Personalized and Optimized Mono- and Combined Thyroid Hormone Replacement Therapies in Male and Female Hypothyroid Patients with Different BMIs using p-THYROSIM

The thyroid, an endocrine gland located in the neck, secretes thyroid hormones (TH) thyroxine (T4) and triiodothyronine (T3) into blood.  Their function is to control development, growth and metabolism throughout the human life cycle.  Hypothyroidism, or under production of the hormones, is by far the most common thyroid malady, resulting in numerous abnormalities in patients with this disease.  Fortunately, it is readily treated and hypothyroid patients usually receive a prescription for oral synthetic thyroxine (LT4) replacement monotherapy. However, how much of this hormone supplement to give  depends  on individual patient factors like gender, body weight and height (BMI), and other patient specific characteristics not yet fully studied clinically. Combined dosing with LT4 plus LT3 (synthetic T3) – an alternative treatment for some patients, is also poorly understood, as is the timing and frequency of its adminstration.  All this makes precise LT4 or LT4 + LT3 dosing difficult to quantify.

Recently, the common practice of monitoring hypothyroidism and setting monotherapy LT4 replacement dosages solely based on TSH readings has come under scrutiny. A personalized strategy that combines examining free T4 (FT4) as well as TSH serum concentrations (and possibly other patient factors) has been suggested as an alternative to merely monitoring TSH for diagnosis and therapeutic effectiveness of hormone replacement therapy.

This overall problem has been addressed by University of California Los Angeles scientists: Mauricio Loya,  Benjamin Chu and distinguished Professor Joseph DiStefano III, in collaboration with clinical Professors Jacqueline Jonklaas at Georgetown University and David Schneider at the University of Wisconsin.  Their goal was to better optimize replacement LT4 and (the somewhat controversial) combined LT4+LT3 dosing strategies for hypothyroid patients, based on BMIs and gender as well as individual hormone levels and, at the same time, better understand how gender and BMI impact thyroid hormone dynamical regulation.  The research is published in the peer-reviewed journal Frontiers in Endocrinology.

This clinical research team developed a personalized simulation tool, naming it p-THYROSIM,  building on the success of their widely available and well-validated model and simulation tool THYROSIM. p-THYROSIM takes into consideration the complex TH dynamics in individual patients to more precisely forecast the results of clinical therapies. They updated and refined the mechanistic representations of TSH regulation and T3 metabolism in THYROSIM, to more accurately reflect existing data, and added routinely measured anthropometric traits of specific hypothyroid patients. The main clinical objective was to modify and improve the model in order to better anticipate the TH dose requirements for particular male and female individuals. Three different clinical datasets were used to quantify the model, while a fourth independent dataset was used to assess model performance and predictive capabilities.

In order to explore if using normal T4 and TSH blood levels together as a marker for euthyroidism would have advantages over using TSH alone, the researchers assumed normal thyroid physiology is largely predicated on maintenance of normal T4 and T3 as well as TSH levels in blood, their numerical goal for optimization.  According to the authors the precisely tuned p-THYROSIM, used first for T4-only dosing, significantly outperformed the usual basis for optimal LT4 dose determination in terms of dose prediction accuracy.  They also used it to determine the best dosages for combination T4+T3 therapy, to show the effectiveness and clinical value of the new p-THYROSIM model, fully quantified from the clinical data.

Their simulations of the combination therapy trial showed how specific T4+T3 combination therapies might successfully restore normal thyroid function in male and female hypothyroid individuals with various BMIs and residual thyroid functions (RTFs). Unmeasurable RTF estimates for individual patients are computable with p-THYROSIM, a unique contribution of the model, and the researchers found that gender and BMI had no bearing on RTF predictions.  They computed optimal combined therapeutic dosages, for once or twice a day, or long-acting continuous dosing, and, importantly, found that very little LT3 is required along with sufficient LT4 to restore euthyroid levels for all dosing modalities.

In conclusion, UCLA researchers developed the pTHYROSIM simulation tool that can compute individualized optimal dosing regimens, for mono- or combined hormone therapy, thereby increasing therapeutic effectiveness, as well as substantially reducing the usual delay in achieving euthyroidism seen with empirical procedures utilized in clinical practice. Every patient can and should receive individualized care, and the pros and cons of mono- versus combined hormone replacement therapy can now be addressed individually. Their results and clinical judgements also suggest that combination therapy (containing only  very small amounts of LT3) should be used only for patients who do not improve on monotherapy with LT4.  As a bonus, they provide nomograms for computing unmeasurable RTF values from untreated patient blood hormone measurements (reproduced with permission below), based on p-THYROSIM simulations of their new model fitted and validated from their large human data base.