Triiodothyronine

Triiodothyronine
[[File:|250px]] Chemical structure of 3,5,3'-triiodo-L-thyronine
Abbreviation	T3
Molecular formula	C15H12I3NO4
Type	Thyroid hormone
Administration	Oral (tablet), intravenous
Bioavailability	95%
Synonyms	Liothyronine, T3, 3,5,3'-triiodo-L-thyronine
Source	Thyroid gland, peripheral conversion from T4
Ray's verdict	Essential for cellular respiration and energy production; functionally the most important thyroid hormone

Introduction

Triiodothyronine (T3) is the biologically active thyroid hormone responsible for regulating metabolic rate and cellular respiration throughout the body. While thyroxine (T4) is often called "the thyroid hormone," triiodothyronine is functionally the most important thyroid hormone, serving as the metabolically active derivative of thyroxine, somewhat analogous to how insulin is the activated form of proinsulin.

The thyroid gland secretes both T4 (approximately 80%) and T3 (approximately 20%), though the majority of circulating T3 (80%) is produced extrathyroidally through the deiodination of T4, primarily in the liver.Sapin R, Schlienger JL. Thyroxine (T4) and tri-iodothyronine (T3) determinations: techniques and value in the assessment of thyroid function. T3 is essential for proper glucose oxidation, mitochondrial function, and the maintenance of body temperature and metabolic homeostasis.

History/Etymology

The history of thyroid hormone research began in 1820 when elemental iodine was first determined to be important for normal thyroid function.Galton VA, Larsen PR, Berry MJ. The Deiodinases: Their Identification and Cloning of Their Genes. Endocrinology. 2021;162(3). Thyroxine (T4) was isolated and identified as the primary active principle of the thyroid gland nearly 100 years later.

The discovery of triiodothyronine as a major thyroid hormone brought international recognition to Rosalind Pitt-Rivers in the 1950s.Pitt-Rivers R. Rosalind Pitt-Rivers and the discovery of T3. Endocrinology. 1990. This discovery fundamentally changed the understanding of thyroid physiology, revealing that T3, rather than T4, was the metabolically active hormone responsible for the calorigenic effects of the thyroid gland.

The name "triiodothyronine" derives from its chemical structure: "tri" (three) + "iodo" (iodine atoms) + "thyronine" (the amino acid backbone derived from tyrosine). It is distinguished from thyroxine (T4), which contains four iodine atoms.

Natural thyroid preparations containing both T4 and T3 were the first pharmacologic treatments available and dominated hypothyroidism treatment for the better part of the 20th century.Hennessey JV. Historical and current perspective in the use of thyroid extracts for the treatment of hypothyroidism. Endocr Pract. 2015;21(10):1161-70.

Structure/Chemical properties

Triiodothyronine has the molecular formula C15H12I3NO4 with a molecular weight of approximately 651 Da. Its IUPAC name is (2S)-2-amino-3-[4-(4-hydroxy-3-iodophenoxy)-3,5-diiodophenyl]propanoic acid.

The crystal and molecular structure of L-triiodothyronine has been determined by x-ray diffraction, revealing that the two phenyl rings are almost perpendicular to each other, with the acute angle between their normals being 82 degrees. The 3'-iodine is situated proximal to the alpha-ring, and theoretical calculations indicate this proximal conformation to be energetically favored.Camerman A, Camerman N. Triiodothyronine: the 3'-iodine is proximal to the α-ring in crystal structure conformation. Science. 1972;175(4022):764-5.

T3 differs structurally from T4 by having one fewer iodine atom, specifically lacking the 5' iodine on the outer phenyl ring. This seemingly minor difference accounts for T3's significantly greater biological activity, as T3 binds to thyroid nuclear hormone receptors with much higher affinity than T4.

In serum, most T3 is bound to transport proteins, with only approximately 0.3% circulating as free (unbound) hormone—the biologically active fraction.Sapin R, Schlienger JL. Thyroxine (T4) and tri-iodothyronine (T3) determinations: techniques and value in the assessment of thyroid function. Ann Biol Clin (Paris). 2003;61(4):411-20.

Function/Mechanism of Action

Triiodothyronine is the primary hormone responsible for the calorigenic (heat-producing) action of the thyroid in adult vertebrates. When T3 is added to any tissue, respiration is increased; by contrast, when thyroxine is added to brain tissue in vitro, it actually suppresses respiration.

The fundamental mechanism of T3 involves:

Mitochondrial Respiration: T3 activates cellular respiration, promoting the efficient conversion of glucose and oxygen into ATP and carbon dioxide. The structures in cells which produce most metabolic energy by respiration—the mitochondria—are directly responsive to thyroid hormones.Peat R. Multiple Sclerosis and Hormone-Related Brain Syndromes. Ray Peat's Newsletter. Administration of thyroid hormone produces an increase in the number, size, and oxidative and phosphorylative capacity of mitochondria.Ismail-Beigi F, Edelman IS. Mechanism of thyroid calorigenesis: role of active sodium transport. Proc Natl Acad Sci USA. 1970;67(2):1071-8.

Glucose Oxidation: Thyroid hormones are essential for proper functioning of enzymes involved in glycolysis and the Krebs cycle, the two key processes involved in glucose oxidation. These hormones regulate the expression and activity of transporters responsible for moving glucose into cells for energy production.Roddy D. 3 Glucose Myths Debunked by Dr Ray Peat. YouTube transcript.

Carbon Dioxide Production: T3 is often called "the hormone of respiration" because it enables cells to efficiently produce carbon dioxide, which plays a crucial role in promoting efficient glucose oxidation. Carbon dioxide production cannot occur efficiently without adequate thyroid hormone.Roddy D. Evil Sugar Radio #33. YouTube transcript.

Sodium-Potassium Pump Activation: A significant portion of T3's calorigenic effect is attributable to increased energy utilization by the Na⁺/K⁺-ATPase pump. Studies in euthyroid rats showed that more than 90% of the increment in oxygen consumption produced by T3 injections was attributable to increased energy utilization by this cellular pump.Ismail-Beigi F, Edelman IS. Mechanism of thyroid calorigenesis: role of active sodium transport. Proc Natl Acad Sci USA. 1970;67(2):1071-8.

Cholesterol Conversion: Thyroid promotes the conversion of cholesterol into steroid hormones and bile acids, including progesterone. There is a very reliable inverse relationship between the level of serum cholesterol and thyroid hormone action.Peat R. Thyroid: Misconceptions. Ray Peat's Newsletter.

Medical uses/Effects

Triiodothyronine supplementation is used therapeutically in several conditions:

Hypothyroidism: T3, or products containing both T3 and T4 (such as Armour thyroid, Cynoplus, or Thyrolar), is used to treat hypothyroidism. The active thyroid hormone T3 is produced mainly in the liver from thyroxine, and the female liver is less efficient than the male liver in producing it, as is the female thyroid gland. Therefore, thyroxine alone often acts as a "thyroid anti-hormone," especially in women.Peat R. Mary Shomon Interview. Ray Peat's Newsletter. March 2001.

High Cholesterol: High cholesterol is closely connected to hypothyroidism. Increased T3 will immediately increase the conversion of cholesterol to progesterone and bile acids. Thyroid hormone supplementation can normalize elevated cholesterol within days.Peat R. Thyroid and Polyunsaturated Fatty Acids. KMUD Radio Transcript. July 2008.

Myxedema and Myxedema Coma: T3 is particularly valuable in acute situations. Intravenous T3 has been used to successfully treat patients in myxedema coma when high doses of T4 failed or even worsened the condition.Peat R. Life-Supporting Substances. Rainmaking Radio Transcript. July 2011.

Heart Disease Prevention: Broda Barnes demonstrated the protective action of thyroid against heart disease. The circulatory complications common in diabetes were avoided in Barnes' diabetic patients who received thyroid supplements.Peat R. Thyroid: Misconceptions. Ray Peat's Newsletter.

Insomnia: Insomnia, the most commonly troublesome symptom of menopause, usually responds immediately to a small bedtime dose of T3, just as T3 rapidly restores the normal quick relaxation rate to the calf muscles and heart muscle.Peat R. Thyroid: Misconceptions. Ray Peat's Newsletter.

Liver Support: The liver has the enzyme for converting T4 to T3, requiring glucose and selenium to make the conversion. In cases of liver dysfunction, T3 supplementation can help bypass the impaired conversion process and support liver recovery.Peat R. Foundations of Bioenergetic Health (Email Wiki compilation).

Dosing

The body produces approximately 4 micrograms of T3 per hour, so whenever supplementation exceeds that amount, careful attention must be given to avoid overwhelming the body's regulatory systems.Peat R. Glycemia, Starch and Sugar in Context. KMUD Radio Transcript. April 2011.

Starting doses:

A starting dose of about 1-5 mcg can produce a noticeable effect and can be repeated at intervals according to effect.Peat R. Foundations of Bioenergetic Health (Email Wiki compilation). For sensitive individuals, even one microgram doses of T3 may be appropriate, held at that level for a week or two before gradually increasing.Peat R. Iodine Supplement Reactions and Hormones. KMUD Radio Transcript. February 2016. 5 mcg with a meal is another common way to start supplementation.

General guidelines:

Most people can tolerate 8-10 micrograms with every meal and 5-10 micrograms at bedtime.Peat R. Q&A Reverse T3, HCG, EMF. John F Interview Transcript. December 2021. Taking more than 10 micrograms at once can signal to the liver that there is an excess, causing it to produce enzymes that break down T3, potentially leading to a hypothyroid state 10-12 hours later.Peat R. Protein Restriction, Lidocaine for Hair Loss. Danny Roddy Podcast #85. It is advisable to take T3 with food so absorption is gradual rather than presenting a sudden surge to the liver.

Monitoring:

The resting pulse rate and temperature should be monitored, ideally seeing temperature rise toward normal by the middle of the day. One or two beats per minute per day increase in pulse is considered appropriate progression.Peat R. Healing The Body. Radio Interview. February 2019. TSH levels below 0.4 are associated with the lowest incidence of thyroid cancer and improved overall health.

Traditional equivalencies:

100 micrograms of T4 are traditionally considered equivalent to 25 micrograms of T3, or one grain (60-65 mg) of desiccated thyroid. The Cynoplus tablet contains 120 micrograms of T4 and 30 micrograms of T3, roughly equivalent to two and a half grains of traditional Armour thyroid.

Side/Adverse effects

Thyroid Gland Suppression:

It is sometimes true that taking thyroid will suppress one's own gland. However, by overdosing people until the output of their own glands had gone to zero, it was demonstrated that everyone's gland was functioning perfectly again within two or three days after stopping supplementation. Unlike the adrenals, which may take a month to recover from suppression by cortisol, the thyroid gland quickly recovers, usually within 24 hours.

Cardiovascular Effects:

When people think of thyroid, they often think it will raise blood pressure and cause heart palpitations. In reality, hypothyroid people often have high adrenaline, which causes these stimulatory effects. Correcting the thyroid deficiency typically lowers blood pressure and reduces heart palpitations by reducing compensatory adrenaline secretion.

For oversensitive individuals, even small doses (15-30 mg of desiccated thyroid) can make the heart race. These individuals should supplement both sugar and magnesium, as thyroid allows cells to retain magnesium and potassium. Without adequate magnesium, muscles can take it away from the heart, causing vessels to constrict and produce heart pain.

Overdosing Symptoms:

• Rapid heart rate
• Increased anxiety
• Heart palpitations

Signs of hyperthyroidism:

If more than 10 micrograms of T3 is taken at once regularly, the liver produces enzymes to destroy T3, leading to extreme ups and downs with potentially dangerous hypothyroid dips 10-12 hours later, which can include sharp drops in heart rate.

Bone Effects:

Contrary to popular concern, even when the diet isn't adequate to sustain normal growth, hyperthyroidism doesn't necessarily cause osteoporosis. Rats given enough Armour thyroid to stop their growth (up to 0.7% of their food) actually had bones that were slightly heavier than rats on a normal diet. Hypothyroidism, not hyperthyroidism, retards bone remodeling and tissue repair in general.

Interactions with Unsaturated Fats:

Unsaturated oils interfere with thyroid function in several ways, including blocking the proteolytic enzymes involved in the release of hormone from thyroglobulin, interfering with binding of the hormone to transport proteins, and blocking conversion of T4 to T3 in the liver and pituitary. The tissue response to thyroid hormone is inhibited by unsaturated fats in proportion to the number of double bonds in the fat.