In Frontiers in Thyrod Endocrinology, Biano has written a review on the desirability of combination therapy in appropriate circumstances. At the moment only the title and abstract have appeared, but the whole article will soon follow - downloadable:
The Swinging Pendulum in Treatment for Hypothyroidism: From (and Toward?) Combination Therapy
Elizabeth A. McAninch1* and Antonio C. Bianco2
1Rush University Medical Center, United States
2University of Chicago, United States
Thyroid hormone replacement for hypothyroidism can be achieved via several approaches utilizing different preparations of thyroid hormones, T3 and/or T4. ‘Combination therapy’ involves administration of both T3 and T4, and was technically the first treatment for hypothyroidism. It was lauded as a cure for the morbidity and mortality associated with myxedema, the most severe presentation of overt hypothyroidism. In the late 19th and the early 20th centuries, combination therapy per se could consist of thyroid gland transplant, or more commonly, consumption of desiccated animal thyroid, thyroid extract or thyroglobulin. Combination therapy remained the mainstay of therapy for decades despite development of synthetic formulations of T4 and T3, because it was efficacious and cost effective. However, concerns emerged about the consistency and potency of desiccated thyroid hormone after cases were reported detailing either continued hypothyroidism or iatrogenic thyrotoxicosis. Development of the TSH radioimmunoassay and discovery of conversion of T4-to-T3 in humans led to a major transition in clinical practices away from combination therapy, to adoption of levothyroxine ‘monotherapy’ as the standard of care. Levothyroxine monotherapy has a favorable safety profile and can effectively normalize the serum TSH, the most sensitive marker of hypothyroidism. Whether levothyroxine monotherapy restores thyroid hormone signaling within all tissues remains controversial. Evidence of persistent signs and symptoms of hypothyroidism during levothyroxine monotherapy at doses that normalize serum TSH is mounting. Hence, in the last decade there has been acknowledgement by all thyroid professional societies that there may be a role for the use of combination therapy; this represents a significant shift in the clinical practice guidelines. Further bolstering this trend are the recent findings that the Thr92AlaD2 polymorphism may reduce thyroid hormone signaling, resulting in localized and systemic hypothyroidism. This strengthens the hypothesis that treatment options could be personalized, taking into consideration genotypes and comorbidities. The development of long-acting formulations of liothyronine and continued advancements in development of thyroid regenerative therapy, may propel the field closer to adoption of a physiologic thyroid hormone replacement regimen with combination therapy.
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That is because he realises that that idea for TSH is under pressure, but since he hasn't discovered it first, but others have, refuses to acknowledge. That's how medicine proceeds nowadays. American "exceptionalism" is what drives academic acceptance in that country. They either find it themselves, or if not ignore until they repeat and claim the finding as theirs. Sorry to be so suspicious, but that's how things go.
We on this forum - members and experts - know that a FT4 and FT3 is more informative than T4 and T3 and that many of us feel well when both are in the top ratio with a TSH 1 or lower except it seems that the guidelines of Endocrinology is that a TSH of 1 or lower means we've gone hyper which isn't true so they adjust dose to 'try to fit us' into a range whilst ignoring symptoms. Also the 'modern method' does not go by relief of clinical symptoms and neither do they know any but will diagnose us with 'other conditions' and prescribe anything other than increasing thyroid hormones.
I was at least lucky that my Endo did aim for those optimised numbers not just anywhere in the range but I never felt well even with a TSH well below 1 (0.2-0.5). I have the DIO2 polymorph so perhaps that is why I felt so bad and much improved on NDT. Oddly, my hypothyroid relatives really like Levothyroxine 😳 due to having thyroid cancer a suppressed TSH was aimed for in their case, but even with that I felt even more unwell. The way thyroid treatment is going in the uk is very worrying. I am ploughing through the article diogenes linked to about the short comings of the current state of affairs
it is very interesting but not a quick read for me I find a lot of numbers and abbreviations in a block hard to digest 🙄. I quite agree with you of course and at the end of the day it is how the person actually feels that is what really matters not a load of numbers. Thank goodness for ThyroidUK and the information it provides, it has certainly allowed me to educate myself about my condition and vastly improve my health 😊
We are all so different but if you have a defective gene, you would expect endocrinologists - at the very least - to be aware of this possiblity.
I'd like a survey to be sent to all doctors/endocrinologists with a few questions for them to answer i.e.
1. When patient is taking levothyroxine, what is the aim for the best TSH result?
2. How often does the patient have Free T4 and Free T3 tested, especially when complaining if they take levothyroxine alone?
3. Do they aim for a TSH of 1 or below when taking levothyroxine? Or do they keep the TSH within the range - even up to 5?
4. Are doses increased every six weeks?
5. How many clinical symptoms do they know?
6. There are a number of scientific reports and the evidence shows that those not recovering on levothyroxine, feel much better when on a T3/T4 combination.
7. What do you do prescribe if you think patient is depressed? (i.e. they should check FT3 to ensure it is not the lack of this hormone that's the problem)
Excellent questions. It should be a compulsory survey or they don’t get paid and if their answers are found wanting they should be sent on a re education programme for hypothyroidism including: signs, symptoms and its correct treatment with individually tailored and optimised thyroid hormones.
I hope one day there will be a sea change in the medical professions’ whole approach to diagnosis with the aim of getting people as healthy as possible again, not the any old number will do and pop an antidepressant that is so prevalent today. UK Endocrinology seems a like a juggernaut - very difficult to turn around.
They have to 'toe the line' due to the cost of T3 nowadays. It can be sourced more cheaply if they were in the least bit interested how to save the NHS money.
I do, too. This is so helpful Diogenes and dare I say encouraging ... my endocrinologist was at first reluctant to recognise the significance of my DI02 result. I shall take a copy of this to next week's appointment at the Thyroid Clinic and discuss it with her again. I am in the midst of a Levothyroxine reduction regime set by the Endo in order to 'qualify' for T3 trial. After two months I am badly feeling the affects of reducing daily prescription by 50mcgms - from 150mcgms to 100mcgms. From my experience, poor conversion seems to play a highly significant role in worsening symptoms when Levothyroxine is reduced.
I feel sorry for you to have to reduce your dose in order to prove that you need T3. This sounds very stupid to me. Why make the patient suffer in order to make a point, i.e. reduce levo which in turn reduces the T3 in order to prescribe some T3. It doesn't make sense.
Thank you diogenes Isn't it petty this failure to acknowledge other's achievements. Spoilt kids! Bianco could have done some good here by acknowledging this, for thyroid patients everywhere, instead..... Tagging linda96
In the NICE draft there is mention that treating SCH under 10 would would normalise TSHR faster. Does this not then follow that they should be treating at the first sign of the TSH rising? And isn't over 10 overt?
The basic problem is that, whenever we put pen to paper, we all fall so easily into the error of categorisation (medics and me as well).. Eg TSH above 10 is overt hypothyroidism. TSH below 10 isn't. The unique response of the individual is lost when such statements are made. Eg again: you are in the "normal" range therefore OK. The ranges simply express the limits for all healthy individuals as a group panel but say nothing at all about where exactly an individual will find the correct values for them and if sick how to find them by appropriate therapy.
Yes I see what you are saying so how do we change the way that researchers report on this. The NICE draft mentions 5 - 10 and this is all the GP's etc are seeing. Even though, in my view they outline the inefficiency of the 'range' when they say that a patient might be in range and have symptoms, out of range and not have symptoms. The even say that out of range + no symptoms may benefit from treatment to reduce long term risk, this coupled with the 'treat under 10' more effective than when over, has me asking why wait for 10? If symptoms and strong suspicion of thyroid then surely a carefully monitored trial would be preferable to avoid long term risk. Had I been treated within that first 10 years, when symptoms were there but biochemistry hadn't caught up, might I have been able to tolerate T4? Might my adrenals not struggle now?
Too many questions.
I do feel that the research being used does seem to focus on thyroid and..... there seems to be little on just thyroid, and I wonder how much is being misunderstood. That said do you know of any research on thyroid and adrenal?
I love the sensible logic expressed in your final sentence. Wouldn’t it be wonderful if medics could acknowledge it... whether or not they’d thought of it first!
I just thought of something! We wrote about "the swing of the pendulum" in our paper "Time for a reassessment of the treatment of hypothyroidism". Copycat Bianco!
I had the gene test hoping to show poor conversion. However My Dio2 was green but I had 3 others double red which I understand show my problem to be with the pituitary. Under these circumstances the pituitary doesn’t respond to the thyroid hormone changes. So remains in range despite having hypothyroidism.
Do you know of any work done in this scenario please ?
I am diagnosed with a pituitary adenoma, none functioning . maybe ‘it’ is too lazy to produce TSH 😁
There are sites that are good for looking at the different genetics. Not sure how useful they would be to you if you have only done specific gene testing. Having done testing through 23andMe - looking specifically for the DIO2 genes to find they had stopped genotyping the rs225014 SNP, I then did Regeneus. I later did Ancestry DNA for more family tree info, they only give raw list of data, not searchable by SNP name. But found they did genotype the DIO2 snp. Hey ho! But Promethease was a site I liked, and Livewello more so. Tend to use Livewello a lot. I use 23 to grab all the snps genotyped, or not, then load them into Livewello, build a report, then run the same report for the Ancestry profile, can then compare reports, so combined get more information. Do have to pay for each profile - was about $20 a time. Lots of linked publications to different snp's.
Hi I’m curious about the long acting formulations mentioned. At recent endo meeting he said it would be much easier to manage if we had a slow release T3. Is this an on going project or just something people are talking about. Also gave him your last paper with Toft to read, I asked him to let me know his thoughts and I will pass them on.
I think there are moves in this direction. For one, he has produced a T3 derivative that has a longer lifetime. First, the field has to acknowledge the existence of patients who need combination therapy and just what fraction of everyone they make. He's in a good position to stimulate the US medical fraternity. One wishes there was someone of equal calibre here in the UK. You have links to Bianco, I read here. Good link and I anticipate his houghts.
I don’t know that I can readily access the longer version. Can you please share any further insights on it you may have when it comes out. Thank you in advance.
My particular interest is the dual roles of TSH, stimulating secretion of hormone and stimulating deiodinase. The latter is invariably ignored. L-T4 monotherapy has a greater effect on TSH suppression ('In the hypothalamus, as a result of localized reduction in D2 ubiquitination, there is increased sensitivity to T4 levels...'). So, L-T4 monotherapy not only denies patients of the small amount of T3 secreted by the thyroid, it also reduces the T3 converted from T4 by peripheral organs (including the thyroid if there is one left). This is in part addressed in some of diogenes papers which I find rather advanced! In summary, the effect of L-T4 monotherapy is not just a loss of a little secreted T3 but also the loss of deiodinase and the intracellular T3 from such deiodinase. This problem might be overcome by tablets that deliver steady T3 and T4 physiological levels. Studies suggest about 15% of hypothyroid patients are affected to a degree that can be measured.
My greater concern is there are many patients whose TSH does not adequately respond to low hormone levels. Not central hypothyroidism but a more subtle form I call 'subnormal TSH secretion'. This can happen in autoimmune hypothyroidism if there is a period of thyrotoxicity which the patient may not notice. The hypothalamic pituitary thyroid axis can be down-regulated. The patient can present with low normal fT3, fT4 and a normal TSH. I've seen over 50 such cases on the forums, patients with 'normal' blood tests and severe signs and symptoms. In these cases L-T4 rapidly lowers TSH leading to further reduced deiodinase, a vicious circle. Some patients even feel worse when given levothyroxine. Restoring physiological hormone levels will not help these patients, intracellular T3 will remain low in tissues that rely on deiodinase for their T3.
Studies that show about 15% of patients do not respond to L-T4 monotherapy are subject to substantial selection bias. These are retrospective studies with cohorts consisting of patients diagnosed on established factors, i.e. an elevated TSH, usually above 10.0. These criteria exclude hypothyroid patients whose TSH is not elevated, exactly the patient group least likely to respond to L-T4 monotherapy. I am writing up a topic on this subject which should be available in a few weeks time. I'll post on this forum when it is ready.
There is also the problem of "over or undershoot" for the TSH response in a changing unstable situation. TSH can often only respond some time after a change in the overall production system from the thyroid occurs. This is true when changing T4 therapy levels suddenly or when trying to increase TSH in hyperthyroidism by carbimazole. So a fluctuating situation for thyroid hormones at one moment isn't necessarily mirrored by the appropriate TSH fluctuation at the same time. This is called hysteresis. So when things are rapidly moving in either direction, the TSH response can get into a considerable delayed "tangle" and not indicate the immediate position.
Yes, and on the opposite side a long-term high TSH can take a long time to respond to restored hormone levels and a long-term suppressed TSH may never come back to normal. I have never seen a study that demonstrates a correlation between TSH and hypothyroid signs and symptoms. I'm sure it does for a subset of patients but this subset has never been identified. An elevated TSH can identify primary hypothroidism (invaluable in neonates) but in general TSH is not so good for titrating therapy or identifying other forms of hypothyroidsm.
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