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Journal of Clinical Endocrinology & Metabolism , doi:10.1210/jc.2007-0297
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The Journal of Clinical Endocrinology & Metabolism Vol. 92, No. 11 4115-4122
Copyright © 2007 by The Endocrine Society

Thyroid Hormone Replacement for Central Hypothyroidism: A Randomized Controlled Trial Comparing Two Doses of Thyroxine (T4) with a Combination of T4 and Triiodothyronine

Marc Slawik, Björn Klawitter1, Edith Meiser1, Marcus Schories, Oliver Zwermann, Katrin Borm, Martin Peper, Beate Lubrich, Martin J. Hug, Markus Nauck, Manfred Olschewski, Felix Beuschlein and Martin Reincke

Division of Endocrinology and Diabetes (M.Sl., B.K., E.M., M.Sc., K.B.), Medicine II, Clinical Pharmacy (B.L., M.J.H.), and Departments of Clinical Chemistry (M.N.) and Medical Biometry and Statistics (M.O.), University Hospital Freiburg, 79104 Freiburg, Germany; Medizinische Klinik Innenstadt (M.Sl., O.Z., F.B., M.R.), University Hospital Innenstadt, Ludwig-Maximilians-University, D-80336 München, Germany; Department of Psychology (M.P.), Albert-Ludwigs University, 79085 Freiburg, Germany; and University Hospital Bern (M.P.), Forensischer Psychitrischer Dienst, University of Bern, 3010 Bern, Switzerland

Address all correspondence and requests for reprints to: Martin Reincke, M.D., Medizinische Klinik Innenstadt, Klinikum der Universität München, Ziemssenstraße 1, D-80336 München, Germany. E-mail: Martin.Reincke{at}med.uni-muenchen.de.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Background: Dosage of T4 in central hypothyroidism is primarily guided by the free serum T4 level (fT4). However, the optimum fT4 range is ill defined, and subtle hypothyroidism might be missed using this approach.

Objectives: Our aim was to investigate the effects of a body weight (bw)-adapted T4 treatment, alone or in combination with T3, on metabolism, well-being, and cognitive function in comparison to a regimen leading to normal fT4.

Design: This was a placebo-controlled trial (double-blind, crossover).

Patients: A total of 29 patients (age 52 ± 2 yr; females/males, 8/21) with hypopituitarism, including TSH deficiency, participated in the study.

Interventions: Three regimens were compared (5 wk each): "EMPIRICAL-T4," empirical T4 dosage (1 ± 0.05 µg/kg bw) leading to normal fT4; BW-ADAPTED-T4 (1.6 µg/kg bw T4); and "BW-ADAPTED-T3T4," bw-adapted combination of T3 and T4 (ratio of 1:10).

Results: BW-ADAPTED-T4 administration increased mean fT4 concentrations to the upper limit of the normal range (peak levels). Compared with EMPIRICAL-T4, BW-ADAPTED-T4 treatment resulted in a lower body mass index (BMI) (29.0 ± 0.7 vs. 29.5 ± 0.7 kg/m2; P < 0.03), lower total cholesterol (198 ± 9 vs. 226 ± 7 mg/dl; P < 0.01), and lower low-density lipoprotein (LDL) cholesterol (116 ± 5 vs. 135 ± 7 mg/dl; P < 0.01). BW-ADAPTED-T3T4 treatment was associated with additional beneficial effects on ankle reflex time and working memory but resulted in supraphysiological free serum T3 (fT3) levels.

Limitations: Long-term side effects may have been missed.

Conclusions: Using a dose of 1.6 µg/kg bw improved markers commonly associated with central hypothyroidism. This suggests that T4 dosage based on bw and aiming at fT4 in the upper reference range is superior to titration of T4 aiming at middle normal fT4 concentrations in those patients.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
TREATMENT OF hypopituitarism has improved over the last two decades, due to refined laboratory tests and availability of more physiological replacement regimens (1, 2). However, it is a well-known clinical notion that quality of life remains impaired despite substitution therapy, including T4, hydrocortisone, sex hormones, and GH. Patients with hypopituitarism have a significantly higher cardiovascular risk, which has been partially attributed to GH deficiency (2, 3, 4). However, these patients display unfavorable lipid parameters, even when GH treatment has been established (5). Adequate T4 treatment in central hypothyroidism (CH) is especially challenging because T4 cannot be titrated according to endogenous TSH. It has been suggested that a free serum T4 level (fT4) in the middle of the reference range indicates appropriate dosage (6, 7), but other clinicians seem to aim for fT4 in the upper reference range. Accordingly, many clinical studies on patients with pituitary deficiency, e.g. exploring GH treatment, assumed euthyroidism when fT4 values were within the reference range (8, 9). In contrast, significantly lower fT4 levels in patients with pituitary deficiency compared with healthy controls have been reported, although both groups have been considered to be euthyroid (10). In addition, GH deficiency, which is common in patients with CH, may impair conversion from T4 into the biologically active T3, thereby masking the lack of adequate T4 dosage (11, 12, 13). Conversely, higher fT4 levels might be necessary in patients with partial GH deficiency to achieve euthyroidism in all tissues.

In a cross-sectional study performed in patients with CH, we found elevated cholesterol levels and increased ankle reflex time (ART) suggesting subtle hypothyroidism, although free serum T3 (fT3) level and fT4 serum concentrations were within the normal range and not different from an age-matched healthy control group (14). The average dose of T4 in our patients with CH was 1.1 µg/kg body weight (bw), which is below the average dose used in primary hypothyroidism (1.6 µg/kg bw) (15, 16, 17, 18). We hypothesized that these results might indicate suboptimal T4 replacement therapy, not detectable by evaluation of serum fT3 and fT4.

Thus, this randomized, double-blind, crossover study was designed to explore whether patients with CH benefit either from a higher T4 dose (1.6 µg/kg bw) or a combination of T4 (1.44 µg/kg bw) and T3 (0.16 µg/kg bw) compared with a usual treatment dose. To our knowledge this is the first randomized trial addressing thyroid hormone dosage in CH.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
This study was performed between February and July 2004, at the outpatient clinic of the Division of Endocrinology and Metabolism (Department of Medicine II, University Hospital Freiburg). The ethics committee of the University Hospital of Freiburg approved the protocol, and all patients gave written informed consent.

Subjects

Patients with CH could participate in the study if they were between 18 and 75 yr of age, and T4 dosage was stable for the last 3 months. Patients were considered in the euthyroid state in the presence of normal fT4 and fT3 values associated with the disappearance of clinical symptoms and signs of hypothyroidism. The T4 dose had been individually adjusted by experienced endocrinologists, and no specific fT4 range was predefined (i.e. "mid-normal" range or "upper third" of normal fT4 range). Further inclusion criteria were: 1) hypopituitarism involving at least three axes (TSH plus gonadotropin, somatotropin, corticotropin deficiency); 2) termination of surgical or radiation treatment of pituitary tumors at least 6 months before study entry; and 3) BMI of 20–39.9 kg/m2. Patients were excluded if they: 1) had a history of cardiovascular or pulmonary diseases; 2) took T4 in a dosage more than 1.6 µg/kg bw; 3) were pregnant; 4) had epilepsy; 5) had a history of cerebrovascular diseases; 6) were smokers; or 7) had a nodular goiter (volume >40 ml or a single nodule >2.5-cm diameter), as assessed by ultrasound because of increased probability of thyroid autonomy in the iodine-deficient region.

A total of 36 patients were evaluated for participation in the trial, and 32 were finally enrolled (Fig. 1Go). Clinical characteristics of the 29 subjects who finished the study are shown in Table 1Go. A total of 26 patients had a pituitary adenoma treated by surgery (n = 21), by a combination of radiotherapy and surgery (n = 3) or dopamine agonists (n = 2). The hypopituitarism in the remaining three persons was idiopathic (n = 2) or posthemorrhagic (n = 1).


Figure 1
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  		FIG. 1. Flow diagram showing number of patients assessed, enrolled, randomized, and analyzed.

 

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  		TABLE 1. Clinical characteristics of the patients at study entry

 
Study design and study medication

The study was performed in a double-blind crossover fashion consisting of three treatment phases of 5 wk each. At visit (V) 1, patients received a study code. Study code and bw were transmitted to the Department of Clinical Pharmacy, which randomly assigned the individual sequence of treatment phases (e.g. EMPIRICAL-T4, BW-ADAPTED-T4 adapted T4, and BW-ADAPTED-T3T4) to the participant, using a computer-based randomization algorithm (Fig. 2Go). After 5-wk treatment, patients visited the study center (V2) for safety parameters, clinical examination, blood tests, ART measurements, quality of life assessment, and neuropsychological assessment. The same tests were applied another 5 wk later on V3 and V4, respectively. Blood was drawn between 0800 and 1000 h, 2 h after ingestion of the study medication (fasting state). Afterward, the patients had a normal breakfast.


Figure 2
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  		FIG. 2. Randomization and possible treatment sequence of phases EMPIRICAL-T4, BW-ADAPTED-T4, and BW-ADAPTED-T3T4.

 
The study medication was administered in hard capsules, which were manufactured by the Department of Clinical Pharmacy (University of Freiburg). The capsules were indistinguishable throughout the three phases of the study. T4 (Levothyroxine) and T3 (Liothyronine) were obtained from ground tablets (L-Thyroxine Henning 200 and Thybon 20; Sanofi-Aventis Berlin, Germany). The capsules contained individually adapted thyroid hormones. In phase EMPIRICAL-T4, the patients received the empirically titrated T4 dosage established before study entry (mean 1 ± 0.05 µg/kg bw); in phase BW-ADAPTED-T4, the patients received 1.6 µg/kg bw T4, and in BW-ADAPTED-T3T4, the patients received 0.16 µg/kg bw T3 and 1.44 µg/kg bw T4 (fixed weight ratio T3 to T4 1:10). The individually prepared and identically packed study medication, labeled with the name, study code, and treatment phase (e.g. one, two, or three), was handed out to the patients at V 1, 2, and 3, respectively. Patients had to bring back leftover study medication, and the number of pills was counted by the Department of Clinical Pharmacy to assess compliance.

Pharmacokinetics of the study drug

To explore the pharmacokinetics of the T3/T4 combination, eight patients participated in an 8-h pharmacokinetic profile test. The subjects took a combined T3/T4 medication (T4 1.44 ± 0.16 µg/kg bw) for 6 d and then underwent an hourly blood sampling on d 7 for 8 h (see Fig. 4Go).


Figure 4
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  		FIG. 4. Serum concentration-time profile of fT3 (gray triangles) and fT4 (black squares) in eight patients on d-8 bw-adapted T3 (0.16 µg/kg bw) and T4 (1.44 µg/kg bw) substitution; time zero: basal levels, before ingestion; time 2 h: peak levels. Values are means ± SEM. Reference ranges for fT3 is 3.1–6.8 pmol/liter and for fT4 is 12–22 pmol/liter (assay: Modular Analytics E 170). The gray boxes depict the reference ranges of the respective parameters.

 
Clinical examination and safety parameters during treatment

Patients’ current medical histories were taken and included a questionnaire for symptoms of hyperthyroidism: sweating, palpitations, diarrhea, insomnia, irritability, nervousness, trembling, appetite, or thirst. Clinical examination included bw, blood pressure, and heart rate measurements. A 12-lead electrocardiogram was assessed. Blood test safety parameters were blood count, creatinine, Na+, K+, Ca2+, phosphate, alanine aminotransferase, {gamma}-glutamyl transpeptidase, and alkaline phosphatase. All safety parameters were evaluated on each V (V1–V4).

Outcome measures

Outcome measures were separated in: 1) lipid parameters; 2) ART; 3) signs and symptoms of hypothyroidism, as assessed by the Zulewski score; and 4) well-being and cognitive function. The principal aim of the trial was to assess whether treatment in phase BW-ADAPTED-T4 and/or BW-ADAPTED-T3T4 was superior to EMPIRICAL-T4 in terms of outcome measures.

Biochemical measurements

All blood samples were collected in the fasting state; serum was frozen, and parameters were measured at the end of the study to avoid interassay variation. Biochemical analyses were performed in the Department of Clinical Chemistry of the University Hospital (Freiburg). Thyroid parameters (fT3, fT4, and TSH) were measured by electrochemiluminescence immunoassays on a Modular Analytics E 170 (Roche Diagnostics, Mannheim, Germany). The reference ranges were 0.27–4.2 µU/ml, and 3.1–6.8 and 12–22 pmol/liter for TSH, fT3, and fT4, respectively (Figs. 3Go and 4Go). Muscle and liver parameters [creatine kinase (CK), myoglobin, and alanine aminotransferase] were analyzed on a Modular Analytics P800 (Roche Diagnostics). Lipid electrophoresis was performed using a REP system (Helena Laboratories, Beaumont, TX). During the enrollment phase, thyroid parameters were determined with a microparticle enzyme immunoassay (MEIA, Abbott AxSym; Abbott Diagnostics, Abbott Park, IL); reference ranges were 2.3–5.4 and 9–27 pmol/liter, for fT3 and fT4, respectively (Table 1Go). Intraassay and interassay variability of all analytics was less than 10%.


Figure 3
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  		FIG. 3. Serum concentrations of TSH (A), fT3 (B), and fT4 (C) during treatment phase EMPIRICAL-T4 ("EMP-T4") (previous T4 treatment), BW-ADAPTED-T4 ("BW-A-T4") (1.6 µg/kg bw T4), or BW-ADAPTED-T3T4 ("BW-A-T3T4") (0.16 µg/kg bw T3 and 1.44 µg/kg bw T4). Data are presented as mean ± SEM. Reference range for TSH is 0.27–4.2 µU/ml, fT3 is 3.1–6.8 pmol/liter, and for fT4 is 12–22 pmol/liter (assay: Modular Analytics E 170). Values in B and C reflect peak serum levels. The gray boxes depict the reference ranges of the respective parameters.

 
ART

ART was assessed as a mean of six readings with an electronic protractor (goniometer) recording three measurements on each side. When Achilles tendon reflex was set off, half-maximal relaxation time was determined by a computer program. Reference values were obtained from 104 healthy volunteers (age 18–75 yr). The mean value (345 ± 47 msec; ± SD) was not different between men or women but lower in individuals of the first two decades (319 ± 35 or 331 ± 47; 20–30 or 30–40 yr, respectively) (19). Because the average age of patients participating in this study was 51 ± 2 yr, we used an age-adjusted mean reflecting the last three decades (351 ± 48); this ART is in excellent accordance with a previous study (20).

Zulewski score

The degree of clinical hypothyroidism was estimated using the score developed by Zulewski et al. (21). Euthyroidism is indicated by a score of 0–2 (negative predictive value for exclusion of hypothyroidism, 94.2%), intermediate range 3–5 points, and hypothyroid more than five points (positive predictive value, 96.9%). One of 11 parameters of the Zulewski score is the ART; a delay was defined as prolongation of more than one SD.

Well-being and cognitive function

Each patient participated in standardized neuropsychological testing to explore well-being and cognitive function on V2, V3, and V4. Patients described their mood and physical symptoms on a visual analog scale (0 mm, excellent; and 100 mm, worst; cf. supplemental Fig. 1Go, which is published as supplemental data on The Endocrine Society’s Journals Online web site at http://jcem.endojournals.org). The Short Form-36 Health Survey was used to evaluate activities of daily life (22), and the Symptom Checklist (SCL)-90 was applied to assess multidimensional psychopathology (23). A close relative was asked to evaluate the ability to participate in activities of daily life using a questionnaire (24). Cognitive function was assessed with the Test Battery for Attention Performance (TAP) (subtests alertness and working memory). This computerized test has been established in neuropsychological studies (25, 26). Moreover, the Digit Span Test from the Wechsler Memory Scale-Revised was applied to evaluate short-term memory (27, 28).

Statistical analysis

Power analysis for calculation of sample size was based on data obtained in a recently performed cross-sectional study (14). According to these results, a sample size of 25 was required to achieve a statistical power of 80% at {alpha} of 0.05 (lipid profile, ART). For well-being and neurocognitive function tests, a sample size of 21 was calculated assuming a statistical power of 80% and an {alpha} of 0.05, as outlined in the test manuals. Statistical analysis of the data was performed according to the intention to treat principle; because the data set of the three patients who discontinued the study was incomplete, they were excluded from the analysis. Data are presented as mean ± SEM. Repeated ANOVA analyses with Huynh-Feldt adjustments for the degrees of freedom were applied, and multivariate analysis of variance (e.g. for SCL-90) was performed; this was followed by post hoc analysis where appropriate (SPSS, version 15; SPSS, Inc., Chicago, IL). In addition, age and GH replacement (absence or presence) were used as a covariate; there was no effect from these parameters. Friedman’s test followed by post hoc Wilcoxon’s rank test was used for nonparametric data.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Hormone measurements

Two hours after ingestion of study medication, the mean TSH concentration was in the reference range during phase EMPIRICAL-T4 but decreased significantly during BW-ADAPTED-T4 and BW-ADAPTED-T3T4 (Fig. 3Go). The mean fT4 values 2 h after ingestion, which reflect peak levels (Fig. 4Go), were in the middle third of the reference range during EMPIRICAL-T4, and increased to levels slightly above the normal limit during BW-ADAPTED-T4 and BW-ADAPTED-T3T4 (Fig. 3Go). FT3 concentrations increased significantly during BW-ADAPTED-T4 compared with EMPIRICAL-T4, and even more pronounced during BW-ADAPTED-T3T4, reaching supraphysiological levels in the latter.

Body weight, lipid metabolism, and muscle function

At the end of BW-ADAPTED-T4 and BW-ADAPTED-T3T4 treatment, mean bw was significantly lower compared with EMPIRICAL-T4 (Table 2Go). There was no change in heart rate or blood pressure, suggesting no overdose in the intervention phases; there was no significant age-related influence (covariate).


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  		TABLE 2. Clinical parameters during EMPIRICAL-T4, BW-ADAPTED-T4, and BW-ADAPTED-T3T4

 
Compared with EMPIRICAL-T4, mean total cholesterol concentrations (226 ± 7 vs. 198 ± 9 vs. 194 ± 7 mg/dl), LDL (135 ± 7 vs. 116 ± 5 vs. 114 ± 6 mg/dl), and mean high-density lipoprotein (HDL) cholesterol concentrations (52 ± 2 vs. 47 ± 3 vs. 45 ± 3 mg/dl) decreased during BW-ADAPTED-T4 and BW-ADAPTED-T3T4 (Fig. 5Go, A–C). Moreover, triglycerides (184 ± 23 vs. 191 ± 24 vs. 168 ± 22 mg/dl) and very low-density lipoprotein (VLDL) (39 ± 4 vs. 42 ± 5 vs. 35 ± 4) tended to be lower after BW-ADAPTED-T3T4 treatment, without reaching a level of significance (Fig. 5Go, D and E).


Figure 5
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  		FIG. 5. Lipid profiles during the study. Normal range: cholesterol, 120–240 mg/dl (A); LDL cholesterol, 90 mg/dl or less (B); HDL cholesterol, 35–100 mg/dl (C); triglycerides, 25–200 mg/dl (D); and VLDL cholesterol, 30 mg/dl or less (E). *, P < 0.05 vs. EMPIRICAL-T4 (EMP-T4). {dagger}, P < 0.5 vs. BW-ADAPTED-T4 (BW-A-T4). Conversion to Systeme International unit mmol per liter for cholesterol: 0.0259; for triglycerides: 0.0113. BW-A-T3T4, BW-ADAPTED-T3T4.

 
The muscle enzyme CK, typically elevated in hypothyroidism, decreased during BW-ADAPTED-T4 (127 ± 13; P < 0.05 vs. EMPIRICAL-A-T4), and even more so during BW-ADAPTED-T3T4 (110 ± 10; P < 0.05 vs. both other phases) compared with EMPIRICAL-T4 (159 ± 16 U/liter). This effect was most pronounced in those 12 patients who had CK values above the normal range during EMPIRICAL-T4. ART, a sensitive method to detect hypothyroidism or hyperthyroidism (19), was prolonged during EMPIRICAL-T4 (389 ± 0.08) and BW-ADAPTED-T4 (380 ± 0.9) but shortened to the age-adjusted normal range during BW-ADAPTED-T3T4 (364 ± 0.08 msec; P < 0.01).

Clinical score of hypothyroidism

Clinical signs of hypothyroidism, as assessed according to the Zulewski score, decreased after BW-ADAPTED-T4 and BW-ADAPTED-T3T4 compared with EMPIRICAL-T4 (Table 3Go).


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  		TABLE 3. Clinical assessment of hypothyroidism according to the Zulewski score (21 )

 
Well-being and cognitive function

Self-reporting of mood and physical symptoms showed no difference among the three treatment phases but indicated overall well-being in most patients already during EMPIRICAL-T4 (supplemental Fig. 1Go). Psychopathological symptoms such as depression, obsessive-compulsive disorder, and phobia were explored with the SCL-90R questionnaire; however, mean normative values (T values in all scales around 50, cf. supplemental Table 1Go) indicated the absence of severe self-reported psychopathological symptoms, and only one parameter improved. The Short Form-36 test focuses on general well-being during activities of daily life and social interaction. Similar to the other questionnaires exploring well-being, no difference between treatment phases was found. Moreover, a close relative was asked to assess the patient’s activities of daily life. This external assessment showed no differences throughout the whole study period either (supplemental Table 1Go). Overall, well-being seemed not to be affected negatively, even though the fT3 levels were supraphysiological during BW-ADAPTED-T3T4.

Patients also participated in a neurocognitive assessment at the end of each treatment period. The Digit Span Subtest of Wechsler Memory Scale did not show differences in short-term memory function between treatment regimens (supplemental Table 1Go). Neurocognitive (executive) functioning was explored using computerized tests focusing on alertness and working memory (TAP); median reaction times assessed were not different between treatment regimens. However, the working memory subtest showed significantly improved performance during BW-ADAPTED-T3T4 compared with EMPIRICAL-T4 (supplemental Table 1Go).

Safety parameters, side effects, and adverse events (AEs)

Of 32 patients, 29 completed the three 5-wk periods. One subject discontinued because of complaints suggestive of hyperthyroidism such as irritability and fatigue during the BW-ADAPTED-T4 phase, another because of development of an erythematous eczema on the trunk, and a third subject for personal reasons. In total, nine AEs were reported during the study (five in EMPIRICAL-T4, three in BW-ADAPTED-T4, and one in BW-ADAPTED-T3T4). This included the three events leading patients to discontinue the trial. Other AEs were impaired blood glucose control (type 2 diabetes) and erythematous eczema (infection with Demodex mites). The overall frequency of side effects was not different between treatment phases and showed no correlation with age (supplemental Table 2Go). Assessment of a 12-lead electrocardiogram showed no abnormalities in any patients during the study.


   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
Several studies in patients with primary hypothyroidism have demonstrated that a dose of approximately 1.6 µg/kg bw is necessary to restore normal TSH levels, although there is a remarkable variability between individual patients (15, 17, 29). The present trial was performed to explore whether in patients with CH treatment with a fixed dose of 1.6 µg/kg bw, T4 is superior to a treatment scheme representing the empirically titrated T4 replacement dose. This dose (mean 1.0 µg/kg bw T4) was established before the trial on the basis of clinical and biochemical assessments, including normal serum fT4. Moreover, possible benefits of substituting 10% T4 by T3 in phase BW-ADAPTED-T3T4 were evaluated. We present evidence that lipid parameters, muscle enzymes, bw, and clinical signs and symptoms of hypothyroidism improved during BW-ADAPTED-T4 compared with the EMPIRICAL-T4 phase. It may be argued that in our study the "titration" phase of T4 before study entry was insufficient, resulting in suboptimal T4 levels. Although our data show that this is true when considered post hoc, clinical judgment based on signs and symptoms of hypothyroidism and biochemical assessment alone, such as performed under "uncontrolled" clinical conditions before study entry, might not be appropriate to detect those subtle abnormalities. Therefore, we believe that using a fixed, bw-adapted dose might be superior to a "titration" dose of T4 because the probability of undertreatment may be reduced. Supplementation of T3 during BW-ADAPTED-T3T4 had additional beneficial effects on muscle function (ART) and working memory but was associated with supraphysiological fT3 concentrations suggesting hyperthyroidism.

To the best of our knowledge, there is only one nonrandomized, interventional study in patients with CH evaluating T4 treatment by adjusting the dosage by bw (11). Ferretti et al. (11) concluded that treatment aiming at "normal" fT3 and fT4 concentrations alone may frequently lead to subtle hypothyroidism if peripheral parameters of thyroid hormone action are not considered. The optimal dose of T4, as assessed by the "titration" approach used by the authors, was 1.6 ± 0.3 µg/kg bw in subjects under 60 and 1.3 ± 0.2 µg/kg bw in subjects over 60 yr of age. The results of this well-designed, but unblinded, study fit nicely with those of our randomized study presented here.

Hypothyroidism is a risk factor contributing to atherosclerosis and coronary heart disease due to increased LDL and cholesterol levels (29, 30, 31, 32). Thus, lowering unfavorable lipid parameters in the long term might reduce the risk of cardiovascular disease. Rosen and Bengtsson (3) have shown that patients with pituitary deficiency have an increased cardiovascular risk, which has been partially explained by GH deficiency. However, elevated cholesterol due to CH might also contribute to this risk, and CH itself could have been masked by the lack of GH in patients with pituitary deficiency (33, 34).

During phase EMPIRICAL-T4, the mean TSH value was in the reference range but decreased significantly during bw-adapted T4 and BW-ADAPTED-T3T4. In accordance with these results, it has been previously reported that TSH levels within the normal range indicate T4 deficiency, and treatment with an adequate dose resulted in suppression in the majority of patients (11, 35, 36). Mean fT4 concentrations increased from the middle third of the reference range during EMPIRICAL-T4 to levels slightly above the upper normal limit in BW-ADAPTED-T4. However, these reflect peak values, and from the pharmacokinetic study (Fig. 4Go), it can be concluded that the average fT4 was within the reference range during most of the day. We recommend the measurement of fT4 values before ingestion of T4, aiming toward achieving fT4 levels in the upper third of the reference range, considering that peak values might be 2–3 pmol higher (2 h after ingestion). However, we cannot draw conclusions about a dosage above 1.6 µg/kg bw, which might be necessary to reach these fT4 levels in some patients.

A T3/T4 ratio of 1:10 has been suggested for combination drug treatment (37). The amount of T3 substitution used in this study was chosen within the upper dosage range because partial GH deficiency has to be assumed in the majority of patients with CH, thereby reducing T4 to T3 conversion (8, 13). Using this regimen, we observed additional beneficial effects on outcome measures compared with BW-ADAPTED-T4 (normalization of ART and improved working memory), but no increase in side effects (e.g. increase in heart rate). However, the phase BW-ADAPTED-T3T4 has to be considered nonphysiological because fT3 levels increased above the reference range. Moreover, a treatment period of 5 wk might be too short to exclude long-term cardiovascular or central nervous system side effects, such as atrial fibrillation or nervousness (15, 16). A similar dose of T3 was used in primary hypothyroidism without inducing supraphysiological fT3 levels (15, 38, 39, 40), which might indicate differences in T3 metabolism. Evidently, a T3 dose and formulation as used in our study cannot be recommended.

ART prolongation has been shown in patients with primary subclinical hypothyroidism (41, 42). In this study ART was normalized only during BW-ADAPTED-T3T4, indicating a requirement of T3 supplementation for restoring regular muscle function in patients with CH. In accordance with this notion, patients with increased serum CK levels during EMPIRICAL-T4 showed normalization during BW-ADAPTED-T4 and BW-ADAPTED-T3T4.

A substantial percentage of treated patients with primary hypothyroidism remain with complaints. Only sparse literature is available on the precise nature of these complaints, complicating the choice of outcome measures (43, 44). In the present study, we explored well-being using several self-rating scales and behavior observation data obtained from assessments by close relatives. However, none of the parameters changed significantly during BW-ADAPTED T4 and BW-ADAPTED-T3T4, compared with EMPIRICAL-T4. It is important to note that most of the patients described their own situation and well-being as "good" already during EMPIRICAL-T4, thus making substantial improvement rather unlikely.

Cognitive effects were assessed with special emphasis on executive functions, such as alertness and working memory. Improvement was evident only in the TAP working memory task during BW-ADAPTED-T3T4 compared with EMPIRICAL-T4. However, due to multiple testing, the interpretation of a single difference that was significant on the original {alpha}-level requires caution.

In conclusion, treatment with 1.6 µg/kg bw T4 improved bw, lipid parameters, and clinical signs and symptoms of hypothyroidism compared with an empirically chosen dosage that was adjusted according to fT4 levels within the normal range. Thus, using a fixed starting dose of T4 (e.g. 1.6 µg/kg bw), combined with thyroid hormone determinations aiming at fT4 levels close to the upper normal limit and fT3 levels in the upper half of the normal range, seems to be a reasonable approach.


   Acknowledgments
 
We thank Mr. A. Rynk and the outpatient clinic team (Division of Endocrinology) for excellent assistance. We also thank Mrs. Kathy Muller-Schertler for language editing of the manuscript, and Ms. K. Göller and Ms. F. Waibel for collecting the reference values of the ankle reflex time measurements. Moreover, we thank all members of the technical workshops for constructing the goniometer for ankle reflex time measurements. We thank Mr. B. Meier and H. Zulewski for advice on the ankle reflex time measurements and the Zulewski score.


   Footnotes
 
This study was financed by intramural grants.

Present address for M.P.: Department of Psychology, University of Marburg, Gutenbergstrasse 18, D-35032 Marburg, Germany.

Disclosure Statement: None of the authors has any conflict of interest.

Author Contributions: As a principal investigator of the study, M.R. had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: M.Sl., K.B., B.L., F.B., and M.R. Drafting of the manuscript: M.Sl., K.B., F.B., and M.R. Acquisition of data: B.K., E.M., M.N., M.Sc., F.B., M.Sl., and M.R. Analysis and interpretation of the data: B.K., K.B., E.M., M.J.H., M.N., M.P., M.Sc., M.O., F.B., M.R., and M.Sl. Critical revision of the manuscript for important intellectual contribution: All authors. Statistical analysis: M.Sl., B.K., E.M., and M.O. Administrative, technical, or material support: M.J.H., B.L., M.P., M.Sl., and M.R. Study supervision: M.Sl., M.Sc., O.Z., M.P., F.B., and M.R.

Trial Registration: clinicaltrials.gov; Identifier: NCT00360074.

First Published Online August 21, 2007

1 B.K. and E.M. contributed equally to this work. Back

Abbreviations: AE, Adverse event; ART, ankle reflex time; BMI, body mass index; bw, body weight; CH, central hypothyroidism; CK, creatine kinase; fT3, free serum T3 level; fT4, free serum T4 level; HDL, high-density lipoprotein; LDL, low-density lipoprotein; SCL, Symptom Checklist; TAP, Test Battery for Attention Performance; V, visit; VLDL, very low-density lipoprotein.

Received February 8, 2007.

Accepted August 10, 2007.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

  1. Minniti G, Esposito V, Piccirilli M, Fratticci A, Santoro A, Jaffrain-Rea ML 2005 Diagnosis and management of pituitary tumours in the elderly: a review based on personal experience and evidence of literature. Hormone replacement therapy in hypopituitarism. Eur J Endocrinol 153:723–735[Abstract/Free Full Text]
  2. Smith JC 2004 Hormone replacement therapy in hypopituitarism. Expert Opin Pharmacother 5:1023–1031[CrossRef][Medline]
  3. Rosen T, Bengtsson BA 1990 Premature mortality due to cardiovascular disease in hypopituitarism. Lancet 336:285–288[CrossRef][Medline]
  4. Tomlinson JW, Holden N, Hills RK, Wheatley K, Clayton RN, Bates AS, Sheppard MC, Stewart PM 2001 Association between premature mortality and hypopituitarism. West Midlands Prospective Hypopituitary Study Group. Lancet 357:425–431[CrossRef][Medline]
  5. Maison P, Griffin S, Nicoue-Beglah M, Haddad N, Balkau B, Chanson P 2004 Impact of growth hormone (GH) treatment on cardiovascular risk factors in GH-deficient adults: a metaanalysis of Blinded, Randomized, Placebo-Controlled Trials. J Clin Endocrinol Metab 89:2192–2199[Abstract/Free Full Text]
  6. Melmed S, Kleinberg D 2003 Anterior pituitary. In: Williams RH, Larsen PR, eds. Williams textbook of endocrinology. 10th ed. Philadelphia: Saunders; 226
  7. Jostel A, Lisset CA, Shalet SM 2006 Hypopituitarism. In: DeGroot LJ, Jameson JL, eds. Endocrinology. Philadelphia: Saunders; 397–409
  8. Salomon F, Cuneo RC, Hesp R, Sonksen PH 1989 The effects of treatment with recombinant human growth hormone on body composition and metabolism in adults with growth hormone deficiency. N Engl J Med 321:1797–1803[Abstract]
  9. Gibney J, Wallace JD, Spinks T, Wallace JD, Spinks T, Schnorr L, Ranicar A, Cuneo RC, Lockhart S, Burnand KG, Salomon F, Sonksen PH, Russell-Jones D 1999 The effects of 10 years of recombinant human growth hormone (GH) in adult GH-deficient patients. J Clin Endocrinol Metab 84:2596–2602[Abstract/Free Full Text]
  10. Sesmilo G, Biller BM, Llevadot J, Hayden D, Hanson G, Rifai N, Klibanski A 2001 Effects of growth hormone (GH) administration on homocyst(e)ine levels in men with GH deficiency: a randomized controlled trial. J Clin Endocrinol Metab 86:1518–1524[Abstract/Free Full Text]
  11. Ferretti E, Persani L, Jaffrain-Rea ML, Giambona S, Tamburrano G, Beck-Peccoz P 1999 Evaluation of the adequacy of levothyroxine replacement therapy in patients with central hypothyroidism. J Clin Endocrinol Metab 84:924–929[Abstract/Free Full Text]
  12. Colao A, Di Somma C, Pivonello R, Loche S, Aimaretti G, Cerbone G, Faggiano A, Corneli G, Ghigo E, Lombardi G 1999 Bone loss is correlated to the severity of growth hormone deficiency in adult patients with hypopituitarism. J Clin Endocrinol Metab 84:1919–1924[Abstract/Free Full Text]
  13. Porretti S, Giavoli C, Ronchi C, Lombardi G, Zaccaria M, Valle D, Arosio M, Beck-Peccoz P 2002 Recombinant human GH replacement therapy and thyroid function in a large group of adult GH-deficient patients: when does L-T(4) therapy become mandatory? J Clin Endocrinol Metab 87:2042–2045[Abstract/Free Full Text]
  14. Göller K, Waibel F, Borm K, Slawik M, Reincke M 2004 Central hypothyroidism: a cross-sectional study evaluating cognitive and metabolic effects of thyroxine replacement therapy. Exp Clin Endocrinol 1(Suppl 1):P151
  15. Appelhof BC, Fliers E, Wekking EM, Schene AH, Huyser J, Tijssen JG, Endert E, van Weert HC, Wiersinga WM 2005 Combined therapy with levothyroxine and liothyronine in two ratios, compared with levothyroxine monotherapy in primary hypothyroidism: a double-blind, randomized, controlled clinical trial. J Clin Endocrinol Metab 90:2666–2674[Abstract/Free Full Text]
  16. 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]
  17. Escobar-Morreale HF, Botella-Carretero JI, Gomez-Bueno M, Galan JM, Barrios V, Sancho J 2005 Thyroid hormone replacement therapy in primary hypothyroidism: a randomized trial comparing L-thyroxine plus liothyronine with L-thyroxine alone. Ann Intern Med 142:412–424[Abstract/Free Full Text]
  18. Fish LH, Schwartz HL, Cavanaugh J, Steffes MW, Bantle JP, Oppenheimer JH 1987 Replacement dose, metabolism, and bioavailability of levothyroxine in the treatment of hypothyroidism. Role of triiodothyronine in pituitary feedback in humans. N Engl J Med 316:764–770[Abstract]
  19. Nuki G, Bayliss RI 1968 The Achilles tendon reflex as an index of thyroid function. Postgrad Med J 44:97–102[Free Full Text]
  20. Nordyke RA, Gilbert Jr FI 1967 Mass screening for hypothyroidism by the Achilles reflex time. Arch Environ Health 14:827–831[Medline]
  21. 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]
  22. Bullinger M, Kirchberger I 1998 SF 36 Fragebogen zum Gesundheitszustand. In: Handanweisung. Göttingen: Hagrefe Verlag für Psychologie
  23. Franke G 2002 SCL 90R. Symptom-Checkliste von L. R. Derogatis. Deutsche Version. Handanweisung. 2nd ed. Göttingen, Germany: Beltz Test Gmbh
  24. Kessler J, Denzler P, Markowitsch HJ 1999 Demenz-Test. 2nd ed. Göttingen, Germany: Hogrefe
  25. Zimmermann MP, Fimm B 2000 Testbatterie zur Aufmerksamkeitsprüfung (TAP). Herzogenrath, Germany: Psytest
  26. Peper M, Klett M, Morgenstern R 2005 Neuropsychological effects of chronic low-dose exposure to polychlorinated biphenyls (PCBs): a cross-sectional study. Environ Health 4:22
  27. Härting C, Markowitsch H, Neufeld H, Calabrese P, Deisinger K, Kessler J 2000 Wechsler Gedächtnis Test-Revidierte Fassung (WMS-R). Herzogenrath, Germany: Hogrefe
  28. Wechsler D 1945 A standardized memory scale for clinical use. J Psychol 19:37–95
  29. Meier C, Staub JJ, Roth CB, Guglielmetti M, Kunz M, Miserez AR, Drewe J, Huber P, Herzog R, Muller B 2001 TSH-controlled L-thyroxine therapy reduces cholesterol levels and clinical symptoms in subclinical hypothyroidism: a double blind, placebo-controlled trial (Basel Thyroid Study). J Clin Endocrinol Metab 86:4860–4866[Abstract/Free Full Text]
  30. Caraccio N, Ferrannini E, Monzani F 2002 Lipoprotein profile in subclinical hypothyroidism: response to levothyroxine replacement, a randomized placebo-controlled study. J Clin Endocrinol Metab 87:1533–1538[Abstract/Free Full Text]
  31. Serter R, Demirbas B, Korukluoglu B, Culha C, Cakal E, Aral Y 2004 The effect of L-thyroxine replacement therapy on lipid based cardiovascular risk in subclinical hypothyroidism. J Endocrinol Invest 27:897–903[Medline]
  32. Canturk Z, Cetinarslan B, Tarkun I, Canturk NZ, Ozden M 2003 Lipid profile and lipoprotein (a) as a risk factor for cardiovascular disease in women with subclinical hypothyroidism. Endocr Res 29:307–316[CrossRef][Medline]
  33. Faglia G, Bitensky L, Pinchera A, Ferrari C, Paracchi A, Beck-Peccoz P, Ambrosi B, Spada A 1979 Thyrotropin secretion in patients with central hypothyroidism: evidence for reduced biological activity of immunoreactive thyrotropin. J Clin Endocrinol Metab 48:989–998[Abstract/Free Full Text]
  34. Laurberg P, Jakobsen PE, Hoeck HC, Vestergaard P 1994 Growth hormone and thyroid function: is secondary thyroid failure underdiagnosed in growth hormone deficient patients? Thyroidology 6:73–79[Medline]
  35. Alexopoulou O, Beguin C, De Nayer P, Maiter D 2004 Clinical and hormonal characteristics of central hypothyroidism at diagnosis and during follow-up in adult patients. Eur J Endocrinol 150:1–8[Abstract]
  36. Shimon I, Cohen O, Lubetsky A, Olchovsky D 2002 Thyrotropin suppression by thyroid hormone replacement is correlated with thyroxine level normalization in central hypothyroidism. Thyroid 12:823–827[CrossRef][Medline]
  37. Toft AD 1999 Thyroid hormone replacement–one hormone or two? N Engl J Med 340:469–470[Medline]
  38. Bunevicius R, Kazanavicius G, Zalinkevicius R, Prange AJ, Jr. 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]
  39. 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]
  40. 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]
  41. Ooi TC, Whitlock RM, Frengley PA, Ibbertson HK 1980 Systolic time intervals and ankle reflex time in patients with minimal serum TSH elevation: response to triiodothyronine therapy. Clin Endocrinol (Oxf) 13:621–627[Medline]
  42. Staub JJ, Althaus BU, Engler H, Ryff AS, Trabucco P, Marquardt K, Burckhardt D, Girard J, Weintraub BD 1992 Spectrum of subclinical and overt hypothyroidism: effect on thyrotropin, prolactin, and thyroid reserve, and metabolic impact on peripheral target tissues. Am J Med 92:631–642[CrossRef][Medline]
  43. Jaeschke R, Guyatt G, Cook D, Harper S, Gerstein HC 1994 Spectrum of quality of life impairment in hypothyroidism. Qual Life Res 3:323–327[CrossRef][Medline]
  44. Wekking EM, Appelhof BC, Fliers E, Schene AH, Huyser J, Tijssen JG, Wiersinga WM 2005 Cognitive functioning and well-being in euthyroid patients on thyroxine replacement therapy for primary hypothyroidism. Eur J Endocrinol 153:747–753[Abstract/Free Full Text]



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