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Front Endocrinol (Lausanne). 2017 Dec 22;8:364. doi: 10.3389/fendo.2017.00364. eCollection 2017.

Recent Advances in Thyroid Hormone Regulation: Toward a New Paradigm for Optimal Diagnosis and Treatment.

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Department for Nuclear Medicine, Klinikum Lüdenscheid, Lüdenscheid, Germany.
North Lakes Clinical, Ilkley, United Kingdom.
Medical Department I, Endocrinology and Diabetology, Bergmannsheil University Hospitals, Ruhr University of Bochum, Bochum, Germany.
Ruhr Center for Rare Diseases (CeSER), Ruhr University of Bochum, Bochum, Germany.
Ruhr Center for Rare Diseases (CeSER), Witten/Herdecke University, Bochum, Germany.


In thyroid health, the pituitary hormone thyroid-stimulating hormone (TSH) raises glandular thyroid hormone production to a physiological level and enhances formation and conversion of T4 to the biologically more active T3. Overstimulation is limited by negative feedback control. In equilibrium defining the euthyroid state, the relationship between TSH and FT4 expresses clusters of genetically determined, interlocked TSH-FT4 pairs, which invalidates their statistical correlation within the euthyroid range. Appropriate reactions to internal or external challenges are defined by unique solutions and homeostatic equilibria. Permissible variations in an individual are much more closely constrained than over a population. Current diagnostic definitions of subclinical thyroid dysfunction are laboratory based, and do not concur with treatment recommendations. An appropriate TSH level is a homeostatic concept that cannot be reduced to a fixed range consideration. The control mode may shift from feedback to tracking where TSH becomes positively, rather than inversely related with FT4. This is obvious in pituitary disease and severe non-thyroid illness, but extends to other prevalent conditions including aging, obesity, and levothyroxine (LT4) treatment. Treatment targets must both be individualized and respect altered equilibria on LT4. To avoid amalgamation bias, clinically meaningful stratification is required in epidemiological studies. In conclusion, pituitary TSH cannot be readily interpreted as a sensitive mirror image of thyroid function because the negative TSH-FT4 correlation is frequently broken, even inverted, by common conditions. The interrelationships between TSH and thyroid hormones and the interlocking elements of the control system are individual, dynamic, and adaptive. This demands a paradigm shift of its diagnostic use.


levothyroxine treatment; setpoint; thyroid homeostasis; thyroid-stimulating hormone

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