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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)
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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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.
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).
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Samuels et al.
Subjects erred when they could not successfully repeat two sequences
of the same length (22).
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 0.71.8, 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.
To investigate associations between changes in TSH, fT4, or fT3
and outcomes, three mixed effects models were developed for each
outcome, with one thyroid hormone as a covariate. In a final model
for each outcome, the association between a single thyroid hormone
measure was adjusted for the two other thyroid hormone measures.
The number of models was large, so we were interested in statistically
significant findings across similar measures and similar hormones
rather than in individual P values.
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.
TABLE 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 SEM)
Euthyroid
(mean SEM)
Thyrotoxic
(mean 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/kgd)
2.58 0.27
1.33 0.04
262.7 6.3
75.86 3.83
27.1 1.2
70.8 1.8
121.0 1.9
72.2 1.8
1.74 0.30
1.62 0.09
2.15 0.31
1.40 0.04
259.3 6.2
74.45 3.79
26.7 1.2
70.6 2.2
120.0 2.7
70.2 2.1
1.94 0.40
1.66 0.09
0.17 0.06
1.70 0.06
320.2 11.4
73.78 3.67
26.6 1.2
73.5 2.3
118.7 2.5
66.7 2.0
2.06 0.39
2.45 0.09
0.001
0.001
0.001
0.38
0.38
0.29
0.52
0.03
0.73
0.001
To convert fT4 levels to International System of Units, multiply by 12.87. To convert fT3 levels to International System of Units, multiply by 0.01536. BMI, Body mass
index.
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Results
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).
TABLE 2.
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).
Working memory. There were no differences between the two
study arms in N-Back number correct, SOP, or Digit Span
Backwards.
Summary statistics and P values for health status and mood measures during the two treatment arms
Measure
Baseline
(mean SEM)
Euthyroid
(mean SEM)
Thyrotoxic
(mean SEM)
SF-36
MCS
PCS
51.72 1.02
51.91 1.33
50.69 1.46
56.59 0.61
52.71 1.16
54.75 0.83
0.15
0.01
76.00 4.09
80.84 2.65
80.38 1.60
59.84 2.83
91.72 2.82
76.56 6.54
86.33 3.86
91.67 2.99
84.43 3.01
85.03 2.23
78.40 2.28
66.83 2.57
96.33 1.10
93.33 3.16
93.33 2.05
86.67 4.40
81.87 3.14
81.55 2.28
84.13 1.55
69.03 1.96
94.52 1.56
93.33 3.38
89.58 3.55
88.89 4.33
0.18
0.06
0.02
0.45
0.50
0.99
0.99
0.73
42.13 0.89
41.78 1.07
41.16 0.73
44.72 1.37
41.66 1.06
51.84 1.10
44.50 1.11
42.44 1.54
42.66 1.06
43.38 1.16
42.53 1.17
53.16 1.39
43.16 1.21
40.00 1.03
40.44 0.65
42.59 1.03
39.16 1.64
55.75 1.28
0.34
0.04
0.06
0.51
0.05
0.11
BP
GH
MH
VT
PFa
RPa
SFa
REa
POMS
A
C
D
F
T
V
P value
(paired t test)
Adjusted
P values
Treatment: 0.15
Treatment: 0.01
Treatment test: 0.008
0.22
0.06
0.01
0.42
Treatment: 0.002
0.11
P values for unadjusted paired t tests comparing the two arms of the study are shown in the fifth column. Adjusted P values in the repeated measures analysis are
shown in the sixth column. These P values were adjusted for age, years of education, WAIS-R, and baseline measure for that particular variable. Significant results are
highlighted in bold. For the adjusted analyses, treatment test P values were examined initially. If the treatment test P value was more than 0.1, indicating no treatmenttest interaction, it is not shown in the table, and only the overall treatment effect is shown. If the treatment test P value was 0.1 or less, indicating a possible treatmenttest interaction, this value is listed in the table, and subsequent analyses were done for individual measures. A, Anxiety; BP, bodily pain; C, confusion; D, depression; F,
fatigue; PF, physical functioning; RE, role emotional; RP, role physical; SF, social functioning; T, tension; V, vigor; VT, vitality.
a
Raw scores compared using an exact McNemars test because many values were at ceiling.
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TABLE 3.
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 SEM)
Euthyroid
(mean SEM)
Thyrotoxic
(mean SEM)
P value
(paired t test)
14.06 0.63
13.13 0.61
15.75 0.61
14.56 0.62
16.22 0.49
15.06 0.48
0.48
0.38
34.25 0.31
28.31 0.72
28.11 0.81
34.78 0.22
29.78 0.82
29.20 0.83
34.84 0.19
31.23 0.66
30.45 0.72
0.83
0.10
0.19
14.59 0.28
9.25 0.40
15.00 0.14
10.31 0.35
15.06 0.16
10.41 0.43
0.71
0.83
0.40 0.08
0.86 0.11
1.32 0.12
1.59 0.18
7.56 0.37
0.32 0.06
0.72 0.11
0.94 0.12
1.23 0.16
8.22 0.42
0.32 0.07
0.62 0.12
0.77 0.11
1.30 0.15
8.53 0.44
0.99
0.35
0.11
0.68
0.33
23.96 1.16
26.69 1.48
28.24 1.84
28.67 1.51
32.85 2.31
33.05 2.01
32.39 2.23
34.44 2.08
35.19 2.16
36.34 2.07
38.08 2.39
39.62 2.31
Adjusted
P values
Treatment: 0.25
Treatment: 0.29
Treatment: 0.67
Treatment: 0.28
Treatment: 0.33
Treatment: <0.001
0.14
0.04
<0.001
0.03
Individual cognitive tests are grouped by the three memory subdomains (first column). P values for unadjusted paired t tests comparing the two treatment arms are
shown in the fifth column. Adjusted P values in the repeated measures analysis are shown in the sixth column. These P values were adjusted for age, years of
education, WAIS-R, and baseline measure for that particular variable. Significant results are highlighted in bold. For the adjusted analyses, treatment test P values were
examined initially. There were no treatment-test interactions, and, thus, only the overall treatment effect is shown.
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.
Discussion
FIG. 2. Pursuit Rotor results at the end of the euthyroid arm (solid line)
and subclinical thyrotoxicosis arm (dashed line). The x-axis shows each of
the four trials, whereas the y-axis shows time on target for each trial (sec).
Results were better during the subclinical thyrotoxicosis arm of the study
(P 0.001 by mixed effects model).
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Acknowledgments
Address all correspondence and requests for reprints to: Mary H. Samuels, M.D., CR107, Oregon Health & Science University, 3181 SW Sam
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