Can anyone recommend peer reviewed journal articles on T3/T4 treatment so my GP can understand I am not making all this up that I have been better on combined treatment these past 5 years, and the recent 'odd' results are not proof of how I shouldn't be self-medicating via an online support group? He frowned heavily on me self-medicating, mocked ThyroidUK asking who are the medical staff and where are they located. He said he will talk to the bio-chemists (who are they?) about my 'unusual case', has requested details of the Erfa I am taking, but has conceded he would like to see a 'few pages only' from peer reviewed articles on T3/T4 combination therapy.
Any help would be SO appreciated!
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The above is a link to just one piece of research on Pub Med - there is lots more. Type T4/T3 PubMed into your search engine and hopefully you will find something useful.
Thank you for that link to the article, I hadn't found that one before; the healthunlocked link doesn't seem to work. I'll look up NHS Choices. Thanks again
Sorry the link did not worked. Type T3/T4 combination - into the Search Box on the Green Bar above - press Enter and hopefully all the earlier discussion will appear. it is a popular topic - so hopefully you will find something meaningful
Shall I suggest the survey to him Really helpful links regarding Thyroid UK, thank you , I will certainly be putting some of that into my 'two pages' of everything (the most I think he is capable of digesting, and there's him on research leave at the moment!).
You could concentrate on one study and just provide links to others.
It's good to know GPs have research leave - so do I - it's called school holidays!
I wonder how much collective research a membership of 28 thousand people bring - let alone what Lyn, Louise and the TUK Charity have already found out over the years.
It'll keep him busy out of mischief anyway!
If reading this << waves! >>
oh & a little ACV or betaine HCL may aid digestion ~~
Ask him if he thinks that 27,000+ people would be on this forum if levothyroxine worked perfectly? Mainly, it is people who cannot and do not recover their health with levo and are forced to purchase their own medication to have some kind of life. Also GPs are very quick to prescribe pain relief, anti-depressants etc instead of a decent dose of hormones (other than levo) instead of taking a Free T3 blood test. (what's that they will probably answer).
Do they know or understand that levo is supposed to convert to sufficient T3 for the patient. I really doubt that. They have been 'trained' to only look at the TSH. Is he aware that the TSH varies throughout the 24 hour day?
Indeed, I wonder if I have to add that basic bit of information for him! I already have stuff saying TSH is not an appropriate measurement, and to give him credit this is the second time he has had my fT3/4 tested, but as you say I suspect he still doesn't get how it all works. He did say yesterday he is not an expert(!), but I am not sure 'the biochemists' are the source of all knowledge on this.
I have asked for a full thyroid test but been told they only do it in special cases. I wasnt told what they were, but I'd have thought that not being able to function every day is pretty special.
Yes i had 2 blood tests done on the same day about 2 hours apart one for the GP the other at the hospital and the TSH was different.When i said how can you treat me by my TSH range if it changes through the day .the subject was changed.
Don't waste your time and energy trying to educate an ignoramus. It's best not to tell them anything and keep contact to a minimum.
Indeed, this has been my approach for the past 5 years. Unfortunately due to various health problems he ordered a full range of tests (usually get tested in Cyprus) for TSH, fT3/4, which showed undetectable TSH but very low fT4 and below the minimum fT3, so suddenly he is taking a great interest in my ridiculous need to self-medicate!
This doesn't link to an actual paper, but to a summary of one, which was published in the European Journal of Endocrinology (it's peer reviewed - I checked!): thyroid.about.com/b/2010/05.... This probably isn't what your GP is looking for as it's written inlaypersons terms by a third party, but I expect it would be fairly easy to find the abstract, and also possibly discussion of it in other papers.
There's also the paper by Panicker et al re combination therapy benefiting those with polymorphism of the DIO2 gene. They claim theirs is the most statistically significant study on this (I don't know if it's since been superseded, though I don't think it has) and their paper was published intThe Journal of Clinical Endocrinology & Metabolism, which claims to be the world’s leading peer-reviewed journal for endocrine clinical research and clinical practice information: press.endocrine.org/doi/ful...
Those are two I've been looking at quite recently; there are probably more out there (though from the sounds of your GP, I'd be careul to ensure they've definitely undergone peer review so he can't find a spurious reason to reject them). Good luck!
Oh, that's fantastic, Sparerib - thank you!! I thought the first paper was only available on subscription; I know what my light reading is going to be next time I have a little energy.
As they say 'ignorance is bliss' and that's why so many of us are doing self-help because the medical profession are still steeped in levothyroxine only.
The latest from the Journal of Orthomolecular Medicine -go to page 80 for the conclusion. Dose Selection in T3/T4 Study RCTs recommends 1 T3 to 3 T4 ratio is best for patients.
Thank you so much, these will be great, at this rate I'll be writing a paper for him rather than giving him the references! But seriously this is why this forum is so amazing. Thank you again.
When we pause for thought - is it not disgraceful that most have us have lost faith in being treated adequately (if we don't get well on levothyroxine or feel worse with it)? Some are lucky to be prescribed the addition of T3 but the Endos then get nervous if our TSH drops and then the adjustment of hormones begins and it may take forever to get stable.
Doctors biggest mistake when treating hypothyroid patients is to 'treat or diagnose' by the TSH alone.
They mistakenly believe that once diagnosed (or if ever) and given levo and if our TSH is 'anywhere within the range' that's fine. NO it isn't. Once diagnosed as hypothyroid and given levothyroxine they should concentrate on the patients symptoms which are 'supposed' to be relieved altogether - not a 'halfway house and should know that some of us need our TSH to be low or even suppressed.
The main aim is for us is to recover our health so they should be au fait with clinical symptoms about which they don't appear to have one clue or how to relieve them - which is by thyroid hormones and if levo alone doesn't do the trick they have to add or try an alternative. Not prescribe a multitude of prescriptions for the symptoms which may not have the desired effect.:
All of us help to contribute to educate our medical students: Properly medicated patients saves the NHS money (as well as ours), i.e. not forever at the doctors. Puzzled as to why we are not feeling much better: wondering why we are still unwell or feeling worse: being thought of as hypochondriacs: doctors hearts drop when, yet again, we've gone to see them: getting useless prescriptions for the symptoms: unable to do our jobs properly and/or being told to leave: families unable to understand as we are"taking meds" for the illness: insomnia or pain. The post a few years ago from a bereaved husband whose wife committed suicide leaving him with 3 young children.
Thank you so much to all those who helped with my search for peer-reviewed evidence on T4/T3 therapy. I have sent my review to the GP this morning and can only keep my fingers crossed now; if I get told no, then it is not for lack of trying.
Will try to paste my response here, I know it's not brilliant, but it's the best my foggy brain can do!:
Restoration of patient well-being using combined T3/T4 therapy in hypothyroid patients
A Review of Peer-reviewed/Academic Research Evidence
The treatment of hypothyroidism is controversial due to the persistence of “clinical studies indicat[ing] that 5%–10% of L-T4–treated hypothyroid patients with normal serum TSH have persistent symptoms that can be related to the disease” (de Castro et al, 2015). Put another way, there are a “significant minority of patients [who] only achieve the desired sense of well-being if serum TSH is suppressed” (Toft 2002), frequently achieved via combined T4/T3 treatment. Reflecting this, Wiersinga (2014) notes: “Impaired psychological well-being, depression or anxiety are observed in 5-10% of hypothyroid patients receiving levothyroxine, despite normal TSH levels.” Indeed, the British Medical Association’s patient guidance states: “some patients do not achieve the sense of well-being expected, even if a little extra thyroxine is taken, which results in a low rather than a normal TSH level… If you are one of this small group of patients, there is some evidence… that a combination of thyroxine and the other thyroid hormone T3, may be beneficial” (Toft/Family Doctor Books, P46). In the US, in 2003, the US National Institute of Health affirmed: "TSH determination is diagnostically misleading and only free hormone measurements are reliable for thyroid function assessment."
The Maidstone and Tunbridge Wells NHS Trust have used Armour Thyroid (see below) since 2003 “as a third line agent in selected patients who have not responded adequately to T4 monotherapy, and combination T4/T3 therapy” (Lewis et al, 2008). They conducted research in 2005-6 “To assess changes in symptoms of hypothyroidism in patients treated with Armour” (also known as dessicated thyroid, “porcine-derived thyroid replacement with 1 grain containing 38 mcg levothyroxine (T4) and 9 mcg L-triiodothyronine (T3)”. Forty patients using Armour were surveyed, “[o]f the patients still taking Armour, 72% found improvement in energy levels, 52% dry skin, 52% hair loss and 55% cold intolerance. There was no difference in constipation, arthragia, myalgia or ability to lose weight. Most patients (62%) had improvements in 3 or more symptoms of hypothyroidism.” This led the authors to conclude: “In appropriately selected hypothyroid patients, Armour appears to improve the quality of life in patients who have either had an inadequate clinical response to conventional T4/T3 therapy or are unable to tolerate such therapy.” (Lewis et al, 2008). Toft (2002) similarly reported: “In patients in whom long-term T4 therapy was substituted by the equivalent combination of T3 and T4 scored better in a variety of neuropsychological tests.”
Biondi and Wartofsky (2012) acknowledged the current controversy in appropriate treatment of thyroid disorders to achieve patient well-being thus: “Levothyroxine therapy is the traditional lifelong replacement therapy for hypothyroid patients. Over the last several years, new evidence has led clinicians to evaluate the option of combined T3 and T4 treatment to improve the quality of life, cognition, and peripheral parameters of thyroid hormone action in hypothyroidism.” Earlier studies into T4 treatment alone, compared with combined T4/T3therapy, conducted on rats, had shown that “it is not possible to restore euthyroidism completely in all tissues of thyroidectomized rats infused with T4 alone” (Escobar-Morreale et al, 1996). Research on rats by these authors concluded “[c]ombined replacement therapy with T4 and T3 … completely restored euthyroidism … at much lower doses of T4 than those needed to normalize T3 in most tissues when T4 alone was used. If pertinent to man, these results might well justify a change in the current therapy for hypothyroidism.” The same authors had previously concluded in 1995 “euthyroidism is not restored in plasma and all tissues of thyroidectomized rats on T4 alone. These results may well be pertinent to patients on T4 replacement therapy” (Escobar-Morreale et al, 1995). Bunevicius et al (1999) similarly concluded, following a study of 33 patients: “In patients with hypothyroidism, partial substitution of triiodothyronine for thyroxine may improve mood and neuropsychological function; this finding suggests a specific effect of the triiodothyronine normally secreted by the thyroid gland.”
Later work by Pepper and Casanova-Romero (2014) noted that “desiccated thyroid in the treatment of hypothyroidism has generated debate among endocrinologists although there is evidence that a significant percentage of patients prefer this medication to T4-only replacement strategies” in particular those “with persistent subjective symptoms of hypothyroidism on T4-only treatment who subsequently switched to Armour Thyroid” (combined T4/T3 treatment). Studying 154 patients on Armour Thyroid, “Armour treatment was preferred over LT4 replacement therapy by 78% of patients with hypothyroidism in the sub-group with persistent subjective complaints while on T4-only therapy. No serious adverse events were noted while on Armour treatment including 30 subjects aged 65 yrs or older. Armour could be a reasonable alternative choice for treating this sub-group of patients with hypothyroidism.”
Attempting to resolve these controversies, Bioni and Wartofsky (2012) conducted a meta-analysis drawing on Medline references dating mostly to 1970 (a number of references were found prior to this date, when combined therapy was more the norm “[t]he first treatment for hypothyroidism introduced at the end of the 19th century was animal thyroid extract which contained both T3 and T4. Because of variable potency it was widely replaced by synthetic T4 from the 1960s in high doses of 200-400 ug daily to compensate for the lack of T3.” (Toft 2002)). Bioni and Wartofsky concluded “Further prospective randomized controlled studies are needed to clarify this important issue. Innovative formulations of the thyroid hormones will be required to mimic a more perfect thyroid hormone replacement therapy than is currently available.”
The conclusions of Bioni and Wartofsky are echoed across a variety of research papers investigating combined therapy in the treatment of hypothyroidism and what might account for differing patient responses and research findings. Wiersinga (2009) in an article entitled Do we need still more trials on T4 and T3 combination therapy in hypothyroidism? was critical of previous meta-analyses that failed to take account of proper dosing for combined therapy: “Development of a sustained-release T3 preparation given as a single nighttime dose (together with levothyroxine once daily) might maintain physiological serum FT4–FT3 ratio's throughout 24 h.” Paniker et al (2009) proposed that weaknesses in our understanding may be due to “commonly inherited variation in the DIO2 gene is associated both with impaired baseline psychological well-being on T(4) and enhanced response to combination T(4)/T(3) therapy, but did not affect serum thyroid hormone levels.” Wartofsky (2013) commented that [a]lthough our professional organizations continue to recommend L-T4 alone for the treatment of hypothyroidism, the possibility of a D2 gene polymorphism should be considered in patients on L-T4 monotherapy who continue to complain of fatigue in spite of dosage achieving low normal serum thyroid stimulating hormone levels.” In 2014, Wiersinga returned to the debate, finding “Evidence is mounting that levothyroxine monotherapy cannot assure a euthyroid state in all tissues simultaneously, and that normal serum TSH levels in patients receiving levothyroxine reflect pituitary euthyroidism alone. Levothyroxine plus liothyronine combination therapy is gaining in popularity; although the evidence suggests it is generally not superior to levothyroxine monotherapy, in some of the 14 published trials this combination was definitely preferred by patients and associated with improved metabolic profiles. Disappointing results with combination therapy could be related to use of inappropriate levothyroxine and liothyronine doses, resulting in abnormal serum free T₄:free T₃ ratios. Alternatively, its potential benefit might be confined to patients with specific genetic polymorphisms in thyroid hormone transporters and deiodinases that affect the intracellular levels of T₃ available for binding to T₃ receptors.”
In 2010, Nasr and Pantalone proposed some possible explanations and considerations for doctors treating hypothyroid patients. “Confronted with a low serum level of thyrotropin (thyroid-stimulating hormone, TSH), physicians should not jump to the conclusion that it is due to a hyperthyroidstate, as other conditions and some drugs can be associated with a TSH level that is slightly low (0.1–0.4 μIU/mL) or frankly suppressed (< 0.1 μIU/mL). This review discusses how to approach a low TSH, stressing the frequent need to reassess thyroid function before making a diagnosis, the underlying processes and the drugs that can be responsible, and the degree of TSH suppression and its role in the evaluation.
Low TSH, LOW FREE T4, LOW FREE T3
The history of present illness (especially if the illness is prolonged and critical), a review of previous thyroid function tests, and, sometimes, a complete evaluation of the remaining hypothalamic-pituitary axes are crucial in correctly interpreting this combination of thyroid function tests. Clinical judgment is required, and referral to an endocrinologist is warranted. The diagnostic possibilities are:
Central hypothyroidism. A low TSH level is not always due to suppression caused by high thyroid hormone levels, other conditions, or medications. If thyroid hormone levels are low, a low TSH value can be the result of a central process (hypothalamic or pituitary or both).
Severe euthyroid sick syndrome (also called “nonthyroidal illness” or “low T3 syndrome”). In this condition, the free T3 level is usually low, and in severe cases the free T4 level can also be low.
Disequilibrium state, which is seen in the hypothyroid phase of resolving thyroiditis.
State of Health TSH T4 T3 Temperature Pattern Commentary
Adrenal Fatigue Low Low Low Low, average is typically 97.8 or lower. Very unstable Symptoms: Predominate in adrenal column. Often confused with hypothyroidism because of low T4 and T3. Some doctors mistakenly interpret the low TSH here to mean pituitary trouble.
Estrogen Dominance (ED) Low Low Low Low, average is typically 97.8 or lower and unstable Is the same as adrenal fatigue in that both are related to each other. In adrenal fatigue, the adrenals often sequester the progesterone to help make cortisol. The drop in progesterone creates the progesterone / estrogen imbalance called ED.
Hypothyroidism due to low thyroid function as a primary cause, e.g., Surgical removal of thyroid with insufficient replacement of T4 High Low Low but to the right of T4 Low and very stable Note there is high conversion of T4 to T3. There is a high demand for T4/T3 (high TSH) and the body is extracting as much T3 out of the T4 as it can.
Hypothyroidism due to low pituitary function Low Low Low but to the right of T4 Low and very stable Looks just like primary hypothyroidism but TSH is low. We know there is demand because of high conversion of T4 to T3 but the TSH doesn’t rise to help T4 production.
Late Hashimoto’s Thyroiditis or Hypothyroid and Adrenal fatigue Optimal to high Low Low and mildly to the Right of T4 Low and unstable The most common presentation of disease. Similar to adrenal fatigue but symptoms are predominately in the mixed column.
Bibliography
Biondi, B and Wartofsky, L (2012), Combination Treatment with T4 and T3: Toward Personalized Replacement Therapy in Hypothyroidism?, The Journal of Clinical Endocrinology and Metabolism, Volume 97, Issue 7
Bunevicius R1, Kazanavicius G, Zalinkevicius R, Prange AJ Jr (1999), Effects of thyroxine as compared with thyroxine plus triiodothyronine in patients with hypothyroidism, New England Journal of Medicine, Feb 11;340(6):424-9
H F Escobar-Morreale, M J Obregón, F Escobar del Rey, and G Morreale de Escobar (1995), Replacement therapy for hypothyroidism with thyroxine alone does not ensure euthyroidism in all tissues, as studied in thyroidectomized rats, Journal of Clinical Investigation, Dec 1995; 96(6): 2828–2838
Escobar-Morreale HF1, del Rey FE, Obregón MJ, de Escobar GM (1996), Only the combined treatment with thyroxine and triiodothyronine ensures euthyroidism in all tissues of the thyroidectomized rat, Endocrinology. 1996 Jun;137(6): 2490-502.
Joao Pedro Werneck de Castro, Tatiana L. Fonseca, Cintia B. Ueta, Elizabeth A. McAninch, Sherine Abdalla, Gabor Wittmann, Ronald M. Lechan, Balazs Gereben, and Antonio C. Bianco (2015), Differences in hypothalamic type 2 deiodinase ubiquitination explain localized sensitivity to thyroxine, Journal of Clinical Investigation, Feb 2; 125(2): 769–781
Lewis, DH, Kumar, J, Goulden, P, Barnes, DJ (2008), Improvements in quality of Life in Hypothyroid Patients taking Armour thyroid, Endocrine Abstracts 2008 15, P359
Nasr, K and Pantalone, C (2010), Approach to a low TSH level: Patience is a virtue, Cleveland Clinic Journal of Medicine, Vol 77, No 11, November 2010
Panicker V1, Saravanan P, Vaidya B, Evans J, Hattersley AT, Frayling TM, Dayan CM (2009), Common variation in the DIO2 gene predicts baseline psychological well-being and response to combination thyroxine plus triiodothyronine therapy in hypothyroid patients, The Journal of Clinical Endocrinology and Metabolism, May;94(5): 1623-9
Pepper, GM and Casanova-Romero (2014), Conversion to Armour Thyroid from Levothyroxine Improved Patient Satisfaction in the Treatment of Hypothyroidism, Journal of Endocrinology, Diabetes & Obesity, Volume 2, Issue 3 July-September 2014
Toft, A (2002), T3/T4 Combination Therapy, Endocrine Abstracts 3 S40, British Endocrine Societies Joint Meeting 2002, Harrogate, UK, 08 April 2002 - 11 April 2002
Toft, A (year not given), Understanding Thyroid Disorders, The British Medical Association/Family Doctor Books
Wartofsky, L (2013), Combination L-T3 and L-T4 therapy for hypothyroidism, Current Opinion in Endocrinology, Diabetes, and Obesity, 2013 Oct;20(5):460-6
Wiersinga, WM (2009), Do we need still more trials on T4 and T3 combination therapy in hypothyroidism? European Journal of Endocrinology, December 1, 2009 161 955-959
Wiersinga, WM, (2014), Paradigm shifts in thyroid hormone replacement therapies for hypothyroidism, National Review of Endocrinology, Mar;10(3):164-74
Journal of Orthomolecular Medicine, Vol 28, No 2, 2013, Eric K. Pritchard, Reducing the Scope of Guidelines and Policy Statements in Hypothyroidism: tpauk.com/images/docs/reduc...
This is a very useful digest, thank you for taking the time to share it.
Angela.I would give him this huge list of peer reviewed articles and also suggest that he take a look at the study being quoted by Bristish thyroid association to support the reduction to thyroid hormones in the elderly due to falls ( which is embaressing in its lack of proper science )and tell him you wouldlike to discuss this issue in a extended appointment in a weeks time. Although he is sounding difficault I think he is asking questions which most doctors stop doing once qualified and therefore able to learn which most doctors arnt once qualified.WE could havea posssible convert and every doctor supportive is a good thing.
Also ask him to come on the forum, join and follow dioganes as he posts and hasposted research most weeks and is a scientist. There are also doctors who follow his posts that you GP can communicate with not that it is obvious who the doctors are.
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Really helpful links regarding Thyroid UK, thank you , I will certainly be putting some of that into my 'two pages' of everything (the most I think he is capable of digesting, and there's him on research leave at the moment!). 
My GP needs your help!
GP increased T4 while T3 was reduced. Please help decipher bloods so I can direct her to the next best step with unsympathetic Endo. Thanks!
How stable can we expect to be on T4/T3 combination therapy? / Hashis and jobs. 
when to increase NDT dosage....
