What happens to T3?

If you are familiar with thyroid hormones, you will probably be aware that the interaction of the T3 hormone (tri-iodo-thyronine) with the T3 receptor is how it has its effects on cells.

We need enough T3 - much of which will be transported into our cells from the bloodstream. (Some might be formed by de-iodinating T4 within cells. But I'm desperately trying to simplify this to the extreme!)

The diagram below illustrates T3 (whether supplied to the cell as T3 or converted within the cell) to the T3 receptors in the nucleus. 

We often see descriptions of T3 (and many other substances) reaching their receptors as if a key is being put into a lock. And that makes it very clear that only the specific substance can actually properly activate the receptor. Other substances could potentially block a receptor, or act rather like the the proper substance - but often with less (or more) stimulation of the receptor.

For example:

• Blocking TSH-receptor antibodies prevent the usual TSH stimulating the thyroid gland to produce and release thyroid hormone.
• Stimulating TSH-receptor antibodies act more powerfully than the usual TSH thus stimulating the thyroid gland to produce and release excess thyroid hormone. Which is the fundamental issue in Graves disease.

But what is almost never discussed is what happens to the T3 when it has locked into the receptor. How long does it remain there? What eventually makes the receptor releasee it? Why doesn't that T3 molecule immediately re-attach to that same receptor? Or, if that receptor has become exhausted, why does it not attach to another T3 receptor?

Or does the T3 attach to several T3 receptors in succession?

I find it difficult to see how to combine the processes that would appear obvious with the extremely tight requirement for T3.

If one T3 molecule can attach to multiple receptors, what controls the total number?

Does the T3 molecule released by the T3 receptor get expelled from the cell?

Does the T3 molecule get degraded in some way? Or converted into T2? In which case we need to go through the same questions regarding T2 and T2 receptors!

 

Intramuscular and Subcutaneous Levothyroxine: Success in Treating Refractory Hypothyroidism

An interesting case. Not least that it ends up with self-administration of subcutaneous injections. After all, we see B12 patients being told they cannot self-administer because the B12 products are only licensed for intramuscular administration. And the current Serb injectable levothyroxine says intramuscular or intravenous. But not subcutaneous.

If you at all interested, it is strongly recommended that you read the full paper - which is well-written and easy to follow.

Intramuscular and Subcutaneous Levothyroxine: Success in Treating Refractory Hypothyroidism

Eur Thyroid J. 2025 Mar 1:ETJ-25-0012. doi: 10.1530/ETJ-25-0012. Online ahead of print.
Authors

Nadia Chaudhury  1 , Winston Crasto  2 , Ponnusamy Saravanan  3 , Vinod Patel  4

1 N Chaudhury, Department of Diabetes and Endocrinology, George Eliot Hospital NHS Trust, Nuneaton, CV10 7DJ, United Kingdom of Great Britain and Northern Ireland.
2 W Crasto, George Eliot Hospital NHS Trust, Nuneaton, United Kingdom of Great Britain and Northern Ireland.
3 P Saravanan, University of Warwick Medical School, Coventry, United Kingdom of Great Britain and Northern Ireland.
4 V Patel, University of Warwick Medical School, Coventry, United Kingdom of Great Britain and Northern Ireland.
PMID: 40163437
DOI: 10.1530/ETJ-25-0012

Abstract

Introduction: 

Refractory hypothyroidism often poses a clinical problem as treatment regimens are difficult to individualise to the patient and feasibility of its delivery is difficult to organise within a health care system. We present a patient who became intolerant of intramuscular (IM) levothyroxine (LT4) after 18 years of treatment, thus subcutaneous (SC) LT4 was initiated.

Case presentation: 

13-year-old female with newly-diagnosed hypothyroidism, remained hypothyroid despite escalating doses of oral LT4 and LT3. Thyroxine malabsorption was further suggested by nasogastric administration of LT4, whereby high dose thyroxine administration resulted in only 2.8 pmol/L increase in free T4 level (normal >5.14pmol/L). She eventually achieved long-term euthyroid status at age of 18 with fortnightly IM LT4, alongside oral LT4 and LT3. This was maintained for 18 years. Unfortunately, scar tissue developed around injection sites, resulting in increased pain and difficulty of administration. SC LT4 was trialled with success, and she has remained euthyroid for the last six years with self-administration and minimal side effects.

Conclusion: 

Refractory hypothyroidism often presents a challenge for clinicians, both for diagnosis and management. We discuss a patient with longest follow-up to-date within the published literature for both IM and SC LT4 for patient-administered treatment of refractory hypothyroidism and review the literature on alternative formulations available.

PubMed index link here:

https://pubmed.ncbi.nlm.nih.gov/40163437/

Full paper accessible here:

https://etj.bioscientifica.com/view/journals/etj/aop/etj-25-0012/etj-25-0012.xml

Prevalence and characteristics of adults avoiding gluten without celiac disease: a long-term population-based follow-up study

This paper is not directly a thyroid issue but the number of those with thyroid issues who choose to avoid gluten seems to be significant. Hence it could be relevant.

The paper doesn't explain the issues. Rather it reports on the prevalence and makes a few observations. Of course, until an issue is reported, there is unlikely to be research which explains them. That makes it potentially important.

Prevalence and characteristics of adults avoiding gluten without celiac disease: a long-term population-based follow-up study.

Tiainen M 1 , Kurppa K 1 , Jääskeläinen T 2 , Kaartinen N 2 , Huhtala H 3 , Kaukinen K 1 , Taavela J 1

BMC Gastroenterology, 25 Mar 2025, 25(1):199
https://doi.org/10.1186/s12876-025-03799-x PMID: 40133823 PMCID: PMC11938570

Abstract

Objective

Nationwide prevalence studies on people avoiding gluten without celiac disease (PWAG) are lacking, and in particular, long-term follow-up studies are unavailable. We aimed to evaluate the prevalence, incidence, and characteristics of PWAG in a population-based cohort in 2000 and 2011.

Methods

Health and diet-related data were collected in nationwide Health 2000 and 2011 surveys, which comprised 5,777 and 3,866 individuals, respectively, representing 2,682,733 and 1,967,876 Finnish adults. Serum samples were taken for the measurement of transglutaminase autoantibodies. In total 3,296 individuals participated in both surveys, forming a prospective cohort. PWAG refers to subjects avoiding gluten without celiac disease or positive autoantibodies. Psychological health was assessed with General Health Questionnaire and the Beck Depression Inventory.

Results

The prevalence of PWAG increased significantly from 0.2% (2000) to 0.7% (2011) (p < 0.001), with the highest prevalence (1.3%) detected in individuals > 70 years old. An annual incidence rate of 42 (95% confidence interval 25-71) per 100,000 persons was noted. The PWAG group was more likely to maintain additional special diets than those not avoiding gluten, including e.g. lactose-free diet (41.7% vs. 12.0% in 2011, p < 0.001) and food restriction for allergy (12.5% vs. 3.0%, p = 0.007). Beck Depression Inventory indicated more depression (p = 0.023) among PWAG in 2000, while no difference was seen in 2011 or in General Health Questionnaire. Celiac disease-related risk factors, including female gender, anemia, autoimmune diseases or antibody levels near the upper limit of normal in 2000, did not predict later gluten avoidance.

Conclusions

The prevalence of PWAG multiplied over a decade, reaching 0.7% in 2011 in Finland. The PWAG group maintained more likely additional dietary restrictions than those not avoiding gluten and had signs of psychosocial burden. No predicting factors for the condition were identified.

Full text open access from both links:

https://europepmc.org/article/MED/40133823

https://doi.org/10.1186/s12876-025-03799-x

The role of the hypothalamic–pituitary–thyroid axis in thyroid cancer

Use of TSH-suppressing doses of thyroid hormone after thyroidectomy or radioactive iodine treatment for thyroid cancers has long been a common practice.

In more recent years, opinion appears to have moved to using a TSH-suppressing dose to begin with, then reducing it to a more standard dosing level (e.g. one which sees TSH rise towards the reference interval).

While this paper continues down this route, without access to the full paper it is difficult to properly and fully appreciate their rationale.

ReviewVolume 13, Issue 4p 333-346 April 2025

The role of the hypothalamic–pituitary–thyroid axis in thyroid cancer

Laura Abaandou, PhD† ∙ Raisa Ghosh, MD† ∙ Joanna Klubo-Gwiezdzinska, MD PhD joanna.klubo-gwiezdzinska@nih.gov

DOI: 10.1016/S2213-8587(24)00364-4

Summary

The hypothalamic–pituitary–thyroid axis plays a crucial role in the pathogenesis, diagnosis, risk stratification, effectiveness of radioiodine therapy, and treatment response evaluation in epithelial thyroid cancer. Supraphysiological doses of levothyroxine are used in patients with intermediate-risk and high-risk thyroid cancer to suppress thyroid-stimulating hormone (TSH) to prevent tumour progression. However, free thyroxine and tri-iodothyronine have also been found to promote tumour growth in thyroid cancer preclinical models. Moreover, current evidence remains inconclusive about the role of TSH suppression in improving survival outcomes and reveals an increased risk of cardiovascular and skeletal adverse events after long-term exposure to excess levothyroxine. Stimulation of the axis with either recombinant human TSH or thyroid hormone withdrawal has been proven equally effective for diagnostic purposes and for facilitating radioiodine uptake for thyroid remnant ablation, but evidence is insufficient for non-inferiority of recombinant human TSH-based vs thyroid hormone withdrawal-based stimulation before radioiodine therapy of distant metastases.

This paper is, as so many papers are, behind a paywall:

https://www.thelancet.com/journals/landia/article/PIIS2213-8587(24)00364-4/abstract

This is also available on link below - which includes  few extra snippets:

https://www.sciencedirect.com/science/article/abs/pii/S2213858724003644

We keep hearing of doctors who deny that cholesterol levels are linked to hypothyroidism. The comments on forum often say something like “they used to use cholesterol as an indicator of thyroid levels”. However, rarely has this actually been complemented by a link, a quote, of an actual example.

I found this case report, one of nine in the paper, when I was looking for something else. It was published in the British Medical Journal in 1950.

In addition to the specific cholesterol issue, some may find interest in what was happening around the time thyroxine started to become available.

ORAL THYROXINE IN TREATMENT OF
MYXOEDEMA
BY
F. DUDLEY HART, M.D., F.R.C.P.
Assistant Physician, Westminster Hospital; Lecturer in
Applied Pharmacology, Westminster Medical School
AND
N. F. MACLAGAN, D.Sc., M.D., M.R.C.P.
Professor of Chemical Pathology in University of London
at Westminster Medical School; Chemical Pathologist to
Westminster Hospital

Case 2 (See Fig. 2)

A married woman aged 63 was diagnosed as a case of myxoedema in 1936, and treated with dried thyroid extract.

1946, after ten years' treatment, she ceased to attend. After eighteen months there was a gradual return of symptoms.

On examination typical myxoedema was noted. Her blood pressure was 170/100. Renal function was 64% of normal.

The initial B.M.R. was -21%, and serum cholesterol 437 mg. per 100 ml.

Treatment.-

DL-thyroxine 1 mg. daily was given. Within a week she began to feel better and lost weight. In a fortnight her voice had almost returned to normal. Serum cholesterol dropped to 205 mg., and urea clearance rose to 81% of normal.

Improvement was in every way satisfactory. Thyroxine was increased to 1.4 mg. a day. Her only disability was that the hair continued to fall out. Her energy was still slightly sub-
normal. Thyroxine was increased to 1.8 mg. a day. One month later she stated that she had stopped "falling about” and was now entirely steady on her feet, although her gait had always been unsteady since the onset of myxoedema. Her hair was now falling out much less. Treatment was changed to DL-sodium thyroxine 1 mg. a day, then reduced to 0.6 mg. after two months. Two months later treatment was changed to L-sodium thyroxine (0.3 mg. a day).

Comment.-

Improvement was entirely satisfactory when on 1 mg. of DL-thyroxine sodium. Her B.M.R. rose to +22% and serum cholesterol dropped to 206 mg. On the reduced dosage she continues to be well. She appears to be at her best when [u]the cholesterol reading is slightly raised[/u] and the B.M.R. is within the normal range. The only time the cholesterol figure has been within normal limits was when other symptoms suggested that dosage was excessive. She has been on L-thyroxine sodium for four months. Her present dose is 0.2 mg. a day. The observation period was one year five months.

https://europepmc.org/backend/ptpmcrender.fcgi?accid=PMC2037331&blobtype=pdf

Explanatory notes:

B.M.R. - Basal Metabolic Rate 

DL-thyroxine-sodium - a mixture of L-thyroxine (which we widely call levothyroxine) and D-thyroxine which is no longer used. D-thyroxine is not the form found in our bodies. It required much higher doses and was eventually recognised as causing heart issues. Which is why we now only see L-thyroxine. It also partly the doses quoted appearing much higher than we see today. It is also possible that the less exacting purity of the product, and issues about how it was delivered, also affected requirements.

Application of Thyroid Hormones in Women's Hair for the Non-Invasive Prediction of Graves' Disease

An interesting development in the realm of FT4 and FT3 testing.

Application of Thyroid Hormones in Women's Hair for the Non-Invasive Prediction of Graves' Disease
Kouhei Igarashi  1   2 , Chie Takita  1   2 , Masako Matsumoto  3 , Wataru Kitagawa  4 , Atsuko Ota  2 , Naoko Miyazaki  5 , Koichi Ito  4 , Kazutaka Ikeda  1   6
Affiliations

    PMID: 40149889 DOI: 10.3390/biom15030353

Abstract

Graves' disease (GD) is an autoimmune disorder that can be difficult to distinguish from other diseases due to symptom similarity. The exacerbation of GD owing to delayed diagnosis is a serious issue, and a novel accessible health screening system is needed. Therefore, this study investigated the association between GD and thyroid hormone levels in women's hair and evaluated the prediction accuracy of this non-invasive type of sample. By optimizing pretreatment and analysis techniques using liquid chromatography-mass spectrometry (LC-MS), free triiodothyronine (FT3) and thyroxine (FT4) could be detected in only 2 mg of hair with high sensitivity. Compared with healthy controls, the thyroid hormone levels in the hair of GD patients were significantly higher in correlation with blood levels. The predictive ability of hair thyroid hormones was analyzed using a receiver operating characteristic (ROC) curve, and the optimal cut-off value was determined via the Youden index. As a result, the area under the curve (AUC) was 0.974 (95% confidence interval (CI): 0.935-1.000) for FT3 and 0.900 (95% CI: 0.807-0.993) for FT4. The cut-off value was 0.133 pg/mg (sensitivity: 91.2%; specificity: 100%; positive predictive value (PPV): 100%; negative predictive value (NPV): 76.9%) for FT3 and 0.067 pg/mg (sensitivity: 70.6%; specificity: 100%; PPV: 100%; NPV: 50.0%) for FT4. Collectively, our new approach offers the possibility of accurately and non-invasively detecting GD using hair samples. Since hair can be stored and transported at room temperature, this system facilitates large-scale screening at locations including hair salons and homes, potentially enabling the early determination of GD outside of medical facilities.

Keywords: Graves’ disease; health check; lipidomics; mass spectrometry; non-invasive hair screening; thyroid hormone.

Igarashi, K., Takita, C., Matsumoto, M., Kitagawa, W., Ota, A., Miyazaki, N., Ito, K., & Ikeda, K. (2025). Application of Thyroid Hormones in Women's Hair for the Non-Invasive Prediction of Graves' Disease. Biomolecules, 15(3), 353. https://doi.org/10.3390/biom15030353

https://pubmed.ncbi.nlm.nih.gov/40149889/

29/03/2025

Thyroid Hormones and Metabolism Regulation: Which Role on Brown Adipose Tissue and Browning Process?

We have two types of adipose tissue (fat cells) - white and brown.

White adipose tissue is primarily fat storage.

Brown adipose tissue is capable of generating heat directly by metabolic processes. Not by shivering. Not by any muscle actions.

White fat cells, adipocytes, can convert to brown adipocytes. 

This conversion is controlled, at least in part, by thyroid hormones.

(You might occasionally see discussion of beige adipocytes.)

Thyroid Hormones and Metabolism Regulation: Which Role on Brown Adipose Tissue and Browning Process?
Laura Sabatino  1 , Cristina Vassalle  2
Affiliations

    PMID: 40149897 DOI: 10.3390/biom15030361

Abstract

Thyroid hormones (THs) are important modulators of many metabolic processes, being strictly associated with the control of energy balance, mainly through activities on the brain, white and brown adipose tissue, skeletal muscle, liver, and pancreas. In this review, the principal mechanisms of TH regulation on metabolic processes will be discussed and THs' relevance in metabolic disease progression will be evaluated, especially in the cardiovascular context and correlated diseases. Moreover, we will discuss THs' regulatory role on metabolic events in white and brown adipose tissue, with a special focus on the process of "browning", which consists of the gradual acquisition by white adipocytes of the physical and functional characteristics of brown adipocytes. The advancements in research on molecular mechanisms and proposed physiopathological relevance of this process will be discussed.

Keywords: brown adipose tissue; browning; metabolism; thyroid hormones.

Sabatino, L., & Vassalle, C. (2025). Thyroid Hormones and Metabolism Regulation: Which Role on Brown Adipose Tissue and Browning Process? Biomolecules, 15(3), 361. https://doi.org/10.3390/biom15030361

https://www.mdpi.com/2218-273X/15/3/361

29/03/2025

helvella - Fasting for blood tests

My view is this: Always fast for blood tests.

My logic is this:

For most tests, most of the time, fasting might make no difference. Sometimes fasting might make a modest difference. But there are some tests which must be done fasting.

Say we don’t usually fast. Then we are scheduled to have a test which definitely requires fasting.

If that is the only test we are having, fine.

If we have that test in combination with other tests, ones which do not need fasting, this time they are done in a fasting state. Though previously the same tests might have been done without fasting.

Any effects due to fasting (or not), even if small, make comparison with previous tests just a bit more questionable. Was that a real and potentially important difference? Or was it due solely to fasting?

Always fast and the question disappears.

helvella - Testing Companies

This links to Lola Health who have possibly the best range of testing offers which include visiting phlebotomists. For some people, this option makes the difference between being able to get a test done - and not.

Personal experience showed that they are efficient and the doctors' interpretations were properly considered and helpful. Obviously this is on a very small number of tests.

Link to Lola Health

(You can avoid using the referral link above, if you wish: Lola Health without referral.)

Thyroid UK lists several private testing labs. However, there are other private testing labs which are NOT listed but might be particularly helpful to some people.