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

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.

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.