Plasma testosterone and sex hormone-binding globulin concentrations and the risk of prostate cancer among Japanese men: a nested case-control study

Sex hormones, particularly androgens, have been implicated in prostate carcinogenesis. Overall, however, prospective studies have reported no association between circulating levels of sex hormones and the risk of prostate cancer. However, despite the possible difference in the effects of hormones on prostate cancer risk by stage, age, body mass index (BMI) and isoflavones, evidence for these is sparse. Moreover, few studies have been conducted in Asian populations, who are relatively lean and have high isoflavone consumption. We examined the hypothesis that plasma concentrations of circulating testosterone and sex hormone-binding globulin (SHBG) are associated with the risk of prostate cancer in a case-control study nested in the Japan Public Health Center-based Prospective Study. Concentrations of total testosterone and SHBG were measured in plasma samples from 201 patients with prostate cancer and 402 matched control participants, and concentrations of free testosterone were calculated. No overall association between the plasma levels of any hormone and total prostate cancer was observed. Odds ratios (95% confidence interval [CI]) in the highest versus lowest group were 0.71 (95% CI = 0.36-1.41, Ptrend = 0.43) for total testosterone, 0.70 (95% CI = 0.39-1.27, Ptrend = 0.08) for free testosterone and 1.38 (95% CI = 0.69-2.77, Ptrend = 0.23) for SHBG. When stratified by cancer stage, age, BMI and plasma isoflavone level, free testosterone was inversely associated with localized cancers and equol producers, while SHBG was associated with an increased risk of prostate cancer in younger men. In conclusion, in this nested case-control study, concentrations of circulating total testosterone, free testosterone or SHBG were not strongly associated with a risk for total prostate cancer.     

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.     

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.     

Sex steroid hormones in young manhood and the risk of subsequent prostate cancer: a longitudinal study in African-Americans and Caucasians (United States)

Objective To investigate the relation of sex hormone levels in young adults to subsequent prostate cancer risk. Methods From 1959 to 1967, the Child Health and Development Studies collected sera from 10,442 men (median age: 34 years) and followed them for a median of 32 years. In this analysis, we selected 119 African-Americans and 206 Caucasians diagnosed with prostate cancer during the follow-up period. Two prostate cancer-free men were chosen to match each prostate cancer case on race and birth year. We compared the levels of testosterone, estradiol, and sex hormone-binding globulin in cases to those of their matched controls using conditional logistic regression. Results There was no significant association between absolute levels of sex hormones in youth and prostate cancer risk in either race. However, among Caucasians, but not African-Americans, prostate cancer risk was positively associated with the ratio of total testosterone to total estradiol (odds ratio relating the fourth to the first quartile: 3.01; 95% confidence interval: 1.42–6.39). Conclusions The association between testosterone to estradiol ratio and prostate cancer risk in young Caucasians is consistent with similar findings in older Caucasians. The absence of this association in African-Americans needs confirmation in other data involving larger numbers of African-Americans.     

Serum testosterone and sex hormone-binding globulin concentrations and the risk of prostate carcinoma: a longitudinal study.

BACKGROUND: It has been hypothesized that high androgen levels are determinants of prostate carcinoma. METHODS: Serum concentrations of testosterone, sex hormone-binding globulin (SHBG), and androstenedione were analyzed to determine their role as predictors of prostate carcinoma in a longitudinal, population-based, nested case-control study. The serum concentrations of testosterone, SHBG, and androstenedione were determined from serum samples collected by the Finnish Mobile Clinic Health Examination Survey between 1968-1972 and stored at -20 degrees C. During a follow-up period of 24 years, a total of 166 prostate carcinoma cases occurred among men who originally were cancer free. Two controls (matched for age and municipality) were chosen. RESULTS: There was no association between serum testosterone, SHBG, or androstenedione concentrations and the occurrence of subsequent prostate carcinoma in the total study population or in subgroups determined based on age or body mass index. The association was not strengthened by simultaneous adjustment for the hormonal variables. CONCLUSIONS: The results of the current study do not appear to corroborate the hypothesis that serum testosterone, SHBG, or androstenedione are determinants of the subsequent occurrence of prostate carcinoma.     

Hyperglycemia and insulin resistance in men with prostate carcinoma who receive androgen-deprivation therapy

BACKGROUND: Prostate carcinoma (PCa) is one of the most common malignancies in men. Androgen-deprivation therapy (ADT) is used frequently in the treatment of recurrent and metastatic PCa, rendering these men hypogonadal. Because male hypogonadism is associated with an unfavorable metabolic profile, and men with PCa have high cardiovascular mortality, the authors evaluated the effects of long-term ADT on fasting glucose levels, insulin levels, and insulin resistance. METHODS: To evaluate the long-term effects of ADT on fasting glucose and insulin resistance in men with PCa who received ADT and to determine whether these metabolic alterations are a result of hypogonadism, the authors conducted a cross-sectional study at a university-based research institution in the United States. In total, 53 men were evaluated, including 18 men with PCa who received ADT for at least 12 months prior to the onset of the study (the ADT group), 17 age-matched men with nonmetastatic PCa who had undergone prostatectomy and/or received radiotherapy and who were not receiving ADT (the non-ADT group), and 18 age-matched controls (the control group). None of the men had a known history of diabetes mellitus. RESULTS: The mean age was similar in all 3 groups (P=0.33). Serum total testosterone levels (P<0.0001) and free testosterone levels (P<0.0001) were significantly lower in the ADT group compared with the other groups. Men in the ADT group had a higher BMI compared with the other groups (overall P=0.005). After adjustment for age and BMI, men in the ADT group had significantly higher fasting levels of the following parameters: 1) Glucose levels were 131.0+/-7.43 mg/dL in the ADT group compared with 103.0+/-7.42 mg/dL in the non-ADT group (P=0.01) and 99.0+/-7.58 mg/dL in the control group (P<0.01). 2) Insulin levels were 45.0+/-7.25 uU/mL in the ADT group compared with 24.0+/-7.24 uU/mL in the non-ADT group (P=0.05) and 19.0+/-7.39 uU/mL in the control group (P=0.02). 3) Leptin levels were 25.0+/-2.57 ng/mL in the ADT group compared with 12.0+/-2.56 ng/mL in the non-ADT group (P<0.01) and 6.0+/-2.62 ng/mL in the control group (P<0.01). 4) The homeostatic model assessment for insulin resistance (HOMAIR)=17.0+/-2.78 in the ADT group compared with HOMAIR=6.0+/-2.77 in the non-ADT group (P<0.01) and HOMAIR=5.0+/-2.83 in the control group (P=0.01). There was a significant negative correlation between total and free testosterone levels with fasting glucose, insulin, leptin, and HOMAIR. CONCLUSIONS: The current data suggested that men with PCa who are receiving long-term ADT are at risk for developing insulin resistance and hyperglycemia, thus leading to their increased risk of cardiovascular disease. This adverse metabolic profile developed independent of age and BMI and appeared to be a direct result of androgen deprivation.     

The association between polymorphisms in the CYP17 and 5alpha-reductase (SRD5A2) genes and serum androgen concentrations in men.

Prospective studies suggest that prostate cancer risk may be increased in association with high serum concentrations of free testosterone and androstanediol glucuronide (A-diol-g). Polymorphisms have been identified in the 17-hydroxylase cytochrome P450 gene (CYP17) and the steroid 5alpha-reductase type II gene (SRD5A2), two genes that are involved in the biosynthesis and metabolism of androgens in men. The CYP17 MspA1 I polymorphism has been associated with increased prostate cancer risk, and the SRD5A2 V89L polymorphism has been associated with low A-diol-g in Asian men, a serum marker of 5alpha-reductase activity. The purpose of this study was to investigate the association between these two polymorphisms and serum sex hormone concentrations in 621 British men. In particular, we wanted to test the hypotheses that the A2 allele in the CYP17 gene is associated with increased serum testosterone concentrations, and the L allele in the SRD5A2 gene is associated with reduced A-diol-g concentrations. Mean hormone concentrations were evaluated in each genotype and adjusted for age and other relevant factors. We found no evidence that the CYP17 MspA1 I polymorphism was associated with higher testosterone levels. The L/L genotype of the SRD5A2 V89L polymorphism was associated with a 10% lower A-diol-g concentration, but this was not significant at the 5% level. However, the L/L genotype of the V89L polymorphism was associated with significantly lower concentrations of testosterone and free testosterone (by 12% and 16%, respectively) and an 8% higher sex hormone-binding globulin concentration. These results suggest that the CYP17 MspA1 I polymorphism is not associated with testosterone concentrations and that the SRD5A2 V89L polymorphism is not a strong determinant of A-diol-g concentration in Caucasian men.     

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.     

Resveratrol suppresses prostate cancer progression in transgenic mice

Resveratrol, a natural polyphenolic phytochemical, has been reported to act as an antioxidant and provide anticancer activities. We hypothesized that resveratrol would exert a chemopreventive effect against prostate cancer via regulation of sex steroid receptor and growth factor signaling pathways. In the current study, Transgenic Adenocarcinoma Mouse Prostate males were fed resveratrol (625 mg resveratrol per kg AIN-76A diet) or phytoestrogen-free, control diet (AIN-76A) starting at 5 weeks of age. Mechanisms of action and histopathology studies were conducted at 12 and 28 weeks of age, respectively. Resveratrol in the diet significantly reduced the incidence of poorly differentiated prostatic adenocarcinoma by 7.7-fold. In the dorsolateral prostate, resveratrol significantly inhibited cell proliferation, increased androgen receptor, estrogen receptor-beta, and insulin-like growth factor-1 receptor, and significantly decreased insulin-like growth factor (IGF)-1 and phospho-extracellular regulating kinase 1 (phospho-ERK 1). In the ventral prostate, resveratrol significantly reduced cell proliferation and phospho-ERKs 1 and 2, but did not significantly alter insulin-like growth factor-1 receptor and IGF-1. Serum total testosterone, free testosterone, estradiol, dihydrotestosterone and sex hormone-binding globulin (SHBG) concentrations and Simian Virus-40 large T antigen expression in the prostate were not altered in resveratrol-treated mice. Total resveratrol concentration in the blood serum of 12-week-old mice treated for 3 weeks with 625 mg resveratrol per kg diet was 52 +/- 18 nM. The decrease in cell proliferation and the potent growth factor, IGF-1, the down-regulation of downstream effectors, phospho-ERKs 1 and 2 and the increase in the putative tumor suppressor, estrogen receptor-beta, provide a biochemical basis for resveratrol suppressing prostate cancer development.     

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.     

Dietary intervention in prostate cancer patients: PSA response in a randomized double-blind placebo-controlled study

The objective of this study was to show or to exclude an effect of dietary supplement on rising prostate-specific antigen (PSA) levels. We have studied the effect of a dietary supplement (verum, administered for 6 weeks) containing plant estrogens, antioxidants, including carotenoids, selenium and other putative prostate cancer inhibiting substances in a randomized placebo-controlled double-blind crossover study in 37 hormonally untreated men with prostate cancer and increasing PSA levels. Outcome measures were changes in the rates of change of serum concentrations of total and free PSA and changes in male sex hormone levels. Male sex hormone levels were significantly lower during the verum phase (DHT: -0.11 nmol/L, p = 0.005; testosterone: -1 nmol/L, p = 0.02). Total PSA doubling time was unaffected. Free PSA, which increased during the placebo phase (average doubling time of 68 weeks), decreased during the verum period (average half-life of 13 weeks; p = 0.02). In those men in whom the free androgen index decreased (21 out of 32), a significant decrease in the slopes of both total and free PSA was observed (p = 0.04). Overall total PSA doubling times did not increase significantly during verum. However, the study demonstrates that this dietary intervention reduces DHT and testosterone levels and increases free PSA doubling time (and total PSA doubling time in a relevant subgroup). If future studies confirm that these observations translate into a slowing of disease progression, a dietary intervention may become an attractive option for prostate cancer treatment and prevention.     

Hormonal predictors of prostate cancer: a meta-analysis.

PURPOSE: Although there is strong circumstantial evidence that androgens are implicated in the etiology of prostate cancer, epidemiologic investigations have failed to demonstrate consistently that one or more steroid hormones are implicated. In contrast, recent epidemiologic studies unequivocally link serum insulin-like growth factor 1 (IGF-1) levels with risk for prostate cancer. METHODS: We have performed the first meta-analysis of all previously published studies on hormonal predictors of risk for prostate cancer. RESULTS: A meta-analysis restricted to studies that performed mutual adjustment for all measured serum hormones, age, and body mass index indicated that men whose total testosterone is in the highest quartile are 2.34 times more likely to develop prostate cancer (95% confidence interval, 1.30 to 4.20). In contrast, levels of dihydrotestosterone and estradiol do not seem to play a role of equal importance. The only study that provides multivariably adjusted sex hormone-binding globulin data indicates that this binding protein is inversely related to prostate cancer risk (odds ratio, 0.46; 95% confidence interval, 0.24 to 0.89). Finally, all three studies that examined the role of serum IGF-1 have consistently demonstrated a positive and significant association with prostate cancer risk that is similar in magnitude to that of testosterone. CONCLUSION: Men with either serum testosterone or IGF-1 levels in upper quartile of the population distribution have an approximately two-fold higher risk for developing prostate cancer.     

Birthweight and body size throughout life in relation to sex hormones and prolactin concentrations in premenopausal women.

The association of birthweight and body size throughout life with premenopausal breast cancer risk may be due, in part, to relationships with sex hormones. Therefore, we assessed whether birthweight, body shape at ages 5 and 10, body mass index (BMI) at age 18 and adulthood, adult waist circumference and waist-to-hip ratio (WHR), and attained height were associated with the plasma concentrations of estrogens, androgens, progesterone, prolactin, and sex hormone-binding globulin (SHBG) in 592 premenopausal women, ages 33 to 52 years old, from the Nurses' Health Study II. About 85% of women provided blood samples during follicular and luteal menstrual phases; other women had a single untimed sample. We observed few associations between sex hormone levels and birthweight or body shape in childhood. However, adult BMI was inversely associated with SHBG (P trend < 0.001) and positively associated with free testosterone (P trend < 0.001) concentrations. Adult BMI was not associated with follicular or luteal free estradiol levels (P trend >or= 0.15) because it was inversely associated with total estradiol levels (P trend < 0.001 for follicular and luteal estradiol levels). Testosterone, androstenedione, and progesterone were inversely associated with BMI. Comparing women with a BMI of >or=30 versus <20 kg/m2, levels were higher by 53% for free testosterone and lower by 51% for SHBG, 39% for follicular estradiol, 20% for luteal estradiol, 14% for androstenedione, 13% for testosterone, and 20% for progesterone. We observed no clear associations between BMI at age 18, waist circumference, WHR, or height, and sex hormone concentrations. Our results suggest that effects on premenopausal sex hormone levels may be one mechanism through which adult adiposity, but not birthweight or childhood body size, affects premenopausal breast cancer risk.     

Adiposity and sex hormones in postmenopausal breast cancer survivors.

PURPOSE: Overweight and obese women with breast cancer have poorer survival compared with thinner women. One possible reason is that breast cancer survivors with higher degrees of adiposity have higher concentrations of tumor-promoting hormones. This study examined the association between adiposity and concentrations of estrogens, androgens, and sex hormone-binding globulin (SHBG) in a population-based sample of postmenopausal women with breast cancer. METHODS: We studied the associations between body mass index (BMI), body fat mass, and percent body fat, measured by dual-energy x-ray absorptiometry scan, waist circumference, and waist-to-hip circumference ratio, with concentrations of estrone, estradiol, testosterone, SHBG, dehydroepiandrosterone sulfate, free estradiol, and free testosterone in 505 postmenopausal women in western Washington and New Mexico with incident stage 0 to IIIA breast cancer. Blood and adiposity measurements were performed between 4 and 12 months after diagnosis. RESULTS: Obese women (BMI > or = 30) had 35% higher concentrations of estrone and 130% higher concentrations of estradiol compared with lighter-weight women (BMI < 22.0; P =.005 and.002, respectively). Similar associations were observed for body fat mass, percent body fat, and waist circumference. Testosterone concentrations also increased with increasing levels of adiposity (P =.0001). Concentrations of free estradiol and free testosterone were two to three times greater in overweight and obese women compared with lighter-weight women (P =.0001). CONCLUSION: These data provide information about potential hormonal explanations for the association between adiposity and breast cancer prognosis. These sex hormones may be useful biomarkers for weight loss intervention studies in women with breast cancer.     

Inhibition of testosterone production with ketoconazole alone and in combination with a gonadotropin releasing hormone analogue in the rat

Ketoconazole is a well-tolerated, synthetic, imidazole derivative currently in widespread therapeutic use against mycotic infections. Recent evidence that it depresses testosterone synthesis in humans prompted us to investigate the effects in rats of its administration alone or in combination with the gonadotropin releasing hormone superagonist analogue leuprolide. Plasma luteinizing hormone, testosterone, and ketoconazole levels as well as ventral prostate weight and tumor growth in rats bearing the androgen-dependent Dunning R3327H model of prostate adenocarcinoma were measured. Doses of 30 mg/kg twice daily of ketoconazole alone depressed plasma testosterone levels by approximately 75% to a nadir of 0.47 +/- 0.08 (SE) ng/ml on day 20 (P less than 0.001 versus basal). This effect of ketoconazole was exerted directly at the testicular level since plasma luteinizing hormone levels were not suppressed. In response, ventral prostate weight declined and growth of the Dunning R3327H tumor was retarded to rates observed in castrate controls. Leuprolide alone lowered basal testosterone levels to 0.20 +/- 0.02 ng/ml after 35 days of daily administration but persistent androgen increments after each injection (acute-on-chronic effect) were observed (i.e., to 4.41 +/- 0.62 ng/ml). The addition of ketoconazole to leuprolide inhibited the acute-on-chronic rise in testosterone to 0.33 +/- .07 ng/ml and also lowered basal testosterone levels further to 0.11 +/- 0.01 on day 10 of combined administration. Ketoconazole also blunted the response to the first injection of leuprolide from a 3-h peak level of 8.74 +/- 0.53 to 4.17 +/- 0.80 with the 40 mg/kg dose. These results indicate that combining ketoconazole with leuprolide achieves greater suppression of testosterone than either agent alone. When such protocols are applied to humans with prostate cancer, more extensive effects may be expected because of the greater sensitivity of patients than of the rodent species to these agents.     

Peripheral hormone levels in controls and patients with prostatic cancer or benign prostatic hyperplasia: results from the Dutch-Japanese case-control study.

The possible relationship between changes in peripheral hormone levels and the occurrence of prostatic pathology was studied in a case-control study, involving estimation of various plasma hormones in 368 Dutch and 258 Japanese men, who were grouped as controls and patients with benign prostatic hyperplasia, focal prostatic carcinoma, or clinically evident prostatic carcinoma. Results of a number of previous, smaller studies concerning interrelationships between hormone levels in elderly men were confirmed within the Dutch and Japanese groups. Plasma levels of testosterone and estradiol were significantly lower in the Japanese men, when compared with those in Dutch men. Probably as a result of this difference in testosterone levels, the ratio between serum levels of testosterone and sex hormone-binding globulin (SHBG) was decreased in the Japanese men, while the ratio between the concentrations of dihydrotestosterone and testosterone was increased. These differences were also found when results from Japanese subgroups (controls and patients with prostate pathology) were compared with those from the Dutch subgroups. There were no significant differences in plasma androgen levels between Japanese or Dutch prostate cancer cases and their respective control subgroups. These findings do not support a correlation between the lower plasma testosterone levels and a lower incidence of prostate cancer in the Japanese men. Furthermore, no significant differences were found between salivary levels of testosterone or the ratio between testosterone and SHBG in the various Dutch subgroups. In Japanese benign prostatic hyperplasia patients, the testosterone to SHBG ratio was significantly increased. In conclusion, the results of this retrospective, cross-sectional study do not indicate that hormonal levels play a primary role in the origin or promotion of prostatic abnormalities. The finding of a lower plasma testosterone in the Japanese men, however, remains suggestive, warranting a more extensive prospective study.     

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.     

A prospective, population-based study of androstenedione, estrogens, and prostatic cancer

Endogenous androgens have been suggested as determinants of risk of prostatic cancer. To examine this possibility, baseline sex hormone levels were measured in 1008 men ages 40-79 years who had been followed for 14 years. There were 31 incident cases of prostatic cancer and 26 identified from death certificates with unknown dates of diagnosis. In this study, total testosterone, estrone, estradiol, and sex hormone-binding globulin were not related to prostate cancer, but plasma androstenedione showed a positive dose-response gradient. Age-adjusted relative risks of prostatic cancer for low (0-2.2 nM), middle (2.3-3.1 nM), and high (3.2+ nM) tertiles of androstenedione were 1.00, 1.34, and 1.98, respectively (P trend less than 0.05). The linear gradient of risk persisted after adjustment for age and body mass index. If confirmed, these data suggest that androstenedione might increase the occurrence of clinically manifest prostatic cancer.     

Physical activity in relation to circulating hormone concentrations in 117,100 men in UK Biobank

Purpose

Physical activity may reduce the risk of some types of cancer in men. Biological mechanisms may involve changes in hormone concentrations; however, this relationship is not well established. Therefore, we aimed to investigate the associations of physical activity with circulating insulin-like growth factor-I (IGF-I), sex hormone-binding globulin (SHBG, which modifies sex hormone activity), and total and free testosterone concentrations, and the extent these associations might be mediated by body mass index (BMI).

Methods

Circulating concentrations of these hormones and anthropometric measurements and self-reported physical activity data were available for 117,100 healthy male UK Biobank participants at recruitment. Objectively measured accelerometer physical activity levels were also collected on average 5.7 years after recruitment in 28,000 men. Geometric means of hormone concentrations were estimated using multivariable-adjusted analysis of variance, with and without adjustment for BMI.

Results

The associations between physical activity and hormones were modest and similar for objectively measured (accelerometer) and self-reported physical activity. Compared to men with the lowest objectively measured physical activity, men with high physical activity levels had 14% and 8% higher concentrations of SHBG and total testosterone, respectively, and these differences were attenuated to 6% and 3% following adjustment for BMI.

Conclusion

Our results suggest that the associations of physical activity with the hormones investigated are, at most, modest; and following adjustment for BMI, the small associations with SHBG and total testosterone were largely attenuated. Therefore, it is unlikely that changes in these circulating hormones explain the associations of physical activity with risk of cancer either independently or via BMI.