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CLINICAL CASE SEMINAR |
Department of Hygiene and Epidemiology (E.P., N.D., P.K., D.T.) and First Department of Obstetrics and Gynecology (Z.V.), Athens University Medical School, Athens 115-27, Greece; Department of Epidemiology (E.P., D.T.), Harvard School of Public Health, Boston, Massachusetts 02115; Division of Endocrinology and Metabolism, Department of Internal Medicine (C.M., C.A.), Beth Israel Deaconess Medical Center, Boston, Massachusetts 02215; Endocrinology, Diabetes, and Hypertension Division, Department of Internal Medicine (C.A.), Brigham and Women’s Hospital, Boston, Massachusetts 02215; Department of Pediatric and Reproductive Endocrinology (G.C.), National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892; and First Department of Pediatrics (G.C.), Ag. Sophia Children’s Hospital, Athens University Medical School, Athens 115-27, Greece
Address all correspondence and requests for reprints to: Eleni Petridou, M.D., M.P.H., Associate Professor of Epidemiology, Department of Hygiene and Epidemiology, Athens University Medical School, 75 Mikras Asias str, Goudi, Athens 115-27, Greece. E-mail: epetrid{at}med.uoa.gr.
Abstract
Adiponectin is a hormone secreted exclusively by adipocytes, and obesity is an established risk factor for endometrial cancer. We have, thus, evaluated the association of adiponectin with the occurrence of endometrial cancer. Questionnaire information and blood samples were taken before treatment from 84 women with newly diagnosed, histologically confirmed endometrial cancer and 84 control women who were admitted for minor gynecologic problems, mainly pelvic prolapse. Adiponectin levels were measured by immunoassay. The results were analyzed through multiple logistic regression and controlled for known risk factors for endometrial cancer, leptin, as well as major components of the IGF system (IGF-I, IGF-II, and IGF-binding protein 3). Among control women, there was no significant association of adiponectin with age or parity. Although there was no association of adiponectin with endometrial cancer among women 65 yr or older, there was an inverse, fairly strong, and statistically significant inverse association among younger women. Among women younger than 65 yr, an increase of adiponectin by 1 SD was associated with a more than 50% reduction of the risk for endometrial cancer [odds ratio (OR) 0.44; 95% confidence interval (CI) 0.24–0.81], even after controlling for body mass index and other potential confounders. Among all women, the adjusted OR for a 1 SD increase in adiponectin was not significant (OR, 0.78; 95% CI, 0.56–1.10) but was significant for a one quintile increase in adiponectin (OR, 0.74; 95% CI, 0.56–0.97). In women younger than 65 yr, among whom obesity represents a powerful risk factor for endometrial cancer, adiponectin is inversely and significantly related to the risk of this disease. This association is independent of possible effects of major components of the IGF system, leptin, body mass index, sociodemographic variables, and known endometrial cancer risk factors. Future studies are needed to prove causality and provide insight on both the mechanism of action of this hormone and its potential role in endometrial cancer.
ADIPONECTIN (ACRP30, ADIPOQ, apM1 gene product) is a newly discovered protein, which is secreted exclusively by adipocytes (1, 2, 3, 4). Although secreted only in adipose tissue, adiponectin levels are paradoxically decreased in obesity and type 2 diabetes mellitus, conditions often associated with insulin resistance (3, 5, 6, 7). Adiponectin stimulates the sensitivity of peripheral tissues to insulin, and its decreased levels in obesity and type 2 diabetes mellitus may contribute to the insulin resistance that characterizes these conditions.
Endometrial cancer (EC) has consistently been associated with obesity, which is currently accepted as a risk factor for the development of the disease (8). It is hypothesized that adipose tissue serves as the site of peripheral aromatization of the circulating adrenal androgen androstenedione to estrone. This increase in endogenous estrogen production acts as an agonist of endometrial cell growth (9, 10, 11). Another link between endometrial cancer and obesity may be insulin resistance (12). Because obesity could be associated with insulin resistance through decreased levels of adiponectin, it is reasonable to speculate that adiponectin may explain, in part, the association between endometrial cancer and insulin resistance.
To study the association of adiponectin with endometrial cancer, we performed a case-control study of 84 women with histologically confirmed EC and 84 women admitted during the same time period for gynecological surgery not related to malignancy.
Subjects and Methods
During 1999, 84 eligible women with newly diagnosed histologically confirmed EC were admitted to the First Department of Obstetrics and Gynecology of the University of Athens teaching hospital "Alexandra," at which one of us (P.K.) served as chief resident. All these women were included in this investigation, and the vast majority (82%) presented with an early stage I EC. For each woman with EC, a control woman was enrolled among those admitted during the same week to the same clinical department for small gynecological operations, mainly for pelvic prolapse. Both cases and controls had to be residents of the Greater Athens area and free from any form of current or past malignancy. Case and control women could not be formally matched, but their origin from the same study base assured socioeconomic and age similarity. In any case, these variables were controlled for in the analysis. All study participants provided informed consent and were interviewed in the hospital by the same gynecology resident using the same questionnaire. The study protocol was approved by the Ethics Committee of the University of Athens Medical School
Blood samples were collected before therapy. A fasting morning blood sample was taken for measurements of adiponectin, major components of the IGF system [IGF-I, IGF-II, and IGF-binding protein (IGFBP)-3], and leptin. Adiponectin was measured by RIA with a sensitivity of 2 ng/ml, and the intra-assay coefficient of variation was 8.1%. IGF-I was run on the Nichols Advantage automated specially system (Nichols Institute, San Juan Capistrano, CA). No cross-reactivity with IGF-II, pro-insulin, insulin, TSH, or LH was detected. The sensitivity of the assay was 6 ng/ml, whereas the intra-assay coefficient of variation was 4.8%. IGF-II was determined by using the DSL-2600 ACTIVE nonextraction IGF-II coated-tube immunoradiometric assay (IRMA) kit (Diagnostic Systems Laboratories, Inc., Webster, TX). The procedure uses a two-site IRMA. The DSL nonextraction IGF-II IRMA kit was used instead of ELISA because the laboratory that runs these tests has set up and validated that IRMA assay is more sensitive than the corresponding ELISA assay. The sensitivity was 12 ng/ml, and the intra-assay coefficient of variation was 4.7%. IGFBP-3 concentrations were measured using a commercially available RIA kit (IGFBP-3100T kit; Nichols Institute). The sensitivity of the assay was 0.0625 µg/ml, and the intra-assay coefficient of variation 3.8%. Leptin was determined by using the DSL-23100 leptin coated-tube IRMA kit (Diagnostic Systems Laboratories, Inc.). The procedure uses a two-site IRMA principle designated to detect leptin. The sensitivity of the assay was 0.10 ng/ml, and the intra-assay coefficient of variation was 2.6%.
For the statistical analysis, representative values (mean, SD, percentiles) of adiponectin were calculated among the case and control women. Subsequently, serum adiponectin values were evaluated in relation to a series of independent variables in order to identify possible predictors of adiponectin levels among healthy women. To study a possible association of adiponectin with endometrial cancer, we modeled the data through multiple logistic regression using case control as the outcome variable and adiponectin (in increments of 1 SD of the compound among controls) and a series of possible confounders as predictor variables. Potential confounders were sociodemographic characteristics, notably age (in 10-yr increments), education (in 6-yr increments), and established or suspected risk factors for endometrial cancer, specifically height (in 5-cm increments), body mass index (BMI) before onset of symptoms (in 2 kg/m2 increments), age at menarche (two categories, with cutoff point at age 14 yr), and parity (two categories: ever or never pregnant). There were too few still-menstruating women to allow evaluation of the impact of menopausal status in this investigation. Also, hormone replacement therapy was not included as a variable because this practice is uncommon in Greece and particularly uncommon among low-income women like those included in the present study. In additional models, IGF-I, IGF-II, IGFBP-3, and leptin were included as covariates, all in increments of 1 SD.
To evaluate possible interaction between age and adiponectin in the etiology of EC, we repeated the analysis among women younger than 65 yr and those 65 yr or older. The cut-off point of 65 yr represents the approximate median age in our study sample.
Results
Table 1
shows the baseline characteristics of women, with and without endometrial carcinoma. Parity, BMI, age at menarche, and educational level could have a confounding influence on the association of adiponectin with EC, whereas age is a variable of central importance, and height is a prerequisite for the calculation of BMI. BMI tended to be higher in women with EC (P = 0.001), and these women also had significantly earlier menarche, compared with control women (P = 0.04). All variables in Table 1 were controlled for in subsequent models.
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Table 2 shows data from the regression of adiponectin on a series of variables that were chosen either for descriptive purposes or because they are known or suspected to be risk factors for EC. There is no evidence that any of the studied variables is an important predictor of serum adiponectin levels among control women. However, Spearman’s correlation coefficient between adiponectin and BMI among all women did show a marginally significant inverse association between these variables (r = -0.14, P = 0.07) (Fig. 1).
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We next performed multiple logistic regression to determine the odds ratio for endometrial cancer for a 1 SD increment of adiponectin (Table 3). The odds ratios (ORs) were derived from three different models. Among all women (Table 3, top), the crude OR was 0.83 and was reduced to 0.78 after adjustment for sociodemographic, reproductive, and relevant hormonal variables. Nevertheless, the inverse association between adiponectin and EC remained statistically nonsignificant. However, when the association between adiponectin and EC was separately evaluated among women younger and older than 65 yr, respectively, post hoc evidence for interaction emerges: Among younger women, adiponectin was significantly inversely related to EC, whereas no such association was noted among older women. The age group/adiponectin interaction with respect to EC was statistically significant (OR, 0.56; P = 0.001). Adjustment of the model for potential confounders, including BMI, did not diminish this association. It should be noted that in similar multiple logistic regression models, adjusted ORs and 95% confidence intervals (CIs) for EC for an increase of adiponectin by one quintile (rather than 1 SD) was statistically significant for the entire study group (OR, 0.74; 95% CI, 0.56–0.97; data not shown) and for the subgroup of women younger than age 65 yr (OR, 0.51; 95% CI, 0.32–0.81; data not shown) but not for those 65 yr and older (OR, 1.03; 95% CI, 0.57–1.68; data not shown). Controlling also for tobacco use and oral contraceptives, both rarely used by women of the age group and socioeconomic status included in the study, changed the point estimates shown in Table 3 from 0.78 to 0.77 (all women), from 0.44 to 0.44 (women less than 65 yr), and from 1.26 to 1.28 (women 65 yr or more). Exclusion of height from the models had essentially no effect on the significance of the models.
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The results of the present case-control study suggest an inverse association of serum adiponectin levels with endometrial carcinoma. The observed association was highly significant in younger women (age, <65 yr). However, this association was not observed in older women, nor was there an association between adiponectin and the stage of endometrial carcinoma. The inverse association noted in the younger age group was strengthened after adjustment for potential confounders such as age; BMI; known reproductive risk factors for endometrial cancer; hormones that have been linked to carcinogenesis (IGF-I, IGF-II, and IGFBP-3); and leptin, a hormone associated with body fat mass.
Obesity is a known risk factor for endometrial cancer, with the purported mechanism being increased peripheral aromatization of adrenal androgens to estrogens in adipose tissue leading to increased circulating estrogens. Although EC is primarily a disease of postmenopausal women, a fraction of cases are found in premenopausal women (13, 14). Epidemiologic studies have shown that of women diagnosed with EC, obesity is more prevalent in premenopausal, compared with postmenopausal, women (13, 15), although it is important to note that these studies may have included premenopausal women with polycystic ovarian syndrome, a disease characterized by chronic anovulation, increased circulating androgens and estrogens, insulin resistance, and obesity. In the present study, there were too few menstruating women enrolled to meaningfully compare premenopausal and postmenopausal women with EC.
One could speculate that the significant inverse association of adiponectin with EC in the younger women in our study may somehow be related with an increased prevalence of obesity in this subgroup. Insulin resistance, characterized by hyperinsulinemia and frequently coexisting with obesity, has been associated with EC (16, 17). Type 2 diabetes, a disease state characterized by early hyperinsulinemia and persistent insulin resistance, has also been linked to EC (18, 19, 20). Insulin was initially hypothesized to be a mitogen because it induces mammary carcinomas in rodents (21, 22). It is now believed that insulin stimulates the growth of endometrial stromal cells through direct binding to insulin receptors on endometrial cell membranes (23). Other studies have shown that IGFs also bind to IGF receptors found on endometrial cell membranes and, along with insulin, may potentiate endometrial carcinogenesis (24, 25, 26). Also, hyperinsulinemia has been associated with suppression of IGFBP-1, a protein that decreases free IGF, hence causing tissue elevations of the active form of this cell growth promoting peptide. Because insulin and IGFs can bind to both the respective receptors, a role of hyperinsulinemia in the pathogenesis of EC can be inferred. Additionally, recent in vitro studies have demonstrated that insulin up-regulates the secretion and mRNA expression of vascular endothelial growth factor, a potent angiogenic factor that may contribute to an increased risk for EC (27, 28).
Although adiponectin has been recently associated with several disease states, little is known about the regulation of its secretion or its mechanism of action. Prior studies have demonstrated an inverse association of adiponectin with obesity, type 2 diabetes mellitus, insulin resistance, and congenital lipodystrophic syndromes (3, 5, 6, 7, 29). Visceral fat is linked to metabolic abnormalities such as insulin resistance (30, 31). Based on in vivo animal studies in which adiponectin reduced insulin resistance when administered to lipodystrophic mice with diabetes mellitus and hypoadiponectinemia, adiponectin appears to act as an insulin sensitizer (32). In the present study, reduced adiponectin levels in younger women may reflect increased insulin resistance, which is associated with EC, possibly through an interaction with circulating estrogens that potentiates the effect of low adiponectin levels by sensitizing the endometrium to circulating insulin and one or more of the IGFs.
In conclusion, we found evidence that adiponectin is inversely related to the risk of EC, especially among women younger than 65 yr, and that this association is independent of possible effects of IGF-I, IGF-II, IGFBP-3, leptin, other known risk factors of the disease, and BMI. The mode of action of adiponectin is not clear at present, but, if substantiated by other investigations, future studies should be performed to provide insight on both the action of this hormone and its role in EC.
Footnotes
Abbreviations: BMI, Body mass index; CI, confidence interval; EC, endometrial cancer; IGFBP, IGF-binding protein; IRMA, immunoradiometric assay; OR, odds ratio.
Received August 1, 2002.
Accepted November 22, 2002.
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