A surprise this morning - a new Bianco paper that I did not know of.
Definitely on the levothyroxine monotherapy issues - albeit in mice.
Mice are different, but the conclusion supports moving away from levothyroxine monotherapy.
Variable transduction of thyroid hormone signaling in structures of the mouse brain.
Sinkó R 1 , Salas-Lucia F 2 , Mohácsik P 1 , Halmos E 1 , Wittmann G 3 , Egri P 1 , Bocco BMLC 2 , Batistuzzo A 2 , Fonseca TL 2 , Fekete C 3 , Bianco AC 2 , Gereben B 1
Author information
Proceedings of the National Academy of Sciences of the United States of America, 04 Feb 2025, 122(6):e2415970122
L-thyroxine (L-T4) monotherapy is the standard treatment for hypothyroidism, administered daily to normalize TSH levels. Once absorbed, T4 is converted to T3 to alleviate most symptoms. However, this treatment abnormally elevates plasma T4 levels in over 50% of patients. Using L-T4-treated Thyroid Hormone (TH) Action Indicator mice, which express a T3-regulated luciferase (Luc) reporter, we examined whether these T4 elevations disrupt TH signaling. Hypothyroid mice exhibited reduced Luc expression across brain regions, and L-T4 treatment failed to restore T3 signaling uniformly. There was also variability in the activity of type 2 deiodinase (D2), the enzyme that generates most brain T3. Intracerebroventricular T4 administration achieved higher elevation of Luc expression in the mediobasal hypothalamus compared to the cortex, and studies on cultured cortical astrocytes and hypothalamic tanycytes revealed cell-type-specific responses to T4. In tanycytes, exposure to T4 sustained D2 activity, leading to progressive T3 signaling, whereas in astrocytes, T4 exposure triggered a drop in D2 activity, limiting T3 production through a ubiquitin-dependent, self-limiting mechanism. The sustained D2 activity in tanycytes was linked to rapid deubiquitination by USP33, as confirmed using a ubiquitin-specific protease (USP) pan-inhibitor and USP33 knockout mice. In conclusion, the brain's response to L-T4 treatment is heterogeneous, influenced by cell-specific regulation of D2-mediated T3 production. While cortical astrocytes exhibit limited T3 signaling due to D2 ubiquitination, tanycytes coexpressing USP33 amplify T3 signaling by rescuing ubiquitinated D2 from proteasomal degradation. These findings provide mechanistic insights into the limitations of L-T4 therapy and highlight the need for tailored approaches to managing hypothyroidism.
I have just finished Bianco’s book Rethinking Hypothyroidism. His research is motivated by listening to his patients and he is involved in developing a delivery system for combining T3 with T4. Unfortunately, in the UK the person with perhaps the most influence seems to be focusing their research towards proving patients wrong and that many are taking Levothyroxine unnecessarily.
Full of VERY interesting stuff, packs so much in, like this work on T3 tissue values rather than serum T3. Looks like his move to the University of Texas, with access to huge data records, will prove valuable for all of us in thyroid-world. e.g. the dementia statistics (patients on combined T4+T3 have noticeably LESS RISK of dementias than if on T4 only). The range of questions he is raising makes a nonsense of the dangerous work of Imperial Trust to deliberately remove T3 from patients jimh111 .
I took the link to (very nice) GP yesterday. The more we can pass on this kind of information the better. More power to Bianco and his team - I'm now a fan.
Why do I get the feeling that so much of this research has its roots in basically things that have been already proven, time after time? I realise it’s ‘updating’ old known information but none of it gets used anyway. Monotherapy by Levothyroxine only! Where is the funding coming from which gets these interesting results which are entirely unlikely to become mainstream usage. How are researchers able to convince funding providers for thyroid research? As long as we have ‘deniers’ like Pearce in place, this is wasted effort.
Whilst I am glad someone is still doing thyroid research, I would very much like to see it being employed in practice.
Ive been on Levothyroxine for 30 years and have had no problem . I have Hashimotos Thyroiditis . My thyroid levels and TSH are tested every year, and more often if I have a change in dosage. Ive never had a problem with it. I have gone up and down over the years in dosage, from 50mcg to 150mcg. Ive only had over-active thyroid once, when my TSH was below zero.
There is a natural desiccated thyroid hormone (Armour) made from porcine (pig) thyroid, I used once when I was younger ,but i feel the Levothyroxine worked better.
I think it’s all our individual choice as what works best for ! Last time they tested me , my antithyroid antibodies, antithyroglobulin , anti-microsomal antibodies,and thyroid peroxidase were not elevated.
Many people with primary hypothyroidism do perfectly well on levothyroxine monotherapy but there is growing evidence that a high normal fT4 is associated with reduced life expectancy.
We don’t see much of the approximately 80% of patients who reportedly do well on Levothyroxine mono therapy, on this Forum. It’s wonderful you are doing well. I am certain many of us are very envious. Best wishes.
I was hoping there would be single line conclusion as I can't face reading the research today -
so I'll make my own conclusion that we are going full circle back to the beginning and the original first treatment option we have used successfully to treat hypothyroidism for over 100 years
but it will be a synthetic T3/T4 combo tablet as this will be more PC and kinder on the pigs -
and as for those ill with hypothyroidism - I'm not sure there is sufficient haste in any of this to help anyone, anytime soon.
One of the interesting things I picked up from Bianco is his statistic that nowadays at least 10% of hypothyroid patients in the US are insisting on combined LT4+LT3 medication. About 2 million patients. And 75% of them take NDT/DTEs, about 1.5 million, and that number has been increasing over the last 10 years.
So I agree we may, thank heavens, be coming full circle. Making a slow-release LT3 medication seems to be an agenda now ("think of the money...") but so far no-one has succeeded. And now that key medics and drug makers have conceded that a combination of LT3/LT4 may be better for 10-20% of patients, we may be able to openly access NDT/DTEs, nature's own slow release T3.
My guess is that when someone is able to produce a slow-release LT3, it'll be bloody expensive! - and our old NDT will look really cost-effective to bulk payers like the NHS or insurance companies.
I have many reservations about the current White House occupant, but one thing which may be a benefit is the potential shake-up of the US pharmaceutical and regulatory system. 🤞
I'm sure I've read of there already being a ' slow release T3 ' -
I think it all about $$$ and vested interests -
We certainly need a medical ' shake up ' !!!
The NHS has encouraged its own demise of failing O/P waiting list targets by taking T3 and NDT out of the remit of primary care doctors.
How does the UK medical establishment manage this research, stand down from its stance on T3 and NDT - and re write the NHS guidelines without losing face ?
Not that those suffering with hypothyroidism and knowing that they have been ' bumped and/or dumped ' have any respect left anyway.
Bianco was talking about polyzincliothyronine - and I think it was patented - so being taken seriously.
But it seems to have gone quiet.
I'm very wary of traditional slow/delayed/controlled release mechanisms in relation to thyroid hormones. Basically, I'm not convinced most of them could ever provide predictable, reliable release of these hormones.
I'm somewhat more optimistic of other approaches such as implanted dosing devices. Though they would be extremely limited due to cost.
The results of a pharmacokinetic study of a sustained release T3 preparation (polyzincliothyronine) have been published online130 and a sustained release T4 and T3 combination might be forthcoming.
so guess all these research papers just build up in a box file - or a ' cloud ' -
until it is so heavy it falls off the shelf - or ' rains down ' so heavily - and gets washed down the drain -
or maybe someone somewhere suggests RAI thyroid ablation for Graves be withdrawn as a NHS treatment option and research begins again looking for a better outcome to that already found and filed away.
My NHS endo told me it was still about two years in the pipeline for the NHS. Slow release. He then chose not to treat me! It will ((hopefully) work for some patients but I am inclined to think along the same lines as helvella . It strikes me with horror that extra T3 might be released at a most inopportune moment, making me ill, or indeed not releasing some when I need it, giving me a lot of the same problems I have now. ‘Playing statues’ in public places.
I asked for a short summary for patients to understand! His reply was: "Physicians use TSH levels to ensure patients are taking the correct dose of LT4. Here we show that under these circumstances some areas of the brain remain hypothyroid. Meaning, that TSH may not reflect the treatment status of all tissues."
The assumption that a TSH test and, if you are lucky, a Free T4 test can identify whether you have adequate thyroid hormone in all 200-or-so tissue types across all the organs of a human body is childishly naive.
We KNOW that people (and rats!) with MCT8 or MCT10 genetic variations cannot transport thyroid hormone across the blood-brain barrier as needed.
We KNOW that people have issues with thyroid binding proteins, cell membrane variations, etc., which affect thyroid hormone distribution.
We KNOW that people have issues with hypothalamus and pituitary hormone production.
We KNOW that astrocytes and tanycytes perform some complex dance in our brains.
But let’s ignore all that and assume a TSH test once a year (which is somewhere in the ridiculously wide reference interval) tells us everything we need to know.
Knowing how good they are at gaslighting, I would suggest they just deny ever having said any such thing in the first place! Works for most narcissists.
This study was mentioned by Tony Bianco in his recent presentation to The Thyroid Trust. It’s a great piece of work but very technical. Type-2 deiodinase (D2) converts T4 to T3 locally, in the endoplasmic reticulum which is close to the cell nucleus. D2 regulates local T3 and is the main source of circulating T3. D2 expression and action is reduced by the presence of T4 in all tissues except the hypothalamus and pituitary. It was demonstrated in the hypothalamus in 2015 healthunlocked.com/redirect... . Tony Bianco’s team showed that D2 activity was constant in the pituitary in 2023 healthunlocked.com/redirect... .
A new study “Variable transduction of thyroid hormone signalling in structures of the mouse brain” healthunlocked.com/redirect... confirms this mechanism and in very technical detail describes the mechanisms involved. In addition it shows T4 suppression of D2 varies in different regions of the brain, the hippocampus in particular is very sensitive to T4 levels. The hippocampus has a role in memory processing and perhaps brain fog.
This is vital research because it shows that brain T3 levels are substantially independent of circulating T3 (the brain gets most T3 from D2 converting T4, far less coming directly from blood T3). It shows levothyroxine monotherapy will not achieve uniform brain euthyroidism, although I suspect the effect is small.
Much more important from my viewpoint is that D2 activity in the brain is crucial, anything that disrupts it will have substantial consequences on cognition and brain function. Reverse T3 and endocrine disruptors impair D2 activity in the brain healthunlocked.com/redirect... . This will lead to brain hypothyroidism which is not corrected by restoring normal serum fT3, fT4. Additional T4 further reduces D2 activity. Supraphysiological serum T3 levels, although undesirable, will be needed to restore relatively normal brain function. This is my experience, I need a minimum of 45 mcg liothyronine to get reasonable brain function. When concentrating on text I tend to lose focus and get brain fog within 20 minutes, I have to rest my brain for a while. I suspect I use up my brain T3 reserves, I am unable to convert T4 to T3 quickly enough. If I increase my liothyronine I can concentrate for longer but I fear it will damage my heart in the long run.
This is a terrific study, it demonstrates one of the ways thyroid action in the pituitary is different to peripheral actions (the pituitary also has different thyroid hormone receptors). It clearly shows pituitary T3 levels can be different to serum T3 and that normal D2 activity is crucial. As I like to say “where the T3 comes from matters”, substituting D2 derived T3 with liothyronine or higher D1 activity is not the same. Those addicted to the blood test dogma will likely object with spurious arguments, we should respond by asking “where’s the evidence”.
Bianco has been ‘called out’ many times on his position re: TSH on the Forum. I guess it’s because we are frustrated and in a hurry (me). However it is gratifying that he has been working away at the issue with the science. I posted earlier about the re-examination of stuff “we know” and it never reaching practice, on this very post. However, reading other comments, especially jimh111 I see more particularly what Bianco is up to and appreciate it more. If he is going to change the common view on limitations of TSH, he has to back it up with the science - off course he must.
I too get the brain fog but my heart issues bother me more. As I understand, the heart can’t do its own conversion to T3, it needs to be available in the blood from conversion elsewhere. I must say that sounds like glitch in the arrangement of the body workings. Can’t remember the arrangement for the brain (maybe the brain fog is worse than I think). I feel like I have been damaged beyond repair in the heart department because of lousy testing, rules, ignorance. It’s pretty annoying.
This is very interesting!! I have read so much on the Thyroid over the years and never come across D2! Thank you for highlighting!!
My T4 is in the gutter <5.4 as is my brain fog most days! There could be a link!
My T3 mid range and TSH 0.01. My energy levels are still not brilliant and my brain fog certainly not great. Above all, I now have high cholesterol for the first time ever. I feel this is linked to hypo! I eat very healthily. Mainly only keto diet.
I also get heart palpitations randomly with shortness of breath. Cardio said my heart is good, therefore, it must be my thyroid meds. What a friggin minefield this all is.
I am booked to see a different endo from Harley Street next month for a second opinion after having been with the same endo for years. I want a specialist who is not a NHS specialist to see if they have a different take. I am tired of my life being dominated by my thyroid and trying to find the best med and dose.
Hi Angie, I too have heart palpitations (and arrhythmia heard by my vet daughter) and shortness of breath. If you find the cause and/or resolution please would you post on here ? Thanks
Hi, I am so sorry for my delayed reply. Of course I will update you if I get anywhere with my non NHS endocrinologist. Hoping Harley Street will prove more successful as I am at my wits end with this. I had another episode this afternoon when my heart rate leaped from 67 bpm to 210 bpm whilst sitting. Cardio stated my heart is fine. However, I have been reading that if hypo isn't treated properly it does lead to a constant tight chest and shortness of breath and when thyroid hormone levels are low, the body may retain fluid, including in the chest area, contributing to a feeling of tightness. Oh the joys! I wish some professional out there could help me get my head around this. I am tired of reducing my meds when my T3 is only mid range and T4 <5.4. TSH is always around 0.01. Can't help but think this is the reason. However, with hypo, my TSH will always be low...
Hi, thank you for taking the time to reply. Yes, l’m on HRT. 100 everol patches. Maybe too high. Yeah, really hoping my new endo will do a full range of bloods 🙏 and resolve these worrying symptoms. Xx
Thank you Angie. I agree with you, wish there was someone or somewhere we could find the answers and treatment. I can see why you are concerned with that he art rate leap, (I have concluded that my heart must be in good shape to cope with these episodes, yours too?) I am similar with the meds, TSH too low so meds reduced because DEXA scan showed osteoporosis - devil and the deep blue sea come to mind! Very best of luck.
This is for both you and Angie33. “I have concluded that my heart must be in good shape to cope with these episodes.” I have found myself saying this for about forty years. Mine are painful as well as distressing. Mine has a name - coronary spasm.
Unfortunately because of extremely late diagnosis, combined with very poor treatment my arteries are full of plaque. This in itself is distressing. However it’s been known for over a century that this is the end product of undiagnosed and untreated hypothyroidism.
Why, because even a hundred years and more down the road, doctors know precious little about thyroid issues and worse, they show no sign whatsoever of wanting to learn.
In my view it’s criminal to attempt to treat us all the same. A friend of mine (hypo) recently had a conversation with her GP - she is extra quick off the mark sharp sometimes. She got an answer after disputing the old “we have to reduce your Levo because your TSH is too low” without the GP lifting her head from her computer but pointing at it. Patient’s reply. “Ah but I am not a computer so I won’t be accepting a dose reduction” and left the GP at her computer.
Oh arTistapple that sounds awful, really distressing. Mine are very mild compared with yours and Angie33s. So sad to suffer through no fault of your own, I don't know what we can do. I also was very late diagnosis and my TSH was over 95 with 95 being coma level by the time I saw the endo. You have to laugh though, the last thing my GP said to me just before the endo appointment was "Well, you don't look hypothyroid"!!!
OMG their education is so lacking but worse than that is their condescending attitude when they don’t know nearly enough about what they are talking about! They so don’t understand hypothyroidism. It’s safe to treat us patients with disdain - “after all, I know is it’s very rare to hear of anyone going into a coma. I should be quite safe doing nothing/being as disparaging as I like”. They don’t even wonder if they might have the wrong end of the stick.
It’s hard to have a conversation with someone who should be knowledgable and just are not. I end up disgracing myself by trying to avoid disgracing them!?!? Why?
Thank you so much for your reply. I agree, and a positive outlook, our hearts must be in a good place to withstand these episodes! It saddens me so much that this diagnosis is through Dr's negligence! My GP as well as endo are of no help to me at all. If I hear anything refreshing from my new endo in Harley Street, I will definitely share my information. I feel this site is a godsend! I'd feel I was going mad otherwise. Love the response your friend had to her GP. I am at the stage of falling out with medical professionals too! xx
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