Serum androgens and prostate cancer among 643 cases and 643 controls in the European Prospective Investigation into Cancer and Nutrition

We examined the hypothesis that serum concentrations of circulating androgens and sex hormone binding globulin (SHBG) are associated with risk for prostate cancer in a case-control study nested in the European Prospective Investigation into Cancer and Nutrition (EPIC). Concentrations of androstenedione, testosterone, androstanediol glucuronide and SHBG were measured in serum samples for 643 prostate cancer cases and 643 matched control participants, and concentrations of free testosterone were calculated. Conditional logistic regression models were used to calculate odds ratios for risk of prostate cancer in relation to the serum concentration of each hormone. After adjustment for potential confounders, there was no significant association with overall risk for prostate cancer for serum total or free testosterone concentrations (highest versus the lowest thirds: OR, 1.02; 95% CI, 0.73-1.41 and OR, 1.07, 95% CI, 0.74-1.55, respectively) or for other androgens or SHBG. Subgroup analyses showed significant heterogeneity for androstenedione by cancer stage, with a significant inverse association of androstenedione concentration and risk for advanced prostate cancer. There were also weak positive associations between free testosterone concentration and risk for total prostate cancer among younger men and risk for high-grade disease. In summary, in this large nested case-control study, concentrations of circulating androgens or SHBG were not strongly associated with risk for total prostate cancer. However, our findings are compatible with a positive association of free testosterone with risk in younger men and possible heterogeneity in the association with androstenedione concentration by stage of disease; these findings warrant further investigation.     

Sex steroid hormones and the androgen receptor gene CAG repeat and subsequent risk of prostate cancer in the prostate-specific antigen era.

OBJECTIVE: Sex steroid hormones are thought to contribute to the growth, differentiation, and progression of prostate cancer. We investigated plasma levels of sex steroid hormones and length of the androgen receptor gene CAG repeat in relation to incident prostate cancer diagnosed in the prostate-specific antigen (PSA) era.METHODS: Using a nested case-control design, we included 460 prostate cancer cases diagnosed after providing a blood specimen in 1993 but before February 1998 among men in the Health Professionals Follow-up Study. Controls were 460 age-matched men without prostate cancer who had a screening PSA test after the date of providing a blood specimen. We measured plasma concentrations of total testosterone, free testosterone, dihydrotestosterone, androstanediol glucuronide, estradiol, and sex hormone binding globulin (SHBG) and determined the length of the androgen receptor gene CAG repeat. Conditional logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI) of prostate cancer.RESULTS: Mean concentrations of the sex steroids adjusted for SHBG, and mean CAG repeat length did not differ significantly between the prostate cancer cases and controls. No significant associations with total prostate cancer were detected for plasma total testosterone concentration (comparing highest versus lowest quartiles: OR, 0.78; 95% CI, 0.48-1.28; P(trend) = 0.73) or the other sex hormones after adjusting for SHBG. However, plasma total testosterone concentration was positively associated with low-grade disease (Gleason sum < 7: OR, 1.91; 95% CI, 0.89-4.07; P(trend) = 0.02) and inversely associated with high-grade disease (Gleason sum > or = 7: OR, 0.26; 95% CI, 0.10-0.66; P(trend) = 0.01). Similar patterns for grade were observed for free testosterone. Short CAG repeat length was not associated with total prostate cancer (< or = 19 versus > or = 24: OR, 0.84; 95% CI, 0.57-1.23; P(trend) = 0.22) or grade of disease. No clear associations with regionally invasive or metastatic (> or = T3b, N1, or M1) were found for any of the hormones or the CAG repeat, although the number of these cases was small.CONCLUSIONS: The overall lack of association of prostate cancer diagnosed in the PSA era with sex steroid hormones and the androgen receptor gene CAG repeat length is consistent with the hypothesis that these factors do not substantially contribute to the development of early prostate cancer in the PSA era. The influence of plasma total and free testosterone concentrations on prostate cancer grade merits further evaluation.     

High levels of circulating testosterone are not associated with increased prostate cancer risk: a pooled prospective study

Androgens stimulate prostate cancer in vitro and in vivo. However, evidence from epidemiologic studies of an association between circulating levels of androgens and prostate cancer risk has been inconsistent. We investigated the association of serum levels of testosterone, the principal androgen in circulation, and sex hormone-binding globulin (SHBG) with risk in a case-control study nested in cohorts in Finland, Norway and Sweden of 708 men who were diagnosed with prostate cancer after blood collection and among 2,242 men who were not. In conditional logistic regression analyses, modest but significant decreases in risk were seen for increasing levels of total testosterone down to odds ratio for top vs. bottom quintile of 0.80 (95% CI = 0.59-1.06; p(trend) = 0.05); for SHBG, the corresponding odds ratio was 0.76 (95% CI = 0.57-1.01; p(trend) = 0.07). For free testosterone, calculated from total testosterone and SHBG, a bell-shaped risk pattern was seen with a decrease in odds ratio for top vs. bottom quintile of 0.82 (95% CI = 0.60-1.14; p(trend) = 0.44). No support was found for the hypothesis that high levels of circulating androgens within a physiologic range stimulate development and growth of prostate cancer.     

Endogenous sex hormones and the risk of prostate cancer: a prospective study

Sex steroid hormones influence prostate development and maintenance through their roles in prostate cellular proliferation, differentiation and apoptosis. Although suspected to be involved in prostate carcinogenesis, an association between circulating androgens and prostate cancer has not been clearly established in epidemiologic studies. We conducted a nested case-control study with prospectively collected samples in the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial, to examine associations of prostate cancer with androstenedione (Delta4-A), testosterone (T), sex hormone-binding globulin (SHBG) and 3alpha-androstanediol glucuronide (3alpha-diolG). A total of 727 incident Caucasian prostate cancer cases (age >/= 65 years, N = 396) and 889 matched controls were selected for this analysis. Overall, prostate cancer risks were unrelated to serum T, estimated free and bioavailable T, and SHBG; however, risks increased with increasing T:SHBG ratio (p(trend) = 0.01), mostly related to risk in older men (>/=65 years, p(trend) = 0.001), particularly for aggressive disease [highest versus lowest quartile: odds ratio (OR) 2.76, 95% confidence interval (CI) 1.50-5.09]. No clear patterns were noted for Delta4-A and 3alpha-diolG. In summary, our large prospective study did not show convincing evidence of a relationship between serum sex hormones and prostate cancer. T:SHBG ratio was related to risk in this older population of men, but the significance of this ratio in steroidal biology is unclear. (c) 2008 Wiley-Liss, Inc.     

High levels of circulating insulin-like growth factor-I increase prostate cancer risk: a prospective study in a population-based nonscreened cohort.

PURPOSE: Insulin-like growth factor-I (IGF-I) stimulates proliferation and inhibits apoptosis in prostate cancer cells, and IGF-I has been associated with increased prostate cancer risk in some, but not all, epidemiologic studies. SUBJECTS AND METHODS: We extended our previous case-control study nested in the Northern Sweden Health and Disease Cohort, a population-based cohort from a region where little prostate specific antigen (PSA) screening is done. Levels of IGF-I and IGF binding protein-3 (IGFBP-3) were measured in prediagnostic blood samples from a total of 281 men who were subsequently diagnosed with prostate cancer after recruitment (median, 5 years after blood collection) and from 560 matched controls. RESULTS: Logistic regression analyses showed increases in prostate cancer risk with increasing plasma peptide levels, up to an odds ratio (OR) for top versus bottom quartile of IGF-I of 1.67 (95% CI, 1.02 to 2.71; Ptrend = .05), which was attenuated after adjustment for IGFBP-3 to an OR of 1.47 (95% CI, 0.81 to 2.64; P (trend) =.32). For men younger than 59 years at recruitment, OR for top versus bottom quartile of IGF-I was 4.12 (95% CI, 1.01 to 16.70; Ptrend = .002), which was significantly stronger than for men older than 59 years (P (interaction) = .006). For men with advanced cancer, OR for top versus bottom quartile of IGF-I was 2.87 (95% CI, 1.01 to 8.12; Ptrend = .10). CONCLUSION: Our data add further support for IGF-I as an etiologic factor in prostate cancer and indicate that circulating IGF-I levels measured at a comparatively young age may be most strongly associated with prostate cancer risk.     

Reproductive steroid hormones and recurrence-free survival in women with a history of breast cancer.

Epidemiologic studies fairly consistently show in postmenopausal women that reproductive steroid hormones contribute to primary breast cancer risk, and this association is strongly supported by experimental studies using laboratory animals and model systems. Evidence linking sex hormone concentrations with risk for recurrence in women diagnosed with breast cancer is limited; however, beneficial effects of antiestrogenic therapy on recurrence-free survival suggest that these hormones affect progression and risk for recurrence. This study examined whether baseline serum concentrations of estradiol, testosterone, and sex hormone binding globulin were associated with recurrence-free survival in a nested case-control cohort of women from a randomized diet trial (Women's Healthy Eating and Living Study) who were followed for >7 years after diagnosis. In 153 case-control pairs of perimenopausal and postmenopausal women in this analysis, total estradiol [hazard ratio (HR), 1.41 per unit increase in log concentration; 95% confidence interval (95% CI), 1.01-1.97], bioavailable estradiol (HR, 1.26; 95% CI, 1.03-1.53), and free estradiol (HR, 1.31; 95% CI, 1.03-1.65) concentrations were significantly associated with risk for recurrence. Recurred women had an average total estradiol concentration that was double that of nonrecurred women (22.7 versus 10.8 pg/mL; P = 0.05). Testosterone and sex hormone binding globulin concentrations did not differ between cases and controls and were not associated with risk for recurrence. Although genetic and metabolic factors likely modulate the relationship between circulating sex hormones and risk, results from this study provide evidence that higher serum estrogen concentration contributes to risk for recurrence in women diagnosed with early stage breast cancer.     

Endogenous sex hormones and breast cancer in postmenopausal women: reanalysis of nine prospective studies

BACKGROUND: Reproductive and hormonal factors are involved in the etiology of breast cancer, but there are only a few prospective studies on endogenous sex hormone levels and breast cancer risk. We reanalyzed the worldwide data from prospective studies to examine the relationship between the levels of endogenous sex hormones and breast cancer risk in postmenopausal women. METHODS: We analyzed the individual data from nine prospective studies on 663 women who developed breast cancer and 1765 women who did not. None of the women was taking exogenous sex hormones when their blood was collected to determine hormone levels. The relative risks (RRs) for breast cancer associated with increasing hormone concentrations were estimated by conditional logistic regression on case-control sets matched within each study. Linear trends and heterogeneity of RRs were assessed by two-sided tests or chi-square tests, as appropriate. RESULTS: The risk for breast cancer increased statistically significantly with increasing concentrations of all sex hormones examined: total estradiol, free estradiol, non-sex hormone-binding globulin (SHBG)-bound estradiol (which comprises free and albumin-bound estradiol), estrone, estrone sulfate, androstenedione, dehydroepiandrosterone, dehydroepiandrosterone sulfate, and testosterone. The RRs for women with increasing quintiles of estradiol concentrations, relative to the lowest quintile, were 1.42 (95% confidence interval [CI] = 1.04 to 1.95), 1.21 (95% CI = 0.89 to 1.66), 1.80 (95% CI = 1.33 to 2.43), and 2.00 (95% CI = 1.47 to 2.71; P(trend)<.001); the RRs for women with increasing quintiles of free estradiol were 1.38 (95% CI = 0.94 to 2.03), 1.84 (95% CI = 1.24 to 2.74), 2.24 (95% CI = 1.53 to 3.27), and 2.58 (95% CI = 1.76 to 3.78; P(trend)<.001). The magnitudes of risk associated with the other estrogens and with the androgens were similar. SHBG was associated with a decrease in breast cancer risk (P(trend) =.041). The increases in risk associated with increased levels of all sex hormones remained after subjects who were diagnosed with breast cancer within 2 years of blood collection were excluded from the analysis. CONCLUSION: Levels of endogenous sex hormones are strongly associated with breast cancer risk in postmenopausal women.     

Circulating steroid hormones and the risk of prostate cancer.

Epidemiologic studies have failed to support the hypothesis that circulating androgens are positively associated with prostate cancer risk and some recent studies have even suggested that high testosterone levels might be protective particularly against aggressive cancer. We tested this hypothesis by measuring total testosterone, androstanediol glucuronide, androstenedione, DHEA sulfate, estradiol, and sex hormone-binding globulin in plasma collected at baseline in a prospective cohort study of 17,049 men. We used a case-cohort design, including 524 cases diagnosed during a mean 8.7 years follow-up and a randomly sampled sub-cohort of 1,859 men. The association between each hormone level and prostate cancer risk was tested using Cox models adjusted for country of birth. The risk of prostate cancer was approximately 30% lower for a doubling of the concentration of estradiol but the evidence was weak (P(trend)=0.07). None of the other hormones was associated with overall prostate cancer (P(trend) >or= 0.3). None of the hormones was associated with nonaggressive prostate cancer (all P(trend) >or= 0.2). The hazard ratio [HR; 95% confidence interval (95% CI)] for aggressive cancer almost halved for a doubling of the concentration of testosterone (HR, 0.55; 95% CI, 0.32-0.95) and androstenedione (HR, 0.51; 95% CI, 0.31-0.83), and was 37% lower for a doubling of the concentration of DHEA sulfate (HR, 0.63; 95% CI, 0.46-0.87). Similar negative but nonsignificant linear trends in risk for aggressive cancer were obtained for free testosterone, estradiol, and sex hormone-binding globulin (P(trend)=0.06, 0.2, and 0.1, respectively). High levels of testosterone and adrenal androgens are thus associated with reduced risk of aggressive prostate cancer but not with nonaggressive disease.     

Endogenous sex hormones and colorectal cancer survival among men and women

Although previous studies have suggested a potential role of sex hormones in the etiology of colorectal cancer (CRC), no study has yet examined the associations between circulating sex hormones and survival among CRC patients. We prospectively assessed the associations of prediagnostic plasma concentrations of estrone, estradiol, free estradiol, testosterone, free testosterone and sex hormone-binding globulin (SHBG) with CRC-specific and overall mortality among 609 CRC patients (370 men and 239 postmenopausal women not taking hormone therapy at blood collection) from four U.S. cohorts. Multivariable hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using Cox proportional hazard regression. We identified 174 deaths (83 CRC-specific deaths) in men and 106 deaths (70 CRC-specific deaths) in women. In men, higher circulating level of free testosterone was associated with lower risk of overall (the highest vs. lowest tertiles, HR = 0.66, 95% CI, 0.45–0.99, p_trend = 0.04) and possibly CRC-specific mortality (HR = 0.73, 95% CI, 0.41–1.29, p_trend = 0.27). We generally observed nonsignificant inverse associations for other sex steroids, and a positive association for SHBG with CRC-specific mortality among male patients. In women, however, we found a suggestive positive association of estrone with overall (HR = 1.54, 95% CI, 0.92–2.60, p_trend = 0.11) and CRC-specific mortality (HR = 1.96, 95% CI, 1.01–3.84, p_trend = 0.06). Total estradiol, free estradiol and free testosterone were generally suggestively associated with higher risk of mortality among female patients, although not statistically significant. These findings implicated a potential role of endogenous sex hormones in CRC prognosis, which warrant further investigation.     

Premenopausal serum androgens and breast cancer risk: a nested case-control study

Introduction

Prospective epidemiologic studies have consistently shown that levels of circulating androgens in postmenopausal women are positively associated with breast cancer risk. However, data in premenopausal women are limited.

Methods

A case-control study nested within the New York University Women's Health Study was conducted. A total of 356 cases (276 invasive and 80 in situ) and 683 individually-matched controls were included. Matching variables included age and date, phase, and day of menstrual cycle at blood donation. Testosterone, androstenedione, dehydroandrosterone sulfate (DHEAS) and sex hormone-binding globulin (SHBG) were measured using direct immunoassays. Free testosterone was calculated.

Results

Premenopausal serum testosterone and free testosterone concentrations were positively associated with breast cancer risk. In models adjusted for known risk factors of breast cancer, the odds ratios for increasing quintiles of testosterone were 1.0 (reference), 1.5 (95% confidence interval (CI), 0.9 to 2.3), 1.2 (95% CI, 0.7 to 1.9), 1.4 (95% CI, 0.9 to 2.3) and 1.8 (95% CI, 1.1 to 2.9; P _trend = 0.04), and for free testosterone were 1.0 (reference), 1.2 (95% CI, 0.7 to 1.8), 1.5 (95% CI, 0.9 to 2.3), 1.5 (95% CI, 0.9 to 2.3), and 1.8 (95% CI, 1.1 to 2.8, P _trend = 0.01). A marginally significant positive association was observed with androstenedione (P = 0.07), but no association with DHEAS or SHBG. Results were consistent in analyses stratified by tumor type (invasive, in situ), estrogen receptor status, age at blood donation, and menopausal status at diagnosis. Intra-class correlation coefficients for samples collected from 0.8 to 5.3 years apart (median 2 years) in 138 cases and 268 controls were greater than 0.7 for all biomarkers except for androstenedione (0.57 in controls).

Conclusions

Premenopausal concentrations of testosterone and free testosterone are associated with breast cancer risk. Testosterone and free testosterone measurements are also highly reliable (that is, a single measurement is reflective of a woman's average level over time). Results from other prospective studies are consistent with our results. The impact of including testosterone or free testosterone in breast cancer risk prediction models for women between the ages of 40 and 50 years should be assessed. Improving risk prediction models for this age group could help decision making regarding both screening and chemoprevention of breast cancer.     

Endogenous sex hormones and prostate cancer risk: a case-control study nested within the Carotene and Retinol Efficacy Trial.

To examine whether endogenous androgens influence the occurrence of prostate cancer, we conducted a nested case-control study among participants enrolled in the Carotene and Retinol Efficacy Trial. We analyzed serum samples of 300 cases diagnosed between 1987 and 1998, and 300 matched controls. Higher concentrations of testosterone (T) were not associated with increased prostate cancer risk. Relative to men with levels in the lowest fourth of the distribution, men in the upper fourth of total T had a risk of 0.82 [95% confidence interval (CI), 0.52-1.29]. The corresponding relative risks for free T (0.72; 95% CI, 0.45-1.14), percentage of free T (0.74; 95% CI, 0.46-1.19), and total T:sex hormone binding globulin ratio (0.52; 95% CI, 0.32-0.83) similarly were not elevated. Higher concentrations of androstenedione, dehydroepiandrosterone sulfate, and 3 alpha-androstanediol glucuronide were weakly associated with risk. Relative risks associated with being in the highest fourth for androstenedione, dehydroepiandrosterone sulfate, and 3 alpha-androstanediol glucuronide were 1.20 (95% CI, 0.76-1.89), 1.38 (95% CI, 0.86-2.21), and 1.27 (95% CI, 0.80-2.00), respectively. Men in the upper fourth of total estradiol (E2), free E2 and percentage of free E2 had relative risks of 0.71 (95% CI, 0.42-1.13), 0.52 (95% CI, 0.33-0.82), and 0.65 (95% CI, 0.40-1.05), respectively. The inverse association between E2 and prostate cancer risk was largely restricted to men with blood collection within 3 years of diagnosis. Our results add to the evidence that serum testosterone is unrelated to prostate cancer incidence. The suggestions that intraprostatic androgen activity may increase risk and that serum estrogens may decrease risk, warrant additional study.     

Endogenous sex hormones and prostate cancer: a quantitative review of prospective studies.

This paper presents a quantitative review of the data from eight prospective epidemiological studies, comparing mean serum concentrations of sex hormones in men who subsequently developed prostate cancer with those in men who remained cancer free. The hormones reviewed have been postulated to be involved in the aetiology of prostate cancer: androgens and their metabolites testosterone (T), non-SHBG-bound testosterone (non-SHBG-bound T), di-hydrotestosterone (DHT), androstanediol glucuronide (A-diol-g), androstenedione (A-dione), dehydroepiandrosterone sulphate (DHEAS), sex hormone binding globulin (SHBG), the oestrogens, oestrone and oestradiol, luteinizing hormone (LH) and prolactin. The ratio of the mean hormone concentration in prostate cancer cases to that of controls (and its 95% confidence interval (CI)) was calculated for each study, and the results summarized by calculating the weighted average of the log ratios. No differences in the average concentrations of the hormones were found between prostate cancer cases and controls, with the possible exception of A-diol-g which exhibited a 5% higher mean serum concentration among cases relative to controls (ratio 1.05, 95% CI 1.00-1.11), based on 644 cases and 1048 controls. These data suggest that there are no large differences in circulating hormones between men who subsequently go on to develop prostate cancer and those who remain free of the disease. Further research is needed to substantiate the small difference found in A-diol-g concentrations between prostate cancer cases and controls.     

Postmenopausal levels of oestrogen, androgen, and SHBG and breast cancer: long-term results of a prospective study

We assessed the association of sex hormone levels with breast cancer risk in a case-control study nested within the cohort of 7054 New York University (NYU) Women's Health Study participants who were postmenopausal at entry. The study includes 297 cases diagnosed between 6 months and 12.7 years after enrollment and 563 controls. Multivariate odds ratios (ORs) (95% confidence interval (CI)) for breast cancer for the highest quintile of each hormone and sex-hormone binding globulin (SHBG) relative to the lowest were as follows: 2.49 (1.47-4.21), P(trend)=0.003 for oestradiol; 3.24 (1.87-5.58), P(trend)<0.001 for oestrone; 2.37 (1.39-4.04), P(trend)=0.002 for testosterone; 2.07 (1.28-3.33), P(trend)<0.001 for androstenedione; 1.74 (1.05-2.89), P(trend)<0.001 for dehydroepiandrosterone sulphate (DHEAS); and 0.51 (0.31-0.82), P(trend)<0.001 for SHBG. Analyses limited to the 191 cases who had donated blood five to 12.7 years prior to diagnosis showed results in the same direction as overall analyses, although the tests for trend did not reach statistical significance for DHEAS and SHBG. The rates of change per year in hormone and SHBG levels, calculated for 95 cases and their matched controls who had given a second blood donation within 5 years of diagnosis, were of small magnitude and overall not different in cases and controls. The association of androgens with risk did not persist after adjustment for oestrone (1.08, 95% CI=0.92-1.26 for testosterone; 1.15, 95% CI=0.95-1.39 for androstenedione and 1.06, 95% CI=0.90-1.26 for DHEAS), the oestrogen most strongly associated with risk in our study. Our results support the hypothesis that the associations of circulating oestrogens with breast cancer risk are more likely due to an effect of circulating hormones on the development of cancer than to elevations induced by the tumour. They also suggest that the contribution of androgens to risk is largely through their role as substrates for oestrogen production.     

Association of breast cancer risk with a common functional polymorphism (Asp327Asn) in the sex hormone-binding globulin gene.

Sex hormones play a central role in the development of breast cancer. Sex hormone-binding globulin (SHBG) modulates the bioavailability of circulating sex hormones and regulates their signaling system in the breast tissue. We evaluated the association of a common functional polymorphism (Asp327Asn) in the SHBG gene with breast cancer risk in a population-based case-control study (1,106 cases and 1,180 controls) conducted in Shanghai, China. The variant Asn allele was associated with a reduced breast cancer risk in postmenopausal women [odds ratio (OR), 0.73; 95% confidence interval (95% CI), 0.53-0.99], but not in premenopausal women (OR, 1.03; 95% CI, 0.82-1.27). The protective association was much stronger in postmenopausal women with a low body mass index (BMI; OR, 0.46; 95% CI, 0.29-0.75) or waist-to-hip ratio (OR, 0.51; 95% CI, 0.32-0.83) than those with a high BMI or waist-to-hip ratio (P for interaction < 0.05). Furthermore, the association was stronger for estrogen receptor-positive (OR, 0.64; 95% CI, 0.42-0.98) than for estrogen receptor-negative breast cancer (OR, 0.85; 95% CI, 0.50-1.45). Among postmenopausal controls, blood SHBG levels were 10% higher in carriers of the variant Asn allele than noncarriers (P = 0.06). Postmenopausal control women with the Asn allele and low BMI or waist-to-hip ratio had 20% higher SHBG levels (P < 0.05). This study suggests that the Asn allele in the SHBG gene may be related to a reduced risk of breast cancer among postmenopausal women by increasing their blood SHBG levels.     

Circulating steroid hormone concentrations in postmenopausal women in relation to body size and composition

Steroid hormones are associated with the risk of postmenopausal breast cancer and evidence suggests that increased concentrations of oestrogens from peripheral aromatisation in adipose tissue partly explains the association between body mass index (BMI) and risk of postmenopausal breast cancer. This study examined the associations between circulating concentrations of steroid hormones and anthropometric measurements in a sample of naturally postmenopausal women from the Melbourne Collaborative Cohort Study, not using hormone replacement therapy. We measured plasma concentration of total oestradiol, oestrone sulphate, dehydroepiandrosterone sulphate, androstenedione, testosterone and sex hormone binding globulin (SHBG) and calculated concentration of free oestradiol. Body measurements included height, weight, BMI, waist circumference, fat mass and fat-free mass, the last two estimated by bioelectrical impedance analysis. BMI was positively associated with both oestrogens and androgens and negatively with SHBG. Fat mass was the principal measure responsible for the association observed between body size and total oestradiol. The associations between oestrone sulphate and androgens and body size were mainly with waist circumference. The associations between oestrogens and body size were close to null for the first 6 years since menopause and became positive thereafter. Our results are compatible with the hypothesis that after the menopause excess fat mass increases oestrogen concentrations through the peripheral aromatisation of androgens in adipose tissue. This effect requires around 6 years to be detectable by way of circulating steroid hormone levels.     

Serum testosterone and the risk of prostate cancer: potential implications for testosterone therapy.

OBJECTIVE: A potential risk of testosterone replacement therapy is an increase in the incidence of prostate cancer, but it is unclear whether higher levels of serum testosterone are associated with a higher risk of prostate cancer. We prospectively evaluated serum androgen concentrations and prostate cancer risk. METHOD: Included were 794 members of the Baltimore Longitudinal Study of Aging. We estimated the rate ratio (RR) of prostate cancer by entering serial measures of serum total testosterone, dehydroepiandrosterone sulfate, sex hormone binding globulin, calculated free testosterone, and free testosterone index (FTI) into a Cox proportional hazards regression model with simple updating. RESULTS: Higher calculated free testosterone was associated with an increased age-adjusted risk of prostate cancer {RRs by quartile: 1.00, 1.52 [95% confidence interval (95% CI), 0.93-2.50], 1.16 (95% CI, 0.61-2.20), 2.59 (95% CI, 1.28-5.25); P(trend) = 0.03}, which persisted after excluding measures in men <45 years of age [RRs by quartile: 1.00, 1.33 (95% CI, 0.78-2.25), 1.26 (95% CI, 0.68-2.33), 1.89 (95% CI, 0.99-3.61); P(trend) = 0.03]. Compared to men with eugonadal FTI (> or = 0.153), men with hypogonadal FTI had a decreased risk of prostate cancer (RR, 0.51; 95% CI, 0.31-0.82). CONCLUSION: Higher levels of calculated serum free testosterone are associated with an increased risk of prostate cancer. These findings suggest that men receiving testosterone therapy should be regularly monitored for prostate cancer and underscore the need for prospective trials of testosterone therapy incorporating incidence of prostate cancer as a primary safety end point.     

Circulating sex hormone levels and colorectal cancer risk in Japanese postmenopausal women: The JPHC nested case–control study

Previous epidemiological studies evaluated endogenous sex hormone levels and colorectal cancer (CRC) risk have yielded inconsistent results. Also, it is unknown if consumption of dietary isoflavones may influence the endogenous sex hormones and CRC relationships. We conducted a nested case–control study within the JPHC Study Cohort II wherein 11,644 women provided blood samples at the 5-year follow-up survey. We selected two matched controls for each case from the cohort (185 CRC cases and 361 controls). Multivariable conditional logistic regression was used to estimate odds ratios (ORs), 95% confidence intervals (CIs) for the association between circulating sex hormone levels and CRC risk. Comparing extreme tertiles, circulating testosterone levels were positively associated with CRC risk (OR = 2.10, 95% CI = 1.11–3.99, p for trend = 0.03). Levels of estradiol, SHBG, and progesterone were not associated with CRC risk. In a subgroup analysis by dietary isoflavone intake, SHBG levels were positively associated with CRC risk among those with low total isoflavone intake (p for trend = 0.03), with a statistically nonsignificant inverse association among those with high total isoflavone intake (p for trend = 0.22; p for interaction = 0.002). Endogenous levels of testosterone were positively associated with CRC among postmenopausal women. The association of endogenous SHBG with CRC development may be altered by the level of dietary isoflavone intake.     

Plasma prolactin and prostate cancer risk: A prospective study

Prolactin, a pituitary peptide hormone with multiple effects, stimulates prostate growth in experimental models. In humans, prolactin receptors are present in the prostate and are particularly abundant in pre-cancerous lesions. This suggests that prolactin could also be involved in the development of prostate cancer. In this study, we tested the hypothesis that elevated levels of circulating prolactin are associated with an increase in prostate cancer risk. We conducted a case-control study nested within the Northern Sweden Health and Disease Cohort using plasma samples collected from 29,560 men at a health survey. We measured prolactin in plasma from 144 men who had a diagnosis of prostate cancer after a median follow-up time of 4 years after health survey and from 289 controls matched for age and date of recruitment. Risk was not associated with plasma prolactin levels in univariate regression analysis. Odds ratios of prostate cancer for increasing quartiles of prolactin were 1.0, 0.92 (95% CI 0.51-1.65), 0.82 (0.45-1.51) and 0.85 (0.49-1.47). Relative risk estimates remained unchanged after adjustments for height and weight or for plasma levels of testosterone, sex hormone-binding globulin, IGF-I and IGF-binding protein-3. Elevated circulating levels of prolactin were not related to an increase in prostate cancer risk, indicating that high circulating prolactin is not associated with development of prostate cancer.     

Endogenous sex steroids in premenopausal women and risk of breast cancer: the ORDET cohort

Introduction

Previous studies showed that higher testosterone levels are associated with greater risk of breast cancer in premenopausal women, but the literature is scant and inconsistent.

Methods

In a prospective nested case-control study of 104 premenopausal women with incident breast cancer and 225 matched controls, all characterized by regular menstrual cycles throughout their lifetime, we measured the concentration of estradiol, total and free testosterone (FT), progesterone, sex hormone-binding globulin (SHBG), follicle-stimulating hormone (FSH), and luteinizing hormone (LH) in blood samples collected on days 20 through 24 of their cycles.

Results

In logistic regression models, the multivariate odds ratios (ORs) of invasive breast cancer for women in the highest tertile of circulating FT compared with the lowest was 2.43 (95% confidence interval (95% CI), 1.15 to 5.10; P_trend = 0.03), whereas for total testosterone, the association had the same direction but was not statistically significant (OR, 1.27; 95% CI, 0.62 to 2.61; P_trend = 0.51). Endogenous progesterone was not statistically associated with breast cancer (OR, 1.16; 95% CI, 0.60 to 2.27; P_trend = 0.75), nor were the other considered hormones.

Conclusions

Consistent with previous prospective studies in premenopausal women and our own earlier investigation, we observed that higher levels of FT are positively associated with breast cancer risk in women with regular menstrual cycles throughout their lifetimes. No evidence of risk was found associated with the other endogenous sex steroids.     

Testosterone,sex hormone-binding globulin,insulin-like growth factor-1 and endometrial cancer risk: observational and Mendelian randomization analyses

Background Dysregulation of endocrine pathways related to steroid and growth hormones may modify endometrial cancer risk; however, prospective data on testosterone, sex hormone-binding globulin (SHBG) and insulin-like growth factor (IGF)−1 are limited. To elucidate the role of these hormones in endometrial cancer risk we conducted complementary observational and Mendelian randomization (MR) analyses.Methods The observational analyses included 159,702 women (80% postmenopausal) enrolled in the UK Biobank. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using Cox proportional hazards models. For MR analyses, genetic variants associated with hormone levels were identified and their association with endometrial cancer (12,906 cases/108,979 controls) was examined using two-sample MR.Results In the observational analysis, higher circulating concentrations of total (HR per unit inverse normal scale = 1.38, 95% CI = 1.22–1.57) and free testosterone (HR per unit log scale = 2.07, 95% CI = 1.66–2.58) were associated with higher endometrial cancer risk. An inverse association was found for SHBG (HR per unit inverse normal scale = 0.76, 95% CI = 0.67–0.86). Results for testosterone and SHBG were supported by the MR analyses. No association was found between genetically predicted IGF-1 concentration and endometrial cancer risk.Conclusions Our results support probable causal associations between circulating concentrations of testosterone and SHBG with endometrial cancer risk.Subject terms: Cancer epidemiology, Endometrial cancer, Cancer prevention