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Journal of Clinical Endocrinology & Metabolism, doi:10.1210/jc.2004-1672
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The Journal of Clinical Endocrinology & Metabolism Vol. 90, No. 2 805-812
Copyright © 2005 by The Endocrine Society

Partial Substitution of Thyroxine (T4) with Tri-Iodothyronine in Patients on T4 Replacement Therapy: Results of a Large Community-Based Randomized Controlled Trial

Ponnusamy Saravanan, Dawn J. Simmons, Rosemary Greenwood, Tim J. Peters and Colin M. Dayan

Henry Wellcome Laboratories for Integrative Neuroscience and Endocrinology (P.S., D.J.S., C.M.D.) and Academic Unit of Primary Health Care, Department of Community-Based Medicine (T.J.P.), University of Bristol, Bristol BS1 3NY, United Kingdom; and Research and Development Support Unit (R.G.), Bristol Royal Infirmary, Bristol BS2 8HW, United Kingdom

Address all correspondence and requests for reprints to: Dr. Colin M. Dayan, Henry Wellcome Laboratories for Integrative Neuroscience and Endocrinology, Dorothy Hodgkin Building, University of Bristol, Whitson Street, Bristol BS1 3NY, United Kingdom. E-mail: colin.dayan{at}bris.ac.uk.


   Abstract
Top
 Abstract
Introduction
 Patients and Methods
 Results
 Thyroid function
 Discussion
 References
 
Conflicting results have recently been published about the benefits of combined T4 and T3 in treating hypothyroid patients. However, these studies may have been underpowered to detect differences in psychological well-being specifically related to T4 replacement. We conducted a large, double-blind, randomized controlled trial of partial substitution of 50 µg T4 by 10 µg T3 vs. the original dose of T4 in 697 hypothyroid patients. Thyroid function showed a rise in TSH (132%), a fall in free T4 (35%, P < 0.001), and unchanged basal free T3 levels (P = 0.92). At 3 months, there was a large (39%) placebo effect improvement in psychiatric caseness defined by the General Health Questionnaire (GHQ) 12 score in the control group compared with baseline, and this was sustained at 12 months. Differences vs. the intervention (T3) group were more modest with improvements in GHQ caseness (odds ratio, 0.61; 95% confidence interval, 0.42, 0.90; P = 0.01) and Hospital Anxiety and Depression questionnaire-anxiety scores at 3 months (P < 0.03) but not GHQ Likert scores, Hospital Anxiety and Depression questionnaire-depression, thyroid symptoms, or visual analog scales of mood and the initial differences were lost at 12 months. These results may be consistent with a subgroup of patients showing transient improvement after partial substitution with T3 but do not provide conclusive evidence of specific benefit from partial substitution of T4 by T3 in patients on T4 replacement. They also emphasize the large and sustained placebo effect that can follow changes in thyroid hormone administration.


   Introduction
Top
 Abstract
 Introduction
Patients and Methods
 Results
 Thyroid function
 Discussion
 References
 
AROUND 1% OF THE population in iodine-sufficient countries receives T4 replacement therapy, and over 5% have untreated subclinical hypothyroidism (1, 2, 3). Although the thyroid gland produces T4 and T3, standard thyroid hormone replacement comprises T4 only, because it has a much longer half-life, yielding more stable serum levels with T3 being generated from T4 in the peripheral tissues. However, rodent data suggests that such replacement may not provide normal T3 levels in all tissues (4, 5).

Since the introduction of sensitive TSH assays in the 1980s, it has been recommended that thyroid hormone replacement with T4 be titrated to achieve TSH levels in the laboratory reference range (6, 7, 8). For many individuals, this change resulted in a significant reduction in T4 dose, and several studies indicate that titration to these levels results in high normal free T4 but free T3 levels in the low reference range (9, 10, 11). Anecdotally, many patients began to complain of impaired psychological well-being and symptoms suggestive of hypothyroidism when their dose was adjusted in this way (12). Carr et al. (13) reported that patients preferred doses of T4 50 µg greater than the dose that achieved a normal TSH level. In an attempt to quantify this, we used the General Health Questionnaire (GHQ) in a cross-sectional study involving 1922 subjects (14). A categorical score ≥ 3 (maximum score, 12) on this scale indicates significant psychiatric morbidity (psychiatric caseness) and is predictive of similar outcome at complex psychiatric interview (15). We identified a 6.7% absolute increase in psychiatric caseness in patients on T4 with a TSH in the normal range compared with a matched control group (14), although this was not apparent in a smaller study (16). Such an increase, if true, could account for 150,000 excess psychiatric cases in the United States alone.

In 1999, a 5-wk crossover study of 33 patients suggested that substitution of 50 µg T4 with 12.5 µg T3 significantly improves mood although not cognitive function (17), but more recently, five other trials have shown either no benefit (18, 19, 20, 21) or a worse outcome (22). However, the differences in psychological well-being potentially attributable to T4 replacement between patients and controls that we saw in our cross-sectional study, although important for the population as a whole, were relatively small and could have been missed in these studies. Here, we report a much larger and longer term study with greater power to resolve the issues raised by these studies.


   Patients and Methods
Top
 Abstract
 Introduction
 Patients and Methods
Results
 Thyroid function
 Discussion
 References
 
Subjects

Potentially eligible subjects were recruited from 28 family practices in the Bristol and Weston-super-Mare area, West of England, United Kingdom. Inclusion criteria were: age, 18–75; T4 dose ≥ 100 µg/d; TSH level recorded in the last 15 months and the last level known to be within the local laboratory reference range; and no T4 dose adjustments in the last 3 months. Exclusion criteria were: a history of myocardial infarction, unstable angina or heart failure in the previous 3 months; thyroid cancer or secondary hypothyroidism; cholestyramine use; and use of antidepressants in the previous 3 months or amiodarone in the previous 12 months. The study was approved by the local research ethics committees.

Study protocol

The investigation was designed as a double-blind randomized controlled trial. Information about the study was sent to all the eligible patients with a stamped reply slip. On receiving the replies, interested patients were contacted by telephone to arrange appointments for the randomization visit. Patients were given opportunity to ask questions about the study, and then written, informed consent was obtained. They were then randomized by sequential allocation of study numbers (to which treatment groups had been randomly preallocated). Patients were given a trial pot, which either contained 10 µg T3 (T3 group) or matched tablet of 50 µg T4 indistinguishable from the T3 tablet (placebo/T4 alone group). The remaining T4 dose (original dose minus 50 µg) was given in open-label packs. Patients were assessed at 3 months (visit 2) and 12 months (visit 3) and reminded before these visits to take their medication at the same time of day as their appointment time for 7 d before review.

Evaluations: physical and biochemical measurements

Detailed thyroid and other medical history was taken at visit 1. The following physical measurements were taken at each visit: weight, electrocardiogram, blood pressure (twice at 10-min intervals), resting pulse rate, and body composition (Bodystat1500, Bodystat, Ltd., Isle of Man, United Kingdom). A serum sample was taken at baseline (visit 1, not timed) and 24-h postthyroid hormone dose (visits 2 and 3) for the following estimations: creatinine kinase [normal range (NR), 30–150 U/liter]; total cholesterol, alkaline phosphatase (NR, 40–110 IU/liter); calcium [NR, 9–10.5 mg/dl (2.25–2.7 mmol/liter)] (all Beckman LX20 analyzer, Beckman, Highwycombe, United Kingdom), free T3 [NR, 0.18–0.457 ng/dl (2.8–7.1 pmol/liter); Elecsys system 1010, Roche Diagnostics, Mannheim, Germany], free T4 [NR, 0.78–1.86 ng/dl (10.0–24.0 pmol/liter)], TSH [NR, 0.3–4.0 mU/liter (0.3–4.0 mIU/ml)], SHBG [NR, 0.27–2.15 µg/dl (10–80 nmol/liter)], and antithyroid peroxidase (anti-TPO) antibodies (+ve if titer is ≥100) (all from Diagnostic Product Corporation, Los Angeles, CA). Samples for thyroid function and SHBG from all three visits were analyzed together.

Psychological measurements

At each visit, the patient’s psychological well-being was assessed by the following scales: the GHQ-12 (15, 23, 24), a disease-specific thyroid symptom questionnaire (TSQ) (14), the Hospital Anxiety and Depression questionnaire (HADS) (25), and 23 visual analog scales of mood, cognitive behavior, and physical symptoms used in the study of Bunevicius et al. (17). In addition, patients completed a satisfaction question on a five-point scale and devised-questions on sleep and neuromuscular symptoms. The GHQ-12 and the TSQ were scored both by the Likert method (0–3 per question, maximum score 36-most dissatisfied, linear method) and by the GHQ method (0, 0, 1, 1, maximum score 12-most dissatisfied) to assess caseness (using a threshold score of 3 or more, categorical method) (23, 24). The changes in the GHQ-12 scores at 3 months, controlling for baseline scores, represented the primary outcomes.

Statistical methods

A sample size of 700 patients was calculated based on our cross-sectional data to detect a 0.7-point difference between the groups on the GHQ-12 Likert scale with 80% power—a difference sufficient to correct the deficit seen in our cross-sectional study (14). All the analyses were conducted in Stata version 8.0 (26). Results were analyzed by intention to treat. The last observation was carried forward to replace missing values at 3 months follow-up due to withdrawal of the patients from the study. For linear and categorical variables, linear and logistic regression analyses, respectively, were used to detect the differences between the groups at 3 months adjusting for baseline values (age, sex, type of diagnosis, T4 dose, duration of hypothyroidism, anti-TPO positivity, and baseline thyroid hormone measurements). Interactions between the baseline thyroid functions (free T3, free T4, TSH, and T3 to T4 ratio) and the treatment group were also investigated in the regression model for the two primary outcome variables (GHQ Likert and GHQ categorical scores). Repeated measures analysis by linear regression was used to detect any differences between the groups between 3 and 12 months follow-up. Median values were used as the summary statistic for TSH measurements because this parameter is not normally distributed, and statistical comparison was done using natural logarithmic values of TSH, yielding a comparison of geometric means.


   Results
Top
 Abstract
 Introduction
 Patients and Methods
 Results
Thyroid function
 Discussion
 References
 
Twenty-eight family practices expressed interested in taking part in the study of the 37 contacted. Patients (n = 3621) on T4 identified from prescribing records were assessed for eligibility. Patients (n = 1689) failed the inclusion and exclusion criteria on review of practice records, and a further 64 patients were considered inappropriate to take part by their general practitioners, mainly because of severe physical or mental disability. The remaining 1868 patients were contacted, 1460 replied, and 1014 showed interest in taking part in the study. On further chart review and telephone screening, 242 of these patients were excluded, mainly due to abnormal TSH or recent use of antidepressants. Of the patients, 772 finally attended the screening visit (visit 1). Sixty-eight patients did not fulfill all the inclusion and exclusion criteria. Seven patients changed their mind. The remaining 697 patients were randomized (Fig. 1Go, consort diagram).



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  		FIG. 1. Consort diagram. Note that the number of patients followed up is greater than the number on trial medication because some individuals declined to continue taking their trial medication (see text for reasons) but agreed to follow-up evaluations.

 
Baseline characteristics were similar between the two groups (Table 1Go). Baseline free T4 levels [1.64 ± 0.28 ng/dl (20.99 ± 3.66 pmol/liter)] were in the upper part of the reference range [0.78–1.86 ng/dl (10.0–24.0 pmol/liter)], whereas free T3 levels [0.248 ± 0.04 ng/dl (3.85 ± 0.7 pmol/liter)] were in the lower part of their reference range [0.18–0.457 ng/dl (2.8–7.1 pmol/liter)]. Eighty-one patients declined to continue with their study medication at or before visit 2 (36 in T3 group), but follow-up data were obtained on 660 patients (94.7%). A further 41 patients declined to continue with study medication before visit 3 (25 on T3), and a further 47 patients overall were lost to follow-up over this second period. Two patients (1 in each group) died of unrelated causes (hemorrhagic pancreatitis and subarachnoid hemorrhage). Reasons for patient withdrawals from study medication were obtained in 109 of 124 patients and considered to represent possible hyperthyroid symptoms (including headache, palpitations, tremors, nightmares, and difficulty in sleeping) in 27 patients (11 on T3), hypothyroid symptoms (sluggish, increasing tiredness, sleepy, depressed, and weight gain) in 47 patients (30 on T3), and a combination of both in six patients (three on T3). The remaining withdrawals were due to adverse reaction (13), protocol violation (5), and unexplained withdrawal of consent (11). Compliance with medication as assessed by returned tablet counts in those continuing with medication was good, both at 3 (T3, 96.7%; T4 alone, 96.4%) and at 12 (T3, 97.4%; T4 alone, 97.8%) months.


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  		TABLE 1. Baseline characteristics

 

   Thyroid function
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Thyroid function
Discussion
 References
 
Three months after intervention, the mean free T4 in the T3 group had fallen from the upper part to the lower part of the reference range and was significantly lower than in the T4 alone group [1.07 vs. 1.52 ng/dl (13.73 vs. 19.59 pmol/liter), P < 0.001; Table 2Go]. Mean basal free T3 levels were unchanged in both groups, but a 132% rise in median TSH was seen in the T3 group (2.28 vs. 0.728 mIU/ml, P < 0.001 for ratio of geometric means; Table 2Go; Fig. 2Go, A–C). In a pharmacokinetic substudy of 20 patients involved in the current study, basal levels were not different in the T3 group, but free T3 levels reached a peak 2–4 h after ingestion (40% higher than the baseline), and total 24-h exposure to T3 represented by area under the curve was higher in the T3 group (27). Similar results over a 9-h period have recently been reported by Hennemann et al. (28).


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  		TABLE 2. Primary and secondary outcomes

 


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  		FIG. 2. TSH, free T4, and free thyroid hormone levels at 0, 3, and 12 months. Median levels of TSH are shown. For conversion into SI units, multiply by: T3, 15.55; T4, 12.87

 
The relationship between TSH and free T3 or free T4 in patients on T4 was investigated using the pooled baseline thyroid function test results in the two groups. Although both correlated well with log TSH, the gradient of the relationship was more marked with free T4 than with free T3. The regression coefficients were log TSH vs. T4 = –0.53 [95% confidence interval (CI), –0.47, – 0.6; P < 0.001] and log TSH vs. T3 = –0.25 (95% CI, –0.17, – 0.32; P < 0.001; Fig. 3Go).



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  		FIG. 3. Relationship between baseline TSH and free T3 and free T4 levels. T3 and T4 levels are expressed as SD scores to enable comparison of gradients. Regression coefficient (b) with 95% CI is expressed at the bottom of each figure. Left, a, Relationship using all the 697 observations. Right, b, Relationship after removing six outlying observations. The circles indicate the observations removed. Note that the x-axis scale in b is different from a, but the same between the two parameters (T3 and T4) to enable visual comparison of gradients.

 
Psychological well-being and other outcomes

At 3 months, the GHQ scores by the Likert method improved markedly in both the placebo (T4 alone) and the intervention (T3) groups compared with baseline (baseline to 3 months, T4 alone, 13.48–11.13, P < 0.001; T3 group, 13.42–10.67, P < 0.001) with a 39% relative improvement in psychiatric caseness in the placebo group (43.9 reducing to 26.6% caseness). These changes are consistent with a marked placebo effect, although improved compliance with medication in the placebo group as evidenced by a significant fall in the serum TSH levels (baseline to 3 months, T4 alone, 0.94–0.728 mIU/ml, P < 0.05) could have contributed (Fig. 2Go; Table 2Go). Comparisons between the groups revealed a difference of 0.47 points in the GHQ scored by the Likert method, which was smaller, than the difference used to power the trial (0.7) and did not reach significance at the P < 0.05 level (95% CI, –0.26, +1.12; P = 0.218; Fig. 4Go). Using the categorical scoring methods with a threshold ≥ 3, a significantly greater reduction in psychiatric caseness was seen in the T3 group compared with T4 alone [19.2 vs. 26.6%, odds ratio (OR), 0.61; 95% CI, 0.42, 0.90; P = 0.01; Fig. 5Go; Table 2Go). Improvement was also seen in the HADS anxiety score at 3 months (OR, 0.55; 95% CI, 0.32, 0.95; P = 0.033). However, no difference was seen in the TSQ scores, sleep, neuromuscular symptoms, HADS depression category, or visual analog scales, and the percentage of patients reporting that they felt better on direct questioning was not different (well-being question, Table 2Go). No significant differences were seen in any of the physical or biochemical measures other than a slightly lower diastolic blood pressure in the T4 alone group (Table 2Go). The significance of these results was unchanged when controlled for age, sex, type of diagnosis, prestudy T4 dose, use of other chronic medication, baseline GHQ scores, anti-TPO positivity, and baseline thyroid function (free T3, free T4, TSH, and T3 to T4 ratio).



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  		FIG. 4. Comparison of outcomes. Likert score on the GHQ at 0, 3, and 12 months. T3, Combined T3 and T4; T4 alone, placebo.

 


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  		FIG. 5. Comparison of primary outcomes. Caseness according to the GHQ at 0 and 3 months. Percentages of cases are shown above the bars.

 
Subgroup analyses

Predefined subgroup analysis demonstrated a significant interaction on GHQ scores between baseline free T3 (as a continuous variable) and study group allocation (OR, 2.2; 95% CI, 1.28, 3.98; P = 0.005). Division of free T3 values into quartiles revealed that patients with baseline free T3 in the highest quartile, approximately equivalent to the upper half of the reference range [>0.275 ng/dl (>4.27 pmol/liter), reference range, 0.18–0.457 ng/dl (2.8–7.1 pmol/liter)], responded best to the intervention (Table 3Go) (only one patient in the T4 alone group, and none in the T3 group had a free T3 level above the normal range). No such effect was seen with baseline free T4 or baseline values of TSH, T3 to T4 ratio, or GHQ scores.


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  		TABLE 3. Number of cases (GHQ categorical score) at visit 2 according to the baseline free T3 levels

 
Outcomes at 12 months

When the subjects were reassessed at 12 months, GHQ scores in the intervention group (T3) had risen (worsened, P = 0.0034), and there was now no difference between the two groups (T3 vs. T4 alone, P = 0.24) (Table 2Go; Fig. 4Go). Interestingly, in both groups, the free T3 to T4 ratio fell significantly (T3 group, 9% reduction; T4 alone group, 6% reduction, both P < 0.001) (Fig. 2DGo) between months 3 and 12. This change was not explained by assay drift because samples from both visits were analyzed together. No change over this period was seen in TSH levels.


   Discussion
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Thyroid function
 Discussion
References
 
Our results demonstrate a marked placebo effect but an equivocal benefit specifically attributable to the intervention from the partial T3 substitution regime used. On the linear Likert scoring of the GHQ (primary outcome measure), the estimate of the benefit over and above the improvement seen in the control group (0.43 points) was less than the 0.7-point difference used to power the study (14) and was accompanied by a CI that included zero. Using the categorical scoring of the GHQ questionnaire to calculate psychiatric caseness, the estimated risk reduction attributable to the intervention was 0.61 with a CI that did not include zero (0.42, 0.90), and there was also a significant improvement in the HADS anxiety score (OR, 0.55; CI, 0.32, 0.95). However, no difference in psychological well-being was detected using the HADS depression score, visual analog scales of mood, cognitive behavior or physical symptoms, a satisfaction questionnaire, or our TSQ. In addition, the differences in GHQ caseness and HADS anxiety were not apparent after 12 months. Taken together, these results suggest that if there is a benefit from the intervention, it is easily overwhelmed by the size of the placebo effect and is insufficient to completely correct the difference between patients on T4 and age-matched controls seen in the cross-sectional study used to power the trial.

Our protocol was designed to maximize sample size and contains several potential limitations. Firstly, the use of a fixed substitution of 50 µg T4 with 10 µg T3 resulted in a rise in TSH and a fall in T4 to the low reference range in the intervention group indicating underreplacement with T4. Because tissues derive up to 50% of their intracellular T3 directly from serum T4, this may have reduced the benefit gained in the intervention group and underlines the importance of replacing both T3 and T4 appropriately. Secondly, despite limiting study entry to patients on ≥100 µg of T4 (average daily dose 124.3 µg), many of the subjects with primary hypothyroidism in the trial may have had residual thyroid function. This, in combination with the use of a fixed T3 to T4 substitution ratio, might be expected to result in further variability in achieving optimal final T3 and T4 levels in subjects after intervention. Thirdly, the timing of the baseline (visit 1) blood sample was not controlled, whereas the 3- and 12-month samples were taken 24 h postdosing with thyroid hormone. This may underlie the apparent fall in FT4 levels between baseline and 3 months in the T4 group despite a fall in TSH because TSH levels are much less dependent on dose timing over the 24-h period (29). Fourthly, as with previous studies, multiple psychological scales were used, increasing the possibility of positive findings by chance in one or more or the measures. However, primary and secondary analyses were defined in advance both in terms of the parameters to be analyzed and the primary outcome time point. For this reason, formal statistical correction was not made in reporting the results of the secondary analyses.

There have now been six other reported studies of the use of T3 and T4 in combination including the original report of Buneuvicius et al. (17, 18, 19, 20, 21, 22). All used different T4 reduction/T3 substitution regimes, some using a crossover design and apart from the original report showed either no benefit (18, 19, 20, 21) or a worsening of well-being (22) even when a subgroup of dissatisfied patients was examined (22). The major difference with the current report was in the number of participants. Calculations on the basis of the differences seen in our previous cross-sectional study resulted in the current study being over 6 times larger than any of the other studies (n = 23–101). Even on this basis, we were somewhat optimistic in powering the study to detect only a difference equal to or greater than the whole difference between the groups in our cross-sectional study; indeed, the observed difference was only around 60% of this (0.43 vs. 0.7 points on the GHQ Likert score). It remains possible that optimized replacement with T3 and T4 could improve well-being in a small subgroup of patients, but clear predictive markers would be required to help distinguish this group from the changes due to placebo and to guide the design of future studies. Our observation that subjects with higher baseline free T3 levels appear to benefit most is interesting in this respect, possibly suggestive of a threshold effect (Table 3Go), but further evidence using different baseline parameters is required.

The large size and long duration of the current study provide information on other aspects of thyroid hormone replacement. Early studies suggested that TSH levels are more sensitive to T4 than T3 levels (29). Here, we confirm that this relationship holds true even with TSH levels in the laboratory reference range. Baseline thyroid function values showed a greater negative regression gradient between T4 and TSH than between T3 and TSH (Fig. 3Go). In addition, TSH levels rose in response to a fall in T4 levels in the intervention group, even in the face of unchanged or probably higher T3 levels. This sensitivity of the pituitary/hypothalamic feedback to serum T4 and T3 explains how replacement with T4 alone can frequently achieve normal TSH levels with a combination of low T3 and high T4 levels as observed previously in smaller studies (9, 10, 11) and as seen in this study (Table 1Go). In addition, over a 9-month period, a significant fall in the T3 to T4 ratio was seen with no associated change in TSH (Fig. 4Go). This may reflect slow adaptation of tissue deiodinases to changes in thyroid hormone levels (T3 exposure in the intervention group and improved compliance in the T4 group) as reported in in vitro studies (30). Finally, the benefit attributed to placebo was larger (17.3% absolute reduction/39% relative reduction in psychiatric caseness; Table 2Go; Fig. 5Go) and more consistently maintained (no reduction after 12 months; Fig. 4Go) than expected. Indeed, the estimate of the benefit specifically attributable to the intervention (7.4% less psychiatric caseness) was over 2-fold smaller than this effect, suggesting that in clinical practice, much of the improvement with T3 may reflect placebo benefit and that demonstrating a specific effect is difficult even in large clinical trials.

In conclusion, data from this large community-based study do not provide conclusive evidence of specific benefit from partial substitution of T4 by T3 in patients on T4 replacement. However, they do underline the large size and sustained nature of the placebo effect that may be obtained in studies of this nature. It remains possible that a small subgroup of individuals does benefit specifically from partial substitution, but parameters identifying such a group have yet to be clearly identified.


   Acknowledgments
 
We thank Naomi Roberts for instigating this work, Riad Ayech for guidance, and Lindsay Ball for pharmacy support. Dr. Arthur Prange kindly supplied the visual analog scales used by Bunevicius et al. (17 ).


   Footnotes
 
This work was supported by funding from South West NHS R&D and Goldshield Pharmaceuticals PLC.

First Published Online December 7, 2004

Abbreviations: CI, Confidence interval; GHQ, General Health Questionnaire; HADS, Hospital Anxiety and Depression questionnaire; NR, normal range; OR, odds ratio; TPO, thyroid peroxidase; TSQ, thyroid symptom questionnaire.

Received August 20, 2004.

Accepted November 29, 2004.


   References
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Thyroid function
 Discussion
 References
 

  1. Vanderpump MP, Tunbridge WM, French JM, Appleton D, Bates D, Clark F, Grimley EJ, Hasan DM, Rodgers H, Tunbridge F 1995 The incidence of thyroid disorders in the community: a twenty-year follow-up of the Whickham Survey. Clin Endocrinol (Oxf) 43:55–68[Medline]
  2. Hollowell JG, Staehling NW, Flanders WD, Hannon WH, Gunter EW, Spencer CA, Braverman LE 2002 Serum TSH, T(4), and thyroid antibodies in the United States population (1988 to 1994): National Health and Nutrition Examination Survey (NHANES III). J Clin Endocrinol Metab 87:489–499[Abstract/Free Full Text]
  3. Canaris GJ, Manowitz NR, Mayor G, Ridgway EC 2000 The Colorado thyroid disease prevalence study. Arch Intern Med 160:526–534[Abstract/Free Full Text]
  4. Escobar-Morreale HF, del Rey FE, Obregon MJ, de Escobar GM 1996 Only the combined treatment with thyroxine and triiodothyronine ensures euthyroidism in all tissues of the thyroidectomized rat. Endocrinology 137:2490–2502[Abstract]
  5. Escobar-Morreale HF, Obregon MJ, Escobar dR, Morreale dE 1995 Replacement therapy for hypothyroidism with thyroxine alone does not ensure euthyroidism in all tissues, as studied in thyroidectomized rats. J Clin Invest 96:2828–2838
  6. Spencer CA, Demers LM 2002 Laboratory support for the diagnosis and monitoring of thyroid disease. National Academy Of Clinical Biochemistry-Laboratory Medicine Practice Guidelines, 2002. (Accessed June 27, 2004, at http://www.nacb.org)
  7. Wiersinga WM, DeGroot LJ 2002 Adult Hypothyroidism. In: DeGroot LJ, Hennemann G, editors. Thyroid Disease Manager, 2002. (Accessed June 27, 2004, at http://www.thyroiddiseasemanager.org)
  8. Vanderpump MP, Ahlquist JA, Franklyn JA, Clayton RN 1996 Consensus statement for good practice and audit measures in the management of hypothyroidism and hyperthyroidism. The Research Unit of the Royal College of Physicians of London, the Endocrinology and Diabetes Committee of the Royal College of Physicians of London, and the Society for Endocrinology. BMJ 313:539–544[Free Full Text]
  9. Rendell M, Salmon D 1985 "Chemical hyperthyroidism": the significance of elevated serum thyroxine levels in L-thyroxine treated individuals. Clin Endocrinol (Oxf) 22:693–700[Medline]
  10. Liewendahl K, Helenius T, Lamberg BA, Mahonen H, Wagar G 1987 Free thyroxine, free triiodothyronine, and thyrotropin concentrations in hypothyroid and thyroid carcinoma patients receiving thyroxine therapy. Acta Endocrinol (Copenh) 116:418–424[Medline]
  11. Woeber KA 2002 Levothyroxine therapy and serum free thyroxine and free triiodothyronine concentrations. J Endocrinol Invest 25:106–109
  12. Walsh JP 2002 Dissatisfaction with thyroxine therapy: could the patients be right? Curr Opin Pharmacol 2:717–722[CrossRef][Medline]
  13. Carr D, McLeod DT, Parry G, Thornes HM 1988 Fine adjustment of thyroxine replacement dosage: comparison of the thyrotrophin releasing hormone test using a sensitive thyrotrophin assay with measurement of free thyroid hormones and clinical assessment. Clin Endocrinol (Oxf) 28:325–333[Medline]
  14. Saravanan P, Chau WF, Roberts N, Vedhara K, Greenwood R, Dayan CM 2002 Psychological well-being in patients on "adequate" doses of L-thyroxine: results of a large, controlled community-based questionnaire study. Clin Endocrinol 57:577–585[CrossRef][Medline]
  15. Banks MH 1983 Validation of the General Health Questionnaire in a young community sample. Psychol Med 13:349–353[Medline]
  16. Zulewski H, Muller B, Exer P, Miserez AR, Staub JJ 1997 Estimation of tissue hypothyroidism by a new clinical score: evaluation of patients with various grades of hypothyroidism and controls. J Clin Endocrinol Metab 82:771–776[Abstract/Free Full Text]
  17. Bunevicius R, Kazanavicius G, Zalinkevicius R, Prange JR AJ 1999 Effects of thyroxine as compared with thyroxine plus triiodothyronine in patients with hypothyroidism. N Engl J Med 340:424–429.[Abstract/Free Full Text]
  18. Sawka AM, Gerstein HC, Marriott MJ, MacQueen GM, Joffe RT 2003 Does a combination regimen of thyroxine (T4) and 3,5,3'-triiodothyronine improve depressive symptoms better than T4 alone in patients with hypothyroidism? Results of a double-blind, randomized, controlled trial. J Clin Endocrinol Metab 88:4551–4555[Abstract/Free Full Text]
  19. Siegmund W, Spieker K, Weike AI, Giessmann T, Modess C, Dabers T, Kirsch G, Sanger E, Engel G, Hamm AO, Nauck M, Meng W 2004 Replacement therapy with levothyroxine plus triiodothyronine (bioavailable molar ratio 14 : 1) is not superior to thyroxine alone to improve well-being and cognitive performance in hypothyroidism. Clin Endocrinol (Oxf) 60:750–757[CrossRef][Medline]
  20. Levitt A, Silverberg J, T4 plus T3 treatment for hypothyroidism: a double-blind comparison with usual T4. 74th Annual Meeting of American Thyroid Association, Los Angeles, CA, 2002 (Abstract 4)
  21. Clyde PW, Harari AE, Getka EJ, Shakir KMM 2003 Combined levothyroxine plus liothyronine compared with levothyroxine alone in primary hypothyroidism: a randomized controlled trial. JAMA 290:2952–2958[Abstract/Free Full Text]
  22. Walsh JP, Shiels L, Lim EM, Bhagat CI, Ward LC, Stuckey BG, Dhaliwal SS, Chew GT, Bhagat MC, Cussons AJ 2003 Combined thyroxine/liothyronine treatment does not improve well-being, quality of life, or cognitive function compared to thyroxine alone: a randomized controlled trial in patients with primary hypothyroidism. J Clin Endocrinol Metab 88:4543–4550[Abstract/Free Full Text]
  23. Pan PC, Goldberg DP 1990 A comparison of the validity of GHQ-12 and CHQ-12 in Chinese primary care patients in Manchester. Psychol Med 20:931–940[Medline]
  24. Goldberg DP, Gater R, Sartorius N, Ustun TB, Piccinelli M, Gureje O, Rutter C 1997 The validity of two versions of the GHQ in the WHO study of mental illness in general health care. Psychol Med 27:191–197[CrossRef][Medline]
  25. Bjelland I, Dahl AA, Haug TT, Neckelmann D 2002 The validity of the Hospital Anxiety and Depression Scale. An updated literature review. J Psychosom Res 52:69–77[CrossRef][Medline]
  26. StatCorp. 2003 Stata Statistical Software: release 8.0. College Station, TX: Stata Corporation
  27. Siddique H, Saravanan P, Simmons DJ, Greenwood R, Peters TJ, Dayan CM 2003 Twenty-four hour hormone profiles of TSH, free T4 and free T3 in hypothyroid patients on "combined T4/T3" therapy. 29th Annual Meeting of the European Thyroid Association, Edinburgh, United Kingdom, p 111
  28. Hennemann G, Docter R, Visser TJ, Postema PT, Krenning EP 2004 Thyroxine plus low-dose, slow-release triiodothyronine replacement in hypothyroidism: proof of principle. Thyroid 14:271–275[CrossRef][Medline]
  29. Saberi M, Utiger RD 1974 Serum thyroid hormone and thyrotropin concentrations during thyroxine and triiodothyronine therapy. J Clin Endocrinol Metab 39:923–927[Medline]
  30. Bianco AC, Salvatore D, Gereben B, Berry MJ, Larsen PR 2002 Biochemistry, cellular and molecular biology, and physiological roles of the iodothyronine selenodeiodinases. Endocr Rev 23:38–89[Abstract/Free Full Text]



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