This summary blog post will take you through a visual journey as you follow thyroid hormones through bloodstream, transporters, cells, and receptors.
This infographic is not like most others you’ll see that portray a gland-centric view of the HPT axis. Instead, I take a hormone-centric view. The thyroid hormones themselves are the heroes of their journey. Other hormones, substances, receptors, and enzymes are secondary characters that provide turning points, opportunities, or challenges for our thyroid hormones.
You can imagine the entire process like a pinball machine, with hormones entering from the top and being bounced around through the middle, lighting things up along the way.
I’ll present a large and complex infographic that brings all the elements together.
As I zoom in to parts of the graphic, you’ll see hormones go through 6 stages on their journey:
- their synthesis in the thyroid gland
- their absorption from thyroid medications
- their movement across cell membranes, and activation of a membrane receptor,
- their metabolism into other hormones, including Reverse T3 and T2,
- their signalling in the cell’s nucleus receptors and mitochondria,
- and finally, all the hormones, before and after metabolism, mix together in bloodstream, where they are reused, recycled, and cleared.
By following the journey of our hormones from their supply to their clearance, you’ll get a glimpse into the unseen drama inside our bodies and see many points where things can go wrong, or points where you can intervene.
Like a pinball machine
I invite you to imagine the hormones in the infographic below like balls rolling down through a pinball machine of diverse cells all over your body. Their supply is at the top and their exit is at the bottom.
At various points in their journey, hormones get bounced around and light up different signaling pathways in our bodies as they connect with different receptors and then disconnect with them.
The rate and ratio of T3 to T4 coming down from the thyroid and hormone medication can cause very different things to happen in the middle and at the bottom of the pinball machine.
In this special pinball machine, these vital hormones get broken into smaller and smaller pieces in different shapes as they go through the metabolic machinery of our cells. And strangely enough, sometimes the smaller balls are more powerful than the larger ones, even though their half-life gets shorter and shorter. Even the type of T2 hormone can make a big difference.
The thyroid hormone journey
The main action of thyroid hormone metabolism is represented in the very middle of the infographic, inside our cells.
Not every cell expresses DIO1, DIO2, or DIO3, a TSH receptor and an integrin receptor. However, the image represents what occurs across many cells in our bodies.
Part 1: Thyroid synthesis & secretion
In this phase of the thyroid hormone journey, thyroid hormones T3 and T4 are created through a complex cascade of hormones, receptor signals, and enzymes, and then they are secreted directly into the bloodstream.
TRH from the hypothalamus co-regulates TSH secretion from the pituitary, which then stimulates and adjusts all phases of T3 and T4 thyroid hormone synthesis. TSH (and other substances that stimulate the TSH receptor) can upregulate the thyroid gland’s T4 and T3 secretion rate, shifting the T3:T4 synthesis ratio significantly.
Within the thyroid gland, the enzyme thyroid peroxidase, an iron-dependent enzyme, builds thyroid hormones T3 and T4 from the raw ingredients of iodine and tyrosine. The thyroid tissues use thyroglobulin as a backbone and matrix to store hormones prior to release into the bloodstream. Finally, a large percentage of our body’s T4-T3 conversion occurs within the thyroid gland, making it not only a secreting organ but a metabolizing organ.
Daily circadian rhythms achieve a stable yet flexible equilibrium from day to day, week to week, and month to month. The entire system enables the healthy thyroid gland to maintain an individual’s unique and narrow healthy range of T3 supply in the context of T4.
Many powerful forces beyond TSH hormone can skew, inflate, or inhibit thyroidal secretion:
- Central hypothyroidism: substances and medications that can hinder TRH and TSH secretion, and physical or genetic dysfunction in pituitary or hypothalamus
- Iodine deficiency and excess, since T3 and T4 are made from iodine
- Iron deficiency, which handicaps the thyroid peroxidase enzyme
- Excess exposure to endocrine disruptors like fluoride, which can compete with iodine and interfere with hormone synthesis
- Autonomously secreting thyroid nodules (only a small percentage of nodules secrete hormone at a higher rate than the rest of the thyroid),
- TSH receptor antibodies that mimic or block TSH hormone
- Anti-thyroid medications such as methimazole, carbimazole, and propylthiouracil (PTU) taken to control thyroid hypersecretion.
There’s a lot more going on here than the old gland-centric HPT axis diagrams that make it look so simple.
Part 2: Thyroid medications
(Anti-thyroid meds are discussed above because they limit thyroid function.)
Three thyroid pharmaceutical types (synthetic Liothyronine – LT3, synthetic Levothyroxine – LT4, and Desiccated thyroid NDT) and their combinations are a source of medical myths, poorly designed clinical trials, virile anti-pharma attacks, and prejudiced and prohibitory guidelines. These pharmaceuticals’ properties go beyond the equally bioidentical, equally potent hormones they each provide to blood after absorption.
Gastrointestinal (GI) tract absorption is the first major difference between thyroidal secretion and medication dosing. T4 is less efficiently absorbed than T3 by the GI tract, likely because it’s a large and bulky hormone. T4 hormone enters blood mainly through the upper intestines (jejunum and ileum). As T4 takes hours to go through this stage of its journey, a lot can happen en route, as substances, foods, medications and GI tract health conditions can hinder absorption. In contrast, T3 hormone absorption is often too quick for our body’s needs, followed by a short half-life. The time to a lower FT3 level varies depending on the current supply of T3 and T4 in blood. T3 dosing strategies and various formulations can adapt these properties to the individual.
Changing brands of thyroid medication can decrease or increase the dose received from the medication even without a change in the advertised potency of each tablet. Most countries’ regulations permit variation between brands and potency between batches and individual tablets to fall within 10-20%, which is a significant difference to the human body.
No two individuals respond the same way to the same type, dose, ratio, or brand of thyroid medication. This is because of a high degree of individual variation in thyroid disability types and degrees, as well as individual variation in absorption (discussed here) and individual transport, metabolism and signalling (discussed below). Some rare patients have hypersensitivities to pharmaceutical fillers, binders, and coloring. Others have health conditions that cause adverse responses to dosing thyroid hormones that would not occur if the same amount of hormone arrived in blood gradually every minute of the day from a healthy thyroid. As a result, no single thyroid pharmaceutical or combination is superior for all patients.
Bloodstream levels of T4, T3, and TSH will be discussed at the very end of the journey, below, because bloodstream also includes the thyroid hormones that are transported out of cells after metabolism.
Part 3: Cell membrane
The cell membrane, by which I really mean the plasma membrane, divides the bloodstream from the interior of each cell. Various receptors and transport proteins can be embedded in this membrane.
Three very exciting things happen this stage in the journey:
- Various substances in addition to TSH can bind with the TSH receptor and send signals to cell components that interact with thyroid hormones.
- At the integrin avb3 receptor, T4, T3 and even Reverse T3 can also send powerful signals into the cell,
- And a large variety of transmembrane transport proteins carry thyroid hormones (and other substances) into cells and out of them again.
The TSH receptor’s mRNA has been detected in thyroid, thymus and some immune system cells, and even on pituitary cells. The substances known to bind with this receptor include not only TSH, but also TSH-receptor blocking, stimulating, and cleavage antibodies; human chorionic gonadotropin (hCG); and a molecule called thyrostimulin. All these substances can activate the receptor and stimulate the thyroid gland and other tissues — except for the TSH receptor blocking antibody, which, as its name clarifies, blocks TSH receptors to varying degrees. Therefore, lack of TSH in bloodstream does not mean that TSH receptors are unoccupied or unused. Each of these substances has surprising effects that are not exactly the same as TSH when they occupy the receptor.
The integrin αvβ3 receptor on the plasma membrane, discovered in 2005, is the only known receptor in which T4 and even RT3 hormone have measurable activity. It has become an intense subject of research on cancer cell signalling because its activity promotes cancer and tumour cell proliferation. Research has discovered that many beneficial actions are performed through this receptor, which also sends instructions to other receptors and mitochondria in the cell. The T3 hormone can also have activity here, but a T3-exclusive arm of the receptor does not compete with T4 or RT3’s binding location. The receptor functions very differently in T3 monotherapy than it does when T4 is available to bind to this receptor. An acetic-acid thyroid hormone metabolite called Tetrac can block all the activity of this receptor, and therefore pharmaceutical development of tetrac-like substances is an arm in cancer therapy research.
Transporters are gatekeepers that regulate the amount and type of thyroid hormones that can enter and exit cells. The ratio and amount of thyroid hormones in blood can influence how transporters bind to them, and the transporters control the ratios and amounts of hormone that are transported into the cell. Each transporter has vulnerabilities and substances that compete and inhibit transport. However, there is no scientific evidence yet that iron, cortisol or Reverse T3 (RT3) hinder T3 transport into cells, despite the viral internet myths that claim this. The only known syndrome of “T3 pooling” in blood is caused by a rare MCT8 deficiency found in males with severe developmental deficits from birth.
Part 4: Metabolic pathways
The three deiodinases, Deiodinase type 1, 2 and 3, are the most significant enzymes that metabolize our thyroid hormones. The enzymes are commonly abbreviated D1, D2, and D3, but here they are identified by their genes DIO1, DIO2 and DIO3 to distinguish them from Vitamin D. I’ve also used lowercase in Dio1 because capital “I” and “O” can look too much like 1 and 0.
Omitted from the graphic are many other conversion pathways that create slightly different forms of thyroid hormones. In addition, the graphic does not express the fact that a single cell may only express one dominant DIO enzyme at a time, and yet all cells in the body combine to perform the transformations shown in the graphic.
Metabolism by deiodination is like a waterfall. You can imagine the curved, dotted arrows like streams of water. Just as a waterfall’s streams can make contact with rocks that move the water in different directions, these DIOs break off iodine atoms from different positions on the T3 or T4 molecule. Eventually, by going through many cells, a T4 thyroid hormone may be reduced to T1 and then T0 (T-zero). The healthy thyroid gland recycles some of the iodine removed from thyroid hormones by using it to create new thyroid hormones.
The exact positions of a thyroid hormone’s iodine atoms determines its function. Some of the new versions are active, and some are less active or utterly inactive in certain receptors. The three different prefixes for T2, such as 3,3′-T2, designate the exact position of the two iodine atoms that remain on T2’s rings. The apostrophe after a position number designates a hormone located on the outer ring of a thyroid hormone molecule.
Only the thyroid hormones with an iodine atom in position 5 on their inner ring (with no apostrophe after the 5) will have the “key” to enter the door of a nuclear receptor — in biochemical language, only they have significant “affinity” to bind to the receptor in the nucleus. Therefore, 3,5-T2 can bind to nuclear receptors while the other T2 metabolites are more likely to pass by without fitting in.
Reverse T3 also cannot bind with the nuclear receptor (RT3’s iodine positions, not shown, are 3,3′,5′), so it is a myth that RT3 can block T3 from these receptors. The myth arises from not understanding why people can feel hypothyroid when RT3 rises. It’s because of the net loss of T3 supply within cells that express DIO3. T3 can become inactivated by DIO3 before it reaches the nucleus. Essentially, T3 can be shot down in an “intercellular” game of Space Invaders before its ship can land in the nucleus.
The relative activity of each deiodinase throughout the body can change. Each enzyme’s number and activity can be enhanced (“upregulated”) or limited or (“downregulated”), like moving levers on a complex machine. The DIO trio’s natural role is to fine-tune local and global T3 supply in blood by coordinating with a healthy thyroid gland and TSH, or by coordinating with an intelligent doctor and patient using thyroid medications. Genetic polymorphisms in DIO1 and DIO2 can limit, but not prevent, their function.
Just as not every stream of water in a waterfall must hit a rock on its way down, some T3 from circulation will avoid making contact with deiodinases and can flow into the nucleus receptors and bind there in its current form.
Part 5: Nucleus and Mitochondria
Two main receptors enable specific thyroid hormones to signal within the cell:
- The nucleus thyroid hormone receptors send signals to transcribe thousands of different genes across every tissue and organ in our bodies. 3,5-T2 hormone has much weaker affinity with these receptors compared with T3.
- Mitochondria, which are commonly seen as the “powerhouses” of our cells, perform various vital functions. Both T3 and 3,5-T2 hormone have activity in mitochondria.
Most tissues rely on Free T3 from blood (in black text) to fill a certain percentage of their nuclear receptors and to signal within mitochondria. Each tissue needs a certain percentage of its receptors occupied. If bloodstream FT3 levels are too low, the rate of T4-T3 conversion in the cells (T3 formed by DIO1 or DIO2) will not necessarily rise to compensate for this loss, and the tissue will suffer T3 deficiency even if the TSH is normal or low.
Nuclear receptors are controlled by two genes, THRA and THRB. This means each receptor gene can suffer handicaps and may be up- or downregulated independently from the other. Each gene regulates two receptor isoforms, which are spelled with Greek alpha and beta characters. Three of them, TRα1, TRβ1, and TRβ2 can bind with thyroid hormone, but TRα2 does not, even though it is the most common receptor in the brain. The TRα1, TRα2, and TRβ1 are found in almost all tissues in variable ratios, but TRβ2 is found almost exclusively in hypothalamus, pituitary, inner ear, and retina.
Unlike many other hormone receptors, such as TSH receptors, nuclear thyroid hormone receptors are always actively signalling, even in their empty, unbound state. They are like conduits for a river of energy that never stops flowing. Thyroid receptor occupancy merely pushes a toggle switch that moves the direction of the signal one way or the other. This is why lack of T3 hormone and excess T3 are both so harmful; too many unoccupied or occupied receptors pushes the signals in one dominant direction, when the signals are meant to alternate back and forth (not on and off) at a certain rate. In each tissue, euthyroid balance means that for a certain percentage of time, some receptors in the nucleus need to be unoccupied.
Cofactors are often necessary, but not always, to boost the nuclear receptor signal. In technical language, the receptor forms a “heterodimer” — it joins hands with a different hormone’s receptor located nearby in the nucleus. “Coactivators” support the occupied thyroid receptor and “corepressors” actively repress the signal that would have been sent by an unoccupied thyroid receptor. Important coactivators of nuclear T3 signaling include
- Vitamin A (through the retinoic acid receptor RXR)
- Vitamin D (through the vitamin D receptor VDR)
- Cortisol and other steroid hormones (through the steroid hormone receptor)
A local shortage of one of these cofactors may blunt a tissue’s response to increased levels of T3.
Mitochondria rely on having enough T3 and 3,5-T2 hormone for their function. These thyroid hormones can bind to a receptor called “p43” that is a shortened variant of TRα1 receptor in the nucleus. T3 sends a signal to raise the rate of mitochondrial “respiration” which means the rate at which the mitochondria use oxygen to generate energy in the form of ATP. T3 also signals new mitochondria to be born, increasing the number of mitochondria per cell and allowing damaged mitochondria to die and be replaced at a healthy rate. Some cardiology researchers are very interested in the use of T3 to repair tissues after heart attacks, often via T3’s effect on mitochondria.
Part 6: Bloodstream hormones
A roughly equal quantity of thyroid hormones enters and exits cells continually. Some tissues exchange thyroid hormone at a faster rate than others. Converted and unconverted hormones get carried back into the bloodstream and mix with the hormone supply.
Just as a single molecule of water in a river may pass through many people in a city before that water molecule is returned to the river, you can’t know how many cells each T3 or T4 hormone has already passed through, or whether it is freshly supplied from a pill or gland.
As Gross National Product (GNP) is to a country’s economy, blood levels of thyroid hormones are to the entire body’s thyroid hormone economy. The amount and ratio of T4 and T3 in the bloodstream is a total product of the engine of supply and the engines of 2-way transport and a constantly shifting metabolism. Free T3 and Free T4 work together as a holistic and direct measure that gets us as close as we will ever come to measuring thyroid hormone levels within our cells. Our bodies truly care about these levels, so we should, too. Seeing the big picture can boost that knowledge, turning it into wisdom and insight. Like an expert interpreting GNP, people interpreting thyroid hormone data need to understand enough about the entire thyroid hormone economy to know what levels can mean to the body.
Most thyroid hormone circulating in bloodstream is bound to “serum binding proteins,” and only a small fraction, about 0.04% of Total T4 and 0.3% of Total T3, is free to be carried into the cell by transporters. Both T3 and T4 are bound to the same degree by Thyroxine Binding Globulin (TBG), approximately 75%, and the other 25% by two other binding proteins. The bound vs. free ratio of T3 and T4 can shift in pregnancy, in women who dose estrogen, and in various health conditions. People with poor thyroid function cannot maintain FT3 and FT4 by simply making more Total T3 and Total T4; they need dose adjustments.
In most healthy individuals, Free T3 and Free T4 levels are very stable from day to day, week to week, month to month (Abdalla & Bianco, 2014). The T3 (and Free T3) level in blood is the most stable and narrowly regulated of all. TSH fluctuates the most. Scientists interpret this as signifying that the HPT axis revolves around T3 hormone levels as a target, adjusting T4 and TSH to protect circulating T3 supply at a level suitable to the individual. (Abdalla & Bianco, 2014).
The Free T3:T4 ratio is occasionally a biomarker of interest in studies of disease and longevity. Even in untreated people with healthy thyroids, lower ratios tend to be associated with diseases and shorter lifespan. The healthy untreated Free T3:T4 ratio is remarkably stable. Regardless of the TSH level, an average ratio of 0.31 pmol/L was the consistent result in a large study of more than 3800 healthy controls (Gullo et al, 2011). In contrast, ratios are very different in thyroid disease and therapy. This ratio stability in health also confirms that the normal HPT axis revolves not around T3 in isolation, but Free T3 in relationship to Free T4.
Any analyst of lab results needs to know both the absorption and the clearance rates of T4 and T3 hormones, and the time it takes for FT3, FT4 and TSH to rise or fall to their new levels after adjusting one or both of these hormones’ doses. Generally as T4 and T3 levels drop, their clearance rates slow down, and as they rise, their clearance rate is faster. Increasing a thyroid hormone dose will involve a shorter time to achieve the new level of FT4 and FT3 than lowering a dose. An extremely elevated TSH can take a while to fall because the TSH clearance rate must be considered. TSH response may be abnormally low without thyrotoxicosis in cases of central hypothyroidism, secreting thyroid nodules, or T3 hormone dosing more than 10-15 mcg per dose. In patients who have TSH receptor antibodies, antibody flares can block or overstimulate the ultrashort feedback loop on the pituitary gland, making TSH secretion utterly unreliable and inconsistent with thyroid hormone levels.
Thyroid hormone laboratory testing technologies, reference ranges, and their interpretations during therapy are beyond the scope of the thyroid hormones’ journey. Where the hormones end, human interpretation and health care policy begins, and more obstacles and opportunities arise.
Again, the full infographic
Scrolling back up to the top is annoying, so here it is again for your convenience.
What have you learned as you followed this journey? If you’re a thyroid patient with brain fog (slower thought processing, incomplete thoughts), be patient with yourself and be confident that you can learn, you will just need more time and re-reading.
Overall, it’s a beautiful and complex machine that has many backup systems, but systems can fail, especially when a core gland like the thyroid is dying, dysfunctional or destroyed.
Seeing the big picture can help us understand how diseases and therapies can break down different parts of the system, and how wise therapies compensate for breakdowns.
I hope you’ll look forward to the separate posts. They will elaborate on each section of the infographic, and I’ll provide more images, details, metaphors, examples, and references.