It's here at last: a comparison of T4, T4-T3 combination therapy and DTE (NDT) - fuel for using against sceptical doctors/endos

[diogenes]

This is the abstract and conclusion from a brand new paper - not yet published in J Clin Endocrinol Metab. from the Bianco lab. Pls look at it and draw your own conclusions.

COMPARATIVE EFFECTIVENESS OF LEVOTHYROXINE, DESICCATED THYROID EXTRACT, AND LEVOTHYROXINE+LIOTHYRONINE IN HYPOTHYROIDISM

Mohamed K. M. Shakir 1,2 , Daniel I. Brooks 1 , Elizabeth A. McAninch 3 , Tatiana De Lourdes Fonseca 3 , Vinh Q. Mai 1,2 , Antonio C. Bianco 4 , Thanh D. Hoang 1,2

1 Walter Reed National Military Medical Center, Bethesda MD 2 Uniformed Services University of the Health Sciences, Bethesda MD 3 Divsion of Endocrinology and Metabolism, Rush University Medical Center, Chicago IL 4 Section of Adult and Pediatric Endocrinology, University of Chicago, Chicago IL

Clinical trial number: NCT02317926.

Department of Endocrinology, Walter Reed National Military Medical Center, 8901 Wisconsin Ave. Bethesda, MD 20889-5600.

Email: [e-mail]

© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society.

Downloaded from academic.oup.com/jcem/advan... by guest on 01 July 2021 2

Abstract

Introduction: Studies comparing LT4 therapy with LT4+LT3 or desiccated thyroid extract (DTE) did not detect consistent superiority of either treatment. Here we investigated these therapies, focusing on the whole group of LT4-treated hypothyroid patients, while also exploring the most symptomatic patients.

Methodology: Prospective, randomized, double-blind, crossover study of 75 hypothyroid patients randomly allocated to one of three treatment arms, LT4, LT4+LT3 and DTE, for 22 weeks. The primary outcomes were post-treatment scores on the 36-point thyroid symptom questionnaire (TSQ-36), 12-point quality of life general health questionnaire (GHQ-12), the Wechsler memory scale-Version IV (VMS-IV), and the Beck Depression Inventory (BDI). Secondary endpoints included treatment preference, biochemical and metabolic parameters, etiology of hypothyroidism, and Thr92Ala-DIO2 gene polymorphism. Analyses were performed with a linear mixed model using subject as a random factor and group as a fixed effect.

Results: Serum TSH remained within reference range across all treatment arms. There were no differences for primary and secondary outcomes, except for a minor increase in heart rate caused by DTE. Treatment preference was not different and there were no interferences of the etiology of hypothyroidism or Thr92Ala-DIO2 gene polymorphism in the outcomes. Subgroup analyses of the 1/3 most symptomatic patients on LT4 revealed strong preference for treatment containing T3, which improved performance on TSQ-36, GHQ-12, BDI and visual memory index (VMS-IV component).

Conclusions: As a group, outcomes were similar among hypothyroid patients taking DTE vs. LT4+T3 vs. LT4. However, those patients that were most symptomatic on LT4 preferred and responded positively to therapy with LT4+LT3 or DTE.

[helvella Administrator]

At last.

[JGBH]

Thank you. At last BUT will endocrinologists finally use this research study now and accept T3 is important in combination with T4 for hypothyroid patients?

[diogenes Remembering in reply to JGBH]

It at least shakes the foundations of present thinking and blunts the parrot cry of "insufficient evidence" which holds the field back. It's politically good that the work comes from a prime source, as it is harder to disbelieve it. I wouldn't worry yet about the business of keeping TSH in the reference range. At the moment as I wrote before, the authors are trying to hang the new findings on the old TSH hatpeg. It'll take longer to get them off it and on to a sounder footing.

[JGBH in reply to diogenes]

Of course it is a big step forward in shaking their misconceptions and entrenched (mis)beliefs. Let’s hope we can see a change in attitude from the endocrinologists and GPs. Fingers crossed!

[TSH110]

Great! Thanks for posting

[Hoxo]

I suppose this study will also explain why previous ones found no benefit to T3 containing medicines ie these studies did not look specifically at the most symptomatic subgroup like this study did?

[diogenes Remembering in reply to Hoxo]

Exactly- and we were the first to show the reason why lumping everyone together blinds one to the minority who respond differently.

[tattybogle in reply to diogenes]

on the off chance that they neglected to give you any credit for this .. i will say it...

" Many Thanks to You, and your Motley Crew "

*edit * just checked.. yes they seem to have gone to great lengths to pretend you don't exist, as usual. Still , he who laugh's last, laugh's longest .. and that lot will have to live with their names all over papers advocating the great God of Infallable TSH, long after it's fallen off it's pedestal.

[shaws Administrator in reply to tattybogle]

We're all waiting until we can celebrate a 'change of attitude' towards how patients are diagnosed/treated who have dysfunctional thyroid glands.

One of my doctors told me that T3 converts to T4! in a conversation to me to state TSH was too low and was T4 too low. I said "I don't take T4 but T3". He stated that T3 converts to T4 !

[tattybogle]

hooray ! double blinded, for 22 weeks each, so i don't see how anyone can argue with "improvements in all 4 primary outcomes AND a 'strong' preference .."

for the '1/3 most symptomatic'

curious how they managed to keep TSH within range when using anything with T3 in , and therefore you have to wonder how many of the other 2/3 would have seen improvements if they had allowed TSH to go below range .... They don't mention any fT4 /fT3 levels .. does this mean they didn't look ?

[Hoxo in reply to tattybogle]

Yes exactly what I thought when I read it.

[shaws Administrator in reply to tattybogle]

For me, TSH is meaningless when the 'supposed to be experts' know very little about how a dysfunctional thyroid gland affects those who're diagnosed as hypothyroid. Nor do they seem to be aware of how best to put these patients on the road to recovery.

'modern' Doctors have lost the skill that those who were trained when NDT (natural dessicated thyroid hormones) was the only replacement available from 1892 onwards and who diagnosed us by our clinical symptoms alone.

We were then given a trial of NDT- natural dessicated thyroid hormones from animals' thyroid glands. It saved lives from 1892 onwards but it appears that because Big Pharma wanted to have a share of profits, introduced levothyroxine (T4) which was supposed to convert to T3.

Worst of all was when NDT and T3 were removed from being prescribed causing even more distress amongst patients. The removal of T3 because it had become 'expensive' even though it could have been sourced more cheaply from other countries.

T3 is the active thyroid hormone needed in all of our T3 receptor cells and brain and heart have the most and it relieves clinical symptoms.

Many of us have found relief either by accident or changing their dose of thyroid hormone replacements.

Unfortunately, doctors appear to have been directed that only levothyroxine (T4) has to be prescribed despite the patient feeling very, very unwell.

I, for one, had terrible palpitations and the cardiologist was puzzled with the results of my 'overnight recordings' and he was contemplating putting an implant in my heart 'to see what was going on'.

Just then T3 was added to T4 and I never had to consult with the cardiologist again as my awful symptoms resolved when I stopped T4 and took T3 alone.

I still take T3 alone.

Sometimes, even if some has recovered their health, if a change is made within the tablet (i.e. NDT or T3) it can have bad affect on the patient who had been well and symptom-free.

[m7-cola in reply to shaws]

I had a similar experience. As soon as I was properly medicated with T3 the ‘heart problem ‘ ended!

[Gingernut44]

Thanks for posting, it’s a step in the right direction. Let’s hope those who hold the power over us 5-10% (supposedly) will read and inwardly digest.

[tcpace]

Full text can be viewed here:<link redacted>

Not sure how they managed to avoid TSH suppression for those taking T3 or DTE. At least they targeted people who remain hypothyroid after taking T4. Still more work to do. One comment I noted:

Importantly, despite the increase in serum T3 levels seen with LT4+LT3 or DTE, there were no associated cardiovascular adverse reactions or changes in blood pressure; heart rate was only minimally accelerated by therapy with DTE.

[tattybogle in reply to tcpace]

unfortunately that link just gives "Your session has timed out. Please go back to the article page and click the PDF link again."

So they did measure fT3 then ..... that's a start... and good about the "no associated cardiavascular/BP reactions" statement.

Did the full text say what doses they used ?

[tcpace in reply to tattybogle]

OK, go to academic.oup.com/jcem/advan... then click on the PDF.

They did give details of the doses used.

[tattybogle in reply to tcpace]

Thankyou x

[helvella Administrator in reply to tcpace]

I have redacted the tinyurl link you included for two reasons:

First, it didn't work - as tattybogle said.

Second, there is no way a member knows where a tinyurl link is taking them - making such links unverifiable and, potentially, dangerous. (The same applies to any link shortening technology.)

Third, the link in the original post works just fine for me. (It might stop working when the paper progresses to final release. If so, please let me know and I will update the link.)

The HealthUnlocked platform itself shortens how long links are in posts - and then steps to an intermediate page showing the full link and asking if you really want to follow it.

[tcpace in reply to helvella]

Good point. The original link was massive (which is why I shortened it):

watermark.silverchair.com/d...

[jimh111]

Helpful but all the studies conducted so far have been useless, they fail to identify patients who need T3 and fail to give enough T3.

T4 to T3 conversion takes place within cells, mostly by D2 activity which controls local T3 levels. If a patient has impaired D2 activity restoring normal fT3 will do nothing for this loss of local T3. This is especially so for the brain which gets 80% of its T3 from D2 and only 20% from the blood.

Future studies need to select patients with poor T4 to T3 conversion and identify the dose of T3 required to restore normal cognitive function.

[tcpace in reply to jimh111]

Exactly - TSH must be kicked into touch. The attempts to achieve physiological levels of T3 when the T3 is administered exogenously are seriously misguided. They still have some way to go before they recognise this.

[jimh111 in reply to tcpace]

TSH is important because it stimulates deiodinase as well as secretion. Those of us with a subnormal TSH have reduced T4 to T3 conversion but are excluded from the trials because they diagnose on the basis of an elevated TSH, usually above 10.0. Ironically every trial has excluded the very group who need T3.

There have been no attemtps to achieve physiological levels of T3 or even measure them. The attempts have been to achieve serum levels of T3. Physiological levels of T3 could be measured indirectly by e.g. using an EEG to compare brain function with controls or measuring ankle reflex times. Or ... radical, just asking the patient what dose gives them normal brain function.

[tcpace in reply to jimh111]

In the past they have assumed that achieving "normal" serum levels resulted in physiological levels of T3 and, as a result, they have administered subjects tiny amounts of T3 and surprisingly got inconclusive results. That, in turn, gave the advocates of "evidence-based" medicine a basis for saying that there was no evidence to indicate any benefit from T3 despite plenty of anecdotal evidence to the contrary. This latest research makes it clear that the medical profession know far less than they think they do and that T3 administration is very important for some patients.

[FancyPants54 in reply to tcpace]

Those on here who have recently got a trail of T3 only ever seem to get 10mcg a day. That's pitiful for someone who has been left ill for years and years.

[shaws Administrator]

Sigh of relief! Let's hope that whatever/whoever makes the correct response will enable hypothyroid people to have a 'choice' of replacement hromones.

At long, long last!

I do hope the professionals 'listen to the patients more' and forget about 'results' except to make sure that we're on an optimum thyroid hormone (of choice) and not too low a dose.

Thanks Diogenes and also to the researchers.

[megarub]

The paper refers to the thyroid symptom questionnaire TSQ-36.

Is this used routinely or otherwise in the UK?

Can a patient access the TSQ-36 to self-monitor?

[I've failed to find it on a quick search].

many thanks.

[tattybogle in reply to megarub]

onlinelibrary.wiley.com/doi... found definitions of SF-36 and TSQ-12 on here .

it's a bit old , not sure if "TSQ-36" is another way of referring to "SF-36 when used for thyroid studies" .. or perhaps TSQ-12 has since been expanded to TSQ-36

*Edit * Here is how the authors describe what they used (from full text which 'tcpace' provides link to in reply above )

"As there are no well-validated and specific instruments to quantify the severity of hypothyroidism, we designed our own TSQ (12,17), a health-related QoL questionnaire, that was modeled after the hypothyroid-specific questionnaires developed by Jaeschke et al (20) and Cooper et al (21). This questionnaire consisted of 12 questions, presented in the same format as the GHQ-12, that asked patients how they felt over the last 22 weeks."

[Hoxo]

I’ve had a quick read through and 2 points I’ve picked up. First they give what I consider to be a relatively low dose of NDT and secondly they note the TSH of NDT patients is higher than the other groups. Hmmmm. Perhaps the NDT group were under dosed. It’s a shame they use the flawed TSH reading as the main criteria for Euthyroidism. But hey it’s a start and the trial shows good outcomes even so.

[tattybogle in reply to Hoxo]

"ASSESSMENTS . Clinical Biochemistry......blood samples were collected in the morning between 7 and 10 AM, pre-dose in fasting state. Serum TSH, free T4, total T3, "

Good .. if it's the right way to do it for clinical trials , then it's the right way for the GP's blood tests too .. so all those GP's who say "it doesn't matter" or "it's cheating to delay taking meds until after test" can stick that in their pipe and smoke it.

No FT3 tests done then .. just TT3 oh well. better than nowt i suppose.

and there's Lot's more good stuff too;

"DISCUSSION ...The rationale behind thyroid hormone replacement therapy is to administer thyroid hormone in a way that restores thyroid hormone signaling in all tissues.

Serum TSH has traditionally been used to adjust the dose of levothyroxine that presumably achieves this goal.

However, normalization of serum TSH is achieved through a slightly elevated serum T4 and reduced serum T3 levels (25).

TSH was higher in the DTE arm but still within the normal range. It was difficult to make DTE and LT4 doses bioequivalent.

It is not known whether these small changes in serum T3 and T4 modify thyroid hormone signaling.

The observation in the present investigation that replacement therapy containing T3 or DTE (which also contains T3) slightly elevates serum T3 and reduces serum T4, while mitigating the residual symptoms of hypothyroidism suggests a causal relationship.

Nonetheless, our findings are clear that no correlation between serum T3 and outcomes could be established in the present investigation, not even in the sub-analyses.

This apparent conundrum suggests that intracellular T3 levels, which are affected by both serum T3 and locally generated T3, might be playing a role (30).

//

While plasma T3 can be taken up by the brain, most T3 molecules in the brain are produced locally in the glial cells through deiodination of T4 via DIO2.

The fact that some patients on LT4 monotherapy remain symptomatic and prefer therapy containing T3 suggests that therapy with LT4 might not restore cerebral thyroid hormone in all patients.

Hypothetically, this could be explained by defects in thyroid hormone transporters, the DIO2 pathway, or by the relatively low serum T3 levels seen in LT4- treated patients (25), but none of these factors segregated in the most symptomatic LT4-treated patients.

The possibility that the relatively higher plasma T4 levels seen in LT4-treated patients might play a role remains to be investigated.

Thus, the simplest way to interpret the present results is to consider that thyroid hormone signaling in the brain was not fully restored in some LT4-treated patients as a result of one or more mechanisms yet to be identified, and that the elevation in serum T3 resulting from treatment with LT4+LT3 or DTE mitigated this problem.

Importantly, despite the increase in serum T3 levels seen with LT4+LT3 or DTE, there were no associated cardiovascular adverse reactions or changes in blood pressure; heart rate was only minimally accelerated by therapy with DTE.

//

In conclusion, some patients on LT4 therapy remain symptomatic despite normal serum TSH levels.

In the present investigation, the number of these patients was not sufficiently large to affect the outcomes of the whole group.

However, in the subset analysis, these patients were identified as having the worst performance on QoL questionnaires and cognitive tests.

These patients were also the ones that preferred and benefitted from switching to therapy containing T3, either DTE or LT4+LT3 combination, suggesting that thyroid hormone signaling in a minority of the patients on LT4 remain subnormal and can be improved (perhaps restored) with therapy containing T3. "

From results tables at the end ;

"1st Preference ....... T4 23% ....... NDT 45% ......T4/T3 32%"

it's interesting how much NDT was preferred over either T4/3 or T4 , this isn't pointed out in the discussion or conclusions, unless i missed it.

[JGBH in reply to tattybogle]

Good point about the GPs... but I doubt any ot them are even aware of this research never mind reading it....

[tattybogle in reply to JGBH]

i wasn't expecting them to .. lol . anyway i quite like knowing more then they do .. it restores the balance of power nicely.

[JGBH in reply to tattybogle]

Agree but it does not help us, patients, always having to fight and push to get any help. we should not be placed in such an unpleasant position. it's exhausting too and energy is too often lacking.

[jgelliss]

Thank you so much Diogenes. It's great to be at last validated. My question is what took so long? And what are they going to do about it now that the report is out?

[TaraJR]

linda96 MikeM46 this is good reading.

At last something else encouraging.

[Shield-Maiden]

Thank you Diogenes x

And, thank you to Everyone adding their knowledgable comments.

Post saved....

Take care x

[helvella Administrator]

This paper might, or might not, come to be seen as the start of the much needed revolution. But at least we now have a direct contradiction to the oft-repeated assertion “There is no evidence that T3/desiccated thyroid …”

( I’d argue that Hoang’s earlier paper about desiccated thyroid might be a better choice: healthunlocked.com/thyroidu.... )

It is evidence on their own terms – researched by widely known endocrinologists, at respected institutions, published in a high status endocrinology journal. The arguments that the paper was researched by people who don’t understand, in third-rate establishments – likely in far-off countries – and printed in some dismally low quality pay-to-publish or vanity journal with little or no peer-review, must all fall away.

Of course, in the UK a degree of parochial blindness might see the argument enduring as in continuing to be used for many years. Likely with the attitude that it might work like that in the USA but couldn’t possibly in the UK. (With no explanation of the change in biology as we cross the Atlantic. )

Were I anticipating an appointment with an endocrinologist, I think I would print the abstract and have it ready to pass on if needed.