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

Our advisers, Rudolf Hoermann, John E. M. Midgley, Rolf Larisch and Johannes W. Dietrich have just had another paper published in the journal, Frontiers in Endocrinology.

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.

Let's hope the medical fraternity sit up and listen!

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  • That's very exciting Lyn and thanks to all those hard-working gentlemen for not giving up.

  • Thank you - I think this translated means: "Guys, you're being way too simplistic and frankly unscientific in relying on the TSH measurement so much in thyroid diagnosis and treatment."

    Please can someone explain what a "feedforward motif" is?

    What they seem to say is how I feel - that my body adapted to low levels of thyroid hormones long ago, and slowed itself right down to compensate, instead of desperately trying to pump up the levels via TSH.

    I think I had antibodies even as a teenager, and I remember walking more slowly than my peers and having less energy even as a child, a situation which I coped with through my working life, but which really took off into retrospectively unmistakable thyroid symptoms after the birth of my second child. Yet my TSH then was 1.7.

  • 'feedforward motif'. fT3 and fT4 cause the pituitary to lower TSH - a feedback mechanism. There is growing evidence that TSH promotes conversion of T4 to T3 (type 1 and type 2 deiodinase), this is a feedforward mechanism. This would make sense as if the thyroid is struggling a little, increasing the rate of deiodinase would help. This is demonstrated when we see fT3 reduce as fT4 increases as a patient's levothyroxine is increased (provided fT4 is not too low). This team's earlier research suggests that because levothyroxine reduces TSH it can consequently lead to lower fT3 levels than normal. Hence, the picture is much more complicated than it is often assumed to be.

  • I found your post very interesting. I was wondering if you had any thoughts on glandular supplementation?

  • I doubt many in medical world even understand that let alone bother to read it unless we shove it under their noses or up their nose probably

    It certainly confirms everything i have said for ages

    TSH must never never be relied on to guage thyroid function and testing free t3 is absolutely vital

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