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

Although it is believed that normal thyroid hormone levels are set points, representing individually pre-determined reference levels, in this paper, we discuss how analysis of the population distribution of Free Thyroxine/ Thyroid Simulating Hormone (FT4/TSH) levels supports a model of homeostasis in which these levels represent the equilibrium points of the physiologic processes of homeostasis alone. This discussion follows on from our previous work in which we differentiated the curve describing the population distribution of FT4/TSH levels (the ‘population curve’) from the curve describing the physiologic relationship of TSH suppression by FT4 (the ‘TSH curve’). We demonstrated 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. We discuss here how the negative slope of the population curve also provides evidence as to the nature of FT4 homeostasis. The prevailing model of homeostasis, and particularly as it applies to FT4 levels, is a ‘set point’ model. All set-point models require an obvious set point (a physical/physiologic reference signal) or a hidden set point (a “mathematical” reference signal based on some internal property of the system). Apart from the means to specify such a set point, such physiology also requires that the body has the means to identify the desired level of the parameter to be so specified, a means to sense an ‘error signal’ (a deviation from this set point), and a linked ‘corrective’ process. Thus there has arisen a conception that the body aims for a particular but variable FT4 value, and that hypothalamus-pituitary function is controlled to attain and maintain this target level. Research has been directed at identifying individuals’ personal set points, rather than relying on population ranges, so that thyroid disorders may be better diagnosed and treated. In contrast, an equilibrium or balance model requires no reference level; the level of a parameter in this model reflects the balance point of the physiologic processes acting on the parameter. In the case of FT4 levels the balance point is that which results from the closed control-loop of FT4 and TSH, i.e. the TSH and T4 curves, each based on proportional control. In the set point model of FT4 regulation, given that the set point is a reference point set independently of the thyroid, it must be possible for 2 individuals to be identical in terms of thyroid gland sensitivity to TSH (i.e., to have identical T4 curves) but have different FT4 set points. The prevailing set point model of regulation model requires that the hypothalamus/pituitary attains the appropriate different set point levels by maintaining the different appropriate levels of TSH. As the T4 curve has a positive slope, the individual with the higher FT4 set point must have the higher prevailing TSH level. If we extend this to a population with inter-individual variation in FT4 set points and T4 curves, we can divide this population into different groups. For the purposes of this analysis we compare the half with higher set points