BIOCHEMISTRY - Textbook - Ostapchenko L. I. - 2012

Chapter 15. INTEGRATION OF METABOLIC PATHWAYS. HORMONES

15.9. Corticosteroids

More than 40 metabolites, which vary in Structure and biological activity and are derived from Cholesterol, are synthesized in the adrenal cortex.

The First stage of corticosteroid synthesis involves The conversion of cholesterol into pregnenolone, mediated by a cytochrome P450 hydroxylase, through the Cleavage of a 6-carbon fragment from the cholesterol side chain and The oxidation of the C₂₀ carbon atom (Fig. 15.11). Pregnenolone is then converted into progesterone—the precursor of C₂₁-Steroids (cortisol and aldosterone)—and C₁₉-steroids (precursors of androgens). The specific Nature of the final steroid product depends on the Complement of cellular Enzymes and The sequence of hydroxylation reactions.

Class="center">

Fig. 15.11. Synthesis of pregnenolone, the precursor of Steroid Hormones

Initial hydroxylation of progesterone by 17-hydroxylase, followed by 21- and 11-hydroxylase, leads to the synthesis of cortisol. The reactions leading to aldosterone formation involve the initial hydroxylation of progesterone by 21-hydroxylase, followed by 11-hydroxylase, along with the oxidation of C18 to an aldehyde group (Fig. 15.12).

Steroid hormones are transported through the bloodstream in complexes with specific transport Proteins.

The cholesterol required for corticosteroid synthesis is supplied either by its esters—delivered to The Cell as part of low-density Lipoproteins (LDLs)—or from intracellular stores. The release of cholesterol from its esters and the subsequent synthesis of corticosteroids are stimulated by corticotropin.

The synthesis of cortisol takes place in different cellular compartments of the adrenal cortex: the Mitochondria and The Endoplasmic reticulum (ER). The rate of cortisol Synthesis and Secretion is regulated by the hypothalamic-pituitary axis via a negative feedback mechanism and is stimulated in response to stress, trauma, or infection.

Cortisol synthesis begins with the conversion of pregnenolone to progesterone, catalyzed by the enzyme 3-β-hydroxysteroid dehydrogenase in the Cytosol, to which pregnenolone is transported from the mitochondria.

Subsequent transformations occur on the ER membrane, where 17-α-hydroxylase catalyzes the hydroxylation of progesterone at C17, followed by 21-hydroxylase at C₂₁. The resulting 11-deoxycortisol is then transferred to The inner mitochondrial membrane, where it is hydroxylated at C₁₁ to yield cortisol (Fig. 15.13).

Fig. 15.13. Scheme of cortisol synthesis:

A - progesterone, B - 17-hydroxyprogesterone, C - 11-deoxycortisol, D - cortisol

In Blood Plasma, cortisol circulates primarily bound to the α-globulin transcortin. Unbound, or free, cortisol accounts for approximately 8 % of the total plasma pool and represents the biologically active fraction.

The MECHANISM OF ACTION of glucocorticoids involves their interaction with specific receptors located in the cytosol and Cell Nucleus. The metabolic effects of glucocorticoids are mediated through The regulation of diverse processes (both Catabolic and anabolic).

Cortisol stimulates hepatic glucose production by enhancing Gluconeogenesis and increasing the release rate of Amino Acids from peripheral Tissues to serve as gluconeogenic substrates. In the Liver, cortisol induces the synthesis of amino acid catabolizing enzymes and promotes Glycogen synthesis. In peripheral tissues, cortisol inhibits glucose uptake. In healthy individuals, the effects of cortisol are counterbalanced by Insulin.

The METABOLISM of proteins and Nucleic Acids is regulated by glucocorticoids in opposing ways within the liver versus peripheral tissues: predominantly exerting an anabolic effect in the liver, and a catabolic effect in Skeletal Muscle, adipose tissue, and bone.

The Catabolism of Adrenal Cortex Hormones occurs primarily in the liver, where they undergo hydroxylation, oxidation, and reduction reactions. Corticosteroid catabolites (except for corticosterone and aldosterone) are excreted in the urine as 17-ketosteroids. These metabolic products are eliminated predominantly as conjugates with glucuronic and sulfuric acids. In men, two-thirds of 17-ketosteroids are derived from corticosteroids and one-third from testosterone (totaling 12–17 mg/day). In women, 17-ketosteroids originate mainly from corticosteroids (7–12 mg/day).

Excessive production of corticosteroids—primarily cortisol, known as hypercortisolism—frequently results from a disruption in The regulatory mechanisms governing cortisol synthesis, such as pituitary tumors with elevated corticotropin output (Cushing's Disease) or cortisol-producing adrenal tumors (Cushing's syndrome). The main manifestations of hypercortisolism include impaired glucose tolerance, hyperglycemia, and Hypertension.

Congenital adrenal hyperplasia is attributed to a 21-hydroxylase deficiency in 95 % of cases. This condition presents with elevated 17-OH-progesterone secretion, increased androgen production, precocious Puberty in boys, and virilization in girls. Partial 21-hydroxylase deficiency in women can lead to menstrual irregularities.

Acquired adrenal insufficiency may develop as a consequence of tuberculous or autoimmune destruction. Frequently, it results from the suppression of the hypothalamic-pituitary regulatory axis via feedback inhibition caused by prolonged corticosteroid therapy. The loss of adrenal regulatory control leads to elevated corticotropin secretion. In such cases, patients exhibit hyperpigmentation of the Skin and mucous membranes (Addison's disease), driven by heightened production of corticotropin and other POMC-derived Peptides, including melanocyte-stimulating hormone. The primary clinical manifestations of adrenal insufficiency include hypotension, muscle weakness, hyponatremia, weight loss, and stress intolerance.

The most important mineralocorticoid is aldosterone, which is secreted by the zona glomerulosa of the Adrenal Glands. The Renin-Angiotensin System is the main regulator of its secretion. Renin, synthesized in the Kidneys, catalyzes the conversion of inactive angiotensinogen into angiotensin I, which is subsequently converted into angiotensin II. The Synthesis of the latter depends on the circulating blood volume (CBV) and the level of sodium ions. A decrease in CBV leads to increased synthesis of angiotensin II, which stimulates aldosterone secretion, causing sodium and Water retention and the restoration of CBV.

Aldosterone secretion also depends on ACTH and potassium levels. In hypokalemia, aldosterone secretion is inhibited, while potassium excretion decreases. Conversely, even a slight increase in blood potassium levels triggers enhanced aldosterone secretion and potassium excretion.