Recent Advances in Thyroid Hormone Regulation: Toward a New Paradigm for Optimal Diagnosis and Treatment

Abstract

In thyroid health, the pituitary hormone thyroid-stimulating hormone (TSH) raises glandular thyroid hormone production to a physiological level and enhances formation and conversion of T4 to the biologically more active T3. Overstimulation is limited by negative feedback control. In equilibrium defining the euthyroid state, the relationship between TSH and FT4 expresses clusters of genetically determined, interlocked TSH-FT4 pairs, which invalidates their statistical correlation within the euthyroid range. Appropriate reactions to internal or external challenges are defined by unique solutions and homeostatic equilibria. Permissible variations in an individual are much more closely constrained than over a population. Current diagnostic definitions of subclinical thyroid dysfunction are laboratory based, and do not concur with treatment recommendations. An appropriate TSH level is a homeostatic concept that cannot be reduced to a fixed range consideration. The control mode may shift from feedback to tracking where TSH becomes positively, rather than inversely related with FT4. This is obvious in pituitary disease and severe non-thyroid illness, but extends to other prevalent conditions including aging, obesity, and levothyroxine (LT4) treatment. Treatment targets must both be individualized and respect altered equilibria on LT4. To avoid amalgamation bias, clinically meaningful stratification is required in epidemiological studies. In conclusion, pituitary TSH cannot be readily interpreted as a sensitive mirror image of thyroid function because the negative TSH-FT4 correlation is frequently broken, even inverted, by common conditions. The interrelationships between TSH and thyroid hormones and the interlocking elements of the control system are individual, dynamic, and adaptive. This demands a paradigm shift of its diagnostic use.

Keywords: levothyroxine treatment; setpoint; thyroid homeostasis; thyroid-stimulating hormone.

Figure 1

Theoretical and observed relationships between thyroid-stimulating hormone (TSH) and thyroid hormones. The central system provides an integrated solution to the location of the setpoint (settling point) of thyroid homeostasis, as determined by the various genetic, epigenetic, and allostatic parameters (27, 36). This includes monogenic factors such as polymorphic variants of receptors and transporters, changes in deiodinase activity or variations in T4 production efficiency, and environmental impacts, e.g., nutritional factors, body weight, body composition, age, and extends to diseases of the thyroid and other organs where severe disequilibria may arise and a “euthyroid” solution is not achieved (27, 36). (A) Schematic overview of main regulatory pathways and control loops in the hypothalamic–pituitary–thyroid regulation. External factors of influence include (1) obesity (hyperthyrotropinemia), (2) pregnancy (hCG-mediated suppression of TSH release and stimulation of T4 secretion), (3) non-thyroidal illness (NTI) (both pituitary and thyroid function down-regulated), and (4) certain psychiatric diseases (both pituitary and thyroid function stimulated). (B) The response of the thyroid to TSH by hormone release and corresponding feedback on pituitary TSH secretion produces a finite equilibrium solution, thereby defining interlocking TSH–FT4 pairs (setpoints). These are characteristic for each person and show only little variation unless disturbed by internal or external strain. In the event of progressive thyroid capacity stress, irrespective and independent of other influences, setpoints for FT4 and TSH translocate along a homeostatic pituitary response curve (isocline) unique for the individual. Hence, in the case of a diminished or exaggerated pituitary response the translocation moves along the thyroid isocline. The open circles indicate the expected variation (10% for FT4 and 30% for TSH) surrounding the individual setpoint. The percentiles for the isoclines of the response curves were derived from previous data in a healthy sample and the included area between the 2.5 and 97.5 percentiles represents the population’s reference range (37). (C) Influences additional to direct thyroid activity change (e.g., allostatic changes such as obesity, age, pregnancy, and NTI) may have dislocating effects on isoclines and setpoints. (D) Observed TSH–FT4 pairs (setpoints) in two individual patients (blue and green symbols) and the averaged group of 250 patients (black ellipse) followed long term on stable treatment conditions. Data ellipses indicate the 50 and 95% confidence limits for the setpoint. Levothyroxine dose was 100 μg/day, 1.5 µg/kg body weight for each of the individual patients, and 1.5 (SD 0.27) μg/kg for the whole group. Data are from a published longitudinal study (38). (E) Observed TSH–FT3 pairs depicted in the same patients as in (D). FT3 concentrations vary with conversion efficiency and impact on the location of the TSH–FT4 setpoint (38).