The Relationship between Population T4/TSH Set Point Data and T4/TSH Physiology

Abstract

Context. Population studies of the distribution of T4/TSH set points suggest a more complex inverse relationship between T4 and TSH than that suggested by physiological studies. The reasons for the similarities and differences between the curves describing these relationships are unresolved. Methods. We subjected the curve, derived from empiric data, describing the TSH suppression response to T4, and the more mathematically derived curve describing the T4 response to TSH, to the different possible models of population variation. The implied consequences of these in terms of generating a population distribution of T4/TSH equilibrium points (a “population curve”) were generated and compared to the empiric population curve. The physiological responses to primary hypothyroidism and hyperthyroidism were incorporated into the analysis. Conclusions. Though the population curve shows a similarly inverse relationship, it is describing a different relationship than the curve describing the suppression of TSH by T4. The population curve is consistent with the physiological studies of the TSH response to T4 and implies a greater interindividual variation in the positive thyroid T4 response to TSH than in the central inhibitory TSH response to T4. The population curve in the dysthyroid states is consistent with known physiological responses to these states.

Thyroid stimulating hormone (TSH) autoregulation reduces variation in the TSH response to thyroid hormones

“…In these circumstances of loss of autoregulation in prolonged hypothyroidism, the TSH response to hypothyroidism would be advantageously augmented relative to the euthyroid state, as compared to the TSH response in the absence of there being TSH autoregulation ( Figure 5(c)). This mechanism is consistent with the curvature of the population FT4/log TSH relationship [15,16] and the shift in TSH curves in hypothyroidism previously proposed [17].…”

“…Other workers have claimed, on the basis of population data, that this relationship is not strictly log-linear [15,16], with there being still greater increases and decreases in TSH levels with lower and higher FT4 levels respectively. Our work suggests that such claims are based on a misunderstanding of the population data [17], but for the purposes of this work, this distinction is again not relevant. All that is important for this work is that there is a negative relationship of some description between TSH and varying levels of FT4.…”

New insights into thyroid hormone action

“…Remarkably, the set point of the HPT axis differs between individuals (Fitzgerald & Bean, 2016). This is likely due to genetic factors.…”

Population data indicate that thyroid regulation is consistent with an equilibrium-point model, but not with a set-point model

“…We demonstrated 1 that the population curve theoretically could have a positive, neutral or negative slope depending on the pattern of population inter-individual variation in the TSH curve and the ‘T4 curve’ (the curve describing the stimulation of FT4 by TSH). The fact that the empiric population curve resembles the TSH curve, in also having a negative slope, indicates that in the population inter-individual variation in TSH curves is less than the inter-individual variation in T4 curves.…”