The Thyroid Axis 'Setpoints' are Significantly Altered After Long-Term Suppressive LT4 Therapy

The Thyroid Axis 'Setpoints' are Significantly Altered After Long-Term Suppressive LT4 Therapy

This paper is interesting in its own right - suggesting that thyroid hormone dosing maybe could reduce over time whilst continuing to achieve TSH suppression. It is also to interesting to consider what possible impact it could have on those who already tend to have a lower TSH than would be expected, on those with low or suppressed TSH due to T3, and so on.

Horm Metab Res. 2014 May 27. [Epub ahead of print]

The Thyroid Axis 'Setpoints' are Significantly Altered After Long-Term Suppressive LT4 Therapy.

Verburg FA1, Mäder U2, Grelle I1, Visser TJ3, Peeters RP3, Smit JW4, Reiners C1.

Author information

1Department of Nuclear Medicine, University of Würzburg, Würzburg, Germany.

2Comprehensive Cancer Center, University of Würzburg, Würzburg, Germany.

3Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, The Netherlands.

4Department of Internal Medicine, University Medical Center St. Radboud, Nijmegen, The Netherlands.


The aim of the study was to investigate the changes in the thyroid axis setpoint after long-term suppressive levothyroxine therapy for differentiated thyroid carcinoma and the resulting changes in levothyroxine requirement. Ninety-nine differentiated thyroid cancer patients were reviewed. All patients had at least one known TSH-level≥0.01 mU/l (lower detection limit) and <1.0 mU/l within 2 years of initial treatment (time 1) and had at least one TSH-value≥0.01 mU/l and <1.0 mU/l after continuous LT4 therapy for a minimum of 5 years (time 2).At time 2 the mean LT4 dosage/kg body weight, TSH, FT3, and FT4 levels were significantly lower than at time 1, while body weight was higher. At time 2, the FT3/FT4 ratio rate had dropped significantly (p<0.001). At time 1, patients would require 2.96 μg/kg body weight to reach total TSH suppression. The dose of levothyroxine/kg required for suppression can be lowered by about 0.05 μg/kg body weight for each year of suppressive therapy. After a median of 12.7 years of continuous suppressive levothyroxine therapy, patients would require 2.25 μg/kg body weight (-23.5%) to reach total TSH-suppression. At least part of this reduction was independent of aging. As a result of changes in thyroid hormone metabolism and thyroid axis setpoint, long-term TSH-suppressive therapy contributes to a reduction in the dosage of levothyroxine per kilogram body weight required for full TSH suppression over time.

© Georg Thieme Verlag KG Stuttgart · New York.

PMID: 24867137


Image: Ludwigsbrücke (Löwenbrücke) in Würzburg. 2 May 2006 Author Tors - no relevance except the town!

35 Replies

That's interesting. Rod. I wonder why the set point only adjusts thus far and doesn't continue adjusting. I'm surprised to see suppression is maintained in those patients for 12.7 years, I thought 5 years was the norm.

2.96 x body weight also confirms my suspicion that I was inappropriately over-replaced to suppress my TSH two years ago :x

Mind, that appears to be a mean (average) so some would be on higher doses.

Without really having had anything to do with this approach, I think I had assumed this was a very long-term suppression. More or less rest of life. Obviously I am wrong! :-)


No necessarily, Rod. 5 years may be the norm for papillary & follicular cancers but medullary may be different. They didn't specify in the study.


There are a number of older papers that also show that suppressing the TSH (by thyroid hormone supplementation or by disease e.g. Graves' Disease) also lowers the hypothalamic pituitary thyroid axis. This axis can take a long time, months or years, to recover.

There is also evidence that dosing with TRH promotes recovery of the axis. This is interesting because a number of studies attempting to discover how long the axis takes to recover use a TRH stimulation test to determine whether the patients have a pituitary or hypothalimic disorder. So in a attempt to discover how long it takes for the axis to recover they give the axis an almighty whack with 200 mcg intravenious TRH. These studies find the axis does recover - Doh!

This suppression of the axis means that in patients who have had long term suppression of TSH their thyroid hormone status cannot be reliably determined by TSH, you have to go by fT4 (assuming they are on levothyroxine). If a patient takes high doses of thyroid hormone that suppresses their TSH it will lead to iatrogenic disruption of their axis. For this reason when posting on the forum I always suggest the patient tries normal doses of levothyroxine for a good while before trying higher doses or T3 containing medicines. Of course if nothing else works they have to go onto the higher dose.


Thanks - like your TRH point!

Well aware of the slow recovery of TSH in Graves.

Forgot to add there is growing evidence that TSH stimulates T4 to T3 conversion (via type 2 deiodinase). Thus as fT4 falls and TSH rises it causes a compensatory rise in fT3. This is a homeostasis mechanism. The problem is that if the axis is disrupted with an inappropriately low TSH there will be some impaired T4 to T3 conversion. The patient will present with low TSH, low fT3, low fT4, all of which may be within the reference intervals.


jimh111, you are refering here to people who have had their thyroid removed?

I haven't but it was the same: low everything. No antibodies.

Doesn't matter if thyroid is removed, damaged or normal. The axis set point is lower and type 2 deiodinase is regulated by TSH (and fT4, D2 reduces as fT4 increases).

There is something I don't understand here. I was seriously undertreated for several years. The highest the TSH went was 0.9. And yet both fT4 and fT3 were below range. I have a thyroid gland. (My heart did not appreciate this.) How could the levo dose have suppressed the TSH to this extent? It seems neither the pituitary nor the thyroid were doing much of anything.

Does this mean that for the few years in the late 80s and early 90s when I was given the 'right dose' it caused a permanent life long suppression of TSH? It was due to the low TSH that the geniuses kept lowering my levo dose until finally my heart was going to give out. TSH never recovers?

If both fT3 and fT4 were both below the lower limit of the 95% reference interval and TSH was lowish it is not the effect described above. Most likely is what is called 'secondary hypothyroidism' where either the pituitary or hypothalamus is not working correctly. This condition should be investigated by an endocrinologist not a GP.

Low TSH, fT3, fT4 can also be caused by an unrelated (fairly severe) illness or by depression.

If the 'right' dose you received in the 80s and 90s was sufficient to take your fT3 or fT4 above the the upper levels of their reference intervals it may lead to subsequent low TSH. In which case the TSH figure is not meaningful but the fT3 and fT4 are.

jimh111, "Forgot to add there is growing evidence that TSH stimulates T4 to T3 conversion (via type 2 deiodinase). Thus as fT4 falls and TSH rises it causes a compensatory rise in fT3."

This is the circadian pattern that occurs naturally at night and is what is behind CT3M working. PR

Isn't TSH stimulating production of FT4 that causes FT3 to rise?



This was a cross-sectional study in 33 healthy individuals with 24-h blood sampling (TSH in 33 and FT4 and FT3 in 29 individuals) and cosinor analysis.


Of the individuals, 100% showed a sinusoidal signal in TSH, for FT4 76%, and for FT3 86% (P < 0.05). For FT4 and FT3, the amplitude was low. For TSH the acrophase occurred at a clock time of 0240 h, and for FT3 approximately 90 minutes later at 0404 h. The group cosinor model predicts that TSH hormone levels remain above the mesor between 2020 and 0820 h, and for FT3 from 2200-1000 h. Cross correlation of FT3 with TSH showed that the peak correlation occurred with a delay of 0.5-2.5 h. When time-adjusted profiles of TSH and FT3 were compared, there was a strong correlation between FT3 and TSH levels (rho = 0.80; P < 0.0001). In contrast, cross correlation revealed no temporal relationship between FT4 and TSH.


FT3 shows a circadian rhythm with a periodicity that lags behind TSH, suggesting that the periodic rhythm of FT3 is due to the proportion of T(3) derived from the thyroid. Optimizing thyroid hormone replacement may need to take these rhythms into account.

Paul Robinson figured this out before this study was published. I have also read, somewhere, that glycosylation changes the TSH isoforms towards the peak and that the bioactivity decreases by 30% or so and I think that this is what must cause the rhythms described in the abstract above. Paul has repeated the results in 100s of other people and 'repeatable results' is supposed to be a cornerstone of science, or it used to be. Science is pretty much totally unaware but nothing new there. PR

PS The full PDF is still available.

Thanks, PR, I've seen the study and Rod also posted a graph showing FT3 rhythms lagging about 90 minutes after TSH rhythms.

I wonder whether circadian thyroid rhythms can be applicable to people without a thyroid as they won't receive any FT3 from the thyroid?

Clutter, one would think that would alter things considerably but I have never seen a study where they looked at the rhythms after a TT. The strength of the rhythm also varies between people as shown by a couple of the graphs in the study. I'd also love to see a study done on shift workers and what their rhythms looked like. There is just so much we still don't know. We always seem to end up experimenting on ourselves to find what works best for each one of us. PR

Early day science, PR. Often more reliable than trying to squeeze into EBM ranges which don't suit all of us :)

I think the problem with that is, although the higher FT4 might allow the FT3 to rise, it doesn't necessarily happen because of that. The mechanisms are more subtle than that.

It is a much more complicated system then we tend to view it as. Every time I think I know something, I end up proving to myself how little I really know. PR

This is precisely what happened when I was initially over-replaced. TSH undetectable, FT4 low and FT3 below range. Reducing from 200mcg to 100mcg over 18 months improved FT4 but FT3 remained very low in range until T3 was added and TSH remains suppressed with FT4 and FT3 in the top of range.

I started burying my TSH at 1 grain and by 3 grains it was totally buried 25 years ago, now I'm at 4 grains. A couple of years ago I checked FT3 and it was over the top of the range, somewhat similar to dosing with T3. I'm an outlier, some genetic polymorphisms or possible epigenetics, hard to tell. PR

I suspect my FT3 may be above range at my next TFT as my T3 was increased just after last bloods. If my endo is daft enough to want to reduce my meds according to the blood test I shall have to remind him he did nothing when my FT3 was below range last year.

Which is another very interesting point.

This paper is a very interesting addition to work we're in the process of (hopefully) publishing. We studied thyroiditis and cancer patients and found that the set points for FT4/TSH relationships are altered from the start, compared with healthy people, and that not only T4 therapy, but age, weight (body mass index) and thyroid gland size all have their independent influences on the setpoints. FT3 influences and relationships with the other parameters are also altered especially in T4 monotherapy. However, as always it's a strain getting publication through, because the reviewing process nowadays is something of a lottery: if the reviewers don't like the message, then in spite of our scientific care and attention to detailed argument, they simply find dismissive, irrelevant and specious reasons to deny publication. And editors support the reviewers regardless of the poor quality of reviewing, if only for a quiet life. A sad state of affairs in science nowadays, my masters!

This study seems to show that the body becomes progressively more resistant to T4 monotherapy with time. Therefore T4-T3 conversion appears to become less efficient (a lower FT3/FT4 ratio) whilst the pituitary becomes more sensitive to T4 itself. in this picture, I see that in order to maintain the same FT3 then we have the contradictory situation that the T4 has simultaneously to be raised to get a good FT3, but also the pituitary is more sensitive to T4. Suppressed TSH therefore can arise when a normal FT3 has been achieved for a given T4 dose, in people longterm on T4. But in such cases this shouldn't lead to AF etc. so long as the FT3 is at good levels. This might also help to explain why some people suppress their TSH whilst not getting enough FT3 from T4 alone - they have a parallel with the long term group described here.

Diogenes, I was talking to an endo here in the US who did a study with a colleague showing 80% preferred NDT and they have not been able to get it published in any of the main journals. I just finished reading a book by another endo, with a PhD in chemistry, who uses exactly the kind of protocol that you proposed. He also feels that about 20% due just fine on T4 only and that 80% could benefit from adding a little T3. He uses T4 at 98.5% and T3 or thyroid extract at 1.5%, plus or minus about 0.5% either side, and compounds the T3 or thyroid extract for time release. He does a lot of seasonal adjustment for his patients. I had completely missed his earlier book and the work he has been doing for about the last twenty years. I admit that I didn't think such a small amount of T3 would be effective but obviously I was wrong on that point. He is thinking about retiring but can't find another endo to take over his practice because they are all scared to be different. It is curious that there is such a herd mentality in endocrinology and so much fear about being different. PR

PS I don't suppose you included any patients on NDT in your study?

I'm trying to see if Thyroid UK are interested in a questionnaire for NDT, T3/T4 or T3 only patients to see if they have any increased incidence of AF or osteoporosis. I don't know if it can be arranged and get big enough numbers, but at least we might get an epidemiological study to compare with T4-only patients especially those whose TSH is suppressed.

Diogenes, How will you determine who may have had or been developing osteoporosis prior to diagnosis and medication? My sister had osteopenia prior to RAI for Graves and Levothyroxine after ablatement. I've been suppressed on T4 only for 18 months and T4+T3 combination for 5/6 months and am only having a Dexa scan on Friday.

It will have to be a bit naive, in that what we could do is simply compare FT3 values with AF and or OS incidence and age. Genetic tendencies etc will play a part but may not be strong enough to distort the results. Have to see if the study is possible and what it might show. If it shows something then further questions might be needed to separate the various possibilities and firm up the analysis.

If TUK numbers aren't big enough it may be possible to crowdsource other thyroid charities and patient advocate sites via Facebook and Twitter.

You would also have to account for the genetic factor. In my family osteoporosis comes down on the female side of the family and not the male. It came down from my maternal grandmother to my mother and my sister but not so much to me, yet. My TSH has been completely suppressed for about 25 years. PR

It's curious, but also incredibly sad that there are so many people in medicine who seem not to care about helping patients! I had hoped, in my naive way, that people went into medicine to make lives better for people. :-(

HarryE, I still believe that most people go into medicine because they want to help their fellow humankind, the problem is they go to medical school. PR

Mmmmm, where they get it all battered out of them!

Harry, I agree with PR, but it is sad that somewhere along the line vested interests interfere with ideology.

Thank you all for this very interesting post. It has helped me with my son's problems and given me something tangible to show his less than competent 'diabetologist' in place of a competent Endocrinologist. All his problems stem from Hypopituitarism with Septo-Optic Dysplasia. Because my son's TSH is very low at 0.11 this diabetologist wants to lower his very low dose of Levo, which only gives him a T4 of 13 (6-14) and a T3 of 2.9 (2.5 - 5.5). Never seen such low levels as we have here in Mid-Essex!

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