Selenium Kinetics in Humans Change Following 2 Years of Supplementation With Selenomethionine.

Background: Selenium (Se) is a nutritionally essential trace element and health may be improved by increased Se intake. Previous kinetic studies have shown differences in metabolism of organic vs. inorganic forms of Se [e.g., higher absorption of selenomethionine (SeMet) than selenite (Sel), and more recycling of Se from SeMet than Sel]. However, the effects on Se metabolism after prolonged Se supplementation are not known. Objective: To determine how the metabolism and transport of Se changes in the whole-body in response to Se-supplementation by measuring Se kinetics before and after 2 years of Se supplementation with SeMet. Methods: We compared Se kinetics in humans [n = 31, aged 40 ± 3 y (mean ± SEM)] studied twice after oral tracer administration; initially (PK1), then after supplementation for 2 y with 200 µg/d of Se as selenomethionine (SeMet) (PK2). On each occasion, we administered two stable isotope tracers of Se orally: SeMet, the predominant food form, and selenite (Na276SeO3, or Sel), an inorganic form. Plasma and RBC were sampled for 4 mo; urine and feces were collected for the initial 12 d of each period. Samples were analyzed for tracers and total Se by isotope dilution GC-MS. Data were analyzed using a compartmental model, we published previously, to estimate fractional transfer between pools and pool masses in PK2. Results: We report that fractional absorption of SeMet or Sel do not change with SeMet supplementation and the amount of Se absorbed increased. The amount of Se excreted in urine increases but does not account for all the Se absorbed. As a result, there is a net incorporation of SeMet into various body pools. Nine of the 11 plasma pools doubled in PK2; two did not change. Differences in metabolism were observed for SeMet and Sel; RBC uptake increased 247% for SeMet, urinary excretion increased from two plasma pools for Sel and from two different pools for SeMet, and recycling to liver/tissues increased from one plasma pool for Sel and from two others for SeMet. One plasma pool increased more in males than females in PK2. Conclusions: Of 11 Se pools identified kinetically in human plasma, two did not increase in size after SeMet supplementation. These pools may be regulated and important during low Se intake.

A human model of selenium that integrates metabolism from selenite and selenomethionine.

Selenium (Se) metabolism is affected by its chemical form in foods and by its incorporation (specific vs. nonspecific) into multiple proteins. Modeling Se kinetics may clarify the impact of form on metabolism. Although the kinetics of Se forms have been compared in different participants, or the same participants at different times, direct comparisons of their respective metabolism in the same participants have not been made. The aim of this study was to simultaneously compare kinetics of absorbed Se from inorganic selenite (Sel) and organic selenomethionine (SeMet) in healthy participants (n = 31). After oral administration of stable isotopic tracers of each form, urine and feces were collected for 12 d and blood was sampled over 4 mo. Tracer enrichment was determined by isotope-dilution-GC-MS. Using WinSAAM, a compartmental model was fitted to the data. Within 30 min of ingestion, Se from both forms entered a common pool, and metabolism was similar for several days before diverging. Slowly turning-over pools were required in tissues and plasma for Se derived from SeMet to account for its 3-times-higher incorporation into RBC compared with Se from Sel; these presumably represent nonspecific incorporation of SeMet into proteins. Pool sizes and transport rates were determined and compared by form and gender. The final model consisted of 11 plasma pools, 2 pools and a delay in RBC, and extravascular pools for recycling of Se back into plasma. This model will be used to evaluate changes in Se metabolism following long-term (2 y) Se supplementation.

Effects of selenomethionine supplementation on selenium status and thyroid hormone concentrations in healthy adults.

BACKGROUND: Selenium, a potential cancer prevention agent currently being tested against prostate cancer in the Selenium and Vitamin E Cancer Prevention Trial (SELECT), plays an integral role in thyroid metabolism. The effects of long-term selenium supplementation on thyroid hormone concentrations are unknown. OBJECTIVE: The objective was to investigate the effects of long-term selenium supplementation on thyroid hormone concentrations. DESIGN: Twenty-eight healthy adults took 200 microg selenomethionine/d for 28 mo. The thyroid hormones triiodothyronine (T3), thyroxine (T4), and thyrotropin (TSH) were measured in plasma for 4 mo before supplementation and quarterly during supplementation. The assay methods were changed midstudy; the results of the 2 methods were not comparable. Therefore, one analysis was conducted based on the results of the first method, and a second analysis was based on all of the data, adjusted for the change. Serial data collection permitted a test for trends rather than simply a difference between initial and final values. RESULTS: By 9 mo, mean (+/-SEM) plasma selenium concentrations had increased from 1.78 +/- 0.07 micromol/L at baseline to 2.85 +/- 0.11 micromol/L for men and from 1.64 +/- 0.04 to 3.32 +/- 0.1.2 micromol/L for women. T3 concentrations in men increased 5% per year (P = 0.01). T4 and TSH concentrations were unchanged. CONCLUSIONS: Selenium supplementation produced no clinically significant changes in thyroid hormone concentrations. A small but statistically significant increase in T3 concentrations was noted in men, with no corresponding decreases in TSH. A subset of SELECT subjects might be monitored periodically for changes during long-term selenium supplementation.

Racial differences in serum selenium concentration: analysis of US population data from the Third National Health and Nutrition Examination Survey.

Lower intake of the essential trace element selenium may be a risk factor for prostate cancer and other cancers. In the United States, many racial disparities in cancer incidence, such as the 61% higher incidence of prostate cancer among Blacks relative to Whites, remain unexplained. Using data from a large, nationally representative survey, the authors explored Black/White differences in serum selenium concentration. Mean serum selenium concentrations, both crude and adjusted for known predictors of serum selenium, were determined for 10,779 Black and White males and females aged >or=12 years who participated in the Third National Health and Nutrition Examination Survey (1988-1994). Crude mean serum selenium concentrations were 126.35 ng/ml for Whites and 118.76 ng/ml (approximately 6% lower) for Blacks. Adjustment for known serum selenium predictors, including a proxy for residence at the county level, reduced the racial disparity, although concentrations remained approximately 3% lower in Blacks than in Whites of both sexes (p<0.0001). The observation that Blacks had lower unadjusted and adjusted serum selenium concentrations relative to Whites is intriguing, given the racial disparity in incidence of prostate cancer and other cancers.

Diet and sex hormones in boys: findings from the dietary intervention study in children.

CONTEXT: Diet reportedly alters serum sex hormone concentrations in adults, but little is known about the influence of diet during puberty on these hormones. OBJECTIVE: We aimed to determine whether an intervention to lower fat intake during adolescence alters serum sex hormone concentrations and progression through puberty. DESIGN: In 1990-1997, we conducted an ancillary study to the Dietary Intervention Study in Children, a multicenter, randomized, controlled clinical trial to test the safety and efficacy of a cholesterol-lowering dietary intervention in children. PARTICIPANTS: Healthy, prepubertal, 8 to 10 yr olds with elevated low-density lipoprotein cholesterol were randomized to usual care or a behavioral intervention. Of 362 randomized Dietary Intervention Study in Children boys, 354 participated in the ancillary study. Eighty-four percent of boys attended last visits when their median time on trial was 7.1 yr. INTERVENTION: The behavioral intervention continued throughout the duration of the trial and promoted a diet with 28% energy from total fat, less than 8% from saturated fat, 9% or less from polyunsaturated fat, and less than 75 mg cholesterol per 1000 kcal. OUTCOME MEASURES: The main outcome measure for boys formulated before study initiation was non-SHBG bound testosterone concentration. Secondary outcomes included serum total testosterone, dihydrotestosterone, androstenedione, estradiol, estrone, SHBG, and Tanner stage. RESULTS: There were no significant treatment group differences in boys' serum hormone levels, SHBG, or Tanner stages at any individual visit or over the course of the trial when evaluated by longitudinal models. CONCLUSION: Modest reductions in total fat, saturated fat, and possibly energy intake do not alter progression through puberty or serum sex hormone concentrations in adolescent boys.

Evaluating markers for the early detection of cancer: overview of study designs and methods.

BACKGROUND: The field of cancer biomarker development has been evolving rapidly. New developments both in the biologic and statistical realms are providing increasing opportunities for evaluation of markers for both early detection and diagnosis of cancer. PURPOSE: To review the major conceptual and methodological issues in cancer biomarker evaluation, with an emphasis on recent developments in statistical methods together with practical recommendations. METHODS: We organized this review by type of study: preliminary performance, retrospective performance, prospective performance and cancer screening evaluation. RESULTS: For each type of study, we discuss methodologic issues, provide examples and discuss strengths and limitations. CONCLUSION: Preliminary performance studies are useful for quickly winnowing down the number of candidate markers; however their results may not apply to the ultimate target population, asymptomatic subjects. If stored specimens from cohort studies with clinical cancer endpoints are available, retrospective studies provide a quick and valid way to evaluate performance of the markers or changes in the markers prior to the onset of clinical symptoms. Prospective studies have a restricted role because they require large sample sizes, and, if the endpoint is cancer on biopsy, there may be bias due to overdiagnosis. Cancer screening studies require very large sample sizes and long follow-up, but are necessary for evaluating the marker as a trigger of early intervention.

Diet and sex hormones in girls: findings from a randomized controlled clinical trial.

BACKGROUND: Results of several studies have suggested that diet during adolescence may influence the risk of breast cancer in adulthood. We evaluated whether an intervention to lower fat intake among adolescent girls altered their serum concentrations of sex hormones that, in adults, are related to breast cancer development. METHODS: We conducted an ancillary hormone study among 286 of the 301 girls who participated between 1988 and 1997 in the Dietary Intervention Study in Children, in which healthy, prepubertal, 8- to 10-year-olds with elevated low-density lipoprotein cholesterol were randomly assigned to usual care or to a behavioral intervention that promoted a low-fat diet. Median time on the intervention was 7 years. Blood samples collected before randomization and at the year 1, year 3, year 5, and last visits were assayed to determine the girls' serum levels of sex hormones. All P values are two-sided. RESULTS: At the year 5 visit, girls in the intervention group had 29.8% (95% confidence interval [CI] = 5.4% to 47.9%; P =.02) lower estradiol, 30.2% (95% CI = 7.0% to 47.7%; P =.02) lower non-sex hormone binding globulin-bound estradiol, 20.7% (95% CI = 4.7% to 34.0%; P =.02) lower estrone, and 28.7% (95% CI = 5.1% to 46.5%; P =.02) lower estrone sulfate levels during the follicular phase of the menstrual cycle and 27.2% (95% CI = 5.7% to 53.1%; P =.01) higher testosterone levels during the luteal phase of the menstrual cycle than did girls in the usual care group. At the last visit, the luteal phase progesterone level was 52.9% (95% CI = 20.0% to 72.3%) lower for girls in the intervention group than for girls in the usual care group (P =.007). CONCLUSION: Modest reductions in fat intake during puberty are associated with changes in sex hormone concentrations that are consistent with alterations in the function of the hypothalamic-pituitary-ovarian axis. Whether these changes influence breast cancer risk is currently unknown.

Serum selenium and the risk of cervical cancer among women in the United States.

OBJECTIVE: To explore the relationship between serum selenium and cervical cancer. METHODS: We conducted a case-control study of cervical cancer in five areas around Birmingham, AL; Chicago, IL; Denver, CO; Miami, FL; and Philadelphia, PA. Community controls were selected by random-digit dialing and were matched to invasive cervical cancer cases by age, race/ethnicity, and telephone exchange. Serum selenium was determined by neutron activation analysis. Logistic regression analysis controlling for known risk factors of cervical cancer, including human papillomavirus (HPV) type-16 measured serologically, was performed on 227 invasive cases, 127 in-situ cases, and 526 controls. RESULTS: Values of serum selenium ranged from 67.5 to 185.0 ng/ml. Adjusted odds ratios for invasive cervical cancer by quintile were: 1.0 (highest selenium), 1.1, 1.0, 0.8, and 1.0 (lowest selenium), p for trend = 0.82. Similar patterns were observed for Stage I invasive, and Stages II-IV invasive cases, suggesting severity of disease did not influence the null results. Although no associations were seen among current or never smokers, a protective effect of selenium was suggested among former smokers. Effect modification was not evident for other variables examined. CONCLUSIONS: This study does not support a relationship between serum selenium and invasive cervical cancer at typical serum selenium levels in the US.

Changes in vegetable and fruit consumption and awareness among US adults: results of the 1991 and 1997 5 A Day for Better Health Program surveys.

OBJECTIVE: The purpose of this study is to assess population-based changes in vegetable and fruit consumption and psychosocial correlates. DESIGN: Two nationally representative random digit dial surveys conducted in 1991 and 1997; respondents were queried regarding consumption of and attitudes and knowledge about vegetables and fruit. SUBJECTS/SETTING: Respondents were 2,755 and 2,544 adults (in 1991 and 1997, respectively) older than 18 years. STATISTICAL ANALYSIS PERFORMED: Vegetable and fruit consumption and message awareness were measured using weighted-only and regression model-adjusted analyses to assess changes. RESULTS: Mean vegetable and fruit consumption was significantly (P=.007) higher in 1997 than in 1991 using weighted-only analyses, but remained significant only for Hispanic (P=.03) and nonsmoker (P=.004) subgroups when adjusted for demographic shifts. Significantly higher percentages were found in the model-adjusted analyses for those consuming 5 or more (daily servings (23.4% to 25.8%), message awareness (7.7% to 19.2%), and knowledge of the 5 A Day Program (2.0% to 17.8%). APPLICATIONS/CONCLUSIONS: A significantly positive change in vegetable and fruit consumption occurred between 1991 and 1997 according to traditional methods of survey data analysis, but null findings resulted when the data were adjusted for demographic shifts. Nutrition professionals should continue targeting specific demographic subgroups with tailored interventions to move all Americans toward achievement of dietary guidelines for vegetable and fruit consumption.

Measurement of steroid sex hormones in serum: a comparison of radioimmunoassay and mass spectrometry.

Concern has been raised about the adequacy of radioimmunoassays to measure steroid sex hormones in population studies. We compared steroid sex hormone measurements in serum by radioimmunoassay with mass spectrometry. Four male and four female serum pools with known relative concentrations of steroid sex hormones were measured multiple times by both methods. Because measurements are expected to increase linearly with concentration for each sex, we examined whether the linear regressions of hormone measurements on concentration were the same for radioimmunoassay and mass spectrometry. Estradiol, estrone, androstenedione, testosterone, and dehydroepiandrosterone sulfate were measured in female pools; testosterone, dihydrotestosterone, androstenedione, and dehydroepiandrosterone sulfate were measured in male pools. Regression slopes for radioimmunoassay and mass spectrometry measurements were comparable for all hormones except androstenedione, which had a steeper slope when measured by mass spectrometry (P < or = 0.02). Intercepts for radioimmunoassay and mass spectrometry were similar and close to zero for estradiol, androstenedione, dehydroepiandrosterone sulfate, and in male samples, testosterone. For testosterone in female samples, estrone, and dihydrotestosterone, radioimmunoassay and mass spectrometry intercepts differed significantly. Standard deviations of individual measurements by radioimmunoassay and mass spectrometry differed by hormone and serum concentration; neither method consistently measured hormone concentrations with less variability. Our findings suggest that although absolute concentrations may differ for some hormones, radioimmunoassay and mass spectrometry can yield similar estimates of between subject differences in serum concentrations of most steroid sex hormones commonly measured in population studies. Relative power of studies using radioimmunoassay and mass spectrometry will depend on the hormones measured and their serum concentrations.