Progress in fully understanding the HPT axis working and control and what happens when it goes wrong

[diogenes]

It's been over a year since we started this mammoth project, which is nothing less than a full explanation of how the hypothalamus, pituitary and thyroid together with body T4-T3 conversion, actually works. The hypothalamus input was hardest to discover. We're getting near a conclusion so I'll summarise:

Question 1. Which mechanisms at the hypothalamus preserve FT3 homeostasis ?

FT4 + FT3 feedback (system 1) yes

FT4 feedback alone (system 2) yes

FT3 feedback alone (system 3) no

Conclusion: To preserve FT3 homeostatss, FT4 feedback at the hypothalamus is required, FT3 feedback is optional, neither required nor harmful.

This is counterintuitive at first, that FT3 homeostasis requires FT4 (not FT3) feedback at the hypothalamus.

However, it makes sense, because if FT4 is changed, this change must be reported to the hypothalamus for correction (to preserve FT3).

This is achieved at level 1 (hypothalamus), in conjunction with 2 levels from level 3 (thyroid). Level 1 corrects level 2 (pituitary) setting. Sort of self-referencing. More than simple feedback.

Every action of the system is aimed at preserving FT3 levels

[jimh111]

Thanks. I assume there will be a (complex) study to follow. This is an incredibly important area as I see so many patients on the forum with a down-regulated axis that leads to quite severe hypothyroidism in spite of what appears to be quite minor falls in fT3 and fT4. The hypothalmus / pituitary (via TSH) has quite profound effects throughout the body.

PS If you can find a way to boost feed-forward or resotre a down-regulated axis I'd be most interested!

Although we struggle to understand some of your groups' papers it's vitally important work. It's all too easy to appreciate the simple studies and overlook the more difficult work that is perhaps more important. Thank-you.

[diogenes Remembering in reply to jimh111]

In health, feedforward of T3 from the thyroid , under TSH stimulation, will always be increased if body conversion can't suffice (either because T4 production has reduced or the body conversion isn't adequate.

[jimh111 in reply to diogenes]

... and feedforward of peripheral deiodinase under TSH stimulation, which keeps local T3 levels stable in tissues such as the brain and skeletal muscles. These tissues are more dependent upon local conversion of T4 to T3, they take less T3 from the blood.

I believe this why some patients with primary hypothyroidism can do quite well with low or marginal fT4 but patients with insufficient TSH become very hypo even though they have similar or slightly better fT4 levels. They lose out both on circulating T3 and on locally generated T3.

[Lalatoot]

Echo what Jimh says. Thanks diogenes

[pennyannie]

Can I please ask - I have had RAI thyroid ablation for Graves Disease.

I read that my feedback loop is broken and that is why it is essential to be dosed and monitored on T3 and T4 levels and not my TSH.

So, if one has " lost " their thyroid - through fair means or foul - the reliance on this HPT axis is null and void as the " T " in thyroid isn't there any more and the loop broken.

[diogenes Remembering in reply to pennyannie]

Absolutely correct. Losing the thyroid means that a key part of the whole system is lost. Substituting with oral T4 or T4/T3 or T3 alone cannot fully restore the status quo. This is because the thyroid when complete is incredibly sensitive to changes in FT3 and reacts instantaneously to re-equilibrate.

[pennyannie in reply to diogenes]

Thank you so much :

Maybe if this information were fed into the computer it might think more kindly on thyroid-less patients, invest a couple of pounds and run the appropriate T3 and T4 blood tests as standard and advise on a T3 / T4 ratio ?

[diogenes Remembering in reply to pennyannie]

Yes, but only in general terms. Extra fine tuning by trial and error is needed to get the best result (because you didn't know your values in health because they were never measured then). A health check on where you lie in the ranges for FT4 and FT3 when healthy would save a lot of searching to find the right answer in treatment.

[pennyannie in reply to diogenes]

Yes of course, nothing is cast in stone.

Fine tuning is, of course a necessity, but at least for those doctors with little thyroid knowledge they would have ball park numbers to work in and out from should they listen to the patient's feedback.

Of course, one has to ask the question, but if doctors in primary care can only prescribe T4 - what's the point and why waste the couple pounds doing the appropriate blood test and finding a problem that currently isn't acknowledged.

Thank you :

[Tythrop in reply to diogenes]

I'm thinking that in a perfect world NHS and resesrch world would spend more time/money on working out what is "healthy" than on jow to make money out of sick people.

[TSH110 in reply to diogenes]

Pity this is not done routinely, say where there is a strong familial tendency to thyroid disorders, for those family members with no sign of it. I wonder if this is done anywhere. It has happened with a close relative who has tests including ultrasound every year but I was only offered one thyroid function blood test I was told it was normal, which did surprise me because I thought I already had some symptoms, I think I was right too and the interpretation of that test was wrong. My mother’s endocrinologist said we should be all tested for thyroid abnormalities but why I got a perfunctory one off blood test and no scan, yet the relative has had such extensive long term testing, mystifies me. Ironically I became severely hypothyroid and the relative who is tested annually has not or at least not yet as all is not well with nodules and slightly elevated TSH plus quite a few symptoms, the two other remaining close relatives have developed thyroid problems I don’t know if they got better monitoring at all. 3 out of 4 is quite a high hit rate. Totally different health authorities must have completely different ideas of what constitutes monitoring for thyroid abnormalities. I understood it was a structural abnormality of the gland that was closely associated with a very rare form of thyroid cancer and one out of four of us got the same cancer too. I’d say a one off blood test was a poor monitoring tool to employ, as if the problem would just be lurking there and if it wasn’t then it would never occur in the future, and how on earth could a blood test determine a structural abnormality, surely a scan is the way to reveal that. I have never seen what was tested or what the test results were and my medical records from this time were lost. I also wonder if emulating results pre thyroid disorder, once thyroid hormone therapy was initiated would restore health or if it might still need fine tuning further as nothing seems to be truly static with thyroid function, it’s very dynamic. Perhaps the set point is set for life?

[LindaC in reply to TSH110]

exactly! Exactly!! EXACTLY!!! 🦋💚

[LindaC]

Thank you! Given the critical importance of thyroid hormones to pretty much the whole of our system, would full 'standard testing throughout key stages of life' help?

[DippyDame in reply to LindaC]

Totally agree!

[diogenes Remembering in reply to LindaC]

Yes, with the proviso that the FT3 measurement shouldn't be done if the patient has any other apparent illness.

[LindaC in reply to diogenes]

Thank you diogenes. Then their whole charabanc is certainly on shady grounds! By the time hypothyroidism is grudginly half-acknowledged, who can tell what patients have acquired on their way to...?

[TSH110 in reply to LindaC]

Very good point

[linda96]

Getting quite excited here about this latest project. Lots to ponder, including how it will be received. I have had pituitary apoplexy and have little thyroid gland left.. if any, and have had to fight my corner with Endo’s who are less than sympathetic to my situation. Thank you to the Team, Diogenes.

[helvella Administrator]

I'm looking forward to the Sesame Street (Childrens Television Workshop) series on thyroid issues.

The wheels on the HPT axis go round and round...

(Might need bit of work. )

[RedApple in reply to helvella]

😀😀😀

[pennyannie in reply to helvella]

Well, my " T " has fallen off the axis but I'll try and find it, stick it back on and catch you up later !!!

[jgelliss in reply to helvella]

Helvella love your Great sense of humour. Trust me we can well use it. After all laughter is the Best Medicine.

[tattybogle]

I'm trying to understand... but, because i'm weird, i need to translate it into 'plumbing' first....

So if you had a kid that had to live in a bath full of water, and the water temperature must be maintained precisely. (it's a very fussy kid )

And your bath plug constantly leaks a bit, and so you must keep hot and cold taps trickling all the time and adjust their flow.

FT3 = WATER TEMPERATURE , and despite loss of heat to the air, loss of water through the ill fitting plug, and random losses like the kid splashing water out if the bath. ... you have to maintain temperature by adjusting the flow of the Cold taps (T4) and Hot tap (T3) ....and pull the plug out occasionally (RT3)..... to keep the temperature the same without overflowing the bath.

So intuitively we'd think the way to automate the flow rate of the hot and cold taps would be 'a thermometer in the bath water' to tell the taps what to do .....

But you've now discovered that its not controlled by a thermometer in the bathwater, but instead our hypothalamus is acting more like a 'thermostatic bath mixer tap ' ? e.g , if someone downstairs flushes the loo and the cold tap loses pressure and flow slows down, then hypothalamus/pituitary/TSH very quickly adjusts hot tap to compensate.

Kinda thing ?

( .... and if some part of this goes wrong, we may get less than ideal results if we just get told to chuck a bucket of cold water in once a day instead..... and sometimes we end up with pissed off kid sitting in a cold bath and sometimes we end up overflowing the bath and ruining the ceiling. )

[diogenes Remembering in reply to tattybogle]

Quite a neat analogy!

[tattybogle in reply to diogenes]

I've had a long time to think it up . I live in a tall house with knackered plumbing, and random water pressure

And i sit in the bath a lot ........

[pennyannie in reply to tattybogle]

So, guessing not very pruney,

as it sounds like your Heating, Plumbing and Temperature controls - your other HPT axis - isn't working too well !!!

[fuchsia-pink in reply to tattybogle]

I've just had a nice long bath thinking about your analogy - which I very much like ... but I'm wondering if it isn't perhaps more like washing up (rather than a bath) - with a mixer tap (T4) which for lots of people produces the "right" amount of hot and cold, plus a boiling water tap (T3) which tops up a mixer set at too cold ...

Then TSH in all this is presumably the number of clean dinner plates you have (not refined to show how many you actually own or need...) x

[tattybogle in reply to fuchsia-pink]

I'll have to go and do the washing up while i think about that for a bit .....

[Jacs in reply to tattybogle]

😂

[TSH110 in reply to tattybogle]

Brilliant I like it much better than leaky buckets!