Longitudinal analysis of carotenoid content in preterm human milk.

To describe the variability in carotenoid content of human milk (HM) in mothers of very to extremely low birth weight preterm infants throughout lactation and to explore the relationship between lutein in HM and the occurrence of retinopathy of prematurity (ROP) in preterm infants. We recruited healthy mothers along with their preterm infants that were born at gestational age 24 + 2 to 29 + 6 weeks or with a birth weight under 1500 g and were exclusively breastfed HM. Each participant provided up to 7 HM samples (2-10 ml) on day 0-3 and once a week until 6 weeks. Additionally, when possible, a blood sample was collected from the infant at week 6. Concentrations of the major carotenoids (lutein, zeaxanthin, beta-carotene, and lycopene) in all HM and blood samples were assessed and compared. Thirty-nine mother-infant dyads were included and 184 HM samples and 21 plasma samples were provided. Mean lutein, zeaxanthin, beta-carotene, and lycopene concentration decreased as lactation progressed, being at their highest in colostrum samples (156.9 vs. 66.9 vs. 363.9 vs. 426.8 ng/ml, respectively). Lycopene (41%) and beta-carotene (36%) were the predominant carotenoids in colostrum and up to 2 weeks post-delivery. Inversely, the proportion of lutein and zeaxanthin increased with lactation duration to account for 45% of the carotenoids in mature HM. Lutein accounted for 58% of the carotenoids in infant plasma and only 28% in HM. Lutein content of transition and mature HM did not differ between mothers of ROP and non-ROP infants.Conclusion Carotenoid content of HM was dynamic and varied between mothers and as lactation progressed. Infant plasma displayed a distinct distribution of carotenoids from HM.

Higher circulating α-carotene was associated with better cognitive function: an evaluation among the MIND trial participants.

There is emerging evidence linking fruit and vegetable consumption and cognitive function. However, studies focusing on the nutrients underlying this relationship are lacking. We aim to examine the association between plasma nutrients and cognition in a population at risk for cognitive decline with a suboptimal diet. The Mediterranean-DASH Intervention for Neurodegenerative Delay (MIND) trial is a randomized controlled intervention that examines the effects of the MIND diet to prevent cognitive decline. The primary outcome is global cognition. A multivariate linear model was used to investigate the association between blood nutrients and global and/or domain-specific cognition. The model was adjusted for age, sex, education, study site, smoking status, cognitive activities and physical activities. High plasma α-carotene was associated with better global cognition. Participants in the highest tertile of plasma α-carotene had a higher global cognition z score of 0⋅17 when compared with individuals in the lowest tertile (P 0⋅002). Circulating α-carotene levels were also associated with higher semantic memory scores (P for trend 0⋅007). Lutein and zeaxanthin (combined) was positively associated with higher semantic memory scores (P for trend 0⋅009). Our study demonstrated that higher α-carotene levels in blood were associated with higher global cognition scores in a US population at risk for cognitive decline. The higher α-carotene levels in blood reflected greater intakes of fruits, other types of vegetables and lesser intakes of butter and margarine and meat. The higher circulating levels of lutein plus zeaxanthin reflected a dietary pattern with high intakes of fruits, green leafy, other vegetables and cheese, and low consumption of fried foods. Objective nutrient markers in the blood can better characterize dietary intake, which may facilitate the implementation of a tailored dietary intervention for the prevention of cognitive decline.

Application of blood concentration biomarkers in nutritional epidemiology: example of carotenoid and tocopherol intake in relation to chronic disease risk.

BACKGROUND: Biomarkers provide potential to objectively measure the intake of nutrients and foods, and thereby to strengthen nutritional epidemiology association studies. However, there are only a few established intake biomarkers, mostly based on recovery of nutrients or their metabolites in urine. Blood concentration measures provide a potential biomarker source for many additional nutritional variables, but their use in disease-association studies requires further development. OBJECTIVE: The aim of this study was to apply recently proposed serum-based carotenoid and tocopherol intake biomarkers and to examine their association with the incidence of major cardiovascular diseases, cancers, and diabetes in a subset of Women's Health Initiative (WHI) cohorts. METHODS: Serum concentrations of α- and ß-carotene, lutein plus zeaxanthin (L + Z), and α-tocopherol were routinely measured at baseline in a subset of 5488 enrollees in WHI cohorts. Intake biomarkers for these 4 micronutrients, obtained by combining serum concentrations with participant characteristics, were recently proposed using a 153-woman feeding study within WHI. These biomarker equations are augmented here to include pertinent disease risk factors and are associated with subsequent chronic disease incidence in this WHI subset. RESULTS: HRs for a doubling of micronutrient intake differed only moderately from the null for the outcomes considered. However, somewhat lower risks of specific cardiovascular outcomes, breast cancer, and diabetes were associated with a higher intake of α- and ß-carotene, lower risk of diabetes was associated with higher L + Z intake, and elevated risks of certain cardiovascular outcomes were associated with a higher intake of α-tocopherol. These patterns remained following the exclusion of baseline users of dietary supplements. CONCLUSIONS: Concentration biomarkers can be calculated from blood specimens obtained in large epidemiologic cohorts and applied directly in disease-association analyses, without relying on self-reported dietary data. Observed associations between carotenoid and tocopherol biomarkers and chronic disease risk could be usefully evaluated further using stored serum specimens on the entire WHI cohort. This study was registered at www.clinicaltrials.gov as NCT00000611.

Relationship of fruit and vegetable intake to dietary antioxidant capacity and markers of oxidative stress: A sex-related study.

OBJECTIVES: Oxidative stress contributes to the development of chronic diseases. Fruits and vegetables contain several phytonutrients (carotenoids, polyphenols) that exert antioxidant effects. The aim of this study was to investigate sex differences in fruit and vegetable intake, and the relationship to plasma levels of carotenoids as well as to total antioxidant capacity (pTAC). We studied also sex differences in the relationship between fruit and vegetables intake and plasma levels of lipid hydroperoxides, as well as of oxidized low-density lipoprotein (ox-LDL). METHODS: This study included 83 healthy adults (35 men and 48 women, mean age 40 ± 10 y). Dietary intake of carotenoids and total antioxidant capacity (dTAC) were evaluated on the basis of a 15-d food frequency questionnaire. Plasma levels of ß-carotene, lutein, and pTAC were studied. Moreover, levels of plasma lipid hydroperoxides and ox-LDL were evaluated using the ferrous oxidation-xylenol orange 2 (FOX2) assay and a monoclonal antibody-based enzyme-linked immunosorbent assay procedure, respectively. RESULTS: Dietary habits were sex-related with a higher intake of fruits and vegetables (P < 0.05) and ß-carotene (P < 0.001) in women than in men. Mean values of plasma lutein and ß-carotene were higher in women than in men. Mean values of ox-LDL and lipid hydroperoxides were higher in men than in women (P < 0.05). Significant negative correlations were established between the individual values of ox-LDL and the levels of lutein versus ß-carotene and versus pTAC values in plasma in both groups. Individuals belonging to the tertile with the highest daily intake of fruits and vegetables or the highest daily dTAC showed the lowest levels of plasma ox-LDL. In each category, sex-related differences were observed with men showing higher levels of ox-LDL than women. Moreover, lower levels of plasma ß-carotene were observed in men in each tertile of daily intake of fruits and vegetables compared with females. CONCLUSIONS: Based on the data obtained, we confirm that high fruit and vegetable consumption exerts a positive effect on antioxidant defenses and decreases oxidative damage of plasma lipoproteins for both sexes. The results suggest that the protective effect can be found to a higher extent in women than in men. Sex-based differences are apparent in many chronic diseases. Thus, a higher consumption of antioxidant-rich fruits and vegetables should be recommended in efforts to prevent diseases in which sex-related differences in oxidative stress play a considerable role.

Lutein Intake and Blood Lutein Concentration Are Positively Associated with Physical Activity in Adults: A Systematic Review.

Lutein is a carotenoid that reduces the risk of some chronic diseases, possibly by altering physical activity behavior. The objective of this study was to conduct a systematic review of studies examining the relationship between lutein status (dietary intake/blood concentration) and physical activity. Peer-reviewed studies published in Medline, Web of Science, Cumulative Index to Nursing and Allied Health Literature (CINAHL), Scopus, and Embase were included if they reported a measure of association between lutein status and physical activity. Seventeen studies met the inclusion criteria. Eleven reported positive associations, three reported mixed results, and three reported no association. Two studies used objective measures of lutein status (blood concentration) and physical activity (accelerometry) and reported positive associations, with correlations of ≥0.36 and differences of ≥57% in physical activity between upper and lower tertiles. Studies using self-report measures reported weaker correlations (r = 0.06 to 0.25), but still more physical activity (18% to ≥600% higher) in those with the highest compared with the lowest lutein status. Higher lutein status may be associated with higher levels of physical activity, which may contribute to a reduced risk of chronic disease.

Opposite Effects of the Spinach Food Matrix on Lutein Bioaccessibility and Intestinal Uptake Lead to Unchanged Bioavailability Compared to Pure Lutein.

SCOPE: Food matrix is generally believed to alter carotenoid bioavailability, but its effect on xanthophylls is usually limited. This study thus aims to decipher the digestion-absorption process of lutein in the presence or not of a food matrix. METHODS: Lutein transfer to gastric-like lipid droplets or artificial mixed micelles was assessed when lutein was added to test meals either as a pure molecule ((all-E)-lutein) or in canned spinach ((Z) + (all-E)-lutein). The obtained mixed micelles were delivered to Caco-2 cells to evaluate lutein uptake. Finally postprandial plasma lutein responses were compared in minipigs after the two test meals. RESULTS: Lutein transfer to gastric-like lipid droplets and to mixed micelles was higher when lutein was added in spinach than when it was added as pure lutein (+614% and +147%, respectively, p < 0.05). Conversely, lutein uptake was less effective when micellar lutein was from a meal containing spinach than from a meal containing its pure form (-55%, p < 0.05). In minipigs, postprandial lutein response was delayed with spinach but not significantly different after the two test meals. CONCLUSION: Opposite effects at the micellarization and intestinal cell uptake steps explain the lack of effect of spinach matrix on lutein bioavailability.

Serum Carotenoids Are Inversely Associated with RBP4 and Other Inflammatory Markers in Middle-Aged and Elderly Adults.

(1) Background: Carotenoids may be inversely associated with inflammatory markers (i.e., TNF-α, IL-6, IL-1ß). However, data are scarce on retinol binding protein 4 (RBP4) in humans. We examined the associations among serum carotenoids, RBP4 and several inflammatory markers in a Chinese population. (2) Methods: This community-based cross-sectional study included 3031 participants (68% males) aged 40-75 years in Guangzhou, China. Serum concentrations of carotenoids, RBP4, and inflammatory markers were measured. (3) Results: Generally, serum individual and total carotenoids were significantly and inversely associated with retinol-adjusted RBP4, RBP4, hsCRP, MCP1, and TNF-alpha levels. Age- and gender-adjusted partial correlation coefficients between total carotenoids and the above inflammatory markers were -0.129, -0.097, -0.159, -0.079, and -0.014 (all p < 0.01, except for TNF-alpha with p >0.05), respectively. The multivariate-adjusted values of partial correlation coefficients for these inflammation-related markers were -0.098, -0.079, -0.114, -0.090, and -0.079 (all p < 0.01), respectively. Among the individual carotenoids, those with the most predominant association were lutein-zeaxanthin and total carotenoids for retinol-adjusted RBP4 and RBP4, alpha- and beta-carotene for hsCRP, and alpha-carotene for MCP1 and TNF-alpha. No significant associations were observed for IL-6 and IL-1beta. (4) Conclusions: Serum carotenoids were inversely associated with RBP4, hsCRP, MCP1 and TNF-alpha among middle-aged and elderly Chinese adults.

Modeling the dose effects of soybean oil in salad dressing on carotenoid and fat-soluble vitamin bioavailability in salad vegetables.

Background: Previously, we showed that vegetable oil is necessary for carotenoid absorption from salad vegetables. Research is needed to better define the dose effect and its interindividual variation for carotenoids and fat-soluble vitamins.Objective: The objective was to model the dose-response relation between the amount of soybean oil in salad dressing and the absorption of 1) carotenoids, phylloquinone, and tocopherols in salad vegetables and 2) retinyl palmitate formed from the provitamin A carotenoids.Design: Women (n = 12) each consumed 5 vegetable salads with salad dressings containing 0, 2, 4, 8, or 32 g soybean oil. Blood was collected at selected time points. The outcome variables were the chylomicron carotenoid and fat-soluble vitamin area under the curve (AUC) and maximum content in the plasma chylomicron fraction (Cmax). The individual-specific and group-average dose-response relations were investigated by fitting linear mixed-effects random coefficient models.Results: Across the entire 0-32-g range, soybean oil was linearly related to the chylomicron AUC and Cmax values for α-carotene, lycopene, phylloquinone, and retinyl palmitate. Across 0-8 g of soybean oil, there was a linear increase in the chylomicron AUC and Cmax values for ß-carotene. Across a more limited 0-4-g range of soybean oil, there were minor linear increases in the chylomicron AUC for lutein and α- and total tocopherol. Absorption of all carotenoids and fat-soluble vitamins was highest with 32 g oil (P < 0.002). For 32 g oil, the interindividual rank order of the chylomicron AUCs was consistent across the carotenoids and fat-soluble vitamins (P < 0.0001).Conclusions: Within the linear range, the average absorption of carotenoids and fat-soluble vitamins could be largely predicted by the soybean oil effect. However, the effect varied widely, and some individuals showed a negligible response. There was a global soybean oil effect such that those who absorbed more of one carotenoid and fat-soluble vitamin also tended to absorb more of the others. This trial was registered at clinicaltrials.gov as NCT02867488.

Lutein exerts anti-inflammatory effects in patients with coronary artery disease.

BACKGROUND AND AIMS: Many coronary artery disease (CAD) patients exhibit chronic low-grade inflammation. Carotenoids are anti-oxidants with potential anti-inflammatory properties. Here, we first assessed relationships between interleukin (IL)-6 and individual carotenoids in plasma from CAD patients. Based on the results, we proceeded to assess anti-inflammatory effects of one carotenoid, lutein, in peripheral blood mononuclear cells (PBMCs) from CAD patients. METHODS: Lutein + zeaxanthin (isomers with lutein being dominant), ß-cryptoxanthin, lycopene, α- and ß-carotene and IL-6 were measured in plasma from 134 patients with stable angina (SA) and 59 patients with acute coronary syndrome. In 42 patients, plasma measurements were also performed 3 months after coronary intervention. PBMCs from SA patients were pre-treated with lutein (1, 5 and 25 µM) for 24 h followed by 24 h incubation ± lipopolysaccharide (LPS). Cell pellets were collected for IL-6, IL-1ß and TNF mRNA and intracellular lutein. Cytokine secretion was measured in cell media. RESULTS: Only lutein + zeaxanthin were inversely correlated with IL-6 in SA patients at baseline (r = -0.366, p < 0.001) and follow-up (r = -0.546, p < 0.001). Ex vivo, lutein was taken up by PBMCs from SA patients in a dose- and time-dependent manner. Pre-treatment with lutein dose-dependently lowered LPS-induced secretion of IL-6, IL-1ß (p < 0.01) and TNF (p < 0.05), and also reduced IL-6, IL-1ß and TNF mRNA expression (p < 0.05). CONCLUSIONS: Clinical findings highlighted the inverse association between lutein and IL-6 in CAD patients. Anti-inflammatory effects of lutein in PBMCs from CAD patients were consolidated in ex vivo experiments. Taken together, these results show that lutein has the potential to play a role in resolution of chronic inflammation in CAD patients.

Non-Dietary Correlates and Determinants of Plasma Lutein and Zeaxanthin Concentrations in the Irish Population.

OBJECTIVE: To investigate non-dietary correlates and determinants of plasma lutein (L) and zeaxanthin (Z) concentrations in The Irish Longitudinal Study on Ageing (TILDA) sample. DESIGN: Cross-sectional study. SETTING: Community dwelling adults in the Republic of Ireland (ROI). PARTICIPANTS: 3,681 participants aged 50 years and older. MEASUREMENTS: TILDA is a nationally representative prospective cohort study of community dwelling adults aged 50 years and over in the ROI. Demographic and health variables were collected during a face-to-face interview carried out in the home (n=8175), and a substantial proportion of these (n=5035; 62%) also attended a study visit in a health assessment centre. Blood samples collected at baseline (wave 1, the subject of the current study), were analysed for plasma concentrations of L and Z by reversed-phase high performance liquid chromatography, and macular pigment (MP) optical density was also measured (using customized heterochromatic flicker photometry). RESULTS: After excluding participants with eye disease, data from 3,681 participants were available for analysis. For this group of participants, plasma L and Z were inversely and significantly associated with body mass index (BMI), and were positively and significantly associated with MP, total cholesterol, high-density lipoprotein (HDL) and low-density lipoprotein (LDL) (p<0.001, for all). Plasma L and Z were significantly lower in males, current smokers, participants reporting less physical exercise, and participants reporting lower levels of education (p<0.05, for all). Plasma L was significantly higher in participants reporting a family history of age-related macular degeneration (AMD) (p=0.001), and in the group of ≥75 years old (p<0.05). For each of these variables, the significant associations remained after controlling for other potential confounding variables. CONCLUSION: The findings of this large study indicate that plasma concentrations of L and Z were lower in association with indicators of a poor lifestyle (high BMI, tobacco use, and less physical exercise) and in association with lower education, indicating that modifying lifestyle in a positive way is likely to be reflected in higher concentrations of plasma carotenoids, with consequential and putative health benefits.

Lutein attenuates oxidative stress markers and ameliorates glucose homeostasis through polyol pathway in heart and kidney of STZ-induced hyperglycemic rat model.

PURPOSE: Lutein's role on chronic hyperglycemia-induced oxidative stress and associated glucose homeostasis in heart and kidney is limited. Purpose of the study is to investigate the effect of lutein on cardiac and renal polyol pathway enzymes and oxidative stress markers under hyperglycemia-induced oxidative stress condition using streptozotocin (STZ)-injected rat model. METHODS: STZ-induced hyperglycemic (fasting blood glucose ≥11 mM) male Wistar rats were divided into two groups (n = 11/group). Group 1 received micellar lutein (39 nmol/day/rat) and group 2 (negative control) received micelle without lutein for 8 weeks. A separate group (no STZ injected) served as a positive control (n = 11/group). Oral glucose tolerance test (OGTT), biweekly urine glucose and activities of aldose reductase (AR) and sorbitol dehydrogenase (SDH) enzymes were assessed. Activities of antioxidant enzymes and antioxidant level were also evaluated. RESULTS: Lutein-administered hyperglycemic rats showed better glucose tolerance as evidenced with OGTT and biweekly urine glucose when compared to negative control. Activities of AR and SDH were decreased in heart and kidney of lutein-fed hyperglycemic rats. Also, they had significantly (p < 0.05) decreased malondialdehyde levels (66, 34, and 33 %) and increased reduced glutathione level (81, 18 and 92 %) in serum, heart and kidney, respectively. Altered antioxidant enzyme activities such as superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase and glutathione transferase were also affected in serum, heart and kidney of lutein-fed diabetic group. CONCLUSION: Lutein prevented cardiac and renal injury in STZ-induced hyperglycemic rats due to potential amelioration of altered activities in polyol pathway and oxidative stress markers.

Lutein and atherosclerosis: Belfast versus Toulouse revisited.

In 1995 we reported that mean plasma lutein concentrations in salaried men and women from Toulouse in Southern France were double those in subjects recruited from general practitioner lists in Belfast, Northern Ireland. At the time incidence of coronary heart disease (CHD) in Southern France was among the lowest in Europe and was much higher in Northern Ireland. Plasma lutein is a biomarker of vegetable and fruit intake and evidence suggests that high concentrations are generally associated with better cardiometabolic health. At the time we speculated like others that role of the carotenoids may well have been to prevent oxidation of lipid in the lipoproteins and so reduce the uptake of oxidised lipid by macrophages and its deposition within the intimal layers of the major arteries as plaque. It is now widely accepted that CHD is an inflammatory disease and that macrophages within plaque together with tissue damage contribute to this inflammation. Stimulated macrophages release cytokines to activate the immune system both locally and systemically. Precursor complement proteins in the blood are activated to assist immune cells in phagocytosis and cell repair. Individuals with a history of arteriosclerosis display significantly higher concentrations of complement factors C3 and C3a than subjects without such a history. Metabolism of C3 via the alternate complement pathway can give rise to the membrane attack complex (MAC) which creates a hole or pore in pathogens or host cells, killing the cell. Recent studies in patients with early age related macular disease (AMD) who also exhibit similar elevated concentrations of complement proteins in their blood, showed supplementation with lutein progressively decreased the amount of the MAC and other complement factors in the blood. Lutein was used in the supplementation experiments because it is an important constituent of macular pigment. Thus the healthier cardiometabolic features displayed by the people in Toulouse may have been due to the effects of concurrent high concentrations of plasma lutein on the immune system and complement in particular. Other carotenoids may exert similar antioxidant effects but we and others found no differences in antioxidant nutrients between subjects in Toulouse and Belfast or between subjects with asymptomatic markers of atherosclerosis and controls.

Plasma Carotenoids, Tocopherols, and Retinol in the Age-Stratified (35-74 Years) General Population: A Cross-Sectional Study in Six European Countries.

Blood micronutrient status may change with age. We analyzed plasma carotenoids, α-/γ-tocopherol, and retinol and their associations with age, demographic characteristics, and dietary habits (assessed by a short food frequency questionnaire) in a cross-sectional study of 2118 women and men (age-stratified from 35 to 74 years) of the general population from six European countries. Higher age was associated with lower lycopene and α-/ß-carotene and higher ß-cryptoxanthin, lutein, zeaxanthin, α-/γ-tocopherol, and retinol levels. Significant correlations with age were observed for lycopene (r = -0.248), α-tocopherol (r = 0.208), α-carotene (r = -0.112), and ß-cryptoxanthin (r = 0.125; all p < 0.001). Age was inversely associated with lycopene (-6.5% per five-year age increase) and this association remained in the multiple regression model with the significant predictors (covariables) being country, season, cholesterol, gender, smoking status, body mass index (BMI (kg/m²)), and dietary habits. The positive association of α-tocopherol with age remained when all covariates including cholesterol and use of vitamin supplements were included (1.7% vs. 2.4% per five-year age increase). The association of higher ß-cryptoxanthin with higher age was no longer statistically significant after adjustment for fruit consumption, whereas the inverse association of α-carotene with age remained in the fully adjusted multivariable model (-4.8% vs. -3.8% per five-year age increase). We conclude from our study that age is an independent predictor of plasma lycopene, α-tocopherol, and α-carotene.

Critical Difference and Biological Variation in Biomarkers of Oxidative Stress and Nutritional Status in Athletes.

UNLABELLED: The longitudinal monitoring of oxidative stress (OS) in athletes may enable the identification of fatigued states and underperformance. The application of OS biomarker monitoring programs in sport are hindered by reliability and repeatability of in-the-field testing tools, the turnaround of results, and the understanding of biological variation (BV). Knowledge of BV and critical difference values (CDV) may assist with data interpretation in the individual athlete. METHODS: We aimed firstly to assess the repeatability of the clinical point of care redox test, Free Oxygen Radical Test (FORT) and the Free Oxygen Radical Defence (FORD) in trained participants and elite athletes and secondly to calculate the analytical, BV, CDV and index of individuality (II) for FORT, FORD, red blood cell glutathione, lutein, α and γ-tocopherol. Part 1: Fifteen elite athletes were sampled in duplicate for calculation of the repeatability of the FORT and FORD tests. Part 2: Twelve well-trained athletes had venous samples drawn every 2 hours from 0800 to 1800 for calculation of BV, CDV, II for FORT, FORD, RBC GSH, lutein, α-tocopherol and γ-tocopherol. RESULTS: Repeatability of the FORT and FORD assay was 3.9% and 3.7% respectively. Biomarker CDV ranged from 12.8% to 37%, with a circadian effect for FORT, α-tocopherol and γ-tocopherol (p<0.01), with all biomarker indices of individuality < 0.8 arbitrary units. CONCLUSION: We report that the use of the novel redox test in athletes is practical, and the generation of BV and CDV for biomarkers of OS enhances the interpretation of physiologically meaningful changes in individuals above the use of clinical reference ranges alone.

Serum Antioxidants Are Associated with Serum Reproductive Hormones and Ovulation among Healthy Women.

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 ß-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.

Association of carotenoids with risk of gastric cancer: A meta-analysis.

BACKGROUND & AIMS: Prior studies on carotenoids and gastric cancer risk have generated inconsistent results. We performed a meta-analysis of observational studies to summarize the evidence regarding the relation of carotenoids and gastric cancer risk. METHODS: A comprehensive search was performed to identify all observational studies providing quantitative estimates between gastric cancer risk and carotenoids. The fixed or random effect model was selected based on the homogeneity test among studies in the highest vs. lowest categorical analyses. RESULTS: 13 published case-control studies with 14 results including 3919 cases and 7400 controls, and 8 cohort studies involving 1972 cases of gastric cancer and 96,691 participants, met the inclusion criteria. For case-control studies, only intake of ß-carotene and α-carotene were significantly associated with a reduced gastric cancer risk. The summary OR(95%CI) for ß-carotene, α-carotene, lycopene and lutein were 0.52(0.46-0.59), 0.59(0.37-0.92), 0.88(0.55-1.41) and 0.85(0.56-1.30) respectively. In contrast, the summary RR(95%CI) for ß-carotene, α-carotene, lycopene and lutein were 0.72(0.50-1.03), 0.79(0.58-1.07), 0.80(0.60-1.07) and 0.95(0.77-1.18), respectively. CONCLUSION: Although data from case-control studies suggested that ß-carotene, α-carotene were inversely associated with risk of gastric cancer, there was no conclusive evidence on this association because of inconsistencies between case-control and cohort studies.

The effects of lutein on respiratory health across the life course: A systematic review.

BACKGROUND: Lutein, a fat-soluble carotenoid present in green leafy vegetables and eggs, has strong antioxidant properties and could therefore be important for respiratory health. DESIGN: We systematically reviewed the literature for articles that evaluated associations of lutein (intake, supplements or blood levels) with respiratory outcomes, published in Medline, Embase, Cochrane Central, PubMed, Web of Science and Google Scholar, up to August 2014. RESULTS: We identified one Randomized Control Trial (RCT), two longitudinal, four prospective and six cross-sectional studies. The individual studies obtained a Quality Score ranging between 3 and 9. Six studies were performed in children, which examined bronchopulmonary dysplasia (BPD), asthma and wheezing. In adults, 7 studies investigated asthma, respiratory function and respiratory mortality. The RCT found a borderline significant effect of lutein/zeaxanthin supplementation in neonates on the risk of BPD (OR 0.43 (95% CI 0.15; 1.17). No association was found between lutein intake or levels and respiratory outcomes in children. A case-control study in adults showed lower lutein levels in asthma cases. Three studies, with a prospective or longitudinal study design, in adults found a small but a significant positive association between lutein intake or levels and respiratory function. No association was found in the other two studies. In relation to respiratory mortality, one longitudinal study showed that higher lutein blood levels were associated with a decreased mortality (HR 0.77 (95% CI 0.60; 0.99), per SD increase in lutein). CONCLUSION: The published literature suggests a possible positive association between lutein and respiratory health. However, the literature is scarce and most studies are of observational nature.

Intakes of Lutein, Zeaxanthin, and Other Carotenoids and Age-Related Macular Degeneration During 2 Decades of Prospective Follow-up.

IMPORTANCE: Despite strong biological plausibility, evidence from epidemiologic studies and clinical trials on the relations between intakes of lutein and zeaxanthin and age-related macular degeneration (AMD) has been inconsistent. The roles of other carotenoids are less thoroughly investigated. OBJECTIVE: To investigate the associations between intakes of carotenoids and AMD. DESIGN, SETTING, AND PARTICIPANTS: Prospective cohort study, with cohorts from the Nurses' Health Study and the Health Professionals Follow-up Study in the United States. A total of 63,443 women and 38,603 men were followed up, from 1984 until May 31, 2010, in the Nurses' Health Study and from 1986 until January 31, 2010, in the Health Professionals Follow-up Study. All participants were aged 50 years or older and were free of diagnosed AMD, diabetes mellitus, cardiovascular disease, and cancer at baseline. MAIN OUTCOMES AND MEASURES: Predicted plasma carotenoid scores were computed directly from food intake, assessed by repeated food frequency questionnaires at baseline and follow-up, using validated regression models to account for bioavailability and reporting validity of different foods, and associations between predicted plasma carotenoid scores and AMD were determined. RESULTS: We confirmed 1361 incident intermediate and 1118 advanced AMD cases (primarily neovascular AMD) with a visual acuity of 20/30 or worse by medical record review. Comparing extreme quintiles of predicted plasma lutein/zeaxanthin score, we found a risk reduction for advanced AMD of about 40% in both women and men (pooled relative risk comparing extreme quintiles = 0.59; 95% CI, 0.48-0.73; P for trend < .001). Predicted plasma carotenoid scores for other carotenoids, including ß-cryptoxanthin, α-carotene, and ß-carotene, were associated with a 25% to 35% lower risk of advanced AMD when comparing extreme quintiles. The relative risk comparing extreme quintiles for the predicted plasma total carotenoid index was 0.65 (95% CI, 0.53-0.80; P for trend < .001). We did not identify any associations of carotenoids, either as predicted plasma score or calculated intake, with intermediate AMD. CONCLUSIONS AND RELEVANCE: Higher intake of bioavailable lutein/zeaxanthin is associated with a long-term reduced risk of advanced AMD. Given that some other carotenoids are also associated with a lower risk, a public health strategy aimed at increasing dietary consumption of a wide variety of fruits and vegetables rich in carotenoids may reduce the incidence of advanced AMD.

Joint Associations of Diet, Lifestyle, and Genes with Age-Related Macular Degeneration.

PURPOSE: Unhealthy lifestyles have been associated with increased odds for age-related macular degeneration (AMD). Whether this association is modified by genetic risk for AMD is unknown and was investigated. DESIGN: Interactions between healthy lifestyles AMD risk genotypes were studied in relation to the prevalence of AMD, assessed 6 years later. PARTICIPANTS: Women 50 to 79 years of age in the Carotenoids in Age-Related Eye Disease Study with exposure and AMD data (n=1663). METHODS: Healthy lifestyle scores (0-6 points) were assigned based on Healthy Eating Index scores, physical activity (metabolic equivalent of task hours/week), and smoking pack years assessed in 1994 and 1998. Genetic risk was based on Y402H in complement factor H (CFH) and A69S in age-related maculopathy susceptibility locus 2 (ARMS2). Additive and multiplicative interactions in odds ratios were assessed using the synergy index and a multiplicative interaction term, respectively. MAIN OUTCOME MEASURES: AMD presence and severity were assessed from grading of stereoscopic fundus photographs taken in 2001-2004. AMD was present in 337 women, 91% of whom had early AMD. RESULTS: The odds of AMD were 3.3 times greater (95% confidence interval [CI], 1.8-6.1) in women with both low healthy lifestyle score (0-2) and high-risk CFH genotype (CC), relative to those who had low genetic risk (TT) and high healthy lifestyle scores (4-6). There were no significant additive (synergy index [SI], 1.08; 95% CI, 0.70-1.67) or multiplicative (Pinteraction=0.94) interactions in the full sample. However, when limiting the sample to women with stable diets before AMD assessment (n=728) the odds for AMD associated with low healthy lifestyle scores and high-risk CFH genotype were strengthened (odds ratio, 4.6; 95% CI, 1.8-11.6) and the synergy index was significant (SI, 1.34; 95% CI, 1.05-1.70). Adjusting for dietary lutein and zeaxanthin attenuated, and therefore partially explained, the joint association. There were no significant additive or multiplicative interactions for ARMS2 and lifestyle score. CONCLUSIONS: Having unhealthy lifestyles and 2 CFH risk alleles increased AMD risk (primarily in the early stages), in an or additive or greater (synergistic) manner. However, unhealthy lifestyles increased AMD risk regardless of AMD risk genotype.

Relationship between Carotenoids, Retinol, and Estradiol Levels in Older Women.

BACKGROUND: In vitro evidence suggests anti-estrogenic properties for retinol and carotenoids, supporting a chemo-preventive role of these phytochemicals in estrogen-dependent cancers. During aging there are significant reductions in retinol and carotenoid concentrations, whereas estradiol levels decline during menopause and progressively increase from the age of 65. We aimed to investigate the hypothesis of a potential relationship between circulating levels of retinol, carotenoids, and estradiol (E2) in a cohort of late post-menopausal women. METHODS: We examined 512 women ≥ 65 years from the InCHIANTI study. Retinol, α-caroten, ß-caroten, ß-criptoxantin, lutein, zeaxanthin, and lycopene levels were assayed at enrollment (1998-2000) by High-Performance Liquid Chromatography. Estradiol and testosterone (T) levels were assessed by Radioimmunometry (RIA) and testosterone-to-estradiol ratio (T/E2), as a proxy of aromatase activity, was also calculated. General linear models adjusted for age (Model 1) and further adjusted for other confounders including Body Mass Index (BMI) BMI, smoking, intake of energy, lipids, and vitamin A; C-Reactive Protein, insulin, total cholesterol, liver function, and testosterone (Model 2) were used to investigate the relationship between retinol, carotenoids, and E2 levels. To address the independent relationship between carotenoids and E2 levels, factors significantly associated with E2 in Model 2 were also included in a fully adjusted Model 3. RESULTS: After adjustment for age, α-carotene (ß ± SE = -0.01 ± 0.004, p = 0.02) and ß-carotene (ß ± SE = -0.07 ± 0.02, p = 0.0007) were significantly and inversely associated with E2 levels. α-Carotene was also significantly and positively associated with T/E2 ratio (ß ± SE = 0.07 ± 0.03, p = 0.01). After adjustment for other confounders (Model 2), the inverse relationship between α-carotene (ß ± SE = -1.59 ± 0.61, p = 0.01), ß-carotene (ß ± SE = -0.29 ± 0.08, p = 0.0009), and E2 persisted whereas the relationship between α-carotene and T/E2 ratio was attenuated (ß ± SE = 0.22 ± 0.12, p = 0.07). In a fully adjusted model (Model 3), only ß-carotene (ß ± SE = -0.05 ± 0.02, p = 0.03) was significantly and inversely associated with E2 levels independent of α-carotene. No association was found between retinol, total non-pro-vitamin A carotenoids, lutein, zeaxanthin, and lycopene, and E2 levels. CONCLUSIONS: In older women, ß-carotene levels are independently and inversely associated with E2.