Thyroid Allostasis–Adaptive Responses of Thyrotropic Feedback Control to Conditions of Strain, Stress, and Developmental Programming

Abstract

The hypothalamus–pituitary–thyroid feedback control is a dynamic, adaptive system. In situations of illness and deprivation of energy representing type 1 allostasis, the stress response operates to alter both its set point and peripheral transfer parameters. In contrast, type 2 allostatic load, typically effective in psychosocial stress, pregnancy, metabolic syndrome, and adaptation to cold, produces a nearly opposite phenotype of predictive plasticity. The non-thyroidal illness syndrome (NTIS) or thyroid allostasis in critical illness, tumors, uremia, and starvation (TACITUS), commonly observed in hospitalized patients, displays a historically well-studied pattern of allostatic thyroid response. This is characterized by decreased total and free thyroid hormone concentrations and varying levels of thyroid-stimulating hormone (TSH) ranging from decreased (in severe cases) to normal or even elevated (mainly in the recovery phase) TSH concentrations. An acute versus chronic stage (wasting syndrome) of TACITUS can be discerned. The two types differ in molecular mechanisms and prognosis. The acute adaptation of thyroid hormone metabolism to critical illness may prove beneficial to the organism, whereas the far more complex molecular alterations associated with chronic illness frequently lead to allostatic overload. The latter is associated with poor outcome, independently of the underlying disease. Adaptive responses of thyroid homeostasis extend to alterations in thyroid hormone concentrations during fetal life, periods of weight gain or loss, thermoregulation, physical exercise, and psychiatric diseases. The various forms of thyroid allostasis pose serious problems in differential diagnosis of thyroid disease. This review article provides an overview of physiological mechanisms as well as major diagnostic and therapeutic implications of thyroid allostasis under a variety of developmental and straining conditions.

The role of functional thyroid capacity in pituitary thyroid feedback regulation

“…Both indices define pituitary thyrotroph function more accurately, compared to TSH measurement, and proved to be useful for clinical disease classification. 40,41 The classical concept of negative hypothalamic-pituitary feedback regulation by thyroid hormones has recently been improved to describe more appropriately the diverse facets of pituitary control. Pituitary enlargement and thyrotropic cell hyperplasia have long been recognised in association with primary hypothyroidism.…”

“…24,25 The concept of estimating functional reserve capacity theoretically exploits a similar principle to the obsolete TRH test where, to render it estimable, the preformed TSH reserve was mobilised upon supraphysiological TRH stimulation and released into the circulation. 40,41 This includes the important role of a TSH-T3 feedforward shunt. 38 Finally, to measure the T4 to T3 conversion rate, we used global step-up deiodinase activity (GD, see Methods), because it is superior to the more simple FT3-FT4 ratio in accounting for nonlinear enzyme kinetics.…”

“…[26][27][28] As a limitation, this study relied on cross-sectional data. 41 Pituitary TSH receptors are involved in short-loop feedback control of TSH on its own secretion. Measuring TSH immunological activity may have slightly overestimated its biological effect at higher concentrations because TRH simulation may produce biologically less active variants of the hormone.…”

“…46 According to the present study, the effectiveness of the achievable adjustment by the shunt depends on functional thyroid capacity. 21,40,41 Treatment indication in subclinical hypothyroidism and LT4 dose finding may be highly misleading when guided by TSH measurements alone. 47 Progressive loss of system stability thus results in higher variability, thereby considerably increasing the uncertainty of measured TSH values.…”

“…Sensitivity of TSH to functional thyroid capacity increases with decreasing GT values, 46 explaining wide fluctuations in TSH concentrations in patients with subclinical hypothyroidism. 36,41 Studies in humans cannot address open questions about tissue T3 effects in various organs. The present study focused on patients with thyroid autoimmune disease experiencing varying degrees of capacity loss.…”