Faculty Bibliography

BACKGROUND: Obesity is associated with increased breast cancer risk among postmenopausal women. We examined whether this association could be explained by the relationship of body mass index (BMI) with serum sex hormone concentrations. METHODS: We analyzed individual data from eight prospective studies of postmenopausal women. Data on BMI and prediagnostic estradiol levels were available for 624 case subjects and 1669 control subjects; data on the other sex hormones were available for fewer subjects. The relative risks (RRs) with 95% confidence intervals (CIs) of breast cancer associated with increasing BMI were estimated by conditional logistic regression on case-control sets, matched within each study for age and recruitment date, and adjusted for parity. All statistical tests were two-sided. RESULTS: Breast cancer risk increased with increasing BMI (P(trend) =.002), and this increase in RR was substantially reduced by adjustment for serum estrogen concentrations. Adjusting for free estradiol reduced the RR for breast cancer associated with a 5 kg/m2 increase in BMI from 1.19 (95% CI = 1.05 to 1.34) to 1.02 (95% CI = 0.89 to 1.17). The increased risk was also substantially reduced after adjusting for other estrogens (total estradiol, non-sex hormone-binding globulin-bound estradiol, estrone, and estrone sulfate), and moderately reduced after adjusting for sex hormone-binding globulin, whereas adjustment for the androgens (androstenedione, dehydroepiandrosterone, dehydroepiandrosterone sulfate, and testosterone) had little effect on the excess risk. CONCLUSION: The results are compatible with the hypothesis that the increase in breast cancer risk with increasing BMI among postmenopausal women is largely the result of the associated increase in estrogens, particularly bioavailable estradiol

BACKGROUND: Follicle-stimulating hormone (FSH), a member of gonadotropin family, is critical for follicular maturation and ovarian steroidogenesis. Serum FSH levels are known to fluctuate during different phases of menstrual cycle in premenopausal women, and increase considerably after the menopause as a result of ovarian function cessation. There is little existing evidence to guide researchers in estimating the reliability of serum FSH measurements. The objective of this study was to assess the reliability of FSH measurement using stored sera from an ongoing prospective cohort - the NYU Women's Health Study. METHODS: Sixty healthy women (16 premenopausal, 44 postmenopausal), who donated at least two blood samples at approximately 1-year intervals were studied. An immunoradiometric assay using a sandwich monoclonal antibodies technique was used to measure FSH levels in serum. RESULTS: The reliability of a single log-transformed FSH measurement, as determined by the intraclass correlation coefficient, was 0.70 for postmenopausal women (95% confidence interval (CI), 0.55-0.82) and 0.09 for premenopausal women (95% CI, 0-0.54). CONCLUSIONS: These results suggest that a single measurement is sufficient to characterize the serum FSH level in postmenopausal women and could be a useful tool in epidemiological research. For premenopausal women, however, the reliability coefficient was low, suggesting that a single determination is insufficient to reliably estimate a woman's true average serum FSH level and repeated measurements are desirable

Experimental and epidemiological evidence supports a role for sex steroid hormones in the pathogenesis of ovarian cancer. We investigated the association between ovarian cancer risk and pre-diagnostic blood concentrations of testosterone, androstenedione, DHEAS, estrone and SHBG. A case-control study nested within 3 cohorts, in New York (USA), Umea (Sweden) and Milan (Italy), included 132 subjects with primary invasive epithelial ovarian cancer. For each case subject, 2 controls were selected who matched a case on cohort, menopausal status, age and date of recruitment and, if premenopausal, day of the menstrual cycle at blood donation. Only women who did not use exogenous hormones at blood donation were included in the study. Conditional logistic regression was used to relate cancer risk to sex steroid hormone concentrations with adjustment for potential confounders. No clear association was observed between ovarian cancer risk and any of the 5 hormones under study. In the premenopausal group, the risk appeared to increase with increasing blood concentrations of androstenedione (upper vs. lower tertile OR = 2.35; 95% CI = 0.81-6.82.), but the small number of subjects in the sub-group precluded reaching unambiguous conclusions about such association. Our study does not support previous observations relating elevations in blood levels of the major sex steroid hormones to an increased risk of ovarian cancer, but offers some evidence that elevated circulating androstenedione before menopause may be associated with increased ovarian cancer risk

Reliability of serum levels of iron, ferritin and nitrite (NO(2)(-)) over a 2-year period were evaluated in 40 healthy women (20 pre-menopausal and 20 post-menopausal), ages 39-65 years, from the New York University Women's Health Study (NYUWHS). Three blood samples per woman collected at yearly intervals were analyzed. Reliability coefficients (RCs) of serum iron, ferritin, and nitrite were 0.03 (95% confidence interval (CI), 0-0.33), 0.90 (95% CI, 0.79-0.95), and 0.72 (95% CI, 0.50-0.86), respectively, for pre-menopausal women, and 0.26 (95% CI, 0-0.56), 0.77 (95% CI, 0.59-0.89), and 0.55 (95% CI, 0.30-0.77), respectively, for post-menopausal women. In a case-control study nested within NYUWHS cohort, serum levels of nitrite, ferritin, and iron were measured in women apparently healthy at the time of blood donation but diagnosed with renal cancer 1.8-12.2 years later (n=24) and in individually matched controls (two per case). The results suggest that high serum levels of ferritin and nitrite may be associated with a decreased risk of renal cancer (odds ratio (OR), 0.55, 95% CI, 0.15-2.01 for ferritin, and OR, 0.52, 95% CI, 0.17-1.60 for nitrite in women with above median level as compared to women with below median level). The possible role of ferritin and nitrite in renal cancer is discussed

Migrant and experimental animal studies suggest that differences in breast cancer incidence rates may be related, in part, to intake of dietary fat. The experimental evidence indicates that total fat, saturated, and n-6 polyunsaturated fatty acids (PUFAs) may stimulate both mammary tumor growth and metastasis, whereas n-3 PUFAs may have a tumor-inhibiting effect. Overall, epidemiological studies do not appear to confirm such observations. Within a cohort of women in the New York University Women's Health Study, the fatty acid composition of serum phospholipids was analyzed by gas chromatography among 197 pre- and postmenopausal clinically identified breast cancer subjects and their matched controls. Individual fatty acids in serum phospholipids were expressed as a percentage of total fatty acids. No significant difference was observed in the proportion of saturated fatty acids (SFAs), monounsaturated fatty acids, or n-6 and n-3 PUFAs between cases and controls. After menopause, total SFAs were positively associated with the risk of breast cancer [odds ratio (OR) = 1.96, 95% confidence interval (CI): 0.73-5.25; P = 0.05] after adjustment for potential confounding factors. Myristc acid (C14:0) was suggestive of a small increase in breast cancer risk in premenopausal women (OR = 2.22, 95% CI: 0.78-6.31), whereas palmitic acid (C16:0) showed similar trends in postmenopausal women (OR = 2.57, 95% CI: 0.99-6.61). Overall, total PUFAs (n-6 and n-3) were suggestive of a small protective effect (OR = 0.59, 95% CI: 0.31-1.09). No significant associations were found between other fatty acids and the risk of breast cancer. The study suggested evidence of an association between serum levels of SFAs and the risk of breast cancer in postmenopausal women. Neither individual n-3 fatty acids of marine origin, eicosapentaenoic acid (C20:5 n-3), and docosahexaenoic acid (C22:6 n-3), nor n-6 PUFAs were related to cancer risk in this study

Since 1967, a chemical plant in the town of Chapaevsk (Samara province, Russia) has produced large amounts of chlorinated compounds and is suspected to be a major source of local environmental dioxin contamination. Dioxins have been detected in the local air, soil, drinking water, vegetables, and cow's milk. Human exposure to dioxins is suspected as a factor in the deteriorating local public health. In an effort to characterize nonoccupational dioxin exposure among local residents, during the summer of 1998, 24 volunteers were recruited to donate blood and to provide information about their residence, employment, demographics, medical history, and dietary habits. Selected polychlorinated dibenzodioxins, dibenzofurans, and coplanar biphenyls were measured in blood serum samples. The mean concentration of total dioxin World Health Organization toxic equivalents (WHO-TEQ(98)) based on polychlorinated dibenzo-para-dioxins (PCDDs), polychlorinated dibenzofurans (PCDFs), and coplanar polychlorinated biphenyls (PCBs) was 61.2 (range 16.4-168.1) pg/g lipid. Subjects living in close proximity to the plant (less than 5 km) had significantly higher dioxin levels (mean WHO-TEQ(98), 75.7 pg/g lipid), as compared to subjects living more than 5 km from the plant (mean WHO-TEQ(98), 44.1 pg/g lipid) (P<0.04). Comparisons of the study results with available published data indicate that average blood dioxin levels were substantially higher in Chapaevsk residents than in nonoccupationally exposed populations of other parts of Russia, Europe, and North America. Chronic exposures of such magnitude may have appreciable adverse effects on public health

Insulin-like growth factor (IGF)-I, a mitogenic and anti-apoptotic peptide, has been implicated in the development of several cancers. We hypothesized that high circulating IGF-I concentrations may be associated with an increased risk of ovarian cancer. A case-control study was nested within 3 prospective cohorts in New York (USA), Umea (Sweden) and Milan (Italy). One hundred thirty-two women with primary invasive epithelial ovarian cancer diagnosed at least 1 year after blood donation were case subjects. For each case, 2 control subjects were selected, matching the case subject on cohort, menopausal status, age and date of recruitment (n = 263). Only women who did not use exogenous hormones at blood donation were included in the study. There was no association between IGF-I concentrations and ovarian cancer risk in the study group as a whole. In analyses restricted to subjects who had developed ovarian cancer at a young age (<55), circulating IGF-I was directly and strongly associated with ovarian cancer risk (OR = 4.97; 95% CI = 1.22-20.2 for the top vs. the bottom IGF-I tertile after adjustment for parity, BMI categories and smoking). There was no significant association of IGF binding protein-3 with ovarian cancer risk. We found a strong direct relationship between circulating IGF-I levels and risk of developing ovarian cancer before age 55. Additional, larger studies of this association are needed to provide more precise estimates of effect

In this study, we validated measurements of free testosterone (fT) and free estradiol (fE(2)) concentrations calculated from total serum concentrations of testosterone (T), estradiol (E(2)), and sex hormone-binding globulin (SHBG), measured by direct, commercial radioimmunoassays, by comparison with reference measurements obtained by dialysis plus an in-house radioimmunoassay after extraction and chromatographic purification. The study was conducted in serum samples from 19 postmenopausal women who were part of an ongoing prospective cohort study. We also performed sensitivity analyses to examine the robustness of the theoretical calculations. Sensitivity analyses showed that in this population, competitive binding of dihydrotestosterone and total T could be ignored in the calculation of fE(2), and competitive binding by dihydrotestosterone does not need to be taken into account for calculation of fT. Furthermore, variations in albumin and SHBG concentrations had negligible effects on fT and fE(2) calculations. Values of fT and fE(2), calculated from total T and E(2) concentrations obtained by the same in-house radioimmunoassay used for the dialysis method, correlated highly with the measurements by dialysis (Pearson's coefficients of correlation above 0.97). When calculating fT and fE(2) using total T and total E(2) concentrations obtained by different direct radioimmunoassays, almost all kits gave good correlations with the reference method for fT (Pearson's r > 0.83), but only a few gave good correlations for fE(2) (Diagnostic System Laboratories and DiaSorin; r > 0.80). The direct radioimmunoassays giving the best correlation for fT and fE(2) with the dialysis method were those that best measured total concentrations of T and E(2). Furthermore, mean values of fT and fE(2) corresponded well to mean values by the reference method if SHBG measurements were also well calibrated. We conclude that in postmenopausal women, theoretical calculations are valid for the determination of fT and fE(2) concentrations and can give reliable estimation of cancer risk in epidemiological studies when the total concentrations of T, E(2), and SHBG are measured accurately

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