How the T4 and T3 bound on to thyroglobulin are released as free hormones

[diogenes]

A bit of pure chemistry for a change.

I've wanted for some time to discover how the products of thyroid T4- and T3-thyroglobulin are degraded by enzymes into the hormonal T4 and T3. This is because I wanted to get a handle on the probable degradation of these products in NDT(DTE). And thereby get an impression of how fast the T4 and T3 are released. In the intact thyroid, the thyroglobulin-T4 is degraded by gland-linked enzymes that can degrade the protein to a small breakdown product, with T4 still bound. That is, the release of T4 has to take place well after the enzyme has begun its work. Now let us consider the product NDT. This is given by mouth and doesn't come from the thyroid. So the usual methods of T4-globulin degradation will be slowed (there isn't now a close physical relation of globulin and specific enzyme.). So this leads me to believe that, because NDT is taken orally, the release of T4 in the stomach could well be delayed because the stomach enzymes degrading thyroglobulin are not the same. That is, T4 and T3 in NDT are more slowly taken into the circulation as their released form as opposed to native T4 and T3 in combination therapy using chemically produced molecules. Ironically therefore, NDT is quite as efficient in smoothing T4/3 uptake as specially adapted pure molecules.

0013-7227/96/

Endocrinology

The Combined Action of Two Thyroidal Proteases Releases T4 from the Dominant Site of Thyroglobulin*Hormone-Forming

Virginia School of Medicine and endocrinolgy

,ANN D. DUNN, HELEN E.MYERS, 

[Hidden]

Ironically therefore, NDT is quite as efficient in smoothing T4/3 uptake as specially adapted pure molecules.

Forgive my potential ignorance, but does this mean that NDT is taken into circulation as smoothly as T4 and T3 would be in someone euthyroid?

[diogenes Remembering in reply to Hidden]

Impossible to say if different protein-degrading enzymes are used, naturally if at the thyroid's gateway, orally and different by stomach/intestinal enzymes.

[amala57]

i have no thyroid gland & this would explain why I cannot tolerate synthetic t3 & t4. I get palpitations & feel such a rush with synthetic t3, it's very unpleasant. NDT is the only medication I can tolerate. Thank you for sharing this.

[StitchFairy in reply to amala57]

I'd like to understand why you think that not having a thyroid gland is the reason you can't tolerate synthetic T4 and T3? How is the absence of thyroid gland different to someone whose thyroid gland is shriveled and dead due to autoimmune disease?

[cjrsquared in reply to StitchFairy]

Possibly as those of us without a thyroid are completely reliant on hormone replacement as we have no underlying natural hormone. This means that absorption across the intestine is of greater significance than those who still have some endogenous hormone.

[StitchFairy in reply to cjrsquared]

But my thyroid doesn't produce any hormones either. It's been killed off by autoimmune disease. So I'm also completely reliant on thyroid meds to keep me alive, as are probably most people who have autoimmune hypothyroidism.

[cjrsquared in reply to StitchFairy]

I absolutely agree that in end stage hypothyroidism from autoimmune disease, the thyroid is completely destroyed. But many people when first diagnosed still have some hormone produced by their own thyroid. This varying amount makes balancing hormones very difficult. I completely accept that if your thyroid gland is completely atrophied then someone is in the same state as someone who has had their gland surgically removed. As someone in the latter category it has been difficult to balance t3 and t4 and trying to get ft3 and ft4 to equivalent pre surgical levels. Looking at this paper it is in an interesting explaination about absorption, nothing more.

[Hidden in reply to StitchFairy]

Sorry to butt in but I was told that even a very atrophied thyroid will emit at least very minuscule amounts of T4, and even smaller amounts of T3, but it will still be trying. Also, there is a wide variety of thyroiditis - I had a scan 9 years after diagnosis and my thyroid is basically in the same shape as it was 9 years ago - inflamed but not atrophied and likely to be at least partially working. My endo told me when I was diagnosed that 10 years down the line I’d have nothing but a gnarled walnut for a thyroid left in 10 years… well it’s 10 years later and I’m in exactly the same position anatomically as I was then! The assumption that all our thyroids are withering into nothingness seems to be a myth perpetuated by endos. I can see how someone like me, having hashi’s but having somewhat of a thyroid, would be different to no thyroid whatsoever. Anyway, so sorry to butt in but thought that might be food for thought x

[StitchFairy in reply to Hidden]

You're not butting in, the conversation is open to everyone 😊 There will no doubt be varying degrees of atrophy, depending on the stage the autoimmune disease is at. But even if, as you say, the most shriveled up atrophied thyroid actually does produce miniscule amounts of hormone, I still can't see how that makes us so vastly different from someone without a gland in terms of medication tolerance?

[Hidden in reply to StitchFairy]

yes I’m not sure how I understand that link to begin with tbh, but maybe having some background circulating hormone helps in some way? At least when attempting to start thyroid hormone therapy? I know Paul Robinson has a totally atrophied and shrivelled thyroid on t3 only still shows up some t4 on his bloods which is very intriguing! For that to happen even when tsh is so suppressed on t3 only… it’s almost quite endearing how much our bodies will try their best for us 🥹

[helvella in reply to Hidden]

There are people who had effectively NO thyroid hormone at diagnosis. And that was subsequently shown to be due to autoimmune processes.

I suggest that they are likely to have suffered many years, decades, of low and variable thyroid hormone levels. Which makes a big difference.

[Hidden in reply to helvella]

yes exactly - varying degrees of atrophy, but those atrophied tissues still making some hormone. What’s interesting is that atrophy doesn’t equate to symptomatology. My mother’s thyroid is in much worse shape than mine, we both have hashi’s but she is only affected by fatigue and lives happily on T4. I have huge range of symptoms and cannot live on T4 alone… the complexities just keep multiplying! 😅

[helvella in reply to Hidden]

With an undetectable FT4 and TSH in the stratosphere?

(For me, it is abundantly clear that my thyroid does make thyroid hormone. Not convinced in some other people.)

[Hidden in reply to helvella]

well Paul Robsonson is the example I am best aware of. His thyroid is totally atrophied, decades of suppressed tsh and t3 only treatment but he still makes some t4.

[Stourie in reply to Hidden]

when I was on t3 only my t4 reading was 2. 3 or there about. So still putting out some t4.

[TSH110 in reply to helvella]

Also I don’t think it just suddenly stops it takes a very long time to pack up. But when it does it’s pretty dramatic a long slow decline that gathers pace to about a month of really crazy symptoms with one last mega hyper swing and then a plunge into sudden and eternal hypo and if not addressed, death. Or that was my experience bar the death bit! If the thyroid cells only divide five times in a lifetime it’s in it for the long haul. Not sure how taking thyroid hormones as it fails would affect output, albeit reduced. Some here say it shuts it down completely but I get the impression it tops up T3 if it’s wanting from what I’ve read so perhaps it retains a dynamic quality? Does anyone actually know? Has it been studied? I am sure someone on here said they had had a TT and after 30 or 40 years she started making some thyroid hormones again. I don’t think the gland can regenerate but bits of tissue that were not fully excised can still keep functioning.

[waveylines in reply to TSH110]

Actually I don't think mine was a very slow decline. It was pretty fast covering a couple of years at best. Am not sure how relevant this is to the post tbh. At the end if the day once your on a high replacement dose whether your thyroid can produce anything is pretty irrevelant because it will be far from sufficient or you would need a much lower dose of thyroid meds. I also know that if I stop taking them after a few days I decline rapidly.....so pretty sure if there is an output from my thyroid gland its so miniscule it wouldn't keep me alive or help me.

[TSH110 in reply to Hidden]

Two of my close relatives had no thyroid (both primary NHL thyroid cancer one had chemotherapy the other total thyroidectomy) and felt tickety boo on Levothyroxine, one is still going strong after 30 years, I had atropic autoimmune thyroiditis but no cancer thank goodness, but I felt lousy on T4 only, NDT put me right. It’s complicated for sure.

[Hidden in reply to TSH110]

I wonder if autoimmunity makes us less likely to do well on T4 due to conversion being affected by inflammation? I also know someone who has partial thyroidectomy due to cancer and lives perfectly on T4.

[TSH110 in reply to Hidden]

I don’t know, it’s an interesting thought. I think those relatives may have had toxic nodules one had the biggest goitre imaginable, they had to initiate emergency chemo or they’d have suffocated it was that advanced but it shrunk by half with one dose of chemo and they survived - a blooming miracle, the other had loads of egg sized lumps throughout the thyroid which went right down into the chest cavity so they whipped it out fast, it was still functioning. Their problems may have been autoimmune in origin but I am not at all sure. Does cancer kick it all off or is the cancer a result of it all going wrong? I have the DIO2 poor converter combination but not the double allele for it, only one and a thyroid resistance gene but I don’t know if they have the same or not. Or if this is why I didn’t do well on Levothyroxine. Another close relative is hyperthyroid and another has nodules and there are ancestors with hypothyroidism, so it’s got some sort of genetic component to it. You’d think someone might like to study us, as it could be rather interesting but they prefer fit young men - as if they are going to be of any value in understanding thyroid disorder, it’s those that have it that need studying if you hope for any scientific revelations.

[JaneChapple in reply to TSH110]

You would think they would want to study people like you - its the same as how they work out thyroid ranges and use normal people with healthy thyroids. . We are not normal people and our ranges wont be like ours?

Janexxx😐😎❤

[Imaaan in reply to TSH110]

Can you pls share which ndt you're on?

[TSH110 in reply to Imaaan]

Thyroid S. I did try Naturethroid some years ago but it was changed and I’m not sure you can get it now, and Acella. I found ThyroidS was just as good if not better than the FDA approved NDTs . I have been taking NDT for about 8 years now and most of that time it has been ThyroidS.

Hope that helps

[Imaaan in reply to TSH110]

It sure does help and I thank you for your response. Have you ever considered trying metavive over thyroid s? I'm always curious to know why members try one over the other?

[TSH110 in reply to Imaaan]

I don’t really know what metavive is. I have no thyroid so can’t really experiment if the thyroid hormones are not quantified as they are in NDT . I know there was a bovine NDT but it was expensive and very hard to get hold of and seemed to be not as strong from reviews.

[Imaaan in reply to TSH110]

Its a glandular that is sold in the UK that some do well on. I can respect and understand your hesitancy to not want to experiment. I'm glad that you were able to find thyroid s work for you. I'm hesitant to order it because of its fillers and also I have tachycardia and I dont know how I would react. The smallest dose changes trigger symptoms for me. It took me over 9 months to get to 2 grains of Erfa.

Thank you for taking the time to respond and wish you an enjoyable Sunday

[TSH110 in reply to Imaaan]

I think it has got a few things added.

Listed here if you scroll down: stopthethyroidmadness.com/a...

It hasn’t been a problem for me, thank goodness.

I used this guide for dosing:

tpauk.com/main/article/trea...

Trouble is it used to be very affordable and easy to source but now it’s a lot of money to shell out if it doesn’t suit and much harder to find . You used to able to get 120 grains but that’s still a lot for a test in both volume and cost.

[Imaaan in reply to TSH110]

Awesome and kind of you to provide the links, thank you.I wish they had sample sizes since they charge so much.

[TSH110 in reply to Hidden]

my endo said mine was a crisp of a thing, funny that they choose food analogies isn’t it!

[radd in reply to TSH110]

TSH110,

Mine was likened to a shrivelled up dried pea!

[TSH110 in reply to radd]

We could get a meal out of our descriptors at this rate 🤣🤣🤣

Yours really was a serious atrophy if it was pea sized! I think you win on that score 😁👏🏽👏🏽👏🏽

[Imaaan in reply to radd]

Can you pls share which ndt you're on?

[radd in reply to Imaaan]

Armour with a bit of Levo added as found Armour too T3 potent.

[Imaaan in reply to radd]

Thanks for letting me know and wishing you a lovely Sunday

[diogenes Remembering in reply to Hidden]

In such a case, T3 production will be maintained as high as possible at the expense of T4 production.

[Hidden in reply to diogenes]

so does that mean then, at least comparing a snapshot moment side by side of someone with a minuscule shrivelled thyroid vs someone with a partially working thyroid that the person with the partially working thyroid may be more “hypo” than that person with nothing because their tsh will work harder (because it’s pushing harder against an unresponsive tissue) and therefore convert more t3? I sometimes think I’d be better off with no thyroid than one that’s partially damaged because my body seems to have not enough motivation to be pushed to convert for me, but then enough gland to produce some t4 for basic function?

[diogenes Remembering in reply to Hidden]

What happens as the thyroid dies is that increasing TSH stimulates gland T3 production at the expense of T4. This goes on further on more decay, with T3 production kept as high as possible at the expense of T4. This is TSH-stimulated. At the end, the thyroid remnant will be making nearly all as T3. Then when you get down to less than 10% thyroid left, the whole situation collapses, and oral T4 or T4/T3 or NDT has to take over which it does, but doesn't replicate what happens in health..

[Hidden in reply to diogenes]

I see. But why is it that some people’s TSH will be like 10 and they are minimal gland destruction while others will have a TSH of 5 but they’re basically totally atrophied? Is that an indicator of something broken between the pituitary feedback and the thyroid?

[diogenes Remembering in reply to Hidden]

I'd rather put it down to an individual's particular and unique response to thyroid decay.

[waveylines in reply to diogenes]

Fascinating as ever Diogenes. Thankyou. Have you written a book for us non medics yet or thought about it? You explain things so eloquently & also you have so much knowledge to share....that isn't in the books - well the ones I have at least.....in fairness they may be out of date.

[mauschen in reply to Hidden]

I am the same as you!

In 2011, I was diagnosed with primary hypothyroidism. Then in 2016 with Hashimoto thyroiditis. This autoimmune condition was punching holes in my thyroid gland. However, when the attack subsided, my hormones went back to normal and no further damage has been caused.

I am stable on T4 75 mcg and 10mcg T3

[TSH110 in reply to StitchFairy]

I don’t suppose the end result is any different - a complete inability to generate thyroid hormones ourselves, so synthetics might be a tad severe if they are not moderated to slow release.

Mine was death by shrivelling rather than extraction it’s a tiny crisp of a thing but it has no function.

[StitchFairy in reply to TSH110]

I agree. NDT is a much 'smoother' experience for me, if that makes any sense to anyone 😊

[TSH110 in reply to StitchFairy]

I find it completely smooth too, I get no turbulence/blips/low points on it whatsoever it feels about as normal as you can get without a working thyroid. It’s so good, I have to make sure I don't forget to take it some mornings. Even when I do very occasionally forget to take it, I still feel ok for the rest of the day without it. I try and do everything in exactly the same order after waking up to minimise the change of omitting to take it! I tried it at night but I often nod off and timing was a bit haphazard and it kept me awake so I had to give up on it and stick with mornings. I haven’t needed to split the dose since about 1-2 years in of taking it. I did have to initially, probably because I had been starved of t3 for so long it was too much in one go to begin with.

[Imaaan in reply to TSH110]

Im glad to hear that its possible to take 1 dose when you started out with split dosing.

[TSH110 in reply to Imaaan]

I think it was at the 1/2 grain I had to split it to 2x 1/4 ot I felt a bit weird I stuck to a split dose for about two years but found I could just take one dose by then, which was simpler.

[Imaaan in reply to TSH110]

I'm currently on 4 doses. I'll get to 1 or 2 doses, Godwillingly

[TSH110 in reply to Imaaan]

it may take a while but I hope you will after a time, if my experience is anything to go on ☘️🍀☘️

[waveylines in reply to StitchFairy]

Totally agree StitchFairy.

[diogenes Remembering in reply to StitchFairy]

Not saying that at all. Synthetic T4/3 is perfectly adequate, but T3 dosing this way leads to spikes temporarily in blood FT3. Perhaps T3 on NDT is released more slowly so you don't get as big a spike.

[Charlie-Farley]

Hi diogenes

Two hours in and sharing that knowledge is already making a difference- just brilliant 😊

[TSH110]

Very fascinating. But I found the actual text highly impenetrable, I’m afraid. I’m no chemistry boffin for sure!

As an aside, I still take my NDT sublingually, do you know if any of it actually gets into the blood stream via the bucal mucosa? It might not be quite as slow release that way if it does. It still seems to do the job I suppose it could well all end up in the stomach nevertheless. Only acella states sublingually as the way to take the NDT as far as I know. I have searched to find out if the molecules could get in that way. Some here say t3 is too big but I can’t find anything definitive on the matter.

[Litatamon in reply to TSH110]

I too would love to know. I feel completely different taking mine sublingually, versus complete swallowing.

[diogenes Remembering in reply to TSH110]

Probably the T3 tablet dissolves better in a neutral environment and thus gets absorbed. In the acid stomach it probably has to wait until the dose enters the more neutral small intestine before absorption. It could just be a matter of timing delay.

[TSH110 in reply to diogenes]

Thanks for your explanation, it’s very helpful

[waveylines in reply to diogenes]

If that's the case why do we only have to wait an hour after taking it orally not sublingual? Wouldn't it be 3 hrs re stomach emptying or is that a myth?

[tattybogle in reply to waveylines]

waveylines TSH110 Litatamon re. sublingual .

I went looking for evidence for/ against 'sublingual' and found this : endocrine-abstracts.org/ea/... "Study of the efficacy of sublingual route administration of levothyroxine Na nablets vs oral route in cases with refractory primary hypothyroidism" .

it's about levo , not T3 ... and compares sublingual absorption with intestinal absorption for patients with known intestinal absorption problems (their TSH not going down despite large doses)

Sublingual was more effective than oral in people with that problem ...... they made no comparison with people who don't have intestinal absorption problems though .

~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~

A collection of my references about absorption : healthunlocked.com/thyroidu.... where-and-how-is-levo-absorbed-....-a-collection-of-information.

[helvella]

Since Tirosint became available (not in the UK, sadly), there has been a stream of people saying how they couldn't take it.

Given improved absorption is a major selling point (and relative lack of interference by other substances), I have wondered if the suddenness has been a reason for this intolerance?

One obvious approach that might help would be dose splitting. But given that all dosages of Tirosint are the same (very) high price, that is probably out of reach of virtually all of us.

[adin in reply to helvella]

I don't understand how in the Hungary (for exmpl) the tirosint (syntroxine) is aprox. 7 EUR (for 30 caps) but in usa is 120 USD.

[helvella in reply to adin]

Lack of competition and drugs markets that operate very differently.

Though it is, I agree, madness.

[BB001]

pubmed.ncbi.nlm.nih.gov/875... abstract only

Abstract is available here, and full text available as a pdf

academic.oup.com/endo/artic...