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American Journal of Clinical Nutrition, Vol. 87, No. 2, 370-378, February 2008
© 2008 American Society for Nutrition

ORIGINAL RESEARCH COMMUNICATION

Randomized controlled trial of the effect of selenium supplementation on thyroid function in the elderly in the United Kingdom1,2,3,4

Margaret P Rayman, Alexander J Thompson, Bram Bekaert, Janet Catterick, Rachel Galassini, Emma Hall, Margaret Warren-Perry and Geoffrey J Beckett

1 From the Nutritional Sciences Division, Faculty of Health and Medical Sciences, University of Surrey, Guildford United Kingdom (MPR, AJT, BB, JC, RG, and MW-P); Clinical Trials & Statistics Unit, Section of Clinical Trials, Institute of Cancer Research, Sutton, United Kingdom (EH); Clinical Biochemistry, University of Edinburgh, The Royal Infirmary of Edinburgh, Edinburgh, United Kingdom (GJB)

2 Presented at the Nutrition Society Winter Meeting, 11-12 February 2004, London, United Kingdom. Abstract published as Selenium and thyroid function in the elderly: results from the UK PRECISE Trial pilot study. Proc Nut Soc 2004;63:33A.

3 Supported by the Cancer Research UK (formerly the Cancer Research Campaign) for the UK pilot of the PRECISE Trial (grant reference SP2484/0101). EH is supported by Cancer Research UK (C1491/A4129). The extra costs associated with the thyroid substudy were generously provided by Wassen International Ltd (Leatherhead, UK). The selenium tablets and placebo supplements were generously supplied by Pharma Nord (Vejle, Denmark).

4 Reprints not available. Address correspondence to MP Rayman, Nutritional Sciences Division, Faculty of Health and Medical Sciences, University of Surrey, Guildford GU2 7XH, United Kingdom. E-mail: m.rayman{at}surrey.ac.uk.


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Background:Thyroid function depends on the essential trace mineral selenium, which is at the active center of the iodothyronine deiodinase enzymes that catalyze the conversion of the prohormone thyroxine (T4) to the active form of thyroid hormone, triiodothyronine (T3).

Objective:Because selenium intake in the United Kingdom has fallen during the past 25 y, we wanted to determine whether current selenium status might be limiting conversion of T4 to T3 in the elderly, in whom marginal hypothyroidism is relatively common.

Design:We investigated the effect of selenium supplementation in a double-blind, placebo-controlled trial in 501 elderly UK volunteers. Similar numbers of men and women from each of 3 age groups, 60–64 y, 65–69 y, and 70–74 y, were randomly allocated to receive 100, 200, or 300 µg Se/d as high-selenium yeast or placebo yeast for 6 mo. As part of the study, plasma selenium, thyroid-stimulating hormone, and total and free T3 and T4 were measured. Data from 368 euthyroid volunteers who provided blood samples at baseline and 6 mo were analyzed.

Results:Although selenium status at baseline correlated weakly with free T4 (r = –0.19, P < 0.001) and with the ratio of free T3 to free T4 (r = 0.12, P = 0.02), we found no evidence of any effect of selenium supplementation on thyroid function, despite significant increases in plasma selenium. However, baseline plasma selenium in our study (x: 91 µg/L) was somewhat higher than in previous supplementation studies in which apparently beneficial effects were seen.

Conclusion:We found no indication for increasing selenium intake to benefit T4 to T3 conversion in the elderly UK population.

Key Words: Selenium • thyroid • T3 • T4 • randomized controlled trial • UK elderly


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Thyroid hormones control, directly or indirectly, many processes crucial to growth, development, and metabolism. Development of thyroid insufficiency in adulthood is associated, among other symptoms, with decreased basal metabolic rate, poor resistance to cold, weight gain, fatigue, muscle weakness, lethargy, malaise, hypercholesterolemia, and adverse mental states such as impaired cognition and depression (1-3). The elderly are at increased risk of thyroid insufficiency. By 55–64 y of age, as many as 13% of women and 6% of men will have an underactive thyroid, as defined by a plasma thyroid-stimulating hormone (TSH) concentration above the normal range, whereas the percentages rise to 21 and 16, respectively, in those aged ≥ 74 y (4). Serum 3,3',5-triiodothyronine (T3) concentrations in the elderly are often low, largely attributable to nonthyroidal illness rather than age itself, although both result in decreased conversion of thyroxine (T4) to T3 (5, 6). T3 concentrations in healthy centenarians are {approx}30% lower than those of healthy subjects aged 20–64 y (7). Even subclinical hypothyroidism, defined as normal T4 and T3 with elevated TSH, may be associated with some thyroid insufficiency symptoms and is present in 4–8.5% of the general population; it may be as high as 20% in women > 60 y (8).

It is now recognized that adequate supplies of both iodine and the essential trace element selenium are required for optimal thyroid function. Incorporated into the amino acid selenocysteine, selenium is at the active center of a number of selenoenzymes required for thyroid function (9). The selenoenzymes, glutathione peroxidase and thioredoxin reductase, are crucial to the protection of the thyroid from the hydrogen peroxide that is produced there to oxidize iodide for thyroid hormone synthesis (9, 10). This is consistent with the inverse association found between selenium status and thyroid volume, thyroid tissue damage, and goiter in French women (11) and with the positive association between the incidence of thyroid cancer and low prediagnostic serum selenium concentration in Norway (12, 13). Furthermore, the protective effects of selenium on the thyroid are confirmed by the finding that supplementation with 200 µg/d of sodium selenite or selenomethionine decreased inflammation and thyroid autoantibody concentrations in patients with autoimmune thyroiditis (14-16), although, interestingly, a dose of 100 µg selenomethionine/d was ineffective (16).

In addition to this protective function, 3 selenoenzymes, the iodothyronine deiodinases, are required for the interconversion of the active and inactive forms of the thyroid hormones (9). Type 1 and type 2 deiodinases are required for the systemic and local synthesis of biologically active T3 from T4, whereas type 3 deiodinase catalyzes the conversion of T4 to biologically inactive reverse T3 and catabolizes T3 to produce inactive 3,3'-diiodothyronine (9, 10). The combination of these enzymes allows the precise regulation of thyroid hormone metabolism in specific tissues. Some evidence of the relevance of adequate selenium status to thyroid function was found in a Czech population of low selenium status (mean serum selenium: 49 µg/L) wherein thyroid hormone concentrations were correlated with serum and urinary selenium (17). Clearly then, there are a number of reasons why low or marginal selenium availability may cause problems with thyroid metabolism.

Although current iodine intake in the United Kingdom is believed to be sufficient for thyroid hormone metabolism (18), it is not clear that this is true for selenium. In light of the above information, it is of concern that intakes of selenium in the United Kingdom have fallen in recent years and now stand at around half government-recommended amounts (19). Although the UK Reference Nutrient Intake is 75 and 60 µg Se/d for men and women, respectively, current UK intakes average from 29 to 39 µg Se/d (20, 21). Although deiodinase activity is believed to be relatively well protected in conditions of marginal selenium availability (22), there are some indications that, nonetheless, marginally deficient selenium intake may be compromising thyroid hormone metabolism in some locations. For example, in Scottish subjects supplemented with 50 µg Se/d as sodium selenite or selenomethionine for 28 d, although no change was observed in plasma concentrations of TSH, total T3, total T4, free T3, or free T4, a significant correlation was found between the plasma total T3-to-T4 ratio (T3:T4) and plasma selenium concentration, consistent with incomplete conversion to T3 at the baseline concentration (x: 79.7 µg/L) of plasma selenium (23).

A further factor relevant to an elderly population is that selenium status tends to decline in persons >60–65 y of age (24, 25). Thus, selenium supplementation (100 µg sodium selenite/d) in a group of 36 elderly Italian subjects (mean baseline plasma selenium: 64 µg/L) significantly decreased plasma total T4 concentrations, consistent with increased deiodinase activity, although there was no change in serum concentrations of TSH, total T3, or free T4 (6).

In light of the above reports, we hypothesized that the current selenium intake in the United Kingdom might be limiting the conversion of T4 to T3 in the elderly. We therefore investigated the effect of selenium on thyroid function in a study ancillary to the UK PRECISE (PREvention of Cancer by Intervention with SElenium) pilot study (26). In this double-blind, placebo-controlled trial, 501 UK volunteers aged 60–74 y were randomly allocated to receive 100, 200, or 300 µg Se/d as high-selenium yeast or a placebo yeast. Of these volunteers, 368 were euthyroid and provided blood samples at baseline and at 6 mo that were used for evaluation of thyroid function and selenium status.


   SUBJECTS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 SUBJECTS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
The UK pilot study for the planned international PRECISE (Prevention of Cancer by Intervention with Selenium) trial was set up to assess the viability of conducting the main trial in the United Kingdom. It was performed in 4 general practices of the Medical Research Council General Practice Research Framework in the United Kingdom with differing demographic characteristics: Guisborough and Linthorpe (North East), Bromsgrove (West Midlands), and Bungay (East Anglia). No formal power calculations were performed for the pilot study, and the target accrual (510 subjects in 12 mo) was chosen to give sufficient subjects from which to be able to draw reasonable inferences about recruitment, compliance, and loss to follow-up, while keeping costs within reasonable bounds. Assessment of thyroid function was a planned subsidiary analysis on blood samples stored for research within the trial.

Subjects and recruitment
Between June 2000 and July 2001, research nurses recruited similar numbers of male and female volunteers from each of 3 age groups: 60–64 y, 65–69 y, and 70–74 y. Exclusion criteria were 1) a Southwest Oncology Group performance status score >1 (ie, incapable of doing light housework or office work), 2) active liver or kidney disease, 3) prior diagnosis of cancer (excluding nonmelanoma skin cancer), 4) diagnosis of HIV infection, 5) on immunosuppressive therapy, 6) diminished mental capacity, and 7) taking ≥50 µg/d of selenium supplements in the previous 6 mo (by patient report).

Subjects with known thyroid disease (n = 24) or who showed biochemical evidence of hypothyroidism or hyperthyroidism in the trial by having a baseline TSH measurement outside the reference range (0.15–3.5 mU/L) were excluded from the thyroid substudy (n = 27). The reason for the latter restriction is because elevated TSH may indicate the presence of autoimmune thyroiditis, whereas lowered TSH may indicate overt or subclinical hyperthyroidism; both situations could result in changes in thyroid function tests with time and disease progression. In neither case is an abnormal TSH value amenable to alteration by selenium supplementation. Use of a euthyroid population therefore reduces noise in the data and gives a better chance of seeing any modification of the T3:T4 resulting from selenium supplementation. The study had approval from the appropriate UK Local Research Ethics Committees, and participants provided written informed consent to participate.

Protocol
After a 4-wk placebo run-in, 501 volunteers were randomly assigned to 1 of 4 treatment regimes: placebo or 100, 200, or 300 µg Se/d for a minimum of 6 mo. The intervention agent was high-selenium yeast, SelenoPrecise (Pharma Nord, Vejle, Denmark), or an identical placebo yeast. Central randomization was by computer-generated permuted blocks stratified by general practice, sex, and age group. Research nurses telephoned the independent randomization service at the Clinical Trials and Statistics Unit, Institute of Cancer Research, to obtain an anonymous code for each volunteer. Participants collected their corresponding prelabeled tablets from the research nurses.

Participants and general practice personnel were blinded to study treatment. Participants provided a blood sample at both baseline and 6 mo (when visiting the general practices for the purpose of the PRECISE pilot). Heparinized plasma was prepared and frozen at the practices. Plasma samples were transferred to the University of Surrey where they were stored at –80 °C. All transfer of samples between centers was done on dry ice.

Questionnaires were used to collect demographic data and medical history at baseline and to ascertain use of medication and supplements at baseline and 6 mo. Compliance with randomized treatment was determined by pill count and by measuring each participant's plasma selenium and comparing it with the mean of the group. Reasons for participant withdrawal were noted.

Thyroid function assessment
Thyroid function was determined from the plasma samples from the baseline and 6-mo follow-up visits. Although strictly speaking free thyroid hormone should be measured, sample stability and analytic reliability of assays for total thyroid hormone are greater than those for free hormone (27, 28). We therefore chose to assess thyroid function by measuring all of the following in each plasma sample: total T4, total T3, free T4, free T3, and TSH.

Thyroid analyses were performed at the University Department of Clinical Biochemistry, Edinburgh Royal Infirmary, with the use of an enhanced chemiluminescence automated immunoassay system (Vitros ECi; Ortho Clinical Diagnostics, Amersham, United Kingdom) (29). This system uses a third-generation assay for TSH (functional sensitivity <0.02 mU/L). Furthermore, labeled antibody methods for free thyroid hormone measurements have been shown to correlate well with equilibrium dialysis values in a range of clinical conditions (30). Over the concentration ranges measured in the study, the within- and between-run CV for these assays were all <5%.

Selenium measurement
Lithium-heparin plasma was measured for selenium at the Central Science Laboratory, Sand Hutton, United Kingdom, by hydride-generation inductively coupled-plasma mass spectrometry. Weighed plasma samples were prepared by microwave digestion (Multiwave; Perkin-Elmer, Bucks, United Kingdom) and reduced to selenium (IV), before being made up to volume for analysis. All reagents were "Analar" grade (or better), and the water used was Millipore grade (18 M{Omega}). Quality control procedures were accredited under the UK Accreditation Scheme. Accuracy was assured by analysis of certified reference materials, namely, seronorm serum, mean value (10 determinations) 85.5 ng/g, RSD 12.7% (certified 86 ng/g); NIST 1598 bovine serum, mean value (16 determinations) 43.5 ng/g, RSD 6.2% (certified 42.4 ± 3.5 ng/g). The limit of detection was 5 ng/g and the mean recovery was 108% (12 determinations). Plasma selenium measurements can be converted from ng/g to µg/L by multiplying by 1.027, the density of plasma (31).

Statistical analysis
TSH, free and total T3, and free and total T4 were log10 transformed to better approximate the normal distribution. The effect of selenium supplementation on markers of thyroid function was assessed by analysis of covariance with intervention dose included as a 4-level factor. Subsequent models were adjusted for baseline concentrations of the relevant thyroid marker, sex, age group, and clinic location. Baseline comparisons were made with 1-factor analysis of variance, with Fisher's least significant difference test used for post hoc comparisons as appropriate. The correlations between the various thyroid markers and selenium status at baseline were assessed with Pearson's product-moment correlation. The correlation between baseline and follow-up measurements in participants assigned to placebo was used to assess the extent of within-person variation in the markers measured. Withdrawals were analyzed with chi-square tests. Participants were excluded if they did not provide a blood sample at both time points, were taking thyroid medication, or had baseline TSH measurements outside the laboratory reference range of 0.15–3.5 mU/L. The remaining 368 participants were included regardless of their compliance with allocated treatment. Statistical analysis was performed with the use of SPSS version 11.5 for WINDOWS (SPSS Inc, Chicago, IL). Unless otherwise stated, data are expressed as mean (±SD). To account for multiple comparisons, P values of <0.01 are considered statistically significant throughout.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 SUBJECTS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Participants
Participants (n = 501) were recruited between June 2000 and July 2001. Of those participants, 34 withdrew from treatment and were unable to be evaluated in this analysis because they had no 6-mo blood sample, 39 were excluded because of thyroid problems, and a further 60 were missing at least one of the baseline or 6-mo follow-up laboratory measures (see Figure 1Go for reasons). Results for the remaining 368 participants with complete records are reported below.


Figure 1
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  		FIGURE 1.. Participant flow through the study. TSH, thyroid-stimulating hormone.

 
Compliance with treatment
Of the 368 participants, 356 (97%) included in this analysis were compliant (missed <10% of the total number of tablets they should have taken) according to pill count. Nonprotocol use of over-the-counter selenium ("drop-ins") was assessed by inspection of the distribution of plasma selenium concentrations in the placebo group at 6 mo. Two (2.2%) of the 90 participants taking placebo had a selenium status >2 SDs above the mean, reasonably consistent with the 2.5% expected (being approximately normally distributed). We have made the assumption, therefore, that drop-ins were rare. One participant (of 368) reported using supplements that provided 25 µg of selenium; because this was within the 50-µg daily limit imposed by our exclusion criteria, this participant was included in the analysis.

Withdrawals
Thirty-four (7%) of the initial 501 participants withdrew from study treatment within the first 6 mo. No significant difference was observed in the numbers of participants withdrawing from treatment between groups (7 in the placebo group, 10 in the 100-µg group, 5 in the 200-µg group, and 12 in the 300-µg group; chi-square test = 3.5, df = 3, P = 0.31). Of those participants, 13 withdrew because of adverse events, 7 of which were abdominal or stomach problems. Other reasons for discontinuation appeared unrelated to treatment (Figure 1Go).

Selenium status
Overall mean plasma selenium at baseline was 88.9 ng/g (95% CI: 86.9, 90.8 ng/g) [equivalent to 91.3 µg/L; 95% CI: 89.2–93.3 µg/L (31)]. No significant differences were observed in the initial selenium concentration between the 4 treatment groups (P = 0.54). After 6 mo of supplementation, plasma selenium had risen significantly in the 100-, 200-, and 300-µg/d treatment groups (Figure 2Go) [mean differences: 53.5 ng/g (95% CI: 48.2, 58.8 ng/g), 96.4 ng/g (95% CI: 89.2, 103.6 ng/g), and 129.7 ng/g (95% CI: 119.9, 139.5 ng/g), respectively; P < 0.001 for all]. Selenium status did not differ significantly in the placebo group between baseline and 6 mo (mean difference: –2.5 ng/g; 95% CI: –5.7, 0.6 ng/g; P = 0.11).


Figure 2
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  		FIGURE 2.. Selenium status was significantly altered by supplementation with 100, 200, and 300 µg Se/d (P < 0.001 for all, paired t tests). Data are means and 95% CIs at baseline (•) and at 6-mo follow-up ({circ}) for the 4 intervention doses. Plasma selenium concentration can be converted to µg/L by multiplying by 1.027, the density of plasma (31).

 
Baseline thyroid function
At baseline, free T3, free T3:T4, and total T3:T4 were significantly higher in men than in women (all P ≤ 0.001), whereas total T4 was lower (P < 0.001; Table 1Go). Free T4 was higher in the oldest age group than in the younger 2 age groups (P = 0.001) with a corresponding tendency toward a lower free T3:T4 (P ≤ 0.05). No further evidence was observed of any other age- or sex-related difference in the baseline thyroid function.


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  		TABLE 1. Markers of thyroid function at baseline in 368 participants by sex and age group and the correlation of these markers with baseline plasma selenium concentration1

 
Free T4 correlated negatively with baseline selenium status (r = –0.19, P < 0.001), with this association also reflected in the free T3:T4, which showed a marginal positive correlation with selenium status (r = 0.12, P = 0.02). None of the other measured markers was significantly associated with baseline selenium status.

Within-person variability
The extent of within-person variability for selenium concentration and the markers of thyroid function were assessed by correlating baseline and 6-mo values in the 90 participants assigned to the placebo group. Scatterplots (Figure 3Go) show the correlations obtained. Total T4, TSH, and free T4 were the most stable during the 6-mo time period, although all measured variables exhibited moderate-to-strong repeatability during this period. This would suggest that the total T3:T4 and free T3:T4 represent suitable markers for detecting any increase in T4 to T3 conversion that might result from selenium supplementation.


Figure 3
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  		FIGURE 3.. Extent of within-person variation between baseline and 6-mo values in the 90 participants taking placebo. Correlations were expressed as Pearson's correlation coefficients (P < 0.001 for all). TSH, thyroid-stimulating hormone; TT4, total thyroxine; FT4, free T4; TT3, total 3,3',5-triiodothyronine; FT3, free T3; TT3:TT4, ratio of TT3 to TT4; FT3:FT4, ratio of FT3 to FT4.

 
Effect of treatment
Concentrations of TSH, free and total T4, free and total T3, as well as free T3:T4 and total T3:T4, at baseline and after 6 mo for the 4 treatment groups are shown in Table 2Go. At baseline, no evidence was observed of any significant differences in these values between the 4 randomized treatment groups (P > 0.18 for all markers). Furthermore, no evidence was observed of an effect of selenium intervention on any of the measured markers of thyroid function at 6 mo, either unadjusted or after adjustment for baseline values of the relevant thyroid marker, participant sex, age group, and clinic location (Table 2Go). In particular, no evidence was observed of an effect of selenium supplementation on the free T3:T4 or total T3:T4.


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  		TABLE 2. Markers of thyroid function at baseline and 6 mo after supplementation with high-selenium yeast or placebo yeast in 368 participants1

 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
The effect of selenium supplementation on thyroid function was investigated previously in a number of studies of which our randomized trial is the largest: 368 subjects as opposed to 160, 172, and 60 (32, 33); 60 (23); 52 (34); 52 (35); 36 (6); and 11 (36) subjects. The duration of treatment in our study was also somewhat greater: 26 wk as opposed to 20, 14, 13, 9, and 4 wk.

We found no effect of daily supplementation with 100, 200, or 300 µg of selenium on thyroid function, as measured by TSH, total or free T4, total or free T3, total T4:T3, or free T4:T3, despite significant increases in plasma selenium. This is in contrast to the findings of supplementation studies in subjects of low or relatively low selenium status that found a reduction in serum or plasma T4 (6, 34, 35). For instance, in subjects from Otago, New Zealand, with a baseline intake of {approx}30 µg/d (a little lower than UK intakes) and mean plasma selenium of 65 µg/L, an additional 10 µg/d as L-selenomethionine (and a combination of 10-, 20-, 30-, and 40-µg/d doses) significantly decreased total T4 concentrations during a period of 20 wk, implying that such a baseline intake was limiting conversion of T4 to T3 (35). In contrast to those findings, 2 later New Zealand supplementation studies in volunteers of somewhat higher selenium status (77 and 85 µg/L) showed only a nonsignificant trend toward a decrease in total T4 (32, 33), in line with our results.

Mean baseline plasma selenium in our study (89 ng/g, equivalent to 91 µg/L) was considerably higher than in intervention studies that found a beneficial effect of selenium supplementation on thyroid function, as represented by a significant change in total or free T4 (6, 34, 35) or a significant correlation between plasma selenium and the total T3:T4 (23). Thus, initial selenium status of our participants was arguably in the replete range where most selenoproteins should show maximal activity (35, 37, 38). Because animal studies have shown that thyroid function is successfully maintained over 6 generations of selenium deficiency and that iodothyronine deiodinase activity is preferentially preserved, ranking high in the hierarchy of selenium supply to selenoproteins, it is unlikely that the baseline activity of the iodothyronine deiodinases was limited by selenium status in most of our participants (38-40).

Although we saw no effects of supplementation, we did find a number of differences at baseline. With regard to sex wherein differences have previously been reported (41-43), we found significantly lower total T4 and significantly higher free T3 in men than in women, resulting in men having higher free T3:T4 and total T3:T4. We saw some effect of age on thyroid function; free T4 was higher in the oldest age group (P = 0.001) and the free T3:T4 tended to be correspondingly lower (P ≤ 0.05), paralleling the results reported by Olivieri et al (6, 44) on T4 and T3:T4. Furthermore, baseline selenium status correlated negatively with free T4 and marginally positively with free T3:T4, suggesting a potential benefit of higher selenium status in this population. However, the relation was not strong, with selenium status accounting for only 3.6% and 1.4%, respectively, of the variation seen, suggesting that, at least within the baseline status range pertaining in this population group, selenium status is not an important factor in determining thyroid function.

In fact, mean baseline selenium status in our participants, at 89 ng/g (equivalent to 91 µg/L), was considerably higher than the mean value of 79 µg/L measured in free-living subjects aged 65–74 y from 80 areas of England, Scotland, and Wales (25). This is perhaps not too surprising because our participants were somewhat younger (60–74 y compared with 65–74 y) and were healthy volunteers, a quarter of whom came from East Anglia where selenium status is relatively high (25, 45). It is likely that our healthy volunteer subjects had intakes toward the upper end of the range of mean intakes in the United Kingdom of 29–39 µg/d (20), which, in the opinion of Thomson (46), is adequate for optimal iodothyronine deiodinase activity.

Although our highest selenium dose (300 µg) was similar to the amount of selenium supplied in the high-selenium diet fed to 5 male volunteers by Hawkes and Keim (36), we did not see the decrease in serum total T3 or significant increase in serum TSH that they described, which they attributed to subclinical hypothyroidism induced by this selenium dose. Given that they achieved this high selenium intake by dietary means alone, varying in particular sources of beef and rice (47), it is possible that other components of the diet (eg, iodine, iron, zinc, copper, manganese, or goitrogens) were responsible for the changes that they saw (48-50), as they have acknowledged (47).

In conclusion, we found no evidence of an effect of selenium supplementation on thyroid function in a subset of 368 apparently euthyroid, elderly, UK volunteers of moderate selenium status, participating in a randomized, double-blind, placebo-controlled trial. In particular, no effect was observed on the conversion of T4 to T3 as evidenced by the free T4:T3 or total T4:T3, a finding consonant with the weakness of the baseline correlations found with selenium status. Although this suggests that selenium intake is adequate for thyroid function in the UK regions where our study was conducted, this might not be the case for elderly persons living in areas of lower selenium intake (17, 23, 51) nor for those with autoimmune thyroiditis for whom additional selenium may be of benefit (14-16). Our study is, however, reassuring in that no adverse effects of selenium on thyroid metabolism were seen up to a total intake (food plus supplement) of {approx}350 µg/d.


   ACKNOWLEDGMENTS
 
We thank Mary Stoddart of the Clinical Biochemistry Department, Edinburgh Royal Infirmary, for her help in organizing the thyroid function tests; Judith Bliss of the Clinical Trials and Statistics Unit, Institute of Cancer Research, for help and statistical advice in setting up the PRECISE pilot study; Dr John Lewis of CSL for performing the selenium analysis; Dr David Lovell of the University of Surrey for statistical advice; and the personnel of the MRC General Practice Research Framework, in particular the research nurses, Anna Williams, Angela Ince, Anne Hall, Gill Wilkinson, Lesley Hand, and Cynthia Dixon who recruited and followed the subjects. We also thank Drs Marr (The Garth Surgery, Guisborough), Leci (Churchfields Surgery, Bromsgrove), Hand (Bungay Medical Practice, Bungay), and Robertson (Cambridge Medical Group, Linthorpe) and particularly to their patients who generously agreed to take part in the study.

The author's responsibilities were as follows—MPR (principal investigator): raised the funding, designed the study, supervised the selenium measurements, and wrote the manuscript with the help of AJT, GJB, and EH; AJT: performed the data analysis and prepared the figures and tables with the help of BB and EH; GJB: advised on the design of the thyroid study and performed the thyroid measurements; EH, one of the trial statisticians for the UK PRECISE Pilot Study, was involved in its design and fund raising and helped with manuscript preparation. RG, JC, and AJT were study managers for the UK PRECISE Pilot Study, and AJT and MWP managed the data. None of the authors had a personal or financial conflict of interest.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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Received for publication March 21, 2007. Accepted for publication September 17, 2007.




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