The thyroid hormones (T3 & T4) stimulate energy metabolism, regulate immunity, support cognitive development, and more. Due to their complex metabolic roles, it’s essential for overall health to keep them in the normal range. Read on to learn the diverse functions of thyroid hormones, blood test reference values, and the consequences of high/low levels.
What are T3 and T4?
The thyroid gland is located in the base of your neck 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 and allows the body to better control the more active T3.
If there are not enough thyroid hormones in the bloodstream, the hypothalamus will signal the pituitary gland (via TRH) to produce TSH for the thyroid to release more T3 and T4.
Reverse T3 (rT3) is the mirror image of T3. It competes with T3 and binds to the thyroid receptor but does not activate it.
Thyroid Hormones Roles and Functions
T3 and T4 affect [1]:
- Breathing
- Metabolism
- Heart rate
- The nervous system
- Bodyweight
- Muscle strength
- Menstrual cycles
- Body temperature
- Cholesterol levels
- Growth and development
- Intestinal flow
- Digestion
Metabolism
T3 changes gene expression (cellular production of certain proteins and hormones) of multiple metabolism-related genes.
These genes include PPAR-gamma, NRF1, NRF2, and other transcription factors that work with them [2].
Thyroid hormone may work in synergy with other receptors, including RXR (vitamin A receptor), or VDR (vitamin D receptor) [3].
Mitochondrial Function
T3 stimulates oxygen consumption and heat production by the mitochondria, and the production of new mitochondria [4, 5].
Therefore, mitochondrial dysfunction can result in symptoms of hypothyroidism, even in the presence of healthy levels of thyroid hormones.
Immunity
Immune cells have receptors for T3, and the administration of T3 increases the size and growth of cells in the thymus [6].
In mice, T4 treatment suppresses antibody synthesis and growth of white blood cells [7].
Both T4 and T3 enhance interferon-induced (stimulated) natural killer cells but don’t impact the baseline natural killer cell activity [8].
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 [9].
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) [10].
A study found that newly-born rats used their thyroid hormones to regulate the number of neural mast cells, which release histamine as an inflammatory immune response [11].
Histamine decreases T3 and T4 for a short amount of time (15 to 30 minutes) [12].
Circadian Rhythm
TSH is lower during the 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 [13].
In depressed people, the nighttime TSH surge doesn’t happen. In addition, this fluctuation of TSH is abnormal in certain other diseases [13].
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 [14].
Nerve cells that control the TRH production and release have receptors for a-MSH [15].
Cognitive Function
Thyroid hormones are essential for cognitive development and functions. People with sufficient levels generally perform better on cognitive tasks and process information more efficiently. The lack of thyroid hormones can result in a range of cognitive disorders, from mild impairments to severe developmental disorders [16].
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 [17].
While fixing thyroid problems may help normalize mood and cognitive ability, a severe hypothyroidism cognitive failure will not be completely cured [18].
Subclinical hyperthyroidism (an elevated level of TH with a decreased level of TSH) and higher free T4 within the normal range may cause decreases in thinking ability [18, 19].
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, visuospatial skills, planning, and emotional regulation [20].
Based on 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 patients [21].
Anticancer Effects
Thyroid hormone receptors may be useful as tumor suppressors [22, 23, 24].
Incorrectly formed thyroid hormone receptors might lead to acute erythroleukemia (immature red and white blood cells crowd out the body) and sarcomas (connective or nonepithelial tissue cancers). Defects in the production of thyroid hormone receptors may correlate with a higher prevalence of breast, lung, and thyroid cancers [22].
Heart Health
T3 can make heart contractions harder and dilate the blood vessels [25].
Overt hyperthyroidism induces a state of a faster heart rate, especially atrial fibrillation (irregularly quick heart rate that causes poor circulation), whereas overt hypothyroidism is characterized by the opposite changes.
Subclinical hypothyroidism causes heart rate problems and an enhanced risk for atherosclerosis and myocardial infarction (heart attack). L-thyroxine (L-T4) or 3,5-diiodothyropropionic acid administered in a timely manner help prevent heart complications [26, 27, 28].
Glucose Metabolism
Thyroid hormones increase oxygen consumption and glucose uptake because oxygen and glucose are used in providing energy for the body [29].
In rats, lower thyroid hormones correlated with lower levels of insulin (a storage hormone for glucose) [30, 31].
Thyroid hormones encourage protein breakdown and glucose exchange throughout cells and insulin [32].
Thyroid dysfunction often goes hand in hand with insulin resistance [33].
T3 improved insulin production and blood glucose control in mice [34].
Bone Health
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 [35, 36, 37].
T4 and T3 supplements can be used for hypothyroid children with inadequate bone development [36].
Thyroid Blood Tests & Panels
| Measurement | Full Name | Unit | Reference Range |
| fT3 | Free T3 | pg/ml | 2.5 – 4.3 |
| fT4 | Free T4 | ng/dL | 0.9 – 1.7 |
| rT3 | Reverse T3 | pg/mL | 90.0-350.0 |
| T3 | Triiodothyronine (free and bound) | ng/dL | 75 – 200 |
| T4 | Tetraiodothyronine or Thyroxine (free T4) | ug/dL | 6 – 12 |
| TBG | Thyroxine Binding Globulin | mg/dL | 1.1 – 2.1 |
| TGAb | Thyroglobulin Antibody | IU/ml | <4 |
| 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 |
Adequate Iodine Intake
Iodine builds thyroid hormones, and it’s essential for their optimal functioning. Optimal iodine intake is a major factor of thyroid health, while both excessive and insufficient intake can contribute to different thyroid disorders [38].
| Age | Male | Female | Pregnancy | Lactation |
| 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.
Source: https://ods.od.nih.gov/factsheets/Iodine-HealthProfessional/
A benign goiter is the swelling of the thyroid gland which may occur due to inadequate iodine intake.
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 [39].
Thyrotropin-releasing hormone (TRH) made in the hypothalamus binds to the receptors in the pituitary, causing it to release thyroid-stimulating hormone (TSH), which then stimulates T4 production.
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.
Low free T3 and free T4 increase TSH, so TSH is a valuable marker for diagnosing hypothyroidism.
Somatostatin and dopamine from the hypothalamus also reduce TSH levels, thus reducing thyroid hormones.
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).
Most T3 is produced by removing iodine from T4 in a process that requires selenium [40].
The total activity of the T3 thyroid hormone in the body depends on the enzyme that converts T4 to T3, which is found outside of the thyroid. This includes:
- 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.
Thyroxine Binding Globulin is made by the liver [41].
- 99.97% of T4 is bound, and 0.03% is free.
- 99.7% of T3 is bound and 0.3% of T3 is free.
Thyroid Disorders and Risk Factors
If you notice any of the signs and symptoms described low and suspect a thyroid disorder, make sure to seek medical attention. Adequate treatment can keep the symptoms under control and prevent dangerous complications.
Hyperthyroid Symptoms
Higher levels of thyroid hormones (hyperthyroidism) may cause the following symptoms:
- Faster heart rate
- Diarrhea
- Weight loss
- Anxiety
- Irritability or moodiness
- Nervousness
- Hyperactivity
- Sweating or sensitivity to high temperatures
- Hand trembling
- Hair loss
- Missed or light menstrual periods
Hypothyroid Symptoms
Low levels of thyroid hormones (hypothyroidism) may cause:
- Slower heart rate
- Constipation
- Weight gain
- Trouble sleeping
- Tiredness and fatigue
- Difficulty concentrating
- Dry skin and hair
- Depression
- Sensitivity to cold temperature
- Frequent, heavy periods
- Joint and muscle pain
Mood Disorders
Hypothyroidism in adults causes mild anxiety in mice. T3 is suggested to lower the sensitivity of the part of the brain that makes hypothyroid test subjects anxious. More T4 in the body corresponds to less severe anxiety. More severe panic attacks were associated with higher TSH levels [42, 43].
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 [44].
Fatigue
Thyroid dysfunction is often one of the reasons behind chronic fatigue [45].
General fatigue and fatigue due to strain are associated with lower free T4. Physical fatigue was associated with lower T3 [46].
Risk Factors
Stress
Mental stress triggers the release of cortisol, which can increase thyroid hormone production [47].
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) [47].
Too much physical stress can trigger severe thyroid problems in those with prior thyroid disorders, such as untreated hyperthyroidism or Graves’ disease [47].
Winding down mentally through sleep or meditation and light exercise to increase endorphins (hormones to make the body feel happier) helps with thyroid conditions [48].
Sleep Deprivation
Sleep deprivation leads to increases in thyroid hormone activity. In this way, the hormone may inhibit sleep [49, 50, 51].
A full day of no sleep caused a 1.5X increase of T4 to convert into T3 (levels of T4 stayed the same in the study) [52].
Half a typical dose of sleep deprivation led to higher levels of TSH in the blood; this elevation continued for another day [51].
Infections
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 [53].
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 [54, 55].
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 [56].
Often, people with the thyroid receptor beta gene will develop an autoimmune disease [57, 58].
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 [57].
In addition, the thyroid hormones then regulate the release of growth-related factors (IGF-I and IGFBP-3) [59].
A common related AD is Hashimoto’s Thyroiditis (HT), which results in thyroid destruction and insufficient thyroid hormones [57, 56].
In Graves’ Disease, there’s excessive production of thyroid hormones because the antibodies stimulate the thyroid by activating the TSH receptor [56].
