Thyroid Homeostasis

Thyroid hormones (TH) are essential for a wide array of physiological processes, including growth, development, differentiation, and metabolism. The body’s ability to maintain flexible homeostatic equilibria of TH in response to environmental challenges is a key indicator of a healthy state. While traditional understanding focused on a proportional negative feedback control between the thyroid and pituitary glands, recent research indicates a more complex and dynamic system. This updated view highlights that homeostatic equilibria are governed by intricate inter-relationships between thyroid hormones and pituitary thyrotropin (TSH), displaying significant individuality, a hierarchical structure based on thyroid state, and adaptive conditionality.

Homeostatic Control of the Thyroid-Pituitary Axis A basic understanding of thyroid control, mediated by pituitary TSH, has been extensively utilised in the diagnosis of thyroid disorders. As a result, TSH measurement, despite being an indirect marker of thyroid homeostasis, has become a central component of modern thyroid function testing.

The concept of a feedback control loop between the thyroid and the pituitary was first proposed in 1940 and experimentally confirmed by 1950. Early models posited an inverse linear correlation between TSH and T4, which was later revised to a log-linear relationship and adopted as the standard model. However, current knowledge suggests this simplistic log-linear concept requires reconsideration due to the inherent complexity of the underlying system.

More detailed analyses reveal that the TSH-FT4 relationship is curvilinear and exhibits a damped response in the middle portion of the euthyroid range, with steeper gradients observed at the hypothyroid or hyperthyroid extremes. This non-linear characteristic facilitates a dampened response, which is more effective at maintaining the controlled parameter at a stable level with minimal fluctuation. This adaptable response is thought to originate from the integrated action of multiple feedback loops operating at various levels of biological organisation.

The integrated control system of thyroid homeostasis incorporates several major feedback loops:

• Negative Feedback Control: Thyroid hormones exert a repressive action on pituitary TSH and hypothalamic TRH.

• Positive Stimulatory Control: TRH actively stimulates TSH secretion.

• Ultrashort Feedback: TSH is involved in a feedback loop that suppresses its own secretion.

• Feedforward Control: TSH directly influences deiodinase activity, thereby regulating the conversion of T4 to T3.

Molecular Mechanisms Involved in Feedback Control The complexity and non-proportional nature of thyroid homeostasis are underpinned by various molecular mechanisms:

• Thyroid Hormone Receptors (TRs): Both T3 and T4 (after its conversion to T3) bind to specific intracellular TR receptors, leading to the repression of several genes, including TSHβ and, to a lesser extent, α-subunit. The TRβ2 isoform, found in the central nervous system, hypothalamus, and pituitary, exhibits up to a 10-fold enhanced sensitivity to thyroid hormones compared to TRβ1, which allows central tissues to anticipate T3/T4 oversupply before it affects less sensitive peripheral tissues.

• Deiodinases: These enzymes are crucial for regulating T3 conversion and provide a sophisticated mechanism for sensitive responses to changes in FT4 within the feedback loop. Specifically, type 2 deiodinase (D2) ubiquitination is critical for hypothalamic negative feedback regulation and is expressed non-uniformly across different tissues. D2 facilitates the conversion of the pro-hormone thyroxine (T4) into its active metabolite, T3, particularly in glial cells and tanycytes in the hypothalamus, while type 3 deiodinase (D3) inactivates both T4 and T3. This local enzymatic activity can result in tissue-specific states of hypothyroidism or thyrotoxicosis, even when systemic euthyroidism is maintained.

• Thyroid Hormone Transporters: T3 and T4 do not freely diffuse across cell membranes but are actively transported by specialised proteins such as MCT8, MCT10, and OATP1C1. Intracellular trafficking also involves internal binding substrates (IBS) of thyroid hormones. These transporters are essential components of the feedback control system.

• TRH and TSH: Thyrotropin-releasing hormone (TRH) functions as a potent defensive mechanism against thyroid hormone undersupply, stimulating pituitary TSH secretion and modulating its bioactivity. TSH stimulation of thyroid hormone production is vital, as the basal capacity of the thyroid gland is limited without it. Tissue-specific glycosylation of TSH also contributes to targeted signalling. Long feedback control of TRH release by TH involves both hypophysiotropic TRH neurons and tancytes, which can adjust the set point and integrate energy metabolism and thyroid function.

• Pulsatility of TSH Secretion: TSH is secreted in a pulsatile manner, with rapid oscillations superimposed on a circadian rhythm that typically peaks shortly after midnight. This pulsatile release may be advantageous by preventing homologous desensitisation of the thyrotropin receptor. Furthermore, a direct link between TSH and deiodinase activity may partly explain the circadian rhythm observed in T3 levels that parallels TSH.

• Non-Classical Thyroid Hormones: Emerging research suggests an active physiological role for less recognised non-classical thyroid hormones, including reverse triiodothyronine (rT3), 3,5-diiodothyronine (T2), iodothyroacetates, and thyronamines. Some of these molecules, such as 3,5-T2, TRIAC, and TETRAC, exert thyromimetic effects at TR-β receptors, leading to TSH-suppressive actions, which implies their role as important modulators of the overall control system.

• Other Modulating Influences: A multitude of physiological and pathophysiological factors, including age, body mass index (BMI), genetic polymorphisms, and conditions like non-thyroidal illness (NTI) syndrome, modulate the relationship between TSH and thyroid hormones and influence the position of the set point in both health and disease.

Consequences for Thyroid Function Testing and Treatment The traditional paradigm of TSH as the sole and primary diagnostic parameter for thyroid function is increasingly being challenged.

• Limitations of TSH Measurement: TSH is fundamentally an indirect measure of thyroid hormone homeostasis and a controlling element, not a simple, isolated statistical parameter. Its interpretation is complicated by its non-proportional (non-log-linear) and conditional relationship with thyroid hormones, as well as its high degree of individuality. Consequently, the same TSH value can be considered “normal” for one individual but “pathological” for another.

• Controversy over Reference Ranges: There is ongoing debate regarding the appropriate reference limits for TSH, particularly its upper limit used to define subclinical hypothyroidism. Conventional methods for establishing these ranges may be insufficient, leading to exploration of more personalised and multivariate approaches for TSH referencing. Furthermore, circadian and ultradian rhythms of TSH levels can reduce diagnostic accuracy unless reference intervals are adjusted or blood sampling is restricted to specific times, such as morning.

• Subclinical Thyroid Dysfunction: Current definitions of subclinical hypothyroidism and hyperthyroidism, which are based on abnormal TSH levels while FT3 and FT4 remain within their reference ranges, may not consistently and accurately classify disease states. Patients diagnosed with subclinical hypothyroidism, for instance, are identified as a heterogeneous population comprising both truly dysfunctional and truly euthyroid subjects.

• Challenges in L-T4 Treatment: The assumption that a patient’s own pituitary gland is a reliable determinant for establishing the correct dosage of L-T4 treatment has been challenged. In athyreotic patients receiving L-T4, the intricate inter-relationships between FT3, FT4, and TSH are not rigidly fixed but are instead conditionally and homeostatically determined. Three significant phenomena have been observed in L-T4-treated patients:

    1. A dissociation between FT3 and FT4 concentrations.

    2. A discernible disjoint between TSH and FT3 levels. Approximately 15% of athyreotic patients may experience a chronically low-T3 state, even if their TSH levels are normalised.

    3. An L-T4-related conversion inefficiency. This means that increasing the L-T4 dose may not always resolve T3 deficiency and could, in fact, impede its attainment. Rodent models further suggest that these disequilibria may indicate widespread tissue hypothyroidism in various organs, despite normal TSH levels.

• Re-evaluating TSH’s Role: The sources propose that the use of TSH, while valuable in certain situations, should be relegated to a supporting role that more accurately reflects its conditional interaction with peripheral thyroid hormones. It is underscored that the measurement and consideration of FT3 and conversion efficiency are equally important, especially in scenarios where TSH and FT3 levels diverge.

• Need for Standardisation and New Biomarkers: The discussion around measuring free thyroid hormones is re-opened, and the identification of suitable biomarkers is encouraged. While TSH assays are traceable to a single WHO standard, methods for FT4 and particularly FT3 urgently require equivalent standardisation and harmonisation to play a clinically acceptable role within an integrated diagnostic concept.

Summary and Future Outlook The concept of thyroid homeostasis offers fresh perspectives for optimising the interpretation of thyroid function tests and mitigating the inappropriate diagnostic reliance on an isolated statistical interpretation of TSH. TSH is not considered a precise marker of euthyroidism nor is it optimal for fine-tuning thyroid control, and TSH levels defined for optimum health may not be applicable to many L-T4-treated patients. The observed disjoint between FT3 and TSH concentrations in athyreotic patients indicates that T4 monotherapy may be insufficient to adequately meet their therapeutic needs, as FT3 levels become unstably dependent on exogenous T4 supply.

Homeostatic principles advocate for a more personalised approach to diagnosis and a consideration of thyroid function within a more conditional, adaptive context, thereby challenging the isolated interpretation and disease-defining value of TSH measurements. Future research should prioritise exploring multivariate reference limits, personalised set point reconstructions, and the additional clinical value of FT3 in defining thyroid status and assessing the adequacy of thyroid hormone replacement therapy. Furthermore, the potential adverse effects and long-term risks associated with the unphysiological FT3-FT4 ratio, FT3-TSH disjoint, and impaired deiodinase activity seen with current L-T4 replacement warrant careful investigation. This supports the potential role of combined T3 and T4 treatment for selected patients who exhibit poor conversion efficiency. It remains general good clinical practice to interpret laboratory test results in conjunction with a comprehensive clinical assessment of the patient’s history and symptoms.

Hypothyroid treatment

The sources indicate that while T3 is crucial for physiological processes, it is not as widely considered in hypothyroid treatment as TSH for several reasons, primarily stemming from historical diagnostic practices and the perceived limitations in its measurement and interpretation:

• Historical Reliance on TSH: The discovery that pituitary Thyrotropin (TSH) responds inversely and with exaggerated sensitivity to underlying thyroid hormone concentrations greatly influenced clinical thyroid testing. This led to TSH becoming the central and dominant parameter in contemporary thyroid function testing, largely due to its ease of measurement and cost-effectiveness. The clinical community embraced TSH as a simple and efficient diagnostic tool, which inadvertently obscured the complex relationship between TSH and the hormonal milieu. It was widely assumed that the patient’s own pituitary gland would reliably determine the adequate dosage of L-T4 treatment, making TSH a sufficient target for therapy.

• Complexity and Individuality of Homeostasis: The long-held, simpler concept of a log-linear relationship between TSH and Free T4 (FT4) has been challenged by more recent studies. Research now shows the TSH-FT4 relationship is curvilinear and damped in the middle portion of the euthyroid range, with steeper gradients at the extremes, allowing for a more flexible and robust defense of the thyroid state. TSH is understood to be an indirect measure and a controlling element, not a simple isolated statistical parameter. TSH values are highly individual; the same TSH value might be considered “normal” for one person but “pathological” for another. This individuality and the complex, conditional nature of thyroid homeostasis complicate relying solely on TSH as a precise marker of euthyroidism or for fine-tuning treatment.

• Limitations in L-T4 Monotherapy and T3 Stability: In patients treated with L-Thyroxine (L-T4) monotherapy, the intricate inter-relationships between Free Triiodothyronine (FT3), FT4, and TSH are often not fixed as in healthy individuals but are conditionally determined. The sources highlight several issues in L-T4-treated patients:

    ◦ A dissociation between FT3 and FT4 concentrations.

    ◦ A discernible disjoint between TSH and FT3 levels. Approximately 15% of athyreotic patients (those without a thyroid gland) receiving L-T4 may experience a chronically low-T3 state, even if their TSH levels are normalised.

    ◦ An L-T4-related conversion inefficiency, meaning that increasing the L-T4 dose may not resolve T3 deficiency and could even hinder its attainment.

    ◦ Rodent models suggest that these observed disequilibria may indicate widespread tissue hypothyroidism in various organs (e.g., brain, liver, skeletal muscle) despite normal TSH levels.

    ◦ L-T4 treatment, which lacks the approximately 10% naturally secreted T3 component, is described as an “unphysiological treatment modality,” where homeostatic responses differ from normality.

    ◦ The quality of life for a substantial portion of hypothyroid patients on levothyroxine may be reduced, even with normal TSH levels.

• Lack of Standardization for FT3 Measurement: While TSH assays are traceable to a single WHO standard, methods for FT4 and especially FT3 urgently require equivalent standardisation and harmonisation to be clinically acceptable in an integrated diagnostic concept. This lack of standardisation significantly limits the widespread clinical utility and reliability of FT3 measurements compared to TSH.

• Limited Human Data on Tissue T3: There is a general lack of corresponding data on tissue T3 levels in humans, which hinders a full understanding of T3 adequacy at the cellular level despite circulating hormone levels.

In light of these findings, the sources advocate for TSH to be scaled back to a supporting role, emphasizing that the measurement and consideration of FT3 and conversion efficiency are equally important, especially when TSH and FT3 levels diverge. This approach pushes for a more personalised and adaptive context for diagnosing and treating thyroid dysfunction, moving away from an isolated interpretation of TSH measurements.

References:

• Hoermann, R., Midgley, J.E.M., Larisch, R. and Dietrich, J.W. (2015) ‘Homeostatic Control of the Thyroid–Pituitary Axis: Perspectives for Diagnosis and Treatment’, Frontiers in Endocrinology, 6, p.177. doi: 10.3389/fendo.2015.00177.

    ◦ This primary source was instrumental in detailing the complexities of the thyroid-pituitary axis, the limitations of TSH as a sole diagnostic marker, and the issues arising from L-T4 monotherapy, particularly concerning T3 stability and conversion efficiency.

• McAninch, E.A. and Bianco, A.C. (2014) ‘Thyroid hormone signaling in energy homeostasis and energy metabolism’, Annals of the New York Academy of Sciences, 1311, pp. 77–87. doi: 10.1111/nyas.12374.

    ◦ This source provided supporting context on the physiological roles of thyroid hormones, particularly T3, in energy homeostasis, cellular metabolism, and the activity of deiodinases at the tissue level, reinforcing the idea that T3’s actions are highly regulated at the cellular and organismal levels.