Relationship of serum levels of dehydroepiandrosterone and dehydroepiandrosterone sulfate to the risk of developing postmenopausal breast cancer

Dehydroepiandrosterone and dehydroepiandrosterone sulfate are endogenous steroids that are produced in the adrenal cortex. A number of studies have suggested that circulating levels of these hormones are related in some way to the risk of developing breast cancer. We measured serum levels of these steroids in 30 postmenopausal women who donated blood in 1974 for a community-based serum bank and who subsequently, at least 9 years later, developed breast cancer and in 59 matched controls from the same group of volunteers. Significantly elevated serum levels of dehydroepiandrosterone were found among cases prior to diagnosis compared to controls; serum levels of dehydroepiandrosterone sulfate were slightly increased among cases. In controls, current cigarette use was associated with increased serum levels of these steroids, and levels of both steroids decreased with age.     

Serum levels of dehydroepiandrosterone and its sulfate and the risk of developing bladder cancer.

Dehydroepiandrosterone and dehydroepiandrosterone sulfate are endogenous steroids largely produced in the adrenal cortex and excreted in the urine. Many studies have demonstrated that administration of dehydroepiandrosterone to animals protects against a variety of chemical carcinogens. Epidemiological studies suggest that the circulating levels of these steroids in humans are related to the risk of developing some cancers and of dying from atherosclerotic cardiovascular disease. We measured serum levels of both of these steroids in 35 individuals who donated serum to a community-based serum bank in 1974 and who subsequently developed bladder cancer and in 69 matched controls from the same cohort of volunteers. Prediagnostic serum levels of dehydroepiandrosterone and dehydroepiandrosterone sulfate were significantly lower among cases compared with controls. The risk of developing bladder cancer increased monotonically with decreasing serum levels of both steroids. The observed associations were not affected by adjustment for smoking or the time interval between serum collection and diagnosis. These results support a role for dehydroepiandrosterone and/or dehydroepiandrosterone sulfate in the prevention of bladder cancer.     

Association of serum adiponectin levels with breast cancer risk.

PURPOSE: Adiponectin is a peptide hormone secreted from the adipose tissue, affecting the proliferation and insulin sensitivity of various types of cells. Because association of obesity with breast cancer risk is well established, it is possible that adiponectin plays some role in the development of breast cancer. Thus, in the present study, the association of the serum adiponectin levels with breast cancer risk was investigated. EXPERIMENTAL DESIGN: A case-control study was conducted on 102 breast cancer patients (cases) and 100 healthy women (controls). The serum adiponectin levels of cases and controls were examined in their association with breast cancer risk after adjustment for the various classical risk factors (family history, age at menarche, parity, body mass index, and so forth). In addition, the relationship between the serum adiponectin levels and the various clinicopathological characteristics of breast cancers was studied. RESULTS: Women in the low tertile of serum adiponectin levels were associated with a significantly (P < 0.005) increased risk for breast cancer compared with women in the high tertile [odds ratio (OR), 3.63; 95% confidence interval (CI), 1.61-8.19]. Such an association was observed both in the premenopausal women (OR, 3.46; 95% CI, 0.89-13.50) and in the postmenopausal women (OR, 3.90; 95% CI, 1.23-12.44). The frequency of large (>2 cm) tumors and that of high histological grade (2+3) tumors were significantly (P < 0.005 and P < 0.05, respectively) higher in breast cancer patients in the low tertile of the serum adiponectin levels than those in the high and intermediate tertiles. CONCLUSIONS: These results suggest that the low serum adiponectin levels are significantly associated with an increased risk for breast cancer and that tumors arising in women with the low serum adiponectin levels are more likely to show a biologically aggressive phenotype. The association between obesity and breast cancer risk might be partly explained by adiponectin.     

Serum levels of sex hormones and breast cancer risk in premenopausal women: a case–control study (USA)

High levels of serum estrogens and androgens have been convincingly linked with an increased risk of breast cancer among postmenopausal women. By contrast, the role of blood levels of these hormones in the etiology of premenopausal breast cancer is not well understood. In a case-control study, we sought to examine associations between levels of serum estradiol, sex-hormone binding globulin (SHBG), dehydroepiandrosterone (DHEA), testosterone, androstenedione and progesterone and risk of premenopausal breast cancer. Cases of breast cancer under age 45 were identified using rapid ascertainment systems in Seattle/Puget Sound, Washington and control subjects were identified from the same area through random digit dialing methods. A total of 169 eligible breast cancer cases and 195 control subjects donated blood (either before or six or more weeks after surgery) and were interviewed using a standardized questionnaire. The fully adjusted risk ratios and 95% confidence intervals for the highest versus lowest tertiles of estradiol, according to menstrual cycle phase, were 3.10 (0.8-12.7) for early follicular, 0.54 (0.2-1.7) for late follicular and 0.60 (0.3-1.4) for luteal. Risks for highest versus lowest quartiles of SHBG and androgens were 0.81 (0.4-1.6) for SHBG, 2.42 (1.1-5.2) for DHEA, 1.12 (0.6-2.5) for testosterone, and 1.33 (0.6-2.8) for androstenedione. For luteal progesterone, the RR for the highest versus lowest tertile was 0.55 (0.2-1.4). In summary, we did not find a convincing association between serum SHBG, estradiol, testosterone or androstenedione and premenopausal breast cancer risk. Observed differences between cases and controls subjects in serum levels of DHEA and luteal phase progesterone should be investigated further in large prospective studies.     

Serum dehydroepiandrosterone and dehydroepiandrosterone sulfate and the subsequent risk of developing colon cancer.

This purpose of this study was to evaluate whether serum dehydroepiandrosterone (DHEA) and its sulfate conjugate, dehydroepiandrosterone sulfate (DHEAS), are associated with the likelihood of developing colon cancer. A nested case-control study was conducted using the serum bank and cancer registry in Washington County, Maryland. From a population of 20,305 county residents who donated blood in 1974, incident cases of colon cancer that occurred from 1975 to 1991 (n = 117) were matched to one cancer-free control by age, race, and sex. Serum specimens that were stored at -70 degrees C since 1974 were assayed for DHEA and DHEAS. Compared with the controls, the mean serum concentrations of cases were 3% lower for DHEA (P = 0.90) and 13% lower for DHEAS (P = 0.60). When DHEA levels were analyzed according to fourths, no noteworthy associations were observed. Compared with the lowest fourth, the highest fourth of serum DHEAS was nonsignificantly associated with a halving in the risk of colon cancer (odds ratio, 0.50; 95% confidence limits, 0.18, 1.37; Ptrend = 0.22), and further analyses showed the potential protective association was confined largely to males (highest-versus-lowest fourth odds ratio, 0.26; 95% confidence limits, 0.06, 1.16; Ptrend = 0.06). This prospective study does not provide strong evidence that circulating DHEA and DHEAS concentrations are associated with the risk of colon cancer. Among men, DHEAS was associated with a decreased risk of colon cancer, but the association was within the bounds of chance. Further studies are needed to either support or refute the potentially promising lead hinted at by the results for DHEAS.     

Relation of serum levels of estrogen and dehydroepiandrosterone sulfate to hormone receptor status among postmenopausal women with breast cancer

Background: It is hypothesized that breast cancer may consist of heterogeneous diseases with different hormonal environments classified by hormone receptor status. Epidemiologic studies evaluating risk factors for breast cancer by hormone receptor status have supported the hypothesis. However, there are inconsistencies in the risk factor profiles by estrogen receptor (ER) and progesterone receptor (PR) across the studies. To clarify the heterogeneity of the disease, it is necessary to understand not only risk factor profiles but also the biologic characteristics such as the relationships among endogenous sex hormone levels and hormone receptors. Methods: We measured serum levels of estrone (E1), estradiol (E2), dehydroepiandrosterone sulfate (DHEAS), and sex hormone-binding globulin (SHBG) in 142 postmenopausal women aged 50 and over with primary breast cancer who had undergone surgical treatment, and investigated the heterogeneity in the relations of endogenous sex hormone levels to hormone receptor status, using the case-series study method. Subjects were categorized into 3 classes based on tertiles of each hormone level in receptor-negative subjects, and odds ratios (ORs) for receptor-positive status compared with receptor-negative status were computed, taking the lowest category as a reference category. Results: There were clear trends toward higher serum levels of E1, E2, and DHEAS in women with PR+ cancer. The case-series approach revealed that PR+ status might be strongly associated with serum sex hormone levels. In particular, the OR of PR+ was large for a high DHEAS level (OR for the highest category = 4.28). No significant association between serum hormone levels and ER status was observed. Conclusion: The association of serum sex hormone levels with hormone receptor status may differ by PR status, but not by ER status. This finding suggests that PR status may be related to the heterogeneity in hormonal environments associated with breast cancer risk.     

Body fat distribution in relation to breast cancer in women participating in the DOM-project

Summary The association between body fat distribution and breast cancer risk was studied in 5923 pre- and 3568 postmenopausal women, participating in a breast cancer screening project (the DOM-project in Utrecht, the Netherlands). Cases were fifty six premenopausal women and thirty eight postmenopausal women with breast cancer detected at screening or afterwards. Controls were women participating in the breast cancer screening project without breast cancer. Waist- and hip circumferences, height and weight were measured at screening, before diagnosis of breast cancer.In postmenopausal women the estimated relative risk of women in the upper tertile of waist/hip ratio compared with women in the lower tertile was 1.89 (95% CI 0.80–4.48), (test for trend p = 0.11). The estimated relative risk of women in the upper tertile of waist circumference compared with women in the lower tertile was 2.86 (95% CI I 1.12–7.32), (test for trend p = 0.08). The association between waist circumference and breast cancer was stronger than the association between any of the other anthropometric variables and breast cancer.In premenopausal women the association between fat distribution and breast cancer was equivocal.     

Insulin-like growth factor-I, IGF-binding protein-3, and mammographic breast density.

Some studies have suggested that insulin-like growth factor (IGF) pathway is related to premenopausal breast density, one of the strongest known breast cancer risk factors. This study was designed specifically to test the hypothesis that higher levels of IGF-I and lower levels of IGF-binding protein (IGFBP)-3 are associated with high mammographic breast density among premenopausal but not among postmenopausal women. A total of 783 premenopausal and 791 postmenopausal healthy women were recruited during screening mammography examinations. Blood samples were collected at the time of mammography, and plasma IGF-I and IGFBP-3 levels were measured by ELISA. Mammographic breast density was estimated using a computer-assisted method. Spearman's partial correlation coefficients (r(s)) were used to evaluate the associations. Adjusted mean breast density was assessed by joint levels of IGF-I and IGFBP-3 using generalized linear models. Among premenopausal women, high levels of IGF-I and low levels of IGFBP-3 were independently correlated with high breast density (r(s) = 0.083; P = 0.021 and r(s) = -0.124; P = 0.0005, respectively). Correlation of IGF-I with breast density was stronger among women in the lowest tertile of IGFBP-3 than among those in the highest tertile of IGFBP-3 (r(s) = 0.138; P = 0.027 and r(s) = -0.039; P = 0.530, respectively). In contrast, the correlation of IGFBP-3 with breast density was stronger among women in the highest tertile of IGF-I than among those in the lowest tertile of IGF-I (r(s) = -0.150; P = 0.016 and r(s) = -0.008; P = 0.904, respectively). Women in the combined top tertile of IGF-I and bottom tertile of IGFBP-3 had higher mean breast density than those in the combined bottom tertile of IGF-I and top tertile of IGFBP-3 (53.8% versus 40.9%; P = 0.014). No significant association was observed among postmenopausal women. Our findings confirm that IGF-I and IGFBP-3 are associated with breast density among premenopausal women. They provide additional support for the idea that, among premenopausal women, these growth factors may affect breast cancer risk, at least in part, through their influence on breast tissue morphology as reflected on mammogram.     

Soybean products and reduction of breast cancer risk: a case-control study in Japan

Components of the Japanese diet, which might contribute to the relatively low breast cancer incidence rates in Japan, have not been clarified in detail. Since soybean products are widely consumed in Japan, a case-control study taking account of the menopausal status was conducted using data from the hospital-based epidemiologic research program at Aichi Cancer Center (HERPACC). In total, 167 breast cancer cases were included and 854 women confirmed as free of cancer were recruited as the control group. Odds ratios (OR) and 95% confidence intervals (95% CI) were determined by multiple logistic regression analysis. There were reductions in risk of breast cancer associated with high intake of soybean products among premenopausal women. Compared with women in the lowest tertile, the adjusted ORs for top tertile intake of tofu (soybean curd) was 0.49 (95% CI, 0.25-0.95). A significant decrease in premenopausal breast cancer risk was also observed for increasing consumption of isoflavones (OR=0.44; 95% CI, 0.22-0.89 for highest vs lowest tertile; P for trend=0.02). The present study found a statistically inverse association between tofu or isoflavone intake and risk of breast cancer in Japanese premenopausal women, while no statistically significant association was evident with the risk among postmenopausal women.     

Androgens and breast cancer in premenopausal women

We investigated the role of androgens in premenopausal breast cancer by comparing serum testosterone, dihydrotestosterone, androstenedione, dehydroepiandrosterone sulfate, progesterone, sex-hormone-binding globulin-binding capacity, and urinary testosterone and androstanediol in 63 women with breast adenocarcinoma and 70 healthy controls of similar age. With variables dichotomized at the 75th percentile, the age-adjusted relative risk was 3.4 (95% confidence interval, 1.6-7.3) for high versus low levels of serum testosterone, 2.1 (0.9-4.8) for urinary testosterone, and 2.5 (1.1-5.9) for serum dihydrotestosterone. We observed no differences in other hormones. The strength of the associations changed markedly with increasing time to the onset of the next menses. The risk for testosterone and dihydrotestosterone, which was negligible in women with onset within 5 days of sampling, increased progressively to nearly 10-fold higher than in unstratified data in women with onset 10 days or more after sampling. This study provides arguments in favor of a role for increased androgenic activity in premenopausal breast cancer. It also suggests that unknown factors related to cycle length may be important in modulating the strength of the association with testosterone. The results are discussed also in reference to possible biases and inadequacies in study design.     

The relationship between a polymorphism in CYP17 with plasma hormone levels and breast cancer

The A2 allele of CYP17 has been associated with polycystic ovarian syndrome, elevated levels of certain steroid hormones in premenopausal women, and increased breast cancer risk. We prospectively assessed the association between the A2 allele of CYP17 and breast cancer risk in a case-control study nested within the Nurses' Health Study cohort. We also evaluated associations between this CYP17 genotype and plasma steroid hormone levels among postmenopausal controls not using hormone replacement to assess the biological significance of this genetic variant. Women with the A2 allele were not at an increased risk of incident breast cancer [OR (odds ratio), 0.85; 95% CI (confidence interval), 0.65-1.12] or advanced breast cancer (OR, 0.84; 95% CI, 0.54-1.32). We did observe evidence that the inverse association of late age at menarche with breast cancer may be modified by the CYP17 A2 allele. The protective effect of later age at menarche was only observed among women without the A2 allele (A1/A1 genotype: for age at menarche > or =13 versus <13; OR, 0.57; 95% CI, 0.36-0.90; A1/A2 and A2/A2 genotypes: OR, 1.05; 95% CI, 0.76-1.45; P for interaction = 0.07). Among controls, we found women with the A2/A2 genotype to have elevated levels of estrone (+14.3%, P = 0.01), estradiol (+13.8%, P = 0.08), testosterone (+8.6%, P = 0.34), androstenedione (+17.1%, P = 0.06), dehydroepiandrosterone (+14.4%, P = 0.02), and dehydroepiandrosterone sulfate (+7.2%, P = 0.26) compared with women with the A1/A1 genotype. These data suggest that the A2 allele of CYP17 modifies endogenous hormone levels, but is not a strong independent risk factor for breast cancer.     

Association of serum estrone levels with estrogen receptor-positive breast cancer risk in postmenopausal Japanese women.

PURPOSE: Several reports have demonstrated the association between high serum estrogens levels and breast cancer risk in postmenopausal women. It is hypothesized that breast cancers arising in postmenopausal women with high serum estrogens levels are more likely to be estrogen receptor (ER)-positive. Thus, we have investigated whether or not high serum estrone (E(1)) levels are associated with ER-positive breast cancer risk in postmenopausal women. EXPERIMENTAL DESIGN: A case-control study was conducted on 71 cases (postmenopausal breast cancer patients) and 73 controls (postmenopausal healthy women). Serum E(1) levels were examined in their association with breast cancer risk after adjustment for the various epidemiological risk factors. In addition, clinicopathological characteristics of breast cancers arising in the women with high E(1) levels were investigated. RESULTS: Women in the high tertile of E(1) levels had a significantly (P < 0.01) increased risk of breast cancer as compared with women in the low tertile [odds ratio (OR), 4.14; 95% confidence interval (CI), 1.44-11.87]. Subset analysis according to the ER status showed that women in the high tertile of E(1) levels had a significantly increased risk for ER-positive breast cancer (OR, 23.79; 95% CI, 3.50-161.59) but not for ER-negative breast cancer (OR, 1.45; 95% CI, 0.41-5.15) as compared with women in the low tertile. Tumor size and lymph node status were not significantly different between women in the high tertile and those in the intermediate and low tertiles. But the frequency of low-histological-grade tumors and ER-positive tumors (88 and 67%, respectively) showed a greater trend toward an increase (P = 0.06 and P = 0.07, respectively) in women in the high tertile than those (69 and 46%, respectively) in the intermediate and low tertiles. In addition, ER levels in ER-positive tumors were significantly (P < 0.05) higher in women in the high tertile (245.3 +/- 37.1 fmol/mg protein) than those in the intermediate and low tertiles (134.0 +/- 31.3 fmol/mg protein). CONCLUSIONS: Postmenopausal women with high serum E(1) levels have a significantly increased risk for ER-positive, but not ER-negative, breast cancer. Breast cancers arising in women with high E(1) levels show a high ER positivity as well as high ER content. Measurement of serum E(1) levels would be clinically useful in the selection of postmenopausal women who can benefit from prophylactic use of tamoxifen because tamoxifen can prevent ER-positive, but not ER-negative, breast cancer.     

Urinary cadmium and serum levels of estrogens and androgens in postmenopausal Japanese women.

BACKGROUND: Recent laboratory studies have suggested that cadmium is an estrogenic compound and may be a potential risk factor for breast cancer. METHODS: We investigated the relationship between urinary cadmium concentrations and serum concentrations of estrone, testosterone, and dehydroepiandrosterone sulfate in 164 postmenopausal Japanese women. RESULTS: There was a significant positive association between the urinary cadmium and serum testosterone levels after controlling for age and body mass index. The mean testosterone level was 28% higher in women with high urinary cadmium (> or = 3.00 microg/g creatinine) than in those with low urinary cadmium (< 2.00 microg/g creatinine). Urinary cadmium was not significantly associated with serum estrone and dehydroepiandrosterone sulfate levels. Additional adjustment for smoking, alcohol and reproductive factors including known risk factors for breast cancer did not substantially alter the results. CONCLUSION: Data suggested that cadmium exposure is associated with increased testosterone levels. As high testosterone levels have been associated with the risk of breast cancer, the involvement of cadmium exposure in breast cancer risk should be evaluated in future studies.     

A case-control study of lactation and cancer of the breast.

We have examined the relation of lactation, by total duration, with breast cancer risk among pre- and post-menopausal women. In a hospital-based case-control study conducted in Athens (1989-91), involving 820 patients with confirmed breast cancer and 795 orthopaedic patient controls and 753 hospital visitor controls, logistic regression was used to analyse the data controlling for demographic, nutritional and reproductive factors, including parity and age at any birth. Among post-menopausal women, there was no association between breastfeeding and breast cancer risk, but among premenopausal women those who has breastfed for > or = 24 months had an odds ratio of 0.50 (95% confidence interval 0.23-1.41). A reduction of the odds ration was also evident among premenopausal women who had breastfed between 12 and 23 months (odds ratio 0.70; 95% confidence interval 0.34-1.60). In conjunction with several other recent reports these results support the hypothesis that breastfeeding of prolonged duration may reduce the risk of breast cancer among premenopausal women but not among post-menopausal women. The biology underlying this different effect remains unknown, and the practical implication of the finding is a marginal importance.     

Serum concentration of thyroid hormones in abnormal and euthyroid ranges and breast cancer risk: A cohort study

The impact of variations in serum thyroid hormone concentration within the euthyroid range on breast cancer risk remains unclear. We investigated the effect of serum thyrotropin (TSH) and thyroid hormone concentration on breast cancer risk. This cohort study involved 62,546 Korean women, aged ≥40 years, who were free of breast cancer at baseline and underwent health examination with determination of free thyroxine (FT4) and TSH. A parametric proportional hazard model was used to estimate the adjusted hazard ratio (aHR) and 95% confidence interval (CI). During a median follow-up of 4.8 years (interquartile range: 2.8–7.3 years), 834 incident breast cancers were identified. Compared to normal FT4 level, abnormally high serum FT4 level was associated with an increased risk of incident breast cancer with a corresponding multivariable aHR (95% CI) of 1.98 (1.02–3.83). This association tended to be stronger in postmenopausal women than in premenopausal women. Within the euthyroid range, the highest TSH tertile was associated with a lower risk of breast cancer than the lowest TSH tertile with a corresponding aHR (95% CI) of 0.68 (0.55–0.84). In contrast, highest FT4 tertile was associated with a higher risk of breast cancer than the lowest FT4 tertile. Abnormally high FT4 as well as higher FT4 within the euthyroid range were positively associated with breast cancer risk, while higher TSH concentration within the euthyroid range was negatively associated with breast cancer risk. Our findings indicate that thyroid function within both the abnormal and euthyroid ranges may contribute to the development of breast cancer.     

Insulin-like growth factors and breast cancer risk in Chinese women.

Insulin-like growth factor (IGF)-I has mitogenic and antiapoptotic effects on breast cancer cells. High-circulating IGF-I was found to be associated with increased risk of breast cancer in several previous epidemiological studies, mostly conducted in the Caucasian populations. Little is known about the association between IGF and breast cancer in Asian women whose dietary habits differ considerably from their Caucasian counterparts. A population-based case-control study was conducted to assess the associations of IGFs and IGF binding protein-3, a major IGF binding protein in the circulation, with breast cancer risk in Chinese women. The study included 300 incident breast cancer patients diagnosed between August 1996 and March 1998 in Shanghai and 300 age- and menopause-matched controls selected randomly from the general population. Plasma levels of IGF-I, IGF-II, and IGFBP-3 were measured using commercial ELISA kits (Diagnostic Systems Laboratories, Webster, TX). Conditional logistic regression analysis was performed to examine the association between IGF and breast cancer risk after adjusting for potential confounding factors. Breast cancer patients had higher plasma levels of IGF-I and IGFBP-3. A dose-response relationship was observed between breast cancer risk and the level of IGF-I or IGFBP-3. The adjusted odds ratios were 2.01 (95% confidence interval, 1.26-3.19) or 3.01 (95% confidence interval, 1.81-4.99), respectively, for women with the highest tertile of IGF-I or IGFBP-3 compared with those with the lowest tertile of these molecules. These associations were more evident in premenopausal women or women with high body mass index or high waist-to-hip ratio. No significant association was found for IGF-II. The study confirms that high circulating levels of IGF-I are associated with elevated risk of breast cancer. In contrast to the findings from several studies conducted in Caucasian women, we found that IGFBP-3 was positively associated with breast cancer risk in Chinese women.     

Circulating levels of insulin-like growth factors, their binding proteins, and breast cancer risk.

BACKGROUND: Earlier data support the hypothesis that the relation between circulating insulin-like growth factor-I (IGF-I) levels and breast cancer risk differs by menopausal status. The strong association of IGF-I with height in childhood and weak or no association between adult levels and adult height also suggest that IGF levels in young women may better reflect an exposure time period of importance to breast cancer. Few studies have assessed IGF binding protein-1 (IGFBP-1) or free IGF and breast cancer risk. MATERIALS AND METHODS: We conducted a large case-control study nested within the prospective Nurses' Health Study. Plasma concentrations of IGF-I, free IGF, IGFBP-3, and IGFBP-1 were measured in blood samples collected in 1989 to 1990. Eight hundred women were identified who had a diagnosis of invasive or in situ breast cancer after blood collection, up to 1998, 27% of whom were premenopausal at blood collection. To those 800 women, one to two controls were age-matched for a total of 1,129 controls. We used logistic regression models to estimate the relative risk (RR) of breast cancer associated with IGF levels.Findings: Among postmenopausal women, neither IGF-I, IGFBP-3, IGFBP-1, nor free IGF was associated with breast cancer risk [RRs, top versus bottom quintile: IGF-I, 1.0; 95% confidence interval (95% CI), 0.7-1.4; IGFBP-3, 0.8; 95% CI, 0.6-1.1; IGFBP-1, 0.9; 95% CI, 0.6-1.5; and free IGF, 1.0; 95% CI, 0.6-1.4]. Among premenopausal women, IGFBP-3, IGFBP-1, and free IGF similarly were not associated with breast cancer risk (RRs, top versus bottom quintile: IGFBP-3, 1.2; 95% CI, 0.8-2.3; IGFBP-1, 1.5; 95% CI, 0.8-3.0; and free IGF, 1.1; 95% CI, 0.7-2.1). Higher IGF-I plasma levels, however, were associated with a modestly elevated breast cancer risk (RR, 1.6; 95% CI, 1.0-2.6) among the premenopausal women, with a stronger association among premenopausal women ages < or =50 (RR, 2.5; 95% CI, 1.4-4.3); further adjustment for IGFBP-3 did not greatly change these estimates. INTERPRETATION: Circulating IGF-I levels seem to be modestly associated with breast cancer risk among premenopausal women, but not among postmenopausal women. IGFBP-3, IGFBP-1, and free IGF are not associated with breast cancer risk in either premenopausal or postmenopausal women in this cohort.     

Endogenous sex hormones and subsequent breast cancer in premenopausal women

Because of large intra-individual variation in hormone levels, few studies have investigated the relation of serum sex hormones to breast cancer (BC) in premenopausal women. We prospectively studied this relation, adjusting for timing of blood sampling within menstrual cycle. Premenopausal women (5,963), recruited to the Hormones and Diet in the Etiology of Breast Tumors (ORDET) cohort study, provided a blood sample in the 20-24th day of their menstrual cycle. After 5.2 years of follow-up, 65 histologically confirmed BC cases were identified and matched individually to 4 randomly selected controls. Sera, stored at -80 degrees C, were assayed blindly for dehydroepiandrosterone sulfate, total and free testosterone (FT), androstenedione, androstanediol-glucoronide, progesterone, 17-OH-progesterone, sex hormone-binding globulin, follicle-stimulating hormone (FSH) and luteinizing hormone (LH). Fifty-five cases had information for multivariate analyses. Compared to controls, BC cases had shorter cycles and intervals between blood sampling and bleeding, and lower LH and FSH. FT was significantly associated with BC risk: relative risk (RR; adjusted for age, body mass index and ovarian cycle variables) of highest vs. lowest tertile was 2.85 [95% confidence interval (CI) = 1.11-7.33, p for trend = 0.030]. Progesterone was inversely associated with adjusted RR for highest vs. lowest tertile of 0.40 (95% CI = 0.15-1.08, p for trend = 0.077), significantly so in women with regular menses, where adjusted RR was 0.12 (95% CI = 0.03-0.52, p for trend = 0.005). These findings support the hypothesis that ovarian hyperandrogenism associated with luteal insufficiency increases the risk of BC in premenopausal women.     

Serum enterolactone and risk of breast cancer: a case-control study in eastern Finland.

Phytoestrogens have been linked to a risk of breast cancer. The main phytoestrogens in the Finnish diet are lignans, and enterolactone is quantitatively the most important circulating lignan. The purpose of this study was to examine the association between serum enterolactone and risk of breast cancer in Finnish women. The subjects were participants of the Kuopio Breast Cancer Study: This analysis concerns 194 breast cancer cases (68 premenopausal and 126 postmenopausal) who entered the study before diagnosis and 208 community-based controls. They completed a validated food frequency questionnaire referring to the previous 12 months and gave serum samples before the examinations. The measurement of serum enterolactone was performed by time-resolved fluoroimmunoassay. The statistical analyses were done by the logistic regression method. The mean serum enterolactone concentration was 20 nmol/l for the cases and 26 nmol/l for the controls (P 0.003). The mean serum enterolactone concentration in the lowest quintile was 3.0 nmol/l and 54.0 nmol/l in the highest. The odds ratio in the highest quintile of enterolactone values adjusted for all of the known risk factors for breast cancer was 0.38 (95% confidence interval,0.18-0.77; P for trend, 0.03). The inverse association between serum enterolactone and risk of breast cancer was seen both among premenopausal and postmenopausal women. High enterolactone level was associated with higher consumption of rye products and tea and higher intake of dietary fiber and vitamin E compared with those with low serum enterolactone values. Serum enterolactone level was significantly inversely associated with risk of breast cancer.     

Markers of insulin resistance and sex steroid hormone activity in relation to breast cancer risk: a prospective analysis of abdominal adiposity, sebum production, and hirsutism (Italy)

Objective: Insulin resistance and increased levels of serum steroids have been hypothesized to be relevant etiological factors for breast cancer. Measurements of markers of insulin resistance and elevated serum steroids may identify women at high risk for breast cancer. The present study analyzed the association of breast cancer with markers of insulin resistance and elevated serum sex steroids, abdominal adiposity, increase in sebum production and hirsutism in a case–control study nested in a prospective cohort study. Methods: Between 1987 and 1992, 10,786 women (aged 35–69) were recruited in a prospective study on breast cancer in Italy, the ORDET study. Women with a history of cancer and on hormone therapy were excluded at baseline. At recruitment, abdominal adiposity was calculated from the ratio of waist-to-hip circumferences. Sebum production was measured on the forehead under standardized conditions using a sebumeter. Nine androgen-sensitive body areas were evaluated for hirsutism and a total hirsutism score was computed. After an average of 5.5 years of follow-up, 144 breast cancer cases were identified among the participants of the cohort. For each breast cancer case, four matched controls were randomly chosen from members of the cohort who did not develop breast cancer during the follow-up period. Results: Waist-to-hip ratio was associated with breast cancer in premenopausal women: age and body mass index (BMI) adjusted relative risk (RR) for the highest tertile of waist-to-hip ratio was 2.2 [95% confidence interval (CI) 1.04–4.75], p for trend 0.03. In the analysis conducted within strata of BMI, the effect of waist-to-hip ratio was confined to the group of thinner women: RR for the highest tertile of waist-to-hip ratio was 3.4 (95% CI 1.2–9.5). Sebum production and hirsutism were associated with breast cancer among postmenopausal women. Age and BMI adjusted RRs for the upper tertiles were 2.2 (95% CI 1.1–4.6), p for trend 0.01, and 2.3 (95% CI 1.1–4.9), p for trend 0.03, for sebum and hirsutism, respectively. Conclusion: These results add evidence for a role of hormones and metabolic alterations in breast cancer etiology and for different relations of these risk factors with breast cancer in premenopausal and postmenopausal women.