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Research Articles and Papers on:


Integration of Peripheral and Glandular Regulation of Triiodothyronine Production by Thyrotropin in Untreated and Thyroxine-Treated Subjects.

Hoermann R1, Midgley JE2, Larisch R1, Dietrich JW3.

Department of Nuclear Medicine, Klinikum Luedenscheid, 58515 Luedenscheid, Germany
2North Lakes Clinical, Ilkley, UK
3Medical Department I, Endocrinology and Diabetology, Bergmannsheil University Hospitals, Ruhr University of Bochum, Bochum, Germany

Horm Metab Res. 2015 Mar 6.

The objective of the study was to evaluate the roles of central and peripheral T3 regulation.

In a prospective study involving 1 796 patients, the equilibria between FT3 and TSH were compared in untreated and L-T4-treated patients with varying functional states, residual thyroid secretory capacities and magnitudes of TSH stimulation. T3 concentrations were stable over wide variations in TSH levels (from 0.2 to 7 mU/l) and endogenous T4 production in untreated patients, but unbalanced in L-T4-treated athyreotic patients where T3 correlated with exogenous T4 supply. T3 stability was related to TSH-stimulated deiodinase activity by clinical observation, as predicted by theoretical modelling. Deiodinase activity in treated patients was reduced due to both diminished responsiveness to TSH and lack of thyroidal capacity. Deiodinase activity was increased in high thyroid volume, compared to lower volumes in euthyroid patients (<5 ml, p<0.001). While deiodinase differed between euthyroid and subclinically hypothyroid patients in high volume, 26.7 nmol/s (23.6, 29.2), n=214 vs. 28.9 nmol/s (26.7, 31.5), n=20, p=0.02, it was equivalent between the 2 functional groups in low volume, 23.3 nmol/s (21.3, 26.1), n=117 vs. 24.6 nmol/s (22.2, 27.5), n=38, p=0.22.

These findings suggest that the thyroid gland and peripheral tissues are integrated in the physiological process of T3 homeostasis in humans via a feed-forward TSH motif, which coordinates peripheral and central regulatory mechanisms. Regulatory and capacity deficiencies collectively impair T3 homeostasis in L-T4-treated patients.




Common variation in the DIO2 gene predicts baseline psychological well-being and response to combination T4/T3 therapy in patients on thyroid hormone replacement.

Vijay Panicker, Ponnusamy Saravanan, Bijay Vaidya, Jonathan Evans, Andrew T. Hattersley, Timothy M. Frayling and Colin M. Dayan

The Journal of Clinical Endocrinology & Metabolism Vol. 94, No. 5 1623-1629

Introduction: Animal studies suggest that up to 80% of intracellular T3 in the brain is derived from circulating T4 by local deiodination. We hypothesized that in patients on T4 common variants in the deiodinase genes might influence baseline psychological well-being and any improvement on combined T4/T3 without necessarily affecting serum thyroid hormone levels.

Methods: We analyzed common variants in the three deiodinase genes vs. baseline psychological morbidity and response to T4/T3 in 552 subjects on T4 from the Weston Area T4 T3 Study (WATTS). Primary outcome was improvement in psychological well-being assessed by the General Health Questionnaire 12 (GHQ-12).

Results: The rarer CC genotype of the rs225014 polymorphism in the deiodinase 2 gene (DIO2) was present in 16% of the study population and was associated with worse baseline GHQ scores in patients on T4 (CC vs. TT genotype: 14.1 vs. 12.8, P = 0.03). In addition, this genotype showed greater improvement on T4/T3 therapy compared with T4 only by 2.3 GHQ points at 3 months and 1.4 at 12 months (P = 0.03 for repeated measures ANOVA). This polymorphism had no impact on circulating thyroid hormone levels.

Conclusions: Our results require replication but suggest that commonly inherited variation in the DIO2 gene is associated both with impaired baseline psychological well-being on T4 and enhanced response to combination T4/T3 therapy, but did not affect serum thyroid hormone levels.



Free Triiodothyronine Has A Distinct Circadian Rhythm That Is Delayed But Parallels Thyrotrophin Levels

Clin Endocrine Metab.  First published ahead of print March 25, 2008 as doi:10.1210/jc.2007-2674

Authors: W Russell*: R. F. Harrison*:
N Smith: K Darzy: S Shalet: A P Weetman: R J Ross (corresponding Author):

* These two Authors made equal contributions.

According to the report, whilst it is known that TSH has a circadian (daily) rhythm, the relationship between this and any similar rhythm in T4 and T3 has never been demonstrated.  Previous studies have shown that TSH reaches its maximum at between 2 and 4am and it its minimum between 4 to 8pm.  TSH controls the circulating levels of T4 and T3, and a deficiency in TSH leads to a deficiency in thyroid hormone.   It is therefore expected that T4 and T3 might also have daily rhythms. 

The report states that in humans all T4 but only 20% of T3 is secreted by the thyroid gland.  As the half-life of T4 in the body is estimated to be about seven days, very much longer than the eighteen hours of T3, the authors were not surprised that no daily rhythms had been observed in T4.  The report also notes that the levels of hormones circulating in the blood are determined by both how fast the hormones are produced and how fast they cleared from the body. 
The objective of the study was to use modern assays to investigate the daily rhythms of FT3 and FT4 with a view to optimising thyroid hormone replacement therapy.  In order to do this, a study of thirty-three healthy individuals was conducted by taking blood samples from them every twenty-minutes over a period of twenty-four hours. 

All individuals showed a daily variation in TSH, 86% of them a daily variation in FT3 and 76% a variation in FT4.  The highest TSH reading occurred at 2.40am and the highest FT3 reading about 90 minutes later at 4.04am.  The rhythms were more marked in some individuals than others and we are told that the clinical significance of the variations has yet to be established.  However, the anterior pituitary gland produces TSH and all hormones from this source, including ACTH which control cortisol levels, have daily rhythms. 

Current T3 and T4 preparations, which are usually taken in the morning, release the hormones immediately and T4 levels rise within 2 hours.  According to the authors, a recent study shows that better biochemical control is achieved when thyroxine is taken in the evening but they say that although combination therapies of T3 and T4 have been tested the normal daily rhythms were not produced and there was no clear evidence of any benefits to patients.


Dr Jacob Teitlebaum notes that the new study shows that TSH and Free T3 and Free T4 levels fluctuate during the day.  Surprisingly, TSH levels start to rise around 9pm, hitting bottom again around 9am.  T3 levels follow a similar pattern following TSH levels by around 90 minutes (as would be expected if the TSH stimulates T3 release from the thyroid).  T4 variability was not associated with TSH variability.
This means that thyroid hormone levels are highest at night while we sleep - NOT while we're awake, and even though TSH regulates T4 over the long term (days to weeks), TSH variability during the day mostly seems to play a role in fine tuning T3 levels during the day, having little to no effect on T4 variations during the day.  This suggests that fine-tuning the timing of giving T3 is more important than T4.  
The implications are:

  • With TSH varying so widely during the day (increasing by 72% from it's daily low to its daily high - almost 1 mU on average and sometimes over 2 units in some people in the study), strictly interpreting a TSH level as the sole determinant of whether someone needs thyroid hormone becomes an even more ridiculous approach than it has been in the past (unless they want to define the normal range based on a set time of day the test was done - even if one does, TSH is still horribly unreliable).
  • Data has suggested that people do better taking their thyroid hormone at bedtime instead of in the morning, and clinical experience has shown that this is also often the case.  This study further suggests that thyroid hormone (especially if it also contains T3) may best be taken at night instead of in the morning.  I have often had patients take part of their thyroid later in the day.  Years from now, we may find this to be the preferred approach (perhaps even giving the entire dose at bedtime).  Even now, for those not doing well on thyroid hormone, its worth a try for a few weeks to see which way feels best.
  • Giving T3 as well as T4 may be important.  It is interesting watching the authors tiptoe around this issue.  One can almost feel the politics as they say " Following the first publication that a combination replacement therapy of T4 and T3 may improve quality of life for hypothyroid patients13 there has been considerable debate as to actual benefits.  Despite a large number of studies there is no conclusive evidence that combination therapy with T4 and T3 improves efficacy of therapy or health related quality of life14." This statement, of course, ignores that there is no conclusive evidence that using only T4 (e.g.Synthroid) does so either.  That simple observation is irrelevant though, as I suspect the authors were simply spouting the current dogma so they could avoid being attacked for proposing that perhaps T3 may be worth adding to treatment (as they hint at).


Supraphysiological cyclic dosing of sustained release T3 in order to reset low basal high temperature.

Friedman M, Miranda-Massari JR, Gonzalez MJ.
Puerto Rico Health Sciences Journal 2006 Mar;25(1):23-9.

The use of sustained release tri-iodothyronine (SR-T3) in clinical practice, has gained popularity in the complementary and alternative medical community in the treatment of chronic fatigue with a protocol (WT3) pioneered by Dr. Denis Wilson. The WT3 protocol involves the use of SR-T3 taken orally by the patient every 12 hours according to a cyclic dose schedule determined by patient response. The patient is then weaned once a body temperature of 98.6 degrees F has been maintained for 3 consecutive weeks. The symptoms associated with this protocol have been given the name Wilson's Temperature Syndrome (WTS).

There have been clinical studies using T3 in patients who are euthyroid based on normal TSH values. However, this treatment has created a controversy in the conventional medical community, especially with the American Thyroid Association, because it is not based on a measured deficiency of thyroid hormone. However, just as estrogen and progesterone are prescribed to regulate menstrual cycles in patients who have normal serum hormone levels, the WT3 therapy can be used to regulate metabolism despite normal serum thyroid hormone levels. SR-T3 prescription is based exclusively on low body temperature and presentation of symptoms. Decreased T3 function exerts widespread effects throughout the body. It can decrease serotonin and growth hormone levels and increase the number of adrenal hormone receptor sites.

These effects may explain some of the symptoms observed in WTS. The dysregulation of neuroendocrine function may begin to explain such symptoms as alpha intrusion into slow wave sleep, decrease in blood flow to the brain, alterations in carbohydrate metabolism, fatigue, myalgia and arthralgia, depression and cognitive dysfunction. Despite all thermoregulatory control mechanisms of the body and the complex metabolic processes involved, WT3 therapy seems a valuable tool to re-establish normal body functions.

We report the results of 11 patients who underwent the WT3 protocol for the treatment of CFS. All the patients improved in the five symptoms measured. All patients increased their basal temperature. The recovery time varied from 3 weeks to 12 months.

Unfortunately, there are not many doctors in the UK who treat thyroid problems with this protocol.  Perhaps this study will persuade more doctors to look into this form of treatment.

European Journal of Endocrinology, Vol 153, Issue 3, 367-371
Copyright © 2005 by Society of the European Journal of Endocrinology


Changes in Serum Triiodothyronine (T3) Kinetics after Prolonged Antarctic Residence: The Polar T3 Syndrome

H. Lester Reed, Eugene D. Silverman, K. M. Mohamed Shakir, Robert Dons, Kenneth D. Burman, And John T. O'brian

Received: April 14, 1989
First Published Online: July 01, 2013

Humans who live in Antarctica for greater than 5 continuous months demonstrate alterations in the hypothalamic-pituitary-thyroid axis. These changes are characterized by 1) increased pituitary release of TSH in response to iv TRH, 2) increased serum clearance of orally administered T3, and 3) normal serum total, free T4, and unstimulated TSH levels. To clarify the mechanism responsible for these findings, serum kinetic studies of 125I-labeled T4 and T3 were carried out in a group of normal men, first in California, then after 20 and 42 weeks of continuous Antarctic residence. The kinetic parameters were calculated by noncompartmental analysis. The mean T4 residence time (MRT) was not different before and after 42 weeks (5.54 ± 0.50 and 5.08 ± 0.43 days). The total T4 volume of distribution (TVd) tended to fall over the same period (4.30 ± 0.12, 3.56 ± 0.27 L/m2), but was not significantly different (P = 0.075). In contrast to T4, there was an increase from control values for the T3 MRT from 0.83 ± 0.03 to 1.10 ± 0.03 days (P < 0.002) and a more than doubling of the T3 TVd from 15.55 ± 0.52 to 47.24 ± 5.09 L/m2 (P < 0.002) after 42 wk of Antarctic residence. Energy intake increased approximately 40% throughout the study without a change in body weight. The changes in T3 kinetic parameters may be accounted for by increased extravascular tissue binding. The marked increase in T3 TVd and the small increase in MRT are associated with increased T3 production and clearance and only minor changes in T4 kinetics. This is the first description of a mechanism for the change in thyroid hormone economy occurring with extended residence in Antarctica.





Combined Therapy with Levothyroxine and Liothyronine in Two Ratios, Compared with Levothyroxine Monotherapy in Primary Hypothyroidism: a Double-Blind, Randomized, Controlled Clinical Trial

Bente C. Appelhof, Eric Fliers, Ellie M. Wekking, Aart H. Schene, Jochanan Huyser, Jan G. P. Tijssen, Erik Endert, Henk C. P. M. van Weert and Wilmar M. Wiersinga –
The Journal of Clinical Endocrinology & Metabolism Vol. 90, No. 5 2666-2674

The researchers conducted a double-blind, randomized, controlled trial in 141 patients (18–70 yr old) with primary autoimmune hypothyroidism, recruited via general practitioners. 

Decrease in weight, but not decrease in serum TSH was correlated with increased satisfaction with study medication. Of the patients who preferred combined LT4/LT3 therapy, 44% had serum TSH less than 0.11.  Patients preferred combined LT4/LT3 therapy to usual LT4 therapy, but changes in mood, fatigue, well-being, and neurocognitive functions could not satisfactorily explain why the primary outcome was in favor of LT4/LT3 combination therapy.


Thyroid Hormone replacement therapy in primary hypothyroidism: a randomized trial comparing L-thyroxine plus liothyronine with L-thyroxine alone.

Escobar-Morreale HF, Botella-CarreteroJI, Gomez-Bueno M, Galan JM, Barrios V, Sancho J – Archives of Intern Med 2005 Mar 15;142(6)155

This study looked at 28 women with overt hypothyroidism.  They were given 100mcg thyroxine for 8 weeks, then 75mcg thyroxine and 5mcg liothyronine for 8 weeks.  All patients were then given 87.5mcg thyroxine and 7.5 mcg liothyronine.  The doctors noted that the last combination resulted in over-replacement.   The results were that 12 patients preferred combination treatment, 6 patients preferred the add-on combination treatment, 2 patients preferred standard treatment an d 6 patients had no preference.

Amazingly, the conclusions were that “Physiologic combinations of L-thyroxine plus liothyronine do not offer any objective advantage over l-thyroxine along, yet patients prefer combination treatment.”

I think the important word here is “objective”.  Research is not accepted as good unless results can be seen in blood tests, never mind how the patient feels!