Diabetes and onset of natural menopause: results from the European Prospective Investigation into Cancer and Nutrition.

STUDY QUESTION: Do women who have diabetes before menopause have their menopause at an earlier age compared with women without diabetes? SUMMARY ANSWER: Although there was no overall association between diabetes and age at menopause, our study suggests that early-onset diabetes may accelerate menopause. WHAT IS KNOWN ALREADY: Today, more women of childbearing age are being diagnosed with diabetes, but little is known about the impact of diabetes on reproductive health. STUDY DESIGN, SIZE, DURATION: We investigated the impact of diabetes on age at natural menopause (ANM) in 258 898 women from the European Prospective Investigation into Cancer and Nutrition (EPIC), enrolled between 1992 and 2000. PARTICIPANTS/MATERIALS, SETTING, METHODS: Determinant and outcome information was obtained through questionnaires. Time-dependent Cox regression analyses were used to estimate the associations of diabetes and age at diabetes diagnosis with ANM, stratified by center and adjusted for age, smoking, reproductive and diabetes risk factors and with age from birth to menopause or censoring as the underlying time scale. MAIN RESULTS AND THE ROLE OF CHANCE: Overall, no association between diabetes and ANM was found (hazard ratio (HR) = 0.94; 95% confidence interval (CI) 0.89-1.01). However, women with diabetes before the age of 20 years had an earlier menopause (10-20 years: HR = 1.43; 95% CI 1.02-2.01, <10 years: HR = 1.59; 95% CI 1.03-2.43) compared with non-diabetic women, whereas women with diabetes at age 50 years and older had a later menopause (HR = 0.81; 95% CI 0.70-0.95). None of the other age groups were associated with ANM. LIMITATIONS, REASONS FOR CAUTION: Strengths of the study include the large sample size and the broad set of potential confounders measured. However, results may have been underestimated due to survival bias. We cannot be sure about the sequence of the events in women with a late age at diabetes, as both events then occur in a short period. We could not distinguish between type 1 and type 2 diabetes. WIDER IMPLICATIONS OF THE FINDINGS: Based on the literature, an accelerating effect of early-onset diabetes on ANM might be plausible. A delaying effect of late-onset diabetes on ANM has not been reported before, and is not in agreement with recent studies suggesting the opposite association. STUDY FUNDING/COMPETING INTERESTS: The coordination of EPIC is financially supported by the European Commission (DG-SANCO) and the International Agency for Research on Cancer. The national cohorts are supported by Danish Cancer Society (Denmark); Ligue Contre le Cancer, Institut Gustave Roussy, Mutuelle Générale de l'Education Nationale, Institut National de la Santé et de la Recherche Médicale (INSERM) (France); German Cancer Aid, German Cancer Research Center (DKFZ) and Federal Ministry of Education and Research (BMMF) (Germany); Ministry of Health and Social Solidarity, Stavros Niarchos Foundation and Hellenic Health Foundation (Greece); Italian Association for Research on Cancer (AIRC) and National Research Council (Italy); Dutch Ministry of Public Health, Welfare and Sports (VWS), Netherlands Cancer Registry (NKR), LK Research Funds, Dutch Prevention Funds, Dutch ZON (Zorg Onderzoek Nederland), World Cancer Research Fund (WCRF), Statistics Netherlands (The Netherlands); ERC-2009-AdG 232997 and Nordforsk, Nordic Centre of Excellence programme on Food, Nutrition and Health (Norway); Health Research Fund (FIS), Regional Governments of Andalucía, Asturias, Basque Country, Murcia (no. 6236) and Navarra, ISCIII RETIC (RD06/0020) (Spain); Swedish Cancer Society, Swedish Scientific Council and Regional Government of Skåne and Västerbotten (Sweden); Cancer Research UK, Medical Research Council, Stroke Association, British Heart Foundation, Department of Health, Food Standards Agency, and Wellcome Trust (UK). None of the authors reported a conflict of interest.

Anti-Mullerian hormone and risk of invasive serous ovarian cancer.

PURPOSE: Epithelial ovarian cancers either arise directly from Mullerian-type epithelium or acquire Mullerian characteristics in the course of neoplastic transformation. The anti-Mullerian hormone (AMH) causes regression of Mullerian structures during fetal development in males and has been shown to inhibit the growth of epithelial ovarian cancer. Therefore, we hypothesized that pre-diagnostic serum concentrations of AMH are inversely associated with risk of invasive serous ovarian cancer. METHODS: A case-control study (107 cases, 208 controls) was nested within the population-based Finnish Maternity Cohort (1986-2007). The sample donated during the first trimester of the last pregnancy preceding cancer diagnosis of the case subjects was selected for the study. For each case, two controls, matched on age and date at sampling, as well as parity at sampling and at cancer diagnosis were selected. AMH was measured by a second-generation AMH ELISA. Conditional logistic regression was used to compute odds ratios (OR) and 95 % confidence intervals (CI) for invasive serous ovarian cancer associated with AMH concentrations. RESULTS: Overall AMH concentrations were not associated with risk of invasive serous ovarian cancer (OR 0.93; 95 % CI 0.49-1.77 for top vs. bottom tertile, P trend=0.83). In women older than the median age at sampling (32.7 years), a doubling of AMH was associated with decreased risk (OR 0.69; 95 % CI 0.49-0.96), whereas an increased risk (OR 1.64; 95 % CI 1.06-2.54) was observed in younger women, P homogeneity = 0.002. CONCLUSIONS: In this first prospective investigation, risk of invasive serous ovarian cancer was not associated with pre-diagnostic AMH concentrations overall; however, the association may depend on age at AMH measurement.

Physical activity, sex steroid, and growth factor concentrations in pre- and post-menopausal women: a cross-sectional study within the EPIC cohort.

PURPOSE: Increased physical activity (PA) is associated with a reduced risk of several cancers. PA may reduce cancer risk by changing endogenous hormones levels, but relatively little research has focused on this topic. The purpose of this study was to elucidate the relation between PA and endogenous hormone concentrations. METHODS: A cross-sectional analysis of 798 pre- and 1,360 post-menopausal women included as controls in case-control studies on endogenous hormones (steroids, progesterone, sex-hormone-binding globulin (SHBG), and growth factors) levels, and cancer risk nested within European Prospective Investigation into Cancer and Nutrition cohort was performed. Multivariate regression analyses were performed to compare geometric mean levels of hormones and SHBG by categories of PA. RESULTS: In pre-menopausal women, active women had 19 % significantly lower concentrations of androstenedione, 14 % lower testosterone, and 20 % lower free testosterone than inactive women, while no differences were observed for estrogens, progesterone, SHBG, and growth factors. In post-menopausal women, active women had 18 % significantly lower estradiol and 20 % lower free estradiol concentrations than inactive women, while no differences were observed for the other hormones and SHBG. More vigorous forms of physical activity were associated with higher insulin-like growth factor-I concentrations. Adjustment for body mass index did not alter the associations. Overall, the percentage of variance in hormone concentrations explained by PA levels was <2 %. CONCLUSIONS: Our results support the hypothesis of an influence, although small in magnitude, of PA on sex hormone levels in blood, independent of body size.

Consumption of fish and meats and risk of hepatocellular carcinoma: the European Prospective Investigation into Cancer and Nutrition (EPIC).

BACKGROUND: While higher intake of fish and lower consumption of red/processed meats have been suggested to play a protective role in the etiology of several cancers, prospective evidence for hepatocellular carcinoma (HCC) is limited, particularly in Western European populations. METHODS: The associations of fish and meats with HCC risk were analyzed in the EPIC cohort. Between 1992 and 2010, 191 incident HCC were identified among 477 206 participants. Baseline diet was assessed using validated dietary questionnaires. A single 24-h diet recall from a cohort subsample was used for calibration. Multivariable proportional hazard regression was utilized to estimate hazard ratios (HR) and 95% confidence intervals (CI). In a nested case-control subset (HCC = 122), HBV/HCV status and liver function biomarkers were measured. RESULTS: HCC risk was inversely associated with intake of total fish (per 20 g/day increase, HR = 0.83, 95% CI 0.74-0.95 and HR = 0.80, 95% CI 0.69-0.97 before and after calibration, respectively). This inverse association was also suggested after adjusting for HBV/HCV status and liver function score (per 20-g/day increase, RR = 0.86, 95% CI 0.66-1.11 and RR = 0.74, 95% CI 0.50-1.09, respectively) in a nested case-control subset. Intakes of total meats or subgroups of red/processed meats, and poultry were not associated with HCC risk. CONCLUSIONS: In this large European cohort, total fish intake is associated with lower HCC risk.

Glycemic index, glycemic load, dietary carbohydrate, and dietary fiber intake and risk of liver and biliary tract cancers in Western Europeans.

BACKGROUND: The type and quantity of dietary carbohydrate as quantified by glycemic index (GI) and glycemic load (GL), and dietary fiber may influence the risk of liver and biliary tract cancers, but convincing evidence is lacking. PATIENTS AND METHODS: The association between dietary GI/GL and carbohydrate intake with hepatocellular carcinoma (HCC; N = 191), intrahepatic bile duct (IBD; N = 66), and biliary tract (N = 236) cancer risk was investigated in 477 206 participants of the European Prospective Investigation into Cancer and Nutrition cohort. Dietary intake was assessed by country-specific, validated dietary questionnaires. Hazard ratios and 95% confidence intervals were estimated from proportional hazard models. HBV/HCV status was measured in a nested case-control subset. RESULTS: Higher dietary GI, GL, or increased intake of total carbohydrate was not associated with liver or biliary tract cancer risk. For HCC, divergent risk estimates were observed for total sugar = 1.43 (1.17-1.74) per 50 g/day, total starch = 0.70 (0.55-0.90) per 50 g/day, and total dietary fiber = 0.70 (0.52-0.93) per 10 g/day. The findings for dietary fiber were confirmed among HBV/HCV-free participants [0.48 (0.23-1.01)]. Similar associations were observed for IBD [dietary fiber = 0.59 (0.37-0.99) per 10 g/day], but not biliary tract cancer. CONCLUSIONS: Findings suggest that higher consumption of dietary fiber and lower consumption of total sugars are associated with lower HCC risk. In addition, high dietary fiber intake could be associated with lower IBD cancer risk.

Metabolic risk factors and skin cancer in the Metabolic Syndrome and Cancer Project (Me-Can).

BACKGROUND: Little is known about the associations of metabolic aberrations with malignant melanoma (MM) and nonmelanoma skin cancer (NMSC). OBJECTIVES: To assess the associations between metabolic factors (both individually and combined) and the risk of skin cancer in the large prospective Metabolic Syndrome and Cancer Project (Me-Can). METHODS: During a mean follow-up of 12 years of the Me-Can cohort, 1728 (41% women) incident MM, 230 (23% women) fatal MM and 1145 (33% women) NMSC were identified. Most NMSC cases (76%) were squamous cell carcinoma (SCC) (873, 33% women). Hazard ratios (HRs) were estimated by Cox proportional hazards regression for quintiles and standardized z-scores (with a mean of 0 and SD of 1) of body mass index (BMI), blood pressure, glucose, cholesterol, triglycerides and for a combined metabolic syndrome score. Risk estimates were corrected for random error in the measurements. RESULTS: Blood pressure per unit increase of z-score was associated with an increased risk of incident MM cases in men and women [HR 1·17, 95% confidence interval (CI) 1·04-1·31 and HR 1·18, 95% CI 1·03-1·36, respectively] and fatal MM cases among women (HR 2·39, 95% CI 1·58-3·64). In men, all quintiles for BMI above the reference were associated with a higher risk of incident MM. In women, SCC NMSC risk increased across quintiles for glucose levels (P-trend 0·02) and there was a trend with triglyceride concentration (P-trend 0·09). CONCLUSION: These findings suggest that mechanisms linked to blood pressure may be involved in the pathogenesis of MM. SCC NMSC in women could be related to glucose and lipid metabolism.

Oral contraceptive use and reproductive factors and risk of ovarian cancer in the European Prospective Investigation into Cancer and Nutrition.

BACKGROUND: It is well established that parity and use of oral contraceptives reduce the risk of ovarian cancer, but the associations with other reproductive variables are less clear. METHODS: We examined the associations of oral contraceptive use and reproductive factors with ovarian cancer risk in the European Prospective Investigation into Cancer and Nutrition. Among 327,396 eligible women, 878 developed ovarian cancer over an average of 9 years. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using Cox proportional hazard models stratified by centre and age, and adjusted for smoking status, body mass index, unilateral ovariectomy, simple hysterectomy, menopausal hormone therapy, and mutually adjusted for age at menarche, age at menopause, number of full-term pregnancies and duration of oral contraceptive use. RESULTS: Women who used oral contraceptives for 10 or more years had a significant 45% (HR, 0.55; 95% CI, 0.41-0.75) lower risk compared with users of 1 year or less (P-trend, <0.01). Compared with nulliparous women, parous women had a 29% (HR, 0.71; 95% CI, 0.59-0.87) lower risk, with an 8% reduction in risk for each additional pregnancy. A high age at menopause was associated with a higher risk of ovarian cancer (>52 vs ≤ 45 years: HR, 1.46; 95% CI, 1.06-1.99; P-trend, 0.02). Age at menarche, age at first full-term pregnancy, incomplete pregnancies and breastfeeding were not associated with risk. CONCLUSION: This study shows a strong protective association of oral contraceptives and parity with ovarian cancer risk, a higher risk with a late age at menopause, and no association with other reproductive factors.

Postmenopausal circulating levels of 2- and 16α-hydroxyestrone and risk of endometrial cancer.

BACKGROUND: It has been suggested that the relative importance of oestrogen-metabolising pathways may affect the risk of oestrogen-dependent tumours including endometrial cancer. One hypothesis is that the 2-hydroxy pathway is protective, whereas the 16α-hydroxy pathway is harmful. METHODS: We conducted a case-control study nested within three prospective cohorts to assess whether the circulating 2-hydroxyestrone : 16α-hydroxyestrone (2-OHE1 : 16α-OHE1) ratio is inversely associated with endometrial cancer risk in postmenopausal women. A total of 179 cases and 336 controls, matching cases on cohort, age and date of blood donation, were included. Levels of 2-OHE1 and 16α-OHE1 were measured using a monoclonal antibody-based enzyme assay. RESULTS: Endometrial cancer risk increased with increasing levels of both metabolites, with odds ratios in the top tertiles of 2.4 (95% CI=1.3, 4.6; P(trend)=0.007) for 2-OHE1 and 1.9 (95% CI=1.1, 3.5; P(trend)=0.03) for 16α-OHE1 in analyses adjusting for endometrial cancer risk factors. These associations were attenuated and no longer statistically significant after further adjustment for oestrone or oestradiol levels. No significant association was observed for the 2-OHE1 : 16α-OHE1 ratio. CONCLUSION: Our results do not support the hypothesis that greater metabolism of oestrogen via the 2-OH pathway, relative to the 16α-OH pathway, protects against endometrial cancer.

Changes in pre-diagnostic serum C-reactive protein concentrations and ovarian cancer risk: a longitudinal study.

BACKGROUND: Evidence suggests that inflammation may be associated with increased risk of ovarian cancer but there is paucity of studies investigating this association, especially using over-time changes in inflammatory biomarkers. MATERIALS AND METHODS: We conducted a prospective population-based case-control study nested within the Finnish Maternity Cohort (FMC). Within the FMC, 170 women with ovarian cancer who had donated serum samples to the cohort twice, ≥1 year apart, before cancer diagnoses were identified. One control per case was matched for age, parity and sampling date. RESULTS: Comparing the highest with lowest tertiles, the odds ratio (OR) of ovarian cancer using the first set of serum samples (mean lag time to cancer diagnosis 9.0 years) was 1.62 [95% confidence interval (CI) 0.93-2.83]. However, analysis conducted using the second set of serum samples donated closer to cancer diagnosis (mean lag time 6.4 years) revealed a significantly increased risk of ovarian cancer comparing extreme tertiles of C-reactive protein (CRP) concentrations; OR 1.96 (95% CI 1.11-3.4). Over time, increases in individuals' CRP concentrations were also associated with increased risk; OR 1.90 (95% CI 1.12-3.23). CONCLUSION: The results suggest that inflammation may precede ovarian cancer since increasing CRP concentrations, both across tertiles and longitudinally at the individual level, were associated with increased risk.

Metabolic syndrome and rare gynecological cancers in the metabolic syndrome and cancer project (Me-Can).

BACKGROUND: Risk factors for rare gynecological cancers are largely unknown. Initial research has indicated that the metabolic syndrome (MetS) or individual components could play a role. MATERIALS AND METHODS: The Metabolic syndrome and Cancer project cohort includes 288,834 women. During an average follow-up of 11 years, 82 vulvar, 26 vaginal and 43 other rare gynecological cancers were identified. Hazard ratios (HRs) were estimated fitting Cox proportional hazards regression models for tertiles and standardized z-scores [with a mean of 0 and a standard deviation (SD) of 1] of body mass index (BMI), blood pressure, glucose, cholesterol, triglycerides and MetS. Risk estimates were corrected for random error in the measurement of metabolic factors. RESULTS: The MetS was associated with increased risk of vulvar [HR 1.78, 95% confidence interval (CI) 1.30-2.41) and vaginal cancer (HR 1.87, 95% CI 1.07-3.25). Among separate MetS components, 1 SD increase in BMI was associated with overall risk (HR 1.43, 95% CI 1.23-1.66), vulvar (HR 1.36, 95% CI 1.11-1.69) and vaginal cancer (HR 1.79, 95% CI 1.30-2.46). Blood glucose and triglyceride concentrations were associated with increased risk of vulvar cancer (HR 1.98, 95% CI 1.10-3.58 and HR 2.09, 95% CI 1.39-3.15, respectively). CONCLUSION: The results from this first prospective study on rare gynecological cancers suggest that the MetS and its individual components may play a role in the development of these tumors.

Components of the metabolic syndrome and colorectal cancer risk; a prospective study.

OBJECTIVE: To examine the relation of well-known factors of the metabolic syndrome (MetS) as well as related circulating factors, with risk of colorectal cancer. METHODS: We performed a case control study of 306 colorectal cancer cases and 595 matched controls nested in the Northern Sweden Health and Disease Cohort. Levels of C-peptide, glycated haemoglobin (HbA1c), leptin and adiponectin were measured in cryopreserved samples. Body mass index (BMI), systolic and diastolic blood pressure and fasting and post-load plasma glucose, had been measured in a subcohort. Conditional logistic regression was used to calculate odds ratios (OR) of disease, including risk assessments for the MetS factors: obesity (BMI>30 kg m(-2)), hypertension (blood pressure > or =140/90 mmHg or use of anti-hypertensive drugs) and hyperglycaemia (fasting glucose > or =6.1 mmol l(-1) or post-load glucose in capillary plasma > or =8.9 mmol l(-1)). RESULTS: None of the studied variables were significantly associated with risk across quartiles. Presence of obesity, hypertension and hyperglycaemia significantly increased the risk of colorectal cancer; OR for three vs null factors was 2.57 (95% Confidence Interval [CI] 1.20-5.52; P (trend)=0.0021), as compared to a 30 to 70% increased risk for the factors in single. Similarly, top decile levels of C-peptide, HbA1c and leptin/adiponectin ratio were associated with an increased risk; ORs for top vs deciles 1-9 were 1.56 (95% CI 0.93-2.62; P=0.090), 1.83 (95% CI 1.00-3.36; P=0.051) and 1.50 (95% CI 0.83-2.71; P=0.18), respectively. CONCLUSIONS: Our study support the view that components of the MetS increase risk of colorectal cancer, and further suggests that only very high levels of metabolic factors confer an increased risk.

IGF-I, IGFBP-3 and breast cancer risk in women: The European Prospective Investigation into Cancer and Nutrition (EPIC).

Blood concentrations of insulin-like growth factor-I (IGF-I) and insulin-like growth factor binding protein-3 (IGFBP-3) have recently been associated with breast cancer risk, notably in women who developed breast cancer at a young age. Prospective studies published so far, however, were relatively small and odds ratio (OR) estimates imprecise. We present the results of a large prospective case-control study nested within the European Prospective Investigation into Cancer and Nutrition on total IGF-I, IGFBP-3 and breast cancer risk including 1081 incident cases of invasive breast cancer and 2098 matched control subjects. Increasing IGF-I and IGFBP-3 concentrations were associated with a significant increase in breast cancer risk in women who developed breast cancer after 50 years of age (highest vs lowest quintile OR 1.38 (95% confidence interval (CI) 1.02-1.86), P = 0.01, and 1.44 (95% CI 1.04-1.98), P = 0.01, respectively), but no relationship was observed in younger women (OR = 1.03 (95% CI 0.60-1.77), P = 0.81 for IGF-I, and OR = 0.92 (95% CI 0.50-1.70), P = 0.69 for IGFBP-3). There was, however, significant heterogeneity in the relationship of breast cancer with serum IGF-I and IGFBP-3 levels depending on the time interval between blood donation and tumor diagnosis. A reduction in breast cancer risk with increasing IGF-I concentrations was observed in cases with a diagnosis of cancer less than 2 years after blood donation, (OR = 0.76 (95% CI 0.57-1.03)), while an increase in risk was observed for women with a later diagnosis (above or equal to two years after blood collection, OR = 1.51 (95% CI 1.19-1.91)). A similar pattern was observed for IGFBP-3. This study confirms previous findings for an association of serum IGF-I and IGFBP-3 concentrations with breast cancer risk, particularly for women with a later diagnosis of cancer, but it does not support the hypothesis of an involvement of IGF-I in younger women.

Body mass index, waist circumference and waist-hip ratio and serum levels of IGF-I and IGFBP-3 in European women.

OBJECTIVE: To examine the relationship between body mass index (BMI) and waist-hip ratio (WHR) with serum levels of insulin-like growth factor-I (IGF-I), and its binding protein (IGFBP)-3. DESIGN: Cross-sectional study on 2139 women participating in a case-control study on breast cancer and endogenous hormones. Data on lifestyle and reproductive factors were collected by means of questionnaires. Body height, weight, waist and hip circumferences were measured. Serum levels of IGF-I and insulin-like binding protein (IGFBP)-3 were measured by enzyme-linked immunosorbent assays. Adjusted mean levels of IGF-I and IGFBP-3 across quintiles of BMI, waist circumference, and WHR were calculated by linear regression. Results were adjusted for potential confounders associated with IGF-I and IGFBP-3. RESULTS: Adjusted mean serum IGF-I values were lower in women with BMI<22.5 kg/m(2) or BMI>29.2 kg/m(2) compared to women with BMI within this range (P(heterogeneity)<0.0001, P(trend)=0.35). Insulin-like growth factor-I was not related to WHR after adjustment for BMI. IGF-binding protein-3 was linearly positively related to waist and WHR after mutual adjustment. The molar ratio IGF-I/IGFBP-3 had a non-linear relation with BMI and a linear inverse relationship with WHR (P (trend)=0.005). CONCLUSIONS: Our data confirm the nonlinear relationship of circulating IGF-I to total adiposity in women. Serum IGFBP-3 was positively related to central adiposity. These suggest that bioavailable IGF-I levels could be lower in obese compared to non-obese women and inversely related to central adiposity.

Postmenopausal serum androgens, oestrogens and breast cancer risk: the European prospective investigation into cancer and nutrition.

Considerable experimental and epidemiological evidence suggests that elevated endogenous sex steroids - notably androgens and oestrogens - promote breast tumour development. In spite of this evidence, postmenopausal androgen replacement therapy with dehydroepiandrosterone (DHEA) or testosterone has been advocated for the prevention of osteoporosis and improved sexual well-being. We have conducted a case-control study nested within the European Prospective Investigation into Cancer and Nutrition. Levels of DHEA sulphate (DHEAS), (Delta4-androstenedione), testosterone, oestrone, oestradiol and sex-hormone binding globulin (SHBG) were measured in prediagnostic serum samples of 677 postmenopausal women who subsequently developed breast cancer and 1309 matched control subjects. Levels of free testosterone and free oestradiol were calculated from absolute concentrations of testosterone, oestradiol and SHBG. Logistic regression models were used to estimate relative risks of breast cancer by quintiles of hormone concentrations. For all sex steroids -the androgens as well as the oestrogens - elevated serum levels were positively associated with breast cancer risk, while SHBG levels were inversely related to risk. For the androgens, relative risk estimates (95% confidence intervals) between the top and bottom quintiles of the exposure distribution were: DHEAS 1.69 (1.23-2.33), androstenedione 1.94 (1.40-2.69), testosterone 1.85 (1.33-2.57) and free testosterone 2.50 (1.76-3.55). For the oestrogens, relative risk estimates were: oestrone 2.07 (1.42-3.02), oestradiol 2.28 (1.61-3.23) and free oestradiol (odds ratios 2.13 (1.52-2.98)). Adjustments for body mass index or other potential confounding factors did not substantially alter any of these relative risk estimates. Our results have shown that, among postmenopausal women, not only elevated serum oestrogens but also serum androgens are associated with increased breast cancer risk. Since DHEAS and androstenedione are largely of adrenal origin in postmenopausal women, our results indicated that elevated adrenal androgen synthesis is a risk factor for breast cancer. The results from this study caution against the use of DHEA(S), or other androgens, for postmenopausal androgen replacement therapy.

Body mass index, circulating levels of sex-steroid hormones, IGF-I and IGF-binding protein-3: a cross-sectional study in healthy women.

OBJECTIVE: Excess weight has been associated with increased risk of cancer at several organ sites. In part, this effect may be modulated through alterations in the metabolism of sex steroids and IGF-I related peptides. The objectives of the study were to examine the association of body mass index (BMI) with circulating androgens (testosterone, androstenedione and dehydroepiandrosterone sulfate (DHEAS)), estrogens (estrone and estradiol), sex hormone-binding globulin (SHBG), IGF-I and IGF-binding protein (IGFBP)-3, and the relationship between sex steroids, IGF-I and IGFBP-3. DESIGN AND METHODS: A cross-sectional analysis was performed using hormonal and questionnaire data of 620 healthy women (177 pre- and 443 post-menopausal). The laboratory measurements of the hormones of interest were available from two previous case-control studies on endogenous hormones and cancer risk. RESULTS: In the pre-menopausal group, BMI was not related to androgens and IGF-I. In the post-menopausal group, estrogens, testosterone and androstenedione increased with increasing BMI. The association with IGF-I was non-linear, with the highest mean concentrations observed in women with BMI between 24 and 25. In both pre- and post-menopausal subjects, IGFBP-3 did not vary across BMI categories and SHBG decreased with increasing BMI. As for the correlations between peptide and steroid hormones, in the post-menopausal group, IGF-I was positively related to androgens, inversely correlated with SHBG, and not correlated with estrogens. In the pre-menopausal group, similar but weaker correlations between IGF-I and androgens were observed. CONCLUSIONS: These observations offer evidence that obesity may influence the levels of endogenous sex-steroid and IGF-related hormones in the circulation, especially after menopause. Circulating IGF-I, androgens and SHBG appear to be related to each other in post-menopausal women.

Interrelationships between plasma testosterone, SHBG, IGF-I, insulin and leptin in prostate cancer cases and controls.

Despite strong indirect evidence that androgens stimulate prostate cancer development, data from most analytical studies on this association have been negative. To further investigate this issue, we studied the interrelationships between androgenicity and insulin-like growth factor I (IGF-I), insulin and leptin. Within a prospective cohort study, we measured testosterone, sex hormone-binding globulin (SHBG) and IGF-I, IGF-binding protein (IGFBP)-1, IGFBP-3, insulin and leptin, in plasma from 149 cases and 298 controls. Testosterone correlated positively with SHBG, whereas testosterone and SHBG correlated inversely with IGF-I, IGFBP-3, insulin, leptin and body mass index (BMI). Indices of free testosterone showed an inverse linear correlation with leptin (P<0.01), and a strong drop in the 5th quintile of BMI. However, levels of free testosterone showed non-linear relationships over quintiles of insulin and IGF-I, with a significant increase in the second quintile of IGF-I compared with other levels. The absence of an association between plasma levels of androgens and prostate cancer risk in analytical studies, despite the strong indirect evidence of their tumour-stimulating effects, may reflect the complex and mostly inverse associations of androgenicity to IGF-I, insulin and leptin which are hormones that have also been implicated as risk factors for prostate cancer.

A cross-sectional study of IGF-I determinants in women.

Evidence is accumulating that elevated circulating insulin-like growth factor I (IGF-I) is related to increased cancer risk. The identification of hormonal, reproductive and lifestyle characteristics influencing its synthesis and bioavailability is of particular interest. Data from 400 women, who served as controls in two case-control studies nested within the same prospective cohort study, were combined. IGF-I, IGF-binding proteins 1, 2 and 3 (IGFBP-1, -2, -3) and insulin were measured in serum samples from all subjects and cotinine in 186 samples. Age appears to be the most important determinant of total IGF-I levels in women. Anthropometric measures, such as body mass index (BMI) or waist-to-hip ratio (WHR) do not seem to influence total IGF-I concentrations in peripheral blood, but may modulate IGF-I bioavailability through insulin-dependent changes in IGFBP-1 and -2 concentrations. Age at menarche, phase of the menstrual cycle at blood draw, parity, menopause, past oral contraceptive or hormone replacement therapy use, and tobacco smoking do not appear to exert an independent effect on IGF-I and its binding proteins. There was some suggestion that regular physical activity may increase total IGF-I and that women with positive family history of breast cancer might have higher IGF-I levels than those without such diagnosis in their relatives.