And this, for goodness sake, was published in ... - Thyroid UK

Thyroid UK

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And this, for goodness sake, was published in 2012. Why no strong followup?

diogenes profile image

This 2012 study is actually a very stimulating and forward looking paper on the value of combination treatment. What happened? Why was it ignored? The respected club actually did have doubts but they seem quickly smothered.

Combination Treatment with T 4 and T3 : Toward Personalized Replacement Therapy in Hypothyroidism?

Bernadette Biondi and Leonard Wartofsky

Department of Clinical and Molecular Endocrinology and Oncology (B.B.), University of Naples Federico II, 80131 Naples, Italy; and Washington Hospital Center (L.W.), Washington, D.C. 20010-2975

Context: Levothyroxine therapy is the traditional lifelong replacement therapy for hypothyroid patients. Over the last several years, new evidence has led clinicians to evaluate the option of combined T 3 and T 4 treatment to improve the quality of life, cognition, and peripheral parameters of thyroid hormone action in hypothyroidism. The aim of this review is to assess the physiological basis and the results of current studies on this topic.

Evidence Acquisition: We searched Medline for reports published with the following search terms: hypothyroidism, levothyroxine, triiodothyronine, thyroid, guidelines, treatment, deiodinases, clinical symptoms, quality of life, cognition, mood, depression, body weight, heart rate, cholesterol, bone markers, SHBG, and patient preference for combined therapy. The search was restricted to reports published in English since 1970, but some reports published before 1970 were also incorporated. We supplemented the search with records from personal files and references of relevant articles and textbooks. Parametersanalyzedincludedtherationaleforcombinationtreatment,thetypeofpatientstobeselected, the optimal T4 /T 3 ratio, and the potential benefits of this therapy on symptoms of hypothyroidism, quality of life, mood, cognition, and peripheral parameters of thyroid hormone action.

Evidence Synthesis: The outcome of our analysis suggests that it may be time to consider a personalized regimen of thyroid hormone replacement therapy in hypothyroid patients.

Conclusions: Further prospective randomized controlled studies are needed to clarify this important issue. Innovative formulations of the thyroid hormones will be required to mimic a more perfect thyroid hormone replacement therapy than is currently available.

(J Clin Endocrinol Metab 97: 2256–2271, 2012)

79 Replies

That does sound like it was good .... will be interested to read it later on .

I do sometimes wonder if "not being fascinated by the HPT axis" is a pre-requisite for a career in endocrinology ...

"Medical this the right course for you ?

Are you naturally curious ?

Are you observant ?

Do you like learning from wonderfully individual patients ?

Do you want to be at the forefront of exiting new research , and explore new paradigms in treatment ?

..... if so, then the Endocrinology dept. may not be for you ..... we like to keep things the way they are."

helvella profile image
helvellaAdministrator in reply to tattybogle

I appreciate the humour in what you said. :-)

But I do genuinely wonder what does attract medical students to endocrinology?

Hasn't got a steady-enough hand for surgery.

Doesn't like the pressure (and working hours) of obstetrics and emergency medicine.

I could make a very long list of why some areas of medicine would be unattractive.

But the deceptive simplicity and very largely office-based work must seem like an easy option.

If that is why they choose endocrinology, perhaps it isn't surprising that within the field, they treat thyroid as if it were trivially simple.

Maybe I am entirely wrong. But I really would like to understand their choices.

JGBH profile image
JGBH in reply to helvella

I share your thoughts… easy peasy office based Well paid job! Bingo!

tattybogle profile image
tattybogle in reply to helvella According to this they are the happiest of all medics and get to drive a Honda :)

shaws profile image
shawsAdministrator in reply to helvella

When one qualifies it must give them a huge boost. Unfortunately they must 'toe the line' with regards to how they diagnose/treat patients especially those who cannot recover on levothyroxine. Unless they become 'private' endocrinologists.

UrsaP profile image
UrsaP in reply to shaws

And even then how many get treated properly when they go private, with such a lack of need for change within the discipline? I doubt many. The problem is they think they know it all. Most endos it seems are more diabetic trained, thyroid being such a defined treatment, there is not a lot to learn! Easier to deny their own lack of interest and dismiss their patients who fail to thrive on their treatment as ‘not my fault, I’ve ticked all the boxes, ergo they must be depressed’!

TSH110 profile image
TSH110 in reply to helvella

But it ought to be a really exciting area to be involved in, this TSH, Levothyroxine, job done rot needs binning once and for all. It’s holding everything back and keeping us ill. I fear you are spot on in your analysis - it certainly seems to attract a lot of lazy minded thinking that’s for sure…if you could even call it thinking

shaws profile image
shawsAdministrator in reply to TSH110

There seems to be not one Endocrinologist who is as knowledgeable as our 'old-fashioned' doctors who knew all clinical symptoms and diagnosed the patient through their symptoms alone. Patients were then given a trial of NDTs.

UrsaP profile image
UrsaP in reply to shaws

There seems to be a global acceptance that thyroid health has reached it’s pinnacle, that there is nothing more to know. I wonder how that ethos could ever be considered acceptable in medicine.

Jokaah profile image
Jokaah in reply to UrsaP

It can’t, or at least shouldn’t.

Jokaah profile image
Jokaah in reply to TSH110

The bottom of the barrel??

humanbean profile image
humanbean in reply to helvella

I can't remember where I saw this, but I read once that if medical students were ranked according to their first degree final exam marks that the ones with the lowest marks were most likely to go into endocrinology and anesthesia.

Endocrinology was because students thought it was too complicated and so there was less competition for that than, say, surgery. I can't remember why anesthesia attracted some of the worst students.

Take this with a pinch of salt though since I can't remember where I read this.

Gcart profile image
Gcart in reply to helvella

I worked in the NHS. Most young doctors going thru the system aspired to be GPs. Reason, more and more females training and wanted families in the future, thought it would be easy to have both ! .

For some I knew it was in psychiatry because getting to be a Consultant was easy !

This was 20 years ago. Whilst they were clever people I could see how they worked with people and importantly which ones cared . All I will say is that it varied !!

DippyDame profile image
DippyDame in reply to helvella

Possibly all of that, but I also feel we might look back to the beginning.

Endocrinology education in med schools is a farce!

It's easy to knock the practitioners but...

Did the "attitude" exist when they entered med school or did it develop as they were "shaped" for years by institutions entrenched in outdated and erroneous teaching.

We only see "the end product".

They basically have to toe the line

Those with open minds and different ideas might be ignored

Or worse....pilloried.

Some years ago I visited a former GP with a question about the shocking state of my fingernails.

Also present was a med student who was tasked with diagnosing the problem before reporting back to the GP (in another room) to discuss his diagnosis.

The student took one look at my fingernails and said, " I'm sure that is thyroid related"

Wow! That was my thought too, and I said so.

He then went off to discuss his diagnosis with the GP.

They both returned and I immediately said, " So it appears to be thyroid related"

The GP sounding slightly flustered replied, " Definitely not, it's fungal".


End of discussion!

Collapse of student's face ...he said nothing and to my shame neither did I.

We just looked at one another...

He couldn't afford to disagree.

Incidentally, my nails began to improve very, very slowly once I started to self medicate with T3.

He was correct!

I often wonder what happened to that lovely friendly young man who had such promise.

Was he eventually churned out of the status-quo-sausage-machine of med schools?

Was he pressurised into spouting the "accepted" thyroid mantra.

I hope not.

I'm not defending the shocking treatment so many of us are subjected to!

Just throwing another example into the mix.

I have no idea why so many (incompetents) might have chosen endocrinology.

One of my school friends became an endo because both she and her brother were diabetic. She died many years ago.

Maybe for others it takes them away from the blood and guts of medicine.

An easier option!

For others it may give them a sense of power they crave

Or a certain status in society.

What ultimately shapes any of us?

Nature or nurture?

UrsaP profile image
UrsaP in reply to helvella

During lockdown I was referred back to an Endo, having avoided them for 10 years, and was doing fine without them. Until something else ‘flared’ and threw my thyroid bloods out of kilter. I never saw the man face to face. He did call me up for bloods and tests, which I did appreciate. But, he was like Jekyll and Hyde, Lovely on the phone to start with, the second call he was awful. Dismissive, flippant, no interest in the fact that other things might be affecting my thyroid levels. He even told me I could try stopping my medication and see what happened? I’m on T3 mono. Needless to say I politely declined that offer. He left me on T3, so that’s all I need from him, with that attitude.

I saw him, he walked past the nurses area as I was waiting for bloods, sauntering through the empty hospital, all smiles and waves for the nurses. I said hello, and got a very odd look, like how dare I address him, we were the only two people in that corridor, to me it was manners to say hello. Certainly didn’t look stressed! Funny how nurses, ophthalmologists and dental practitioners could see me during the lock down, up close and personal in my face, yet an Endo could not see me across a desk? Is there a pecking order to the ‘value’ of different practitioners?

jgelliss profile image
jgelliss in reply to helvella

Agreed. Becoming Dr's in today's world is all for the money and not for the patients wellbeing unfortunately. Years ago Dr's cared where involved and took so much interest. New the whole family. Now we become a number. Unfortunately.

Jump1 profile image
Jump1 in reply to helvella

It's all about the easy money

JGBH profile image
JGBH in reply to tattybogle

Great set of prerequisite questions… one really wonders.

Gilbo72 profile image
Gilbo72 in reply to jimh111

jimh111 thanks!

Perhaps it’s just me but I find the final comment in the conclusions in this paper dating back to 2012 one of the saddest things I’ve read in a while.

‘Innovative formulations of the thyroid hormones will be required to mimic a more perfect thyroid hormone replacement therapy than is currently available.’

I have always wondered why, when the thyroid comprises of T1, 2,3 and 4 why on earth do doctors think all of that can be replaced with T4 alone? How on earth did that come about? What happened that this advice given in this paper was never acted on?

JGBH profile image
JGBH in reply to Fruitandnutcase

Simply done for an easy box ticking life! Ask no more, I fear…

So true. Not to mention the previous sentence:

Further prospective randomized controlled studies are needed to clarify this important issue.

If I read one more call for further studies... Grrr.....

Mimicing normal serum thyroid hormone levels will be fine for many patients, I'd advocate it on the basis it is safer than levothyroxine monotherapy. However, if patients have impaired deiodianse due to subnormal TSH secretion (common I believe) or endocrine disruption they will need abnormal fT3 levels to compensate for the loss of T4 to T3 conversion within cells (type 2 deiodinase). This is a cruical point that all endocrinologists miss. TSH stimulates D2 and if TSH is subnormal there will be reduced local T3 levels. Restoring normal serum fT3 is not sufficient to restore T3 levels in tissues that rely on local conversion of T4 to T3.

BB001 profile image
BB001 in reply to jimh111

My Dio2 is normal. I'm homozygous for Dio1. This causes me to have an extremely low conversion rate of 0.16. Yet nobody ever talks about Dio1 genetic mutations causing problems with conversion.

jimh111 profile image
jimh111 in reply to BB001

There are DIO1 polymorphisms but no link with symptoms has been found. If any of these deiodinase polymorphisms matter they should logically be fully compensated for if the patient is given a little T3. My personal view is that the polymorphisms only explain mild symptoms and so I feel we should not be distracted by them. Polymorphisms don’t explain why some patients have severe symptoms that require above average serum fT3 levels.

BB001 profile image
BB001 in reply to jimh111

That's interesting because that disagrees with snpedia.

Perhaps the Dio1 polymorphisms only affect a unique subset of hypothyroid patients. I am one of what I suspect is a very small minority who have a atrophied thyroid and Graves hypothyroidism.

jimh111 profile image
jimh111 in reply to BB001

The way I look at polymorphisms is to compare them to eyes. Most of the world's population has brown eyes but a subset has blue eyes. These are the common polymorphisms, there are other colours that vary in rareness. The same applies to deiodinase polymorphisms, the ones recorded are the common ones, there will be other rarer polymorphisms that aren't investigated.

In any event, if a patient was healthy and becomes hypothyroid I would expect any effects of deiodinase polymorphisms to be overcome if they are given a little T3 to compensate for the loss of T3 from their thyroid. Many patients do very badly after becoming hypothyroid and require high doses of T3 to recover, logically this will not be due to deioodinase polymorphisms. (in this case by 'high doses of T3' I mean more T3 than their thyroid would normally have secreted, a high or high normal fT3).

DippyDame profile image
DippyDame in reply to jimh111

Nice one...

My mother had a cousin with one brown eye and one blue one!!

Maybe compares to my wonky thyroid function/ polymorphisms!!

BB001 profile image
BB001 in reply to jimh111

The eyes example, ironically, supports what I was saying. Yes brown eyes are in the majority and blue eyes in the minority, but blue eyes are more prone to macular degeneration - a subset of a minority. Like Graves TRAb patients being affected to a greater degree by Dio1 mutation (I don't know if this is so, I'm just theorising).

When a person loses their thyroid function, whether by atrophic thyroiditis, RAI etc they don't just lose the T3 that their thyroid would have produced, they also lose their thyroid's T4 to T3 conversion capability. Double whammy. So it makes sense that these people would need to be dosed with more T3. Adding deiodinase polymorphisms on top of this may impact this subset of patients more.

jimh111 profile image
jimh111 in reply to BB001

That's true, I overlooked the conversion that takes place in the thyroid. This thyroidal conversion will no doubt contribute to a robustness, an ability to tolerate fluctuations in thyroid hormone supply and demand. This is lost when there isn't a fully functioning thyroid. It is probably OK when someone has the right doses of T3 and T4 to maintain ideal fT3, fT4 levels but I suspect they would not cope so well during periods of unusual demand. I'm not sure there will ever be a way out of this but I think it might not be a big problem as many people are fine when treated with thyroid hormone.

I hope the way I've expressed myself here makes it clear this is my thinking and none of the above is to be regarded as hard facts.

BB001 profile image
BB001 in reply to jimh111

Your thinking very much matches my experience. I have atrophic thyroiditis and am on T3 mono thyroid therapy. When on NDT I still had some residual hypothyroid symptoms hence my switch to T3. It would have been good to be on T4+T3 so I could tweak the mix of T4 and T3, but I can't tolerate levothyroxine.

DippyDame profile image
DippyDame in reply to BB001

Ah well...

I have blue(ish) eyes and have MD

My late brother had dark brown eyes and also had MD

I have -


The Dio2 snp

Need a supraphysiological dose of T3 to function.

My genes seem to be leading me a (not so) merry dance!

BB001 profile image
BB001 in reply to DippyDame

Are you a member of the macular society?

They do a weekly email and have lots of useful info on their website. I like the updates on research.

DippyDame profile image
DippyDame in reply to BB001

Thank you ....yes, I joined recently.

I'm also interested in any research that may help.....fingers crossed!

Thankfully the sight in my right eye is still "useable", the left, not so!

BB001 profile image
BB001 in reply to DippyDame

I'm sorry to hear that. Unlike you I have no relatives with macular degeneration. My initial research on this seems to indicate that TRAb are implicated.

DippyDame profile image
DippyDame in reply to BB001

Thank you!

My brother was the only other relative to have MD as far as I know ...but nobody left now to ask! He was 13 years older than me.

I don't have Hashi's but I suspect there could be a low cellular T3 connection but haven't started "digging" yet

There again I blame so much on that!!

TSH110 profile image
TSH110 in reply to BB001

Me too -atropic autoimmune thyroiditis. I have DIO2 poor conversion combination but not the worst combination, and my conversion rate T4 to T3 is dire I have some genes for thyroid hormone resistance too. Not sure if those are the cause, only NDT allowed me to get my life back. Close relatives on Levothyroxine all feel/felt great on it so I knew something was wrong when I still felt dreadful after two years of taking it when they got good results after some weeks not years! No doubt there are more unknowns yet to be elucidated that might explain things better.

DippyDame profile image
DippyDame in reply to TSH110

I have some genes for thyroid hormone resistance too.


Please can you expand on this TSH110

Are you referring to genetic testing of the alpha and beta TH receptors?

If so where did you have those genetic tests done?

They are the only genetic tests I'm aware of for RTH, so interested to hear of someone who has been there, so to speak.

jimh111 has written about ECDs as another cause of RTH

I have no idea of the genesis or type of my RTH

A geneticist suggested it may be an as yet unrevealed genetic variant.

I only know that my RTH exists... otherwise the supraphysiological dose of T3 I need to function would be dangerous/ thyrotoxic

Did you initially have a THR test followed by the genetic test to establish abnormalities of the TH beta receptor (or the existence of a pituitary adenoma.)

Was a T3 suppression test then done?

My RTH causes cellular hypothyroidism and I need a supraphysiological dose of T3 to overcome this resistance

Extensive trial and error resulted in this being the only route to improving my health

I also carry the Dio2 snp/ homozygous which research proves has a greater impact on conversion than if heterozygous.

But I really can't say to what degree the overall effect has been for me.

But, the positive result led me to look at low T3 in general and eventually to low cellular T3, and what may have caused this.

Endo would not consider RTH and insisted I should maintain T4 mono treatment which after 20 years left me barely able to function!

So, I've had to "fly solo" on this with support from TUK

My experiences that followed were not in agreement with that endo!

This subject is very complicated and I've only scratched the surface enough to enable me to improve my health so clearly I'm no expert on the deeper scientific aspects of RTH.

Your comment above grabbed my attention so I would be interested in anything related that you are happy to share and that may help me or others in a similar situation

TSH110 profile image
TSH110 in reply to DippyDame

I went on Snpmedia and checked all the rs numbers they listed for thyroid hormone resistance on my raw data in 23&me, it is an old chip that also did DIO2 etc . I had one rs number combination that was significant for THR and the DIO2 was heterozygous for poor conversion. How significant these things are I don’t know, my family are very anti 23&me so I don’t know if any of them with thyroid disorder also have these markers or not - some have passed away before all this genetic testing was accessible too. It is a shame because it would get interesting to know and whether any differences tally with their experience of T4 monotherapy (very positive ) and my highly unsatisfactory time on it. It’s probably not as good as getting the specific genetic testing you mentioned. I didn’t really understand what significance the THR might have but just assumed I’d need to have higher amounts of thyroid hormones to make it all tick ok. I never really took a huge dose of Levo 125mcg but anything more made me feel decidedly weird, on edge all the time and just not right at all and that dose just left me feeling like a shadowy thing and I felt truly dreadful. I used to think what was the point of going through all that hell to end up having a life I felt was simply not worth living I used to wish I had never got any help and just died of it it was really that bad physically and mentally, my depression was very debilitating and highly intractable. Even a small amount of NDT had dramatic effects as I titrated up to 1.25 grains. I felt normal again and the terrible depression simply evaporated. It was fantastic as I had had dreadful depression for decades so I can only think the T3 could not have been reaching my brain in adequate amounts for some decades or only intermittently as my life was like a rollercoaster of crazy emotions. I did wonder if I was bipolar, perhaps that’s what THR does. NDT banished it very rapidly and it could only be the T3 in it unless the other things in NDT matter more than is generally accepted. I need a lot more now 😖😖😖 1.75 to 2 grains I was fine on 1.25 for years so no idea why I suddenly needed more of it to feel well. I suppose nothing is set in stone where the body is concerned - it’s so complex keeping it all in balance I suppose taking tablets can never be as good as having a healthy thyroid gland. I certainly don’t seem to need a lot of T3 but I deffo need some T3 to feel ok

DippyDame profile image
DippyDame in reply to TSH110

Thank you for sharing this...23&me is one way to go that I hadn't considered

But, I sometimes wonder if it's best not to know too much of what might develop and be ahead of us!

I wonder if your THR rs is related to the alpha or beta receptors...or something else.

I have the Dio2 snp/ homozygous which according to Panniker et al has a greater impact on conversion than if heterozygous.

It's main use for me was to set me on a hunt for associated T3 problems.

I have a rare genetic deletion discovered when my younger grandson was born with an equally rare heart condition...he is now well and full of life thanks to a brilliant Italian heart surgeon

Turns out I had passed it on to his father, my elder son, and so to him

As my younger son joked, " we always knew you had dodgy genes Mum!"

Sorry that you suffered so badly with depression, I fully emphasise, there were times when I thought it would be best if I just walked out into the sea beside us...

Couldn't do that to my family.

That was thankfully transient and usually in the middle of the night!

I honestly cannot remember what feeling really well feels like....a new " normal" takes over.

I once said to a GP that it was like putting on smiling mask before going out the door then coming home, exhausted... and binning it until the next time.

Eventually that mask no longer worked.!

T4 for 20+ years left me on my knees, numerous T4/T3 titration did very little, T3-only did little until the dose was supraphysiological.

My then GP was not happy when a routine blood test revealed the obvious!

She now leaves me to it....and I suspect has learned a little.

A nurse said to me recently " I bet she scurried off and looked it up !"

Anyway, I've made it to 76, I function (and thankfully my brain function is so much better now) but part the damage done over decades lingers on.

Despite everything I still don't see myself as old...but I am!

Maybe delusion is another symptom!!!

I fear for all those suffering silently behind closed doors...and possibly dying ...because nobody realised their cellular T3 was low.

The efficiency of our T3 receptors is key....I guess mine went on strike when T3 supply was very low. It looks as if high dose T3 has pushed some of them back to work!

So pleased you find NDT helpful....stay as well as possible

I'm so grateful to the amazing members here who possibly saved my life

Here, we know we are not alone with this hellish condition!

Thanks again for responding TSH110 does help.

TSH110 profile image
TSH110 in reply to DippyDame

When I took NDT within a short time it felt like I was a jigsaw puzzle with a key piece missing that had been suddenly put back into place and I felt whole again it was an incredible feeling and only got better as I titrated up to optimal. I can only think it was the t3 I had lacked, in the NDT doing something very important in my brain.

I am so pleased your grandson had his heart problem sorted out with surgery what a wonderful miracle of health that surgeon delivered for him. I am impressed you have fought on to health and have 13 years up on me it is an inspiration and brings home how important it is to never ever give up on striving to improve things with this disorder.

It is hard thinking if all those who are suffering unnecessarily due to poor diagnosis and treatment but it think the tide is slowly turning against T4 monotherapy the supposed gold standard therapy is rapidly becoming a decidedly tarnished tin plate substandard treatment protocol.

This site and the brilliant people on it have been my salvation ☺️

BB001 profile image
BB001 in reply to TSH110


Having re-read your comment, I now realise you did it the other way round and looked as snpedia for the THR rs numbers, so ignore my post below.

I realise this is a lot to ask, would you post the THR rs numbers here? If you copy and paste you will find it easier and more accurate.

Remember to save a copy of your datafile and work on the copy.

TSH110 profile image
TSH110 in reply to BB001

There are rather a lot of them and you have to go to each one to get details of the combinations.This is the page, you will see them listed in the table they are linked to details for each one:

Hope that helps

BB001 profile image
BB001 in reply to DippyDame

I have a friend who is homozygous for Dio2 and is in T3-only, she does not need extra high doses of T3. So I conclude it must be something else that means you need extra high doses of T3, and THR seems a reasonable candidate (based on logic, not medical knowledge).

DippyDame profile image
DippyDame in reply to BB001

Bottom line....we are all different.Having the Dio2 snp/ homozygous indicates impaired conversion which is usually resolved by the addition of a little T3....not a supraphysiological dose

Having the above variant is not why I need so much T3.

Although the snp did provide a clue as to where to look next!

People with RTH can tolerate doses of T3 which would be dangerous/ fatal in other circumstances.

The large dose of T3 is needed to act as a " battering ram" against the cells

The force (or size of dose) helps push at least some of that dose into the cells from the serum which carries the T3.

The remainder sloshes around in the serum until it is metabolised and eventually excreted by bowel and bladder.

T3 does not become active until it reaches the nuclei of the cells, via T3 receptors.

This helps explain why it is necessary to take a high dose of T3 ( this will depend on the severity of the resistance) to overcome the resistance

It also explains why RTH patients( on the correct dose) do not become thyrotixic...

The dose should be large enough to overcome the resistance but not so large that an excess of T3 reaches the nuclei causing overdose when the hormone becomes active.

Medical knowledge and an understanding of T3 is inevitably important, though logic/ a process of elimination did play a part.

I'm no expert but my health was such that I had to find the answers and stop my body from slowly shutting down because medics had no idea what was making me ill.

Numerous tests, scans and treatments did nothing to help.

So, yes, you are's "something else"!

I hope your friend keeps well and that this reassures her and helps explain why she needs only a small dose of T3

DippyDame profile image
DippyDame in reply to jimh111

I agree!

And for anyone who might be interested..

Discovering that I carry the Dio2 polymorphism/homozygous provided one important link in my search towards recovery.

It did not solve the problem

It made me think more about T3....and more specifically, at what point it becomes active.

There was adequate T3 sloshing around in my blood but I still felt like death warmed up!!

What seems to be overlooked (and what is vital for people like me) is that serum T3/ FT3 is not the end of the journey.

T3 must reach the nuclei of the cells to become active.

For most people this is not an issue, the body works as it should.

But not for everyone!

And we suffer.

Low cellular T3 = poor health.

Medics don't seem to consider this.

They overlook the science.

In short...I discovered my problem when I used a supraphysiological dose of T3

A dose that would be dangerous for " normal" people.

I had to self medicate and take the risks I was told would follow

At last I started to recover.

My Dio2 polymorphism had little to do with the cause of my ill health

Despite the fact that being homozygous it has a greater impact on T4/T3 conversion.

My problem is low cellular T3... the result of some form of thyroid hormone resistance.

The reason...Perhaps an as yet undiscovered genetic variant (that from a geneticist)

And the solution... "above average serum fT3 levels."

Try discussing that with a medic who cannot see beyond TSH!

BB001 profile image
BB001 in reply to DippyDame

I think you would like professor Tania Sona Smith's research-based articles on the subject of cellular T3, on

DippyDame profile image
DippyDame in reply to BB001

Thank you,

Yes, I find Tania Smith's articles very interesting.

Someone once described her as having a brain the size a planet!

jgelliss profile image
jgelliss in reply to jimh111

So well said . Thank you jimh111

helvella profile image
helvellaAdministrator in reply to Fruitandnutcase

I think it is very simple.

Many years ago, in the 1950s, synthesis of levothyroxine (and liothyronine) was achieved.

Person with no thyroid is given T4.

You know that T3 is important.

Person doesn't die. A blood text shows there is T3. Which proves that, in all people, for all time, and in all circumstances, T4 gets converted to T3.

Further proof by TSH dropping into reference interval.

This conversion is done by the patient's body, so there cannot possibly be any need to supply T3 directly.

All that is required is to see TSH drop. That proves everything else is working as it should.

The only other requirement is to run another TSH test annually.

Fast forward sixty years. Everyone who was involved with the early days of levothyroxine and liothyronine has at least retired. The extreme simplistic mantra has become some sort of totem which cannot possibly be wrong. Indeed, even questioning it is unscientific and definitely un-medical.

Thanks helvella, that makes perfect sense. I think you really have hit the nail on the head. We’ll just give the patient T4 - patient doesn’t die and still appears to be functioning so that’s ok. Which brings you back to why did they skip T3 in the first place?Also back in those days patients were much more in awe of their doctors and would have been highly unlikely to question their wisdom which (in my opinion) is quite a big thing - basically it’s probably how a lot of doctors and consultants came to see themselves as Gods.

Plus there were no supports groups like TUK and no internet to do our own research.

helvella profile image
helvellaAdministrator in reply to Fruitandnutcase

The blood level of T3 does tend to be more variable in those who take T3-containing medicines.

And that is assumed to be bad.

Permanently a bit too low isn't even considered because no-one knows what T3 level an individual had before they had any thyroid issues.

We see that those who take T3 appear to split into two groups. The ones who take it as a single dose, and those who split dose. Often mentioned, but we are, I think, in the arena of best guess rather than proof.

I think that, in thyroid as so many other areas, we should count the assumptions.

BB001 profile image
BB001 in reply to helvella

I try to reduce the variability of my T3 by dosing 5 times a day.

BB001 profile image
BB001 in reply to helvella

There's research that shows the variability of T3 produced by a person's thyroid varies from 6.5-43% and that the shortfall is made up by peripheral conversion.

diogenes profile image
diogenes in reply to BB001

That paper is a travesty of science. The absolutely basic error is thinking that adding Lugol's solution (iodine) to the healthy volunteers given radioactive iodine had no direct effect on the thyroid activity. Lugol's suppresses the thyroid's ability to make T3 direct so that the estimates were under what was really happening re T3 production. And of course the enormous difference is T3 production apparently seen in the panel would make me think my experiment was a failure.

BB001 profile image
BB001 in reply to diogenes

However, although you consider by today's standards it is not good research, the thyroid bodies and many researchers are perfectly happy to use the average of the T3 produced by the thyroid of these people. 20% T3 produced by everyone's thyroid is ubiquitous throughout thyroid guidelines and research. It is considered that everyone's thyroid is the same and produces 20% T3 and 80% T4. Yet everywhere else in medicine it is accepted that each person is an individual and reacts differently.

'Patient didn't die and is still functioning', but... they didn't follow up to see what long term health conditions they developed. I like this article

Prevalence rates for 10 chronic disorders at various FT4, TSH and FT3 levels

jimh111 profile image
jimh111 in reply to helvella

This paper from 1988 by Robert D Utiger puts a lot in perspective. Utiger was a leading light in the development of TSH testing. Much of the paper is technical stuff about assays but he raises a couple of fundamental issues: -

1. TSH activity varies according to 'glycosylation' (don't ask me any chemistry questions!), i.e. there are lots of TSH forms with varying activity, the assays just counts how many are present.

2. He advocates TSH testing as an 'inital' test and points out that patients with similar numbers may have different thyroid status.

This early day scientific approach has been lost. TSH is blindly followed by doctors who have no idea what a TSH molecule is composed of (lots of stuff - molecular weight > 7,000 if I remember correctly).

TaraJR profile image
TaraJR in reply to jimh111


DippyDame profile image
DippyDame in reply to jimh111

He advocates TSH testing as an 'inital' test...for hypothyroidism!


But now they have taken one tool specifically designed to do one job and tried use it to do an unsuitable job ...thinking it's a shortcut

It was bound to fail.

Try knocking a screw in with a hammer when you can't be bothered to go and look for a screwdriver.


Monitoring levels/ dosing by TSH alone instead of testing the Frees


Thousands of sick patients.

jimh111 profile image
jimh111 in reply to DippyDame

Do you mind? I was brought up in Birmingham and we were proud to use a "Brummie Screwdriver", always worked fine. So much so that thirty years later or so the big companies caught on to making screws designed to be hammered in.

Seriously, they took Utiger's cautious early research as an excuse for lazyness - no need to study thyroidology, no need to examine the patient.

tattybogle profile image
tattybogle in reply to jimh111

i can confirm 'a hammer' seems to work perfectly well.... i once took the p*** out of someone doing it to hang a long coat rack up at a school i worked at ... his end received the hammer the screw in approach with a couple of turns from a screwdriver at the end for finesse..... my end was done 'properly' ....... my end fell of first .. his end withstood teenage boys hanging on it for several days until i got round to mending it again.... i went and got a big hammer .

jimh111 profile image
jimh111 in reply to tattybogle

The hammer works on recalcitrant endocrinologists too!

DippyDame profile image
DippyDame in reply to jimh111

Ha Ha. Like it!Is that what's known as screw nails!

Thank you…. and yes… what’s new.

shaws profile image

Doctors Prescribe More of a Drug If They Receive Money from a Pharma Company Tied to It,

Thank you for sharing this, and the other educational materials. They really add valuable data for the journey.

I feel blessed to have a youngish, freshly minted endocrinologist who takes a particular interest in bone health and is keen on combination therapy as her standard protocol. On the other hand, she doesn’t know how to palpitate a thyroid gland for nodules, and questioned the presence of multi nodular goiter. I had to show her ultrasounds and biopsy results. 😳

She’s letting me remain on NDT because I passed my recent full-panel blood tests with flying colors. My FT4 was beneath the clinical reference, but TSH was 0.97 and FT3 in the first quartile at 3 in the afternoon. She said the bit about having hormone levels in the higher quartile of the reference range is only a concern when the hypothyroidism is attributed to pituitary malfunction.

After years of following all of the recommendations for keeping food, pharmaceuticals, calcium and mineral supplements well separated from my twice-daily NDT, I tossed caution to the wind about nine months ago. I take the NDT with food, mineral supplements and medications, and the lab results are the same.


I really value the information that’s shared here and I thank the administrators and contributors for the energy and dedication to good care.


Thank You so much Diogenes for your continued hard work and support with our thyroid journey. I have one question. What took so long to come to the conclusion that T4 alone was not always the best solution for thyroid patients wellbeing ? But that there was another hormone called T3 that helps thyroid patients either sole or in combination to feel their very Best.

diogenes profile image
diogenes in reply to jgelliss

I can't answer that question with any authority, but I suspect that because it wasn't common ground, nobody was willing to take up its implications.

jgelliss profile image
jgelliss in reply to diogenes

Thank you Diogenes. Your on top of the game. We are so much better for it. We our the beneficiaries of your hard work.

I want to thank everybody that adds to the conversation of our bouts with hypothyroidism (I have Hashimotos). You all provide valuable information, and a lot of it, to help us better understand this problem and then apply what we gathered to our own situations. I know it gives me hope, finally…..THANK YOU

I wonder how much the ripples of disdain at what the private sector endos do filter back into mainstream NHS thinking?

Certainly I know a few NHS doctors turn their noses up at the number of tests that private doctors are willing to provide. And yet when they, the NHS doctors, receive the results of those privately done and privately paid for tests showing that a patient has a clear brain tumour or other cancer / case of MS, they don’t then investigate why that person wasn’t able to get the test done on the NHS so as to examine why their own diagnostics are faulty. A little prejudice goes a long way and covers a multitude of sins, to mix my NHS metaphors.

I’d like to know if there is any physiology trials going on Re thyroids? Do any do biopsies or examine at autopsy? Is there any money going into research apart from TSH?

My grt grandma had a huge goitre when she was younger, 1940>. She had to eat thyroid raw, I think from a calf- we lived in a farming area.

She also ate liver raw so I assume iron or B12 deficient.

She lived to an old age. She developed diabetes and at 5yrs I used to give her insulin injections, 1952. She must have been about 70 by then. The goitre was hardly noticeable otherwise I’m sure it would be in my memory bc everything else was.

I asssume NDT is the modern equivalent of eating live thyroid.


diogenes profile image
diogenes in reply to Bellaowl

There are lots of studies, but many of them can only be described as statistical analyses of patient panels. That's not physiology. However, our team have published over 30 papers and other articles on the physiology of the HPT axis (hypothalamus/pituitary/thyroid) and we hope to have a complete explanation of how it works in some detail published shortly.

helvella profile image
helvellaAdministrator in reply to Bellaowl

The number of studies over the years is huge. I get an email every day with the studies added to PubMed in the past 24 hours.

The latest one shows 19 new papers. Some days there are only a few, other days even more than this. My selection is based just on mentioning "thyroid". Many papers are not thyroid research as such, but quite a few are.

Lots are focussed on cancer (thyroid and non-thyroid), surgical techniques.

Some are animal studies without being intended to be relevant to human thyroid issues.

Many fall into some obvious traps:

Use of TSH only.

Ignoring that results should be interpreted with due regard to the reference interval of the labs which did the testing.

Ignoring the opinions of the patients.

Poor handling of statistics.

Also, the full papers are often not available (very often because they are behind paywall), and some don't even have an abstract.

A huge proportion of the relevant studies explain why they are not the last word and calling for more studies. But no-one seems to look at these calls and develop some sort of strategy to encourage these additional studies to me done.

It wouldn't seem to be a huge effort for some on the thyroid-directed journals to collected call for more studies in the papers they publish and publish them in a thoughtful, annual overview.


Could the thyroid gland dominate the brain in obsessive-compulsive disorder?

Caykoylu A, Kabadayi Sahin E, Ugurlu M. Neuroendocrinology. 2022 Apr 20. doi: 10.1159/000524627. Online ahead of print. PMID: 35443249 Review.

Thyroid hormones have an essential role in brain maturation and neuronal functioning. The comorbidity of thyroid disorders and several mental disturbances is frequently reported. ...


Paedomorphic salamanders are larval in form and patterns of limb emergence inform life cycle evolution.

Bonett RM, Ledbetter NM. Dev Dyn. 2022 Apr 20. doi: 10.1002/dvdy.479. Online ahead of print. PMID: 35443096

Amphibians undergo a variety of post-embryonic transitions (PETr) that are partly governed by thyroid hormone (TH). Transformation into a terrestrial form follows an aquatic larval stage (biphasic) or precedes hatching (direct development). ...


A rare case of grave's disease after SARS-CoV-2 vaccine: is it an adjuvant effect?

Taieb A, Sawsen N, Asma BA, Ghada S, Hamza E, Yosra H, Amel M, Molka C, Maha K, Koussay A. Eur Rev Med Pharmacol Sci. 2022 Apr;26(7):2627-2630. doi: 10.26355/eurrev_202204_28500. PMID: 35442478

On examination, her pulse was 119 beats per minute, she weighed 63 kg, and she had lost 4 kg in only two months. GD was suspected. Thyroid hormone testing showed low thyroid-stimulating hormone, and an elevated serum free thyroxine hormone T4 level. ...


Wnt3a but not CDX-2 expression is associated with differentiated thyroid cancer.

Biagini GLK, Ribas CAPM, Higashi HD, Hirata VY, Zella MAK, Bartolomei I, Biagini G, Collaço LM. Rev Assoc Med Bras (1992). 2022 Mar;68(3):400-404. doi: 10.1590/1806-9282.20211132. PMID: 35442371

METHODS: We included 194 thyroid tissue surgical specimen and their clinicopathological data: study group (differentiated thyroid cancer, n=154) and control group (multinodular goiter, n=40). ...RESULTS: High Wnt3a expression was significantly associated with differ …


Minimum minimorum: thyroid minimally invasive FNA, less is more concept? Volens nolens?

Sengul D, Sengul I. Rev Assoc Med Bras (1992). 2022 Mar;68(3):275-276. doi: 10.1590/1806-9282.20211181. PMID: 35442348 No abstract available.


Harnessing the Power of Artificial Intelligence in Otolaryngology and the Communication Sciences.

Wilson BS, Tucci DL, Moses DA, Chang EF, Young NM, Zeng FG, Lesica NA, Bur AM, Kavookjian H, Mussatto C, Penn J, Goodwin S, Kraft S, Wang G, Cohen JM, Ginsburg GS, Dawson G, Francis HW. J Assoc Res Otolaryngol. 2022 Apr 20. doi: 10.1007/s10162-022-00846-2. Online ahead of print. PMID: 35441936 Review.


Real-world safety and effectiveness of nivolumab for advanced renal cell carcinoma in Japan: a post-marketing surveillance.

Uemura H, Tomita Y, Nonomura N, Yoshizaki K, Nakao T, Shinohara N. Int J Clin Oncol. 2022 Apr 20. doi: 10.1007/s10147-022-02155-3. Online ahead of print. PMID: 35441907

TRAEs were reported in 275 (49.5%) patients. The most common TRAEs of special interest included thyroid dysfunction (9.5%), hepatic dysfunction (8.6%), and interstitial lung disease (6.7%). The incidence of TRAEs was significantly higher in elderly patients ( 65 vs < 65


Preoperative platelet distribution width-to-platelet ratio combined with serum thyroglobulin may be objective and popularizable indicators in predicting papillary thyroid carcinoma.

Jin J, Wu G, Ruan C, Ling H, Zheng X, Ying C, Zhang Y. J Clin Lab Anal. 2022 Apr 20:e24443. doi: 10.1002/jcla.24443. Online ahead of print. PMID: 35441746

OBJECTIVES: The incidence of papillary thyroid carcinoma (PTC) has increased more rapidly than that of any other cancer type in China. ...METHODS: A total of 1001 participants were included in our study. 876 patients who underwent surgery for nodular goiter were divided in …


A novel prognostic model associated with the overall survival in patients with breast cancer based on lipid metabolism-related long noncoding RNAs.

Shi GJ, Zhou Q, Zhu Q, Wang L, Jiang GQ. J Clin Lab Anal. 2022 Apr 20:e24384. doi: 10.1002/jcla.24384. Online ahead of print. PMID: 35441740


Differential Diagnosis of Thyroid Nodules by the Demetics Ultrasound-Assisted Diagnosis System and Contrast-Enhanced Ultrasound combined with TI-RADS.

Wang G, Nie F, Wang Y, Yang D, Dong T, Liu T, Wang P. Clin Endocrinol (Oxf). 2022 Apr 20. doi: 10.1111/cen.14741. Online ahead of print. PMID: 35441715

OBJECTIVES: To assess and compare the diagnostic value of the Demetics ultrasound-assisted diagnosis system and contrast-enhanced ultrasound (CEUS) combined with the Thyroid Image Reporting and Data Systems (TI-RADS) for thyroid nodules. METHODS: A total of 600 t …


Diabetes mellitus and insulin resistance associated with Kabuki syndrome-A case report and literature review.

Thewjitcharoen Y, Wanothayaroj E, Nakasatien S, Krittiyawong S, Khurana I, El-Osta A, Himathongkam T. Clin Case Rep. 2022 Apr 15;10(4):e05736. doi: 10.1002/ccr3.5736. eCollection 2022 Apr. PMID: 35441024 Free PMC article.


The relationship of marital adjustment and posttraumatic growth in female breast cancer patients and their husbands.

Suo R, Ye F, Xie M, Zhang X, Li M, Zhang Y, Xiong C, Yan J. Psychol Health Med. 2022 Apr 19:1-7. doi: 10.1080/13548506.2022.2067339. Online ahead of print. PMID: 35440230

Individual marital adjustment can affect PTG, however, it is still unknown that the effect of marital adjustment on one's own and their spouses' PTG in breast cancer couples. To investigate the status of PTG and marital adjustment and explore the relation between PTG and m …


Elevated baseline circulating platelet-to-lymphocyte ratio and survival in initial stage Ⅳ gastric cancer patients: A meta-analysis.

Hu G, Wang S, Wang S, Huang L. PLoS One. 2022 Apr 18;17(4):e0265897. doi: 10.1371/journal.pone.0265897. eCollection 2022. PMID: 35436305 Free PMC article.


Diagnosis and prognosis of breast cancer by high-performance serum metabolic fingerprints.

Huang Y, Du S, Liu J, Huang W, Liu W, Zhang M, Li N, Wang R, Wu J, Chen W, Jiang M, Zhou T, Cao J, Yang J, Huang L, Gu A, Niu J, Cao Y, Zong WX, Wang X, Liu J, Qian K, Wang H. Proc Natl Acad Sci U S A. 2022 Mar 22;119(12):e2122245119. doi: 10.1073/pnas.2122245119. Epub 2022 Mar 18. PMID: 35302894


MiR-501-5p alleviates cardiac dysfunction in septic patients through targeting NR4A3 to prevent its binding with Bcl-2.

Gao L, Zhai Z, Shi Q, Yan J, Zhou L, Wu Y, Zeng Q, Tian G, Li H. Cell Cycle. 2022 May;21(9):961-971. doi: 10.1080/15384101.2022.2035618. Epub 2022 Mar 1. PMID: 35230891


Effect of S-1 Plus Oxaliplatin Compared With Fluorouracil, Leucovorin Plus Oxaliplatin as Perioperative Chemotherapy for Locally Advanced, Resectable Gastric Cancer: A Randomized Clinical Trial.

Yu J, Gao Y, Chen L, Wu D, Shen Q, Zhao Z, Liu W, Yang H, Zhang Q, Wang X, Hu P, Zheng Z, Wang X, Liu H, Xu Z, Yan Z, Wu Y, Jin M, Zhang Q, Liu X, Zhu K, Shou C. JAMA Netw Open. 2022 Feb 1;5(2):e220426. doi: 10.1001/jamanetworkopen.2022.0426. PMID: 35226081 Free PMC article. Clinical Trial.

However, the optimal chemotherapy regimen remains unknown. OBJECTIVE: To investigate the safety and efficacy of S-1 plus oxaliplatin (SOX) vs fluorouracil, leucovorin, and oxaliplatin (FOLFOX) as a perioperative chemotherapy regimen for patients with locally advanced gastr …


Cerebrospinal Fluid Extracellular Vesicles with Distinct Properties in Autoimmune Encephalitis and Herpes Simplex Encephalitis.

Li Y, Gu J, Mao Y, Wang X, Li Z, Xu X, Chen H, Gui Y. Mol Neurobiol. 2022 Apr;59(4):2441-2455. doi: 10.1007/s12035-021-02705-2. Epub 2022 Jan 27. PMID: 35083659


Usefulness of brain FDG PET/CT imaging in pediatric patients with suspected autoimmune encephalitis from a prospective study.

Yin Y, Wu J, Wu S, Chen S, Cheng W, Li L, Wang H. Eur J Nucl Med Mol Imaging. 2022 May;49(6):1918-1929. doi: 10.1007/s00259-021-05649-w. Epub 2021 Dec 23. PMID: 34939173


Graves' Disease in the Young: Could We Change the Weather?

Rodien P. J Clin Endocrinol Metab. 2022 Apr 19;107(5):e2186-e2187. doi: 10.1210/clinem/dgab909. PMID: 34928376 Free PMC article. No abstract available.

tattybogle profile image
tattybogle in reply to helvella

i was reading that "Graves disease in the young: Could we change the weather? " paper the other day .. Short , but interesting .

helvella profile image
helvellaAdministrator in reply to tattybogle

I read that too. :-)

I'm glad they are asking the question.

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