Synthesis of iodothyronines
Iodothyronines (T3 and T4) are synthesized as part of thyroglobulin, a glycoprotein containing about 115 tyrosine residues. Thyroglobulin is formed in the basal part of the thyrocyte and accumulates in the extracellular colloid, where iodination of tyrosine residues and formation of iodothyronines take place.
Under the action of thyroperoxidase, oxidized iodine reacts with tyrosine residues to form monoiodotyrosine (MIT) and diiodotyrosine (DIT). Condensation of two DIT molecules yields tetraiodothyronine (T4, thyroxine); condensation of DIT and MIT yields triiodothyronine (T3).
Iodinated thyroglobulin returns to the cell via endocytosis, where lysosomal proteases cleave T3 and T4 from it. The hormones are secreted into the bloodstream.
Transport and activation
In the blood, iodothyronines circulate predominantly in a bound form with thyroxine-binding globulin (TBG). Only about 0.03% of T3 and 0.3% of T4 are in a free (biologically active) state. Transport proteins act as a reservoir.
In the liver and other peripheral tissues, T4 is deiodinated by the enzyme deiodinase into the more active T3 or into inactive reverse T3 (rT3).
Regulation of iodothyronine secretion
The synthesis of T3 and T4 is controlled by the hypothalamic-pituitary system via a negative feedback mechanism:
- The hypothalamus secretes thyrotropin-releasing hormone (TRH);
- The pituitary gland produces thyroid-stimulating hormone (TSH), which stimulates the synthesis of T3 and T4;
- T3 inhibits the secretion of TSH and TRH.
Biological effects of T3 and T4
Iodothyronines control tissue growth and differentiation, as well as energy metabolism. A key effect is an increase in Na⁺/K⁺-ATPase activity, which accelerates ATP consumption. By the mechanism of respiratory control, carbohydrate and lipid catabolism are activated, oxygen consumption and heat production increase.
- Carbohydrate metabolism: enhancement of glycogenolysis and aerobic glucose oxidation;
- Lipid metabolism: enhancement of lipolysis and fatty acid β-oxidation;
- Protein metabolism: activation of amino acid catabolism;
- Nucleic acid metabolism: stimulation of purine and pyrimidine synthesis;
- Adrenal glands: suppression of catecholamine synthesis.
Cortisol synthesis
The common precursor for all corticosteroids (cortisol, aldosterone, sex steroids) is cholesterol. The source of cholesterol is LDL, which delivers its esters to the cells of the adrenal cortex.
Synthesis occurs in different compartments:
- In mitochondria, cholesterol is converted to pregnenolone with the cleavage of a 6-carbon side-chain fragment;
- In the endoplasmic reticulum, pregnenolone → progesterone → 17-hydroxyprogesterone → 11-deoxycortisol;
- In the mitochondria, 11-deoxycortisol is hydroxylated to cortisol.
Key enzymes of cortisol synthesis are 17α-hydroxylase, 21-hydroxylase, and 11β-hydroxylase. The set of enzymes in a cell determines which specific steroid is produced.
Regulation, transport, and catabolism of cortisol
Cortisol secretion is regulated by negative feedback: hypothalamic corticotropin-releasing hormone stimulates the release of ACTH by the adenohypophysis, and ACTH activates cortisol synthesis via the adenylate cyclase–cAMP–protein kinase A system. Cortisol inhibits the secretion of ACTH and corticotropin-releasing hormone.
Being hydrophobic, cortisol is transported in the blood by a specific protein — transcortin. Catabolism takes place in the liver via hydroxylation, oxidation, and reduction; the products are excreted as conjugates with glucuronic or sulfuric acid. Neutral metabolites are 17-ketosteroids; their normal urinary excretion is 12–13 mg/day in men and 7–12 mg/day in women. An elevated level indicates steroid hyperproduction.
Targets and effects of cortisol
Stimuli for secretion: infection, trauma, prolonged fasting, heavy physical exertion, stress. Main targets are lymphoid tissue, adipose tissue, liver, muscle and connective tissue. Cortisol enters the cell and binds to intracellular receptors, regulating gene transcription.
- Protein metabolism: suppression of translation in peripheral tissues → enhancement of protein catabolism, increased urea synthesis;
- Carbohydrate metabolism: induction of phosphoenolpyruvate carboxykinase (PEPCK) → activation of gluconeogenesis, hyperglycemia;
- Lipid metabolism: stimulation of lipolysis through the induction of TAG lipase;
- Mineralocorticoid effect: mild Na⁺ reabsorption and water retention;
- Anti-inflammatory action: inhibition of phospholipase A2 → decreased release of arachidonic acid and formation of prostaglandins, leukotrienes, thromboxanes; suppression of cyclooxygenase transcription;
- Immunosuppression: suppression of antibody synthesis by plasma cells, involution of lymphoid tissue.
Key points
- T3 and T4 are synthesized on thyroglobulin with the participation of thyroperoxidase from iodinated tyrosine residues (MIT and DIT).
- In the blood, iodothyronines are carried by TBG; only the free fraction is active, and T4 is deiodinated to T3 in peripheral tissues.
- Hypothalamic-pituitary-thyroid axis: TRH → TSH → T3/T4 with negative feedback.
- Iodothyronines activate Na⁺/K⁺-ATPase, enhance catabolism, heat production, and oxygen consumption.
- Cortisol is synthesized from cholesterol in the mitochondria and ER of the adrenal cortex; key enzymes are 17α-, 21-, and 11β-hydroxylases.
- Cortisol secretion is regulated by the corticotropin-releasing hormone → ACTH → cortisol axis with feedback.
- Cortisol is a counter-regulatory (anti-insulin) hormone: it activates gluconeogenesis, lipolysis, and protein catabolism.
- The anti-inflammatory and immunosuppressive effects of cortisol are due to the inhibition of phospholipase A2 and suppression of antibody synthesis.