Paper interesting for those on T3 therapy

Santini F, Giannetti M, Ricco I, Querci G, Saponati G, Bokor D, Rivolta G, Bussi S, Braverman LE, Vitti P, Pinchera A. steady state serum T3 concentrations for 48 hours following the oral administration of a single dose of 3,5,3’-triiodothyronine sulfate (T3S). Endocr Pract. February 14, 2014 [Epub ahead of print].

SUMMARY

Background

Athyreotic patients who are given levothyroxine (L-T4) usually have a slightly low serum T3 level (about 80% of normal). Peripheral tissues typically deiodinate the outer ring of T4 to meet each tissue's particular needs for T3 and are presumed to be able to adjust to this slight decrease in the circulating T3 level. However, we need to keep in mind the occasional patient who “doesn't feel normal” even though the dose of T4 she is taking has normalized her serum TSH level, because our understanding of the mechanisms involved in the metabolism of thyroid hormones has improved. To try to mimic thyroid physiology more closely, desiccated thyroid or combinations of L-T3 plus T4 have been tried, but the outcomes of clinical trials have not been very convincing. Furthermore, if T3 is given only once a day, its serum level rises well above normal: even if T3 is given several times a day, the serum level still undergoes unphysiologically wide excursions. Although triiodothyronine sulfate (T3SO4) is often regarded as being a waste product of thyroid hormone metabolism, it clearly can be reactivated by hepatic and intestinal sulfatases (1). This report of a novel investigation shows the effects of a giving single oral dose of unlabeled T3SO4 on serum levels of TSH, T3SO4, T3, and T4 to patients with severe hypothyroidism.

Methods

When patients with thyroid cancer are being prepared for 131I treatment in Pisa, Italy, they are routinely given L-T4 for 6 weeks, which is then discontinued for a week. Next, 20 µg of L-T3 is given twice a day for 3 weeks, and then it too is stopped for 2 weeks. An earlier study indicated that patients receiving 20 µg of T3 orally 2 days before undergoing 131I therapy did not have depressed TSH levels or 131I efficacy. Based on those data, an initial oral dose of 20 µg of T3SO4 was given to 4 patients and blood samples were collected for the next 48 hours, until 131I was administered. Serum levels of TSH, T3SO4, T4, and T3 were measured; the rise in serum T3 did not exceed 197 ng/dl, the level previously shown not to affect TSH levels or 131I efficacy. The same tests were performed in 4 patients give 40 µg of T3SO4 orally 48 hours before undergoing treatment with 131I, then in 4 patients given 80 µg, and finally in 16 patients given 160 µg.

Results

Serum T3SO4 levels peaked between 2 and 4 hours and returned to basal levels in 8 to 24 hours. The peak T3SO4 level, the area under the T3SO4 curve, and the time to return to baseline levels were directly related to the dose. Serum T3 levels rose significantly by 1 hour and peaked at 4 hours; however, in distinct contrast to the T3SO4 levels, T3 levels remained persistently elevated for at least 48 hours. The peak T3 level correlated with the dose of T3SO4, but the area under the T3 curve over the 48-hour period did not correlate with the dose of T3SO4. Reportedly, free T4 levels did not change, while serum TSH levels rose slightly (no data provided).

Conclusions

The serum level of T3SO4 rises quickly and remains elevated for a few hours when patients with hypothyroidism are given a single oral dose of T3SO4. The serum level of T3 also rises quickly, but it remains elevated for at least 2 days. The authors hypothesize that the persistent increase in T3 levels despite a fall in T3SO4 levels indicates that pools of T3SO4 that are sequestered from the bloodstream continue to generate T3, which could be a manifestation of the well-established enterohepatic cycle for T3SO4. If conversion of T3SO4 to T3 also occurs in patients taking T4, T3SO4 could represent a new agent to use in combination with T4 for treating patients whose symptoms do not seem to respond completely to treatment with T4 alone.

ANALYSIS AND COMMENTARY

Previous studies of euthyroid patients given excessive oral doses of T3 or T4 found serum T3SO4 levels to be high (2, 3), and in patients with hyperthyroidism, the basal level of T3SO4 is high (4). The high T3SO4 levels in thyrotoxic conditions may indicate an autoregulatory response: T3SO4 is more water-soluble, promoting its excretion, and it is also a much better substrate for deiodinase I, which deiodinates the outer ring of T3SO4 much more rapidly than it deiodinates T3 (5, 6).

On the other hand, there are sulfatases in intestinal bacteria and in liver, kidney, cerebral cortex, and muscle that can reactivate T3SO4 to form T3. When 125I-labeled T3SO4 was injected intravenously into euthyroid iodine-blocked subjects, 125I and T3 levels in the urine rose progressively from about 7% at 1 hour to over 20% at 8 hours (7). In euthyroid rats, T3SO4 has about one-fifth the molar activity of T3 (5). When thyroidectomized rats were injected with unlabeled T3SO4, serum T3SO4 levels rose rapidly, then fell by 4 hours, whereas serum T3 levels rose rapidly into the normal range and remained there for the entire study period (6), findings that resemble the results reported in the current study.

Thyroid hormone–responsive tissues can express different levels of thyroid hormone/metabolite transporters, intracellular binding proteins, enzymes involved in thyroid hormone metabolism, thyroid hormone receptors, and finally the myriad proteins involved with each of these activities. A relatively minor abnormality in any of these proteins might well affect the ability of specific tissues to adjust to a lower level of circulating T3 or to sequester thyroid hormone metabolic products. A patient's spectrum of intestinal bacteria doubtless also can influence thyroid hormone metabolism; will fecal transplantation become part of endocrinology in the future?

Details provided about the high-performance liquid chromatography method and the T3SO4 immunoassay are scanty. Although cross-reactivity of their antibody with T3 was low (<0.01%), the antibody's cross-reactivity with thyroxine sulfate (T4SO4) and rT3SO4 receptor seems greater than reported in an early assay (4). No data on percent recovery or sensitivity are provided, although apparently the assay is sensitive to T3SO4 levels below 1 ng/dl. Several of the authors are named on patents filed for clinical uses of T3SO4 and on improvements in the T3SO4 immunoassay, but the assay does not appear to be generally available to thyroid researchers.

References

1. M-P Kung, SW Spaulding, JA Roth. Desulfation of 3,5,3′-triiodothyronine sulfate by microsomes from human and rat tissues Endocrinology 1988;122:1195-200.

2. SJ Eelkman Rooda, E Kaptein, TJ Visser. Serum triiodothyronine sulfate in man measured by radioimmunoassay J Clin Endocrinol Metab 1989;69:552-6.

3. WS Huang, SW Kuo, WL Chen, MM Fuh, SY Wu. Increased urinary excretion of sulfated 3,3′,5-triiodothyronine in patients with nodular goiters receiving suppressive thyroxine therapy. Thyroid 1996;6:91-6.

4. IJ Chopra, SY Wu, GN Teco, F Santini. A radioimmunoassay for measurement of 3,5,3’-triiodothyronine sulfate: studies in thyroidal and nonthyroidal diseases, pregnancy, and neonatal life. J Clin Endocrinol Metab 1992;75:189-94.

5. IJ Chopra, D Nguyen. Demonstration of thyromimetic effects of 3,5,3′-triiodothyronine sulfate (T3S) in euthyroid rats. Thyroid 1996;6:229-32.

6. F Santini, RE Hurd, B Lee, IJ Chopra. Thyromimetic effects of 3,5,3′-triiodothyronine sulfate in hypothyroid rats. Endocrinology 1993;133:105-10.

7. JS LoPresti, L Mizuno, A Nimalysuria, KP Anderson, CA Spencer, JT Nicoloff. Characteristics of 3,5,3′-triiodothyronine sulfate metabolism in euthyroid man. J Clin Endocrinol Metab 1991;73:703-9.

23 Replies

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  • Thanks for this, but it's a bit too technical for me. Are you or anyone else able to summarise this more simply for me please?

    Thanks,

    Mary (nice but dim...)

  • I hope diogenes will correct me if I am misinterpreting or misunderstanding, but this is how I read it:

    Taking T3 has problems of roller-coaster levels of T3 in the blood. This is often reported by people taking T3 as well as many scientific studies.

    However, taking T3-sulfate might allow the T3 level in the blood to rise more modestly, and to stay higher for two days. The human body already has mechanisms for converting T3 to T3-sulfate - and back again. So it looks as if the idea simply exploits what the body does anyway.

    T3-sulfate might help the patient who “doesn't feel normal” even on apparently adequate doses of levothyroxine.

    Much, much more needs to be done to get from this small experiment to serious use of T3-sulfate, but at least there now appears to be a reason to go down that road.

    Rod

  • Thank you, Rod. That helps and it's prompted me to take my 2nd dose of T3, too.

    Thanks to Diogenes for posting :)

  • Fantastic - thanks Rod.

  • Thanks Rod - that has helped me to understand. As a T3 user it's important to me.

    Mary

  • I'm struggling with it too, but Janet & John would stretch me right now, so it's bookmarked for tomorrow morning.

  • Interesting, thanks Diogenes and helvella

  • diogenes,

    Apologies if this seems a nonsensical question.

    Is it possible that glucuronidated T3 could behave similarly or are the necessary pathways not present?

    Rod

  • The process of sulphation or glucuronidation is a detoxicification process for the general removal of unwanted substances in the body. But the human body is at base a complicated system with great redundancy - by that I mean lots of solutions to get the same endpoint. Therefore I'd expect not only enzymes that form sulphates etc for removal through kidneys etc but the reverse (for emergencies if the substances are actually needed for a moment) ie enzyme that desulphate. I'd imagine the same might happen for glucuronide formation. But it would have to be tested. The great power of this work is that it raises the idea of offering less immediately powerful T3 compounds for those who need T3 rather than T4, and an alternative pathway to produce T3 rather than the deiodinase T4-T3 conversion which might be compromised in some patients. If this works it would assuage many of the worries that medics have about the powerful and uncontrolled immediacy of raw T3 supplementation and therapy. Because the detox enzymes would as shown more gently release the hormone itself into the system.

  • diogenes, is T3 sulphate available or is it just used for presurgery prep and experiments? Does anyone know?

  • As far as I know it's only an experimental not for treatment chemical. For justification and license for treatment there would have to be a big trial for safety and efficacy.

  • Diogenes, has science ever actually documented any damage that people taking T3 have sustained? PR

    PS The link for those that wish to download a copy.

    online.liebertpub.com/doi/p...

  • I don't think that's the right question. The real question is: first, if you take T4 alone and suppress your TSH, has that got implications for future problems re bones and heart. Yes, I think it does, but only statistically, not certainly. in this case, since there isn't a win-win 100% outcome, you have to choose between health now and problems later (if indeed they come about, they are not certain to). Second if you take T3, the periodic and continual temporary overdoses after taking pills (to give you an average right dose over time) should be subject to the same outcome and prediction. it's known for example that too much T3 does encourage bone loss by stimulating blastocytes. So in summary I think that both TSH suppressive T4 and fluctuating T3 that daily temporarily puts you above normality have about the same predictions. If we could use a T3 metabolite as these authors have presented, the wild swings for T3 could be softened up and possibly an optimum therapy for everyone developed - even those for which T4 works OK.

  • If by taking T3 one experiences periodic and continual temporary overdoses, would a single dose not cause less periodic overdosing as opposed to split dosing? I was taking T3 40mcg+T4 100mcg in one dose but endo advised split dosing as he felt I would physiologically feel peaks and troughs even if I wasn't conscious of them.

  • True, but to get to an averagely OK dose ie averaged over the day, single dosing would have to give you a bigger temporary high to get there. One big wave with a higher peak than two or more smaller ones. Maybe the big wave over time does more damage than the gentler smaller ones.

  • Thank you :) I shall follow endo's advice.

  • Yes, I understand that all the medications we have today are a compromise compared to what the body does naturally and that there are possible tradeoffs, as you illustrated. I think Paul Robinson's CT3M is actually the closest we have come to mimicking the natural circadian rhythms. What concerns me about the T3 metabolite is "The serum level of T3 also rises quickly, but it remains elevated for at least 2 days." This does smooth out the spikes from T3 multi-dosing but again does not match the natural circadian rhythm which seems to affect how the adrenals perform for many people. I guess until they get to the point where they can regrow the thyroid from stem cells, everything we do will be a compromise of some sort. That will not fix all problems of course. The biggest obstacle I see is what you and your collaborators have been fighting for, 'individualized treatment'. Until we get allopathic medicine to understand that we need to 'normalize' the patient, not the 'serum TSH level', it will be an uphill battle.

    I've been watching the "Thyroid Sessions" webinar here is the US and it does give me hope. Naturopathic medicine is much more about finding the 'root cause' and rebalancing the bodies systems, such as the gut. It is about treating the individual, which allopathic medicine seems to have forgotten. Unfortunately little of this is covered by insurance so almost all the practitioners operate on a cash basis because insurance covers little of what they do. Our upside down medical system has forced allopathic doctors into the 5-15 minute appointment and limited their ability to practice medicine, anything more is rarely reimbursed.

    Still there is hope, in talking about the T3 metabolites and how they work in the body the article does make an interesting statement. "A patient’s spectrum of intestinal bacteria doubtless also can influence thyroid hormone metabolism;" Maybe allopathic medicine will get to the point where they realize Hashimotos is an immune system problem and letting the immune system destroy the thyroid is probably not the most intelligent approach. One can only hope. PR

  • Diogenes, there is another T3 metabolite talked about along with T3 sulfate, T3 acetic acid, that is also supposed to be able to be reactivated. Would it have the same potential as the sulfate version?

    One presenter said that T3S and T3AC being reactivated in the gut contribute 20% of the total T3 in the body. For some reason I am suspicious of that statement. Does science have a good understanding of how much they do contribute? And is it a variable amount depending on demand? PR

  • For general interest...

    Tiratricol (also known as TRIAC or triiodothyroacetic acid) is a thyroid hormone analogue.

    en.wikipedia.org/wiki/Tirat...

    Quite a few papers here:

    ncbi.nlm.nih.gov/pubmed/?te...

    E.g.

    ncbi.nlm.nih.gov/pubmed/234...

    Rod

  • Rod, thank you, now if the grass would just stop growing so I would have more time I might get everything read. :) PR

  • Here is a paper suggesting the therapeutic potential of triac and tetrac:

    European J of Endocrinology

    EXPERIMENTAL STUDY

    Differences between the effects of thyroxine and

    tetraiodothyroacetic acid on TSH suppression and

    cardiac hypertrophy

    Nathalie Lameloise, Catherine Siegrist-Kaiser, Maureen O'Connell1 and Albert Burger

  • sorry I didn't put in dates and volume. Here they are

    European J of Endocrinology (2001) 144; pp 145-154

  • Diogenes, thank you. PR

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