Discussion
hypothyroid, primary hypothyroidism, euthyroidism, Graves’ Disease
HYPOTHYROID, PRIMARY HYPOTHYROIDISM
Decreased serum T4 concentrations and increased serum T3 concentration in treatment with 12 µg SR-T3 plus 60 µg LT4 led to a significant increase in serum T3/T4 ratio after intervention; however, serum T3/T4 ratio was lower than the normal serum T3/T4 ratio in euthyroid subjects (~ 1:14–15) and no difference was observed in serum T3, T4 and T3/T4 ratio after intervention between CBT (combination therapy) and LT4 monotherapy groups. Single dose administration of LT4 + SR-T3 was associated with more improved T3-derived Tmax(~ 4–5 h) and Cmax (~ 105 ng/dl) while serum T3 concentration remained within normal ranges with no fluctuation for 24 h after achieving maximum level.The only study by Hennemann et al. with randomized crossover design on fifteen patients (mean age of 50 y.) with primary hypothyroidism showed that T4 plus sustained-release T3 (1:20 ratio) improved serum TSH, T4, and T3 concentrations and the T4/T3 ratio compared to treatment with LT4 alone, while non-physiologic T3 peaks were avoided [Although serum TSH values are comparable and within normal ranges in LT4-treated patients, LT4 as an exogenous pro-drug cannot simulate serum thyroid hormone profile and circadian rhythm in the native euthyroid state.Serum TSH values in the previous clinical trials varied in patients under LT4 + LT3 combination therapy [The studies on the PK properties of sustained-release liothyronine are more coordinated; however, apart from the current study, there is only one other study which assessed PK of SR-T3 in combined preparation with LT4 [The current study is strengthened by including hypothyroid patients under LT4 monotherapy due to radioactive iodine intake for treating Graves’ Disease with no or negligible residual secretion of endogenous T3 and T4 and using the modern technique for measurement of thyroid hormones. Evaluation of the two combinations of the LT4 + SR-T3 enabled us to choose a more appropriate combination based on the participant’s body weight and not a fixed dosage such as the previous studies. Also, to achieve equilibrium in thyroid hormones, the PK study was performed after three months of treatment and not by a single-dose drug intake. However, the study is limited by evaluating PK study only within 24 h and the low potency of the LT4 component in the combined therapy which made us to increase the total dosage to restore euthyroidism.In conclusion, combined treatment with levothyroxine plus sustained-release liothyronine in hypothyroid patients with ratios of 1:5 might restore euthyroidism in hypothyroid patients yielding more improved T3/T4 serum ratio and T3-derived pharmakikinetics,while keeping serum T3 concentrations relatively stable within 24 h with minimal excursions. Single dose administration of LT4 + SR-T3 maintains serum T3 concentration approximate to normal ranges up to 24 h with minimal variation in serum T3 not exceeding 25 ng/dl indicates longer duration of the SR-T3 release in the intestine compared to other preparations. Although maximum serum T3 concentration (Tmax) achieves during 3–4 h, there is minimal difference in serum T3 concentrations at serial measurements during 24 h. Significant increase in serum T3/T4 ratio in combined therapy which is still lower than mean values in euthyroid individuals, could be translated into the assumption that administration of higher ratios of SR-T3 in combination therapy should be provided to achieve the physiological ratio of T3/T4 in treated hypothyroid patients. After attainment of the best appropriate preparation, designing and conducting appropriate randomized controlled clinical trials to compare the efficacy outcomes of combination therapy with sustained- release liothyronine are highly warranted to ensure sustainable delivery of T4 and T3 to thyroid hormone target issues.