New paper that consolidates the notion of FT3 protection as the chief aim of the body's thyroid system

[diogenes]

This paper is mathematical again. It tries to tie in the body's need to protect its FT3 level against disturbing pressures. The discussion and conclusion are most approachable. In short FT3 measurement is strongly recommended because of it being less sensitive to FT4 changes

The role of supporting and disruptive mechanisms of FT3 homeostasis in regulating the hypothalamic–pituitarythyroid axis 

Rudolf Hoermann , Mark J. Pekker, John E. M. Midgley and Johannes W. Dietrich 

Abstract

Background: Thyroid hormones are controlled by the hypothalamic–pituitary–thyroid (HPT) axis through a complex network of regulatory loops, involving the hormones TRH, TSH, FT4, and FT3. The relationship between TSH and FT4 is widely used for diagnosing thyroid diseases. However, mechanisms of FT3 homeostasis are not well understood. 

Objective: We used mathematical modelling to further examine mechanisms that exist in the HPT axis regulation for protecting circulating FT3 levels. 

Methods: A mathematical model consisting of a system of four coupled first-order parameterized non-linear ordinary differential equations (ODEs) was developed, accounting for the interdependencies between the hormones in the HPT axis regulation. While TRH and TSH feed forward to the pituitary and thyroid, respectively, FT4 and FT3 feed backward to both the pituitary and hypothalamus. Stable equilibrium solutions of the ODE system express homeostasis for a particular variable, such as FT3, if this variable stays in a narrow range while certain other parameter(s) and system variable(s) may vary substantially. 

Results: The model predicts that (1) TSH-feedforward protects FT3 levels if the FT4 production rate declines and (2) combined negative feedback by FT4 and FT3 on both TSH and TRH production rates keeps FT3 levels insensitive to moderate changes in FT4 production rates and FT4 levels. The optimum FT4 and FT3 feedback and TRH and TSH-feedforward ranges that preserve FT3 homeostasis were found by numerical continuation analysis. Model predictions were in close agreement with clinical studies and individual patient examples of hypothyroidism and hyperthyroidism. 

Conclusions: These findings further extend the concept of HPT axis regulation beyond TSH and FT4 to integrate the more active sister hormone FT3 and mechanisms of FT3 homeostasis. Disruption of homeostatic mechanisms leads to disease. This provides a perspective for novel testable concepts in clinical studies to therapeutically target the disruptive mechanisms. 

Ther Adv Endocrinol Metab 2023, Vol. 14: 1–16 

doi.org/10.1177/20420188231...  

[Buddy195 Administrator]

Well you’ve certainly stretched my brain power today Diogenes. Even with a background in research, I found it challenging to process, so your summary is very helpful! Thankyou so much for all your hard work in this field and for sharing the research findings with us 🦋👍

[DippyDame]

I'm not a numbers person but the conclusion is hugely welcome!!

I do not understand the reluctance of medics to consider what science presents to them re T3.

Fear or fall from grace perhaps!!

Had I not learned about T3, RTH and cellular hypothyroidism I would most likely now be dead!

Hail T3!!

Congratulations all....and thank you for sharing diogenes

[Pearlteapot]

what is TSH feed forward? I couldn't see it explained in the article.

[diogenes Remembering in reply to Pearlteapot]

It's when, if the thyroid is failing and T4 supply is waning, then TSH rises. In doing so it stimulates what's left of the thyroid to keep on producing T3 as near as possible to that in health. That is feedforward - TSH stimulation but only to maintain T3 production even if T4 production is going down

[Tythrop in reply to diogenes]

Thinking about this article and trying to apply it to my situation which is downregulation of tsh ( basically the top of the tsh range is no longer available to me ) due to an earlier bad episode of hyperthyroid and several years of block and replace therapy .

So trying to apply this article to the context of my case where I have years of an unrecognised/ untreated HypOthyroid state ,I have blood readings like this:- April 2018 tsh 1.58 (official range 0.27-4.2)T4 11.4 ( 12-22) , T3 :4.09 (3.1-6.8) Followed by lots more low t4 readings leading to Dec 2022 : t4:8.6 (12-22) tsh:1.71 (0.27-4.2), t3 :3.2 (3.1-6.8) And most recently in Feb 2023 despite now on 50 mcg Levo my readings are t4: 11 ( 12-22) , tsh 1.910.27-4.2) , t3: 3.5 ( 3.1-6.8)

..So all this time I have an obvious insufficiency of t4 but oddly a sufficiency of t3 . My question to Diogenese is this: are these numbers an example of the t3 being protected in the way this article describes ? I have wondered why my t3 numbers have been in range when t4 obviously below range ,so ma6be this article explaines this phenomena .

PS: I now understand that the Hysteresis phenomena is why the tsh didn't go up high enough for Primary Care practitioners to recognise it as Hypo symptom .

[Pearlteapot]

Thanks. I was apparently healthy until shortly before diagnosis with a TSH of 71 so I guess my TSH was feeding forward very well. I shall now re-read with a better understanding.

[DippyDame in reply to Pearlteapot]

It's the body's way to keep the system functioning when otherwise a failing thyroid could only produce T4 levels too low for good health/ T4 to T3 conversion. I understand that although it maintains T3 level it doesn't relieve symptoms.

I'm not entirely sure how long the body can sustain feedforward before the thyroid fails....hopefully diogenes might come back and set me straight. My knowledge is only basic!!

[Pearlteapot in reply to DippyDame]

I think this section relates to your question

"The sum effect of circulating FT3 is reported back to the hypothalamus and pituitary to adjust FT4 production and systemic FT3 production via TSH-feedforward.1,16–22 This protects FT3 homeostasis, even in the presence of mild thyroid failure, unless the mechanism is disrupted, as in patients with insufficient remaining functional thyroid tissue or pituitary/hypothalamic insufficiency."

I understand it to mean that the TSH feedforward protects FT3 homeostasis but will be disrupted if you have insufficient remaining functional thyroid. I think it means that your system will find homeostasis until thyroid function is pretty far gone and that it would be better to measure thyroid function than high TSH because the high TSH is actually an indicator that the feed forward mechanism is engaged.

The feed forward mechanism is disrupted by introducing T4 medication, which also means that the tissue secretion of T3 is disrupted and suddenly your only source of T3 is from conversion of the exogenous T4. Which is why starting T4 can make you feel so dreadful. So much more sick than before starting medication. That was my experience,

I feel a bit depressed by this TBH (to be honest, not TSH!) because it suggests that my high TSH was not necessarily a key indicator that I needed medication. The functionality of my thyroid tissue should have been assessed (how? I don't know).

[DippyDame in reply to Pearlteapot]

Thank you....yes....understood.

I was hoping that an idea of time scale to thyroid failure might be possible.

It looks as if my younger (grown up) son is on this route to failed thyroid, I'm trying to persuade him that he needs to deal with this asap...and clock watching!

Your FT3 level (followed by FT4) is a more accurate indicator of the need for medication, TSH is not a reliable marker.

thyroidpatients.ca/2021/07/...

[Tythrop in reply to DippyDame]

Good luck with persuading offspring that you know what you're talking about , they are as bad as GPs in believing "we" are delusional .

[DippyDame in reply to Tythrop]

To be fair he did listen but initially is working on essential nutrients....needs a push to consult GP.

I think his knowledge of my experience is holding him back.....fearing similar medical ineptitude.

50mcg to 100mcg T4 over 2 months is too fast...at least 6 weeks between increases....apologies if I'm sticking my nose in here!

[Tythrop in reply to DippyDame]

No to nose ,thankyou all contributions welcome

[Tythrop in reply to Pearlteapot]

Did you feel bad at first on t4 supplementation but then start to feel better ? I'm feeling bad on early stages of titrating up on t4 only ( on 50mcg but expect to increase to 100 over a couple of months / on day 2 of 75mcg )

[Pearlteapot in reply to Tythrop]

Yes I felt bad. Very bad. Much, much worse than before diagnosis. I had super-brain fog which felt like my brain was melting, as if the synapses were unable to connect, not just fatigue. I had heart palpitations, which I had never had before and I cried a lot because I was brain dead and felt completely unable to function in the world. For me, it only started to become bearable when I got over 100mcg although 100mcg was not enough, at least I could function. I'm now on 125mcg plus 10 T3.

[Tythrop in reply to Pearlteapot]

This is interesting... ref brain fog,I referred to our new black rainwater butt as white thismorning when admiring my handiwork of installing ..how I did that I don't know - I felt exhausted after but needed to prove something to myself .

Also interesting that you had t3 with your 125 mcg t4

[Tythrop in reply to Tythrop]

Just trying to understand Diogenese full paper:- one thing I think I'm getting from it is that tsh plays a part in the production of t3 from t4 , i.e not all of the required t3 is made at cell level.I think I'm also getting that ,by getting t4 supplementation ,it has a cat h 22 effect ,because the supplements will reduce the tsh ( feedback effect) And the less tsh the less ability to co vert t4 to t3 .

So the only way we can feel.truely better is to have t4 ( for the thyroid gland illness AND t3 to compensate for the reduced tsh ( feedback( which is needed for some t4 to t3 convertion.........

........

. So that if you have autoimmune thyroid disease with not enough t4 production by the gland ,( or if the gland has been partly or totally removed surgically) the tsh goes up and by having more tsh you are having more "stuff" to convert the remaining( albeit reducing ) t4 into t3 .

So you have less t4 and more tsh and the latter maintains the t3 level by converting . (As an aside I'm guessing that with the tsh using up more of the t4 to convert into t3 there will be even less t4 in the system)

What I'm also wondering is that ,if in this situation ,we then get a nice doctor to prescribe some t4 ( but no t3 because its on the NHS Drop List) ,what we then get is an increase in t4 ( some from the damaged gland and some from the pills ) ; this increase in t4 is then identified by the feedback loop to the Hypothalamus and Pituatory which feedsforward the message ( by reducing tsh) to reduce t4 production by the gland , So when we first start taking t4 ,we will soon get more symptoms and feel worse because there is reduced production by gland AND because with reduction of tsh , we get less t3. .

We will only feel better if we get total amount of t4 required by the body from pills . But there is another problem namely that because there is virtually no tsh now, we will also need t3 from pills because tsh is needed for convertion of some of the t4 to t3, but we have no tsh . Some t3 is converted in cells at tissue level , but that's not enough , we need some conversion by tsh which we dont now have .

Forgive me for too many words.

[DippyDame in reply to Tythrop]

More "nose"!!

because tsh is needed for convertion of some of the t4 to t3,

TSH is not responsible for conversion. It is a "messenger"....it tells your thyroid how much thyroid hormone it needs to make. If the thyroid hormone levels in your blood are too low, your pituitary gland makes larger amounts of TSH to tell your thyroid to work harder.. Your TSH reading will be high reflecting low serum hormone level

what we then get is an increase in t4 ( some from the damaged gland and some from the pills )

When we take exogenous T4 that replaces our glandular T4 it doesn't add to it.

[tattybogle in reply to Tythrop]

when TSH goes up ( eg . in person with a struggling thyroid, not yet taking any thyroid hormone) it 'asks' the thyroid to make a greater proportion of 'ready made' T3 than it usually does. ( ready made as T3 by the thyroid .. not converted from T4)

So for the sake of argument, if your thyroid 'usually' made 80% T4 and 20% T3 when you were healthy .. then if your TSH went up to 10 due to your thyroid struggling to keep up enough T4 production ..then your thyroid would boost it's T3 production to make 40% T3 and 60% T4.

This is why you often see people with sub-clinical hypo with relatively good / highish l fT3 levels, compared to their relatively poor/ lowish fT4 levels.

Adding enough T4 to lower the TSH removes this T3 'boost'.

TSH also has a minor effect on the conversion of T4 to T3 around the rest of the body , but it's only a very minor effect

[diogenes Remembering in reply to DippyDame]

down to about 10% active thyroid remaining

[DippyDame in reply to diogenes]

Thank you diogenes

[Tythrop in reply to DippyDame]

Yeah DD ..I do not "get" why, with this protected t3 thingey ( inspite of low t4) We get the symptoms. Do you?