The hypothalamic–pituitary–thyroid axis (HPT axis for short, a.k.a. thyroid homeostasis or thyrotropic feedback control) is part of the neuroendocrine system responsible for the regulation of

metabolism Metabolism (, from ''metabolē'', "change") is the set of life-sustaining chemical reactions in organisms. The three main functions of metabolism are: the conversion of the energy in food to energy available to run cellular processes; the co ...

and also responds to stress. As its name suggests, it depends upon the

hypothalamus The hypothalamus (: hypothalami; ) is a small part of the vertebrate brain that contains a number of nucleus (neuroanatomy), nuclei with a variety of functions. One of the most important functions is to link the nervous system to the endocrin ...

, the

pituitary gland The pituitary gland or hypophysis is an endocrine gland in vertebrates. In humans, the pituitary gland is located at the base of the human brain, brain, protruding off the bottom of the hypothalamus. The pituitary gland and the hypothalamus contr ...

, and the

thyroid gland The thyroid, or thyroid gland, is an endocrine gland in vertebrates. In humans, it is a butterfly-shaped gland located in the neck below the Adam's apple. It consists of two connected lobes. The lower two thirds of the lobes are connected by ...

. The hypothalamus senses low circulating levels of thyroid hormone (

Triiodothyronine Triiodothyronine, also known as T3, is a thyroid hormone. It affects almost every physiological process in the body, including growth and development, metabolism, body temperature, and heart rate. Production of T3 and its prohormone thyroxi ...

(T3) and

Thyroxine Thyroxine, also known as T4, is a hormone produced by the thyroid gland. It is the primary form of thyroid hormone found in the blood and acts as a prohormone of the more active thyroid hormone, triiodothyronine (T3). Thyroxine and its acti ...

(T4)) and responds by releasing thyrotropin-releasing hormone (TRH). The TRH stimulates the anterior pituitary to produce thyroid-stimulating hormone (TSH). The TSH, in turn, stimulates the thyroid to produce thyroid hormone until levels in the blood return to normal. Thyroid hormone exerts negative feedback control over the hypothalamus as well as anterior pituitary, thus controlling the release of both TRH from hypothalamus and TSH from anterior pituitary gland. The

HPA The pascal (symbol: Pa) is the unit of pressure in the International System of Units (SI). It is also used to quantify internal pressure, stress, Young's modulus, and ultimate tensile strength. The unit, named after Blaise Pascal, is an S ...

, HPG, and HPT axes are three pathways in which the hypothalamus and pituitary direct neuroendocrine function.

Physiology

Thyroid homeostasis results from a multi-loop feedback system that is found in virtually all higher vertebrates. Proper function of thyrotropic feedback control is indispensable for growth, differentiation,

reproduction Reproduction (or procreation or breeding) is the biological process by which new individual organisms – "offspring" – are produced from their "parent" or parents. There are two forms of reproduction: Asexual reproduction, asexual and Sexual ...

and

intelligence Intelligence has been defined in many ways: the capacity for abstraction, logic, understanding, self-awareness, learning, emotional knowledge, reasoning, planning, creativity, critical thinking, and problem-solving. It can be described as t ...

. Very few animals (e.g.

axolotl The axolotl (; from ) (''Ambystoma mexicanum'') is a neoteny, paedomorphic salamander, one that Sexual maturity, matures without undergoing metamorphosis into the terrestrial adult form; adults remain Aquatic animal, fully aquatic with obvio ...

s and

sloth Sloths are a Neotropical realm, Neotropical group of xenarthran mammals constituting the suborder Folivora, including the extant Arboreal locomotion, arboreal tree sloths and extinct terrestrial ground sloths. Noted for their slowness of move ...

s) have impaired thyroid homeostasis that exhibits a very low set-point that is assumed to underlie the

metabolic Metabolism (, from ''metabolē'', "change") is the set of life-sustaining chemical reactions in organisms. The three main functions of metabolism are: the conversion of the energy in food to energy available to run cellular processes; the ...

and

ontogenetic Ontogeny (also ontogenesis) is the origination and development of an organism (both physical and psychological, e.g., moral development), usually from the time of fertilization of the egg to adult. The term can also be used to refer to the stu ...

anomalies of these animals. The pituitary gland secretes thyrotropin (TSH; Thyroid Stimulating Hormone) that stimulates the thyroid to secrete

thyroxine Thyroxine, also known as T4, is a hormone produced by the thyroid gland. It is the primary form of thyroid hormone found in the blood and acts as a prohormone of the more active thyroid hormone, triiodothyronine (T3). Thyroxine and its acti ...

(T4) and, to a lesser degree,

triiodothyronine Triiodothyronine, also known as T3, is a thyroid hormone. It affects almost every physiological process in the body, including growth and development, metabolism, body temperature, and heart rate. Production of T3 and its prohormone thyroxi ...

(T3). The major portion of T3, however, is produced in peripheral organs, e.g.

liver The liver is a major metabolic organ (anatomy), organ exclusively found in vertebrates, which performs many essential biological Function (biology), functions such as detoxification of the organism, and the Protein biosynthesis, synthesis of var ...

adipose tissue Adipose tissue (also known as body fat or simply fat) is a loose connective tissue composed mostly of adipocytes. It also contains the stromal vascular fraction (SVF) of cells including preadipocytes, fibroblasts, Blood vessel, vascular endothel ...

glia Glia, also called glial cells (gliocytes) or neuroglia, are non-neuronal cells in the central nervous system (the brain and the spinal cord) and in the peripheral nervous system that do not produce electrical impulses. The neuroglia make up ...

and

skeletal muscle Skeletal muscle (commonly referred to as muscle) is one of the three types of vertebrate muscle tissue, the others being cardiac muscle and smooth muscle. They are part of the somatic nervous system, voluntary muscular system and typically are a ...

by deiodination from circulating T4. Deiodination is controlled by numerous

hormone A hormone (from the Ancient Greek, Greek participle , "setting in motion") is a class of cell signaling, signaling molecules in multicellular organisms that are sent to distant organs or tissues by complex biological processes to regulate physio ...

s and nerval signals including TSH,

vasopressin Mammalian vasopressin, also called antidiuretic hormone (ADH), arginine vasopressin (AVP) or argipressin, is a hormone synthesized from the ''AVP'' gene as a peptide prohormone in neurons in the hypothalamus, and is converted to AVP. It ...

and

catecholamines A catecholamine (; abbreviated CA), most typically a 3,4-dihydroxyphenethylamine, is a monoamine neurotransmitter, an organic compound that has a catechol (benzene with two hydroxyl side groups next to each other) and a side-chain amine. ...

. Both peripheral thyroid hormones (iodothyronines) inhibit thyrotropin secretion from the pituitary (

negative feedback Negative feedback (or balancing feedback) occurs when some function (Mathematics), function of the output of a system, process, or mechanism is feedback, fed back in a manner that tends to reduce the fluctuations in the output, whether caused ...

). Consequently, equilibrium concentrations for all hormones are attained. TSH secretion is also controlled by thyrotropin releasing hormone (thyroliberin, TRH), whose secretion itself is again suppressed by plasma T4 and T3 in CSF (long feedback, Fekete–Lechan loop). Additional feedback loops are ultrashort feedback control of TSH secretion (Brokken-Wiersinga-Prummel loop) and linear feedback loops controlling

plasma protein Plasma proteins, sometimes referred to as blood proteins, are proteins present in blood plasma. They perform many different functions, including transport of hormones, vitamins and minerals in activity and functioning of the immune system. Other b ...

binding. Recent research suggested the existence of an additional feedforward motif linking TSH release to deiodinase activity in humans. The existence of this TSH-T3 shunt could explain why deiodinase activity is higher in hypothyroid patients and why a minor fraction of affected individuals may benefit from substitution therapy with T3. Convergence of multiple afferent signals in the control of TSH release including but not limited to T3, cytokines and TSH receptor antibodies may be the reason for the observation that the relation between free T4 concentration and TSH levels deviates from a pure loglinear relation that has previously been proposed. Recent research suggests that ghrelin also plays a role in the stimulation of T4 production and the subsequent suppression of TSH directly and by negative feedback.

Functional states of thyrotropic feedback control

* Euthyroidism: Normal thyroid function *

Hypothyroidism Hypothyroidism is an endocrine disease in which the thyroid gland does not produce enough thyroid hormones. It can cause a number of symptoms, such as cold intolerance, poor ability to tolerate cold, fatigue, extreme fatigue, muscle aches, co ...

: Reduced thyroid function **primary hypothyroidism: Feedback loop interrupted by low thyroid secretory capacity, e.g. after thyroid surgery or in case of autoimmune thyroiditis **secondary hypothyroidism: Feedback loop interrupted on the level of pituitary, e.g. in anterior pituitary failure **tertiary hypothyroidism: Lacking stimulation by TRH, e.g. in hypothalamic failure, Pickardt–Fahlbusch syndrome or euthyroid sick syndrome. *

Hyperthyroidism Hyperthyroidism is a endocrine disease in which the thyroid gland produces excessive amounts of thyroid hormones. Thyrotoxicosis is a condition that occurs due to elevated levels of thyroid hormones of any cause and therefore includes hyperth ...

: Inappropriately increased thyroid function **primary hyperthyroidism: Inappropriate secretion of thyroid hormones, e.g. in case of

Graves' disease Graves' disease, also known as toxic diffuse goiter or Basedow's disease, is an autoimmune disease that affects the thyroid. It frequently results in and is the most common cause of hyperthyroidism. It also often results in an enlarged thyro ...

. **secondary hyperthyroidism: Rare condition, e.g. in case of TSH producing

pituitary adenoma Pituitary adenomas are tumors that occur in the pituitary gland. Most pituitary tumors are benign, approximately 35% are invasive and just 0.1% to 0.2% are carcinomas.Thyrotoxicosis: Over-supply with thyroid hormones, e.g. by overdosed exogenously levothyroxine supplementation. * Low-T3 syndrome and high-T3 syndrome: Consequences of step-up hypodeiodination, e.g. in critical illness as an example for type 1 allostasis, or hyperdeiodination, as in type 2 allostasis, including

posttraumatic stress disorder Post-traumatic stress disorder (PTSD) is a mental disorder that develops from experiencing a Psychological trauma, traumatic event, such as sexual assault, domestic violence, child abuse, warfare and its associated traumas, natural disaster ...

. *

Resistance to thyroid hormone Thyroid hormone resistance (also resistance to thyroid hormone (RTH), and sometimes Refetoff syndrome) describes a rare syndrome in which the thyroid hormone levels are elevated but the thyroid stimulating hormone (TSH) level is not suppressed, ...

: Feedback loop interrupted on the level of pituitary thyroid hormone receptors.

Diagnostics

Standard procedures cover the determination of serum levels of the following hormones: * TSH (thyrotropin, thyroid stimulating hormone) * Free T4 *Free T3 For special conditions the following

assay An assay is an investigative (analytic) procedure in laboratory medicine, mining, pharmacology, environmental biology and molecular biology for qualitatively assessing or quantitatively measuring the presence, amount, or functional activity ...

s and procedures may be required: *Total T4 *Total T3 * TBG * TRH test * Thyroid's secretory capacity (GT) * Sum activity of peripheral deiodinases (GD) * TSH Index (TSHI)

Physiology

Functional states of thyrotropic feedback control

Diagnostics

See also

References

Further reading