Homeostatic control of thyroid function represents a classical example of a hypothalamic–pituitary-mediated endocrine feedback mechanism (Figure 2) (18, 35). Its principal mediators are hypothalamic thyrotropin-releasing hormone (TRH), pituitary thyrotropin (TSH), thyroxine (T4), and triiodothyronine (T3).

Thyroid-stimulating hormone is a glycoprotein hormone with a rather short half-life of 50–60 min, which stimulates synthesis and release of T4 and to a lesser degree T3 from the thyroid gland via binding to a specific TSH receptor (35). With respect to classical thyroid hormone actions (effects mediated via nuclear thyroid hormone receptors) T4 is a prohormone requiring activation to the highly agonistic hormones T3 and 3,5-T2 to be effective. However, other non-classical actions of T4, acting, e.g., via integrin receptors, do not require prior activation, rendering T4 an active hormone with respect to non-classical effects (80).

Plasma T3 is derived from several sources, including direct formation in the thyroid gland and release by proteolysis of thyroglobulin (Tg), deiodination from T4 in the thyroid and deiodination in peripheral organs (12). T4 and T3 display prolonged plasma half-lives of 1 week and 1 day, respectively, resulting from intracellular accumulation and a high proportion of plasma protein binding (17, 35, 81). T3 affects most tissues in a pleiotropic manner. It also closes the feedback loop by inhibiting both synthesis and release of TSH from the pituitary gland (17, 18, 35).

This “short” feedback loop is augmented by additional control motifs, including an ultrashort feedback loop of TSH release (17, 82), a long feedback loop, where thyroid hormones inhibit TRH release in the hypothalamus (83, 84), and a direct stimulatory effect of TSH on T3 formation. A TSH–T3 shunt has been predicted in animal and cell culture experiments (85–90), and we recently demonstrated its existence in the human organism (19, 22, 91–94).

The integrative control at the hypothalamic level is mediated by parvocellular hypophysiotropic paraventricular nucleus (PVN) TRH neurons. Their activity provides an interface between thyroid hormone feedback, nutritional status, and stimulatory or inhibitory influences of the circadian rhythms (Figure 3) (95). In this respect, tanycytes lining the third ventricle play a pivotal role in central homeostasis. They are able to fine-tune the sensitivity of PVN via provision of central T3 and to degrade TRH via pyroglutamyl peptidase II (PPII) at the level of the median eminence (Figure 3) (95, 96).

In 1988, Sterling and Eyer extended the classical paradigm of homeostasis with the theory of allostasis (100). Briefly, an allostatic response is defined as a dynamic stress reaction that maintains stability through change (101). This distinct operating mode of homeostatic systems becomes apparent in straining and occasionally life-threatening situations. Allostasis both contains and extends the homeostatic principles by adapting set points and other boundaries of control (Table 1) (101). The primary mediators of allostatic response include but are not limited to catecholamines, hormones of the hypothalamo-pituitary–adrenal (HPA) axis and cytokines (102). Of note, allostasis deals with a trade-off situation. It ensures survival in extreme situations, where, e.g., the demand of energy exceeds supply, but this protective reaction occurs at the expenses of a stress reaction (referred to as allostatic state), which, in turn, may have adverse consequences of its own. The cumulative result of an allostatic state is referred to as allostatic load of the organism (Figure 4). If allostatic load remains excessive or persists over a period of time it may confer pathology and turn out to be life threatening by its own nature (allostatic overload).

Usually, two types of allostatic load are distinguished. Type 1 allostatic load occurs, if energy demands exceed the sum of energy intake and the amount of energy that can be mobilized from stores. Typical examples are breeding birds exposed to inclement weather conditions and the conflict of homeothermic animals resulting from reduced availability of food in cold seasons, when they have both to save energy and to increase energy spending on maintaining body temperature (101). Type 2 allostatic load results from expected increase in energy demand, although the cumulative energy balance is still sufficient. This constellation is typical of psychosocial stress situations, e.g., in predominating competitive social structures within animal populations and, as applied to humans, conflicts arising from differences in socioeconomic status (101). Multiple components of an unhealthy lifestyle including overnutrition, poor sleep, and toxic chemicals are also able to contribute to the phenotype of allostasis (107). Long-term consequences of type 2 allostatic load include obesity, hypertension, type 2 diabetes mellitus, endothelial cell damage, and dyslipidemia, i.e., classical components of metabolic syndrome.

Our group has proposed to extend the concept of allostasis to the adaptive response of thyroid function in defined straining situations (35). This extension goes beyond the simple issue of energy balance, although thyroid hormones have an intricate relationship to energy homeostasis. While stimulating the mobilization of energy for metabolic usage thyroid hormones also increase its consumption. Their activation is coupled with a depletion of reduced glutathione stores involved in regeneration of NADH and NADPH acting as cofactors of deiodinases (86, 87, 108–110). It may therefore be expected that when energy or glutathione availability does not meet their consumption, active thyroid hormones are selectively downregulated. By analogy to classical concepts we will subsequently refer to this situation as type 1 thyroid allostasis. Conversely, in situations, where energy stores have to be mobilized to meet anticipated demands (e.g., in pregnancy, endurance training and adaptation to cold weather conditions), upregulation of active thyroid hormones will be beneficial. Since these situations bear a resemblance to classical type 2 allostatic load, we will sum them up as type 2 thyroid allostasis. This is further justified because a high-T3 constellation in the absence of hyperthyroidism is also observed in obesity (111) and psychosocial stress (112), i.e., type 2 allostatic load according to the classic definition by McEwen and Wingfield.

In summary, unlike classical stress transduction systems the HPT axis produces two phenotypically distinct types of allostatic load if strained: in type 1 allostasis production of thyroid hormones, especially T3, is downregulated, while it is upregulated in type 2 allostasis. In that respect, the thyroid stress reaction differs sharply from that of the HPA axis, the prime example of an allostatically controlled system, as the latter responds invariantly with increased release of cortisol.

In situations of starvation, inflammation, and oxidative stress, a variety of mediators (including nitric oxide, hydrogen peroxide, proteolysis-inducing factor, angiotensin II, TNF-α, and other cytokines) converge in the NF-κB pathway, a key regulatory system of immune response, cell proliferation, and apoptosis (113). Among multiple other effects the NF-κB/IL6 signaling pathway (114, 115) inhibits T3-induced expression of peripheral type 1 deiodinase. Downregulation of D1 and peripheral type 2 deiodinase (D2) results in reduced concentrations of free and total T3 (41, 116).

Recent research revealed a complex interaction of insulin and thyroid hormone signaling in skeletal muscle, which might also extend to lung and liver tissue (117, 118). Via the PI3K–mTORC2–Akt pathway insulin and IGF-1 inactivate FOXO1 by phosphorylation at Ser256, which leads to increased D2 activity (117). T3 again inhibits Akt activity, thereby closing a negative feedback loop (118). This mechanisms might play a pivotal role in linking reduced concentrations of insulin in fasting state (119) as well as decreased IGF-1 levels in a subgroup of critically ill (120) to hypodeiodination and consecutive low-T3 syndrome.

In isolation, decreased peripheral step-up deiodination would lead to increased (disinhibited) TSH release, which would result in elevated serum thyrotropin concentration. This, in turn, would reset the concentrations of T3 to their previous levels, thus neutralizing the effect of hypodeiodination. However, concomitantly with reduced peripheral step-up deiodination, D1 and D2 located in hypothalamic tanycytes (95), and the anterior pituitary gland are upregulated. This change is mediated by bacterial lipopolysaccharide (121, 122), alterations in cytokines, e.g., IL-12 and IL-8 (43) and, possibly, increased concentrations of 3,5-diiodothyronine (61–63), triiodothyroacetate, and tetraiodothyroacetate (123, 124) during the acute phase response. The upregulation of central step-up deiodination results in increased central thyroid hormone signaling and, consequently, suppressed release of TRH and TSH. The seeming paradox that low-T3 syndrome may ensue from hyperdeiodination is resolved by the spatial diversity of deiodinase activity (Figure 5). This was investigated in silico by computer simulations (20) and confirmed by means of animal experiments in vivo (83, 84, 121, 122, 125–127).

A coordinated interaction of central and peripheral deiodinases in the lead-up to low-T3 syndrome is further supported by upregulation of type 3 deiodinase (D3) in TACITUS (129, 130), giving rise to elevated serum concentrations of rT3, a iodothyronine with inhibiting effects on thyroid hormone signaling. Increased D3 activity in starvation may be caused by decreased leptin concentrations as shown in mice experiments (23, 131). During prolonged critical illness, decreased food intake might be an important factor in regulating the activity of liver deiodinases (132). D3 in peripheral organs might also be upregulated by hypoxia due to decreased tissue perfusion during illness (133).

In addition, TSHb is decreased through IL-1b and TNF-α independently of T3 uptake and action in pituitary cells (134, 135). Moreover, supraphysiological concentrations of IL-1a and IL-1b suppress cAMP accumulation, thus inhibiting the TSH-induced Tg mRNA expression and Tg release in human cultured thyrocytes (136, 137).

Thyrotropin-releasing hormone neurons originating from the hypothalamic PVN, the major autonomic output area of the hypothalamus (95, 138–140), play a key role in the central control of thyroid homeostasis by providing a set point for the short loop control (141). The release of TRH is inhibited by central T3, which is predominantly generated by D2 expressed in tanycytes lining the third ventricle (142–145) (Figure 3). This circuit forms an additional long feedback mechanism of thyroid homeostasis (83, 84). Apart from the so defined cascade control mechanism, TRH neurons contribute to the coordination of global energy metabolism by integrating multiple afferent signals (146) including catecholamines (147, 148), cocaine- and amphetamine-regulated transcript (149, 150), leptin (151), and alpha-MSH (146, 152) (all stimulating) as well as neuropeptide Y (NPY) (153–155), agouti-related peptide (141, 146, 156), and glucocorticoids (146) (all inhibiting). Moreover, endocannabinoids have been shown to exert inhibitory effects on TRH neurons via the type 1 cannabinoid receptor (97). Animal experiments revealed that the integration of all afferent projections has profound effects on secretion of TRH and consecutively TSH in straining situations (95).

Depending on the origin of stress (physical or psychogenic), its duration and the animal’s endocrine and energetic status TRH release may be upregulated or downregulated (157) subsequently affecting the set point of the overall homeostatic system. Downregulation with consecutive thyrotropic adaptation, i.e., low or normal TSH levels despite low concentrations of T4 and/or T3, may occur for instance in cases of systemic infection and sepsis, where lipopolysaccharides induce D2 activity in tanycytes (126). Moreover, low TRH expression in the PVN characterizes the NTIS (95). In addition to the effects of NPY as neurotransmitter, elevated fasting serum concentrations of NPY have a stimulatory effect on hepatic thyroid hormone degradation via increased glucuronoconjugation (facilitating biliary clearance) and sulfoconjugation (enabling step-down deiodination to rT3S) (140, 158).

A high proportion of the circulating iodothyronines is bound to thyroxine-binding globulin (TBG), transthyretine, and albumin. This mechanism contributes to the exceptionally long half-lives of thyroid hormones. In case of rapid onset of stress situations, e.g., severe illness, the time frame of the described control mechanisms would be too long to be effective, if plasma protein binding of thyroid hormones remained unchanged. However, in critical illness the extent of plasma protein binding is reduced owing to decreased concentrations of binding proteins and the existence of certain binding inhibitors (57, 58, 159). This effect is putatively mediated via cytokines (160). Consequently, degradation of iodothyronines is considerably accelerated, which represents another underlying mechanism toward the adaptation of the feedback loop to conditions of type 1 allostatic load (161–163).

In an animal model for prolonged critical illness the iodothyronine membrane transporters MCT10 and OATP1C1 (but not MCT8) were increased, suggesting some adaptation at the level of transmembrane transport, however, with uncertain clinical relevance (164).

Finally, alternative metabolic pathways of thyroid hormones in peripheral tissues such as sulfation, conjugation to bile acids and glucuronide, and ether link cleavage may affect the concentrations of thyroid hormones in critical illness (165–169).

Early reports that serum concentrations of T3 are reduced in states of low caloric intake (47, 49) gave rise to the concept of what we now call the Low-T3 syndrome. Reduced T3 concentrations have been described in various conditions associated with energy deprivation, including anorexia nervosa (183–185), calorie-free diet in obesity (47), military combat training with caloric restrictions (186, 187) and other energy-deficient situations (188). Even moderate weight loss may result in hypodeiodination with consecutive decreased T3 concentrations (189). Today, at least three mechanisms explaining this finding are known (Figure 6) (23). In the fed state, peripheral step-up deiodination is stimulated by insulin (119) and bile acids (190–192). In addition, increased leptin concentrations facilitate release of TRH and TSH via the hypothalamic melanocortin pathway (23, 83, 146, 193). Together, these different mechanisms enhance conversion of T4 to T3, thus mediating postprandial thermogenesis. Conversely, in fasting conditions concentrations of insulin, bile acids, and leptin are low, which results in decreased step-up deiodination and thyrotropic adaptation, and eventually in low-T3 syndrome. Additional mechanisms leading to impaired TSH release include increased expression of neuromedin B, a bombesin-related peptide, which is an inhibitor of TSH secretion, and upregulation of hypothalamic D2 expression during fasting (23), resulting in low TRH expression in the PVN (25, 95, 98, 194).

Obesity is a classical consequence of type 2 allostatic load (101). It is linked to multiple metabolic and endocrine responses (111) including thyroid function. The interconnection between thyroid hormones and body weight is bidirectional, and both hypothyroidism and hyperthyroidism are known to result in changes of body mass. Conversely, obesity may result in adaptive responses of thyroid homeostasis: a variety of studies, as recently reviewed by Pacifico et al. (195) and Fontenelle et al. (111), described elevated TSH levels and increased total step-up deiodinase activity (although predominantly within the reference range) in patients with weight gain, while concentration of rT3 has been reported to be decreased. Reversibility of these alterations after weight loss indicates that they are consequence rather than cause of overweight (196). A recent study (42) described a significant rise in TSH in the absence of peripheral hypothyroidism in men with non-metastatic prostate cancer undergoing androgen deprivation therapy. The effect was mediated by body composition changes and by the fat-associated hormone leptin rather than androgen deficiency. Another study interrelated non-alcoholic fatty liver disease with higher fT3 concentrations in euthyroid subjects, probably consequent to central obesity (197). Both central and peripheral components of the feedback loop are apparently involved in the reactive adjustments to obesity (Figure 7). Increased concentrations of adipokines such as leptin have been proposed to be a key element of obesity-related thyroid allostasis, but mitochondrial dysfunction (195, 198), chronic inflammation, and insulin resistance (199) as well as both central and peripheral resistance to thyroid hormone may play additional roles (111).

Since thyroid hormones are potent stimulators of adaptive thermogenesis (202–204), upregulation of TSH release and deiodinase activity stimulates dissipation of energy and therefore may be part of autoregulatory mechanisms of body mass and fat storage. On the other hand, some of the obesity-related changes in thyroid function may contribute to the unfavorable metabolic phenotype of overweight (111). This and significant cardiovascular side effects of hyperthyroidism are the main reasons that intake of thyroid hormones is strongly discouraged as an adjunct in the treatment of obesity (205).

In mammals, thyroid hormones are potent mediators of efficient thermoregulation. This ensues from a complex mechanism tightly integrating deiodinase activity with sympathetic signals (206), which leads to upregulation of the protein UCP1 in mitochondria of skeletal muscle and brown adipose tissue (207–209). This results in uncoupled oxidative phosphorylation and finally non-shivering thermogenesis (202–204, 210, 211). It is therefore not surprising that mammals, typical examples for homeotherm animals (endotherm thermoregulators), usually exhibit elevated serum concentrations of T4 and T3 in winter and during hypothermia as long as they are sufficiently fed (212, 213). Increased concentrations of TSH and/or thyroid hormones in cold seasons and during hypothermia have also been described in humans (214–217). Although the mechanism of thyroid hormone-mediated expression of UCP1 plays a pivotal role in efficient thermoregulation of mammals (202, 218, 219) it has not been described in non-mammal homeotherm vertebrates, e.g., in birds, and it is probably inexistent in homeotherm arthropods. Of note, although some insect species, e.g., bombus and apis, are homeotherm (220, 221), their temperature regulation is less potent and less energy efficient than that of mammals. This may be in part due to the fact that they probably lack endogenous production of thyroid hormones (222–224).

In hibernating mammals, the situation is different to that of non-hibernating mammals, since here concentrations of T4 and T3 are downregulated during hibernation (78, 225–228). This also applies to the endocrine response to cold in starving mammals (229) and poikilotherm vertebrates during torpor (79).

In summary, during cold periods T3 and T4 are upregulated in fed non-hibernating homeotherm mammals, but in an NTIS-like pattern downregulated in hibernating mammals, starving non-hibernating mammals and poikilotherm vertebrates. Both mechanisms support conservation of energy: the first one by making thermoregulation more efficient, and the second one by partly tuning down the metabolism in periods of lower demand and supply.

Iodothyronines are critical for development in the embryonal and fetal periods. Both hypothyroidism (230) and oversupply with thyroid hormones (231) may result in fetal loss and severe developmental disorders. In humans, the fetal thyroid gland starts to secrete hormones in the beginning of the 12th week of gestation (29). However, the feedback loop begins to be functional in the 20th week, i.e., in mid-gestation (29). In the first half of pregnancy, the fetus is largely dependent on maternal supply with thyroid hormones, probably explaining, why production of iodothyronines is upregulated in the mother (230). Despite this anti-NTIS-like pattern in the maternal metabolism, which is mainly mediated via human chorionic gonadotropin (hCG) and estrogens (230), concentrations of free and total T3 are low in the fetus throughout gestation, and concentrations of TBG, free and total T4 are, although rising with increasing gestational age (230), lower in the fetal than in the maternal circulation (Figure 8) (232). TSH levels attain a maximum of about 15 mIU/L in the 20th week, when the feedback loop maturates, and then again at birth (29). Both in fetal serum and in amniotic fluid, concentrations of rT3 are markedly increased (230), which probably results from high activity of type 3 deiodinase in placental tissue and multiple fetal organs (230). Increased concentrations of sulfated metabolites of iodothyronines result from low type 1 deiodinase activity in fetal tissues and because T4 sulfate and T3 sulfate are not substrates for placental type 3 deiodinase (230). At birth, concentrations of TSH, T4, and T3 sharply spike to attain slightly elevated levels in the neonatal metabolism (29).

These patterns of thyroid hormones in the normal fetus closely resemble the constellation of NTIS. The conclusion that the normal fetal concentrations of thyroid hormones are beneficial despite being markedly different from that of both healthy adults and healthy newborns is supported by the observation that this constellation is actively defended in situations of thyroid disorders (233): in hypothyroid fetuses D2 activity increases and activities of D1 and D3 decrease, thus providing support for shunting of T4 to brain tissue (230), while, on the contrary, elevated concentrations of iodothyronines stimulate the activity of D3, which results in increased degradation of active thyroid hormones to rT3, 3,3′-T2 and 3′,5′-T2 (234–236).

The adaptive endocrine response in pregnancy manages a trade-off situation, where the maternal organism is faced with the dual challenge of optimizing conditions for the developing fetus and its own survival. Allostatic changes are mediated both by the central hypothalamic–pituitary unit and the fetal-placental unit. The latter secretes protein and steroid hormones that modify the function of endocrine organs in the mother’s organism throughout pregnancy (237). Due to its high structural similarity with TSH, the glycoprotein hormone hCG stimulates the human TSH receptor, which enables the placenta to gain parallel control over the thyroid system in early gestation (238). In extreme situations, e.g., starvation, the adaptive gestational responses control type 1 allostasis. Mostly, however, resources are sufficient to permit an anticipatory endocrine response of type 2 allostasis. Typical responses of the pituitary–thyroid axis in pregnancy include enhanced secretion of thyroxine from the thyroid gland and increased step-up deiodination. Unlike in obesity or other states of type 2 allostasis, TSH concentrations are low-normal or slightly decreased (230) (Figure 8B). This is a consequence of both elevated concentrations of T4 and hCG (stimulating TSH receptors in the anterior pituitary gland). In addition, plasma protein binding of thyroid hormones is increased. The majority of these effects are mediated by hCG, which displays, in addition to its gonadotropic action, mild TSH-mimicking effects in its sialylated form and TSH-antagonistic effects in a desialylated variant (239). Thyroid overstimulation by hCG is possible in pregnant women in the first trimester resulting in a distinct entity of gestational hyperthyroidism or hyperthyroidism in trophoblastic diseases, which may also affect men with testicular cancer (238, 240–247). This scenario exceeds physiological adaptation and translates into a specific disease entity. It demonstrates the strength of hCG-mediated effects, which confer a not so rare risk of subclinical hyperthyroidism in otherwise normal pregnancies (238).

The “anti-NTIS”-like pattern of maternal thyroid homeostasis in pregnancy results in increased availability of thyroid hormones for the developing fetus, which is especially necessary in the early phases of gestation, when the fetal thyroid is still unable to produce sufficient amounts of thyroid hormones, the more as the transport capacity through the placental barrier is limited.

Pregnancy-related allostatic changes in thyroid function are frequently causing problems in the differential diagnosis of thyroid disease as described below in the Section “Methods of Assessment and Differential Diagnosis.” Because a sufficient supply with levothyroxine is critical for the development of the fetus, thresholds for initiation of substitution in subclinical hypothyroidism and dosage adjustment in hypothyroid women taking L-T4 prior to pregnancy had been lowered by professional societies (248–251). Based on evidence the American Thyroid Association and the Endocrine Society had recommended to lower the upper range of the TSH reference range to 2.5, 3.0, and 3.5 mIU/L in the first, second, and third trimester of pregnancy, respectively. Although several observational studies reported adverse pregnancy outcome in even mild hypothyroidism (252–261), two recent interventional trials did not confirm a beneficial effect of substitution therapy in subclinical hypothyroidism and hypothyroxinemia with respect to children’s IQ at age of 5 years and secondary outcome markers (262, 263). Consequently, the recommended upper limit of the TSH reference range has been raised back to 4 mIU/L in the most recent guideline issued by the American Thyroid Association (264). However, thyroid peroxidase antibodies should be measured in pregnant women with TSH concentration above 2.5 mIU/L and treatment be considered, if antibody titers are positive, even if TSH levels are between 2.5 and 4 mIU/L (264).

The reason for these discrepancies and the lack of success by interventional studies is unknown. Ethnic differences among study populations (265) and the inverted U shape of the relation between maternal FT4 concentration and child IQ (266–268) as well as the relatively late onset of substitution therapy after the 10th week of gestation in the reported substitution trials (262, 263) may play a role. This uncertainty warrants further research.

Intensive muscle activity in sports and training is associated with profound changes in endocrine control (27) and cytokine patterns (269, 270). This suggests modifications of thyroid homeostasis during or after exercise.

The response of thyroid hormones to exercise varies (Figure 9). With a few exceptions (271–273), most studies investigating thyroid hormones during or in a short-time interval after training found elevated concentrations of TSH, T4 and/or T3 (46, 274–276). After resting or in prolonged training programs with repeated heavy strain, however, the majority of studies described reduced concentrations of TSH, T4, and T3 (186, 187, 277–281). This seeming contradiction was attributed to hemoconcentration in or after exercise leading to falsely elevated hormone concentrations in short-time exercise (27). This assumption is supported by trials, where thyroid hormones have been measured both on short and long timescales. Hormone concentrations, while elevated during physical strain or at exhaustion decreased at rest after exercise (46, 186, 275–277). Resting allows for rehydration and represents a more realistic situation. As a consequence it has been recommended to allow for a 24-h recovery period before participants report for laboratory testing (282).

Of note, TSH and thyroid hormone concentrations are elevated in endurance exercise and in the beginning of military combat training before exhaustion (186, 277, 283), even if allowance was made for resting and rehydration before investigation (283). With the onset of exhaustion, the pattern changes and hormone concentrations decrease to subnormal values (186, 187, 277). This suggests that the variable homeostatic response to exercise may possibly result from a second mechanism, where type 1 allostasis ensues from exhaustion and deprivation of energy, thereby leading to downregulation of TSH and peripheral thyroid hormones, whereas in endurance training and before exhaustion allostasis is shifted to type 2 and stimulated release of TSH, T4 and T3.

The NTIS-like pattern of thyroid hormones after exhausting training is confirmed by two studies showing increased rT3 concentrations (187, 283) in physical strain. The type 1 allostatic endocrine responses were more pronounced in military combat training programs, when participants were subject to additional deprivation of sleep and energy (186, 187, 277).

Characteristic patterns of NTIS have been described in a multitude of acute and chronic somatic illnesses including states of shock (284), circulatory arrest (285, 286), respiratory failure (65), community-acquired pneumonia (287), sepsis (288), chronic respiratory (289, 290) and cardiovascular (61, 64, 66, 291, 292) disease, renal failure (293–298), COPD (289), gastrointestinal diseases (299–301), autoimmune diseases (71, 302, 303), and cancer (130, 290, 304). Phenotypes of NTIS with high and high-normal FT4 concentrations have been described in dementia and frailty in elderly persons (305).

While most forms of acute critical illness may be interpreted as a state of starvation, the chronic form of severe illness—a result of modern critical care—represents most commonly a state of adequate nutrition (306). Hence it is not surprising that acute and chronic critical illness elicit different phases of NTIS: the acute phase (Figure 10A) and the chronic or prolonged phase (Figure 10B), also referred to as wasting syndrome (307). The former seems to beneficially affect outcome, the latter to have an impairing effect (308).

Non-thyroidal illness syndrome is a disease-independent risk factor for survival, so it is important to understand the underlying mechanisms (60). Patients with low free T3 show a significantly higher mortality and a significantly longer duration of mandatory ventilation (56, 309). Furthermore, low free T3 is a strong prognostic predictor in B-cell lymphomas (310). The alterations of the acute phase of NTIS in critical illness occur within hours or days and are defined by increased release of anterior pituitary hormones, low levels of anabolic peripheral effector hormones, reduced thyroid hormone-binding protein concentration, reduced binding affinity, reduced expression of thyroid hormone transporters, decreased thyroid hormone uptake and altered expression of D1 and D3 activity and the thyroid hormone receptor alpha1 (TRα1). The prolonged phase, on the other hand, is characterized by a suppression of the hypothalamic-anterior-pituitary-peripheral-hormone axis and low levels of anabolic peripheral effector hormones. Peripheral tissues respond by reactively increasing the expression of monocarboxylate transporters, upregulating D2 activity, reducing D1 activity, and increasing sensitivity to thyroid hormone receptors. The chronic phase is characterized by a loss of pulsatility of TSH secretion, a reduced TRH-gene expression in the hypothalamic PVN, and suppressed hypothalamic stimulation. However, the pathogenesis is unclear. Altered D3 activity and MAPK and hedgehog pathway seem to play a pivotal role in the whole process (311). Despite our current knowledge, critical questions remain unanswered.

The relationship between thyroid hormones and psychological phenomena is a paramount example of mutual and reciprocal influences of mind and body. It had been recognized for more than 150 years that diseases of the thyroid are frequently accompanied by psychiatric symptoms (312, 313). Although depression is a classical symptom of hypothyroidism, and psychosis may result from thyrotoxicosis, the linkage is clearly bidirectional (314). A great number of studies over the last decades showed that characteristic changes of thyroid hormone concentration may arise from mental or psychological disorders (28, 314) in the absence of thyroid disease. This assumption is confirmed by interventional studies that show normalization of formerly changed hormonal parameters after the underlying psychiatric disease has been successfully treated.

As early as in 1968 John Mason predicted thyroid hormone concentrations to rise in response to psychosocial stress (315). Subsequent research revealed that the interaction is complex and non-linear and that it is additionally dependent on the nature of the underlying psychiatric disease. A recent study demonstrated that stress could trigger the onset and the recurrence of hyperthyroidism in patients with Graves’ disease (316). However, hyperthyroxinemia is indeed a nearly universal observation in different expressions of psychiatric disorders (317–322).

A large body of studies reported a characteristic pattern of thyroid hormones in MD (314, 323). Concentrations of T4 or FT4 are commonly increased during depression (324–329) and revert after recovery from MD, irrespective of the modality of treatment (330–339). Despite the presence of elevated T4 concentrations TSH levels tend to be normal in depressive patients, but circadian variation of TSH concentration is impaired (339–342) and the response to TRH test is blunted (323). Both total and free T3 concentrations are reduced in MD (175, 176, 343), but elevated in bipolar I disorder (237, 344). Concomitantly, rT3 concentrations are temporarily increased in both MD and manic disorder; however, not in bipolar I disorder (334, 345, 346).

Similar to the situation in bipolar I disorder, concentrations of free and total T3 are frequently elevated in post-traumatic stress disorder (PTSD) (177–179, 181, 182, 347), another classical example of a type 2 allostatic reaction (112). Except for concomitant borderline personality disorder (348), the common high-T3 syndrome in PTSD is at least partly due to increased step-up deiodination (179, 181, 182). Two studies in combat veterans of World War II and the Vietnam war revealed levels of total T4 and both total and free T3 to significantly correlate to severity of PTSD (181, 349). This anti-NTIS-like pattern is complemented by elevated TBG concentrations and increased plasma protein binding in these patients compared to healthy controls (179). Despite an elevated set point of thyroid homeostasis the response to TRH stimulation is blunted in PTSD (350).

A small number of studies reported elevated concentrations of FT4, TT3, and FT3 in schizophrenia spectrum disorders. This observation was, however, not reproducible in all studies and apparently dependent on severity of symptoms and the time after admission (351, 352).

In summary, MD is accompanied by a partly NTIS-like pattern, whereas bipolar I disorder and PTSD as well as severe and newly diagnosed schizophrenia involve a hormone constellation typical of type 2 allostasis. A relatively high set point for T4 is shared by all four disorders, as evidenced by unsuppressed TSH levels despite high T4 concentrations, whereas the response to the TRH test is mitigated.

Although our knowledge of the precise mechanisms mediating the endocrine response in this class of affective disorders is still limited, recent research revealed some elements that may play a key role in this scenario. For a long time, it was assumed that central TRH, which has in addition to its endocrine function widespread neurotransmitter and neuromodulatory effects, has a pivotal function in the link between depression and altered thyroid hormones. While TRH concentrations in CSF are increased in depressed patients (353, 354) and TRH levels are particularly high in subjects with violent suicidal behavior (353), the results after treatment and in recovery are inconsistent (323). A decisive influence possibly lies in the spatial distribution of neuromodulators and the complex interaction of positive and negative feedback loops between the limbic system and hypothalamus (Figure 11). TRH expression is upregulated in the amygdala in response to stress (355) and amygdala kindling (356), but downregulated in hippocampus (357). Via two pathways, such as the stria terminalis and the ventral amygdalofugal pathway, the amygdala stimulates the PVN, the origin of hypophysiotropic TRH neurons, with cholinergic and glutamatergic terminals (358). As a consequence, TSH release increases in situations of stress-induced type 2 allostasis (359). Of note, amygdala activity is inhibited again by means of feedback loops mediating the anxiolytic-like effect of TRH (360). In addition, the activity of the feedforward path is sensitive to context and circadian conditions, too (361). This complexity warrants further research.

From a teleological perspective, the type 1 allostatic pattern in depression makes sense. Depression and starvation represent sickness behavior, a common final path of the sickness syndrome, which may be beneficial by promoting social immunity (362). In this model, depression is the mediator between inflammation and NTIS.

A large number of drugs is known to influence thyroid function interfering with various mechanisms of thyroid hormone metabolism (363). Lithium and aminoglutethimide decrease thyroid hormone secretion. A high iodine load, as it ensues from amiodarone and/or radiocontrast dye application, decreases both central and peripheral deiodinases activity (364–368). In addition to causing hypodeiodination, amiodarone has antagonistic actions on T3 signaling, presumably due to its molecular similarity to thyroid hormones (369, 370). Dopamine, glucocorticoids, and somatostatin analogs suppress TSH release (371). Thyroxine absorption is altered by multiple substances including caffeine, bile acid sequestrants, sucralfate, ferrous sulfate, and aluminum hydroxide (372). This results in disruption of the enterohepatic circulation of thyroid hormones, thus contributing to reduced half-life. Moreover, many drugs alter thyroxine and triiodothyronine transport in serum such as estrogens, tamoxifen, heroin, methadone, mitotane, androgens, anabolic steroids, furosemide, NSAIDs, and salicylates by either increasing or decreasing TBG concentration or displacing them from protein-binding sites (363, 373). Antiepileptic drugs such as phenobarbital, phenytoin, and carbamazepine increase hepatic metabolism of thyroxine and triiodothyronine. In addition to amiodarone propylthiouracil, macrolides, and unselective beta-adrenergic blockers inhibit the activity of type 1 deiodinase (374), while sorafenib is able to increase D3 activity (375).

Significant problems in FT4 and FT3 assay interpretation can arise in the varying performance of tests from different manufacturing sources (376, 377). For example many tests are affected by residual interference from effects of albumin concentrations that are often considerably reduced in NTIS and thereby lead to artificially low estimates of FT3 or FT4. In addition, some tests are insufficiently robust to the lower concentrations of thyroid hormone-binding proteins overall found in these conditions. Some drugs used in severe illness can also distort the results directly by displacing bound thyroid hormones. FT3 tests appear to suffer more in this regard than FT4 tests, though both can be compromised (377).

This can significantly affect conclusions as to the exact magnitude of allostatic effects on thyroid function and may hinder comparison of any findings from studies using different methods of measurement. The most convincing results will therefore be found using assays with minimal interference and closest adherence to the Mass Action criteria governing the working of such assays.

Multiple industrial substances in the environment are able to profoundly modify thyroid function (378–380). The mechanisms are as heterogeneous as the substances, and there is some overlap to drug effects (see above). This applies, e.g., to perchlorate, which inhibits iodine uptake into the thyroid and may therefore cause primary hypothyroidism (381, 382). Primary hypothyroidism may also result from exposure to polyhalogenated aromatic hydrocarbons (383) and bisphenol A (384). The effects of polychlorinated biphenyls (PCBs) include increased hepatic degradation of thyroid hormones and inhibition of deiodinase activity, which applies predominantly to cerebral D3 (385–387). Typical high-T3 syndromes under PCB exposure are therefore probably caused by decreased D3 activity rather than by stimulated D1 or D2 activity. Some plant-derived substances have thyromimetic effects and lead to decreased concentrations of TSH, FT4, and FT3 (388). In reality, endocrine disruptors are rarely present in isolated forms. Interactions among different disruptors are complex and may be additive, sub-additive, and super-additive, depending on the individual combination of substances and their respective concentrations (389–391). This makes the effects difficult to predict in the individual situation. Endocrine disruptors may result in clinical thyroid disease whose etiology is hard to pinpoint.

Space journeys expose the human organism to multiple challenges. They include low or zero gravity, radiation, and impaired circadian rhythm. It is, therefore, not surprising, that manned space exploration is associated with multiple hormonal changes (392). Among them, alterations of the HPT axis seem to play a minor, but potentially significant role. Crewmembers of the Spacelab D-2 mission had slightly increased TSH concentration during flight, suggesting a form of subclinical hypothyroidism (393). These results are compatible to observations in rats and rhesus monkeys (394–397). The most plausible reason for slightly impaired thyroid function during spaceflight is the utilization of iodinated water (398). Iodine was used as a bactericidal agent in US spacecraft water systems until 1997, when a device was implemented in Space Shuttles (and later the International Space Station) to remove iodine from water before consumption. As a result post-flight TSH elevations are no longer observed in astronauts (399). However, regardless of iodine removal, in male astronauts TT4 concentrations and FT4 index continue to be higher after space flight and T3 concentrations are decreased after flight. Due to unknown reasons this NTIS-like pattern is observed in men only, but not in women (399).