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Division of Endocrinology, Diabetes and Clinical Nutrition (M.H.S., K.G.S.), Division of Biostatistics (N.E.C.), and Department of Behavioral Neurosciences (P.C., J.S.J.), Oregon Health & Science University, Portland, Oregon 97239
Address all correspondence and requests for reprints to: Mary H. Samuels, M.D., CR107, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, Portland, Oregon 97239. E-mail: samuelsm{at}ohsu.edu.
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Abstract |
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Design: This was a double-blinded, randomized, cross-over study of usual dose L-T4 (euthyroid arm) vs. higher dose L-T4 (subclinical thyrotoxicosis arm) in hypothyroid subjects.
Patients: A total of 33 hypothyroid subjects receiving L-T4 were included in the study.
Measurements: Subjects underwent measurements of health status, mood, and cognition: Short Form 36 (SF-36); Profile of Mood States (POMS); and tests of declarative memory (Paragraph Recall, Complex Figure
), working memory (N-Back, Subject Ordered Pointing, and Digit Span Backwards), and motor learning (Pursuit Rotor). These were repeated after 12 wk on each of the study arms.
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Conclusions: We found slightly impaired physical health status but improvements in measures of mental health and mood in L-T4 treated hypothyroid subjects when subclinical thyrotoxicosis was induced in a blinded, randomized fashion. Motor learning was also improved. These findings suggest that thyroid hormone directly affects brain areas responsible for affect and motor function.
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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We recently reported results of a randomized, double-blind, cross-over study in which L-T4 treated subjects received their usual dose of L-T4, or a slightly lower dose (12). Induction of subclinical hypothyroidism led to decrements in specific domains of health status, mood, and working memory. In the current study, we applied a similar experimental design to induce subclinical thyrotoxicosis. We chose to focus on memory, based on our previous data and studies suggesting that memory is preferentially affected in subjects with thyroid dysfunction (2, 12, 13), and because animal studies support a major role for L-T4 in brain areas that subserve memory (14, 15, 16, 17, 18). We studied three distinct forms of memory linked to specific brain systems: declarative memory (medial temporal lobe), working memory (prefrontal cortex), and motor learning (cerebellum and basal ganglia) (19). We included validated measures of health status and mood because these may be altered in subjects with subclinical thyrotoxicosis (3, 4, 5, 6, 7, 8, 11, 20, 21), and may secondarily affect cognition. We hypothesized the following:
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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A total of 33 subjects (31 women, two men), ages 24–45 yr, with adult-onset primary hypothyroidism was recruited. There were 31 subjects that had autoimmune hypothyroidism, and two had received iodine-131 therapy for Graves’ disease. Duration of hypothyroidism averaged 7 yr (range 6 months to 25 yr). All subjects had elevated TSH levels before L-T4 treatment or while on lower L-T4 doses. Subjects were receiving L-T4 as the sole treatment in stable doses for at least 3 months, with normal TSH levels. Subjects did not have any acute or chronic illnesses and were not receiving medications that affect thyroid hormone levels, mood, or cognition. Stable doses of oral contraceptive or estrogen therapy were allowed during the study. Testing was done during the first 10 d after onset of menstrual bleeding, or in the first 10 d of an oral contraceptive cycle.
Experimental design (Fig. 1
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The protocol was approved by the Oregon Health & Science University Institutional Review Board, and subjects gave written informed consent.
Screening visit Subjects were screened for general health, medication use, drug abuse, thyroid status, and mood or cognitive disorders by history, physical examination, laboratory, and electrocardiogram testing. General intelligence was measured by the Wechsler Adult Intelligence Scale-Revised (WAIS-R) Vocabulary subtest, which correlates with intelligence quotient (22). Subjects were excluded if they scored less than eight (scaled). The Symptom Checklist 90-R was administered to screen subjects for psychiatric diseases (23). Subjects who scored outside the normative range were excluded.
Baseline visit Within 3 wk, subjects returned for a 90- to 120-min baseline visit. Subjects refrained from taking their L-T4 dose that morning. Serum TSH, fT4, and fT3 levels were obtained. The Hyperthyroid Symptom Scale (HSS) was completed (24). Subjects completed validated measures of health status and mood.
The Short Form 36 health survey (SF-36), a questionnaire about general health (22).
Higher scores on the SF-36 summary scales and subscales reflect better health status and well-being. This instrument has been used in studies involving thyroid disease (25), and decrements were found in our study of subclinical hypothyroidism (12).
The Profile of Mood States (POMS), a questionnaire about mood (22).
Higher scores on the POMS subscales reflect mood decrements, except for the vigor subscale, in which higher scores reflect improved mood.
Cognitive tests were administered by a single research assistant in a standard fashion. Based on existent literature and our previous study, we did not use a battery of general cognitive measures but, rather, validated measures targeted to specific domains likely to be affected by altered thyroid status.
Tests of declarative memory (hippocampus, medial temporal lobe)
Paragraph Recall (verbal memory) For this subtest of the Wechsler Memory Scale-Revised, subjects were read two brief stories, and verbally recalled each of them immediately and after a 30-min interval. The outcome measure was the total number of story elements recalled at each interval (26).
Complex Figure Test (visual memory) For the Medical College of Georgia Complex Figure Test, subjects copied a standard complex figure, and drew it from memory immediately and after a 30-min interval. The outcome measure was the total number of elements correctly reproduced (22).
Tests of working memory (prefrontal cortex)
N-back test A series of letters was presented one at a time on a screen. Subjects responded when a letter appeared that they had seen on the previous screen (one back). The task was repeated with an increase in memory load by having the subject respond when a letter appeared three back. The outcome measure was the total number correct (27).
Subject Ordered Pointing (SOP) Subjects were presented with stacks of cards (six, eight, 10, or 12 per set). Each card in a set showed the same array of abstract drawings, but in a different spatial arrangement. The subject was instructed to touch one drawing on each card, but not to touch the same drawing on subsequent cards in the set. Subjects erred when they touched a drawing that had been touched on a previous card. Each card set was repeated three times. The outcome measure was the total number of errors across each card set (22).
Digit Span Backwards The examiner read number sequences of increasing length, and after each sequence the subject repeated the sequence backwards. Subjects erred when they could not successfully repeat two sequences of the same length (22).
Motor learning (basal ganglia, cerebellum)
Pursuit Rotor Subjects held a photosensitive wand to maintain contact with a 2-cm light disk rotating on a variable speed turntable (Model 30014; Lafayette Instrument Co., Lafayette, IN). An initial block of four trials was administered at 15, 30, 45, and 60 revolutions per minute to establish the optimal speed for further trials. Two blocks of eight 20-sec trials were then administered, with a 20-sec rest after each trial and a 60-sec rest period after four trials. After a 30-min interval, the two blocks were repeated. The outcome measure was the mean total time the stylus remained on target during each trial (28).
Subjects were randomized to receive either their usual doses of L-T4 (euthyroid arm) or higher doses of L-T4, intended to lead to a TSH level of 0.01–0.4 mU/liter (subclinical thyrotoxicosis arm), while maintaining normal fT4 and T3 levels. Our target TSH level reflects the range seen in clinical practice, while avoiding overtreatment and possible symptoms. Based on average suppressive L-T4 doses in thyroid cancer patients, estimated initial L-T4 dose increases were 30%. The subjects and the physician (M.H.S.) and research assistant (P.C.) with direct subject contact were blinded, whereas the monitoring physician (K.G.S.) was unblinded, to adjust L-T4 doses and assess reported side effects. L-T4 pills were placed in gel capsules to maintain blinding.
Six-week interim visit.
Six weeks later, subjects returned for a brief visit. Compliance was assessed by pill counts. Safety was assessed by questioning for symptoms, performing electrocardiograms, serum TSH, fT4, and total T3 levels. The monitoring physician (K.G.S.) made L-T4 dose adjustments as needed to attain target TSH levels for that arm of the study, keeping fT4 and T3 levels within the normal range.
Cross-over visit.
Twelve weeks after the baseline visit, subjects returned for an extended visit. Serum TSH, fT4, and fT3 levels were measured. The HSS, SF-36, POMS, and cognitive tests were repeated in the same order as the baseline visit. Subjects were crossed over to the second arm of the study and had their new doses of L-T4 dispensed.
Eighteen-week interim visit.
This visit was identical to the 6-wk visit, with subjects now on the alternate L-T4 dose.
End of study visit.
Twelve weeks after the cross-over visit, subjects returned for a visit identical to the cross-over visit. Subjects were asked which arm of the study they thought was the higher dose arm and which arm they preferred. They were then placed back on their usual doses of L-T4.
Analytical methods
TSH was measured by immunochemiluminometric assay (Nichols Institute, San Juan Capistrano, CA): sensitivity 0.003 mU/liter, normal range 0.28–5.00, intraassay coefficients of variation (CVs) 9.5% at 0.03 mU/liter and 4.7% at 11.6 mU/liter, and interassay CVs 17% at 0.02 mU/liter and 4.6% at 14 mU/liter. fT4 was measured by immunochemiluminometric assay: sensitivity 0.08 ng/dl, normal range 0.7–1.8, intraassay CVs 5.7% at 0.27 ng/dl and 1% at 4.6 ng/dl, and interassay CVs 6.8% at 0.3 ng/dl and 1.6% at 3.8 ng/dl. fT3 was measured by tracer dialysis (Nichols Institute): sensitivity 25 pg/dl, normal range 210–440, intraassay CV 6%, and interassay CV 4%.
Statistical methods
Differences in outcomes between the two study arms were explored by paired t tests. Sets of quality of life, mood, and cognitive measures were then analyzed together using mixed effects models. Age, years of education, WAIS-R, and baseline measures were covariates to reduce residual variability. Generalized Estimating Equations (29) were used to estimate group differences for measures with ceiling or floor effects. Each set of tests was analyzed as a group to adjust for within-subject correlation and correlations between responses on similar tests; results are grouped together in the results tables (see Tables 2 and 3). Bonferroni adjustments were used for formal pairwise comparisons, when applicable. P values less than 0.05 were considered significant.
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To assess whether differences in cognitive measures could be explained by differences in health status or mood, the model with significant cognitive differences (Pursuit Rotor) was adjusted for changes in SF-36 and/or POMS measures. Separate models were fitted to assess effects of each individual change in SF-36 and/or POMS score that showed significant euthyroid-thyrotoxicosis differences. In a final analysis, we simultaneously adjusted for significant thyroid hormone and health status or mood associations to assess independent effects on the cognitive measures.
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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)A total of 47 subjects volunteered for the study, and 33 qualified after the screening visit. Interim L-T4 dose adjustment was necessary in four subjects during the euthyroid arm (two increased dose, two decreased dose) and in 27 during the subclinical thyrotoxic arm (20 increased dose further, seven decreased to intermediate dose). Per study design, mean TSH levels decreased to 0.17 mU/liter, whereas mean fT4 and fT3 levels increased at the end of the subclinical thyrotoxicosis arm. A total of 22 subjects had TSH levels less than 0.1 mU/liter, whereas 11 had TSH levels more than 0.1 mU/liter. Four subjects had slightly high fT4 levels, one with a slightly high fT3 level. Thus, we were successful in inducing subclinical thyrotoxicosis, with TSH levels in our target range, and almost all serum fT4 and fT3 levels in the normal range.
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Subjects did not reliably predict which arm was the subclinical thyrotoxicosis arm: 15 guessed correctly, 10 guessed incorrectly, and eight had no opinion [P = not significant (NS) by binomial calculation]. There were 15 that preferred the actual higher dose, seven preferred the actual lower euthyroid dose, and 11 had no preference (P = NS). Sixteen preferred the dose they perceived was the higher dose, five preferred the dose they perceived was the euthyroid dose, and 12 had no preference (P = NS).
Health status and mood (SF-36, POMS) (Table 2)
Physical health status. The SF-36 physical component summary (PCS) scale score was slightly worse at the end of the subclinical thyrotoxicosis arm (P = 0.01), and the general health subscale was marginally worse (P = 0.06).
Mental health (MH) status.
The mental component summary (MCS) scale score was slightly but not significantly better (P = 0.15) at the end of the subclinical thyrotoxicosis arm, and the MH subscale was improved (P = 0.01). The confusion, depression, and tension subscales of the POMS were improved during the subclinical thyrotoxicosis arm (P = 0.04–0.06). There were no significant effects on other SF-36 or POMS subscales.
Changes in the SF-36 MCS and general health subscale scores were directly related to changes in fT3 levels between the two study arms (P = 0.01). Changes in the SF-36 MCS were also directly related to changes in fT4 levels (P = 0.02). There were no other associations between changes in the SF-36 or POMS scales and changes in TSH, fT4, or fT3 levels (data not shown).
Cognitive tests (Table 3 and Fig. 2)
Declarative memory. There were no differences between the two study arms in Paragraph Recall (verbal memory) or performance on the Complex Figure Test (visual memory).
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Motor learning.
The Pursuit Rotor results were significantly better at the end of the subclinical thyrotoxicosis arm, compared with the euthyroid arm (P < 0.001 by adjusted t tests) (Fig. 2). By unadjusted t tests, there was no difference between the two arms for the initial Pursuit Rotor trial, whereas the subsequent trials were all better at the end of the subclinical thyrotoxicosis arm (P < 0.001 to 0.04).
The differences in Pursuit Rotor were marginally related to changes in fT3 levels between the two study arms (P = 0.06). The Pursuit Rotor differences were not related to changes in fT4 or TSH levels (data not shown).
The differences in Pursuit Rotor between the two study arms were also related to changes in the SF-36 PCS scale score (P = 0.003) and the POMS tension subscale (P = 0.008), but not to the other POMS subscales. These relationships were independent of changes in fT3 levels.
There were slight differences between baseline and euthyroid arm levels for some of the health status, mood, and cognitive tests, likely reflecting effects due to close monitoring during the study, and learning effects of repeated testing. We accounted for these differences by randomized order of the two arms, and by using baseline levels as a covariate in our mixed models.
We repeated our analysis after exclusion of four subjects with slightly elevated fT4 levels at the end of the subclinical thyrotoxicosis arm. The results were similar, although the significance level decreased slightly for some of the results due to the smaller sample size. Statistical significance was lost for the SF-36 general health subscale and the POMS depression subscale.
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Our subjects did not experience changes in weight, pulse, or systolic blood pressure during the subclinical thyrotoxicosis arm; the slight decrease in diastolic blood pressure is consistent with known effects of thyroid hormone on systemic vascular resistance (30). There were no changes in the HSS, and our subjects did not accurately guess which arm included the higher L-T4 dose. This confirms adequate blinding during the study.
Our first hypothesis was that subjects would have decrements in health status and/or mood during the subclinical thyrotoxicosis arm. We did find slight decrements in the SF-36 PCS score and general health subscale. In contrast, there were consistent improvements in MH measures, including the SF-36 MCS score and MH subscale, and POMS confusion, depression, and tension subscales. This suggests specific positive effects of mild thyrotoxicosis on MH and mood, despite decrements in physical health indices. These effects are likely to be clinically relevant because the magnitude of the differences in the SF-36 scales are similar to changes reported with weight loss among overweight adults (31), rosiglitazone treatment of polycystic ovarian syndrome (32), and gabapentin treatment of diabetic neuropathy (33).
Previous studies reported variable effects of subclinical thyrotoxicosis on health status and mood, with most finding decrements compared with euthyroid subjects (3, 4, 5, 6, 7, 8, 20, 21), or no differences (9, 10, 34). Only a few studies reported improved mood or well-being in subclinical thyrotoxicosis subjects (11, 35, 36). Our study had the advantage of subjects being blinded to their treatment status. Previous findings may have been influenced by patients’ knowledge of their thyroid status. However, our findings are discordant with a recent large cross-sectional study in elderly subjects, which found no mood alterations in subclinical thyroid disease (9). Our results are also discrepant with the one other randomized, blinded study in hypothyroid subjects (10). Subjects in that study were older (mean age 53 yr), L-T4 dose alterations were less, and no specific measure of mood such as the POMS was used, which may explain the differences.
Our second hypothesis was that subjects would have decrements in memory during the subclinical thyrotoxicosis arm. Instead, we found no changes in declarative or working memory, in agreement with the recent large cross-sectional study (9). Using a similar study design as ours, Walsh et al. (10) also reported no changes in working memory. However, we did find improvements in motor learning, a form of implicit or nondeclarative memory. This was mostly independent of motor speed, and changes in health status and mood. The magnitude of the difference in Pursuit Rotor performance was similar to that seen with acute alcohol ingestion in healthy young men (37) and likely has clinical relevance.
Previous studies investigated motor speed and psychomotor function in hyperthyroidism, reporting either decrements or no differences compared with euthyroid controls (6, 8, 33). However, to our knowledge there are no studies of motor learning in overt or subclinical hyperthyroidism. Our findings suggest that motor learning is an important target for future studies of mild thyroid dysfunction.
Our final hypothesis was that changes in outcomes would be correlated with changes in thyroid hormone levels. This hypothesis was not consistently supported. One explanation is that serum thyroid hormone and TSH levels do not adequately reflect thyroid hormone action in the brain. Thyroid hormone levels are tightly regulated within the brain in a tissue-specific fashion that is not completely dependent on serum levels, and there may also be other mediators of thyroid hormone action in those tissues (38).
It is interesting to compare our current results with our previous study of subclinical hypothyroidism (12). Using an identical design and outcome measures, we found that subclinical hypothyroidism was associated with decrements in the SF-36 general health and POMS fatigue subscales. Together, these studies suggest that there is an optimal "window" of thyroid function for overall health (SF-36 PCS and general health subscale) but that MH and mood may continue to improve (SF-36 MCS and POMS) as thyroid function progresses from subclinical hypothyroidism to subclinical thyrotoxicosis. Subclinical hypothyroidism was associated with decrements in working memory, but not motor learning. In contrast, subclinical thyrotoxicosis was associated with improved motor learning, but no changes in working memory. This suggests that there may be different "optimal" thyroid hormone levels for the brain areas that control these functions.
There are five limitations to this study: sample size, variability in thyroid hormone levels, the study’s duration, the cross-over design, and the age range. Our study was a priori powered on the cognitive measures. We accounted for multiple comparisons by statistical adjustment, and we found positive results for a number of health status and cognitive measures. We do not feel that variability in thyroid hormone levels is a major limitation because analysis excluding subjects with elevated fT4/fT3 levels did not alter our results. We limited the time of subclinical thyrotoxicosis to 12 wk, and we recognize that most subjects required interim L-T4 dose adjustment during this time. It is unclear whether a longer time period would magnify or attenuate our findings. The cross-over design could lead to problems with learning effects during repeated testing, and carryover effects. To minimize this we used alternative test forms and randomized the treatment order. Finally, we studied younger subjects to avoid risks of inducing subclinical thyrotoxicosis, and we recognize our results may not be generalizable to older subjects.
In summary, we induced subclinical thyrotoxicosis in a controlled, blinded fashion in subjects with primary hypothyroidism. We found minor decrements in general and physical health status, but improvements in mood and motor learning. Given these mixed effects, as well as the known deleterious effects of subclinical hyperthyroidism on other organ systems (39), we do not recommend that hypothyroid subjects with benign thyroid disease be treated with suppressive doses of levothyroxine.
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Footnotes |
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Disclosure Summary: The authors have nothing to declare.
First Published Online February 19, 2008
Abbreviations: CV, Coefficient of variation; fT3, free T3; fT4, free T4; HSS, Hyperthyroid Symptom Scale; MCS, mental component summary; MH, mental health; NS, not significant; PCS, physical component summary; POMS, Profile of Mood States; SF-36, Short Form 36; SOP, Subject Ordered Pointing; WAIS-R, Wechsler Adult Intelligence Scale-Revised.
Received September 4, 2007.
Accepted February 8, 2008.
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