Lipid-soluble Micronutrients Research Articles

Overall and Sex-Specific Associations of Serum Lipid-Soluble Micronutrients with Metabolic Dysfunction-Associated Steatotic Liver Disease among Adults in the United States.

This study examined overall and sex-specific associations of serum lipid-soluble micronutrients including α- and γ-tocopherols, 25-hydroxy-vitamin D (25(OH)D), retinol, and six major carotenoids with metabolic dysfunction-associated steatotic lever disease (MASLD) using the 2017-2018 National Health and Nutrition Examination Survey. This analysis included 3956 adults (1991 men, 1965 women) aged ≥ 20 years. Steatotic liver disease was determined through transient elastography examination. Odds ratios (ORs) and 95% confidence intervals (95% CIs) for MASLD associated with micronutrients were estimated using logistic regressions. Higher serum α-tocopherol (highest vs. lowest quartile: OR = 1.53, 95% CI = 1.05-2.22, p = 0.03) and γ-tocopherol (highest vs. lowest quartile: OR = 4.15, 95% CI = 3.00-5.74, p < 0.0001) levels were associated with increased odds of MASLD. Higher serum 25(OH)D levels were associated with reduced odds of MASLD (highest vs. lowest quartile: OR = 0.41, 95% CI = 0.27-0.61, p = 0.0001). Inverse associations with the condition were also observed for carotenoids (α-carotene, β-carotene, α-cryptoxanthin, β-cryptoxanthin, combined lutein and zeaxanthin, and lycopene) in the serum (Ps < 0.05). The results were comparable between men and women, except for those on α-tocopherol, for which a positive association was only observed for men (p = 0.01). Our results suggest potential protective associations of serum 25(OH)D and carotenoids with MASLD. The positive associations between tocopherols and MASLD may reflect pathophysiological conditions associated with the condition.

P29-007-23 Associations of Serum Lipid-Soluble Micronutrients With Hepatic Steatosis Among Adults in the United States

P29-007-23 Associations of Serum Lipid-Soluble Micronutrients With Hepatic Steatosis Among Adults in the United States

Influences of Illumination Pretreatment on Soybean Oil Activated Clay Bleaching Effects and Soybean Oil Quality Evaluation.

Visible light has been widely studied for possible applications in food industry as being a kind of clean energy. Presently, the influences of illumination pretreatment on soybean oil quality followed by conventional activated clay bleaching, including the oil color, fatty acid composition, oxidation stability, and micronutrient content, were investigated. Results demonstrated that the illumination pretreatment increased the color differences between the non-illuminated and illuminated soybean oils, which indicated that the light exposure could improve the decoloring effects. The fatty acids composition and the peroxide value (POV) and oxidation stability index (OSI) of the soybean oils showed little changes during this process. Although the illumination pretreatment affected the content of lipid-soluble micronutrients, including phytosterols and tocopherols, no significant differences could be observed (p > 0.05). Moreover, it showed that the illumination pretreatment showed significant effects for decreasing the following activated clay bleaching temperature, indicating the energy saving potential of this novel soybean oil decoloring process. The present study might provide new insights for developing eco-friendly and efficient vegetable oil bleaching technology.

Mediterranean Diet Affects Blood Circulating Lipid-Soluble Micronutrients and Inflammatory Biomarkers in a Cohort of Breast Cancer Survivors: Results from the SETA Study

Breast cancer (BC) is a major public health concern and substantial research has shown that adhering to a healthy dietary pattern, such as the Mediterranean Diet (MD), may prevent the onset of cancer and BC relapses. This study aims at specifically investigating the association of MD with circulating dietary-related biomarkers in a cohort of BC survivors. Eighty patients (mean age of 54.9 ± 10.6) with a histologically confirmed diagnosis of BC who had not received any pharmacological or radiotherapy treatment for at least two months were enrolled. Fasting serum lipid-soluble vitamins (retinol, tocopherol), plant pigments (β-carotene, lutein + zeaxanthin, cryptoxanthin, lycopene), inflammatory and oxidative stress markers (ceruloplasmin; haptoglobin; paraoxonases; reactive oxygen molecule; thiol groups, Ferric reducing antioxidant power), and cardiometabolic parameters (body mass index (BMI); glucose; insulin; HOMA-IR; total cholesterol; LDL-cholesterol; HDL-cholesterol; triglycerides) were analyzed. Adherence to the MD was assessed through the Mediterranean Diet Score (MDS) questionnaire. Fasting blood samples were collected for the evaluation of selected biomarkers. MDS resulted positively correlated with β-carotene (r 0.331; p < 0.01) and lycopene (r 0.274; p < 0.05) and negatively with retinol (r −0.346; p < 0.05). Among the investigated inflammatory biomarkers, MDS was only correlated with antioxidant capacity (r 0.256; p < 0.05), while none of the investigated cardiometabolic parameters were significantly correlated with this index. The strong significant correlation between β-carotene and MDS encourages us to consider this pro-vitamin as a putative biomarker to take into account for evaluating the adherence to the MD.

Associations of Dietary Lipid-Soluble Micronutrients with Hepatic Steatosis among Adults in the United States.

Lipid-soluble micronutrients may be beneficial to non-alcoholic fatty liver disease due to their important roles in metabolism and maintaining tissue functions. Utilizing 2017–2018 National Health and Nutrition Examination Survey, this study examined the potential overall and race/ethnicity-specific (black, Hispanic and white) associations of dietary lipid-soluble micronutrients (α-tocopherol, retinol, vitamin D, β-carotene and total carotenoids) with hepatic steatosis. The analysis included 4376 adults (1037 blacks, 981 Hispanics, 1549 whites) aged ≥20 years who completed the transient elastography examination with dietary data available. Odds ratios (OR) and 95% confidence intervals (95%CI) were estimated using logistic regressions. The age-adjusted prevalence of steatosis was 20.9% for blacks, 34.0% for Hispanics and 28.7% for whites. Overall, dietary α-tocopherol was inversely associated with steatosis (highest vs. lowest quartile: OR = 0.51, 95%CI = 0.35–0.74, Ptrend = 0.0003). The associations remained significant among blacks (highest vs. lowest tertile: OR = 0.45, 95%CI = 0.26–0.77, Ptrend = 0.002) and whites (highest vs. lowest tertile: OR = 0.56, 95%CI = 0.33–0.94, Ptrend = 0.02). Higher α-tocopherol intake was associated with lower odds of steatosis among all (Ptrend = 0.016) and black participants (Ptrend = 0.003) classified as never/rare/occasional alcohol drinkers. There was a trend suggesting higher β-carotene intake with lower odds of steatosis (Ptrend = 0.01). Our results suggest potential protective effects of dietary vitamin E as α-tocopherol on steatosis particularly among blacks.

Abstract IA38: Racial/ethnic differences in liver fat, an obesity-associated risk factor for liver cancer

Abstract Background: Nonalcoholic fatty liver disease (NAFLD) is thought to be the main driver for the recent rise of chronic liver disease and liver cancer. NAFLD is also associated with other obesity-related metabolic diseases. Relative fat deposition in the liver varies by race/ethnicity and may partially account for liver cancer disparities. Thus, we aimed to compare liver fat content across five racial/ethnic groups, assess their contribution to the metabolic syndrome (MetSx), and predict NAFLD using common blood biomarkers. Methods: We conducted a cross-sectional study within the Multiethnic Cohort. A total of 1,861 healthy men and women aged 60-77 years were recruited, after stratification on sex, ethnicity (African, Japanese, Latino, Native Hawaiian, or white ancestry), and six BMI categories (range, 17.1-49.8 kg/m2). We estimated total fat mass using DXA and liver fat content using abdominal MR imaging. Fasting blood was analyzed for ~50 markers including adipocytokines, insulin and IGFs, lipids and lipid-soluble micronutrients, liver enzymes, and steroid hormones, using multiple assay platforms. Liver fat amounts were compared across sex and ethnic groups after adjustment for age, total fat mass, and height. The contribution of liver fat to MetSx was estimated in multivariable-adjusted mediation analysis. A prediction model for NAFLD was developed using regularized logistic regression. Results: The correlation between liver fat and total fat was only moderate (rSp = 0.34) and varied across ethnic groups (0.20-0.55). Liver fat content was similar between the sexes but differed by ethnicity (p&amp;lt;.0001), with a four-fold range in NAFLD prevalence between Japanese Americans (57% in men, 72% in women) and African Americans (12%, 19%) after adjustment for total fat mass. Total fat-adjusted prevalence of MetSx also differed by ethnicity: compared to whites, it was higher among Japanese Americans and Native Hawaiian women and lower among African Americans and Latinos. This ethnic difference was significantly mediated by liver fat among African Americans (proportion mediated =19-24%), Japanese Americans (22-34%), and Native Hawaiian women (20%). The final prediction model for NAFLD included age, sex, BMI, waist circumference, waist/hip, and top five biomarker predictors (IGFBP2, HOMA-IR, TG, adiponectin, SHBG). Discrimination of NAFLD cases in a validation dataset had high accuracy (AUC=0.90), across ethnic groups (AUCs of 0.80-0.96), and was significantly improved by the biomarkers (p's for contrast&amp;lt;.0001, except in African Americans). Conclusions: Relative fat storage in the liver varies substantially by race/ethnicity. In particular, Japanese Americans and Native Hawaiian women appear to experience a greater metabolic burden from their propensity to store excess fat in ectopic areas, which is consistent with a stronger association of BMI with liver cancer in these groups. Key metabolism markers may be used to successfully detect and monitor NAFLD patients of in various ethnic groups. Citation Format: Unhee Lim, Lynne R. Wilkens, Kristine R. Monroe, Iona Cheng, Bruce S. Kristal, Johanna W. Lampe, Meredith A. Hullar, John Shepherd, Thomas Ernst, Loic Le Marchand. Racial/ethnic differences in liver fat, an obesity-associated risk factor for liver cancer [abstract]. In: Proceedings of the Eleventh AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2018 Nov 2-5; New Orleans, LA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl):Abstract nr IA38.

Plasma carotenoids, tocopherols and retinol - Association with age in the Berlin Aging Study II

Regular consumption of fruits and vegetables, which is related to high plasma levels of lipid-soluble micronutrients such as carotenoids and tocopherols, is linked to lower incidences of various age-related diseases. Differences in lipid-soluble micronutrient blood concentrations seem to be associated with age. Our retrospective analysis included men and women aged 22–37 and 60–85 years from the Berlin Aging Study II. Participants with simultaneously available plasma samples and dietary data were included (n = 1973). Differences between young and old groups were found for plasma lycopene, α-carotene, α-tocopherol, β-cryptoxanthin (only in women), and γ-tocopherol (only in men). β-Carotene, retinol and lutein/zeaxanthin did not differ between young and old participants regardless of the sex. We found significant associations for lycopene, α-carotene (both inverse), α-tocopherol, γ-tocopherol, and β-carotene (all positive) with age. Adjusting for BMI, smoking status, season, cholesterol and dietary intake confirmed these associations, except for β-carotene. These micronutrients are important antioxidants and associated with lower incidence of age-related diseases, therefore it is important to understand the underlying mechanisms in order to implement dietary strategies for the prevention of age-related diseases. To explain the lower lycopene and α-carotene concentration in older subjects, bioavailability studies in older participants are necessary.

Diet Quality and Biomarker Profiles Related to Chronic Disease Prevention: The Multiethnic Cohort Study

Objective: To understand how diet quality affects chronic disease etiology, the associations of 4 a priori diet quality indices with blood levels of lipid-soluble micronutrients and biomarkers of inflammation, lipid, and glucose metabolism were examined in 5 ethnic groups.Methods: In a cross-sectional design, the Adiposity Phenotype Study, a subset of the Multiethnic Cohort in Hawaii and Los Angeles, recruited participants of white, African American, Native Hawaiian, Japanese American, and Latino ancestry. A total of 896 men and 910 women completed a validated quantitative food frequency questionnaire and anthropometric measurements and donated a fasting blood sample. Using general linear models, covariate-adjusted mean levels of lipid-soluble micronutrients (total carotenes, lycopene, total tocopherols, total lutein, cryptoxanthins), biomarkers of inflammation (C-reactive protein [CRP], tumor necrosis factor-), adipokines (adiponectin, leptin), lipids (total cholesterol, high-density lipoprotein cholesterol [HDL-C], triglycerides), and glucose metabolism (glucose, insulin, homeostatic model assessment of insulin resistance [HOMA-IR]) were computed across tertiles of 4 a priori dietary indices Healthy Eating Index (HEI)-2010, Alternative HEI (AHEI)-2010, alternate Mediterranean Diet (aMED), Dietary Approaches to Stop Hypertension (DASH); trends were evaluated in models with diet quality scores as continuous variables.Results: With better diet quality, levels of carotenes, lutein, cryptoxanthin, adiponectin, and HDL-C were significantly higher (ptrend < 0.01), whereas levels of CRP, leptin, total cholesterol, triglycerides, glucose, insulin, and HOMA-IR were inversely associated (ptrend < 0.05) with diet quality. With the exception of cryptoxanthins and triglycerides, the associations were consistent across ethnic groups.Conclusions: These findings confirm the association between diet quality and nutrition-related biomarkers and support the idea that a high-quality diet positively influences biologic pathways involved in chronic disease etiology across different ethnic groups.

Diet quality measured by four a priori-defined diet quality indices is associated with lipid-soluble micronutrients in the Multiethnic Cohort Study (MEC).

Background/ObjectivesThis study examined the long-term relation of lipid-soluble micronutrients with diet quality as assessed by four a priori-defined dietary patterns.Subjects/MethodsIn a prospective design, nutritional biomarkers (carotenoids, tocopherols, retinol, and coenzyme Q10) were measured using a validated HPLC based assay. General linear models were applied to obtain covariate-adjusted means of biomarkers for tertiles of 4 a priori diet quality indices: Healthy Eating Index (HEI) 2010, Alternative HEI (AHEI) 2010, Alternate Mediterranean Diet Score (aMED), and Dietary Approaches to Stop Hypertension (DASH). For a subcohort of 8 367 participants within the Multiethnic Cohort (MEC), diet was assessed by a validated quantitative food frequency questionnaire in 1993–96 and serum was collected in 2001–06.ResultsParticipants with the highest diet quality scores had significantly higher serum concentrations of all carotenoids, total tocopherols, and α-tocopherol, while γ-tocopherol was inversely associated with diet quality. Adjusted means for the lowest vs. highest tertile of HEI 2010 were 1.2 vs. 1.5 mg/L for total carotenoids, 11.4 vs. 12.3 mg/L for total tocopherols, and 1.9 vs. 1.6 mg/L for γ-tocopherol (ptrend<0.0001). The associations for the other dietary indices were similar; no indication for sex and ethnic differences was detected. Vegetable and fruit components were major predictors of most circulating micronutrients, but most other components were also associated.ConclusionsHigher diet quality scores measured by four a priori diet quality indices were significantly associated higher serum concentrations of carotenoids and α-tocopherol, while γ-tocopherol was inversely associated with diet quality.

Mangos and their bioactive components: adding variety to the fruit plate for health.

The diet is an essential factor affecting the risk for development and progression of modern day chronic diseases, particularly those with pathophysiological roots in inflammation and oxidative stress-induced damage. The potential impact of certain foods and their bioactive compounds to reverse or prevent destructive dysregulated processes leading to disease has attracted intense research attention. The mango (Mangifera indica Linn.) is a tropical fruit with distinctive nutritional and phytochemical composition. Notably, the mango contains several essential water- and lipid-soluble micronutrients along with the distinguishing phytochemicals gallotannins and mangiferin. In vitro and in vivo studies reveal various mechanisms through which mangos or their associated compounds reduce risk or reverse metabolic- and inflammation-associated diseases. Health benefits of isolated individual mango compounds and extracts from mango by-products are well described in the literature with less attention devoted to the whole fruit. Here, we review and summarize the available literature assessing the health promoting potential of mango flesh, the edible portion contributing to dietary fruit intake, focusing specifically on modern day health issues of obesity and the risk factors and diseases it precipitates, including diabetes and cardiovascular disease. Additionally, this review explores new insights on the benefits of mango for brain, skin and intestinal health. Overall, the foundation of research supporting the potential role of mangos in reducing risk for inflammation- and metabolically-based chronic diseases is growing.

Oxidative stress markers and micronutrients in maternal and cord blood in relation to neonatal outcome

Oxidative stress and micronutrient deficiencies have been related to lower birth weight (BW), small for gestational age (SGA) offspring and preterm delivery. The relation between neonatal outcome (BW, head circumference, SGA, preterm delivery) with markers of oxidative stress and micronutrients in maternal and cord blood was to be examined. Oxidative stress markers (protein carbonyls (PrCarb), 3-nitrotyrosine (3NT), malondialdehyde (MDA)), total protein concentration and lipid-soluble micronutrients (carotenoids, retinol, tocopherols) were measured in 200 newborns (11% preterms, 13% SGA) and 151 mothers. Associations between target parameters in cord plasma and maternal serum with BW, head circumference and risk of being SGA or preterm were explored. Maternal protein concentration, PrCarb, MDA and all lipid-soluble micronutrients were significantly higher compared with newborns, except for 3NT, which was significantly elevated in newborns. Newborn parameters correlated positively with those of mothers. Preterms had lower proteins and retinol but higher PrCarb than terms. Maternal PrCarb and retinol were inversely associated with BW and head circumference. Mothers with PrCarb, MDA and retinol in the highest quintile had a 3.3-fold (0.9; 12.1), 2.1-fold (0.7; 6.4) and 3.3-fold (1.2; 9.4) risk, respectively, for delivering an SGA newborn, whereas the lowest quintile of retinol in cord blood was associated with an increased risk for preterm delivery. Oxidative stress (elevated PrCarb) was associated with lower BW/head circumference and SGA. Inadequate hemodilution may explain the inverse relation of maternal retinol with BW and head circumference, and the association between highest maternal retinol and risk for SGA.

C-Reactive Protein, Lipid-soluble Micronutrients, and Survival in Colorectal Cancer Patients

Identification of biomarkers associated with survival in patients with cancer is important for elucidating the underlying mechanisms of cancer progression and identifying possible interventions to reduce cancer morbidity and mortality. Using stored patient plasma samples from a multiethnic population-based case-control study of invasive colorectal cancer, we measured posttreatment blood levels of C-reactive protein (CRP) and lipid-soluble micronutrients. Patients (n = 368) were followed after phlebotomy (mean of 8 years), during which time 47% died (25% colorectal cancer specific). HRs were estimated by Cox proportional hazards regression with adjustment for stage, age at diagnosis, ethnicity, sex, smoking status, and month of blood draw. A positive association with overall risk of death was observed for CRP [HR for highest vs. lowest quintile: 1.80; 95% confidence interval (CI), 1.07-3.04; Ptrend = 0.01], whereas inverse associations were generally observed for retinol and carotenoids (HRs for overall risk of death for the highest quintile ranging from 0.5-0.8); these associations were significant for retinol (Ptrend = 0.0002), α-carotene (Ptrend = 0.02), and total carotenoids (Ptrend = 0.02) and were generally consistent across subgroups (sex, ethnicity, cancer anatomical subtype, and stage). HRs for retinol and carotenoids were attenuated somewhat after adjustment for CRP. Similar trends for CRP were observed for colorectal cancer-specific deaths (HR for highest vs. lowest tertile: 2.06; 95% CI, 1.18-3.61; Ptrend = 0.01) as for deaths from all other causes (Pheterogeneity = 0.78). These observations are consistent with a direct relationship between circulating CRP and overall survival among patients with colorectal cancer. These results, if reproduced, suggest that reduction of inflammation should be explored as a potential complementary treatment strategy.

Impact of cooking methods on folates, ascorbic acid and lutein in green beans (Phaseolus vulgaris) and spinach (Spinacea oleracea)

Folates, ascorbic acid (vitamin C) and lutein (antioxidant carotenoid) concentrations were determined after cooking (boiling and steaming) fresh, frozen and canned green beans (Phaseolus vulgaris) and spinach (Spinacea oleracea). The aim of this study was to qualify and quantify the loss of water soluble (folates and ascorbic acid) and lipid soluble (lutein) micronutrients in the cooked products and liquids and the canning liquor. In canned products, folates were found in the canning liquor. Boiling regardless of product reduced plant tissue folates and ascorbic acid but not lutein concentrations. Loss of folates during boiling occurred due to leaching (diffusion) and ascorbic acid due to temperature (heating). Steaming reduced ascorbic acid but not folate or lutein concentrations.

Effects of Vitamin D3 and Calcium Supplementation on Serum Levels of Tocopherols, Retinol, and Specific Vitamin D Metabolites

γ-Tocopherol (γT) protects against DNA-damaging effects of nitrogen oxides, yet its physiologic regulation in vivo is unknown. Observational studies indicate inverse associations of 25[OH]-vitamin D with γT and leptin. To determine whether vitamin D3 supplementation alters levels of lipid-soluble micronutrients, serum samples (N = 85 subjects) from a randomized, double-blind, placebo-controlled clinical trial of vitamin D3 (800 IU) and calcium (2 g), alone and in combination, were analyzed for lipid micronutrients and specific vitamin D metabolites at baseline and after 6 mo of supplementation. Serum 25[OH]-vitaminD3 levels increased 55% (P < 0.0001) and 48% (P = 0.0005), whereas 25[OH]-vitaminD2 levels were lower by 48% (P = 0.26) and 21% (P = 0.36) in the vitamin D3 and vitamin D3 plus calcium groups, respectively. At baseline, γT levels were inversely associated with 25[OH]D (r = −0.31, P = 0.004). With vitamin D3 plus calcium treatment, serum α-tocopherol decreased 14% (P = 0.04), whereas similar changes in γT (19% lower, P = 0.14) were observed. No significant effects were observed for D3 supplementation on leptin or retinol levels. These results are consistent with the hypothesis that vitamin D3 ± calcium affects serum tocopherol and 25[OH]D2 levels; however, studies using larger, more homogeneous populations are warranted.

Associations between obesity and serum lipid-soluble micronutrients among premenopausal women

Elucidating potential pathways that micronutrients may reduce/promote chronic disease may contribute to our understanding of the underlying etiology of disease and their utility as markers of risk. In the current study, we examined associations of serum lipid-soluble micronutrients with body mass index (BMI). We hypothesized that obesity may differentially influence serum micronutrient levels, thereby affecting risk for chronic disease incidence and mortality. Baseline serum samples from 180 premenopausal women from a nutritional trial were analyzed for leptin, C-reactive protein, 25-hydroxyvitamin D, carotenoids, and tocopherols. Participants were stratified into normal-weight (18.5-24.9), overweight (25-29.9), and obese (>or=30) subgroups by BMI (in kilograms per square meter). Differences in serum biomarkers among BMI subgroups were adjusted for Asian ethnicity and smoking status. As expected, obese individuals had significantly higher serum levels of leptin and C-reactive protein (Ps < .05) compared with normal-weight women. gamma-Tocopherol levels were significantly higher in obese individuals (P < .05), whereas alpha-tocopherol levels did not differ among BMI subgroups. Serum levels of 25-hydroxyvitamin D and carotenoids (except lycopene) were significantly lower in obese than in normal-weight women (Ps < .05). The associations between BMI and carotenoids were independent of dietary intake. The obesity-associated reduction for total provitamin A carotenoids (45%) was approximately 3-fold greater than that observed for non-provitamin A carotenoids (16%). Our results indicate potential influences of obesity on serum levels of lipid-soluble micronutrients and suggest that metabolism of provitamin A carotenoids may contribute to the differences observed.

Follicular fluid high density lipoprotein-associated micronutrient levels are associated with embryo fragmentation during IVF

PurposeTo investigate whether follicular fluid lipid-soluble micronutrients are associated with embryo morphology parameters during IVF.MethodsFollicle fluid and oocytes were obtained prospectively from 81 women. Embryo morphology parameters were used as surrogate markers of oocyte health. HDL lipids and lipid-soluble micronutrients were analyzed by high-pressure liquid chromatography. Non-parametric bi-variate analysis and multivariable ordinal logistic regression models were employed to examine associations between biochemical and embryo morphology parameters.ResultsFollicular fluid HDL cholesterol (r = −0.47, p < 0.01), α-tocopherol (r = −0.41, p < 0.01), δ-tocopherol (r = −0.38, p < 0.05) and β-cryptoxanthine (r = −0.42, p < 0.01) are negatively correlated with embryo fragmentation. Ordinal logistic regression models indicate that a 0.1 μmol/L increase in β-cryptoxanthine, adjusted for γ-tocopherol, is associated with a 75% decrease in the cumulative odds of higher embryo fragmentation (p = 0.010).ConclusionFollicular fluid HDL micronutrients may play an important role in the development of the human oocyte as evident by embryo fragmentation during IVF.