Effects of parity on pregnancy hormonal profiles across ethnic groups with a diverse incidence of breast cancer.

Epidemiologic evidence suggests that a full-term pregnancy may affect maternal risk of breast cancer later in life. The objective of this cross-sectional study was to compare circulating levels of maternal hormones affecting breast differentiation (human chorionic gonadotropin and prolactin) and proliferation [alpha-fetoprotein, insulin-like growth factor I (IGF-I), and estradiol] between women at a low to moderate risk (Asians and Hispanics), as compared with women at a high risk for breast cancer (Caucasians and African-Americans). Between May 2002 and December 2004, a total of 586 pregnant women were approached during a routine prenatal visit. Among them, 450 women (206 Caucasian, 126 Asian, 88 Hispanic, and 30 African-American) met the inclusion criteria and signed the informed consent. Only singleton pregnancies were considered. Blood samples were drawn during the second trimester of pregnancy. Laboratory analyses were done using the IMMULITE 2000 immunoassay system. Gestational age standardized mean levels of estradiol, IGF-I, and prolactin were significantly higher in Hispanic women compared with Caucasian women. Mean concentration of IGF-I was significantly higher in African-American women compared with Caucasian and Asian women. No significant differences in pregnancy hormone levels were observed between Caucasian and Asian (predominantly second-generation Chinese) women in this study. Irrespective of ethnicity, women who had their first pregnancy had substantially higher mean levels of alpha-fetoprotein, human chorionic gonadotropin, estradiol, and prolactin compared with women who previously had at least one full-term pregnancy. These data suggest that circulating pregnancy hormone levels may explain some of the ethnic differences in breast cancer risk.     

IGF-I, IGFBP-3 and breast cancer in young women: a pooled re-analysis of three prospective studies.

Prospective cohort studies on breast cancer risk among premenopausal women and insulin-like growth factor I (IGF-I) concentrations have so far included only few cases, and have shown inconsistent relative risk estimates. We pooled 220 cases of breast cancer diagnosed before age 50, and 434 control subjects, from three prospective studies in New York (USA), Ume? (Northern Sweden) and Milan (Italy), and we measured IGF-I and insulin-like growth factor binding protein 3 (IGFBP-3) with common enzyme-linked immunosorbent assays. Overall, IGF-I and IGFBP-3 measurements obtained by the common method showed a positive but not significant relationship with breast cancer risk (odds ratios (ORs) 0.90 [95% confidence intervals (95% CI) 0.50-1.62], 1.63 [0.89-2.97], 1.46 [0.78-2.73] and 1.41 [0.75-2.63] for quintiles of IGF-I, and ORs 0.98 [0.54-1.75], 1.06 [0.59-1.91], 1.04 [0.58-1.87] and 1.77 [0.97-3.24] for quintiles of IGFBP-3). Our results give only moderate support for an association of blood IGF-I with breast cancer risk in young women.     

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

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.     

Body mass index in relation to ovarian cancer: a multi-centre nested case-control study

The incidence of ovarian cancer is up to 10 times higher in Western countries than in rural Asia and Africa. One common consequence of a Western lifestyle is the development of excessive body weight and obesity. A multi‐centre prospective study was conducted to investigate the association between body mass index (BMI) and ovarian cancer risk. A case‐control study was nested within 3 prospective cohorts in New York (USA), Umeå (Sweden) and Milan (Italy). Information on anthropometry, demographic characteristics, medical history and lifestyle was obtained at the time of subjects' recruitment in each cohort. Women diagnosed with primary, invasive epithelial ovarian cancer from the 3 cohorts (n = 122) diagnosed 12 months or later after recruitment into the respective cohort served as case subjects. For each case subject, 2 control subjects that matched the case subject on cohort, menopausal status, age and date of recruitment were randomly identified. Data were analyzed by conditional logistic regression. There was an inverse association between BMI and ovarian cancer risk. For increasing quartiles of BMI above the lowest, the ORs were 0.62 (0.32–1.21), 0.59 (0.30–1.17) and 0.46 (0.23–0.92), p = 0.03. Analyses limited to women diagnosed 3 or more years after recruitment into the cohorts did not alter these findings. When obese women (BMI > 30) were compared to lean women (BMI ≤ 23), the inverse association became stronger, with an OR of 0.38 (0.17–0.85), p < 0.02. There was some evidence of direct association of ovarian cancer with height, which was limited to cancers diagnosed before age 55. Our data suggest that increasing body weight may confer a protection against ovarian cancer. © 2002 Wiley‐Liss, Inc.     

Obesity, endogenous hormones, and endometrial cancer risk: a synthetic review.

Endometrial cancer is a disease of the affluent, developed world, where epidemiological studies have shown that > or =40% of its incidence can be attributed to excess body weight. An additional proportion may be because of lack of physical activity. Alterations in endogenous hormone metabolism may provide the main links between endometrial cancer risk, and excess body weight and physical inactivity. Epidemiological studies have shown increased endometrial cancer risks among pre- and postmenopausal women who have elevated plasma androstenedione and testosterone, and among postmenopausal women who have increased levels of estrone and estradiol. Furthermore, there is evidence that chronic hyperinsulinemia is a risk factor. These relationships can all be interpreted in the light of the "unopposed estrogen" hypothesis, which proposes that endometrial cancer may develop as a result of the mitogenic effects of estrogens, when these are insufficiently counterbalanced by progesterone. In our overall synthesis, we conclude that development of ovarian hyperandrogenism may be a central mechanism relating nutritional lifestyle factors to endometrial cancer risk. In premenopausal women, ovarian hyperandrogenism likely increases risk by inducing chronic anovulation and progesterone deficiency. After the menopause, when progesterone synthesis has ceased altogether, excess weight may continue increasing risk through elevated plasma levels of androgen precursors, increasing estrogen levels through the aromatization of the androgens in adipose tissue. The ovarian androgen excess may be because of an interaction between obesity-related, chronic hyperinsulinemia with genetic factors predisposing to the development of ovarian hyperandrogenism.     

Insulin-like growth factor II and colorectal cancer risk in women.

Recently, a number of prospective studies showed evidence that the growth hormone/insulin-like growth factor I (IGF-I) axis may be important in the development of colorectal cancer. However, only a few studies have reported on the possible relationship of colorectal cancer risk with circulating levels of IGF-II, which are not growth hormone dependent and which do not vary with alterations in energy balance. In a case-control study of 102 cases and 200 matched controls nested within a cohort of 14,275 women in New York, we examined the relationship between colorectal cancer risk and prediagnostic serum levels of IGF-II. Conditional logistic regression analysis showed an odds ratio (OR) for colorectal cancer of 2.02 (95% confidence interval (CI): 0.83-4.93), comparing the upper to lower quintile of IGF-II. This association was slightly attenuated after excluding IGF-II measurements in serum samples taken within 1 year before case diagnosis (OR of 1.81; 95% CI: 0.71-4.64) and moderately attenuated after excluding IGF-II measurements in serum samples taken within 2 years before case diagnosis (OR of 1.47; 95% CI: 0.56-3.91). Adjustment for IGF-1, IGF binding protein (BP)-1, IGFBP-3, smoking, or body mass index did not substantially alter the association, whereas adjustment for IGFBP-2 moderately attenuated the relationship. Our results confirm those of three recent case-control studies, and collectively these results suggest a possible increase in colorectal cancer risk among subjects with comparatively elevated serum IGF-II. Mechanisms that might cause the increase in IGF-II levels are unknown but may include loss of parental imprinting of the IGF-II gene.     

Obesity and colon cancer: Does leptin provide a link?

Obesity, a risk factor for colorectal cancer, is associated with elevated serum levels of leptin, the adipocyte-derived hormone, and insulin. Experimental and epidemiologic studies have indicated a role for insulin in the pathogenesis of colon cancer, and recent experimental studies have suggested a similar role for leptin. In a case-control study nested in the Janus Biobank, Norway, we measured serum levels of leptin and C-peptide (a marker of pancreatic insulin secretion) in cryopreserved prediagnostic sera from men (median age, 45 years) who were diagnosed with cancer of the colon (n = 235) or rectum (n = 143) after blood collection (median time, 17 years), and among 378 controls matched for age and date of blood collection. Conditional logistic regression analyses showed an approximately 3-fold increase in colon cancer risk with increasing concentrations of leptin up to an odds ratio (OR) of 2.72 (95% CI = 1.44-5.12) for top vs. bottom quartile (p(trend) = 0.008). The corresponding OR for C-peptide was 1.81 (95% CI = 0.67-4.86; p(trend) = 0.19). The risk estimates remained unchanged after mutual adjustment. No association of hormone levels with rectal cancer risk was found. Reproducibility of hormone measurements assessed by intraclass coefficients (ICCs) for paired samples taken 1 year apart was high for leptin (ICC = 0.82) but lower for C-peptide (ICC = 0.30). Our results suggest that leptin is a risk factor for colon cancer, and that leptin may provide a link between obesity and colon cancer. Leptin may be directly involved in colon tumorigenesis or it may serve as a sensitive and robust marker of an obesity-induced adverse endocrine environment. Only weak support for an association of insulin with colon cancer was found.     

A prospective study of insulin-like growth factor-I, IGF-binding proteins-1, -2 and -3 and lung cancer risk in women

Insulin-like growth factor-I (IGF-I) has mitogenic and anti-apoptotic properties and has been implicated in the development of breast, colorectum, prostate and lung cancer. IGF binding proteins (IGFBPs) are not only carrier proteins for IGFs but also hold a central position in IGF ligand-receptor interactions through influences on the bioavailability and distribution of IGFs in the extracellular environment. A case-control study nested within the New York University Women's Health Study Cohort included 93 women diagnosed with lung cancer at least 6 months after recruitment into the study. Two controls (n = 186) were matched to each case on age, date of blood sampling, menopausal status, day of menstrual cycle and questionnaire data of smoking status at the time of blood donation. Serum IGF-I, IGFBP-1, -2 and -3, insulin and cotinine were measured. Mean serum levels of IGF-I, IGFBP-1, -2 and -3 were not significantly different between the case and control groups. Univariate logistic regression analyses showed no association of lung cancer risk with serum levels of IGF-I or any of the IGFBPs. These results remained virtually the same in multivariate analyses, including adjustment for cotinine, time since last meal, BMI, IGF-I or IGFBP-3, respectively. Exclusion of cases diagnosed within 3 years of recruitment in the cohort, or restriction of the analyses to adenocarcinomas only, did not alter these results. Our study does not offer evidence in support of an association between prediagnostic serum levels of IGF-I or IGFBP-1, -2 and -3 and lung cancer risk in women.     

Association of serum 25-hydroxyvitamin D (25-OHD) concentrations with maternal sex steroids and IGF-1 hormones during pregnancy

Background  

Vitamin D may influence circulating levels of sex steroid hormones in women during reproductive life, but associations in pregnant women have not been explored.