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.

Keywords: TACITUS syndrome; hypothalamus–pituitary–thyroid feedback control; non-thyroidal illness syndrome; thyroid allostasis; thyroid hormone metabolism.

Figure 1

Altered concentrations of thyroid hormones in certain life situations may result from type 1 allostatic load (comprising thyrotropic adaptation, hypodeiodination, and decreased protein binding of thyroid hormones), type 2 allostatic load [showing increased thyroid-stimulating hormone (TSH) release, hyperdeiodination, and augmented binding of thyroid hormones to plasma proteins], and non-homeostatic mechanisms including methodological interferences (53).

Figure 2

Thyroid homeostasis comprises ultrashort, short, and long feedback mechanisms. In addition, conversion between iodothyronines is adaptively mediated by three distinct deiodinases (18, 35). Deiodination is controlled by multiple local and global mediators including thyroid-stimulating hormone (TSH).

Figure 3

Critical components of the central governor of thyroid homeostasis include parvocellular thyrotropin-releasing hormone (TRH) neurons, which integrate multiple afferent signals relaying information on nutrition and stress, and tanycytes lining the third ventricle at the blood–brain barrier, which are able to control both synthesis and degradation of thyrotropin-releasing hormone (TRH) via type 2 deiodinase (D2) and pyroglutamyl peptidase II (PPII) (, –99).

Figure 4

(A) In a physiological homeostatic system, afferent information is compared with a fixed set point, and the sensed discrepancy leads to counter-regulatory activity of the effector. Negative (degenerative) feedback ensures static stability of the system. (B) In situations of allostasis, stress signals are looped in at a central level, thus resulting in ongoing offset signaling. Due to saturation of receptors and enzymes, this discrepancy reduces the efficiency of the effector and, if ongoing, gives rise to “wear and tear” reactions. Both mechanisms combine as allostatic load, which may be a source of pathology on its own (105, 106).

Figure 5

The phenotype of low-T3 syndrome may result from both peripheral hypodeiodination and central hyperdeiodination. Although FT3 concentrations rise with increasing sum activity of peripheral type 1 deiodinase (GD1), they descend with increasing activity of central type 2 deiodinase (GD2). This seeming paradox is explained by feedback effects (20, 21). Despite research in humans being hindered by ethical and methodological barriers, results of computer simulations [shown is sensitivity analysis based on SimThyr 4.0 (128)] and animal experiments (126, 127) are consistent.

Figure 6

In starvation, both step-up deiodination (via D1 and D2) and thyroid-stimulating hormone (TSH) release are reduced, leading to low-T4 and low-T3 constellations. rT3 concentrations may be increased. Black and red arrows indicate the direction of change from normal, homeostatic conditions in fed state.

Figure 7

High-T3 concentrations (although in most cases within the reference interval), reduced rT3 concentrations, increased activity of type 1 and type 2 deiodinase, and comparatively high thyroid-stimulating hormone (TSH) levels are the typical signature of obesity, a classical phenotypical sequela of type 2 allostatic load. (A) In healthy participants of the NHANES program (200), concentrations of TSH and FT3 as well as Jostel’s TSH index (a measure for the set point of thyroid homeostasis) and SPINA-GD (an estimate for total deiodinase activity) show a significantly positive correlation to body mass index (BMI) and waist circumference, and with the exception of TSH also to body surface area (BSA). In addition, FT3 and SPINA-GD correlate negatively to age, and minor associations exist to creatinine-corrected urinary iodine excretion (UIE). In this circular map, positive correlations are marked in red and negative correlations in blue. The widths of the splines represent the correlation coefficient to denote the strengths of association (201). (B) Mechanisms of adaptive responses in obesity are mediated by elevated leptin concentrations and increased alpha-MSH signaling, while activity of AGRP terminals is reduced.

Figure 8

Fetal and maternal thyroid homeostasis are dovetailed to optimize conditions for both organisms. (A) After maturation of the feedback loop in the 20th week of gestation, fetal thyroid-stimulating hormone (TSH) concentrations and step-down deiodination via D3 are temporarily increased, while step-up deiodination is decreased. This results in a pattern of markedly reduced T3 concentrations and elevated rT3 levels. Black and red arrows indicate the difference compared to normal, homeostatic conditions in healthy newborns and adults. (B) Pregnancy is accompanied by a characteristic “anti-NTIS”-like constellation of thyroid homeostasis including high concentrations of T3 and T4, step-up hyperdeiodination and increased binding of thyroid hormones to plasma proteins.

Figure 9

The adaptive response of the hypothalamic–pituitary thyroid axis to exercise is heterogeneous, depending on duration and intensity of training and on the interval between exercise and laboratory investigations (27). This diversity may result from pre-analytical factors (e.g., hemoconcentration) and from an overlap of type 1 and type 2 allostatic load. (A) Exhausting exercise. (B) Endurance training.

Figure 10

Depending on severity and duration of disease, non-thyroidal illness syndrome presents with two related, but distinct phenotypes. (A) Allostatic reactions of the pituitary–thyroid feedback control system in acute illness lead to slightly decreased T3 and 3,3′-T2 concentrations, slightly elevated T4 and 3′,5′-T2 levels and markedly increased rT3 concentrations. (B) Medium-term and long-term adaptations in ongoing illness (“wasting syndrome”) and chronic disease result in thyrotropic adaptation and slight increases of rT3, 3,3′-T2, and 3,5-T2 concentrations concomitant to low-T3 syndrome.

Figure 11

A complex interaction of positive and negative feedback mechanisms linking centers of the limbic system to hypothalamic nuclei explains the adaptive response of the hypothalamic–pituitary thyroid loop in type 2 allostasis resulting from psychosocial stress situations (355, 356, 358, 359). ARC, arcuate nucleus of the hypothalamus; BNST, bed nucleus of the stria terminalis; CRH, corticotrophin-releasing hormone; DA, dopamine; GABA, gamma-aminobutyric acid; LC, locus coeruleus; NAcc, nucleus accumbens; OT, oxytocin; VTA, ventral tegmental area.