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Further explanation of papers findings

Yesterday I gave notice of a new publication that would be of interest to TUK readers insofar as it discusses the interacting roles of TSH, FT4 and FT3 in normal and T4-treated patients. I received the following from my colleague Rudolf Hoermann which I thought summarised the findings very nicely. Hope you also find it informative if you read the paper (deposited with Louise Warvill) as well. It begins:

A lot of people including authors of guidelines think that when they "throw in" a certain amount of replacement L-T4 that the body would take care of this itself via "peripheral autoregulation"

by getting the right amount of T3 out of it. However, this is not the case.

Unlike in the healthy subject where the FT3 concentration is indeed stable over wide variations in endogenous thyroid hormone production, in an athyreotic patient without a thyroid remnant, FT3 is unstable, varying with exogenous T4 supply. T3 adequacy is no longer guaranteed and "autoregulated" as in the heathy situation.

We believe that T3 stability in the healthy individual is controlled by TSH, which interlocks the central and peripheral regulatory pathways.

Yes, we postulate a novel regulatory pathway and role of TSH in T3 conversion, technically a feed-forward motif.

That way, TSH regulates production of T3 from T4 and it does this particularly in the thyroid gland itself.

Conversely, we observed regulatory and capacity deficiencies in athyreotic patients.

Two mistakes in popular thinking.

1) Exogenous T4 supply is the same as endogenous production. It is not.

2) T3 "autoregulation" still works on L-T4 replacement. It apparently doesn’t in the athyreotic patient, owing to impaired intrathyroidal conversion.

3) The thyroid gland is a production organ, but has no role in T3 homeostasis. It surely has.

The thyroid itself is both a T3 contributor and has a T3-balancing role.

That is why the situation changes so dramatically in the absence of a thyroid gland and the athyreotic patient is so vulnerable to T3 fluctuations and sensitive to dose inadequacies.

By the way, people "feel" their T3, not the TSH so to speak. Another piece of the unfolding story, see abstract to be published soon.

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Diogenes, this also happens to many of us that have a thyroid gland. The bodies control system gets out of balance and we have to override it with adequate supplementation to achieve any sense of normality. It is actually fairly common for many of us to suppress our TSH before any sense of 'being normal' is achieved. I look forward to getting a copy of your study Monday. PR

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Of course what applies to those without any thyroid also applies (at a lesser but still significant frequency) to some of those with residual gland activity. And as the amount of remaining gland activity rises, so the frequency of finding patients who cannot take T4 alone falls but won't reach zero until full healthy gland activity is reached.


Diogenes, that is a fascinating paper. I'm going to have to read it a few more times. I've read quite a few of Dr. Bianco's papers and never got a clear understanding of the control mechanism over the deiodinase. The same is true of Dr. Hollenbergs's work on the CoActivators and CoRepressors, what is the control system. The control systems have to be coordinated or they would just be fighting themselves. Do you think TSH may be the over-riding control factor for both the deiodinase and the CoActivators and CoRepressors?

I will have to go back and see what they say about cAMP. PR

PS Is it OK to send a copy to some doctors that I talk to?


It's likely that TSH has a coordinating body-wide mode of control that integrates all the factors involved in thyroid function. Regarding sending copies of the paper to others - OK so long as you ask them not to disseminate further. The German journal is very teutonically restrictive as regards their papers getting distributed without them getting money for them from scientists wanting to read. The journals screw their contributors as hard as they can, and like sheep we let them. BTW I think Rudolf Hoermann's precise above very useful.


Diogenes, I will wait until the abstract is published and send them that, just to be safe. We appreciate your sharing the studies with us, the expense can be prohibitive for many of us. PR


Diogenes could you please link to the abstract? I'd like to read it. Regards, Jaimie


Its with Louise Warvill at TUK. email: louise.warvill@thyroiduk.org.uk


Diogenes, the abstract is at PubMed. PR

Horm Metab Res. 2015 Mar 6. [Epub ahead of print]

Integration of Peripheral and Glandular Regulation of Triiodothyronine Production by Thyrotropin in Untreated and Thyroxine-Treated Subjects.

Hoermann R1, Midgley JE2, Larisch R1, Dietrich JW3.

Author information

1Department of Nuclear Medicine, Klinikum Luedenscheid, 58515 Luedenscheid, Germany.

2North Lakes Clinical, Ilkley, UK.

3Medical Department I, Endocrinology and Diabetology, Bergmannsheil University Hospitals, Ruhr University of Bochum, Bochum, Germany.


The objective of the study was to evaluate the roles of central and peripheral T3 regulation. In a prospective study involving 1 796 patients, the equilibria between FT3 and TSH were compared in untreated and L-T4-treated patients with varying functional states, residual thyroid secretory capacities and magnitudes of TSH stimulation. T3 concentrations were stable over wide variations in TSH levels (from 0.2 to 7 mU/l) and endogenous T4 production in untreated patients, but unbalanced in L-T4-treated athyreotic patients where T3 correlated with exogenous T4 supply. T3 stability was related to TSH-stimulated deiodinase activity by clinical observation, as predicted by theoretical modelling. Deiodinase activity in treated patients was reduced due to both diminished responsiveness to TSH and lack of thyroidal capacity. Deiodinase activity was increased in high thyroid volume, compared to lower volumes in euthyroid patients (<5 ml, p<0.001). While deiodinase differed between euthyroid and subclinically hypothyroid patients in high volume, 26.7 nmol/s (23.6, 29.2), n=214 vs. 28.9 nmol/s (26.7, 31.5), n=20, p=0.02, it was equivalent between the 2 functional groups in low volume, 23.3 nmol/s (21.3, 26.1), n=117 vs. 24.6 nmol/s (22.2, 27.5), n=38, p=0.22. These findings suggest that the thyroid gland and peripheral tissues are integrated in the physiological process of T3 homeostasis in humans via a feed-forward TSH motif, which coordinates peripheral and central regulatory mechanisms. Regulatory and capacity deficiencies collectively impair T3 homeostasis in L-T4-treated patients.

© Georg Thieme Verlag KG Stuttgart · New York.

PMID: 25750078 [PubMed - as supplied by publisher]


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