THE THYROID HORMONE

THE THYROID

THE THYROID GLAND MAKES THYROXINE (T4). and CALCITONIN, which lowers blood calcium. it also makes perhaps 10 – 20% of our T3, the active form of thyroid hormone.

Thyroxine (T4)

Figure 1: Diagram of T4, with four iodine atoms. The changes made by D1and D2 are shown in Figure 2

Just as with DHEA, testosterone, estrogen, progesterone, Allopregnanolone and melatonin, there is a progressive reduction of T4 production by the thyroid as we age, which may result in true hypothyroidism.Stress causes intracellular hypothyroidism by blocking triiodothyronine (T3) production.

T4 isn”t really a hormone: it’s raw material that TRIIODOTHYRONINE (T3), is made from.
T4 made by the thyroid gland enters the blood and attaches to a protein called thyroid hormone binding globulin (TBG).

Triiodothyronine

Triiodothyronine (T3) increases the efficiency of all cells (including pituitary cells). The scientific literature contains many articles on the subject of thyroid hormones and the conversion of T4 to T3.
Some authors have suggested that T4 – T3 conversion occurs in the liver and kidneys only, but we now know that T3 production in the tissues: each cell takes some T4 from the blood, uses it to make T3 and passes any surplus T3 back into the bloodstream.

Every cell in the body makes T3, from T4.
Each cell uses a “Transporter” protein to import T4 from TBG and in the inner layer of the cell wall, an enzyme called Deiodinase 1 removes an Iodine atom from it, to make T3. Most of the T3 only stays inside the cell for 20 minutes or so. It goes back into the bloodstream through the cell wall and joins the pool of circulating thyroid hormone, by attaching to TBG.
Thus, the individual cell can import both T4 and/or T3 from the blood, without difficulty.

Thyroid function tests

In addition to testing for the thyroid stimulating hormone (TSH), we can test for the total amount of T4 and T3 in the blood, but testing for the portion which is “free” from TBG is more accurate, in terms of judging how much T3 and T4 is available to our cells.
The free T4 (FT4) tells us how much raw material is available to make T3.
The free T3 (FT3) gives an Idea of how much T3 is being made in the cells.

HOW T4-to-T3 CONVERSION HAPPENS

T4 is a protein molecule with 4 Iodine atoms attached to it. It is the “prohormone” (raw material), for T3.
We have 3 “De-iodinase” enzymes (D1, D2, D3), each of which removes an Iodine atom from T4.
All the cells in the body and brain, except in the pituitary, use D1 to make T3, by removing a particular iodine atom from T4 (cells in the body and brain don’t have D2).
Cells in the pituitary gland don’t have D1: they use D2, to change T4 to T3.
T3 has a special shape, which fits into “T3 receptors” * in all cells, including those of the pituitary gland.
T3 receptors accept T3 molecules and when T3 plugs in, it increases cell efficiency. Without T3, the cells don’t work properly.

Deiodinase 3: action on T4

D3 is present in all cells of the body and the brain, except for cells in the pituitary gland, which does not have D3.
D3 removes a different Iodine atom, producing a twisted T3, “reverse T3” (rT3), instead of normal T3 (see figure 2). Reverse T3 is a different shape: it doesn’t fit into the T3 receptors and has no effect on cellular efficiency, but a blood test can tell us when a lot of rT3 is being made: if the cells are making too much rT3, we know that they are not making enough normal T3.

Deiodinase 3: action on T3

D3 does something else: it removes an iodine atom from any T3 (newly-made or imported) which it finds in the cells. This is diabolical, because when D3 is activated, the net result of its effects is complete removal of T3 from the cells.

In summary, this is what the deiodinases do

Deiodinase 1 converts T4 into active T3 throughout the body.
Deiodinase 2 converts T4 into active T3 in the pituitary gland.
Deiodinase 3 converts T4 into rT3 and T3 into T2, but there is no D3 in the pituitary.

D1 is blocked, preventing conversion of T4 to T3 and D3 is activated, so T4 is converted into rT3 and any pre-existing T3, is changed to T2, when cortisol rises in response to stress,

D2 is not affected by cortisol, so the pituitary gland works normally, under stress.

The graphic below shows the process clearly: D3 removes the wrong iodine atom, from T4!
It was copied from “Cardiomyocyte-specific inactivation of thyroid hormone in pathologic ventricular hypertrophy: an adaptative response or part of the problem?”, by Christine J. Pol, Alice Muller, and Warner S. Simonides, in journal “Heart Fail Review, Nov 24, 2008).

Figure 2

STRESS

When a human is subjected to stress – any stress, whether from high or low temperature, famine, natural disaster, animal attack, infection, poisoning, psychological strain, diseases like heart attack, stroke or cancer (any condition which disturbs normal function), every cell in the body, excepting pituitary cells, reduces efficiency so as to save energy which may be needed for repairs.

This is how it works:
UNDER STRESS, cortisol is secreted by the adrenal glands, and ….
A: Cortisol blocks D1, but not D2, so no T3 can be made inside any cell, except in the Pituitary gland!
B: Cortisol activates D3, which removes the wrong iodine atom from T4, making “rT3” and also destroys any T3 present in the cell, by removing one of its iodine atoms, producing “T2”, which is completely inactive.
Thus cortisol removes T3 from all cells except the Pituitary.

The Pituitary doesn’t have the problem, because it doesn’t have D1 or D3.
The Pituitary uses D2 to make T3, so it has enough T3 for itself. Therefore it works normally, including production of thyroid stimulating hormone (TSH), according to the amount of T4 it gets. So when a human is stressed, the level of TSH in the blood tells the doctor that the Pituitary has enough T4, but the TSH does not indicate what is happening in the body.
If the doctor did tests to find out the T3 and rT3 level, the situation would be obvious. However up to now, doctors are specifically taught not to test for T3 or reverse T3.

Obviously, blocking T3 is a disaster

When you are under major stress, there is little or no functioning T3 inside the cells, and all cells lose efficiency. In fact, the most sensitive ones shut down almost completely. The result is lassitude, an overwhelming sense of tiredness and muscle weakness, reduced heat production with a feeling of being cold, “fuzzy thinking” with uncertainty and confusion, and weight gain.
All of the symptoms tend to be worse in the afternoon and if the problem persists for long enough, chronic “low thyroid” symptoms” like dry skin, hoarseness, leg swelling, constipation, hives etc. can set in. I call this “Intracellular Hypothyroidism” (IH), but it is also called “low T3 syndrome”, “euthyroid sick syndrome”, “functional hypothyroidism”and “nonthyroidal illness”.

In terms of the symptoms it produces, IH is indistinguishable from “burnout”, “chronic fatigue syndrome” and “long Covid”.

If IH stays bad enough for long enough, it can progress to serious illness, which will be different from person to person, depending on which of their cells and organs are most sensitive to the absence of T3.
A good example is Takotsubo cardiomyopathy (“broken heart syndrome”), a type of heart failure which happens to genetically predisposed people, when they are emotionally, or physically, stressed. In particular, see a case report of cardiomyopathy, in my blog.
The incidence of Takotsubo Cardiomyopathy is between 2 and 10 cases per 100,000 hospital admissions, but there must be many cases of cardiomyopathy which are not recognized as “Takotsubo”. In my opinion, even mild heart failure should be investigated for IH, because if IH is the because of the heart weakness,, it can be easily and safely treated.

Recap: Details made simple

The thyroid gland lies in the neck, wrapped around the larynx (the voice-box). It secretes all the T4 (about 90 to 100mcg daily) and 20% of the T3, for the body.
Every cell imports T4, removes an iodine atom, to make T3 and uses the T3 to maximise its efficiency.
Every cell exports surplus T3 into the bloodstream, so a normal T3 test proves production.
Remember: Pituitary cells use D #2, but all others use D #1, to convert T4 to T3.

T3 is responsible for metabolic efficiency in all cells: T3 helps to regulate body temperature, muscle power, body weight, glucose, cholesterol and everything else from hair and fingernail growth to mood and “well-being”: it controls every cell in the body and brain.

T3 is essential for the unborn baby’s brain development and the fetus does not begin to make its own T3 until the 14th week of pregnancy.
The baby’s brain connections are started between the 8th and the 14th week of pregnancy and If the mother is hypothyroid, or stressed enough to have intracellular hypothyroidism, while the “wiring” is being done, subtle abnormalities in brain growth may occur. This can lead to cognitive and physical deficits in the newborn.
Autism spectrum, schizophrenia, dyslexia, ADD, obesity and gender dysphoria are all related to maternal hypothyroidism, but no one has thought about intracellular hypothyroidism being a cause.

FAQ:

(1) What is Deiodinase #3 USED FOR?
A: In either physical or psychological high-stress conditions, D3 SHUTS THE WHOLE BODY DOWN, SAVING ENERGY WHEN LIFE IS THREATENED.
(2) Under stress, does the pituitary gland shut down too?
A: No: in the Pituitary, no rT3 is produced, and T3, made by D2, is not converted to T2. Therefore, the pituitary is unaffected and its output of TSH continues, as usual.
(3) WHY DOES THE BODY LOSE EFFICIENCY ?
A: With T3 formation stopped and available T3 changed to T2, there isn’t enough T3 to keep cells going.
(4) What does reverse T3 do?
A: Not much: we used to think that rT3 could hitch itself to the receptors and block the entry of T3, but all it does is to encourage the actions of D3. However, rT3 is a perfect “marker” (a blood test signal) for intracellular hypothyroidism, because it only increases if the cells use D3 instead of D2 for T4 conversion.
(5) What are the symptoms of intracellular (“functional”) hypothyroidism?
A: Feeling tired, weak, confused, anxious and depressed: any “low thyroid” symptoms can occur – for example:
The skeletal muscles don’t work properly and hurt, with effort.
Some people get muscle cramps.
Some get “Hoffman’s syndrome”, or “stiff person syndrome”, because the muscles can’t relax.
There is constipation: the “tight” bowel muscles can’t relax to let the stool go through.
There is cognitive loss, fuzzy thinking and confusion, due to of reduced brain function.
In some organs (varying from individual to individual), “subtotal” stoppage of function can occur (for example, heart muscle paralysis in Takotsubo Cardiomyopathy).
If the problem persists the fingernails get brittle, the hair (e.g. eyebrows) starts to fall out, there may be dry and itchy skin, the voice gets hoarse, the legs and eyelids swell from retained water, there is a feeling of being cold because the brown fat stops burning glucose, cholesterol goes up, there is weight gain and diabetes starts.
(6) If the problem is from insufficient T3, why doesn’t the doctor Prescribe T3?
A: The medical professors and the medical “system” tell the doctors specifically, that testing T3 and are T3 is a waste of money and that prescribing T3 is not good Medicine. So the doctor tests “everything” except T3, T4 and rT3: the only thyroid test done is TSH, which stays normal because the Pituitary is “happy”. So the Doctor can’t “read” the situation and doesn’t recognise the problem.
(7) So what does the doctor do to help the patient?
A: The MD may notice depression or confusion, high cholesterol, high blood pressure due to stress, muscle cramps, constipation, early diabetes, or swollen legs, etc.
So the sufferer gets a pill for each symptom.
(8) What’s the end result of intracellular hypothyroidism?
A: If the Stressful conditions come to an end, a “remission” may occur. However if the situation becomes chronic, serious disease, such as those above, may begin. In the case of heart muscle weakness, there is heart failure and some people die.
(9) What are the normal levels of TSH, T4, T3 and reverse T3, in the blood?
A: TSH: 0.35-4.0 iu/L, but there is a reasonable argument for assuming that 2.5 should be the upper limit of normal (recently, it has been suggested that 1.5 should be the upper limit).
Free T4: 9–19 pmol/litre:
Free T3: 2.6 – 5.8/litre, since 2021: previously, it was 3.1 – 6.1.
note that these are the accepted ranges in the Canadian medical system.
MY OPINION: the limits for TSH should be 0.35 – 2.5, and T3 should be T3 4–6.1
rT3 It is said to have a normal range of 5–25; but in practical terms, there is no normal for rT3, which is not a metabolite. The optimal range is 7 – 13.

Caveats:
(1) For detail regarding normal thyroid hormone levels, please go to the blog on “NORMAL” and scroll down to the section re. the Thyroid.
(2)) Please see the page on intracellular T3 deficiency (Intracellular Hypothyroidism, “IH”).

GENERAL SYMPTOMS OF HYPOTHYROIDISM:

T3 hormone is the efficiency factor for all body parts and the problems resulting from lowered T3 depend on which part of the individual’s body is most sensitive to lack of T3, so symptoms are many and varied.
Virtually any symptom may present, including those from Adrenal slowdown.
Many people with Hypothyroidism (either “true” hypothyroidism from underproduction of thyroid hormone, or “functional” (intracellular) hypothyroidism, with metabolic loss of T3 within the cells), report sluggishness, anxiety, “brain fog”, cognitive loss and a feeling of low energy, in addition to the classical hypothyroid complaints (see below).

SYMPTOMS, SIGNS, DIAGNOSIS AND TREATMENT OF HYPOTHYROIDISM 

SYMPTOMS short list Fatigue Low motivation Depressed mood Impaired memory Poor sleep quality Weight Gain Depression anxiety Reduced sex drive, male or female Heavy or irregular “periods” PMS Infertility Recurrent abortion Subtle abnormality of a baby’s brain development Chronic yeast infections Muscle weakness, including Myocardial weakness (see Ref # 6,7,8). Muscle aches Joint Pain, stiffness, swelling Constipation Difficulty staying warm Hoarseness Difficulty breathing Slower heart rate Puffy face, Dry skin, Acne Brittle hair and nails Calloused heels Headaches Premature gray hair   Brittle fingernails	SIGNS noticed by the doctor Slow pulse, Irregular pulse, Low BP, Temperature < 36°C Dry skin + Dry hair / grey hair Heel calluses Hair loss from the head, legs or eyebrows (outer 1/3) Swelling below lower eyelids Skin swelling over the shins Hoarse, “thick” speech, Dry cough Slow thinking, confusion Memory loss, Untidyness Home in endemic area Economic disadvantage History suggesting FH High-stress job, High-stress job partner High-stress life partner Separation, divorce (Parents): difficult children (Children): difficult parents Childhood abuse of whatever type Chronic illness, eg. Celiac Disease or gluten intolerance Severe illness, with ongoing anxiety Difficult life circumstances Poverty Dependent relatives Anxious personality disorder Other psychopathy, schizophrenia and “bipolar disease” Family history of hypothyroidism Retirement, social isolation Alcohol / tobacco / THC /drug habit
TYPES/CAUSES of HYPOTHYROIDISM 1:   Iodine deficiency 2:   Selenium deficiency 3:   Hashimoto’s thyroiditis 4:   Ionising radiation 5:   Therapeutic radiation 6:   Thyroid/ Pituitary Surgery 7: Unknown cause 8:   Prescribed medication 9:   Stress (IH) 10: Worse IH with Eltroxin * 11: Hypopituitarism	TEST RESULTS ASSOCIATED WITH HYPOTHYROIDISM Elevated blood cholesterol level Borderline blood sugar/A1C High TSH, with or without low T4 Low T3, High reverse T3, Low FT3/rT3 ratio, with or without high TSH “Adrenal Fatigue” Low DHEA, Testosterone, Oestrogen, Progesterone, Allopregnanolone Fluid retention, with or without heart failure   Iodine &/or Selenium deficiency HEAVY METAL OVERLOAD CAN CAUSE SIMILAR SYMPTOMS: the Urine should be checked for Heavy Metal “burden”
TREATMENT Eltroxin*, plus iodine and/or selenium, for # 1 – 8. Compounded, slow-release T3, for # 9, 10 & 11. Selenium (2 Brazil nuts per day will provide enough). Iodine (2 drops of Lugol’s iodine per day). Iron: serum iron (“Ferritin”) should be kept >100. DHEA, 50mg/day (men) and 25-50mg/day (women) reduces symptoms. * Eltroxin makes #9 MUCH worse.	CONDITIONS ASSOCIATED WITH Intracellular Hypothroidism Long-COVID syndrome, POST-FINASTERIDE syndrome, CFS/FM, Gulf war syndrome, PTSD (CHILDHOOD or ADULT), Depression, Lyme Disease, Goitre, Menopause, Psychiatric conditions, autism, Type I or II Diabetes, obesity, peripheral neuropathy, Alzheimer’s, Autoimmune diseases (rheum. arthritis, lupus, sarcoidosis, Sjogren’s, etc.), Fibrillation, heart failure, Takotsubo Cardiomyopathy, Adrenal Fatigue, Crohn’s disease, Ulcerative colitis, Diverticulitis, Heavy-metal overload, Multiple sclerosis (MS), Hypercholesterolaemia, Heart failure, Chronic anxiety/depression, Schizophrenia ALL TYPES OF SEVERE ILLNESS, or admission to an ICU.

REFERENCES:

(1) Trans Am Clin Climatol, 2013;124:26-35, Cracking the code for thyroid hormone signaling: Antonio C Bianco ¹ PMID: 23874007, PMCID: PMC3715916
(2) Endocrinology, 2021 Aug 1;162(8):bqab059. doi: 10.1210/endocr/bqab059.Deiodinases and the Metabolic Code for Thyroid Hormone Action, Samuel C Russo ¹ , Federico Salas-Lucia ¹ , Antonio C Bianco ¹ PMID: 33720335, PMCID: PMC8237994 (available on 2022-03-15),
DOI: 10.1210/endocr/bqab059
(3) Endocr Rev. 2019 Aug 1; 40(4):1000-1047. doi: 10.1210/er.2018-00275. Paradigms of Dynamic Control of Thyroid Hormone Signaling, Antonio C Bianco ¹ , Alexandra Dumitrescu ¹ , Balázs Gereben ² , Miriam O Ribeiro ³ , Tatiana L Fonseca ¹ , Gustavo W Fernandes ¹ , Barbara M L C Bocco ¹ , PMID: 31033998, PMCID: PMC6596318, DOI: 10.1210/er.2018-00275
(5) Clinical Endocrin., Volume81, Issue5, Review, November 2014, Pages 633-641: Defending plasma T3 is a biological priority^† Sherine M. Abdalla, Antonio C. Bianco: 05 July 2014 https://doi.org/10.1111/cen.12538
(5) https://cbhrt.ca/2021/10/23/thinking-about-normal/
(6) Hoffman’s syndrome – A rare facet of hypothyroid myopathy, Swayamsidha Mangaraj and Ganeswar Sethy, Neurosci Rural Pract. 2014 Oct-Dec; 5(4): 447–448. doi: 10.4103/0976-3147.140025PMCID: PMC4173264PMID: 25288869 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4173264/
(7) Hypothyroidism-induced reversible dilated cardiomyopathy, by P Rastogi, A Dua, S Attri, and H Sharma, J Postgrad Med. 2018 Jul-Sep; 64(3): 177–179. doi: 10.4103/jpgm.JPGM_154_17
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6066629/
(8) Myocardial Induction of Type 3 Deiodinase in Dilated Cardiomyopathy (experimental, Mice), Ari J. Wassner,¹Rebecca H. Jugo,¹David M. Dorfman,²Robert F. Padera,²Michelle A. Maynard,¹Ann M. Zavacki,³Patrick Y. Jay,⁴ and Stephen A. Huang¹ Thyroid. 2017 May 1; 27(5): 732–737. Published online 2017 May 1. doi: 10.1089/thy.2016.0570PMCID: PMC5421592PMID: 28314380 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5421592/
(9) Thyroid Hormone Transport into Cellular Tissue, Journal of Restorative Medicine 3(1):53-68, April 2014, DOI:10.14200/jrm.2014.3.0104, by Kent Holtorf, Holtorf Medical Group (HMG),I can supply further references, on request.
(10) “Stiff person syndrome” – https://my.clevelandclinic.org/health/articles/6076-stiff-person-syndrome
(11) Attention deficit hyperactivity disorder and autism spectrum disorder in children born to mothers with thyroid dysfunction: a Danish nationwide cohort study, by
S L Andersen  ¹ , P Laurberg, C S Wu, J Olsen,
PMID: 24605987, DOI: 10.1111/1471-0528.12681