Evaluation of the Optimal Thyroxine Levels for Thyroxine Hormone Replacement in Patients With Central Hypothyroidism

Introduction: Central hypothyroidism results from pituitary or hypothalamic dysfunction. The evaluation of the adequacy of thyroxine replacement is difficult, due to the loss of thyrotropin (TSH) as an accurate feedback marker. This study aim to explore the potential metabolic and clinical effects of different free T4 (fT4) replacement targets in patients with central hypothyroidism. Method: This was a single center, prospective open-label crossover-like trial of 51 patients (mean age 56±12.9 years, 27 male) with hypopituitarism with multiple hormonal deficiencies including central hypothyroidism after excluding those with primary thyroid diseases, high risk for cardiovascular diseases (CVD) and known CVD. Dosage of levothyroxine (L-T4) was titrated to a targeted lower, middle and upper fT4 tertile and maintained for 24 weeks before assessment. Anthropometric and physiological measurements, metabolic and peripheral tissue markers, cognitive and quality of life assessments (SF-36 and Hong Kong Montreal Cognitive Assessment-5 [HK-MoCA-5]) were compared before and after each fT4 tertile change. This was followed by another 24-week cycle of L-T4 dosage adjustment to achieve fT4 in another tertile, with the same assessment as above. Results: We demonstrated that raising fT4 target from lower to upper tertile within the normal reference range resulted in significant decrease in body mass index (27.1±6.0 vs 25.7±5.6 kg/m(2), P<0.01), waist circumference (89.5±12.7 vs 86.4±12.1 cm, p<0.01), diastolic blood pressure (79.1±12.9 vs 74.5±12.9 mmHg, p<0.05) and low density lipoprotein cholesterol (3.94±0.88 vs 2.90±0.71 mmol/L, p<0.01), apart from expected significant effect on tissue markers such as increased sex-hormone binding globulin (SHBG), increased ferritin and reduced creatinine kinase (CPK). The occurrence of metabolic syndrome (48.2% vs 29.0%, p <0.05) was significantly reduced with increasing fT4 from middle to upper tertile, without significant effect on glycemic indexes, heart rate, SF-36 and HK-MoCA-5. Conclusion: In this study, we demonstrated that raising fT4 target to the upper tertile of normal resulted in a favourable improvement in various metabolic indexes without a significant increase in adverse effects over a period of 48 weeks.