I wrote this post as I thought it would be useful to have a collection of useful research papers in one article. I used and referenced many of these in the writing of The Thyroid Patient’s Manual.
Together, these pieces of research point the way to a better approach to thyroid treatment. This new paradigm for thyroid treatment includes several key elements:
- It places the symptoms of the patient much more centre-stage.
- It uses thyroid lab test results but only in a supporting role.
- It watches how all the thyroid laboratory test results change with respect to each other, as treatment is changed and symptoms adjust.
- Critically the thyroid labs tested must include FT3, as this is the only one that tracks symptom improvement, as thyroid medication is adjusted.
- All the thyroid treatments have to be available for the doctor to prescribe – T4, T4/T3, NDT, and T3-Only/T3-Mostly. If one does not work well, another can be tried.
Here is the list with a brief description before each about what each paper is about:
1. The use of TSH in monitoring thyroid hormone therapy is highly unsatisfactory and should be replaced by triple FT4/FT3/TSH measurement. The presentation of symptoms of the patient should be the primary focus, above lab-test results, but supported by them. Unthinking, automatic, biochemical definition of treatment success, independent of the patient must cease. Individuality should be the decision-maker for optimum therapeutic outcomes:
“Time for a reassessment of the treatment of hypothyroidism”
John E. M. Midgley, Anthony D. Toft, Rolf Larisch, Johannes W. Dietrich & Rudolf Hoermann.
BMC Endocrine Disorders volume 19, Article number: 37 (2019)
https://bmcendocrdisord.biomedcentral.com/articles/10.1186/s12902-019-0365-4
2. Previous clinical trials with T4/T3 were flawed and current treatment is flawed. These two papers do several things. They blow away ALL the research that has ever concluded that T3 has little or no benefit. They show the flaws in randomised clinical trials (RCTs) that support the simplistic reference range use of TSH or FT4 in a generalised way to manage treatment. They point to a better way to manage thyroid treatment that is more focused on the patient and on the patient response to treatment. They finally puts a bullet into the crazy conclusions that T3 does not help (that so many doctors and endocrinologists have clung onto for so long). They also show how a proper clinical trial should be run in order to get an unbiased and accurate result:
“Lessons from Randomised Clinical Trials for Triiodothyronine Treatment of Hypothyroidism: Have They Achieved Their Objectives?”
Rudolf Hoermann, John E. M. Midgley, Rolf Larisch, and Johannes W. Dietrich.
https://www.hindawi.com/journals/jtr/2018/3239197/
and this second one, although not about thyroid issues, explains Simpson’s Paradox, which goes a long way to show why past studies have missed the need for T3 in many patients (because studies have mixed up patients who do not need T3 with those that do, and therefore, they have missed the correlation: http://www.pnas.org/content/115/27/E6106
3. T4/T3 study that showed excellent long-term outcomes for thyroid patients on this combination therapy:
“Effects of Long-Term Combination LT4 and LT3 Therapy for Improving Hypothyroidism and Overall Quality of Life”
Anam Tariq, DO, Yijin Wert, MS, Pramil Cheriyath, MD, and Renu Joshi, MD
South Med J. 2018 Jun; 111(6): 363–369.
Published online 2018 Jun 1. doi: 10.14423/SMJ.0000000000000823
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5965938/
4. Only FT3 tracks symptom improvement during treatment. This is a fairly recent and terrific piece of research that clearly places FT3 centre-stage as the most useful lab test measure, as it correlates to symptoms more than the others. In addition to this, the research shows that in T4-monotherapy many patients did not find symptomatic relief until FT3 was elevated in the range and TSH suppressed:
“Symptomatic Relief is Related to Serum Free Triiodothyronine Concentrations during Follow-up in Levothyroxine-Treated Patients with Differentiated Thyroid Cancer”
Rolf Larisch, John E M Midgley, Johannes W Dietrich, Rudolf Hoermann
Exp Clin Endocrinol Diabetes 2018; 126(09): 546-552
DOI: 10.1055/s-0043-125064
https://www.thieme-connect.de/DOI/DOI?10.1055/s-0043-125064
5. Here is another relevant article on why the current paradigm of T4 monotherapy is flawed – this time by Dr. Toft:
“Thyroid hormone replacement – a counterblast to guidelines”
J R Coll Physicians Edinb 2017; 47: 307–9 | doi: 10.4997/JRCPE.2017.401
https://www.rcpe.ac.uk/sites/default/files/jrcpe_47_4_toft.pdf
6. The way TSH is currently used is wrong, the way people are treated as if they are all the same is wrong. Simply being ‘in range’ on levothyroxine (T4) monotherapy is not going to guarantee a good outcome. The next piece of research is undoubtedly one of the most important studies done in the last ten years. It finally begins to be more clear that TSH is one of the least useful tools in assessing thyroid hormone levels and whether someone is actually getting enough T3 in the cells:
“Homeostatic Control of the Thyroid-Pituitary Axis: Perspectives for Diagnosis and Treatment.”
Hoermann, Midgley, Larisch, Dietrich.
Front Endocrinol 2015 Nov 20;6:177. doi: 10.3389/fendo.2015.00177.
Abstract: https://www.ncbi.nlm.nih.gov/pubmed/26635726
Full article:
https://www.frontiersin.org/articles/10.3389/fendo.2015.00177/full
7. This is an older research paper but shows that reverse T3 (rT3) is a T3 blocker and not an inactive metabolite:
“Qualitative and quantitative differences in the pathways of extrathyroidal triiodothyronine generation between euthyroid and hypothyroid rats.”
J E Silva, M B Gordon, F R Crantz, J L Leonard, and P R Larsen
10.1172/JCI111313
https://www.jci.org/articles/view/111313
More recent understanding of the blocking effects on T3 suggests that it is actually D3 enzymes that block T3 binding to receptors. D3 converts T4 to rT3. So, it may not actually be rT3 itself, but rT3 is a marker of this and as such is still useful to test. RT3 also has a small effect on reducing the rate of T4 to T3 conversion, i.e. it reduces the number of D2 enzymes being produced in cells.
8. Here is a new piece of research that further supports patient experience that T4 monotherapy using Levothyroxine is problematic. T4 cannot re-create our previously healthy levels of FT4 and FT3. The study in rats at present actually found that T4 monotherapy resulted in lower than required FT3 levels. This was corrected with continuous release of both T4 and T3 medication in an appropriate ratio:
“Differences in hypothalamic type 2 deiodinase ubiquitination explain localized sensitivity to thyroxine”
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
Journal of Clinical Investigation 10.1172/JCI77588
https://www.jci.org/articles/view/77588
9. A new research paper has been published by Rudolf Hoermann, John E.M. Midgley and Johannes W. Dietrich. It is published in the Clinical Endocrinology Journal. Some of the takeaway conclusions are that “in some people, no amount of T4 will regain normal FT3 levels” and that “…gurus now admit that some people cannot handle T4 and regain health”. The links to the abstract and to download the full paper are:
“Homeostatic equilibria between free thyroid hormones and pituitary thyrotropin are modulated by various influences including age, body mass index and treatment”
Rudolf Hoermann John E.M. Midgley Adrienne Giacobino Walter A. Eckl Hans Günther Wahl Johannes W. Dietrich Rolf Larisch
https://doi.org/10.1111/cen.12527 and
https://onlinelibrary.wiley.com/doi/10.1111/cen.12527/abstract and
http://www.thyroiduk.org.uk/tuk/TUK_PDFs/Homeostatic-equilibria-cen-final-080714.pdf
10. Here is a new 20-year observational piece of research. It dismisses the incorrect views that T3 has adverse effects on the bones and heart! It confirms that T3 has no adverse effects on the heart and bones. This disproves some of the major reasons that doctors use to avoid prescribing T3 – risk to the heart and to bone loss are the two most common reasons used to avoid prescribing T3 to patients, although many of us suspect that cost is the unsaid reason behind non-prescribing of T3:
“Safety review of liothyronine use: a 20 year observational follow up study”
Enrique Soto-Pedre & Graham Leese
Endocrine Abstracts (2015) 38 OC5.6 | DOI: 10.1530/endoabs.38.OC5.6
https://www.endocrine-abstracts.org/ea/0038/ea0038OC5.6.htm
11. Getting TSH into the reference range is no guarantee of good health. Here is a research paper that shows how simplistically and poorly TSH is being used today. TSH is not something that should be relied upon in the way it is being done at the present time:
“TSH Measurement and Its Implications for Personalised Clinical Decision-Making”
Rudolf Hoermann and John E. M. Midgley
Volume 2012 Article ID 438037
https://doi.org/10.1155/2012/438037
https://www.hindawi.com/journals/jtr/2012/438037/
12. It makes very interesting reading and really shows that the current protocols for managing thyroid hormone issues are so very wrong. The way TSH is currently used is wrong, the way people are treated as if they are all the same is wrong, and simply being ‘in range’ on levothyroxine monotherapy is not going to guarantee a good outcome. We are all individuals and many of us require either some T3 with T4 or all T3 in a few cases. We also know that we cannot be managed by simplistic measures like TSH. It is a complex article but well worth the read:
“Recent Advances in Thyroid Hormone Regulation: Toward a New Paradigm for Optimal Diagnosis and Treatment”
Rudolf Hoermann, John E. M. Midgley, Rolf Larisch and Johannes W. Dietrich
Front. Endocrinol., 22 December 2017 https://doi.org/10.3389/fendo.2017.00364
https://www.frontiersin.org/articles/10.3389/fendo.2017.00364/full
13. See also this recent blog post of mine, which references an article by several doctors, that shows the benefits of T3 to the heart:
https://paulrobinsonthyroid.com/physiological-replacement-therapy-with-t3-is-beneficial-in-ischemic-heart-disease-research/
14. FT4 and FT3 ranges for individual people are less than half as wide as the large laboratory test population ranges:
“Narrow Individual Variations in Serum T4 and T3 in Normal Subjects: A Clue to the Understanding of Subclinical Thyroid Disease”
Stig Andersen, Klaus Michael Pedersen, Niels Henrik Bruun, Peter Laurberg
The Journal of Clinical Endocrinology & Metabolism, Volume 87, Issue 3, 1 March 2002, Pages 1068–1072,
https://doi.org/10.1210/jcem.87.3.8165 and
https://academic.oup.com/jcem/article/87/3/1068/2846746
15. There is a need for individualised requirements for the optimal treatment of hypothyroidism. There is no ‘one size fits all’ in both treatment and necessary lab values and patient symptoms need to highly in focus.
The paper highlights that:
- The TSH measure alone is really not sensitive enough to tell a doctor when a patient is properly treated.
- Everyone has their own individual needs and setpoints for levels – there is no one size fits for thyroid levels and lab results for all patients.
- T4 leaves many feeling unwell.
- T3 often needs to be in the treatment, as many conditions and thyroid tissue loss leaves patients low in the conversion of T4 to T3.
- Many issues get in the way of conversion including loss of thyroid tissue, deiodinase defects etc.
- Patient symptoms need to be at the forefront of treatment – not placed after lab results which only include TSH and FT4.
- There need to be other biochemical markers of being adequately treated – TSH, FT4, and FT3 are not enough.
Here is the link to the new paper by Hoermann, Midgley, Larisch and Dietrich:
“Individualised requirements for optimum treatment of hypothyroidism: complex needs, limited options”
Hoermann, Midgley, Larisch and Dietrich.
Drugs in Context
DOI 10.7573/dic.212597
https://www.drugsincontext.com/individualised-requirements-for-optimum-treatment-of-hypothyroidism:-complex-needs,-limited-options/
(You can download the full paper from the link within the abstract)
16. These two papers cover many things.
They show how the loss of the thyroid gland in thyroidectomy patients causes the loss of the ability to achieve a balance of thyroid hormones and a good conversion rate (homeostatic balance). This argument also applies to Hashimoto’s patients who have lost significant thyroid tissue.
They show that the thyroid gland itself is responsible for around 25% of our T3, mostly through conversion, so tissue damage through Hashimoto’s, or through the removal of the thyroid, loses a huge amount of ability to convert from T4 to T3. This can often not be compensated for with T4 alone.
This loss of thyroid tissue means you need more medication to get FT3 up. T4 alone is often not enough to raise FT3 – you need to add T3. TSH often needs to be suppressed:
“Dual control of pituitary thyroid stimulating hormone secretion by thyroxine and triiodothyronine in athyreotic
patients”
Hoermann R, Midgley JEM, Dietrich JW, Larisch R.
See: The Adv Endocrinol Metab (2017) 8:83–95.
doi:10.1177/204201881771640112.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5524252
“Relational stability of thyroid hormones in euthyroid subjects and patients with autoimmune thyroid disease”
Hoermann R, Midgley JEM, Larisch R, Dietrich JW.
See: Eur Thyroid J (2016) 5:171–179.
doi:10.1159/000447967
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5091265/
I hope you found these interesting, instructive and useful in your own struggles to regain your thyroid health. They may also be useful to you when working with medical professionals. Many doctors and endocrinologists may be totally unaware of much of this new research.
Best wishes,
Paul
