Homeostatic Control of the Thyroid–Pituitary Axis: Perspectives for Diagnosis and Treatment

Abstract

The long-held concept of a proportional negative feedback control between the thyroid and pituitary glands requires reconsideration in the light of more recent studies. Homeostatic equilibria depend on dynamic inter-relationships between thyroid hormones and pituitary thyrotropin (TSH). They display a high degree of individuality, thyroid-state-related hierarchy, and adaptive conditionality. Molecular mechanisms involve multiple feedback loops on several levels of organization, different time scales, and varying conditions of their optimum operation, including a proposed feedforward motif. This supports the concept of a dampened response and multistep regulation, making the interactions between TSH, FT4, and FT3 situational and mathematically more complex. As a homeostatically integrated parameter, TSH becomes neither normatively fixed nor a precise marker of euthyroidism. This is exemplified by the therapeutic situation with l-thyroxine (l-T4) where TSH levels defined for optimum health may not apply equivalently during treatment. In particular, an FT3–FT4 dissociation, discernible FT3–TSH disjoint, and conversion inefficiency have been recognized in l-T4-treated athyreotic patients. In addition to regulating T4 production, TSH appears to play an essential role in maintaining T3 homeostasis by directly controlling deiodinase activity. While still allowing for tissue-specific variation, this questions the currently assumed independence of the local T3 supply. Rather it integrates peripheral and central elements into an overarching control system. On l-T4 treatment, altered equilibria have been shown to give rise to lower circulating FT3 concentrations in the presence of normal serum TSH. While data on T3 in tissues are largely lacking in humans, rodent models suggest that the disequilibria may reflect widespread T3 deficiencies at the tissue level in various organs. As a consequence, the use of TSH, valuable though it is in many situations, should be scaled back to a supporting role that is more representative of its conditional interplay with peripheral thyroid hormones. This reopens the debate on the measurement of free thyroid hormones and encourages the identification of suitable biomarkers. Homeostatic principles conjoin all thyroid parameters into an adaptive context, demanding a more flexible interpretation in the accurate diagnosis and treatment of thyroid dysfunction.

Derivation of a multivariate reference range for pituitary thyrotropin and thyroid hormones: diagnostic efficiency compared with conventional single-reference method

“…This renders the adoption of population-based reference limits for individual decision making more difficult. Homeostatically derived individual set points independently of a population-based reference range have been proposed, but not clinically tested (19,20,21). We should note that the biochemical definition of subtle thyroid functional abnormalities does not invariably coincide with symptomatic disease and cannot decide by itself the necessity for treatment.…”

“…Thyroid hormones and pituitary TSH are interrelated, and their relationships are determined by homeostatic (19). Various feedback and feedforward motifs are jointly operative to produce the optimum levels in health and disease, and maintain T3 stability as long as it is physiologically possible (19,27).…”

“…Various feedback and feedforward motifs are jointly operative to produce the optimum levels in health and disease, and maintain T3 stability as long as it is physiologically possible (19,27). This has raised the question as to whether this level of control impacts on the efficiency of diagnostic procedures, which accordingly might be improved to better distinguish normal function from thyroid dysfunction.…”

“…Our studies have shown that individuals possess unique, closely controlled and limited set points for these parameters, which together collaborate to produce the optimum outcome for health (18,20,21). In thyroid insufficiency, this interlocking expression of control is significantly disturbed, leading to a new perspective of treatment modalities (19).…”

“…In previous communications, we have demonstrated that the controlled production of the three hormones TSH, FT4, and FT3 is an intricately entwined interactive process (18,19). This is based on homeostatic principles that employ various feedback and feedforward motifs.…”