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Effects of long-term ?-tocopherol supplementation on serum hormones in older men
Abstract
alpha-tocopherol supplementation significantly reduced risk of prostate cancer in the Alpha-Tocopherol Beta-Carotene Cancer Prevention (ATBC) Study. Sex hormones are thought to be involved in the etiology of prostate cancer. We examined whether long-term supplementation with alpha-tocopherol modified serum hormone levels.
Men who were cancer-free consumed > or = 90% of the study capsules, and who had both baseline and follow-up blood available, were eligible for the study. One hundred men who received alpha-tocopherol were matched on age, study center, and length of time between blood draws to 100 men who received a placebo. Multivariate linear regression models which allowed for a separate intercept for each matched pair were used to evaluate the effect of alpha-tocopherol supplementation on follow-up hormone concentrations.
Compared to men who received a placebo, we found significantly lower serum androstenedione (P = 0.04) and testosterone (P = 0.04) concentrations among men who received alpha-tocopherol, after controlling for baseline hormone level, follow-up serum cholesterol concentration, body mass index, smoking, and fasting time. Geometric mean (95% confidence interval; CI) androstenedione concentration among men who received alpha-tocopherol was 145 ng/dl (CI, 137-153) after adjusting for covariates, compared to 158 ng/dl (CI, 148-167) among men who received a placebo. Mean testosterone concentrations for men who received alpha-tocopherol and placebo were 539 (CI, 517-562) and 573 (CI, 549-598) ng/dl, respectively.
These results suggest that long-term alpha-tocopherol supplementation decreases serum androgen concentrations, and could have been one of the factors contributing to the observed reduction in incidence and mortality of prostate cancer in the alpha-tocopherol treatment group of the ATBC Study.
... The mechanisms for the role of micronutrients in synthesis of sex hormones and IGF-1 include the involvement in steroidogenesis, via the involvement of prostaglandins, on the precursors of sex hormones, for vitamins D, E, the carotenoids, zinc and selenium, as well the effects of vitamin C [38][39][40][41][42][43][44][45][46][47][48][49][50]52,60,64,65,68,69,71,[79][80][81][82][83][84][85][86], and effects on transporter proteins. Zinc is also an inhibitor of two enzymes, aromatase and 5α-reductase, that are involved in testosterone metabolism [60]. ...
... The primary outcomes were changes or differences in sex hormone concentrations, including: androgens (androstenediol, androstenedione, dihydrotestosterone and testosterone), oestrogens (E2, estradiol, estriol, and estrone), DHEAS, SHBG, and IGF-1 (see Supplementary Table S1, A). Relevant micronutrients were those with known or potential relevance to sex hormone or IGF-1 metabolism and physiology, as well as sarcopenia, and included any one, or combination, of vitamin A [48,69]; vitamin C [76]; vitamin D [38][39][40][41][42][43][44][45][46][47]; vitamin E [48,50]; carotenoids [69]; or the minerals zinc [64,65], magnesium [54], selenium, potassium [76,77], iron/ferritin [78] and copper [79]. Where studies included groups of individuals with varying age ranges, they were included if the mean age was greater than 45 years, or more than 75% of individuals were older than 45 years (in both treatment arms). ...
... Despite the biochemical, physiological and mechanistic roles of micronutrients for hormone synthesis in older age our review found a paucity of trials and little direct evidence of significant effects of micronutrient supplementation [38][39][40][41][42][43][44][45][46][47][48][49][50]52,60,64,65,68,69,71,[79][80][81][82][83][84][85][86]. Since the age-related decline in sex-hormones and IGF-1 not only increases the risk of sarcopenia, but also a number of conditions of aging, including falls, osteoporosis, fractures, cardiovascular disease and all-cause mortality, this is unfortunate [5][6][7][8][9][10][11][12][13][14][15][16]. ...
Observational research suggests that micronutrients may be protective for sarcopenia, a key health issue during ageing, potentially via effects on hormone synthesis and metabolism. We aimed to carry out a systematic review of RCTs investigating effects of increasing dietary or supplemental micronutrient intake on sex hormones and IGF-1 in individuals aged 45 years or older. We searched MEDLINE, EMBASE and Cochrane databases for RCTs reporting the effects of different micronutrients (vitamins A, C, D, or E; carotenoids; iron; copper; zinc; magnesium; selenium; and potassium) on sex hormones or IGF-1. Of the 26 RCTs identified, nine examined effects of vitamin D, nine of multi-nutrients, four of carotenoids, two of selenium, one of zinc, and one of vitamin E. For IGF-1 increasing vitamin D (MD: −0.53 nmol/L, 95% CI: −1.58, 0.52), multi-nutrients (MD: 0.60 nmol/L, 95% CI −1.12 to 2.33) and carotenoids (MD −1.32 nmol/L; 95% CI −2.76 to 0.11) had no significant effect on circulating concentrations. No significant effects on sex hormones of other micronutrients were found, but data were very limited. All trials had significant methodological limitations making effects of micronutrient supplementation on sex hormones unclear. Further high quality RCTs with physiological doses of micronutrients in people with low baseline intakes or circulating concentrations, using robust methodology, are required to assess effects of supplementation adequately.
... • Selenium has consistently been reported to reduce risk of prostate cancer [107][108][109][110]. ...
... • Results suggest that long-term vitamin E (alpha-tocopherol) supplementation decreases serum androgen concentrations, which is related to a reduced incidence of and mortality from prostate cancer [110]. ...
... ❍ Many of the studies on vitamin E and prostate cancer have used synthetic forms of vitamin E (dl-alpha-tocopherol) [110,121,131,134]. A recent study, however, reported that the natural form of vitamin E was more effective in the suppression of prostate cancer, and at a lower concentration [131]. ...
Nutrition is apparently a major risk factor for the development and progression of prostate cancer. Based on experimental studies and epidemiologic data mainly from case-control studies or cohort studies, there is strong evidence that reduction of the total energy consumption, a diet comprising less than 30% fat, and increased intake of phytoestrogens, vitamins D and E and selenium could yield a decreased prostate cancer incidence. Furthermore, some of these measures appear to have antitumoral capacity even in the presence of the disease. These observations have provided a rationale to forward large prospective trials on dietary interventions to prove the efficacy of the concept and further delineate the correlation between nutritional compounds and prostate cancer risk. These chemoprevention trials are either aiming a reduction prostate cancer incidence or a decrease in tumor progression. Depending on the study design, large numbers of individuals need to be enrolled and long follow-up intervals are required thus making such trials highly complex and cost-intensive. However, regarding the potential relevance of chemoprevention on public health, further efforts to identify nutritional factors affecting prostate cancer growth are warranted.
... Weinstein et al., 2005 a‐Vitamin E supplementation is associated with low level of serum hormone (androgen) in old men and a reduced risk of PCa. Hartman et al., 2001 Postrial, ...
... from Switzerland on 17‐year follow‐up of the prospective basal study showed that the levels of a‐vitamin E, but not vitamin C, retinol, or carotene, were significantly low in prostate cancer patients (Eichholzer et al., 1999). Furthermore , during the follow‐up in the ATBC study, they also found that long‐term a‐vitamin E supplementation decreases serum androgen (testosterone) concentrations from 573 to 539 ng/dl, suggesting that it could be one of the factors associated to the low incidence and mortality of prostate cancer in ATBC studies (Hartman et al., 2001). However, whether the slightly lower concentration of androgen is a contributory factor to lower the incidence and mortality remains to be elucidated. ...
... The Roles of a‐Vitamin E and Its Analogues in Prostate Cancer from Switzerland on 17‐year follow‐up of the prospective basal study showed that the levels of a‐vitamin E, but not vitamin C, retinol, or carotene, were significantly low in prostate cancer patients (Eichholzer et al., 1999 ). Furthermore , during the follow‐up in the ATBC study, they also found that long‐term a‐vitamin E supplementation decreases serum androgen (testosterone) concentrations from 573 to 539 ng/dl, suggesting that it could be one of the factors associated to the low incidence and mortality of prostate cancer in ATBC studies (Hartman et al., 2001). However, whether the slightly lower concentration of androgen is a contributory factor to lower the incidence and mortality remains to be elucidated. ...
Prostate cancer is the second most commonly diagnosed cancer and the third leading fatal cancer in American men. Comprehensive studies from human epidemiological studies, animal tumor models, and cellular molecular levels suggested that alpha-vitamin E and its derivatives possess remarkable chemopreventive and chemotherapeutic against prostate cancer. This chapter details the facts of alpha-vitamin E and its nonantioxidant functions in prostate cancer, focuses on the biological mechanisms for the alpha-vitamin E and its ester analogue, alpha-vitamin E succinate (VES), in prevention and therapy of prostate cancer, and raises specific questions that remain for intensive investigation in the future.
... Inversely, low vitamin E status has been shown to result in a higher risk of developing this form of tumor (9 -14). Furthermore, long-term a-tocopherol supplementation in man, has been shown to decrease serum levels of testosterone (21), although the biological mechanism behind this inhibitory effect is presently unknown. ...
... As in the case of 7-DCH, our findings of a long-term upregulation of GATA-4 caused by low vitamin E intake, may in part explain the mechanism of action of vitamin E on testosterone synthesis (21). ...
Gene-chip technology was employed to study the effect of dietary vitamin E (VE) on gene expression in rat testes. Male albino rats were fed with either a diet deficient in VE or a standard diet containing VE. Differential gene expression was monitored at five individual time-points over a period of 14 months with all animals individually profiled. Low VE intake resulted in the consistent up-regulation of 7-dehydrocholesterol reductase and GATA binding protein 4, both involved in testosterone synthesis. Cyclin D3, important in cell cycle progression and Wilms tumor 1, related to cancer development, were also up-regulated in the vitamin E deficient animals. This study demonstrates that low dietary VE intake has long-term effects on gene expression in the testes. Our data provides insights into the possible molecular mechanisms underlying the beneficial effects of vitamin E on the male reproductive organ.
... The latter hypothesis is supported by the ATBC Study, which indicated that men who received α-tocopherol had significantly lower serum levels of androstenedione and testosterone than did those who received a placebo. 2 The mechanism behind this inhibitory effect of VE on androgen production remains largely unknown. The objective of this study was the investigation of the molecular mechanisms of action of VE on the pituitary-gonadal axis in male rat. ...
... Adrenals are the primary source of dehydroepiandrosterone (DHEA), which is also synthesized from cholesterol as its precursor. Taken together, these data give new insights into the possible molecular mechanisms underlying the observed decrease in plasma DHEA and testosterone in men supplemented with vitamin E. 2 ...
The Alpha-Tocopherol Beta-Carotene Cancer Prevention Study has provided the first evidence implicating vitamin E in hormone synthesis. The effect of vitamin E on stereoidogenesis in testes and adrenal glands was assessed in growing rats using Affymetrix gene-chip technology. Dietary supplementation of rats with vitamin E (60 mg/kg feed) for a period of 429 days caused a significant repression of genes encoding for proteins centrally involved in the uptake (low-density lipoprotein receptor) and de novo synthesis (for example, 7-dehydrocholesterol reductase, 3-hydroxy-3-methylglutaryl coenzyme A synthase, 3-hydroxy-3-methylglutaryl-coenzyme A reductase, isopentenyl-diphosphate delta-isomerase, and farnesyl pyrophosphate synthetase) of cholesterol, the precursor of all steroid hormones. The present investigation indicates that dietary vitamin E may induce changes in stereoidogenesis by affecting cholesterol homeostasis.
... AA, ATE, and CLP attenuated the levels of testosterone in the LTZ model. An inverse relationship is said to exist between ATE and testosterone [62], which was observed in this study and is due to the reduction of prostaglandins by ATE and subsequently increased testosterone [63]. ...
Polycystic ovary syndrome (PCOS) affects up to 10% of women within reproductive ages and has been a cause of infertility and poor quality of life. Alteration in the oxidant-antioxidant profile occurs in PCOS. This study, therefore, investigates the contribution of ascorbic acid (AA) and alpha-tocopherol(ATE) on different PCOS parameters. The mifepristone and letrozole models were used, and young mature female mice were randomly assigned to groups of six per group. On PCOS induction with either mifepristone or letrozole, mice were administered AA and ATE at doses ranging from 10–1000mg/kg to 0.1–1000 mg/kg in the respective models. Vaginal cytology, body weights, and temperature, as well as blood glucose, testosterone, and insulin levels, were measured. Total antioxidant capacity and malondialdehyde levels were analyzed. Determination of gene expression of some reactive oxygen species and histomorphological analysis on the ovaries and uteri were performed. At the end of the experiments, AA and ATE restored reproductive cycling, with AA being more effective. AA and ATE increased fasting blood glucose but had no significant effect on serum insulin levels. AA decreased testosterone levels, but ATE caused slight increases. AA and ATE both increased total antioxidant capacity and decreased malondialdehyde levels. AA and ATE also slightly upregulated the mRNA expressions of catalase, superoxide dismutase, and heme oxygenase 1 mainly. AA and ATE also decreased ovarian weight and mostly resolved cysts in the ovaries and congestion in the uterus. This study has shown that AA and ATE are beneficial in the therapy of PCOS.
... It was previously observed that α-tocopherol applied in men caused a decrease in serum androstenedione and testosterone levels [Hartman et al., 2001]. Similarly, Hartman et al. [1999] affirmed that androstenedione, testosterone and sex hormone-binding globulin were significantly inversely associated with serum α-tocopherol. ...
The aim of the study was to determine whether consumption of diets containing different fat (rapeseed oil or lard-rich), supplemented with a high level of cholesterol (3% w/w) and/or vitamin E (500 mg/kg of diet) for 6 weeks influenced 17beta-hydroxysteroid dehydrogenase (17 beta-HSD) type 3 activity (measured in vitro), testosterone (Tt) content in testes and plasma testosterone (Tp) concentration (measured by ELISA and RIA, respectively) in male rats. 17 beta-HSD activity was shown to depend on dietary fat type. Supplementation of vitamin E influenced Tt value, whereas none of the investigated dietary factors had effects on Tp. Significant differences between the investigated factors were observed only for groups fed rapeseed oil-rich diets with marked increases of Tt and Tp in rats fed vitamin E-rich diet.
... Previous investigations have proposed biological mechanisms that may explain our findings of increased E 2 and testosterone concentrations associated with a-tocopherol, retinol, and lutein. Some researchers hypothesize that vitamin E affects steroidogenesis by altering prostaglandin concentrations (44,45) or through effects on cholesterol homeostasis (46,47). E 2 can influence the expression of retinol-binding protein and hepatic uptake of retinol-binding protein, which may also influence serum concentrations (48,49). ...
Background:
Evidence is growing that the equilibrium between reactive oxygen species and antioxidants plays a vital role in women's reproductive health.
Objective:
The objective of this study was to evaluate variations in serum antioxidant concentrations across the menstrual cycle and associations between antioxidants and reproductive hormones and anovulation among healthy women.
Methods:
The BioCycle Study, a prospective cohort, followed 259 women aged 18-44 y for up to 2 menstrual cycles. Serum fat-soluble vitamin and micronutrient (α-tocopherol, γ-tocopherol, retinol, lutein, lycopene, and β-carotene), ascorbic acid, and reproductive hormone concentrations were measured 5-8 times/cycle. We used weighted linear mixed models to assess associations between antioxidants and hormone concentrations, after adjustment for age, race, body mass index, parity, sleep, pain medication use, total energy intake, concurrent hormones, serum cholesterol, F2-isoprostanes, and other antioxidants. Generalized linear models were used to identify associations with anovulation.
Results:
Serum antioxidant concentrations varied across the menstrual cycle. Retinol and α-tocopherol were associated with higher estradiol [RR: 1.00 pg/mL (95% CI: 0.67, 1.34 pg/mL); RR: 0.02 pg/mL (95% CI: 0.003, 0.03 pg/mL), respectively] and testosterone [RR: 0.61 ng/dL (95% CI: 0.44, 0.78 ng/dL); RR: 0.01 ng/dL (95% CI: 0.001, 0.01 ng/dL), respectively]. Ascorbic acid was associated with higher progesterone (RR: 0.15 ng/mL; 95% CI: 0.05, 0.25 ng/mL) and with lower follicle-stimulating hormone (RR: -0.06 mIU/mL; 95% CI: -0.09, -0.03 mIU/mL). The ratio of α- to γ-tocopherol was associated with an increased risk of anovulation (RR: 1.03; 95% CI: 1.01, 1.06).
Conclusions:
These findings shed new light on the intricate associations between serum antioxidants and endogenous hormones in healthy premenopausal women and support the hypothesis that concentrations of serum vitamins affect steroidogenesis even after adjustment for oxidative stress.
... Several mechanisms of action have been postulated such as protection of DNA damage by free radicals, induction of apoptosis, modulation of immune function and interference with hormone production [51]. The latter hypothesis was supported by the findings of the ATBC intervention study where men who received a-tocopherol had significantly lower serum androstenedione and testosterone levels than did those who received a placebo [52]. These findings have been proposed as an explanation for the reduction in prostate cancer observed in this study. ...
The recent discovery that vitamin E (VE) regulates gene activity at the transcriptional level indicates that VE may exert part of its biological effects by mechanisms which may be independent of its well-recognised antioxidant function. The objective of this study was the identification of hepatic vitamin E-sensitive genes and examination of the effects of VE on their corresponding biological endpoints. Two groups of male rats were randomly assigned to either a VE-sufficient diet or to a control diet deficient in VE for 290 days. High-density oligonucleotide microarrays comprising over 7000 genes were used to assess the transcriptional response of the liver. Differential gene expression was monitored over a period of 9 months, at four different time-points, and rats were individually profiled. This experimental strategy identified several VE-sensitive genes, which were chronically altered by dietary VE. VE supplementation down-regulated scavenger receptor CD36, coagulation factor IX and 5-α-steroid reductase type 1 mRNA levels while hepatic gamma glutamyl-cysteinyl synthetase was significantly up-regulated. Measurement of the corresponding biological endpoints such as activated partial thromboplastin time, plasma dihydrotestosterone and hepatic glutathione substantiated the gene chip data which indicated that dietary VE plays an important role in a range of metabolic processes within the liver.
... Higher plasma concentrations of a-tocopherol result from supplementation and increased dietary intake, higher cholesterol and triglyceride levels, and some genetic variants related to vitamin E transport and metabolism (22,24,25). Experimental and other human data show a wide range of effects relevant to prostate tumorigenesis for vitamin E compounds, including inhibition of membraneassociated lipid peroxidation, inflammation, angiogenesis, and cell proliferation, enhanced apoptosis, and reduced circulating androgen levels (25)(26)(27)(28)(29)(30)(31). Protective associations have been observed between higher serum a-tocopherol and prostate cancer risk in several (5-13), but not all (32)(33)(34)(35)(36)(37)(38), studies, and one large controlled trial found a one-third reduction in prostate cancer incidence in men taking a relatively low, 50 IU dose of a-tocopheryl acetate daily (1). ...
The Selenium and Vitamin E Cancer Prevention Trial (SELECT) showed higher prostate cancer incidence in men supplemented with high-dose α-tocopherol. We therefore examined whether pre-supplementation plasma α-tocopherol or γ-tocopherol was associated with overall or high-grade prostate cancer. A stratified case-cohort sample that included 1,746 incident prostate cancer cases diagnosed through June, 2009 and a subcohort of 3,211 men was derived from the SELECT trial of 35,533 men. Plasma was collected at entry in 2001-2004, and median follow-up was 5.5 years (range, 0 - 7.9 years). Incidence of prostate cancer as a function of plasma α-tocopherol, γ-tocopherol, and supplementation with α-tocopherol or selenomethionine was estimated by the hazard ratio (HR). Plasma γ-tocopherol was not associated with prostate cancer. Men with higher α-tocopherol concentrations appeared to have risk similar to that of men with lower concentrations [overall HR for fifth (Q5) vs. first quintile (Q1), 1.21 (95% confidence interval (CI), 0.88-1.66, P-trend=0.24; in the trial placebo arm, Q5 HR, 0.85, 95% CI, 0.44-1.62, P-trend=0.66]. We found a strong positive plasma α-tocopherol association among men receiving the trial selenomethionine supplement [Q5 HR, 2.04, 95% CI, 1.29-3.22; P-trend=0.005]. A positive plasma α-tocopherol-prostate cancer association also appeared limited to high-grade disease (Gleason grade 7-10, overall Q5 HR, 1.59, 95% CI, 1.13-2.24, P-trend=0.001; among men receiving selenomethionine, HR, 2.12, 95% CI, 1.32-3.40; P-trend=0.0002). Our findings indicate that higher plasma α-tocopherol concentrations may interact with selenomethionine supplements to increase high-grade prostate cancer risk, suggesting a biological interaction between α-tocopherol and selenium itself or selenomethionine.
... Although laboratory experiments point to several potential mechanisms for a cancer preventive effect of α-tocopherol, 21 its role in prostate carcinogenesis remains unclear. A sub-study within the ATBC Study suggested that α-tocopherol supplementation decreased serum concentrations of androstenedione and testosterone, 22 sex hormones thought to be involved in the etiology of prostate cancer. ...
In the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study among 29,133 Finnish male smokers aged 50-69 years, daily α-tocopherol (50 mg) for a median of 6.1 years decreased the risk of prostate cancer, whereas β-carotene (20 mg) increased risk of lung cancer and overall mortality. To determine the postintervention effects of α-tocopherol and β-carotene, 25,563 men were followed 18 years for cancer incidence and all causes of mortality through national registers. Neither supplement had significant effects on post-trial cancer incidence. Relative risk (RR) for lung cancer (n = 2,881) was 1.04 (95% confidence interval [CI], 0.96-1.11) among β-carotene recipients compared with nonrecipients. For prostate cancer (n = 2,321), RR was 0.97 (95% CI, 0.89-1.05) among α-tocopherol recipients compared with nonrecipients with the preventive effect of α-tocopherol continuing ∼8 years postintervention. Body mass index significantly modified the effect of α-tocopherol on prostate cancer (p for interaction = 0.01) RR 1.00 (95% CI, 0.88-1.14) in normal-weight men, 0.87 (95% CI, 0.77-0.98) in overweight men, and 1.25 (95% CI, 1.01-1.55) in obese men. The post-trial relative mortality (based on 16,686 deaths) was 1.02 (95% CI, 0.98-1.05) for α-tocopherol recipients compared with nonrecipients and 1.02 (95% CI, 0.99-1.05) for β-carotene recipients compared with nonrecipients. α-Tocopherol decreased post-trial prostate cancer mortality (RR, 0.84; 95% CI, 0.70-0.99), whereas β-carotene increased it (RR, 1.20; 95% CI, 1.01-1.42). In conclusion, supplementation with α-tocopherol and β-carotene appeared to have no late effects on cancer incidence. The preventive effect of moderate-dose α-tocopherol on prostate cancer continued several years post-trial and resulted in lower prostate cancer mortality.
... At the transcriptional level, a number of genes may be regulated through a nonantioxidant activity of aT, including a-tropomyosin (51) and collagenase (52). Long-term aT supplementation modified serum hormone levels, including androstenedione and testosterone, which might contribute to the reduced risk of prostate cancer of aT treatment (53). Therefore, it appears likely that some effects of aT supplementation in this study may be due to biological processes unrelated to antioxidant activity. ...
We used high-density oligonucleotide arrays to measure transcriptional alterations in the heart and brain (neocortex) of 30-mo-old B6C3F1 mice supplemented with α-tocopherol (αT) and γ-tocopherol (γT) since middle age (15 mo). Gene expression profiles were obtained from 5- and 30-mo-old control mice and 30-mo-old mice supplemented with αT (1 g/kg) or a mixture of αT and γT (500 mg/kg of each tocopherol) from middle age (15 mo). In the heart, both tocopherol-supplemented diets were effective in inhibiting the expression of genes previously associated with cardiomyocyte hypertrophy and increased innate immunity. In the brain, induction of genes encoding ribosomal proteins and proteins involved in ATP biosynthesis was observed with aging and was markedly prevented by the mixture of αT and γT supplementation but not by αT alone. These results demonstrate that middle age-onset dietary supplementation with αT and γT can partially prevent age-associated transcriptional changes and that these effects are tissue and tocopherol specific.
... (1996) failed to confirm these results. Similarly, vitamin E has been shown to inhibit prostate cancer cell growth in vitro through apoptosis (Sigounas et al. 1997 ). The Alpha- Tocopherol Beta-Carotene Cancer Prevention study found that daily consumption of α-tocopherol reduced the incidence of prostate cancer and mortality (Heinonen et al. 1998). Hartman et al. (2001) also showed that long- term alpha-tocopherol supplementation decreases serum androgen concentrations, and could contribute to the observed reduction in incidence of and mortality from prostate cancer. In contrast, Andersson et al. (1996) observed no affect of α-tocopherol on prostate cancer risk. Several trace elements have also been st ...
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... Several mechanisms of action have been postulated such as protection of DNA damage by free radicals, induction of apoptosis, modulation of immune function and interference with hormone production [51]. The latter hypothesis was supported by the findings of the ATBC intervention study where men who received a-tocopherol had significantly lower serum androstenedione and testosterone levels than did those who received a placebo [52]. These findings have been proposed as an explanation for the reduction in prostate cancer observed in this study. ...
The recent discovery that vitamin E (VE) regulates gene activity at the transcriptional level indicates that VE may exert part of its biological effects by mechanisms which may be independent of its well-recognised antioxidant function. The objective of this study was the identification of hepatic vitamin E-sensitive genes and examination of the effects of VE on their corresponding biological endpoints. Two groups of male rats were randomly assigned to either a VE-sufficient diet or to a control diet deficient in VE for 290 days. High-density oligonucleotide microarrays comprising over 7000 genes were used to assess the transcriptional response of the liver. Differential gene expression was monitored over a period of 9 months, at four different time-points, and rats were individually profiled. This experimental strategy identified several VE-sensitive genes, which were chronically altered by dietary VE. VE supplementation down-regulated scavenger receptor CD36, coagulation factor IX and 5-alpha-steroid reductase type 1 mRNA levels while hepatic gamma glutamyl-cysteinyl synthetase was significantly up-regulated. Measurement of the corresponding biological endpoints such as activated partial thromboplastin time, plasma dihydrotestosterone and hepatic glutathione substantiated the gene chip data which indicated that dietary VE plays an important role in a range of metabolic processes within the liver.
... Of these, vitamin E, selenium, lycopene and isoflavones found in soy beans have anti-oxidant properties, and vitamin E and lycopene are free-radical scavengers in the extracellular environment. Moreover, long-term administration of vitamin E decreases serum androgen concentration, which may contribute to its mode of action in the prevention of prostate cancer [90]. Vitamin E has also been shown to mediate a G1/S-phase arrest as a consequence of the decreasing expression of cell cycle regulatory proteins, such as cyclin D1, D3 and E, cyclin-dependent kinases -2 and -4, and upregulation of p27 [91]. ...
Over the last decade, epidemiological, experimental and clinical studies have implicated oxidative stress in the development and progression of prostate cancer. Oxidative stress may be linked to the effects of androgens, anti-oxidant systems and the pre-malignant condition, high-grade prostatic intraepithelial neoplasia. Cyclooxygenase-2 activity has been linked with prostate carcinogenesis. Evidence suggests that oxidative stress and cyclo-oxygenase-2 activity may be mechanistically linked. Agents such as anti-oxidants and cyclo-oxgenase-2 inhibitors may be of value in the chemoprevention of prostate cancer. The feasibility of intervention with such agents will depend on the development and validation of biomarkers for clinical trials, particularly markers of oxidative damage caused by reactive oxygen species (ROS). A greater understanding of the molecular events associated with oxidative stress will enhance the development of such biomarkers and should result in better strategies for the chemoprevention of prostate cancer.
... Although the incidence of lung cancer paradoxically increased among men receiving -carotene, the incidence of new prostate cancer cases and prostate cancer mortality statistically significantly decreased by 32% and 41%, respectively, among the 14 564 men receiving vitamin E (versus men not receiving vitamin E) (38). Additional substantial preclinical (35,39) and epidemiologic (40,41) data suggesting that vitamin E may inhibit carcinogenesis, including in the prostate, further supported the inclusion of vitamin E in SELECT. Indeed, recent data also suggest that vitamin E can disrupt androgen-receptor signaling in prostate cancer cells (42,43), thus suggesting a mechanism for the potential anticarcinogenic effects of this agent in the prostate. ...
Prostate cancer continues to be a major health threat, especially among African American men. The Selenium and Vitamin E Cancer Prevention Trial (SELECT), which opened on July 25, 2001, was planned to study possible agents for the prevention of prostate cancer in a population of 32,400 men in the United States, including Puerto Rico, and Canada. SELECT is a phase III randomized, placebo-controlled trial of selenium (200 microg/day from L-selenomethionine) and/or vitamin E (400 IU/day of all rac alpha-tocopheryl acetate) supplementation for a minimum of 7 years (maximum of 12 years) in non-African American men at least 55 years of age and African American men at least 50 years of age. SELECT is a large, simple trial that conforms as closely as possible with community standards of care. This commentary discusses the design problems the SELECT investigators had to resolve in developing the trial, including the role of prostate cancer screening, the best forms and doses of the study agents, and estimation of the event (prostate cancer) rate of men on the placebo arm.
... Both nutrients can influence a variety of biologic processes by mechanisms dependently and independently of their antioxidant functions (12)(13)(14)(15)57). They may lower oxidative stress (12,13,58) and affect cell cycle progression (12,(59)(60)(61)(62)(63), hormone and growth factor signaling (46,64,65), cell communication (66,67), and apoptosis (61,(68)(69)(70). Cooperative interaction between lycopene and vitamin E (32,46,49) might result from a different mechanism of action or a direct effect of the nutrients on each other, e.g., by preventing oxidation (49,71,72) or cleavage (73), or by altering pharmacodynamics (33,74). ...
Epidemiologic studies have repeatedly associated a high intake of lycopene and vitamin E with reduced prostate cancer risk. The present study examined the ability of the 2 compounds to reduce tumor growth and prostate-specific antigen (PSA) plasma levels in the PC-346C orthotopic mouse model of human prostate cancer. Three days after intraprostatic tumor injection, NMRI nu/nu mice were administered a daily oral dose of synthetic lycopene [5 or 50 mg/kg body weight (BW)], vitamin E in the form of alpha-tocopheryl acetate (5 or 50 mg/kg BW), a mixture of lycopene and vitamin E (5 mg/kg BW each), or vehicle. Intraprostatic tumor volume and plasma PSA concentrations were measured at regular intervals. Mice were killed when the tumor load exceeded 1000 mm(3) or on d 95 when the study was terminated. Prostate and liver were analyzed by HPLC for lycopene isomers and alpha- and gamma, delta-tocopherol concentrations. None of the single treatments significantly reduced tumor volume. In contrast, combined treatment with lycopene and vitamin E, at 5 mg/kg BW each, suppressed orthotopic growth of PC-346C prostate tumors by 73% at d 42 (P < 0.05) and increased median survival time by 40% from 47 to 66 d (P = 0.02). The PSA index (PSA:tumor volume ratio) did not differ between experimental groups, indicating that PSA levels were not selectively affected. Lycopene was detected only in mice supplemented with lycopene. As in humans, most tissue lycopene was in the cis-isomer conformation, whereas 77% trans-lycopene was used in the dosing material. Liver alpha-tocopherol concentrations were increased in mice supplemented with both 50 mg/kg (226%, P < 0.05) and 5 mg/kg vitamin E (41%, P < 0.05), whereas prostate alpha-tocopherol concentrations were increased only by the higher dose (83%, P < 0.05). Our data provide evidence that lycopene combined with vitamin E may inhibit the growth of prostate cancer and that PSA can serve as a biomarker of tumor response for this treatment regimen.
Vit E is a collective term referring a group of 8 naturally occurring lipid-soluble molecules (homologs), of which 4 are tocopherols (α, β, γ, and δ tocopherols) and 4 are tocotrienols (α, β, γ and δ tocotrienols) [1]. Vit E was discovered in 1922 by Evans and Bishop, of the University of California in Berkeley, and the name “tocopherol” they proposed is derived from the Greek word “tocos” = offspring and the Greek verb “phero” = to bear, since the unknown till that time molecule was required to prevent fetal resorption in pregnant rats fed lard-containing diets that were easily oxidizable [2]. The -ol ending indicates its alcohol functional group. Tocopherol became known as the “antisterility vitamin”, but soon scientists realized that it had this effect only in rats.
Abstract Background & Objectives:In recent times the natural products obtained from organisms such as medicinal plants (secondary metabolites) are known as a powerful source to supplement therapy and prevention of porstate cancer and BPH. In this review article some of the famous and applicable natural products and medicinal plants used in clinic are discussed. The following information is dealing with the developments in the pharmacology and clinical trials of the known agents isolated from medicinal, as well as their suggested mechanisms. Material and Methods: This research was done based on the searching the keywords including Natural products BPH Prostate cancer anticancer Clinical trials, mechanism through the well-known databases from beginning to 2012. Results: In this review nine bioactive compounds isolated from nature and medicinal plants with considerable biological and pharmacological activities in treatment of cancer and benign hyperplasia of prostate are discussed. The main focuses are the clinical usage and biological effects with studying the probable mechanism of their action. Conclusion: During the past years many of these agents have been used in the treatment of the prostate cancer and BPH. Nine considerable bioactive structures are reported in this review. Today the potential for development of leads from natural sources and medicinal plants is growing dramatically, mainly in the area of anticancer investigations. The data prepared and described here are intended to be served as a reference tool to the natural products and chemistry specialists in order to expand the rational drug design.
Prostate cancer is the most common male cancer. Studies show that prostate cancer is a preventable disease. The current studies suggest the role of dietary patterns in the prevention of prostate cancer. There are many epidemiological, clinical, case-control, prospective studies about dietary patterns and prostate cancer. These studies indicate that saturated fats, trans fatty acids, omega-6 fatty acids, meat, whole milk and dairy products, and calcium increase prostate cancer risk, whereas omega-9 fatty acids, omega-3 fatty acids, fruit and vegetables, lycopene, selenium, vitamin E, D, soy, pomegranate and green tea decrease the risk. Consumption of meat, trans fatty acids (margarine, fried foods), whole dairy products (whole milk, cheese, yogurt, or others) should be reduced and high calcium intake should be avoided to reduce prostate cancer risk. On the other hand, consumption of vegetables (such as broccoli, cauliflower, cabbage, kale, Brussels sprouts, and radish), lycopene containing foods (tomato and products), adequate amount of selenium (seafood, grains), vitamin E (vegetable oils, wheat germ, nuts, soybeans, sweet potatoes, and avocado), green tea, soy (soybeans, tofu, soy cheese, soy milk), and pomegranate juice is highly recommended. This study summarizes the association of food and increased/decreased dietary risk factors for prostate cancer and gives recommendations based on these associations.
This chapter reviews the numerous nutrients and food components that have been linked to sex steroids, including dietary fiber, fat, carbohydrate, protein, micronutrients, alcohol, and phytochemicals. The chapter also discusses the effects of obesity on sex steroids as well as studies comparing vegetarians with non-vegetarians. Studies comparing vegetarians to non-vegetarians have suggested that low-fat, high-fiber diets are associated with lower serum estrogens, lower urinary estrogens, and higher fecal estrogens. Subsequent studies focusing on the effects of specific nutrients have revealed that metabolism and concentrations of sex steroids can be modulated by changes in amounts of many nutrients, including fiber, fat, carbohydrate and protein, alcohol, and phytochemicals. The significance of these changes has been linked to associations with increased or decreased risk of hormone-dependent diseases, primarily breast cancer, prostate cancer, and cardiovascular disease. It has also been consistently shown that obesity and body fatness contribute to variation in sex steroids.
Bone remodeling is mediated by the osteoclasts and osteoblasts coupling. Xenoestrogens are endocrines disruptors that could interfere with bone remodeling. We have investigated the effect of tetradifon on bone remodeling. We have shown that disturbance of bone remodeling and metabolism were accompanied with a secondary genotoxic effect via oxidative damages. Bone is the main site of metastases for many cancer diseases such as the breast cancer. We have used Walker 256/B to induce bone metastases in rats. In vitro, ATA effects on these cells have provided acceptable results by inducing apoptosis and reducing ROS releasing. In vivo effects of ATA, have been investigated in a designed several model of breast cancer skeletal metastases. ATA did not prevent the bone loss but reduced the oxidative stress damage in the bone microenvironment. Microtomography and histology were used to detect and differentiate bone alterations due to osteolytic with or without ATA treatment. We have also shown that newly metaplastic, osteosclerotic, apposed bone was observed in the periosteal envelope of cancerous and ATA treated group. A hepatorenal bilan of this animal model of bone metastases was investigated. In this study, it seems that in situ inoculation of Walker 256 cells is not associated with renal and hepatic complications.
Background:
Vitamin E compounds exhibit prostate cancer preventive properties experimentally, but serologic investigations of tocopherols, and randomized controlled trials of supplementation in particular, have been inconsistent. Many studies suggest protective effects among smokers and for aggressive prostate cancer, however.
Methods:
We conducted a nested case-control study of serum α-tocopherol and γ-tocopherol and prostate cancer risk in the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial, with 680 prostate cancer cases and 824 frequency-matched controls. Multivariate-adjusted, conditional logistic regression models were used to estimate odds ratios (OR) and 95% confidence intervals (CIs) for tocopherol quintiles.
Results:
Serum α-tocopherol and γ-tocopherol were inversely correlated (r = -0.24, p<0.0001). Higher serum α-tocopherol was associated with significantly lower prostate cancer risk (OR for the highest vs. lowest quintile = 0.63, 95% CI 0.44-0.92, p-trend 0.05). By contrast, risk was non-significantly elevated among men with higher γ-tocopherol concentrations (OR for the highest vs. lowest quintile = 1.35, 95% CI 0.92-1.97, p-trend 0.41). The inverse association between prostate cancer and α-tocopherol was restricted to current and recently former smokers, but was only slightly stronger for aggressive disease. By contrast, the increased risk for higher γ-tocopherol was more pronounced for less aggressive cancers.
Conclusions:
Our findings indicate higher α-tocopherol status is associated with decreased risk of developing prostate cancer, particularly among smokers. Although two recent controlled trials did not substantiate an earlier finding of lower prostate cancer incidence and mortality in response to supplementation with a relatively low dose of α-tocopherol, higher α-tocopherol status may be beneficial with respect to prostate cancer risk among smokers. Determining what stage of prostate cancer development is impacted by vitamin E, the underlying mechanisms, and how smoking modifies the association, is needed for a more complete understanding of the vitamin E-prostate cancer relation.
Vitamin E has been hypothesized to protect against prostate cancer. The anti-carcinogenic activity of vitamin E is attributed in large part to its potent antioxidant activity -it is the major hydrophobic chain-breaking antioxidant that protects membrane lipids from oxidation. In addition, vitamin E has several important non-antioxidant functions, including inhibition of protein kinase C (PKC) activity, which plays an important role in proliferation, adhesion, immune response, free radical production, and gene expression. Vitamin E also appears to interfere with hormone signaling, which is particularly relevant to prostate carcinogenesis. The concept that common SNPs in genes encoding for proteins responsible for uptake, transport, and delivery of tocopherols and tocotrienols to the prostate may impact upon prostate cancer risk has not been examined and warrants future research. Overall, substantial evidence from mechanistic studies shows a protective effect of vitamin E on prostate carcinogenesis. However, results from observational epidemiologic studies regarding the association between vitamin E and prostate cancer risk are mixed. The available data suggest that vitamin E may more strongly protect against advanced than early-stage prostate cancer, and that the apparent beneficial effect of vitamin E on prostate cancer may be more pronounced among cigarette smokers. At present, the most prudent strategy for prostate cancer prevention regarding vitamin E intake is to adhere to the current U.S. dietary guidelines, which recommend eating a well-balanced diet that is rich in a variety of fruits, vegetables, and whole grains. STRUCTURE OF VITAMIN E Vitamin E is a fat-soluble vitamin that occurs naturally in eight different forms, including four tocopherols (α-, β-, γ-, δ-) and four tocotrienols (α-, β-, γ-, δ-). All tocopherols have a long, saturated phytyl side chain, with differences between them arising from the number and position of methyl groups on the chromanol ring. Tocotrienols have an unsaturated side chain, but are otherwise identical to their corresponding tocopherols. Each of the four tocopherols, including α-tocopherol, has eight possible stereoisomer forms due to the presence of three optically active sites, each with two possible configurations (R and S). However, the RRR-stereoisomer is the only form that occurs naturally in plant foods. Most forms of synthetic vitamin E, which are included in fortified foods and vitamin supplements, contain equal amounts of all eight stereoisomers, although the 2R-forms (RRR-, RSR-, RRS-, RSS-) are the only ones that are maintained in human plasma and tissues [1].
Our systematic review has demonstrated that antioxidant supplements may increase mortality. We have now updated this review.
To assess the beneficial and harmful effects of antioxidant supplements for prevention of mortality in adults.
We searched The Cochrane Library, MEDLINE, EMBASE, LILACS, the Science Citation Index Expanded, and Conference Proceedings Citation Index-Science to February 2011. We scanned bibliographies of relevant publications and asked pharmaceutical companies for additional trials.
We included all primary and secondary prevention randomised clinical trials on antioxidant supplements (beta-carotene, vitamin A, vitamin C, vitamin E, and selenium) versus placebo or no intervention.
Three authors extracted data. Random-effects and fixed-effect model meta-analyses were conducted. Risk of bias was considered in order to minimise the risk of systematic errors. Trial sequential analyses were conducted to minimise the risk of random errors. Random-effects model meta-regression analyses were performed to assess sources of intertrial heterogeneity.
Seventy-eight randomised trials with 296,707 participants were included. Fifty-six trials including 244,056 participants had low risk of bias. Twenty-six trials included 215,900 healthy participants. Fifty-two trials included 80,807 participants with various diseases in a stable phase. The mean age was 63 years (range 18 to 103 years). The mean proportion of women was 46%. Of the 78 trials, 46 used the parallel-group design, 30 the factorial design, and 2 the cross-over design. All antioxidants were administered orally, either alone or in combination with vitamins, minerals, or other interventions. The duration of supplementation varied from 28 days to 12 years (mean duration 3 years; median duration 2 years). Overall, the antioxidant supplements had no significant effect on mortality in a random-effects model meta-analysis (21,484 dead/183,749 (11.7%) versus 11,479 dead/112,958 (10.2%); 78 trials, relative risk (RR) 1.02, 95% confidence interval (CI) 0.98 to 1.05) but significantly increased mortality in a fixed-effect model (RR 1.03, 95% CI 1.01 to 1.05). Heterogeneity was low with an I(2)- of 12%. In meta-regression analysis, the risk of bias and type of antioxidant supplement were the only significant predictors of intertrial heterogeneity. Meta-regression analysis did not find a significant difference in the estimated intervention effect in the primary prevention and the secondary prevention trials. In the 56 trials with a low risk of bias, the antioxidant supplements significantly increased mortality (18,833 dead/146,320 (12.9%) versus 10,320 dead/97,736 (10.6%); RR 1.04, 95% CI 1.01 to 1.07). This effect was confirmed by trial sequential analysis. Excluding factorial trials with potential confounding showed that 38 trials with low risk of bias demonstrated a significant increase in mortality (2822 dead/26,903 (10.5%) versus 2473 dead/26,052 (9.5%); RR 1.10, 95% CI 1.05 to 1.15). In trials with low risk of bias, beta-carotene (13,202 dead/96,003 (13.8%) versus 8556 dead/77,003 (11.1%); 26 trials, RR 1.05, 95% CI 1.01 to 1.09) and vitamin E (11,689 dead/97,523 (12.0%) versus 7561 dead/73,721 (10.3%); 46 trials, RR 1.03, 95% CI 1.00 to 1.05) significantly increased mortality, whereas vitamin A (3444 dead/24,596 (14.0%) versus 2249 dead/16,548 (13.6%); 12 trials, RR 1.07, 95% CI 0.97 to 1.18), vitamin C (3637 dead/36,659 (9.9%) versus 2717 dead/29,283 (9.3%); 29 trials, RR 1.02, 95% CI 0.98 to 1.07), and selenium (2670 dead/39,779 (6.7%) versus 1468 dead/22,961 (6.4%); 17 trials, RR 0.97, 95% CI 0.91 to 1.03) did not significantly affect mortality. In univariate meta-regression analysis, the dose of vitamin A was significantly associated with increased mortality (RR 1.0006, 95% CI 1.0002 to 1.001, P = 0.002).
We found no evidence to support antioxidant supplements for primary or secondary prevention. Beta-carotene and vitamin E seem to increase mortality, and so may higher doses of vitamin A. Antioxidant supplements need to be considered as medicinal products and should undergo sufficient evaluation before marketing.
Vitamin E may protect against prostate cancer, possibly only in smokers and, we hypothesize, through altered sex steroid hormones. A controlled trial in smokers showed that sex hormone levels were inversely associated with baseline serum α-tocopherol and decreased in response to vitamin E supplementation. The vitamin E-hormone relation is understudied in non-smokers.
Serum sex steroid hormones and α-tocopherol were measured for 1,457 men in NHANES III. Multivariable-adjusted geometric mean hormone concentrations by α-tocopherol quintile were estimated.
We observed lower mean testosterone, estradiol, and SHBG concentrations with increasing serum α-tocopherol (Q1 = 5.5 and Q5 = 4.6 ng/ml, p-trend = 0.0007; Q1 = 37.8 and Q5 = 33.1 pg/ml, p-trend = 0.02; Q1 = 38.8 and Q5 = 30.6 pg/ml, p-trend = 0.05, respectively). Interactions between serum α-tocopherol and exposure to cigarette smoke for total testosterone, total estradiol, and SHBG were found with the inverse relation observed only among smokers.
Results from this nationally representative, cross-sectional study indicate an inverse association between serum α-tocopherol and circulating testosterone, estradiol, and SHBG, but only in men who smoked. Our findings support vitamin E selectively influencing sex hormones in smokers and afford possible mechanisms through which vitamin E may impact prostate cancer risk.
Androgens are key regulators of prostate gland maintenance and prostate cancer growth, and androgen deprivation therapy has been the mainstay of treatment for advanced prostate cancer for many years. A long-standing hypothesis has been that inherited variation in the androgen receptor (AR) gene plays a role in prostate cancer initiation. However, studies to date have been inconclusive and often suffered from small sample sizes.
We investigated the association of AR sequence variants with circulating sex hormone levels and prostate cancer risk in 6058 prostate cancer cases and 6725 controls of Caucasian origin within the Breast and Prostate Cancer Cohort Consortium. We genotyped a highly polymorphic CAG microsatellite in exon 1 and six haplotype tagging single nucleotide polymorphisms and tested each genetic variant for association with prostate cancer risk and with sex steroid levels.
We observed no association between AR genetic variants and prostate cancer risk. However, there was a strong association between longer CAG repeats and higher levels of testosterone (P = 4.73 x 10(-5)) and estradiol (P = 0.0002), although the amount of variance explained was small (0.4 and 0.7%, respectively).
This study is the largest to date investigating AR sequence variants, sex steroid levels, and prostate cancer risk. Although we observed no association between AR sequence variants and prostate cancer risk, our results support earlier findings of a relation between the number of CAG repeats and circulating levels of testosterone and estradiol.
Purpose
The purpose of this Phase II randomized-controlled trial was to evaluate the safety and effect of administering several doses of lycopene to men with clinically localized prostate cancer, on intermediate endpoint biomarkers implicated in prostate carcinogenesis.
Methods
Forty-five eligible men with clinically localized prostate cancer were supplemented with 15, 30 or 45 mg of lycopene or no supplement from biopsy to prostatectomy. Compliance to study agent, toxicity, changes in plasma lycopene, serum steroid hormones, PSA and tissue Ki-67 were analyzed from baseline to completion of intervention.
Results
Forty-two of forty-five five subjects completed the intervention for approximately 30 days from the time of biopsy until prostatectomy. Plasma lycopene increased from baseline to post treatment in all treatment groups with greatest increase observed in the 45 mg lycopene-supplemented arm compared to the control arm without producing any toxicity. Overall, subjects with prostate cancer had lower baseline levels of plasma lycopene similar to those observed in previous studies in men with prostate cancer. Serum free testosterone decreased with 30 mg lycopene supplementation and total estradiol increased significantly with 30 mg and 45 mg supplementation from baseline to end of treatment, with no significant increases in serum PSA or tissue Ki-67. These changes were not significant compared to the control arm for this sample size and duration of intervention.
Conclusions
Although antioxidant properties of lycopene have been hypothesized to be primarily responsible for its beneficial effects, our study suggests that other mechanisms mediated by steroid hormones may also be involved.
Previous studies suggest that carotenoids and tocopherols (vitamin E compounds) may be inversely associated with prostate cancer risk, yet little is known about how they affect prostate cancer progression and survival. We investigated whether serum alpha-tocopherol, beta-carotene, and retinol concentrations, or the alpha-tocopherol and beta-carotene trial supplementation, affected survival of men diagnosed with prostate cancer during the alpha-Tocopherol, beta-Carotene Cancer Prevention Study, a randomized, double-blind, placebo-controlled primary prevention trial testing the effects of beta-carotene and alpha-tocopherol supplements on cancer incidence in adult male smokers in southwestern Finland (n = 29,133). Prostate cancer survival was examined using the Kaplan-Meier method with deaths from other causes treated as censoring, and using Cox proportional hazards regression models with hazard ratios (HR) and 95% confidence intervals (CI) adjusted for family history of prostate cancer, age at randomization, benign prostatic hyperplasia, age and stage at diagnosis, height, body mass index, and serum cholesterol. As of April 2005, 1,891 men were diagnosed with prostate cancer and 395 died of their disease. Higher serum alpha-tocopherol at baseline was associated with improved prostate cancer survival (HR, 0.67; 95% CI, 0.45-1.00), especially among cases who had received the alpha-tocopherol intervention of the trial and who were in the highest quintile of alpha-tocopherol at baseline (HR, 0.51; 95% CI, 0.20-0.90) or at the 3-year follow-up measurement (HR, 0.26; 95% CI, 0.09-0.71). Serum beta-carotene, serum retinol, and supplemental beta-carotene had no apparent effects on survival. These findings suggest that higher alpha-tocopherol (and not beta-carotene or retinol) status increases overall prostate cancer survival. Further investigations, possibly including randomized studies, are needed to confirm this observation.
Oxidative stress may cause gastrointestinal cancers. The evidence on whether antioxidant supplements are effective in preventing gastrointestinal cancers is contradictory.
To assess the beneficial and harmful effects of antioxidant supplements in preventing gastrointestinal cancers.
We identified trials through the trials registers of the four Cochrane Review Groups on gastrointestinal diseases, The Cochrane Central Register of Controlled Trials in The Cochrane Library (Issue 2, 2007), MEDLINE, EMBASE, LILACS, SCI-EXPANDED, and The Chinese Biomedical Database from inception to October 2007. We scanned reference lists and contacted pharmaceutical companies.
Randomised trials comparing antioxidant supplements to placebo/no intervention examining occurrence of gastrointestinal cancers.
Two authors (GB and DN) independently selected trials for inclusion and extracted data. Outcome measures were gastrointestinal cancers, overall mortality, and adverse effects. Outcomes were reported as relative risks (RR) with 95% confidence interval (CI) based on random-effects and fixed-effect model meta-analysis. Meta-regression assessed the effect of covariates across the trials.
We identified 20 randomised trials (211,818 participants), assessing beta-carotene (12 trials), vitamin A (4 trials), vitamin C (8 trials), vitamin E (10 trials), and selenium (9 trials). Trials quality was generally high. Heterogeneity was low to moderate. Antioxidant supplements were without significant effects on gastrointestinal cancers (RR 0.94, 95% CI 0.83 to 1.06). However, there was significant heterogeneity (I(2) = 54.0%, P = 0.003). The heterogeneity may have been explained by bias risk (low-bias risk trials RR 1.04, 95% CI 0.96 to 1.13 compared to high-bias risk trials RR 0.59, 95% CI 0.43 to 0.80; test of interaction P < 0.0005), and type of antioxidant supplement (beta-carotene potentially increasing and selenium potentially decreasing cancer risk). The antioxidant supplements had no significant effects on mortality in a random-effects model meta-analysis (RR 1.02, 95% CI 0.97 to 1.07, I(2) = 53.5%), but significantly increased mortality in a fixed-effect model meta-analysis (RR 1.04, 95% CI 1.02 to 1.07). Beta-carotene in combination with vitamin A (RR 1.16, 95% CI 1.09 to 1.23) and vitamin E (RR 1.06, 95% CI 1.02 to 1.11) significantly increased mortality. Increased yellowing of the skin and belching were non-serious adverse effects of beta-carotene. In five trials (four with high risk of bias), selenium seemed to show significant beneficial effect on gastrointestinal cancer occurrence (RR 0.59, 95% CI 0.46 to 0.75, I(2) = 0%).
We could not find convincing evidence that antioxidant supplements prevent gastrointestinal cancers. On the contrary, antioxidant supplements seem to increase overall mortality. The potential cancer preventive effect of selenium should be tested in adequately conducted randomised trials.
Accumulating evidence indicates the involvement of sex hormones in atherogenesis. Endogenous testosterone is inversely related to the majority of risk factors for atherosclerosis and is known to be a potent immunomodulator. Recently, autoantibodies to oxidized LDL (anti-oxLDL Ab) were shown to predict carotid and coronary atherosclerosis. The aim of this study was to investigate the relationship between these antibodies and testosterone level in ageing males. The study group comprised 65 males over 50 years old (42 with coronary artery disease). Serum anti-oxLDL Ab titer was measured by enzyme-linked immunoassay and total serum testosterone by radioimmunoassay. A significant inverse correlation was found between serum anti-oxLDL Ab titer and testosterone concentration (r=-0.346, P=0.0047). Alteration in serum anti-oxLDL Ab titres showed no correlation to classical cardiovascular risk factors, e.g. body mass index, waist/hip ratio, smoking, total cholesterol, triglycerides, HDL-cholesterol, LDL-cholesterol. In multiple regression analysis only testosterone level was independently associated with anti-oxLDL Ab. These data suggest a that fall of testosterone concentration in ageing men can influence either oxidative modification of LDL or the immune response to these lipoproteins which may be important in the pathogenesis of atherosclerosis.
Vitamin E is indispensible for reproduction in female rats. In humans, vitamin E deficiency primarily causes neurologic dysfunctions, but the underlying molecular mechanisms are unclear. Because of its antioxidative properties, vitamin E is believed to help prevent diseases associated with oxidative stress, such as cardiovascular disease, cancer, chronic inflammation, and neurologic disorders. However, recent clinical trials undertaken to prove this hypothesis failed to verify a consistent benefit. Given these findings, a group of European scientists met to analyze the most recent knowledge of vitamin E function and metabolism. An overview of their discussions is presented in this article, which includes considerations of the mechanisms of absorption, distribution, and metabolism of different forms of vitamin E, including the alpha-tocopherol transfer protein and alpha-tocopherol-associated proteins; the mechanism of tocopherol side-chain degradation and its putative interaction with drug metabolism; the usefulness of tocopherol metabolites as biomarkers; and the novel mechanisms of the antiatherosclerotic and anticarcinogenic properties of vitamin E, which involve modulation of cellular signaling, transcriptional regulation, and induction of apoptosis. Clinical trials were analyzed on the basis of the selection of subjects, the stage of disease, and the mode of intake, dosage, and chemical form of vitamin E. In addition, the scarce knowledge on the role of vitamin E in reproduction was summarized. In conclusion, the scientists agreed that the functions of vitamin E were underestimated if one considered only its antioxidative properties. Future research on this essential vitamin should focus on what makes it essential for humans, why the body apparently utilizes alpha-tocopherol preferentially, and what functions other forms of vitamin E have.
Prostate cancer has the highest prevalence of any nonskin cancer in the human body, with similar likelihood of neoplastic foci found within the prostates of men around the world regardless of diet, occupation, lifestyle, or other factors. Essentially all men with circulating androgens will develop microscopic prostate cancer if they live long enough. This review is a contemporary and comprehensive, literature-based analysis of the putative risk factors for human prostate cancer, and the results were presented at a multidisciplinary consensus conference held in Crystal City, Virginia, in the fall of 2002. The objectives were to evaluate known environmental factors and mechanisms of prostatic carcinogenesis and to identify existing data gaps and future research needs. The review is divided into four sections, including 1) epidemiology (endogenous factors [family history, hormones, race, aging and oxidative stress] and exogenous factors [diet, environmental agents, occupation and other factors, including lifestyle factors]); 2) animal and cell culture models for prediction of human risk (rodent models, transgenic models, mouse reconstitution models, severe combined immunodeficiency syndrome mouse models, canine models, xenograft models, and cell culture models); 3) biomarkers in prostate cancer, most of which have been tested only as predictive factors for patient outcome after treatment rather than as risk factors; and 4) genotoxic and nongenotoxic mechanisms of carcinogenesis. The authors conclude that most of the data regarding risk relies, of necessity, on epidemiologic studies, but animal and cell culture models offer promise in confirming some important findings. The current understanding of biomarkers of disease and risk factors is limited. An understanding of the risk factors for prostate cancer has practical importance for public health research and policy, genetic and nutritional education and chemoprevention, and prevention strategies.
Oxidative stress may cause gastrointestinal cancers. The evidence on whether antioxidant supplements are effective in preventing gastrointestinal cancers is contradictory.
To assess the beneficial and harmful effects of antioxidant supplements in preventing gastrointestinal cancers.
We identified trials through the trials registers of the four Cochrane Review Groups on gastrointestinal diseases, The Cochrane Central Register of Controlled Trials on The Cochrane Library (Issue 1, 2003), MEDLINE, EMBASE, LILACS, and SCI-EXPANDED from inception to February 2003, and The Chinese Biomedical Database (March 2003). We scanned reference lists and contacted pharmaceutical companies.
Randomised trials comparing antioxidant supplements to placebo/no intervention examining the incidence of gastrointestinal cancers.
Two reviewers independently selected trials for inclusion and extracted data. The outcome measures were incidence of gastrointestinal cancers, overall mortality, and adverse events. Outcomes were reported as relative risks (RR) with 95% confidence interval (CI) based on fixed and random effects meta-analyses.
We identified 14 randomised trials (170,525 participants), assessing beta-carotene (9 trials), vitamin A (4 trials), vitamin C (4 trials), vitamin E (5 trials), and selenium (6 trials). Trial quality was generally high. Heterogeneity was low to moderate. Neither the fixed effect (RR 0.96, 95% CI 0.88 to 1.04) nor random effects meta-analyses (RR 0.90, 95% CI 0.77 to 1.05) showed significant effects of supplementation with antioxidants on the incidences of gastrointestinal cancers. Among the seven high-quality trials reporting on mortality (131,727 participants), the fixed effect (RR 1.06, 95% CI 1.02 to 1.10) unlike the random effects meta-analysis (RR 1.06, 95% CI 0.98 to 1.15) showed that antioxidant supplements significantly increased mortality. Two low-quality trials (32,302 participants) found no significant effect of antioxidant supplementation on mortality. The difference between the mortality estimates in high- and low-quality trials was significant by test of interaction (z = 2.10, P = 0.04). Beta-carotene and vitamin A (RR 1.29, 95% CI 1.14 to 1.45) and beta-carotene and vitamin E (RR 1.10, 95% CI 1.01 to 1.20) significantly increased mortality, while beta-carotene alone only tended to do so (RR 1.05, 95% CI 0.99 to 1.11). Increased yellowing of the skin and belching were non-serious adverse effects of beta-carotene. In four trials (three with unclear/inadequate methodology), selenium showed significant beneficial effect on gastrointestinal cancer incidences.
We could not find evidence that antioxidant supplements prevent gastrointestinal cancers. On the contrary, they seem to increase overall mortality. The potential cancer preventive effect of selenium should be studied in adequately conducted randomised trials.
The Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study demonstrated a 32% reduction in prostate cancer incidence in response to daily alpha-tocopherol supplementation. We examined baseline serum concentrations of alpha-tocopherol and gamma-tocopherol to compare their respective associations with prostate cancer risk. From the ATBC Study cohort of 29 133 Finnish men, 50-69 years old, we randomly selected 100 incident prostate cancer case patients and matched 200 control subjects. Odds ratios and 95% confidence intervals (CIs) were estimated for the serum tocopherols (measured by high-performance liquid chromatography) using logistic regression models. All P values were two-sided. Odds ratios for the highest versus the lowest tertiles were 0.49 (95% CI = 0.24 to 1.01, P(trend) = .05) for alpha-tocopherol and 0.57 (95% CI = 0.31 to 1.06, P(trend) = .08) for gamma-tocopherol. Further analyses indicated that the association of high serum tocopherols with low prostate cancer risk was stronger in the alpha-tocopherol-supplemented group than in those not receiving alpha-tocopherol. Participants with higher circulating concentrations of the major vitamin E fractions, alpha-tocopherol and gamma-tocopherol, had similarly lower prostate cancer risk.
A meta-analysis of 19 trials suggested a small increase in the risk of all-cause mortality with high-dose vitamin E supplementation. Little is known, however, about the relation between mortality and circulating concentrations of vitamin E resulting from dietary intake, low-dose supplementation, or both.
We examined whether baseline serum alpha-tocopherol concentrations are associated with total and cause-specific mortality.
A prospective cohort study of 29 092 Finnish male smokers aged 50-69 y who participated in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study was carried out. Fasting serum alpha-tocopherol was measured at baseline by using HPLC. Only 10% of participants reported vitamin E supplement use at baseline, and thus serum concentrations of vitamin E mainly reflected dietary intake and other host factors. Risks of total and cause-specific mortality were estimated by using proportional hazards models.
During up to 19 y of follow-up, 13 380 deaths (including 4518 and 5776 due to cancer and cardiovascular disease, respectively) were identified. Men in the higher quintiles of serum alpha-tocopherol had significantly lower risks of total and cause-specific mortality than did those in the lowest quintile [relative risk (RR) = 0.82 (95% CI: 0.78, 0.86) for total mortality and 0.79 (0.72, 0.86), 0.81 (0.75, 0.88), and 0.70 (0.63, 0.79) for deaths due to cancer, cardiovascular disease, and other causes, respectively; P for trend for all < 0.0001]. Cubic regression spline analysis of continuous serum alpha-tocopherol values indicated greater risk reductions with increasing concentrations up to approximately 13-14 mg/L, after which no further benefit was noted.
Higher circulating concentrations of alpha-tocopherol within the normal range are associated with significantly lower total and cause-specific mortality in older male smokers.
We used high-density oligonucleotide arrays to measure transcriptional alterations in the heart and brain (neocortex) of 30-mo-old B6C3F(1) mice supplemented with alpha-tocopherol (alphaT) and gamma-tocopherol (gammaT) since middle age (15 mo). Gene expression profiles were obtained from 5- and 30-mo-old control mice and 30-mo-old mice supplemented with alphaT (1 g/kg) or a mixture of alphaT and gammaT (500 mg/kg of each tocopherol) from middle age (15 mo). In the heart, both tocopherol-supplemented diets were effective in inhibiting the expression of genes previously associated with cardiomyocyte hypertrophy and increased innate immunity. In the brain, induction of genes encoding ribosomal proteins and proteins involved in ATP biosynthesis was observed with aging and was markedly prevented by the mixture of alphaT and gammaT supplementation but not by alphaT alone. These results demonstrate that middle age-onset dietary supplementation with alphaT and gammaT can partially prevent age-associated transcriptional changes and that these effects are tissue and tocopherol specific.
Animal and physiological research as well as observational studies suggest that antioxidant supplements may improve survival.
To assess the effect of antioxidant supplements on mortality in primary or secondary prevention randomised clinical trials.
We searched The Cochrane Library (Issue 3, 2005), MEDLINE (1966 to October 2005), EMBASE (1985 to October 2005), and the Science Citation Index Expanded (1945 to October 2005). We scanned bibliographies of relevant publications and wrote to pharmaceutical companies for additional trials.
We included all primary and secondary prevention randomised clinical trials on antioxidant supplements (beta-carotene, vitamin A, vitamin C, vitamin E, and selenium) versus placebo or no intervention. Included participants were either healthy (primary prevention trials) or had any disease (secondary prevention trials).
Three authors extracted data. Trials with adequate randomisation, blinding, and follow-up were classified as having a low risk of bias. Random-effects and fixed-effect meta-analyses were performed. Random-effects meta-regression analyses were performed to assess sources of intertrial heterogeneity.
Sixty-seven randomised trials with 232,550 participants were included. Forty-seven trials including 180,938 participants had low risk of bias. Twenty-one trials included 164,439 healthy participants. Forty-six trials included 68111 participants with various diseases (gastrointestinal, cardiovascular, neurological, ocular, dermatological, rheumatoid, renal, endocrinological, or unspecified). Overall, the antioxidant supplements had no significant effect on mortality in a random-effects meta-analysis (relative risk [RR] 1.02, 95% confidence interval [CI] 0.99 to 1.06), but significantly increased mortality in a fixed-effect model (RR 1.04, 95% CI 1.02 to 1.06). In meta-regression analysis, the risk of bias and type of antioxidant supplement were the only significant predictors of intertrial heterogeneity. In the trials with a low risk of bias, the antioxidant supplements significantly increased mortality (RR 1.05, 95% CI 1.02 to 1.08). When the different antioxidants were assessed separately, analyses including trials with a low risk of bias and excluding selenium trials found significantly increased mortality by vitamin A (RR 1.16, 95% CI 1.10 to 1.24), beta-carotene (RR 1.07, 95% CI 1.02 to 1.11), and vitamin E (RR 1.04, 95% CI 1.01 to 1.07), but no significant detrimental effect of vitamin C (RR 1.06, 95% CI 0.94 to 1.20). Low-bias risk trials on selenium found no significant effect on mortality (RR 0.91, 95% CI 0.76 to 1.09).
We found no evidence to support antioxidant supplements for primary or secondary prevention. Vitamin A, beta-carotene, and vitamin E may increase mortality. Future randomised trials could evaluate the potential effects of vitamin C and selenium for primary and secondary prevention. Such trials should be closely monitored for potential harmful effects. Antioxidant supplements need to be considered medicinal products and should undergo sufficient evaluation before marketing.
Epidemiologic studies have suggested that vitamin E and beta-carotene may each influence the development of prostate cancer. In the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study, a controlled trial, we studied the effect of alpha-tocopherol (a form of vitamin E) and beta-carotene supplementation, separately or together, on prostate cancer in male smokers.
A total of 29133 male smokers aged 50-69 years from southwestern Finland were randomly assigned to receive alpha-tocopherol (50 mg), beta-carotene (20 mg), both agents, or placebo daily for 5-8 years (median, 6.1 years). The supplementation effects were estimated by a proportional hazards model, and two-sided P values were calculated.
We found 246 new cases of and 62 deaths from prostate cancer during the follow-up period. A 32% decrease (95% confidence interval [CI] = -47% to -12%) in the incidence of prostate cancer was observed among the subjects receiving alpha-tocopherol (n = 14564) compared with those not receiving it (n = 14569). The reduction was evident in clinical prostate cancer but not in latent cancer. Mortality from prostate cancer was 41% lower (95% CI = -65% to -1%) among men receiving alpha-tocopherol. Among subjects receiving beta-carotene (n = 14560), prostate cancer incidence was 23% higher (95% CI = -4%-59%) and mortality was 15% higher (95% CI = -30%-89%) compared with those not receiving it (n = 14573). Neither agent had any effect on the time interval between diagnosis and death.
Long-term supplementation with alpha-tocopherol substantially reduced prostate cancer incidence and mortality in male smokers. Other controlled trials are required to confirm the findings.
A study was conducted to examine the effect of megavitamin E supplementation in healthy college student volunteers. Two hundred two subjects were randomly assigned to either of two treatment groups, one control and the other experimental. Each subject in the experimental group orally received 600 IU dl-α-tocopheryl acetate daily, while each subject in the control group received identical placebo tablets. The experiment was “double blind” and proceeded for a period of 4 weeks. On day 0 and on day 28 each subject had a fasting blood sample taken for laboratory analysis and completed a questionnaire. Results showed that megavitamin E supplementation did not have an effect on work performance, sexuality, and general well-being and did not cause muscular weakness or gastrointestinal disturbances based on subjective evaluations. Megavitamin E supplementation did not have an effect on prothrombin time, total blood leukocyte count, or serum creatine Phosphokinase activity. Serum cholesterol levels were slightly elevated in both males and females by vitamin E supplementation, but the elevations were not statistically significant. Serum triglyceride levels were significantly elevated in vitamin E-supplemented females, but only slightly increased in the supplemented males. High intake of vitamin E significantly elevated the level of this vitamin in serum and the elevation was greater in females than in males. Megavitamin E supplementation significantly decreased serum T-3 and T-4 levels in males and in females not using steroid oral contraceptive agents. This effect was not seen in females using oral contraceptive agents. The study indicated that under our experimental conditions, megavitamin E supplementation does not have a significant effect, beneficial or undesirable, on general health conditions, but it can cause a significant reduction of serum thyroid hormone levels and also an elevation of serum triglyceride levels in females.
Forty healthy men were fed diets providing 40% of energy from fat and a minimum of 25 mg vitamin E for 28 wk. During the first 10 wk diets were supplemented with placebo, 15 g mixed fat/d. During the second 10 wk placebo was replaced by 15 g fish-oil concentrate/d. During the last 8 wk 200 mg vitamin E/d was added to fish oil. Compared with placebo, fish-oil feeding significantly increased plasma glucose and decreased triacylglycerol, insulin, glucagon, growth hormone, and somatomedin C. The changes in plasma cholesterol, cortisol, and dehydroepiandrosterone sulphate (DHEA-S) were not significant. Fish oil plus vitamin E further decreased insulin, growth hormone, and DHEA-S and reversed the effect of fish-oil on somatomedin C. The changes in glucose, glucagon, growth hormone, and cortisol were not significant. Thus, changes in plasma glucose and lipids caused by dietary fish oil alone and with fish oil plus vitamin E appear to be due to alterations in hormones involved in carbohydrate and lipid metabolism.
Several lines of evidence suggest that sex hormones may be involved in the etiology of prostate cancer. We conducted a prospective nested case-control study to evaluate the relationships of serum androgens and estrogens to prostate cancer using serum collected at baseline for the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study. The 29,133 male smokers who participated in the trial were 50-69 years old at baseline. During 5-8 years of follow-up, 246 men were diagnosed with prostate cancer, and 116 of these were randomly selected for inclusion in the current study. For each case, two controls matched on age, date of blood collection, intervention group, and study center were selected. Hormones were measured in serum by RIA using standard procedures. None of the individual androgens or estrogens was significantly related to prostate cancer. These findings were unaltered by simultaneous evaluation of serum androgen and estrogen concentrations in multivariate models. These results do not support a strong relationship of serum androgens and estrogens with prostate cancer in smokers. Within-person variation in concentrations of some hormones may have contributed to the lack of significant associations.
We have tested several prostaglandins for stimulatory effects on ACTH secretion by injecting them into the anterior pituitary, the hypothalamic median eminence, or a tail vein of female rats. Plasma corticosterone levels were used as an index of ACTH secretion. In dexamethasone-pretreated rats, PGs E1, F1a and F2a (1.0, 0.5 and 0.5 jig, respectively) increased ACTH secretion to similar levels when injected into the median eminence. These doses were ineffective when injected into nearby regions of the basal hypothalamus, the anterior pituitary, or a tail vein. The responses were abolished by pretreatment with morphine, and partially inhibited by a higher dose of the dexamethasone. In contrast, upon iv administration to rats not pretreated with dexamethasone, PGEX was more than 30 times as potent as PGF1a in stimulating ACTH secretion. The responses to these PGs given intravenously were equally suppressible by dexamethasone and were absent in hypophysectomized rats. The stimulatory effect of PGF1a when inje...
There is evidence supporting a role for sex hormones in the etiology of prostate cancer. Supplementation with α-tocopherol reduced prostate cancer in the α-Tocoph-erol, β-Carotene Prevention Study (ATBC Study). The objective of this study was to assess the relation of baseline levels of serum α-tocopherol and serum sex hormones in older men. A cross-sectional analysis of serum α-tocopherol and sex hormone concentrations was conducted within a subset of the ATBC Study. Serum was collected in the morning after an overnight fast at baseline from 204 men ages 50-69 years participating in the ATBC Study and free of prostate cancer. Hormones were measured by radioimmunoassay, and α-tocopherol was measured by high-performance liquid chromatography by standard procedures. Multivariate linear regression was used to evaluate the association of serum α-tocopherol with nine androgens and estrogens after controlling for age, body mass index, hormone assay batch, and serum cholesterol. Serum α-tocopherol was significantly inversely associated with serum androstenedione, testosterone, sex hormone-binding globulin, and estrone. The difference in hormone concentration per milligram of α-tocopherol was 1.8-2.6% for these four hormones. These results indicated that α-tocopherol is related to concentrations of several sex hormones in older men and may have implications for the observed protective effect of supplemental vitamin E in relation to prostate cancer in the ATBC Study.
We investigated the modulating effect of vitamin E on pulmonary polyamine biosynthesis, cell proliferation and carcinogenesis in mice treated with urethane. Pulmonary ornithine decarboxylase induction and subsequent polyamine accumulation were observed during the initiation and promotion phases of the urethane-induced lung carcinogenesis in mice. The increases of ODC activity and polyamine level during both phases were almost inhibited when a high vitamin E diet was provided. The urethane-increased level of pulmonary proliferating cell nuclear antigen as a marker of cell proliferation during the carcinogenesis was inhibited by vitamin E treatment. Also, vitamin E suppressed the urethane-induced elevation of pulmonary cyclooxygenase activity as a marker of tumor promotion. In conjugation with these events, vitamin E reduced the development of lung tumors in mice treated with urethane. These results indicated that vitamin E could act as a useful chemopreventive agent against lung carcinogenesis in mice due to the regulation of cell proliferation.
BACKGROUND
Although essential, androgens alone are not sufficient to induce normal growth and functionality of the prostate. Nonandrogenic hormones must also be involved in the proliferation of the prostate cancer cells which do not respond to antiandrogenic therapy and which thus become androgen-independent. Prolactin, but also growth hormone and luteinizing hormone, are potentially able to act on both normal and abnormal prostatic cells.METHODS
In this review we summarize data from the literature concerning the physiological and pathological implications of prolactin, growth hormone, and luteinizing hormone on the prostate.RESULTSIn rodent prostates, prolactin and growth hormone can induce a variety of effects independently of androgens (e.g., transactivation of certain genes, or synthesis of the major secretion products). Moreover, hyperprolactinemia is responsible for inflammation and dysplasia of the gland, while growth hormone promotes the development of prostate tumors in vivo in the mouse and rat. Growth hormone acts on the gland directly, through prostatic growth hormone receptors, and/or indirectly via the stimulation of insulin-like growth factor-I (IGF-I) synthesis in the liver. Luteinizing hormone receptor is expressed in rat and human prostates. Luteinizing hormone increases the amount of various transcripts in the rat prostate through an androgen-independent pathway.CONCLUSIONS
Prolactin, growth hormone, and luteinizing hormone, alone or synergistically with androgens, play physiologically significant roles in the normal prostate. The involvement of these hormones in the development of benign prostatic hyperplasia and prostatic carcinoma is an issue that needs to be addressed. Prostate 38:159–165, 1999. © 1999 Wiley-Liss, Inc.
It has been hypothesized that an alteration in the sex hormone milieu may underlie coronary heart disease (CHD) and its risk factors. Leading to this hypothesis and important to it was the observation that serum testosterone level correlated negatively and the estradiol to testosterone ratio () correlated positively with serum insulin and glucose levels in non-obese men. As a test of the validity of this observation, the present study was conducted to investigate these correlations in men with obesity. Obesity in men is associated with hyperestrogenemia, hypotestosteronemia, hyperinsulinemia, hyperglycemia, and CHD. To determine whether the relationships between sex hormone levels and insulin and glucose levels found in non-obese men also occur in obese men independent of obesity, fasting levels of these substances, as well as free testosterone (FT) and sex-hormone-binding globulin (SHBG), were measured in 55 obese men aged 21 to 70. Correlation coefficients of sex hormones with other risk factors for CHD, ie, cholesterol, triglyceride, high-density lipoprotein cholesterol (HDL-C), blood pressure, and waist to hip circumference ratio (), were also calculated. As found previously, testosterone level correlated negatively with insulin (r = −.31, P = .01) and glucose (r = −.23, P < .05) levels and the insulin to glucose ratio (), and correlated positively with insulin (r = .41, P = .001) and glucose (r = .24, P < .05) levels and (r = .37, P < .005). The above correlations were controlled for body mass index (BMI) and age. Many other correlations were observed. These findings support the hypothesis that an elevation of , or some closely related hormonal alteration, in men underlies the glucose-insulin-lipid defect associated with CHD.
Rats were divided into the following four groups namely (a) sham-operated control, (b) 6-OHDA-treated, (c) sham-operated vitamin E-fed and (d) Vitamin E-fed treated with 6-OHDA. Total glutathione (GSH) and superoxide dismutase (SOD) were measured in brainstem (BS), striatum (ST), hippocampus, frontal cortex, and nucleus accumbens (N. Acc.). GSH and SOD levels were significantly decreased in all regions of 6-OHDA-treated rats compared to controls. Feeding of vitamin E resulted in a significant reduction of GSH in ST and N. Acc. but caused increases in SOD in BS, ST, and N. Acc. Pretreatment of rats with vitamin E caused significant attenuation of the effects of 6-OHDA on GSH and SOD in most of the brain regions. These results show that vitamin E can spare the scavenging systems from the injurious effects of 6-OHDA.
Dietary levels of vitamins C and E have been associated with cancer prevention and to a lesser extent with therapeutic enhancement of cancer treatment. Inhibition of prostaglandins (PGs) by pharmacological agents has been demonstrated to enhance immunocompetence, and to suppress growth of tumors in animals and humans. We report here on the effect of vitamins C and E on PGE2 production by human gingival fibroblasts and SCC-25 oral squamous carcinoma cells. The results indicate: 1. vitamins C and E exert a dose-dependent effect on arachidonic acid (AA) release and PGE2 synthesis; 2. vitamin E has a biphasic effect which is stimulatory at 1 and 10 microM and inhibitory at 100 microM; 3. vitamin E is considerably more potent than vitamin C in its inhibitory effect on AA and PGE2 in both cell types; 4. a combination of the two vitamins has a consistent dose-dependent inhibitory effect on AA and PGE2; 5. vitamin C stimulates PGE2 synthesis from exogenous AA in fibroblasts, and inhibits it in SCC-25 cells. The in vivo significance of these findings requires further investigation.
Rat peritoneal macrophages from vitamin E-treated rats (5 mg per rat for 6 successive days) contained 403.3 +/- 90.7 ng alpha-tocopherol/10(6) cells, whereas control macrophages contained 1.2 +/- 0.4 ng. PGE2 production in the macrophages from vitamin E-treated rats was significantly suppressed when stimulated with PMA and calcium ionophore A23187. The mechanism of vitamin E inhibition of PGE2 production in macrophages was investigated. The release of (14C)-arachidonic acid from pre-labeled macrophages and the conversion of (14C)-arachidonic acid to PGE2 by the homogenate of the cells were remarkably reduced. These results strongly suggested that the inhibition of PGE2 production by vitamin E results from the inhibition of the activities of both phospholipase A2 and cyclooxygenase.
Retinol, alpha-tocopherol, lycopene, and alpha- and beta-carotene can be simultaneously determined in human plasma by reversed-phase liquid chromatography. Plasma--0.5 mL plus added internal standard, retinyl acetate--is deproteinized with 0.5 mL of ethanol, then extracted with 1.0 mL of petroleum ether. The organic layer is removed and evaporated, the residue is redissolved in 0.25 mL of ethanol, and 8-microL samples are injected into a 60 X 4.6 mm column of Hypersil ODS 3-microns particles at 35 degrees C. An isocratic methanol mobile phase, flow rate 0.9 mL/min, is used for the 9-min run. Retinol and retinyl acetate are monitored at 305 nm, the tocopherols at 292 nm, and the carotenoids at 460 nm. Between-run CVs were 3.1, 6.9, 6.1, and 6.5% for retinol, alpha-tocopherol, lycopene, and beta-carotene, respectively. Small sample requirement, simplicity of extraction, short run time, and good reproducibility make this procedure ideal for clinical or research use.
The effect of prostaglandin E1 (PGE1) on rat anterior pituitary cyclic AMP accumulation and luteinizing hormone (LH) release was studied both in vivo and in vitro. Addition of PGE1 to incubation medium over a concentration range of 10-6 to 10-4 M produced a graded increase in pituitary cyclic AMP. At the lowest concentration (10-6 M) there was no significant increase in LH release, but proportional increments in LH release were seen with increasing concentrations of PGE1.Ten minutes after intravenous administration of 5 μg of PGE1 to adult male rats, pituitary cyclic AMP was substantially increased while serum LH levels were not changed. Administration of a higher dose of PGE1 (20 μg) produced a greater increase in pituitary cyclic AMP; and, at this dose serum LH was significantly increased. These results suggest that the PGE1 effect on LH release is mediated by the adenyl cyclase — cyclic AMP system.
Inhibitors of prostaglandin (PG) synthesis, aspirin and indomethacin, were used to assess the role of PG in gonadotrophin secretion. Both drugs reduced plasma PGF content and indomethacin reduced pituitary and hypothalamic concentration of PGF measured by a radioimmunoassay procedure reported herein. Chronic and acute administration of either indomethacin or aspirin blocked ovulation but indomethacin was effective at 1/30 the dose of aspirin. Injection of either LH or a mixture of PGE2 and PGF2α at the time of the expected ovulatory surge of LH was effective in reversing the blockade of ovulation that occurred after a single injection of indomethacin administered about 3 hours before the expected ovulatory surge of LH. However, LH did not reverse the blockade of ovulation produced when indomethacin was administered chronically beginning 30 hours before the expected ovulatory LH-surge. These data support the hypothesis that prostaglandins play a functional role in regulating the release of LH necessary for ovulation in the rat.
Diabetic subjects tend to develop microvascular complications believed to be due to platelet hyperaggregability. This increased platelet sensitivity is though to be the result of an imbalance of PGI2 and TXA2 production in diabetes. This study sought to determine whether megavitamin E supplementation could restore PGI2/TXA2 balance in streptozotocin-diabetic rats. Endogenous release of PGI2 by isolated aorta, determined via radioimmunoassay of its stable metabolite, 6-keto-PGF1 alpha, was significantly greater (P less than 0.05) in rats receiving 100x the normal vitamin E requirement than in untreated diabetic rats. PGI2 synthesis was negatively correlated with plasma glucose levels (r = -0.87, P less than 0.05) in non-fasted rats at sacrifice. Vitamin E supplementation, at both the 10x and the 100x level, significantly depressed (P less than 0.05) thrombin-stimulated synthesis of TXA2 in washed platelet. PGI2 and TXA2 production were expressed as a ratio. Megavitamin E therapy appears to increase this ratio over that seen in the diabetic animal. The data suggest that vitamin E, at high levels, exerts an ameliorating influence of the PGI2/TXA2 imbalance of diabetes.
The role of vitamin E in the endocrine system, in particular the pituitary-gonadal axis, was studied in humans and male rats by examining the hormonal differences between vitamin E deficient and supplemented conditions. In vitamin E deficient rats, pituitary content and basal plasma level of FSH and LH were significantly lower than those of the control rats, but testicular content and basal plasma level of testosterone were not significantly changed. On the other hand, in vitamin E supplemented rats, FSH and LH content in pituitary tissue was significantly higher than that of the controls, but there was no significant rise in basal FSH and LH level in plasma. The testosterone level was significantly elevated in both testicular tissue and plasma. It was also demonstrated that basal plasma testosterone and F.T.I. were increased in normal male subjects following oral vitamin E administration and the responsiveness of plasma testosterone levels to HCG was significantly higher during vitamin E administration than before administration. These results suggest that vitamin E may play an important and potent role in hormone production in the pituitary-gonadal axis in humans and rats.
Concentrations of fatty acids (FA) in prostatic tissue of patients with either benign or malignant prostatic disease have previously been shown to be significantly different. In particular, there was a significant reduction in arachidonic acid (AA, C20:4n-6) and docosapentaenoic acid (DPA, C22:5n-6) concentrations in malignant prostatic tissue (PCa) phospholipids (PL). It was suggested that the decreased AA concentration in PCa may be due to its increased metabolism via the cyclooxygenase (CO) and/or lipoxygenase (LO) pathways to produce eicosanoids such as prostaglandins (PGs) and/or leukotrienes (LTs) rather than an impairment in desaturase activity in situ. The eicosanoid production in benign prostatic tissue (BPH) and PCa was determined using [3H]AA. The only eicosanoid produced in significant amounts by either tissue was PGE2 and PCa converted radiolabelled AA to PGE2 at an almost 10-fold higher rate than BPH. PGE2 production from [3H]AA by PCa was investigated in the presence of oleic acid (OA, C18:1n-9), eicosapentaenoic acid (EPA, C20:5n-3), docosahexaenoic acid (DHA, C22:6n-3), dihomo-gamma-linolenic acid (DGLA, C20:3n-6), eicosatetraynoic acid (ETYA) and ketoprofen (KPN) respectively. OA was found to be the most effective inhibitor of PGE2 production by PCa compared with DHA, EPA, ETYA and KPN, while DGLA was the least effective. Diacylglycerol (DAG) formation from labelled AA by PCa was about 4-fold greater than in BPH. Such high levels of DAG may be a means of promoting tumorigenesis through activation of protein kinase C as found with phorbol esters which can be regarded as DAG analogues.
Sex steroids, particularly androgens, have been implicated in the pathogenesis of prostate cancer. Data from previous studies comparing circulating hormone levels in men with and without prostate cancer are difficult to interpret, since the studies were limited in size, hormone levels were analyzed in blood drawn after the diagnosis of cancer, nonrepresentative control subjects were used, and hormone and hormone-binding protein levels were not simultaneously adjusted.
We conducted a prospective, nested case-control study to investigate whether plasma hormone and sex hormone-binding globulin (SHBG) levels in healthy men were related to the subsequent development of prostate cancer.
Among participants in the Physicians' Health Study who provided plasma samples in 1982, we identified 222 men who developed prostate cancer by March 1992. Three hundred ninety control subjects, matched to the case patients on the bases of age, smoking status, and length of follow-up, were also identified. Immunoassays were used to measure the levels of total testosterone, dihydrotestosterone (DHT), 3 alpha-androstanediol glucuronide (AAG), estradiol, SHBG, and prolactin in the stored (at -82 degrees C) plasma samples. Correlations between individual hormone levels and between hormone levels and SHBG in the plasma of control subjects were assessed by use of Spearman correlation coefficients (r). Odds ratios (ORs) and 95% confidence intervals (CIs) specifying the prostate cancer risk associated with quartile levels of individual hormones, before and after adjustment for other hormones and SHBG, were calculated by use of conditional logistic regression modeling. Reported P values are two-sided.
No clear associations were found between the unadjusted levels of individual hormones or SHBG and the risk of prostate cancer. However, a strong correlation was observed between the levels of testosterone and SHBG (r = .55), and weaker correlations were detected between the levels of testosterone and the levels of both estradiol (r = .28) and DHT (r = .32) (all P < .001). When hormone and SHBG levels were adjusted simultaneously, a strong trend of increasing prostate cancer risk was observed with increasing levels of plasma testosterone (ORs by quartile = 1.00, 1.41, 1.98, and 2.60 [95% CI = 1.34-5.02]; P for trend = .004), an inverse trend in risk was seen with increasing levels of SHBG (ORs by quartile = 1.00, 0.93, 0.61, and 0.46 [95% CI = 0.24-0.89]; P for trend = .01), and a non-linear inverse association was found with increasing levels of estradiol (ORs by quartile = 1.00, 0.53, 0.40, and 0.56 [95% CI = 0.32-0.98]; P for trend = .03). No associations were detected between the levels of DHT or prolactin and prostate cancer risk; for AAG, a marker of 5 alpha-reductase activity, only suggestive evidence of a positive association was found. The results were essentially unchanged when case patients diagnosed within 4 years of plasma collection, case patients diagnosed with localized (i.e., nonaggressive) disease, or control subjects with elevated prostate serum antigen levels (> 2.5 ng/mL) were excluded from the analyses.
High levels of circulating testosterone and low levels of SHBG-both within normal endogenous ranges-are associated with increased risks of prostate cancer. Low levels of circulating estradiol may represent an additional risk factor. Circulating levels of DHT and AAG do not appear to be strongly related to prostate cancer risk.
To clarify the role of vitamin E (alpha-tocopherol) for the induction of cyclooxygenase-2 (COX-2) in rat macrophages stimulated by lipopolysaccharide (LPS), vitamin E-enriched macrophages were prepared by intraperitoneal injection of vitamin E for 6 days at a rate of 5 mg per day. The production of PGE2 was increased in dose- and time-dependent manners by addition of LPS in both control and vitamin E-enriched peritoneal macrophages. The maximum effect of LPS was observed in 12 h at concentration of 5 micrograms/ml. By analyzing COX-2 mRNA level by Northern blot and COX-2 enzyme mass and phosphotyrosine by Western blot, it was revealed that the increase of PGE2 production reflected the induction of COX-2 expression through activation of tyrosine kinase. Vitamin E failed to inhibit PGE2 production in LPS-stimulated macrophages; however, genistein, a tyrosine kinase inhibitor, completely inhibited the production at 100 microM. These results suggest that vitamin E does not inhibit COX-2 expression via LPS-mediated tyrosine kinase signal transduction pathway.
We investigated the modulating effect of vitamin E on pulmonary polyamine biosynthesis, cell proliferation and carcinogenesis in mice treated with urethane. Pulmonary ornithine decarboxylase induction and subsequent polyamine accumulation were observed during the initiation and promotion phases of the urethane-induced lung carcinogenesis in mice. The increases of ODC activity and polyamine level during both phases were almost inhibited when a high vitamin E diet was provided. The urethane-increased level of pulmonary proliferating cell nuclear antigen as a marker of cell proliferation during the carcinogenesis was inhibited by vitamin E treatment. Also, vitamin E suppressed the urethane-induced elevation of pulmonary cyclooxygenase activity as a marker of tumor promotion. In conjugation with these events, vitamin E reduced the development of lung tumors in mice treated with urethane. These results indicated that vitamin E could act as a useful chemopreventive agent against lung carcinogenesis in mice due to the regulation of cell proliferation.
The present study was undertaken to investigate a mechanism of the inhibitory effect of vitamin E in urethane-induced lung tumorigenesis in mice. We assayed ornithine decarboxylase (ODC) activity and the prostaglandin E2 (PGE2) level in lung at 8 weeks after urethane injection (promotion phase). Excessive vitamin E feeding or indomethacin treatment suppressed the urethane-induced increase in ODC activity, while exogenous PGE2 overcame the effect of vitamin E on ODC activity. Furthermore, the amount of PGE, and the level of ODC activity were well correlated. These results indicate that the vitamin E-induced decrease in PGE2 level probably contributes to the inhibition of ODC induction and the prevention of tumor development in the lung.
It is known that change in the arachidonic acid metabolism plays an important role in the development of tumors. This study was undertaken to understand the relationship of changes in lipoxygenase, cyclooxygenase and ornithine decarboxylase (ODC) to the inhibitory effect of vitamin E on urethane-induced lung tumorigenesis in mice. We analyzed the inhibitory effect of vitamin E on ornithine decarboxylase, cyclooxygenase and lipoxygenase activities at a promotion phase of lung tumorigenesis in mice. An increase in the ODC of urethane treated-mice and no significant change in the ODC of VE-treated mice were observed. An increase in the production of PGE2 and all HETES tested in the lungs of the urethane-treated mice was observed at week 8 after injection (promotion phase), showing a significant difference compared to the control group. Excessive vitamin E feeding during the initiation or promotion phases inhibited the increase in PGE2 and HETES produced by urethane treatment. These results suggest that the suppression of prostagrandin metabolism and ODC may be associated with the inhibitory effect of vitamin E against urethane-induced lung tumorigenesis.
Although triiodothyronine (T3) exerts major regulatory actions in both animals and humans, most clinical studies of T3 administration have been relatively short-term. The present study examined the effects of more than 2 months (63 days) of low-dose T3 treatment on overnight pulsatile growth hormone (GH) secretion, short-term insulin secretion, and of sex steroid levels in seven healthy, lean men studied at an inpatient metabolic unit. At baseline, there were strong correlations between sex hormone-binding globulin (SHBG) and several measures of GH production, including total GH production (r = .99), GH interburst interval (r = -.75), and GH mass (r = .82). SHBG was also inversely correlated with basal insulin secretion (r = -.74). There was a 42% increase in serum levels of total testosterone (18.5 +/- 1.3 to 26.3 +/- 1.8 nmol/L, P = .005) and a 150% increase in SHBG (18.0 +/- 2.2 to 44.9 +/- 7.0 nmol/L, P = .008) following T3 treatment. Estradiol and free testosterone levels were unchanged by treatment, although free testosterone decreased from 142.8 +/- 18.4 to 137.3 +/- 19.5 pmol/L. T3 treatment significantly reduced the GH interburst interval (P < .05) and produced slight increases in the measures of GH secretion. There were no statistically significant effects of T3 treatment on insulin secretion, although insulin peak amplitude, mass secreted per burst, and total production all decreased. We conclude that experimentally induced T3 excess in healthy men produces significant and sustained changes in sex hormone levels and GH secretion. Furthermore, there are strong associations between SHBG and both GH and insulin secretion independent of thyroid hormone excess that require additional study.
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.