Textbook - BIOLOGICAL CHEMISTRY - Hubsky Y.I. - 2000

Chapter V. HORMONES IN THE SYSTEM OF INTERCELLULAR INTEGRATION OF BODY FUNCTIONS

CHAPTER 25. HORMONAL REGULATION OF METABOLISM AND CELLULAR BIOLOGICAL FUNCTIONS. III. HORMONES AND OTHER LIPID-DERIVED BIOREGULATORS

25.2. ADRENAL CORTEX STEROID HORMONES

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The Steroid Hormones OF the adrenal cortex, known as corticosteroids, belong to C₂₁-Steroids.

The human adrenal cortex synthesizes about 30 steroids with varying levels of physiological activity. The "true" steroid Hormones of the adrenal cortex (i.e., those secreted into the Blood and acting on sensitive peripheral Tissues) are cortisol (hydrocortisone), corticosterone, and aldosterone.

All three hormones exhibit both glucocorticoid and mineralocorticoid activity, though to varying degrees: cortisol is predominantly a glucocorticoid, aldosterone is primarily a mineralocorticoid, and corticosterone displays both types of activity, albeit to a lesser extent than cortisol and aldosterone, respectively.

Biosynthesis of corticosteroids takes place in the adrenal Cells from a precursor common to all steroid hormones—the C₂₁-Δ⁵-steroid Cholesterol, which is delivered to steroidogenic cells via the bloodstream from the Liver or synthesized in situ from acetyl-CoA.

The KEY STAGES IN the synthesis of corticosteroids, as well as other biologically active steroids that pass through the stages of pregnenolone and progestogen formation, include:

- the release of cholesterol from cytosolic lipid droplets and its entry into Cell/35.html">Mitochondria, where biotransformation takes place;

- the Cleavage of six carbon atoms from the cholesterol side chain (C₂₇ —► C₂₁ conversion) to yield the C₂₁-Δ⁵-steroid pregnenolone;

- The conversion of pregnenolone (via oxidation and isomerization reactions) into the Δ⁴-3-Ketosteroid progesterone;

- the conversion of progesterone into glucocorticoids and mineralocorticoids (through steroid hydroxylation Reactions Catalyzed by cytochrome P-450-dependent mixed-function oxygenases).

The biosynthesis of specific steroid hormones occurs in different Zones of the adrenal cortex: aldosterone and corticosterone are synthesized in the outer zona glomerulosa; cortisol and corticosterone in the middle zona fasciculata; and androgens, along with some cortisol, in the inner zona reticularis.

Biological Properties of Corticosteroids

The physiological function of corticosteroid hormones is to regulate adaptation processes of the whole Organism to changing environmental conditions and to maintain internal Homeostasis, particularly under stress.

Glucocorticoids are corticosteroids whose primary biological effect is the REGULATION OF CARBOHYDRATE METABOLISM, aimed at stimulating glucose synthesis in the liver, i.e., Gluconeogenesis. Glucocorticoids include cortisol (hydrocortisone), cortisone (11-dehydrocortisol), corticosterone, and 11-dehydrocorticosterone. The principal (most active and secreted into the blood) representative of glucocorticoids is cortisol.

Activation of glucose synthesis by cortisol is achieved through the coordinated action of the following biochemical mechanisms:

in the liver—activation of the expression of genes responsible for the synthesis of gluconeogenic Enzymes (PEP carboxykinase, aminotransferases—specifically Tyrosine aminotransferase, and Tryptophan pyrrolase), which supply substrate precursors for glucose synthesis;

in Muscles—inhibition of Protein Biosynthesis, leading to an increased concentration of free Amino Acids that enter hepatocytes to serve as substrates for gluconeogenesis; a similar catabolic effect of cortisol is also observed in lymphoid tissue.

The Effect of cortisol on Lipid Metabolism is manifested mainly through its anti-Insulin action, i.e., stimulation of lipolysis in adipose tissue with a subsequent increase in free fatty acid (NEFA) levels in Blood Plasma. This effect of glucocorticoids on triacylglycerol metabolism is based on their ability to enhance the lipolytic action of catecholamines and somatotropin—the "permissive effect of glucocorticoids."

In addition to controlling these metabolic pathways, cortisol and other glucocorticoids regulate numerous physiological processes in the body by altering cellular responsiveness to Other Hormones and Neurotransmitters. Particularly important are the effects of glucocorticoids (together with catecholamines) aimed at mobilizing the body's defense reactions under stress, such as surgery, trauma, and infections. At high pharmacological doses, glucocorticoids and their synthetic derivatives exhibit pronounced anti-inflammatory properties associated with the inhibition of phospholipase A₂, which is required for the release of arachidonic acid—a precursor in prostaglandin synthesis (see below); this anti-inflammatory effect of glucocorticoid compounds has found widespread clinical application (drugs such as Prednisolone, Dexamethasone, Triamcinolone, etc.).

Regulation of Cortisone Synthesis and Secretion, ng/ml

The biochemical signal that stimulates the synthesis and release of cortisol into the bloodstream is a drop in blood glucose concentration. Hypoglycemia triggers cortisol-dependent gluconeogenesis via sensitive hypothalamic structures that secrete corticoliberin (corticotropin-releasing hormone), which in turn activates the release of corticotropin (ACTH) and, consequently, The production of cortisol in the adrenal cortex.

The daily secretion of cortisol and pituitary corticotropin in The Human Body exhibits a rhythmic pattern peaking in the morning hours—that is, during the postabsorptive period when internal glucose reserves are depleted. The highest surge in serum ACTH levels occurs between 6:00 and 8:00 AM, slightly preceding the rise in cortisol (Fig. 25.2).

Fig. 25.2. Daily rhythm of ACTH (a) and cortisol (b) secretion (according to M.I. Balabolkin, 1998).

Cushing's Disease is a pathological condition characterized by an abnormal increase in the production of glucocorticoids, particularly cortisol, in the human body. This pathology arises from a hormone-producing tumor of the Adrenal Glands or the Pituitary Gland (with a corresponding increase in corticotropin secretion). The main manifestations of the disease include decreased glucose tolerance, persistent hyperglycemia, and glucosuria even in the postabsorptive state (i.e., several hours after the last meal), as well as impaired lipid metabolism. Because natural glucocorticoids also exhibit mineralocorticoid effects (see below), Cushing's disease leads to Na⁺ retention and severe Hypertension.

Mineralocorticoids are corticosteroids whose biological action involves The regulation of Water and Salt Metabolism in tissues; they cause the retention of Na⁺ ions and The excretion of K⁺ and H⁺ in the body. Steroids synthesized in the adrenal glands that possess mineralocorticoid activity include aldosterone, 18-hydroxycorticosterone, 11-deoxycorticosterone (DOC), and several Other Compounds. Among them, aldosterone is the most potent (and the only mineralocorticoid secreted into the blood), with a mineralocorticoid effect approximately 100 times greater than that of Other Steroids.

Aldosterone is the primary mineralocorticoid synthesized in the Cells of the zona glomerulosa of the adrenal cortex. Its main biochemical effect is The stimulation of Na⁺ reabsorption (along with Cl^-) in the distal tubules of the nephrons.

The MOLECULAR MECHANISMS OF aldosterone action, like those of other steroid hormones, involve binding to a specific cytosolic receptor in target cells. This hormone-receptor complex is then translocated to the Cell Nucleus, where the aldosterone-activated receptor triggers the expression of genes required for the synthesis of Proteins that mediate Na⁺ Transport Across the apical and basal membranes of responsive nephron cells.

Aldosteronism

Under normal conditions, the zona glomerulosa of the adrenal cortex produces 60-90 mcg of aldosterone per day. Elevated hormone concentrations resulting from its increased production in the adrenal cortex or reduced hepatic Catabolism due to hepatocyte dysfunction (e.g., in liver cirrhosis) are referred to as aldosteronism syndrome. This condition manifests as hypertension and edema due to increased renal retention of sodium ions and water. Primary aldosteronism (Conn's syndrome) is a disorder caused by an aldosterone-producing Adenoma of the adrenal cortex within the Renin-Angiotensin System.

The renin-angiotensin system is a system of vasoactive Peptides that regulates blood pressure and water-electrolyte balance in the human body. The core component of the system is the octapeptide angiotensin II, which is formed via sequential Limited proteolysis from angiotensinogen, a protein belonging to the serum α₂-globulin fraction:

Upon the action of the proteolytic enzyme renin—synthesized in the juxtaglomerular cells of the afferent arterioles of nephrons—angiotensinogen is cleaved to release the decapeptide angiotensin I. Angiotensin I is subsequently converted into the vasoconstrictor peptide angiotensin II by the protease angiotensin-converting enzyme (ACE). The physiological stimulus for renin production and the activation of the proteolytic cascade generating angiotensin II is a drop in blood pressure.

Angiotensin II is the most potent vasoconstrictor; its biological effects are also mediated by stimulating the secretion of aldosterone and vasopressin (antidiuretic hormone), which collectively results in the retention of Na⁺ ions and water in the body. Angiotensin-converting Enzyme Inhibitors lower blood pressure and exert diuretic (and natriuretic) pharmacological effects. These ACE inhibitor compounds are widely used as effective drugs for the Treatment of hypertension (such as Captopril, Enalapril, etc.).

The natriuretic system

The physiological antagonist of aldosterone and angiotensin II is the natriuretic system, which consists of peptides synthesized predominantly in the myocardium (atrial myocytes) and the Brain. The atrial natriuretic factor (hormone) is a peptide (126 amino acid residues) possessing natriuretic, diuretic, and kaliuretic properties. Upon cleavage by blood and tissue proteases, the precursor peptide (prohormone) breaks down into individual active peptides. Natriuretic peptides have also been detected (albeit in much lower concentrations) in the adrenal glands, Kidneys, and Uterus.