Synthesis of iodothyronines
Iodothyronines (T3 and T4) are synthesized as part of a large glycoprotein, thyroglobulin, containing about 115 tyrosine residues. The protein is formed in the basal part of the thyrocyte and accumulates in the extracellular colloid, where iodination takes place.
Under the action of the enzyme thyroid peroxidase, oxidized iodine reacts with tyrosine residues to form monoiodotyrosine (MIT) and diiodotyrosine (DIT). Further condensation yields active hormones:
- two DIT molecules → thyroxine (T4);
- DIT + MIT → triiodothyronine (T3).
Iodinated thyroglobulin re-enters the cell via endocytosis; in secondary lysosomes, the hormones are cleaved from the protein and secreted into the blood.
Transport and regulation of thyroid hormones
In the blood, iodothyronines are almost entirely in a bound form with thyroxine-binding globulin. Only about 0.03% of T3 and 0.3% of T4 circulate in a free state—these are the biologically active fractions. Transport proteins act as a depot.
Regulation occurs within the hypothalamic-pituitary system via negative feedback:
- the hypothalamus releases thyrotropin-releasing hormone (TRH);
- the pituitary produces thyroid-stimulating hormone (TSH), which stimulates the synthesis of T3 and T4;
- T3 and T4 inhibit TSH production, and T3 additionally suppresses TRH.
In the liver, T4 can be converted by deiodinase into either active T3 or inactive reverse T3.
Biological effects of iodothyronines
Iodothyronines regulate tissue growth and differentiation as well as energy metabolism. The main molecular effect is the activation of Na⁺/K⁺-ATPase, which increases ATP consumption and activates catabolism via respiratory control mechanisms.
- Carbohydrate metabolism: enhancement of glycogenolysis and aerobic glucose oxidation.
- Lipid metabolism: activation of lipolysis and fatty acid β-oxidation.
- Protein metabolism: stimulation of amino acid transamination.
- Nucleic acid metabolism: activation of the early stages of purine and pyrimidine synthesis.
- Energy metabolism: increased oxygen consumption, ATP production, and thermogenesis.
- In the adrenal glands, they suppress catecholamine synthesis.
Synthesis of corticosteroids
The common precursor of all corticosteroids (cortisol, aldosterone, testosterone) is cholesterol, which enters the cell predominantly as part of LDL in the form of esters. During steroidogenesis, more than 40 metabolites are formed, many of which are biologically active.
Cortisol synthesis takes place in different cell compartments:
- In the mitochondria, cholesterol is converted into pregnenolone by cleavage of the six-carbon side-chain fragment and C21 oxidation.
- In the endoplasmic reticulum, pregnenolone → progesterone → 11-deoxycortisol.
- 11-Deoxycortisol returns to the mitochondria, where it is converted into cortisol.
Which specific steroid is formed is determined by the cell's set of enzymes. Cortisol synthesis requires 17α-, 21-, and 11β-hydroxylases. Stimulation is carried out by ACTH via the adenylate cyclase system (cAMP, protein kinase A) with feedback regulation of ACTH and corticotropin-releasing hormone synthesis by cortisol.
Transport and catabolism of corticosteroids
Steroid hormones are hydrophobic, so they are transported in the blood by specific carrier proteins (transcortin). Catabolism occurs in the liver via hydroxylation, oxidation, and reduction, followed by conjugation with glucuronic or sulfuric acid and urinary excretion.
Catabolic products of most corticosteroids (except corticosterone and aldosterone) are excreted as 17-ketosteroids. Normal excretion rate: in men 12–17 mg/day, in women 7–12 mg/day. An elevation indicates steroid hyperproduction.
Targets and effects of cortisol
Stimuli for cortisol secretion: infection, trauma, prolonged fasting, psycho-emotional stress. The hormone enters the cell and binds to intracellular receptors. The main targets are lymphoid and adipose tissue, liver, and connective tissue.
- Protein metabolism: inhibition of translation, predominance of catabolism, increased urea synthesis.
- Carbohydrate metabolism: induction of phosphoenolpyruvate carboxykinase and activation of gluconeogenesis.
- Lipid metabolism: stimulation of lipolysis through increased synthesis of triglyceride lipase.
- Water-electrolyte metabolism: weak mineralocorticoid action — sodium reabsorption and water retention.
- Anti-inflammatory effect: inhibition of phospholipase A2 blocks arachidonic acid release and the formation of prostaglandins, leukotrienes, and thromboxanes.
- Immunosuppressive effect: suppression of antibody synthesis and inhibition of plasma cells.
Key points
- Iodothyronines are synthesized as part of thyroglobulin with the participation of thyroid peroxidase.
- In the blood, T3 and T4 are transported by thyroxine-binding globulin; the free fractions are active.
- Regulation of thyroid and steroid hormones follows the negative feedback principle.
- The main effect of T3/T4 is the activation of Na⁺/K⁺-ATPase and the enhancement of energy metabolism.
- Corticosteroids are synthesized from cholesterol; specificity is determined by the set of hydroxylases.
- Steroid catabolism occurs in the liver, and excretion takes the form of 17-ketosteroids.
- Cortisol enhances gluconeogenesis, protein catabolism, and lipolysis.
- The anti-inflammatory action of cortisol is due to the inhibition of phospholipase A2.