall (Table 3Go) and among postmenopausal women (Table 4GoGo). Conversely, the association between BMI and risk was moderately attenuated after adjustment for adiponectin, such that the RR for obese subjects (BMI ≥ 30 kg/m2), compared with normal-weight subjects (BMI < 25 kg/m2) was reduced by 30% from 2.42 (95% CI 1.63–3.58) to 1.99 (95% CI 1.32–3.01), but the association remained statistically significant (Ptrend = 0.001).

The overall adiponectin-endometrial cancer risk association was further attenuated but remained statistically significant when we included C-peptide, IGFBP-1, IGFBP-2, SHBG, estrone, or free testosterone as separate factors in the model in addition to BMI but only marginally statistically significant after simultaneous adjustment for these factors (Table 3Go). Similarly, the association was partly attenuated after full adjustment for these factors among postmenopausal and perimenopausal/unknown women at baseline and women 55 yr or older at diagnosis but became stronger among younger or premenopausal women (Table 4GoGo). Women diagnosed at 50 to 60 yr also had a slightly stronger association in the fully adjusted model than the BMI-adjusted model [RR for the top vs. the bottom tertile = 0.46 (95% CI 0.21–0.99), Ptrend = 0.02 and 0.57 (95% CI 0.32–1.02), Ptrend = 0.03], respectively (data not shown). Adjustment for other lifestyle risk factors did not appreciably alter the risk estimates and thus were not included in the models.

The relative risk estimates did not appreciably change when we restricted the analysis to the 133 cases (and their matched controls) with known type I histology or when we excluded cases diagnosed less than 2 yr after study entry (n = 85 cases) or women with self-reported diabetes (n = 31). Results were also similar when adiponectin cut-points were country-specific rather than calculated for all countries combined.


   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
In this prospective study, women in the highest quartile of adiponectin levels had a 50% reduced risk of endometrial cancer, compared with women in the lowest quartile. This strong inverse association persisted after adjustment for BMI, suggesting that adiponectin is a predictor of endometrial cancer risk, independent of obesity.

A major strength of this study is its prospective design, which minimizes recall bias and selection bias arising from inappropriate selection of control subjects. Blood samples were collected at baseline, before endometrial cancer diagnosis, avoiding reverse causation bias that could occur if the presence, diagnosis, or treatment of a tumor influences circulating adiponectin and hormone levels or lifestyle changes such as weight loss. Laboratory variability was minimized by using one laboratory for adiponectin and hormone measurements, with blood samples from cases and their matched control subjects collected under similar conditions and assayed in the same batch. Furthermore, the protocols for the collection of questionnaire data and blood samples were standardized to a large extent across study centers.

A limitation of our study was the use of a single adiponectin measurement from one baseline blood sample, which does not fully characterize long-term adiponectin levels. Nevertheless, two other prospective studies that analyzed repeated adiponectin measurements donated on average 1 yr apart reported intraclass correlations of 0.71 (29) and 0.84 (30), indicating high reproducibility. The inclusion of both fasting and nonfasting blood samples in our study were unlikely to bias the results because we were able to match case and control subjects according to fasting status and because circulating adiponectin levels are not acutely influenced by meals (31). As such, the risk estimates for the association between adiponectin and endometrial cancer did not differ appreciably between fasting and nonfasting samples. In this study we measured only plasma total adiponectin levels; however, recent evidence suggests that the high-molecular-weight form of adiponectin, rather than the lower-molecular-weight form, may be the bioactive form of the protein (32).

One major metabolic pathway through which adiponectin could influence endometrial cancer risk is by decreasing blood insulin and glucose levels, mainly through increased fatty acid oxidation in skeletal muscle, inhibition of hepatic glucose production, improved insulin signal transduction, and increased peripheral tissue sensitivity to insulin (1, 5, 6, 7, 33). Circulating insulin and glucose levels are associated with increased endometrial cancer risk, through direct and indirect actions (2, 34, 35, 36). Insulin can down-regulate SHBG and IGFBPs and up-regulate ovarian sex steroid production, thus increasing total and bioavailable estrogen and androgen levels and IGF-I bioactivity (2, 34, 35).

Exposure to elevated estrogen levels that are insufficiently counterbalanced by progesterone is the predominant hypothesis for the etiology of endometrial cancer (2). However, factors that contribute to an imbalance of estrogens and progestogens also tend to increase the exposure of the endometrium to inflammation (14). Adiponectin may have strong antiinflammatory activity and could thereby potentially counteract the proinflammatory and neoplastic effects of cytokines TNF-{alpha}, IL-6, and C-reactive protein by inhibiting their production and action (7, 8, 9, 10, 11, 12, 13). These cytokines are implicated in the initiation and promotion of endometrial carcinogenesis through their effects on increasing nuclear factor-{kappa}B activity and up-regulating cyclooxygenase-2 expression and prostaglandin E2 levels in the endometrium (1, 10, 14). IL-6 and TNF-{alpha} could also stimulate the synthesis of peripheral and tumor estrogens (13, 14, 15). In addition, TNF-{alpha} may mediate insulin resistance and chronic hyperinsulinemia (16).

Through more direct mechanisms, adiponectin could impair the growth and survival of tumor cells by directly activating several signaling pathways in endometrial and other tissues (13). These signaling pathways, including 5'-AMP-activated protein kinase (8, 37), have been shown to exert direct effects on specific enzymes and transcriptional factors that regulate insulin resistance, cell proliferation, protein synthesis, apoptosis, and angiogenesis (13, 37, 38). Finally, adiponectin can inhibit the proliferative actions of several mitogenic growth factors by precluding their binding to the membrane receptors (13, 39).

Excess weight is a strong risk factor for endometrial cancer (2) and is also causally associated with insulin resistance (40). Although adiponectin is secreted almost exclusively by adipocytes, and is negatively correlated with BMI, adiponectin concentrations have been shown to be more closely inversely related to insulin resistance and insulin concentrations than to the degree of obesity (41). Our results, after mutual adjustment for adiponectin and BMI, suggest that both obesity and adiponectin each maintain independent associations with endometrial cancer risk. These findings are consistent with results from three hospital-based case-control studies in Greece (84 cases, 84 controls) (17), Italy (87 cases, 132 controls) (18), and the United States (Texas; 116 cases, 200 controls) (19), which examined the association between adiponectin and endometrial cancer risk after adjustment for BMI and other potential confounders. Petridou et al. (17) reported an odds ratio for endometrial cancer of 0.78 (0.56–1.10) with 1 SD increase in serum adiponectin levels, whereas Dal Maso et al. (18) reported odds ratios of 0.42 (95% CI 0.19–0.94) and 0.30 (95% CI 0.14–0.68) for the highest vs. lowest tertile of plasma and serum adiponectin levels, respectively. Recently Soliman et al. (19) reported an 11-fold (95% CI 4.2–26.4) increased risk among women in the lowest vs. highest tertile of serum adiponectin, although they had limited data on other potential confounders in their study. They noted that the association remained strong, even in the subset of normal-weight women (<25 kg/m2) (19). In our study, the inverse association between adiponectin and endometrial cancer risk was stronger among obese women.

In contrast to previous studies (17, 18), we did not find a stronger association between adiponectin levels and risk among younger or premenopausal women. Rather, the effect appeared stronger for women who were postmenopausal or perimenopausal/unknown status at baseline. However, with only 54 cases that were premenopausal at baseline, we lacked power to examine this association precisely among these women, and hence, the confidence intervals were wide and the risk estimates were not statistically heterogeneous. Furthermore, in women under aged 55 or between 50 and 60 yr at the time of cancer diagnosis, there was an inverse trend between adiponectin levels and risk that was stronger than for older women when fully adjusted for other obesity-related biological markers. Increasing mean BMI with age and the onset of menopause in our cohort may explain the apparent stronger association observed from around the start of menopause.

On the basis of observational data alone, it is difficult to determine the extent to which low adiponectin levels contribute to the etiology of endometrial cancer, over and above other obesity-related physiological risk factors. Adjustments of the adiponectin-risk association for C-peptide or free estradiol suggest that the effects of adiponectin on cancer risk could be either partly mediated through, or confounded by, decreased insulin levels or levels of bioavailable estrogens that are strongly increased among postmenopausal women with elevated BMI (2). In addition, each of these obesity-related parameters is determined with some random measurement error (42), and BMI itself is an imperfect measure of adiposity (43). Thus, on the one hand, there could be residual confounding of the adiponectin-endometrial cancer association after adjustments for any of the other obesity-related physiological parameters. On the other hand, random measurement errors of adiponectin levels could have led to an underestimation of the association between adiponectin and risk. Physiologically, little is known about factors that regulate adiponectin production, secretion, and clearance. Insulin, hormones (e.g. testosterone), weight loss of 10% or greater, proinflammatory cytokines, certain medications, and possibly dietary factors and sustained physical activity are implicated as possible regulators of adiponectin levels (5, 7, 13, 33, 41, 44, 45, 46, 47). Conversely, adiponectin itself has regulating effects on blood levels of glucose and insulin, proinflammatory cytokines, and possibly other hormones (1, 5, 10, 11, 13). Thus, a complex physiological relationship may exist between adiponectin levels and endometrial cancer risk.

In conclusion, prediagnostic, high levels of circulating adiponectin were associated with reduced risk of endometrial cancer, particularly among obese and peri-/postmenopausal women. Low adiponectin concentration is a marker for insulin resistance (41), and our results support the hypothesis that insulin resistance, independent of obesity, is a risk factor for endometrial cancer. The biological mechanisms linking adiponectin with a reduction in endometrial tumors remain unclear. Further experimental studies are needed to determine whether adiponectin has a direct causal biological effect on endometrial carcinogenesis separate from other known physiological risk factors and to elucidate possible indirect effects of adiponectin through insulin sensitivity, inflammation, and estrogen-related pathways.


   Acknowledgments
 
We thank Priscilia Amouyal and Josiane Bouzac for performing the laboratory analyses, Fatiha Louled for secretarial support, Carine Biessy for statistical advice, and all participants and staff involved in the EPIC study.


   Footnotes
 
The EPIC study was funded by the "Europe Against Cancer" Programme of the European Commission [Health and Consumer Protection Directorate General (DG SANCO)]; Ligue contre le Cancer (France); Société 3M (France); Mutuelle Générale de l’Education Nationale; Institut National de la Santé et de la Recherche Médicale; German Cancer Aid; German Cancer Research Center; German Federal Ministry of Education and Research; Danish Cancer Society; Health Research Fund of the Spanish Ministry of Health; the participating regional governments and institutions of Spain; ISCIII, Red de Centros RCESP, C03/09, RETICC C03/10; Cancer Research United Kingdom; Medical Research Council, United Kingdom; Stroke Association, United Kingdom; British Heart Foundation; Department of Health, United Kingdom; Food Standards Agency, United Kingdom; Wellcome Trust, United Kingdom; Greek Ministry of Health; Greek Ministry of Education; Italian Association for Research on Cancer; Italian National Research Council; Dutch Ministry of Public Health, Welfare and Sports; Dutch Ministry of Health; Dutch Prevention Funds; LK Research Funds; Dutch Zorg Onderzoek Nederland; World Cancer Research Fund; Swedish Cancer Society; Swedish Scientific Council; Regional Government of Skane, Sweden; and Norwegian Cancer Society. Results from this nested case-control study were obtained with financial support from the Fondation de France (2005011204&207). A.E.C. received a Ph.D. scholarship (University Postgraduate Award) from the University of Sydney and a Research Scholar Award from the Cancer Institute, New South Wales, Australia.

Disclosure Statement: The authors have nothing to disclose.

First Published Online October 24, 2006

Abbreviations: BMI, Body mass index; CI, confidence interval; EPIC, European Prospective Investigation into Cancer and Nutrition; HRT, hormone replacement therapy; IARC, International Agency for Research on Cancer; IGFBP, IGF binding protein; MET, metabolic equivalent; OC, oral contraceptive; RR, relative risk.

Received June 26, 2006.

Accepted October 16, 2006.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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