Endogenous sex hormones and endometrial cancer risk in women in the European Prospective Investigation into Cancer and Nutrition (EPIC)

Abstract

Epidemiological data show that reproductive and hormonal factors are involved in the etiology of endometrial cancer, but there is little data on the association with endogenous sex hormone levels. We analyzed the association between prediagnostic serum concentrations of sex steroids and endometrial cancer risk in the European Prospective Investigation into Cancer and Nutrition using a nested case-control design of 247 incident endometrial cancer cases and 481 controls, matched on center, menopausal status, age, variables relating to blood collection, and, for premenopausal women, phase of menstrual cycle. Using conditional regression analysis, endometrial cancer risk among postmenopausal women was positively associated with increasing levels of total testosterone, free testosterone, estrone, total estradiol, and free estradiol. The odds ratios (ORs) for the highest versus lowest tertile were 2.66 (95% confidence interval (CI) 1.50-4.72; P=0.002 for a continuous linear trend) for estrone, 2.07 (95% CI 1.20-3.60; P=0.001) for estradiol, and 1.66 (95% CI 0.98-2.82; P=0.001) for free estradiol. For total and free testosterone, ORs for the highest versus lowest tertile were 1.44 (95% CI 0.88-2.36; P=0.05) and 2.05 (95% CI 1.23-3.42; P=0.005) respectively. Androstenedione and dehydroepiandrosterone sulfate were not associated with risk. Sex hormone-binding globulin was significantly inversely associated with risk (OR for the highest versus lowest tertile was 0.57, 95% CI 0.34-0.95; P=0.004). In premenopausal women, serum sex hormone concentrations were not clearly associated with endometrial cancer risk, but numbers were too small to draw firm conclusions. In conclusion, relatively high blood concentrations of estrogens and free testosterone are associated with an increased endometrial cancer risk in postmenopausal women.

Figure 1

Odds ratio (and their corresponding 95% confidence intervals (CIs)) for endometrial cancer by serum levels of SHBG and sex steroids (in tertiles) among postmenopausal women. Solid squares represent odds ratios (ORs), estimated by conditional logistic regression, for tertiles of serum hormone concentrations (cut points based on the distribution of control subjects) and horizontal lines represent 95% CIs. Analysis based on 192 case patients and 374 control subjects. Case patients and control subjects were matched on EPIC (European Prospective Investigation into Cancer and Nutrition) recruitment center, age at blood donation, time of day at blood donation, and fasting status. DHEAS, dehydroepiandrosterone sulfate. ¹P_trend=P value for a test of linear trend across categories based on median hormone values for the three tertiles. ²P_trend=P value for a test of linear trend based on log-transformed continuous variable.

Figure 2

Odds ratio (and their corresponding 95% confidence intervals (CIs)) for endometrial cancer by serum levels of SHBG and sex steroids (in tertiles) among postmenopausal women after adjustment for BMI*. Solid squares represent odds ratios (ORs), estimated by conditional logistic regression, for tertiles of serum hormone concentrations (cut points based on the distribution of control subjects) and horizontal lines represent 95% CIs. Analysis based on 192 case patients and 374 control subjects. Case patients and control subjects were matched on EPIC (European Prospective Investigation into Cancer and Nutrition) recruitment center, age at blood donation, time of day at blood donation, and fasting status. DHEAS, dehydroepiandrosterone sulfate. *BMI included as a continuous variable. ¹P_trend=P value for a test of linear trend across categories based on median hormone values for the three tertiles. ²P_trend=P value for a test of linear trend based on log transformed continuous variable.