- Introduction to T3 and T4
- How Thyroid Hormones Works
- Thyroid Panels
- What Do Thyroid Hormones Control
- Hyperthyroid Symptoms
- Hypothyroid Symptoms
- Adequate Iodine Intake
- The Hypothalamus-Pituitary-Thyroid (HPT) Axis
- Conversion of T4 to the more active T3
- T3 and T4 and the Immune System
- TRH and TSH Fluctuates with the Circadian Rhythm
- Stress Elicits Thyroid Problems
- Surgery or Other Medical Treatments Combat Serious Thyroid Malfunctions
- The Body Attacks its Own Thyroid Factors in Thyroid Autoimmunity
- Hyper/Hypothyroidism Causes Digestive Problems
- Histamine and Thyroid Hormones Affect The Amount of the Other Present
- Higher Thyroid Hormone Levels Led to Higher Cognitive Function
- Thyroid Hormones Obstructs Sleep
- Hypothyroidism Increases Severity of Mood Disorders
- More T4 and Less T3 May Indicate Severity of Depression
- Infections Lower Thyroid Activity
- Cytokines Stop Actions When Dealing with the Thyroid
- Weight Loss and T3 Levels
- Infections Cause Lower T3 Levels
- Fatigue Causes a Drop in Thyroid Hormones
- Severe Pain Raises T3 and T4 Levels
- Thyroid Hormone Receptors and Their Genes Can Lower the Risk of Cancers
- Thyroid Hormones Can Combat Heart Problems
- Thyroid Hormones Increase Glucose Absorption From the Blood
- Hypothyroidism Leads to Too Little Skeletal Development While Hyperthyroidism Leads to Too Early Development
- T3 May Be Used To Heal Dermal Injuries
- Thyroid Hormones Make Mitochondria More Efficient
- Less Thyroid Hormones Contribute to a Longer Lifespan
- Thyroid Supplements Benefit Athletes
Introduction to T3 and T4
The thyroid gland is located in the base of the neck in a typical body and is involved in secreting important hormones T4 (thyroxine) and T3 (triiodothyronine).
T3 contains 3 iodine atoms and is created from the breakdown of T4. The breakdown of T4 is encouraged by the thyroid stimulating hormone.
T4 is synthesized from residues of the amino acid tyrosine, found in thyroglobulin (a protein created in the thyroid). It contains 4 iodine atoms.
T4 allows the body to control the more active T3 better.
Once there is enough of these hormones, the hypothalamus will be signaled to stop the release of TRH and the cascade of actions to increase T3 and T4.
How Thyroid Hormones Works
Thyroid Hormones Increase Metabolism
T3 binds to thyroid hormone receptors outside of the cells and gets internalized into the nucleus, which then subsequently changes gene expression (cellular production of certain proteins and hormones).
Thyroid Hormone Stimulates the Mitochondria
T3 stimulates increases oxygen consumption and heat production by the mitochondria (R).
Therefore, mitochondrial dysfunction can results in symptoms of hypothyroidism, even in the presence of healthy levels of thyroid hormones.
|Measurement||Full Name||Unit||Reference Range||Optimum Range||Explanation||Reference|
|fT3||Free T3||pg/ml||2.5 - 4.3||3.0 - 4.5|
|fT4||Free T4||ng/dL||0.9 - 1.7||1.0 - 1.5|
|T3||Triiodothyronine (free and bound)||ng/dL||75 - 200||100 - 280|
|T4||Tetraiodothyronine or Thyroxine (free T4)||ug/dL||6 - 12||4.5 - 11.5|
|TBG||Thyroxine Binding Globulin||mg/dL||1.1 - 2.1|
|TPO||Thyroid Peroxidase Antibody||IU/ml||<35|
|TRH||Thyrotropin Releasing Hormone||U/mL||5 - 25|
|TSH||Thyroid Stimulating Hormone||U/mL||0.27 - 4.2||1.4-2.0|
|T3 uptake||%||28 - 35 in females, 32 - 38 in males|
What Do Thyroid Hormones Control
T3 and T4 aid cells into creating energy.
- Metabolism (creating energy from calories)
- Heart rate
- The nervous system
- Body weight
- Muscle strength
- Menstrual cycles
- Body temperature
- Cholesterol levels
- Growth and development
- Intestinal flow
Hyperthyroid (too much T3 or T4) symptoms include:
- Irritability or moodiness
- Sweating or sensitivity to high temperatures
- Hand trembling
- Hair loss
- Missed or light menstrual periods
Low levels of T3 will cause slower heart rate, constipation and potentially weight gain.
Hypothyroidism (too little T3 or T4) symptoms include:
- Trouble sleeping
- Tiredness and fatigue
- Difficulty concentrating
- Dry skin and hair
- Sensitivity to cold temperature
- Frequent, heavy periods
- Joint and muscle pain
Adequate Iodine Intake
Everyone should have an adequate dose of iodine everyday.
|Birth to 6 months||110 mcg*||110 mcg*|
|7–12 months||130 mcg*||130 mcg*|
|1–3 years||90 mcg||90 mcg|
|4–8 years||90 mcg||90 mcg|
|9–13 years||120 mcg||120 mcg|
|14–18 years||150 mcg||150 mcg||220 mcg||290 mcg|
|19+ years||150 mcg||150 mcg||220 mcg||290 mcg|
- Adequate Intake (AI)
*mcg stands for micrograms.
A benign goiter is the swelling of the thyroid gland when adequate iodine is not received from the body’s diet.
The Hypothalamus-Pituitary-Thyroid (HPT) Axis
The hypothalamus, pituitary, and the thyroid gland (also called the hypothalamic/pituitary/thyroid or HPT axis) control thyroid hormone levels (R).
Thyrotropin-releasing hormone (TRH) made in the hypothalamus binds to the receptors in the pituitary, causing it to release the thyroid stimulating hormone (TSH), which then stimulates T4 production (R).
If there is too little of the thyroid hormones in the bloodstream, the hypothalamus signals the pituitary gland (via TRH) to produce TSH for the thyroid to release more T3 and T4.
Once there is enough of these hormones, the hypothalamus is signaled to stop the release of TRH and the cascade of actions to increase T3 and T4.
High free T4 and free T3 levels signal the pituitary to adjust TSH and TRH levels (R).
Low free T3 and free T4 increase TSH, so TSH is typically the only hormone measured in a blood test to screen for hypothyroidism.
Somatostatin and dopamine from the hypothalamus also reduce TSH levels, thus reducing thyroid hormones (R).
Iodine is required for the synthesis of thyroid hormones.
rT3 is the mirror image of T3. It binds to the thyroid receptor but does not activate the receptor. It competes with T3, and prevents T3 from binding to and activating the thyroid receptor.
Conversion of T4 to the more active T3
Both T3 and T4 are produced in the thyroid gland, although T3 is much more potent than T4.
In the blood, T4 levels are around 45 fold higher (90 nM) than T3 (2 nM) (R).
Most T3 is produced by removing an iodine from T4 in a process that requires selenium (R).
The total activity of T3 thyroid hormone in the body depends on the enzyme that converts T4 to T3, which is found outside of the thyroid. This includes (R):
- Type 1 deiodinase, which generates T3 for circulation, is found in the liver and kidney.
- Type 2 deiodinase converts T4 to T3 within the cells of the brain, pituitary, and brown fat tissue.
- Type 3 deiodinase, found in the placenta, brain, and skin, leads to the generation of rT3
Carrier proteins bind to most thyroid hormones, leaving only a very small fraction available. These include thyroxine binding globulin (TBG), albumin, and thyroid binding prealbumin (R).
Thyroxine Binding Globulin is made by the liver (R).
- 99.97% of T4 is bound, and 0.03% is free.
- 99.7% of T3 is bound and 0.3% of T3 is free.
T3 and T4 and the Immune System
Immune cells have receptors for T3, and administration of T3 increases size and growth of cells in the thymus (R).
In mice, T4 treatment suppresses antibody synthesis and growth of white blood cells (R).
However, in a cell-based study, T4 potentiates rabbit lymphocyte to grow, while T3 suppressed it (R).
Both T4 and T3 enhanced interferon-induced (stimulated) natural killer cells but were ineffective at baseline natural killer cell activity (R).
TNF-alpha and interferons induce production of class I and II HLA antigens in human thyroid cells (thyrocytes), which cause autoimmunity, as patients with autoimmune thyroid disorders have increased HLA class I and II antigens. The thyroid cells themselves produce IL-1 and IL-6 (R).
The immune system is weakened with stress, making the body more receptive of autoimmune (a condition where the immune system attacks itself) thyroid conditions (eg, Hashimoto’s thyroiditis) (R).
Too much physical stress may trigger potentially fatal thyroid problems in those with prior thyroid insufficiencies, such as untreated hyperthyroidism or Graves’ disease (R).
Human lymphocytes, when stimulated by toxin from the bacteria Staphylococcus, produce an immunoreactive TSH-like substance. Macrophage stimulated with LPS also produces TSH. While typically TSH production in the pituitary is inhibited by T3 hormones, this production of TSH in the immune cells is not (R).
TRH and TSH Fluctuates with the Circadian Rhythm
TSH is lower during daytime and increases at night around the time we go to sleep. Our biological clock (suprachiasmatic nucleus or SCN) communicates with cells that produce TRH in the hypothalamus. However, T3 and T4 fluctuate much less than TSH, perhaps because they take much longer to produce and degrade in the blood (R)
In depressed people, the nighttime TSH surge doesn’t happen. In addition, this fluctuation of TSH is abnormal in certain other diseases (R).
In healthy men, leptin and TSH fluctuate similarly over 24 hours. The fluctuation of TSH was not observed in men who are deficient in leptin (R).
Nerve cells that control TRH production and release have receptors for a-MSH (R).
Stress Elicits Thyroid Problems
Surgery or Other Medical Treatments Combat Serious Thyroid Malfunctions
Thyroid hormone as a treatment to substitute a faulty gland’s hormones and to prevent further growth of thyroid tissue especially in those with thyroid cancer to prevent the return or advancement of the cancer (R).
Hypothyroidism, a condition where not enough of the correct thyroid hormones are produced, by disorders such Hashimoto’s disease where the thyroid gland is not properly operating. Common treatments are to eradicate the current gland with surgery or radiation. Thyroid hormone replacement will be employed subsequently (R).
The Body Attacks its Own Thyroid Factors in Thyroid Autoimmunity
Thyroid Autoimmunity occurs when the body creates particles (called antibodies, etc) that, though normally is supposed to attack foreign substances, attacks the body’s own thyroid hormone (R).
An autoimmune disease (AD) against thyroid hormones will exhibit a rise in TSH (a hormone by the pituitary gland which triggers the release of T3 and T4 from the thyroid) levels in the blood (R).
HT leads to too little thyroid hormones being created because the thyroid gland is being attacked (R).
In Grave’s Disease, too much thyroid hormone is created because antibodies produced against the thyroid hormone receptor block places on them that TSH inhibitors are originally suppose to bind to to stop T3 and T4 production bind (R).
Hyper/Hypothyroidism Causes Digestive Problems
Sometimes, absorption of T3 and T4 become abnormal in the small and large intestines (major thyroid hormone holding tanks). Too much T4 (a characteristic of hypothyroidism) overly limits thyroid hormone absorption. The liver returns some T3 and T4 from the blood back into the gut via its chemical secretion, bile. T4 and T3 directly returns to the gut via abdominal blood circulation (R).
Specific digestive diseases may be associated with autoimmune thyroid processes, such as Hashimoto’s thyroiditis and Grave’s disease. In the esophagus, thyroid hormone excess leads to faster contractions. Thyrotoxic (too much thyroid hormone in the body) patients report symptoms of fullness, lower-abdominal pain, oral gassiness, tachygastria (faster electrical pacemaker action in the stomach than normal), throwing up, less electrical pacemaker activity in their digestive tract and hypergastrinemia (results in the excess of stomach acid), which all may affect how food is pushed along the digestive tract. Slight appetite increase and slight diarrhea (because fat reabsorption in the body is weakened) occurs. All of these secondary symptoms of hyperthyroidism forces the liver to work harder and may lead to liver tissue scarring over time. Treatment for hyperthyroidism can cause hypothyroidism (underproduction of thyroid hormones) and prevents the body from gaining as much energy from food in addition to difficulty swallowing in severe cases, constipation, and a decreased appetite (R, R2).
Histamine and Thyroid Hormones Affect The Amount of the Other Present
Histamine decreases T3 and T4 for a short amount of time (15 to 30 minutes) (R).
Histamine can regulate how 3-iodothyroacetic acid (produced by the breakdown of thyroid hormones) breaks down particles into energy (R).
Higher Thyroid Hormone Levels Led to Higher Cognitive Function
For women and african americans, increased levels of free T4 in the blood correlated with enhanced ability to see the relationship of objects in space. A higher total T4 count coincided with higher speeds between thinking about an action and ability to perform that action in people without Ehlers- Danlos Syndrome (a condition that lowers joint capacity). Men with higher free T3 and T4 in the blood had better language and verbal aptitude. Higher T3 absorption, for whites, demonstrated higher speeds between thinking and doing and enhanced ability to see the relationship between objects in space. Overall, higher free T4 levels was related to faster speeds of transmitting signals to muscles and visual-spatial skills while a lower TSH level was related to faster speeds of transmitting signals to muscles and higher focus (R).
Thyroid hormones regulate nervous system-related growth. In particular the central nervous system (which consists of the brain and spinal cord) needs T3 and T4 to upkeep normal development. A drug, L-T4 (which consists of T4), when administered to rats, enhanced spatial memory (R).
While fixing thyroid problems may help normalize mood and cognitive ability, a severe hypothyroidism cognitive failure will not be completely cured (R).
Increased total T3 count was related to lower overall cognitive ability in people with mild cognitive impairment. Those with higher than average total T3 counts had trouble with remembering, visuaospatial skills, planning, and emotional regulation. Lower total T3 in patients showed cognitive ability equal to those without thyroid disorders (R).
Based off of studies in rats, T3 along with electroconvulsive shock therapy may be a viable alternative to lithium with electroconvulsive shock therapy because the lithium treatment has shown cognitive damage in patient (R).
The body maintains thyroid hormone concentrations within a strict range. Aging changes these concentrations. Because aging and thyroid hormone level changes are simultaneous, studies suggest that hormone changes and cognitive decline are correlated. In those the euthyroid (those with normally-functioning thyroid glands) individuals aged between 61 and 79 years may be more affected by differences in T4 (the actual hormone) than TSH (stimulates the production of thyroid hormones). In those above 80 (euthyroids), TSH concentration increases compared to thyroid hormones, possibly as an evolutionary advantage as thyroid hormones have the role of breaking down components in the body for energy, which the very elderly would not need (R).
Thyroid Hormones Obstructs Sleep
A full day of no sleep caused a 1.5 times increase of T4 to convert into T3 (levels of T4 stayed the same in the study) (R).
Patients with obstructive sleep apnea, though rarely caused by too little thyroid hormone in the body, who undergo hormone therapy often show improvement. Those with no thyroid disorder do not improve from such therapy for sleep apnea (R).
Hypothyroidism Increases Severity of Mood Disorders
Hypothyroidism in adults cause mild anxiety in mice. T3 is suggested to lower the sensitivity of the part of the brain that makes hypothyroid test subjects anxious (R). More T4 in the body corresponds to less severe anxiety. More severe panic attacks were associated with higher TSH levels (R).
Major depressive and anxious depressive women showed lower T3,T4, and TSH levels than their non-depressive female counterparts. Furthermore, these depressive women showed less sensitivity to TSH (R).
More T4 and Less T3 May Indicate Severity of Depression
Depression can accompany thyroid problems. The mental disorder, in turn, adds further abnormalities such as high T4 levels, low T3, high reverse T3, a blunted TSH response to TRH (chemical signal that triggers TSH), positive antithyroid antibodies, and high TRH (in the spinal fluid) concentrations. Those on antidepressant drugs report elevated positive response to antidepressants when simultaneously coupled on thyroid hormone therapy. Dysphoria, anxiety, irritability, emotional lability, and lack of focus are common mental disorders following hyperthyroidism. The older, affected with overly high levels of thyroid hormones, appear to experience a depressive-like condition. Anxiety is also prevalent among thyrotoxicosis.
Hypothyroid patients experience depression-like conditions. The lower TSH levels were from the normal state, the more severe the depressive conditions. T4 seems to be ineffective as treatment. Conversely there is some evidence that more T4 and less TSH are found in those with deeper depression due to thyroid problems. In those with only depression, low T3 and high reverse T3 levels were observed (R, R2).
Infections Lower Thyroid Activity
The body enters a state of rest by slowing production of thyroid hormones to decrease bodily levels of energy extraction from food sources when fighting an infection (a conditioned called non-thyroid illness syndrome or NTIS), however, this state may prove disadvantageous when not enough energy is taken for the muscles, which leads to failure of muscle-dependent body processes like breathing (R).
Hyper and hypothyroidism have both been associated with weakened ability to detoxify free radicals that enter the body (oxidative stress). NTIS displays oxidative stress, supporting the idea that this condition is a mechanism of immunity in addition to being a condition of hypothyroidism (R).
Cytokines Stop Actions When Dealing with the Thyroid
Cytokines part of the hypothalamic-pituitary-thyroid system is primarily to stop actions during euthyroid sick syndrome and AITD (autoimmune thyroid disease) (R).
Cytokines that inhibit responses can signal for additional T cells (which are immune cells from the thyroid) to help fight off an infection (R).
Weight Loss and T3 Levels
Weight loss follows treatment for hypothyroidism (of which weight gain is a symptom, although much of this loss may be only water when the patient is treated with L-T4. Those with higher fat contents contain higher levels of TSH and T3 (R, R2,R3).
Severe weight loss after hypothyroidism showed signs of decrease in total T4 and free T3 but an increase in reverse T3. NTIS patients showed decreased sensitivity of TSH to TRH and even, more rarely, reduced thyroid-binding proteins (which means reduced ability for thyroid hormones to perform actions) (R).
Infections Cause Lower T3 Levels
When a mouse is infected, after food consumption, it will contain 75% less T3, T4, and liver nuclear T3 receptors when compared to uninfected mice. Mice that have not eaten but are infected showed a stagnation in the normal rise of reverse T3 levels when the mice did not eat (R).
Because the pituitary gland stops producing TSH to stimulate thyroid hormone secretion, T4 is converted into T3 more intensely during serious infection. Less thyroid hormone in the body translates to less extensive energy extraction from food molecules, which means there would be less energy wasted for the body. Regular TSH levels reboot after the infection (R, R2).
Fatigue Causes a Drop in Thyroid Hormones
Severe Pain Raises T3 and T4 Levels
Thyroid diseases are not thought to cause tendinopathies (tendon disease) and tendons tears. New research indicates presence of thyroid hormone receptors in tendons and their possible role killing off tendon cells isolated from tendons (R).
Pain signals that reach the brain from any injury in the peripheral nervous system activate three releasing hormones in the hypothalamus. Thyroid releasing hormone(TRH) is one of three. These three releasing hormones, in turn, cause the anterior pituitary to release other hormones including TSH to the thyroid gland, which release into the serum hormones necessary for pain control including triiodothyronine (T3), and thyroxine (T4). Since normal blood hormone levels usually mean that the patient’s pain is not extreme, there would be less need for immediate intense treatment. Hormone levels return to equilibrium after the pain has passed (R).
Thyroid Hormone Receptors and Their Genes Can Lower the Risk of Cancers
Incorrectly formed thyroid hormone receptors might lead to acute erythroleukemia (immature red and white blood cells crowd out the body) and sarcomas (connective or non epithelial tissue cancers). If the thyroid hormone receptor beta gene is not as involved in making thyroid hormone receptors, there is a higher prevalence of breast, lung, and thyroid cancers (R).
Thyroid Hormones Can Combat Heart Problems
Thyroid hormone therapies have been considered as treatment for hypothyroid patients with weak blood flow because T3 can make heart contractions harder as well as make arteries wider so that more blood can pump through (R).
Overt hyperthyroidism induces a state of a faster heart rate, enhanced left ventricular (LV) systolic (blood pressure when heart beats) and diastolic (blood pressure when heart rests) function, and increased prevalence of supraventricular tachyarrhythmias (overly rapid heart rate originating in the lower chambers of the heart) – especially atrial fibrillation (irregularly quick heart rate that causes poor circulation), whereas overt hypothyroidism is characterized by the opposite changes. Subclinical hyperthyroidism is associated with increased heart rate, reduced exercise performance, and increased risk of cardiovascular mortality. Subclinical hypothyroidism is heart rate problems and an enhanced risk for atherosclerosis (fat buildup in the arteries) and myocardial infarction (heart attack). L-thyroxine (L-T4) or 3,5-diiodothyropropionic acid adminsitered in a timely manner to these patients reverses almost all of these symptoms (R, R2, R3).
Thyroid Hormones Increase Glucose Absorption From the Blood
Thyroid hormones encourage protein breakdown and glucose exchange throughout cells and insulin (R).
T3 may be a viable treatment for type 2 diabetes because it improved insulin production and communication with other chemical signals in mice (R).
Hypothyroidism Leads to Too Little Skeletal Development While Hyperthyroidism Leads to Too Early Development
Hypothyroidism in children leads to delayed growth, while thyrotoxicosis makes bones mature so quickly that children’s bones fuse before the child is ready. T3 builds up bone mass but also can break down bones in adults to increase new bone growth (R, R2, R3).
T4 and T3 supplements can be used for hypothyroid children to grow the bone they had not in the lack of thyroid hormone (R).
T3 May Be Used To Heal Dermal Injuries
Hypothyroidism leads to yellowed, pale, scaly, and dry skin. Hyperthyroidism leads to thinning (but not wasting away) skin resulting from autoimmunity (R).
Topical T3 quickened skin tear restoration because it stimulated keratinocytes (cells that produce keratin, which gives skin an elastic characteristic) and fibroblasts (cells that allow the skin to heal itself). T4 treatments have also been suggested as a topical ointment, but changed hair growth and coloration in tested cows (R, R2, R3).
Thyroid Hormones Make Mitochondria More Efficient
Mitochondria, which are responsible for powering the cell by breaking down chemical compounds into energy, which is an action thyroid hormones control by stopping the energy extraction (R). This is beneficial because sometimes, the energy extracted is wasted as heat. Thyroid hormones increase the efficiency of process.
T3 in the mitochondria, early in the organelle’s life, makes sure it forms correctly (R).
T3 may mollify mitochondrial wear and improve mitochondrial function in those cells with defective mitochondria (R).
Less Thyroid Hormones Contribute to a Longer Lifespan
Hypothyroidism becomes increasingly prevalent with age (R).
In those with healthy thyroid glands, lower free thyroid hormones (within the normal range) was correlated with higher chance of any type of health-related death, especially liver cancer (R).
Older age was correlated to less T3 and free T4 (R).
Higher levels of free T4 was related to lower levels of liver tissue scarring (R).
In older men, lower free T4 and reverse T3 concentrations correlated with higher physical ability (R).
Thyroid Supplements Benefit Athletes
When the body is overworked, unnecessary cells (at the moment) decrease activity in converting molecules into energy stop to save energy. Too much overworking will lead to increased cytokine (molecules which signal others) levels while decreasing secretion of insulin (which stores glucose) and the breakdown rate of fats. TSH may be an indicator to controlling these fats and sugars. Because the hypothalamus normally regulates these changes, repeated overworking will cause the hypothalamus to become less sensitive to changes in the body and lead to fatigue and poor performance, which would lead to development of slow muscle fibers (R).
There is speculation that thyroid supplementation to athletes improves their performance. However, experts are leaning both ways, though those who dispel this idea are more popular in number. Thyroid hormone supplements for athletes may prevent or treat thyroid gland damage from intense training (R, R2, R3). A few experts believe that more T3 and T4 may slightly increase physical ability (R).
- Thyroid hormone receptor is encoded by two different genes: TRalpha (THRA) and TRbeta (THRB), each with two spliced isoforms
- Thyroid hormones heterodimerize with retinoic acid receptors, vitamin D receptors, and PPARs (R)
- For example, both psychological stressors and metabolic stressors from starvation have been shown to cause a decrease in TRH production levels within the PVN (R1, R2)
- In a genetic network analysis, hub (highly connected) genes that are most connected to thyroid hormones include CREB, thyroid hormone receptors (THRA and THRB), AP-1 (Jun and Fos), STAT-3, and Nf-kB (R)
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