Objective
Obesity and estrogen are strong risk factors for endometrial cancer (EC). Whereas diabetes also increases the risk, little is known about related insulin resistance (IR). The purpose of this study was to determine the prevalence of IR in newly diagnosed EC patients.
Study Design
EC patients from a large, metropolitan county were prospectively enrolled from 2005 to 2008. Fasting serum was analyzed for glucose and insulin. IR was defined as a history of diabetes or a quantitative insulin sensitivity check index (QUICKI) (1/[log fasting insulin + log fasting glucose]) value of less than 0.357.
Results
Among 99 patients, diabetes was present in 30, and an abnormal QUICKI was found in 36 additional patients. Increased risk of IR was significantly associated with higher body mass index ( P < .001), lower socioeconomic status ( P = .007), and nulliparity ( P = .029).
Conclusion
IR was highly prevalent in endometrial cancer patients, including nonobese women. Better characterization of metabolic risks in addition to obesity may provide avenues for targeted cancer prevention in the future.
Endometrial cancer is the most common gynecologic malignancy and the fourth most common cancer overall in women in the United States, accounting for an estimated 43,470 new cancer diagnoses and 7950 cancer-related deaths in 2010. Increased risk of endometrial cancer is attributed to reproductive conditions resulting in relative estrogen excess such as early menarche, late menopause, nulliparity, and chronic anovulation. Endometrial cancer is also strongly associated with obesity. Although this association has been classically attributed to peripheral aromatization of androstenedione to estrone, some studies have suggested that this relationship is not entirely explained by unopposed estrogen.
Insulin resistance (IR) is a spectrum of disease that includes not only overt diabetes but also prediabetes as well as varying degrees of preclinical insulinemia and glycemia. Although diabetes has been shown to be a mild independent risk factor for endometrial cancer, little is known about the relationship between IR and endometrial cancer. IR is difficult to study retrospectively because it requires fasting blood samples, and consequently, few previous reports have investigated this relationship. However, an association between IR and endometrial cancer has been suggested by several retrospective case-control studies and a large prospective, nested case-control study using a surrogate that does not require fasting blood, adiponectin.
Additionally, preclinical studies have shown that IR accompanied by high circulating levels of insulin potentiates the effect of estrogen on endometrial proliferation. Thus, IR may further clarify the link between obesity and endometrial cancer. We hypothesized that the risk of endometrial cancer associated with diabetes alone results in an underestimation of the true relationship between IR and endometrial cancer. We performed a geographically limited, case-case study to determine the prevalence of insulin resistance among women with endometrial cancer. In addition, we sought to describe the relationship of IR with other previously described risk factors for endometrial cancer.
Materials and Methods
A prospective, multiinstitutional study evaluating IR and endometrial cancer was performed in a single metropolitan county in Texas, Harris County. Institutional review board approval was obtained, and patients with newly diagnosed endometrial cancer were recruited from 5 different hospitals and 1 private practice. Participating institutions included 2 private hospitals (St Luke’s Episcopal Hospital and The Woman’s Hospital of Texas), 1 private practice group (Gynecologic Oncology of Houston), 2 public/county hospitals (Ben Taub General Hospital and Lyndon B. Johnson General Hospital), and 1 tertiary referral center (The University of Texas M. D. Anderson Cancer Center). English- and Spanish-speaking patients within 12 weeks of their primary diagnosis who were residents of Harris County, Texas, were considered eligible.
Participants were required to complete a structured, self-administered questionnaire that addressed demographics, menstrual and reproductive history, family history, and personal medical history. Medical records were reviewed for tumor histology, stage, and grade. Height and weight were measured and body mass index (BMI) was calculated by the Quetelet Index as weight (kilograms)/height (meters) .
Normal weight was defined as a BMI less than 25 kg/m 2 , overweight as a BMI 25-29.9 kg/m 2 , obese as a BMI 30-39.9 kg/m 2 , and morbidly obese as a BMI 40kg/m 2 or greater. Socioeconomic status (SES) was classified by a combination of income and education levels. Low SES was defined as an annual household income of less $20,000 or an income between $20,000 and $40,000 and education level less than high school graduate or equivalent or an income between $40,000 and $60,000 and education level of 8th grade or less. Middle-level SES was defined as an income between $20,000 and $40,000 and education level of at least a high school graduate or income between $40,000 and $60,000 and education level of at least some high school attendance or income level between $60,000 and $80,000 and education level less than college graduate. High SES was defined as an income greater than $80,000 and any education level or income between $60,000 and $80,000 and education of college or beyond. Infertility was defined as the inability to conceive after 1 year of trying or undergoing medical evaluation for difficulty conceiving. Chronic anovulation was characterized by self-reported irregular menses, decreased frequency of menses (>35 days or never regular), or assessment and/or treatment for irregular menstruation.
Fasting blood samples were collected after a minimum 8 hour fast from each participant. Serum insulin was determined by enzyme-immunoassay in triplicate (ALPCO Diagnostics, Salem, NH). Serum glucose levels were ascertained by the University of Texas M. D. Anderson Cancer Center Clinical Laboratory Improvement Amendments–certified laboratory. A quantitative insulin sensitivity check index (QUICKI) was calculated by the formula [(1/[log fasting insulin + log fasting glucose]). Insulin resistance was defined as either a history of type 2 diabetes mellitus or a QUICKI value less than 0.357.
Descriptive statistics were utilized to report demographic characteristics, anthropometrics, and pathologic and reproductive/menstrual variables. A Fisher’s exact test was used to examine associations with IR. The Cochran-Armitage trend test was use to evaluate ordinal data. SAS version 9 (SAS Inc, Cary, NC) software was used for data analysis. Logistic regression was used to estimate the risk of IR associated with other factors among endometrial cancer patients. The initial model was created with all terms that were statistically significant in the univariate analysis with P < .10, and backward selection was used to create the final model, with all terms in the final model statistically significant at P < .10. A P < .05 was used as an indicator of statistical significance in the final model.
Results
Ninety-nine patients with endometrial cancer were enrolled in the study and completed study requirements between November 2005 and June 2008. The mean age at diagnosis was 59.3 years (range, 26–87 years) ( Table 1 ). The majority of patients were white, non-Hispanic (58.6%). IR was identified in 66 of the 99 total study participants, of which 30 (45%) patients had a known, previous diagnosis of diabetes. However, in 36 of the patients with IR (55%), the diagnosis was based on a low QUICKI ( Figure 1 ).
| Characteristic | Total (n = 99) | Insulin resistant (n = 66) | Non-insulin resistant (n = 33) | P value a |
|---|---|---|---|---|
| Age, y, mean (SD), n (%) | .028 | |||
| 59.3 (11.8) | 57.4 (12.3) | 62.9 (10.0) | ||
| .281 | ||||
| <50 | 18 (18.2) | 15 (22.7) | 3 (9.1) | |
| 50-59 | 32 (32.3) | 22 (33.3) | 10 (30.3) | |
| 60-69 | 31 (31.3) | 19 (28.8) | 12 (36.4) | |
| ≥70 | 18 (18.2) | 10 (15.2) | 8 (24.2) | |
| Race/ethnicity, n (%) | .178 | |||
| White, non-Hispanic | 58 (58.6) | 38 (57.6) | 20 (60.6) | |
| White, Hispanic | 15 (15.2) | 12 (18.2) | 3 (9.1) | |
| Black | 11 (11.1) | 8 (12.1) | 3 (9.1) | |
| Asian | 7 (7.1) | 2 (3.0) | 5 (15.2) | |
| Other | 2 (2.0) | 1 (1.5) | 1 (3.0) | |
| Not reported | 6 (6.1) | 5 (7.6) | 1 (3.0) | |
| Recruiting site, n (%) | .004 | |||
| Private hospitals | 48 (48.5) | 32 (48.5) | 16 (48.5) | |
| Public hospitals | 14 (14.1) | 14 (21.2) | 0 (0.0) | |
| Tertiary referral center | 37 (37.4) | 20 (30.3) | 17 (51.5) | |
| SES, n (%) | .002 b | |||
| Low | 22 (22.2) | 19 (28.8) | 3 (9.1) | |
| Middle | 36 (36.4) | 25 (37.9) | 11 (33.3) | |
| High | 29 (29.3) | 13 (19.7) | 16 (48.5) | |
| Not reported | 12 (12.1) | 9 (13.6) | 3 (9.1) | |
| BMI, kg/m 2 , median (range) | < .001 | |||
| 32.9 (19.5–71.1) | 37.6 (22.6–71.1) | 27.3 (19.5–47.5) | ||
| < .001 | ||||
| Normal weight (<25) | 17 (17.2) | 4 (6.1) | 13 (39.4) | |
| Overweight (25-29.9) | 23 (23.2) | 13 (19.7) | 10 (30.3) | |
| Obese (30-39.9) | 28 (28.3) | 23 (34.8) | 5 (15.2) | |
| Morbidly obese (≥40) | 28 (28.3) | 24 (36.4) | 4 (12.1) | |
| Not reported | 3 (3.0) | 2 (3.0) | 1 (3.0) |
a Univariate analysis; missing values were not included in statistical testing;
Age ( P = .028), recruiting site ( P = .004), socioeconomic status ( P = .002), and BMI ( P < .001) were significantly associated with IR in univariate analysis ( Table 1 ). Among reproductive and menstrual factors, chronic anovulation ( P = .038) was the only factor more prevalent in IR patients by univariate analysis ( Table 2 ). However, secondary to a P < .10, nulliparity ( P = .063) was included in the regression analysis along with age, SES, BMI, and chronic anovulation to determine factors independently associated with risk of insulin resistance ( Table 3 ). Although endometrial cancer patients enrolled from public hospitals were significantly more likely to be insulin resistant than other patients, this variable could not be modeled because 100% of women from the 2 public hospitals were found to have IR. Higher BMI, lower SES, and nulliparity remained significant in the final reduced model.
