ORIGINAL

E n d o c r i n e

ARTICLE
C a r e

Health Status, Mood, and Cognition in Experimentally
Induced Subclinical Thyrotoxicosis
M. H. Samuels, K. G. Schuff, N. E. Carlson, P. Carello, and J. S. Janowsky
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

Objective: Our objective was to determine whether subclinical thyrotoxicosis alters health status,
mood, and/or cognitive function.
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.
Results: Mean TSH levels decreased from 2.15 to 0.17 mU/liter on the subclinical thyrotoxicosis arm
(P ⬍ 0.0001), with normal mean free T4 and free T3 levels. The SF-36 physical component summary
and general health subscale were slightly worse during the subclinical thyrotoxicosis arm, whereas
the mental health subscale was marginally improved. The POMS confusion, depression, and tension
subscales were improved during the subclinical thyrotoxicosis arm. Motor learning was better
during the subclinical thyrotoxicosis arm, whereas declarative and working memory measures did
not change. This improvement was related to changes in the SF-36 physical component summary
and POMS tension subscales and free T3 levels.
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. (J Clin Endocrinol Metab 93: 1730 –1736, 2008)

S

ubclinical thyroid dysfunction [abnormal serum TSH with
normal free T4 (fT4) and free T3 (fT3) levels] may have
central nervous system effects. This has been best studied in subclinical hypothyroidism, with some (but not all) reports showing
adverse effects on mood and cognition, and improvements after
L-T4 treatment (reviewed in Refs. 1 and 2). Subclinical hyperthyroidism has been less well studied in this regard, with reports
showing increased levels of anxiety or depression and decrements in cognitive domains (3– 8). However, this is not uniform
(5, 9 –11), and there is little information on treatment effects.

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

0021-972X/08/$15.00/0

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.

Printed in U.S.A.
Copyright © 2008 by The Endocrine Society
doi: 10.1210/jc.2007-1957 Received September 4, 2007. Accepted February 8, 2008.
First Published Online February 19, 2008

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jcem.endojournals.org

J Clin Endocrinol Metab. May 2008, 93(5):1730 –1736

Stable doses of oral contraceptive or estrogen therapy were allowed during the study. a questionnaire about general health (22). Higher scores on the POMS subscales reflect mood decrements. changes in health status. mood. We hypothesized the following: 1. validated measures targeted to specific domains likely to be affected by altered thyroid status. We studied three distinct forms of memory linked to specific brain systems: declarative memory (medial temporal lobe). eight. or cognition. Experimental design (Fig. Subjects erred when they touched a drawing that had been touched on a previous card. Tests of declarative memory (hippocampus. Subjects completed validated measures of health status and mood. fT4.org 1731 vised (WAIS-R) Vocabulary subtest. working memory (prefrontal cortex). There were 31 subjects that had autoimmune hypothyroidism. subjects copied a standard complex figure. Subjects and Methods Experimental subjects A total of 33 subjects (31 women. The subject was instructed to touch one drawing on each card. The task was repeated with an increase in memory load by having the subject respond when a letter appeared three back. but not to touch the same drawing on subsequent cards in the set. Complex Figure Test (visual memory) For the Medical College of Georgia Complex Figure Test. The Hyperthyroid Symptom Scale (HSS) was completed (24). drug abuse. We included validated measures of health status and mood because these may be altered in subjects with subclinical thyrotoxicosis (3– 8. rather. and may secondarily affect cognition. Subjects were excluded if they scored less than eight (scaled). 1. All subjects had elevated TSH levels before L-T4 treatment or while on lower L-T4 doses. and mood or cognitive disorders by history. but in a different spatial arrangement. Subjects responded when a letter appeared that they had seen on the previous screen (one back). medication use. 10. and/or fT3 levels. This instrument has been used in studies involving thyroid disease (25). Tests of working memory (prefrontal cortex) Screening visit Subjects were screened for general health. except for the vigor subscale. 93(5):1730 –1736 brain areas that subserve memory (14 –18). laboratory. Based on existent literature and our previous study. and drew it from memory immediately and after a 30-min interval.endojournals. 20. 11. and two had received iodine-131 therapy for Graves’ disease. a questionnaire about mood (22). in which higher scores reflect improved mood. 21).to 120-min baseline visit. May 2008. Higher scores on the SF-36 summary scales and subscales reflect better health status and well-being. and/or cognition are correlated with changes in TSH. The outcome measure was the total number of errors across each card set (22). and after each sequence the subject repeated the sequence backwards. The outcome measure was the total number of elements correctly reproduced (22). subjects returned for a 90. Each card in a set showed the same array of abstract drawings. The Short Form 36 health survey (SF-36). Subjects with induced subclinical thyrotoxicosis have specific decrements in memory. physical examination. Testing was done during the first 10 d after onset of menstrual bleeding. The outcome measure was the total number correct (27). Serum TSH. and decrements were found in our study of subclinical hypothyroidism (12). and verbally recalled each of them immediately and after a 30-min interval. Subjects who scored outside the normative range were excluded. The Symptom Checklist 90-R was administered to screen subjects for psychiatric diseases (23). Duration of hypothyroidism averaged 7 yr (range 6 months to 25 yr). thyroid status. with normal TSH levels. fT4. we did not use a battery of general cognitive measures but. The Profile of Mood States (POMS). The outcome measure was the total number of story elements recalled at each interval (26). and fT3 levels were obtained. 2. Each card set was repeated three times. subjects were read two brief stories. 3.J Clin Endocrinol Metab. Subjects with induced subclinical thyrotoxicosis have decrements in health status and mood compared with the euthyroid state. Baseline visit Within 3 wk. Study flow diagram. Subjects were receiving L-T4 as the sole treatment in stable doses for at least 3 months. which may be related to changes in health status or mood. 1) The protocol was approved by the Oregon Health & Science University Institutional Review Board. two men). The examiner read number sequences of increasing length. with adult-onset primary hypothyroidism was recruited. medial temporal lobe) Paragraph Recall (verbal memory) For this subtest of the Wechsler Memory Scale-Revised. . jcem. ages 24 – 45 yr. Digit Span Backwards FIG. and electrocardiogram testing. Subject Ordered Pointing (SOP) Subjects were presented with stacks of cards (six. General intelligence was measured by the Wechsler Adult Intelligence Scale-Re- N-back test A series of letters was presented one at a time on a screen. Subjects refrained from taking their L-T4 dose that morning. or in the first 10 d of an oral contraceptive cycle. which correlates with intelligence quotient (22). Cognitive tests were administered by a single research assistant in a standard fashion. mood. In subjects with induced subclinical thyrotoxicosis. and motor learning (cerebellum and basal ganglia) (19). and subjects gave written informed consent. Subjects did not have any acute or chronic illnesses and were not receiving medications that affect thyroid hormone levels. or 12 per set).

normal range 210 – 440.27 ng/dl and 1% at 4. Each set of tests was analyzed as a group to adjust for within-subject correlation and correlations between responses on similar tests.15 ⫾ 0.001 ⬍0. 93(5):1730 –1736 and which arm they preferred. Six-week interim visit. The subjects and the physician (M. San Juan Capistrano.78 ⫾ 3. P values less than 0. while avoiding overtreatment and possible symptoms. fT4.31 1.38 0. . intraassay coefficients of variation (CVs) 9.6% at 14 mU/liter. L-T4 pills were placed in gel capsules to maintain blinding.7% at 0. The number of models was large.86 ⫾ 3.2 70.1 1. and fT3 levels were measured.94 ⫾ 0.) made L-T4 dose adjustments as needed to attain target TSH levels for that arm of the study.03 0. Mood and Memory in Subclinical Thyrotoxicosis Subjects erred when they could not successfully repeat two sequences of the same length (22). Subjects were randomized to receive either their usual doses of L-T4 (euthyroid arm) or higher doses of L-T4. and 60 revolutions per minute to establish the optimal speed for further trials. Motor learning (basal ganglia.8 ⫾ 1.2 74. POMS.5 66.2 ⫾ 2. and total T3 levels. or fT3 and outcomes. when applicable.S.001 To convert fT4 levels to International System of Units.) and research assistant (P. CA): sensitivity 0. and cognitive tests were repeated in the same order as the baseline visit.7 ⫾ 6. fT3 was measured by tracer dialysis (Nichols Institute): sensitivity 25 pg/dl.30 1. so we were interested in statistically significant findings across similar measures and similar hormones rather than in individual P values.06 ⫾ 0. IN).73 ⬍0.83 27. results are grouped together in the results tables (see Tables 2 and 3).7 ⫾ 2.66 ⫾ 0. Separate models were fitted to assess effects of each individual change in SF-36 and/or POMS score that showed significant euthyroid-thyrotoxicosis differences.45 ⫾ 0.6 ⫾ 2.70 ⫾ 0. Generalized Estimating Equations (29) were used to estimate group differences for measures with ceiling or floor effects.04 262. May 2008.001 ⬍0. After a 30-min interval.4 mU/liter (subclinical thyrotoxicosis arm). with a 20-sec rest after each trial and a 60-sec rest period after four trials. Twelve weeks after the baseline visit.39 2. subjects returned for a visit identical to the cross-over visit. Body mass index. intended to lead to a TSH level of 0.67 26. fT4 was measured by immunochemiluminometric assay: sensitivity 0.02 mU/liter and 4.1 ⫾ 1. Clinical parameters and thyroid function tests at baseline and the end of each arm of the study (euthyroid and subclinical thyrotoxicosis) Measure Baseline (mean ⴞ SEM) Euthyroid (mean ⴞ SEM) Thyrotoxic (mean ⴞ SEM) P value (paired t test) TSH (mU/liter) fT4 (ng/dl) fT3 (pg/dl) Weight (kg) BMI (kg/m2) Pulse (beats/min) Systolic blood pressure (mm Hg) Diastolic blood pressure (mm Hg) HSS L-T4 dose (␮g/kg䡠d) 2. three mixed effects models were developed for each outcome.5 ⫾ 2. with subjects now on the alternate L-T4 dose.3 ng/dl and 1.87.8 ng/dl.5% at 0.08 ng/dl.40 ⫾ 0. BMI. Lafayette Instrument Co. Based on average suppressive L-T4 doses in thyroid cancer patients. Analytical methods TSH was measured by immunochemiluminometric assay (Nichols Institute.0 ⫾ 2.6 ⫾ 1. To convert fT3 levels to International System of Units.3 75.0 2.06 1. Serum TSH. estimated initial L-T4 dose increases were 30%.4 73.S.3 ⫾ 6. Age. Statistical methods Differences in outcomes between the two study arms were explored by paired t tests. keeping fT4 and T3 levels within the normal range.6 mU/liter. SF-36.00. while maintaining normal fT4 and T3 levels.2 ⫾ 1.74 ⫾ 0.9 72.01– 0. and interassay CVs 17% at 0. fT4. with one thyroid hormone as a covariate.0 ⫾ 1.2 73. WAIS-R. and interassay CVs 6. multiply by 0.01536. 45. to adjust L-T4 doses and assess reported side effects. In a final model for each outcome.04 259.79 26. subjects returned for a brief visit.40 1. multiply by 12. TABLE 1. and interassay CV 4%.S.6 ng/dl.03 mU/liter and 4. Eighteen-week interim visit.09 2. Cross-over visit. End of study visit.05 were considered significant. the association between a single thyroid hormone measure was adjusted for the two other thyroid hormone measures. intraassay CVs 5.) with direct subject contact were blinded. intraassay CV 6%.. Our target TSH level reflects the range seen in clinical practice. Subjects were crossed over to the second arm of the study and had their new doses of L-T4 dispensed. Twelve weeks after the cross-over visit. The outcome measure was the mean total time the stylus remained on target during each trial (28). subjects returned for an extended visit. and cognitive measures were then analyzed together using mixed effects models.G.09 ⬍0. years of education.8 1. whereas the monitoring physician (K.06 320. This visit was identical to the 6-wk visit. mood. An initial block of four trials was administered at 15. 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. To assess whether differences in cognitive measures could be explained by differences in health status or mood.29 0. In a final analysis. and baseline measures were covariates to reduce residual variability.8% at 0. Lafayette.2 120. we simultaneously adjusted for significant thyroid hormone and health status or mood associations to assess independent effects on the cognitive measures.45 ⫾ 3.001 0.2 70. Safety was assessed by questioning for symptoms.7 70.62 ⫾ 0. the model with significant cognitive differences (Pursuit Rotor) was adjusted for changes in SF-36 and/or POMS measures.G.17 ⫾ 0. Two blocks of eight 20-sec trials were then administered. normal range 0.09 0. Sets of quality of life.7% at 11. 30. Subjects were asked which arm of the study they thought was the higher dose arm J Clin Endocrinol Metab.6% at 3.38 0. serum TSH.28 –5.7 ⫾ 2.7–1.) was unblinded. Six weeks later.8. normal range 0.1732 Samuels et al.8 121. the two blocks were repeated.52 0. Compliance was assessed by pill counts.27 1. fT4.58 ⫾ 0.7 ⫾ 1.33 ⫾ 0. The monitoring physician (K.2 ⫾ 11. performing electrocardiograms. The HSS.003 mU/liter.C. Bonferroni adjustments were used for formal pairwise comparisons.H. They were then placed back on their usual doses of L-T4.3 118. To investigate associations between changes in TSH.

33 ⫾ 3. tension. 93(5):1730 –1736 jcem.28 66.83 ⫾ 2.96 94.38 89. Cognitive tests (Table 3 and Fig.73 44.55 69. one with a slightly high fT3 level.73 42.008 0. There were no significant effects on other SF-36 or POMS subscales. There were no differences in weight. and tension subscales of the POMS were improved during the subclinical thyrotoxicosis arm (P ⫽ 0. treatment test P values were examined initially. years of education.06 51. There were no other associations between changes in the SF-36 or POMS scales and changes in TSH. systolic blood pressure.06 0.02 0. and almost all serum fT4 and fT3 levels in the normal range.52 ⫾ 1. Four subjects had slightly high fT4 levels.01 Treatment test: 0.14 81.04 – 0.21 40. vigor. Thus. or HSS at the end of the two arms of the study.11 P values for unadjusted paired t tests comparing the two arms of the study are shown in the fifth column. Anxiety.endojournals.33 50. vitality. mean TSH levels decreased to 0. or fT3 levels (data not shown). and 12 had no preference (P ⫽ NS).03).69 ⫾ 1.66 ⫾ 1.01).15 Treatment: 0. A.44 ⫾ 1. this value is listed in the table.07 41. bodily pain. seven decreased to intermediate dose).51 0. five preferred the dose they perceived was the euthyroid dose.43 ⫾ 3.50 ⫾ 1.65 80.54 86. BP. SOP.06 0.15) at the end of the subclinical thyrotoxicosis arm.02). with TSH levels in our target range.1 mU/liter.67 ⫾ 4.50 ⬎0.55 88.44 ⫾ 0. TABLE 2.84 ⫾ 2.09 80. Physical health status. role emotional.J Clin Endocrinol Metab. fT4.99 ⬎0. If the treatment test P value was 0. POMS) (Table 2) Clinical parameters and thyroid function tests (Table 1) A total of 47 subjects volunteered for the study. 10 guessed incorrectly.59 ⫾ 0. and the general health subscale was marginally worse (P ⫽ 0.99 0.13 ⫾ 1. There were no differences between the two study arms in N-Back number correct.38 ⫾ 1. indicating a possible treatmenttest interaction.75 ⫾ 0. 2) Declarative memory.34 0.16 ⫾ 1. or Digit Span Backwards. Mental health (MH) status. RE.83 91. a Raw scores compared using an exact McNemar’s test because many values were at ceiling.01 76.10 93. and 33 qualified after the screening visit. These P values were adjusted for age.06). and 11 had no preference (P ⫽ NS).84 ⫾ 1.06). role physical. Sixteen preferred the dose they perceived was the higher dose.17 53.03 40. and only the overall treatment effect is shown.22 0. physical functioning. V. whereas mean fT4 and fT3 levels increased at the end of the subclinical thyrotoxicosis arm. confusion.16 42.18 0.33 ⫾ 3. Adjusted P values in the repeated measures analysis are shown in the sixth column.78 ⫾ 1.33 ⫾ 3. depression. Working memory.53 ⫾ 1.03 39.org 1733 Results Health status and mood (SF-36.10 44. T.72 ⫾ 1.84 ⫾ 2.65 42.01). Significant results are highlighted in bold. If the treatment test P value was more than 0.002 0. depression. There were no differences between the two study arms in Paragraph Recall (verbal memory) or performance on the Complex Figure Test (visual memory). it is not shown in the table. and subsequent analyses were done for individual measures. May 2008.40 81.72 ⫾ 1.61 52. C.1 or less.89 ⫾ 4. seven preferred the actual lower euthyroid dose.33 ⫾ 2.01 0.17 mU/liter.04 0.11 42.11 BP GH MH VT PFa RPa SFa REa POMS A C D F T V P value (paired t test) Adjusted P values Treatment: 0.16 54.33 ⫾ 1.87 ⫾ 3. pulse. The confusion. indicating no treatmenttest interaction. .75 ⫾ 1.06 43.60 59. There were 15 that preferred the actual higher dose. we were successful in inducing subclinical thyrotoxicosis.16 ⫾ 1. and eight had no opinion [P ⫽ not significant (NS) by binomial calculation].1. The mental component summary (MCS) scale score was slightly but not significantly better (P ⫽ 0. whereas 11 had TSH levels more than 0.82 76.05 0. social functioning.05 86.13 ⫾ 0.03 ⫾ 1. A total of 22 subjects had TSH levels less than 0.16 93. Subjects did not reliably predict which arm was the subclinical thyrotoxicosis arm: 15 guessed correctly. two decreased dose) and in 27 during the subclinical thyrotoxic arm (20 increased dose further. SF.83 0. VT. WAIS-R. Changes in the SF-36 MCS were also directly related to changes in fT4 levels (P ⫽ 0.59 ⫾ 1.42 Treatment: 0. Interim L-T4 dose adjustment was necessary in four subjects during the euthyroid arm (two increased dose.16 ⫾ 0.56 ⫾ 6. diastolic blood pressure was slightly lower at the end of the subclinical thyrotoxicosis arm (P ⫽ 0.15 0.00 ⫾ 1. Summary statistics and P values for health status and mood measures during the two treatment arms Measure Baseline (mean ⴞ SEM) Euthyroid (mean ⴞ SEM) Thyrotoxic (mean ⴞ SEM) SF-36 MCS PCS 51. PF.64 55.39 43. All subjects completed the study. The SF-36 physical component summary (PCS) scale score was slightly worse at the end of the subclinical thyrotoxicosis arm (P ⫽ 0.55 ⫾ 2.72 ⫾ 2. D.46 56.40 ⫾ 2.86 91. Per study design.37 41.23 78.89 41.01 85.54 42.91 ⫾ 1.66 ⫾ 1.28 84.33 0.38 ⫾ 1. fatigue.28 0.1 mU/ liter.57 96. RP.00 ⫾ 4. 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 ⫽ 0.06 0. and the MH subscale was improved (P ⫽ 0.02 51.16 ⫾ 1. and baseline measure for that particular variable. For the adjusted analyses.56 93.03 ⫾ 2.45 0.71 ⫾ 1.99 84. F.67 ⫾ 2.01).58 ⫾ 3.

32 ⫾ 0. Walsh et al.48 28.99 0.61 14.45 ⫾ 0.31 ⫾ 0. The results were similar.08 35. there was no difference between the two arms for the initial Pursuit Rotor trial.22 ⫾ 0.001 by mixed effects model). (10) also safely .19 ⫾ 2.22 29.82 29.56 ⫾ 0.23 ⫾ 0.11 0.12 0.53 ⫾ 0.07 38.001 0.68 0. mood. and subjects’ awareness of their thyroid status.12 1.56 ⫾ 0.40 15.66 30.62 ⫾ 0.84 28.20 ⫾ 0.39 39. In one previous report of a similar model.39 ⫾ 2. There were slight differences between baseline and euthyroid arm levels for some of the health status. We accounted for these differences by randomized order of the two arms.001 to 0.35 15. 2). For the adjusted analyses.16 8. May 2008. 93(5):1730 –1736 Summary statistics and P values for cognitive measures during the two treatment arms of the study Declarative memory Paragraph Recall Immediate 30-min delay Complex Figure Copy 3 min 30 min Working memory N-Back number correct 1 back 3 back SOP errors 6 8 10 12 Digit Span Backwards Motor learning Pursuit Rotor Trial 1 2 3 4 Baseline (mean ⴞ SEM) Euthyroid (mean ⴞ SEM) Thyrotoxic (mean ⴞ SEM) P value (paired t test) 14.15 8.86 ⫾ 0.33 23. P values for unadjusted paired t tests comparing the two treatment arms are shown in the fifth column.23 34.31 ⫾ 0. The Pursuit Rotor differences were not related to changes in fT4 or TSH levels (data not shown).25 ⫾ 0.72 0.31 Adjusted P values Treatment: 0. mood.16 26.16 10.72 28.06 ⫾ 0.75 ⫾ 0.28 Treatment: 0.001 0.32 ⫾ 0.31 33.96 ⫾ 1.11 ⫾ 0. thus.29 Treatment: 0.62 ⫾ 2.69 ⫾ 1.30 ⫾ 0.13 ⫾ 0.04 <0. but not to the other POMS subscales.22 ⫾ 0.71 0.61 15.01 32.40 ⫾ 0. The differences in Pursuit Rotor between the two study arms were also related to changes in the SF-36 PCS scale score (P ⫽ 0.84 ⫾ 0.48 0. Motor learning.008).08 0.63 13. By unadjusted t tests.67 Treatment: 0. We repeated our analysis after exclusion of four subjects with slightly elevated fT4 levels at the end of the subclinical thyrotoxicosis arm.12 1.003) and the POMS tension subscale (P ⫽ 0. years of education.18 7. 2.19 31.06 0. Discussion FIG.78 ⫾ 0. and cognition by controlling L-T4 doses in subjects with treated hypothyroidism.07 0.94 ⫾ 0.11 0.14 0.35 0. There were no treatment-test interactions.25 Treatment: 0.06 ⫾ 0.14 10.19 14. These P values were adjusted for age.62 16. The x-axis shows each of the four trials.06).83 0.23 ⫾ 0. We investigated effects of subclinical thyrotoxicosis on health status.08 ⫾ 2. and. whereas the y-axis shows time on target for each trial (sec).41 ⫾ 0.81 34. and baseline measure for that particular variable. only the overall treatment effect is shown.83 34.31 28.67 ⫾ 1.59 ⫾ 0. This model circumvents limitations in studying endogenous subclinical hyperthyroidism: subject recruitment and heterogeneity.11 1. Significant results are highlighted in bold.43 0. Statistical significance was lost for the SF-36 general health subscale and the POMS depression subscale.59 ⫾ 0. It also circumvents limitations in studying patients receiving suppressive L-T4 doses for nodular thyroid disease or thyroid cancer. compared with the euthyroid arm (P ⬍ 0.00 ⫾ 0.05 ⫾ 2.72 ⫾ 0. The differences in Pursuit Rotor were marginally related to changes in fT3 levels between the two study arms (P ⫽ 0. who may have health status alterations due to the underlying disease.16 36. although the significance level decreased slightly for some of the results due to the smaller sample size. The Pursuit Rotor results were significantly better at the end of the subclinical thyrotoxicosis arm.44 ⬎0. Adjusted P values in the repeated measures analysis are shown in the sixth column.28 9.42 0.1734 Samuels et al. and by using baseline levels as a covariate in our mixed models. and cognitive tests.33 Treatment: <0. TABLE 3. WAIS-R.34 ⫾ 2. variable natural history.06 ⫾ 0. likely reflecting effects due to close monitoring during the study.44 ⫾ 2.001 by adjusted t tests) (Fig.51 32.10 0.48 0.24 ⫾ 1.85 ⫾ 2. treatment test P values were examined initially.11 1.32 ⫾ 0.78 ⫾ 0. Results were better during the subclinical thyrotoxicosis arm of the study (P ⬍ 0.83 0.77 ⫾ 0. Mood and Memory in Subclinical Thyrotoxicosis J Clin Endocrinol Metab.25 ⫾ 0. Pursuit Rotor results at the end of the euthyroid arm (solid line) and subclinical thyrotoxicosis arm (dashed line). and learning effects of repeated testing.37 0.38 34. whereas the subsequent trials were all better at the end of the subclinical thyrotoxicosis arm (P ⬍ 0.04).49 15.03 Individual cognitive tests are grouped by the three memory subdomains (first column). These relationships were independent of changes in fT3 levels.

8. including the SF-36 MCS score and MH subscale. We did find slight decrements in the SF-36 PCS score and general health subscale. or systolic blood pressure during the subclinical thyrotoxicosis arm. In contrast. and there may also be other mediators of thyroid hormone action in those tissues (38). 93(5):1730 –1736 and effectively induced subclinical thyrotoxicosis in a blinded. and carryover effects. we do not recommend that hypothyroid subjects with benign thyroid disease be treated with suppressive doses of levothyroxine. we studied younger subjects to avoid risks of inducing subclinical thyrotoxicosis.J Clin Endocrinol Metab. but improvements in mood and motor learning. There were no changes in the HSS. This suggests specific positive effects of mild thyrotoxicosis on MH and mood. We limited the time of subclinical thyrotoxicosis to 12 wk. a form of implicit or nondeclarative memory. and POMS confusion. L-T4 dose alterations were less. we found that subclinical hypothyroidism was associated with decrements in the SF-36 general health and POMS fatigue subscales. the cross-over design.org 1735 Our final hypothesis was that changes in outcomes would be correlated with changes in thyroid hormone levels. However. Thyroid hormone levels are tightly regulated within the brain in a tissue-specific fashion that is not completely dependent on serum levels. 10. Our subjects did not experience changes in weight. 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. 3181 SW Sam . Acknowledgments Address all correspondence and requests for reprints to: Mary H. This hypothesis was not consistently supported. and we recognize that most subjects required interim L-T4 dose adjustment during this time. There are five limitations to this study: sample size. One explanation is that serum thyroid hormone and TSH levels do not adequately reflect thyroid hormone action in the brain.D. This suggests that there may be different “optimal” thyroid hormone levels for the brain areas that control these functions. and changes in health status and mood. 33). In summary. We found minor decrements in general and physical health status. (10) also reported no changes in working memory. May 2008. Previous studies investigated motor speed and psychomotor function in hyperthyroidism. Samuels. we induced subclinical thyrotoxicosis in a controlled. M. and the age range. Finally. the study’s duration. 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. and we found positive results for a number of health status and cognitive measures. It is interesting to compare our current results with our previous study of subclinical hypothyroidism (12). or no differences (9. It is unclear whether a longer time period would magnify or attenuate our findings. Our study was a priori powered on the cognitive measures. 36). blinded study in hypothyroid subjects (10). jcem. Our second hypothesis was that subjects would have decrements in memory during the subclinical thyrotoxicosis arm. Our results are also discrepant with the one other randomized.. and we recognize our results may not be generalizable to older subjects. which may explain the differences. In contrast. but no changes in working memory. despite decrements in physical health indices.endojournals. However. reporting either decrements or no differences compared with euthyroid controls (6. variability in thyroid hormone levels. This was mostly independent of motor speed. our findings are discordant with a recent large cross-sectional study in elderly subjects. Our study had the advantage of subjects being blinded to their treatment status. with most finding decrements compared with euthyroid subjects (3– 8. rosiglitazone treatment of polycystic ovarian syndrome (32). pulse. 35. the slight decrease in diastolic blood pressure is consistent with known effects of thyroid hormone on systemic vascular resistance (30). Using a similar study design as ours. 34). Only a few studies reported improved mood or well-being in subclinical thyrotoxicosis subjects (11. Given these mixed effects. we found no changes in declarative or working memory. To minimize this we used alternative test forms and randomized the treatment order. and gabapentin treatment of diabetic neuropathy (33). Using an identical design and outcome measures. The cross-over design could lead to problems with learning effects during repeated testing. Walsh et al. to our knowledge there are no studies of motor learning in overt or subclinical hyperthyroidism. Instead. as well as the known deleterious effects of subclinical hyperthyroidism on other organ systems (39). and no specific measure of mood such as the POMS was used. but not motor learning. 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). in agreement with the recent large cross-sectional study (9). depression. Our first hypothesis was that subjects would have decrements in health status and/or mood during the subclinical thyrotoxicosis arm. 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. Subclinical hypothyroidism was associated with decrements in working memory. We accounted for multiple comparisons by statistical adjustment. Previous findings may have been influenced by patients’ knowledge of their thyroid status. However. which found no mood alterations in subclinical thyroid disease (9). Subjects in that study were older (mean age 53 yr). and our subjects did not accurately guess which arm included the higher L-T4 dose. Our findings suggest that motor learning is an important target for future studies of mild thyroid dysfunction. we did find improvements in motor learning. controlled fashion. 21). subclinical thyrotoxicosis was associated with improved motor learning. blinded fashion in subjects with primary hypothyroidism. Together. Oregon Health & Science University. Previous studies reported variable effects of subclinical thyrotoxicosis on health status and mood. 20. and tension subscales. CR107. there were consistent improvements in MH measures. This confirms adequate blinding during the study.

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