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The Low-Down on Thyroid Hormones

Updated: Jun 23, 2020

Thyroid gland is a butterfly shaped organ (imagine a bowtie), which sits a little above the pit of your throat. It is responsible for synthesizing and releasing four (yes 3+1) key thyroid hormones. These are Tetra-iodo-thyronine (T4 or thyroxine) and tri-iodo-thyronine (T3) and reverse T3 (rT3 - more on this later). Thyroid gland also makes another hormone called calcitonin (kal-si-to-nin), which plays a key role in reducing the concentration of calcium in the body fluids when calcium levels become elevated. Lets leave calcitonin alone for now and dig into the other three.


During development (inside the womb) the thyroid gland originates in the back of the tongue,

but it normally migrates to the front of the neck before birth.


The function of the thyroid gland is take iodine, found in our diet, combine it with an amino acid called tyrosine, and convert it into T3 (containing three iodine atoms - is the active form) and T4 (containing four iodine atoms - is the inactive form).


The thyroid gland synthesizes and stores mass quantities of T3 and T4 within the protein Thyroglobulin. The thyroid hormones are released into the bloodstream and transported throughout the body. Most are bound to plasma proteins and only released on a need basis, while a smaller portion circulates as free hormones that enter cells and trigger metabolism. A minimal amount, about 0.02%, of T4 in the serum is free, or unbound and about 0.5% of T3 in the serum is free.


It is the free T3 and T4 concentrations in the blood that are responsible for biologic activity. So ideally these are what you got to get looked into when getting Thyroid tests done.


Biologically, T3 is much more important than T4 although the total concentration of T4 in the circulation is ~50 fold higher than that of total T3. Nevertheless, T3 has greater biological activity for three reasons.

  1. T4 is bound (only 0.01 to 0.02% is free) more tightly to plasma proteins than is T3 (0.50% is free). The net effect is that the amounts of free T4 and free T3 in the circulation are pretty much the same.

  2. The target cell converts some T4 once it has entered the cell to T3, it turns out that T4 and T3 are present in similar concentrations in the cytoplasm of target cells.

  3. The Thyroid Receptor (TR) in the nucleus has ~10 fold greater affinity for T3 than for T4, so that T3 is more potent on a molar basis. As a result, T3 is responsible for ~90% of the occupancy of TRs in the euthyroid state.


So what does T4, T3 and rT3 do?

T3 is the key active hormone which is responsible for all of the thyroid related effects on the body. It is four times as potent as T4. T4 is the bulk of the hormones produced and gets converted to T3 on a need basis. These hormones are essential for a host of physiological functions in the body. Thyroid hormones act on many body tissues to exert both metabolic and developmental effects. These are often referred to as metabolic hormones because their levels influence the body’s basal metabolic rate, the amount of energy used by the body at rest. When T3 and T4 bind to intra-cellular receptors located on the mitochondria, they cause an increase in nutrient breakdown and the use of oxygen to produce ATP.


The normal rate of metabolism (conversion of oxygen and calories to energy) for an individual depends on an adequate supply of thyroid hormone, which increases the rate at which glucose, lipids, and protein are metabolized. The metabolic rate can increase 60–100% when blood T3 and T4 are elevated, whereas low levels of T3 and T4 lead to the opposite effect. Because the increased rate of metabolism produces heat, normal body temperature is partly due to adequate thyroid hormones.


In addition to metabolism, T3 and T4 regulate the normal growth and maturation of organs. For example, the growth of bone, hair, teeth, connective tissue, and nervous tissue requires thyroid hormone. One reason tissues require thyroid hormones for normal growth is that T3 and T4 play a permissive role for Growth Hormone (GH), which means that GH does not have its normal effect on target tissues if T3 and T4 are not present.


Failure to maintain homeostatic amounts of thyroid hormone dramatically affects the body’s functions. Hyper-secretion of T3 and T4 increases the rate of metabolism. High body temperature, weight loss, increased appetite, rapid heart rate, and an enlarged thyroid gland are major symptoms. This results in a condition called Hyperthyroidism. Hypo-secretion of T3 and T4 decreases the rate of metabolism. Low body temperature, weight gain, reduced appetite, reduced heart rate, reduced blood pressure, weak skeletal muscles, and apathy are some of the major symptoms resulting in a condition called Hypothyroidism.

Another key hormone often neglected and hardly ever tested is reverse T3 or rT3. Reverse T3 is a competitive inhibitor of T3, blocking T3 from binding to its receptor (but it doesn’t evoke a response, which is why it is considered inactive), thereby slowing metabolism and other functions attributed to T3. It is a biologically inactive form of T3 and has the exact opposite effect and is a natural ‘buffer’ against hyper-thyroidism. It is also called the 'hibernation hormone' for obvious reasons. It comes into play in conditions associated with a reduction in the metabolic rate, notably starvation, extreme carbohydrate restriction, chronic heart failure, chronic stress and chronic inflammatory states.


Reverse T3 is present in varying concentrations in different tissues. It’s important to remember that reverse T3 is always produced as a natural consequence of thyroid hormone production. It is an important regulatory mechanism in the body. It is generally not a problem as long as T3 levels are within a good range as well. It is up-regulated (activated more) with chronic physiologic stress and illness and is an indicator for reduced T4 to T3 conversion and low intra-cellular T3 levels even if the TSH (Thyroid Stimulation Hormone) is normal.


Factors that inhibit the conversion of T4 to T3 and increase rT3 include:

  • Stress (our stress hormone cortisol increases conversion of T4 into reverse T3)

  • Poor blood sugar management and insulin resistance

  • Inflammation

  • Starvation or crash dieting

  • Chronic illness

  • Certain nutritional deficiencies (Iron, Selenium, Zinc, B2,6,12 etc)

  • Certain medications (such as glucocorticoids, heart medications like beta-blockers etc)


If T3 drives energy production, rT3 puts the brakes on that energy production, which is not all bad as we need to put the brakes on when the situation demands (We don’t wanna run over someone do we now). Without the brakes the body might get out of control. So this balance of pushing the pedal and braking is rather a synergistic relationship. A bit like Yin to your Yang. Too much T3 and you go so fast that you cannot control your vehicle, too much rT3 and you get stuck and your metabolism comes to almost a standstill. rT3 might be an inactive metabolite, so might be ignored however it parks itself on the cell’s receptor thereby inhibiting T3 from binding to the cell., which means it cannot promote energy production or burn fat. So your metabolism starts dragging and get sluggish.


From an evolutionary point of view, it makes total sense to have this counter mechanism. In times of stress, famine or starvation, reverse T3 production increases, to slow the metabolic rate and conserve energy so that. However in today's world where stress takes shape in so many forms, your body responds to all kinds of stress in the exact same manner. Increased conversion of T4 to reverse T3, resulting in less T3 and thereby a lower metabolic rate as a result.


Researchers have recently learned that rT3, not cortisol, may be the 'real cause' of our inability to lose weight, and the reason why we gain or regain weight so quickly after a diet.


Because increased serum and tissue level of reverse T3 will result in blocking of the thyroid receptors, even small increases in reverse T3 can result in a significant decrease in thyroid action and result in severe hypothyroidism not detected by standard blood tests. This is why some patients may be experiencing symptoms of hypothyroidism, despite having adequate T3 levels in the blood


T3/rT3 ratio is a good indicator to ascertain if the person is veering towards Hypo/Hyperthyroidism.


So lets look at how these numbers would look like. Bear in mind these two are counter regulatory. So if one is high the other one goes down and vice versa.


Free T3 = 2.0

rT3 = 20

T3:rT3 = 2/20 = 0.1 -> Leaning towards Hypo -> Slower Metabolism


Free T3 = 10

rT3 = 5

T3:rT3 = 10/5 =2.0 -> Leaning towards Hyper -> Faster Metabolism

So how are these hormones regulated, factors that influence the production and regulation, what does the test results mean and how can we balance them naturally if they get out of whack. All of these and more in the next blog/s.





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