Sorry to ask this question, I am sure it has been asked many times before, but I need some ammunition to confront my own doctor when I next go.
I saw another doctor in the surgery last week, which I don't usually do, as my doctor was away. I wanted another TSH test and possibly iron, as like so many others with a TSH of 4.57 (in February) I am still feeling awful. And... you know whats coming next, TSH in normal range, endo's and dr's take the view I am well medicated and symptoms are not taken into account.
So, my question is:-
I know that TSH is the pituitary's response to not enough hormone in the blood, but where is it getting its information from? T4 is a pre-hormone which is converted to the active T3 so will the pituitary know whether there is enough T4 in the tank, or will it go on the T3 alone.
Within the pituitary, T3 is detected and affects the amount of TSH produced. That T3 arrives both as T3 from the bloodstream and as T3 converted from T4 locally within the pituitary. The rate of local conversion within the pituitary can be different to that in the rest of the body - that would cause the TSH level (potentially) to be inappropriate.
The pituitary is also influenced by the TRH received from the hypothalamus which, in turn, is affected by both bloodstream carried T3 and locally converted T4.
You can end up with the pituitary being resistant to thyroid hormone. Apparently due to oddity in Thyroid Receptor alpha.
The Dynamic Pituitary Response to Escalating-Dose TRH Stimulation Test in Hypothyroid Patients Treated With Liothyronine or Levothyroxine Replacement Therapy.
Yavuz S, Linderman JD, Smith S, Zhao X, Pucino F, Celi FS.
Source
MD, MHSc, Diabetes, Endocrinology, and Obesity Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Building 10, Clinical Research Center, Room 6-3940, 10 Center Drive, Bethesda, MD 20892-1613. fc93a@nih.gov.
Abstract
Context: A recent trial showed that 1:3 µg:µg liothyronine (L-T3) substitution for levothyroxine (L-T4) achieving near-identical TSH levels resulted in a significant decrease in weight and cholesterol levels with no appreciable changes in cardiovascular parameters, suggesting a differential peripheral response to the therapy.
Objective: We characterized the pituitary-thyroid axis in hypothyroid patients receiving equivalent doses of L-T3 or L-T4 by escalating-dose TRH stimulation test.
Design: A secondary analysis of a L-T3 vs L-T4 therapy trial was performed.
Setting: The study was conducted at the National Institutes of Health.
Patients: Thirteen patients were studied.
Interventions: Escalating-dose (5, 15, and 200 µg) TRH stimulation test on both treatment arms.
Main Outcome Measures: Study outcomes were peak serum TSH concentration (Cmax), time to peak TSH concentration (Tmax), area under the curve from 0 to 60 minutes (AUC0-60) after TRH injection.
Results: Thirteen patients aged 51.2 ± 8.29 years completed escalating-dose TRH stimulation test. No significant difference between L-T3 and L-T4 treatments was observed in TSH Cmax or area under the curve. L-T4 resulted in a small but significantly shorter Tmax compared to L-T3 (3.5 ± 0.73 min on 200 µg TRH dose, P < .03). In addition, 5 µg TRH dose compared to 200 µg resulted in a shorter Tmax on both treatment arms (6.9 ± 0.59 min L-T3, 4 ± 0.3 min L-T4; P = .0002).
Conclusions: The assessment of the dynamic pituitary response to escalating doses of TRH confirms that substitution of L-T3 for L-T4 on a 1:3 ratio achieves a near-identical degree of pituitary euthyroidism. Furthermore, the data suggest that lower doses of TRH might provide clinically relevant information of thyrotroph function, particularly when investigating partial pituitary insufficiency states.
Thank you Rod, that was very helpful. The hypothalamus is a whole new area for me so I am going to have to read that a few times.
So, what you are saying is that Dr's (NHS) rely on the TSH so implicitly because they are convinced it is a good indication that your body has sufficient T3 (the pituitary says so). However, this is flawed because it does not always reflect the T3 in the rest of the body. Did I get that right?
This leads to another question then, when blood T3 is tested is this a better indication?
The advantage of the TSH test is that TSH levels change relatively slowly. That is, they end up reflecting, within their technical limits, something like the average thyroid hormone levels over days/weeks.
Specific T4 and T3 tests can be rather more dynamic and varied.
However, there are still daily rhythms of thyroid hormones and TSH which are almost entirely ignored by medics.
And, of course, the TSH level can fail to reflect the thyroid hormone levels for lots of reasons. See PR4NOW's reply below.
Hi Rod. I've been struggling to make sense of this paper jci.org/articles/view/61231, but it seems to suggest (?) that while plasma T3 levels may feed back to influence TSH levels, that plasma T3 levels are in fact under the control of a different system/subject to a separate control loop: jci.org/articles/view/61231
I'd be interested to hear some more views on what it's actually saying.
It's signficant, because if the above is true then the TSH control loop is presumably about ensuring appropriate levels/reserves of T4 (precursor hormone) in the blood to support likely T3 (active hormone) needs - but that if the actual rate of conversion of T4 to T3 is controlled elsewhere then it's no wonder that TSH is not a very good predictor of 'wellness'.
On the basis that the amount of T3 (the active form of the hormone that's needed at the cellular level to support/drive metabolism) actually converted has little to do with TSH levels...
Just to add a bit more which came up a few minutes ago in the context of another thread linked below.
This paper confirms that quite a lot of our T3 is normally produced directly by the thyroid, and not by conversion from T4. It suggests that after thyroidectomy we may need either TSH suppressing levels of T4 and/or the dosing of T3 with T4 to achieve normal levels of T3 in the tissues:
Which (a) seems to add to the above suggestion that T3 levels are not naturally controlled by the TSH loop, (b) to suggest that the stock TSH test is as a result probably not a good measure of normal/correct levels of blood/tissue T3 - because there's lots more that determines the rate of direct production and conversion of T4 to T3; and (c) that we don't naturally produce all of the T3 we require by conversion from T4.
i.e. it looks like TSH ensures an adequate supply of T4 is maintained in the blood for conversion to T3, but that the actual rate of production and conversion may be determined elsewhere.
One consequence of this ( see thread thyroiduk.healthunlocked.co... ) may be that individuals who have had thyroidectomies may be more likely to need replacement T3 with their T4.
This because with removal of the thyroid direct production of T3 ceases, leaving them (as is not naturally the case) entirely dependent conversion from T4 for their supply of T3.
I'm not sure if all of the above is correct, but if so it's more reasons why the management of replacement by the T4/TSH blood test based protocol often fails to leave us feeling well....
Ta very much PR4NOW - that's a nice set of papers covers the matter of production of T3 in the tissues and how the deiodination process regulated - at a level deeper than the norm but still fairly accessible. There's times I struggle to get it for lack of understanding of terms/uncertainty regarding excatly what he's saying.
It confirms that most T3 is produced by conversion of T4 at the tissue level, with maybe 10 - 20% produced directly by the thyroid.
He seems to say (as do most sources) that TSH is basically about regulation of the output of the thyroid, but has little to do (although it responds to) what's going on in the tissues to control plasma T3 levels.
What drives me nuts about all of this (having struggled with undiagnosed hypothyroidism and related illnesses for many years) is how de-facto medical practice basically ignores all of this - to take the position that if your T4 and TSH levels are OK that then all is well.
When even a cursory reading of material like this shows that this assumption relies 100% on downstream tissue based conversion and activation processes operating perfectly. When clearly in many of us they don't.
Even a fairly concise piece like this very helpful Wiki article which seems to more or less to set out the same T4/TSH party line ( en.wikipedia.org/wiki/Hypot... ) talks of the 'major portion of T3 being produced in peripheral organs: e.g. liver, adipose tissue, glia and skeletal muscle by deiodination from circulating T4' - and of the associated 'deiodination processes being controlled by numerous hormones and nerval signals including TSH, vasopressin and catecholamines'.
It seems to me (and i'm far from the first the conclude this) that there's mountains of research out there showing that (a) blood T4/TSH levels cannot be a good sole indicator of effective thyroid replacement, (b) that it's much more related to achieveing correct plasma T3 levels, and that (c) that there's probably lots more in addition going on at the peripheral/cellular and more holistic levels that determine well being.
I doubt either (relevant in the case of those of us that have had total thyroidectomies) that the 10 - 20% of T3 produced directly by the thyroid is by accident. i.e. That conversion can be relied upon to seamlessly take up the slack in the case of thyroidectomy patients replaced with T4 alone. It's certainly not been my experience....
There also seems to be more than enough data out there to suggest that when the replacement dose of hormone is set to maintain the currently regarded as 'normal' levels of TSH that these peripheral processes are likely left sub optimal, and the patient effectively hypothyroid.
My endo only a few weeks ago accepted this view, but said that the core issue is that there is no practical (perhaps that means financially feasible) means of testing available to determine what's going on at the peripheral/cellular levels.
Which begs the question. Why is the work not being done to establish one given such a widespread and basic need?
Ian, we all struggle to wrap our minds around the science. I would kill for a PhD in biochemistry. Speaking of testing, if you missed these they will round out the testing dilemma. Check out Dr. Lee's presentation from the 2003 ATA symposium on "TSH reference Range Redefined:
What Does It Mean and What Should We Do." This only works on a PC, not a Mac.
The others are also interesting if you have the time.
And Dr. Carole Spencer's presentation "Contemporary Issues in Thyroid Disease Measurements " from 2009. You have to download both the slide presentation and the notes pdf's and open them side by side so you can read the notes as you look at the slides.
There are two methods that I know of for checking peripheral/cellular levels.
The BMR, which has been around since the 1930's, it was actually the first thyroid laboratory standard, and can be fraught with problems and the indirect calorimeter. Dr. Lowe used both of these at times. Although Dr. Barnes's "resting basal temperature test" is not specific to thyroid it is also a means of checking the effect of what the metabolism is doing.
By two years after the TSH was adopted as the Gold Standard in 1973, medical schools stopped teaching doctors how to clinically diagnose thyroid problems. Great for the doctors, one less thing to learn, not so great for thyroid patients. The extent of most doctors clinical knowledge is to subject us to the tyranny of the TSH test which is an inferior standard of treatment that leaves many of us sick, or makes us sicker, or destroys our lives, and occasionally kills some of us.
If you really like a challenge try reading up on the co-activators and co-repressors like SMRT and NCOR. They think NCOR1 might be involved in setting the set point in the pituitary. As Dr. Hollenberg said in one presentation, "By the time you look at transport, the deiodinase's, and the co-activators and co-repressors, it almost makes the blood tests seem irrelevant." That of course is a bit of an exaggeration, but he does have a point. PR
That Dr. Hellenberg for me hits the nail on the head. "By the time you look at transport, the deiodinase's, and the co-activators and co-repressors, it almost makes the blood tests seem irrelevant."
It's not an exaggeration. Relying on the T4 and TSH blood tests to manage thyroid replacement is analogous to trying to resolve a breakdown in a car by use of not only the fuel gauge but an unreliable one that gives bum readings at times.
Yes, you need an adequate petrol in the tank if it's to go, but there's a gazillion likely downstream causes of breakdowns to be considered if you are to actually trouble shoot the problem.
In our case we need an adequate supply of hormone, but relying solely on blood TSH levels to diagnose hypothyroidism is the equivalent of relying on the wonky fuel guage. Not to mention that there's lots of us driving bangers where the perfect operation of everything downstream of the fuel tank (i.e. the ability to use the fuel) can't be presumed.
TBH i just wish the system would give over on trying to diagnose everything from first principles in general practice. Of course do the research to figure out what matters and what may be an indicator of status. But in the end if it's blowing blue smoke out the exhaust and burning oil it doesn't take a PhD to figure that the piston rings are likely worn.
Trial something if you're not 100% sure - if it blows more smoke on harder acceleration then it's almost certainly the rings. That there's a minor risk involved in the test (as in trialling some hormone if the patient is showing hypo symptoms) is neither here nor there - there's at least as much risk in resorting to an unreliable but 'scientific' test, getting the diagnosis wrong and leaving the problem unresolved so that chronic disease can develop.
It's hard not to think that the profession prefers to leave a problem unresolved and ill defined than to risk the possibility of making a call that might just give rise to a minor risk of subsequent liability.
I'm just one, but i've more or less given up on the stock blood tests as more than one of many inputs, and rely mostly on the sort of indicators you mention - basal body temperature, resting pulse rate, feeling cold/warm, breaking out in spots, feel of the pulse (irregular and anaemic beats in my experience suggest hypothyroidism), aches, gout flares, gut function, energy levels/fatigue and so on.....
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