BIOCHEMISTRY: A TEXTBOOK FOR MEDICAL UNIVERSITIES - E. S. Severin - 2004

SECTION 11. HORMONAL REGULATION OF METABOLISM AND BODY FUNCTIONS

III. Structure, Biosynthesis, and Biological Action of Hormones

Hormones are produced by specialized Cells, many of which are organized into glands that secrete hormones directly into the bloodstream (Hypothalamus, Pituitary gland, islet Cells of the Pancreas, thyroid and Parathyroid glands, Adrenal Glands, and Gonads). Many Endocrine glands produce several hormones with different structures and Functions.

Excess production or deficiency of a hormone can cause endocrine disorders. Among the causes of hormone hypersecretion, hormone-secreting tumors take first place. Hyposecretion is frequently caused by Genetic Defects in the Structure and function of Enzymes involved in hormone synthesis, or by damage to hormone-producing cells resulting from infection, tumors, or autoimmune reactions. The Clinical presentation of hormone hyper- and hyposecretion can also be caused by the THERAPEUTIC USE OF hormones. In some cases, hormone administration leads to the suppression of its secretion by the glands, which is why abruptly discontinuing hormone therapy causes hypofunction of the endocrine glands.

Causes of endocrine disorders may also include structural defects in the hormones themselves or their receptors, impaired hormone METABOLISM, and disruptions in the mechanisms of hormonal signal Transduction into target cells.

A. Hypothalamic hormones

The hypothalamus occupies a critical position in the hierarchical system, linking higher Central Nervous system (CNS) centers with the endocrine glands. The Neurons of the hypothalamus synthesize Two Types of Peptide Hormones. Some are transported via the hypothalamo-pituitary Vascular System to the anterior pituitary, where they stimulate or inhibit the synthesis of tropic hormones; others, such as oxytocin and vasopressin, travel along nerve Cell axons to the posterior pituitary, where they are stored in vesicles and secreted into the Blood in response to appropriate signals.

Currently, several hypothalamic hormones are known to regulate the Synthesis and Secretion of Pituitary Hormones (Table 11-5).

Class="center">Table 11-5. STRUCTURE AND FUNCTIONS of Hypothalamic Hormones

¹ aa — amino acid residue.

² The structure of prolactoliberin remains currently unknown; thyroliberin, serotonin, oxytocin, and acetylcholine also exhibit similar effects.

³ Another hypothalamic factor that suppresses prolactin synthesis is dopamine, which inhibits the Transcription of the prolactin Gene. One of the hypothalamic Neuropeptides, consisting of 56 amino acid residues, exhibits both gonadoliberin and prolactostatin activity. It is referred to as gonadotropin-releasing hormone-associated peptide (GAP).

1. Thyroliberin — a tripeptide composed of pyroglutamic acid, Histidine, and prolinamide (Fig. 11-9).

Fig. 11-9. Structure of certain hypothalamic hormones. A. Structure of thyroliberin: a — pyroglutamic acid; b — histidine; c — prolinamide. B. Structure of somatostatin.

The synthesis of thyroliberin occurs in various Regions of the hypothalamus, but predominantly

in the paraventricular Nucleus, as well as in other CNS areas where it acts as a neurotransmitter that increases motor activity and blood pressure. The human preprothyroliberin precursor comprises 242 amino acid residues. The active hormone is formed via partial proteolysis. In the anterior pituitary, thyroliberin stimulates the synthesis and secretion of thyrotropin, and also exerts a stimulatory effect on the synthesis of numerous Other Hormones. The interaction of thyroliberin with Plasma Membrane Receptors of pituitary cells leads to an increase in intracellular cAMP and Ca²⁺ concentrations. Signal transduction occurs via both the adenylate cyclase and Inositol phosphate systems.

Thyroliberin is degraded in target cells and in the blood by specific proteases. The T_1/2 in the blood is 3–4 min.

2. Corticoliberin

Corticoliberin is a polypeptide containing 41 amino acid residues. Like other peptide hormones, corticoliberin is synthesized as a prohormone. The plasma T_1/2 of corticoliberin is 60 min. The bulk of corticoliberin is produced in the hypothalamus; however, it is also detected in other CNS regions, where it functions as a neurotransmitter participating in responses to various stressful situations.

In the anterior pituitary, corticoliberin increases the synthesis and secretion of pro-opiomelanocortin and The production of corticotropin. Corticoliberin receptors are located in The Plasma Membrane of cells as part of the adenylate cyclase complex. Stimulation of ACTH secretion requires the presence of Ca²⁺ ions. The increase in intracellular calcium levels is likely the result of calcium channel protein phosphorylation.

3. Gonadoliberin

Gonadoliberin is a decapeptide. The human gonadoliberin precursor consists of 92 amino acid residues and has a Molecular Weight of approximately 10 kDa. Gonadoliberin stimulates the synthesis and secretion of two pituitary hormones — LH and FSH. In addition to the hypothalamus, gonadoliberin-containing neurons are found in other CNS areas that control emotional and Sexual Behavior. The gonadoliberin receptor in the plasma membrane is part of the inositol phosphate complex, the activation of which stimulates protein phosphorylation and Ca²⁺ mobilization, leading to hormone release. The plasma T_1/2 of gonadoliberin is 5–7 min. Inactivation of gonadoliberin occurs with the participation of specific proteases.

4. Somatoliberin

Somatoliberin is a polypeptide consisting of 44 amino acid residues. In the anterior pituitary gland, somatoliberin stimulates the synthesis and secretion of somatotropin. Signal transduction is accompanied by an increase in the concentration of both cAMP and Calcium Ions. The T1/2 of somatoliberin in the blood is about 7 min. Somatoliberin is used in clinical practice to diagnose pituitary function disorders.

5. Somatostatin

Somatostatin was originally isolated from the hypothalamus, but it was subsequently found to be synthesized in many cells located outside the hypothalamus: in The Stomach, intestines, pancreas, in the area of peripheral nerve endings, Placenta, adrenal glands, and retina. Somatostatin functions as both a hormone and a neurotransmitter, causing the inhibition of secretory processes, a decrease in The activity of smooth Muscle and neurons. Somatostatin consists of 14 amino acid residues and has a cyclic structure formed by a disulfide bond between two Cysteine residues (Fig. 11-10).

Fig. 11-10. Human Growth Hormone. The polypeptide chain comprises 191 amino acid residues. Two Disulfide Bonds are formed between cysteine residues at positions 183-189 and 53-165.

The acyclic reduced form of the peptide also exhibits biological activity. In Tissues, somatostatin is present as a peptide containing 28 amino acid residues and can serve as a precursor to the 14-amino acid peptide. Both forms exhibit biological activity, but to varying degrees. Somatostatin-14 is found mainly in the central nervous system, whereas somatostatin-28 is predominantly located in the intestine.

Like other peptide hormones, somatostatin interacts with plasma membrane receptors of cells. There are 5 types of G protein-coupled somatostatin receptors. All receptor types are expressed in the anterior pituitary and hypothalamus and exhibit varying degrees of affinity for different structural forms of somatostatin. Somatostatin receptors are present in many hormone-secreting tumor cells. This circumstance is used to develop Methods for the early Diagnosis of pancreatic tumors, pheochromocytoma, thyroid Cancer, Kidney Cancer, and breast cancer.

The result of somatostatin signal transduction is a decrease in the intracellular concentration of cAMP and Ca²⁺ in The Cell Cytosol. Somatostatin inhibits the secretion of growth hormone, Glucagon, Insulin, gastrin, secretin, vasoactive intestinal peptide (VIP), cholecystokinin, Calcitonin, parathyroid hormone, IMMUNOGLOBULINS, and renin; it also inhibits the secretion of bicarbonates and pancreatic enzymes, reduces blood flow throughout the gastrointestinal tract, and decreases Bile secretion.

B. Pituitary hormones

The pituitary gland secretes A large number of Hormones Involved in The regulation of various biochemical processes and physiological functions. The anterior lobe of the pituitary gland (adenohypophysis) synthesizes so-called tropic hormones, which stimulate the synthesis and secretion of hormones from other endocrine glands or influence metabolic reactions in other target tissues (Table 11-6).

Table 11-6. Structure and BIOLOGICAL FUNCTIONS OF Anterior Pituitary Hormones

The posterior lobe of the pituitary gland, or neurohypophysis, secretes hormones that primarily regulate Water Balance and lactation.

The secretion of pituitary hormones is driven by a combination of neural and humoral signals. Furthermore, the same agonist (e.g., norepinephrine) can cause opposite Changes in the secretion of pituitary hormones. On the other hand, the secretion of each hormone can be controlled by numerous factors.

The synthesis and secretion of anterior pituitary hormones are regulated by hypothalamic hormones, which reach the pituitary gland via the portal vascular system connecting the hypothalamus and the anterior pituitary. In addition, the secretion of Hypothalamic and pituitary hormones is regulated by a feedback mechanism involving the hormones whose production they stimulate in target Organs.

The anterior pituitary synthesizes hormones that are Peptides and Glycoproteins in their chemical structure.

Based on their synthesis mechanism and biological functions, these hormones are divided into 3 groups.

1. Growth hormone, prolactin

Growth hormone is synthesized in somatotrophs, which are the most abundant cells in the anterior pituitary gland. The content of growth hormone is 5–16 mg per 1 g of glandular tissue, whereas the amounts of other pituitary hormones are measured in μg/g. The T_1/2 of the hormone in Blood Plasma is about 50 min.

In all mammalian species, growth hormone is a single-chain peptide with a molecular weight of 22 kD, consisting of 191 amino acid residues and containing 2 intramolecular disulfide bonds (Fig. 11-10).

Growth hormone is produced from a prohormone with a molecular weight of 28 kD, which lacks hormonal activity. The level of growth hormone in blood plasma does not exceed 3 ng/mL. Growth hormone secretion is pulsatile, with intervals of 20–30 min. One of the highest peaks is observed shortly after falling asleep.

Under The Influence of various stimuli (stress, exercise, hypoglycemia, fasting, protein-rich food, The amino acid Arginine), even in non-growing adults, blood levels of growth hormone can rise to 30–100 ng/mL.

The regulation of growth hormone synthesis and secretion is carried out by multiple factors. The main stimulating effect is exerted by somatoliberin, and the main inhibitory effect by hypothalamic somatostatin.

Growth Hormone Receptors are located in the plasma membrane of cells in the Liver, adipose tissue, Testes, corpus luteum, Skeletal Muscle, Cartilage, Brain, Lungs, pancreas, intestines, Heart, kidney, and lymphocytes. The growth hormone receptor is a single-transmembrane-domain protein with a molecular weight of 70 kD. Binding of the receptor to growth hormone causes dimerization of 2 receptors, leading to the activation of receptor-associated Janus Kinases and the phosphorylation of Janus kinases and the receptor at Tyrosine residues. Activation of the growth hormone receptor is accompanied by an increase in the activity of tyrosine kinases and phospholipase C, followed by an increase in DAG and IP₃ levels and the activation of protein kinase C (see Section 5).

The initial effects of growth hormone are short-lived and insulin-like, primarily manifested in lipid and Carbohydrate Metabolism. In adipose tissue, glucose uptake and Lipogenesis are enhanced, leading to a decrease in blood glucose concentration. However, slower effects (largely opposing those of insulin) subsequently manifest: lipolysis in Adipose tissue is amplified, blood fatty acid concentrations rise, and in the case of insulin deficiency, blood ketone body levels increase. The energy generated from this elevated fat breakdown is channeled into anabolic processes. Concurrently, the utilization of glucose by adipose and muscle cells declines, while hepatic Gluconeogenesis is accelerated, which can result in hyperglycemia, particularly under conditions of insulin insufficiency (Fig. 11-11).

Fig. 11-11. Biological action of growth hormone.

The principal function of growth hormone is the Regulation of Protein metabolism and processes associated with somatic GROWTH AND DEVELOPMENT. Under the influence of growth hormone, the Transport of Amino acids into muscle cells is promoted, and Protein Synthesis is stimulated in bones, cartilage, Muscles, the liver, and other Internal Organs, along with an increase in the total content of RNA, DNA, and overall cell count.

The impact of growth hormone on the growth of the skeleton and soft tissues requires the participation of substances synthesized in response to the interaction of growth hormone with plasma membrane receptors on cells of various tissues, predominantly the liver; these substances are termed somatomedins. Because these molecules exhibit high Sequence Homology to one another as well as to proinsulin, and possess insulin-like activity alongside potent growth-promoting properties, they are designated as Insulin-like Growth Factors (IGF-1, or somatomedin C; IGF-2, or somatomedin A). IGF-1 is a basic single-chain polypeptide comprising 70 amino acid residues, whereas IGF-2 is acidic in character and consists of 67 amino acid residues. In the blood, approximately 95% of somatomedins circulate bound to carrier Proteins. The synthesis of IGF-1 is far more dependent on blood growth hormone concentrations than is the synthesis of IGF-2. Conversely, hepatic IGF-1 inhibits the synthesis and secretion of growth hormone via a negative feedback loop acting at the pituitary and hypothalamic levels (Fig. 11-12).

Fig. 11-12. Regulation of growth hormone secretion. Somatoliberin stimulates (1), while somatostatin inhibits (2) the release of growth hormone (GH) from the anterior pituitary. IGF-1 inhibits somatoliberin secretion (3) and stimulates somatostatin secretion (4). IGF-1 also inhibits growth hormone secretion at the pituitary level (5).

Insulin-like growth factors exert their effects through various pathways: endocrine, paracrine, and autocrine (Fig. 11-13).

Fig. 11-13. Action of growth hormone mediated by IGFs. Growth hormone interacts with plasma membrane receptors on cells, stimulating IGF synthesis (1). The IGFs, in turn, interact with specific cellular receptors on the same or neighboring tissues (2) and stimulate the phosphorylation of proteins involved in mitosis and growth (3).

Much like the insulin receptor, the IGF-1 receptor possesses tyrosine kinase activity and initiates a cascade of phosphorylation reactions involving other proteins that participate in various intracellular processes, including the activation of gene transcription. In most instances, IGF-1 triggers cellular development similarly to insulin, yet at significantly lower, nearly physiological concentrations. This indicates that insulin-like growth factors are considerably more potent regarding their effects on cell growth and development.

Under the influence of growth hormone, bone width and thickness increase, accompanied by the accelerated growth of other tissues, including Connective Tissue, muscles, and internal organs.

Prolactin is synthesized by lactotropic cells of the anterior pituitary gland as a prohormone with a molecular mass of 40 kDa. The population of these cells increases dramatically during Pregnancy under the influence of estrogens. Prolactin is structurally similar to growth hormone. It consists of 199 amino acid residues forming a single polypeptide chain cross-linked by three disulfide bonds. Thirty-five percent of the Amino Acid Sequence of prolactin is identical to that of growth hormone. Both hormones share common antigenic determinants, analogous receptor structures, and intracellular signal transduction pathways.

Prolactin receptors are present in the cells of numerous tissues, including the liver, Kidneys, adrenal glands, testes, Ovaries, and Uterus, among others.

The primary physiological function of prolactin is The stimulation of lactation. Prolactin induces the synthesis of α-lactalbumin and casein, and activates the Synthesis of Phospholipids and TAGs.

Prolactin influences growth processes to a markedly lesser extent than growth hormone does.

In males, prolactin enhances the sensitivity of Leydig cells to luteinizing hormone, thereby maintaining the requisite level of testosterone synthesis; in the kidneys, prolactin decreases water excretion and affects the reabsorption of Na⁺ and K⁺ ions; prolactin also enhances both humoral and cellular Immunity.

The synthesis and secretion of prolactin are stimulated by thyroliberin, serotonin, oxytocin, and acetylcholine, whereas dopamine exerts an inhibitory effect.

Like the majority of hormones, prolactin is secreted into the bloodstream episodically at intervals of 30–90 min. Peak secretion occurs 6–8 hours after the onset of Sleep. The plasma concentration of prolactin is 8–10 ng/mL in women and 5–8 ng/mL in men. The half-life ($T_{1/2}$) of prolactin is 15–20 min.

The placenta produces a hormone (placental lactogen) that is homologous in Amino Acid Composition to growth hormone and prolactin. All three hormones share common antigenic determinants and exhibit growth-promoting and lactogenic activities. It is hypothesized that the genes encoding these hormones originated from the duplication of a single ancestral gene.

2. Thyrotropin, Luteinizing Hormone, and Follicle-Stimulating Hormone

Thyrotropin, LH, and FSH are glycoproteins. Thyrotropin (TSH), with a molecular mass of approximately 30 kDa, is synthesized in thyrotrophic cells of the anterior pituitary gland.

Thyrotropin secretion is stimulated by thyroliberin, whereas elevated levels of THYROID HORMONES exert the primary inhibitory effect. The peak of TSH secretion occurs during the hours immediately preceding sleep, followed by a decline throughout the night.

The principal biological function of thyrotropin is the stimulation of iodothyronine synthesis and secretion ($T_3$ and $T_4$) in The Thyroid Gland. Signal transduction of thyrotropin into thyroid cells occurs via plasma Membrane receptors and the activation of adenylate cyclase.

The thyrotropin receptor consists of two domains, one of which is a glycoprotein, while the second is a ganglioside (a glycolipid containing sialic acid). The binding of thyrotropin to both receptor domains is required for the manifestation of its biological effect.

Thyrotropin exerts two types of effects on the thyroid gland. Some appear rapidly (within a few minutes) and involve the stimulation of all stages of iodothyronine synthesis and secretion (see subsection III, B below). The manifestation of others requires several days; these include the stimulation of protein, phospholipid, and nucleic acid synthesis, as well as an increase in the size and number of thyroid cells.

Certain class G immunoglobulins interact with thyrotropin receptors, mimicking the effects of the hormone. Such immunoglobulins are found in the majority of patients with hyperthyroidism (see subsection III, B below). In addition to stimulating Antibodies, antibodies that cause the destruction of thyroid cells are also detected. The production of antibodies that mimic the effects of thyrotropin is a frequent cause of thyroid dysfunction.

The group of glycoprotein hormones also includes the pituitary gonadotropic hormones LH and FSH, as well as human chorionic gonadotropin (hCG) (Figs. 11-14).

Fig. 11-14. Structure of anterior pituitary hormones and human chorionic gonadotropin. TSH, FSH, LH, and hCG are glycoproteins consisting of 2 subunits; the α-subunits of all 4 hormones are identical; the β-subunits differ in Primary Structure, the composition of oligosaccharide fragments, and glycosylation sites, and they determine biological activity; both α- and β-subunits contain oligosaccharide fragments.

3. Group of hormones derived from pro-opiomelanocortin

Pro-opiomelanocortin (POMC), with a molecular mass of 28.5 kDa, is synthesized in the anterior and intermediate lobes of the pituitary gland and in certain other tissues (such as the intestine and placenta). The polypeptide chain of POMC consists of 265 amino acid residues (Fig. 11-15).

Fig. 11-15. Peptide hormones derived from POMC. A — POMC consists of 265 amino acid residues (aa), including an N-terminal signal peptide of 26 Amino acids; B — after Cleavage of the signal peptide, the polypeptide chain is cleaved into 2 fragments: ACTH (39 aa) and β-lipotropin (42–134 aa); C, D, E — further proteolysis yields α- and β-MSH and endorphins. Lipotropin- and corticotropin-related intermediate lobe peptide (CLIP).

Following the cleavage of the signal peptide, partial proteolysis of the remaining polypeptide chain occurs, yielding ACTH and α-lipotropin (β-LPH). In different cells, selective proteolysis produces a varying set of peptides: α- and β-melanocyte-stimulating hormones (α- and β-MSH) and endorphins. β-MSH and corticotropin-like intermediate lobe peptide are practically not produced in humans, as the intermediate lobe is underdeveloped in adults. β-lipotropin, γ-lipotropin, and β-endorphin have been found in the human pituitary gland. The functions of all POMC degradation products are not yet fully understood.

Corticotropin (ACTH) is a peptide hormone consisting of 39 amino acid residues; it is synthesized in the cells of the anterior pituitary gland under the influence of corticotropin-releasing hormone.

Corticotropin is secreted in a pulsatile manner. The secretion rate is 5–25 µg/day. During stress (trauma, Burns, surgery, chemical intoxication, Hemorrhage, pain, psychological trauma), the concentration of ACTH in the blood increases manifold. In healthy individuals, the lowest blood level of ACTH is observed at the end of the day and immediately before sleep, while the highest occurs between 6:00 and 8:00 AM upon waking. T_1/2 in the blood is 15–25 min.

The MECHANISM OF ACTION of ACTH involves interaction with plasma membrane receptors on cells, activation of adenylate cyclase, and phosphorylation of proteins involved in corticosteroid synthesis (see subsection III, D below). These effects are enhanced in the presence of Ca²⁺ ions. In adrenal cortex cells, ACTH stimulates the Hydrolysis of Cholesterol esters, increases the uptake of LDL-bound cholesterol into cells, stimulates The conversion of cholesterol to pregnenolone, and induces the synthesis of mitochondrial and microsomal enzymes involved in corticosteroid synthesis. The stages of corticosteroid synthesis are discussed in more detail in subsection III, D.

4. Hormones of the posterior pituitary gland

The posterior pituitary gland, or neurohypophysis, secretes two active hormones: vasopressin (also known as antidiuretic hormone, or ADH) and oxytocin. Oxytocin and vasopressin are nonapeptides with a similar primary structure (Fig. 11-16).

Fig. 11-16. Structure of Vasopressin and Oxytocin. Each nonapeptide contains cysteine residues at positions 1 and 6 linked by disulfide bonds. In most animals and humans, position 8 of vasopressin contains arginine instead of Lysine, which is why it is designated as arginine vasopressin.

Both hormones are synthesized in the hypothalamus within neurons of various hypothalamic nuclei as prohormones. Through post-translational modification, these prohormones yield the hormone and the transport peptide neurophysin (oxytocin + neurophysin I and vasopressin + neurophysin II). During transport to the posterior pituitary cells, the hormones remain non-covalently bound to their transport peptides. In the blood, the hormones are not bound to neurophysin. The T_1/2 is 2–4 min.

The main BIOLOGICAL EFFECTS OF vasopressin are mediated through interaction with two types of receptors. V₁ receptors are located on vascular smooth muscle cells in a complex with phospholipase C. The result of signal transduction in these cells is vasoconstriction. V₂ receptors are located on renal tubule cells. The interaction of vasopressin with V₂ receptors activates the adenylate cyclase system, increasing the intracellular concentrations of

cAMP and the activity of protein kinase A. This activation results in the phosphorylation of proteins that stimulate the expression of genes encoding proteins responsible for forming water channels, which ensure water reabsorption (see subsection VI, A below).

Oxytocin stimulates the contraction of the smooth muscle of the uterus and also plays a vital role in stimulating lactation. It causes the contraction of myoepithelial cells in the Mammary Glands, resulting in the ejection of milk from the alveolar ducts toward the nipple.

The act of suckling at the mother's breast stimulates prolactin secretion, ensuring milk production and release.

C. Disorders of the hypothalamic-pituitary system

Disorders of the hypothalamic-pituitary system are characterized by diverse clinical manifestations.

Hypofunction may result from a reduction or complete suppression of trophic hormone production (panhypopituitarism) or a partial deficiency involving impaired synthesis and secretion of one or more hormones. A deficit in pituitary trophic hormones leads to a sharp decline in the function of peripheral endocrine glands.

Impaired gonadotropic function of the pituitary gland leads to ovarian insufficiency, Amenorrhea, uterine atrophy, and mammary gland atrophy. Due to decreased corticotropin production, chronic adrenocortical insufficiency develops.

Growth hormone deficiency is particularly dangerous in children. Several types of impaired normal growth capacity resulting from absolute or relative GH deficiency are known.

Pituitary dwarfism (from the Greek nanos – dwarf). The cause of impaired growth and physical development is a deficiency of growth hormone. Most forms of pituitary dwarfism develop due to growth hormone Gene Mutations. In most patients with pituitary dwarfism, growth impairment is combined with other endocrine disorders. In some cases, growth hormone hyposecretion may result from autoimmune damage to pituitary somatotropic cells, traumatic brain injury, or radiation.

Laron dwarfism occurs due to a defect in hepatocyte growth hormone receptors and reduced synthesis of IGF-1 and IGF-2. In this condition, blood GH levels are elevated.

African pygmy dwarfism is the result of impaired post-receptor transmission of the GH hormonal signal. In this form of dwarfism, plasma growth hormone levels are normal, while IGF-1 levels are significantly reduced.

Growth hormone hyperfunction usually results from The formation of a hormone-producing tumor of pituitary somatotropic cells, which leads to increased growth activity. If growth hormone hypersecretion occurs in children and adolescents in whom Ossification of the epiphyseal cartilages is incomplete while growth of the long bones continues, gigantism develops (from the Greek gigantos – giant). In gigantism, the enlargement of bones, soft tissues, and organs oc-

curs relatively proportionally. Growth hormone hypersecretion in adults leads to acromegaly (from the Greek akros – extreme, megas – large), in which body growth is accelerated not in length, but in width, accompanied by disproportionate enlargement of facial features, hands, feet, the Skull, and internal organs.

In many (about 40%) patients with acromegaly, a mutation is found in the $\alpha$-subunit of the G-protein in the plasma membrane of somatotropic cells, As a result of which the $\alpha$-subunit loses its GTPase activity. Consequently, prolonged activation of adenylate cyclase, excessive cAMP production, and excessive secretion of growth hormone develop.

G. Thyroid hormones

The thyroid gland synthesizes hormones that are iodinated tyrosine derivatives. They are collectively called iodothyronines. These include 3,5,3'-triiodothyronine (triiodothyronine, T₃) and 3,5,3',5'-tetraiodothyronine (T₄), or thyroxine (Fig. 11-17).

Fig. 11-17. Structure of thyroid hormones.

Iodothyronines are involved in the regulation of numerous metabolic processes, development, cellular differentiation, and the Introduction/30.html">Regulation of Gene Expression.

Diseases resulting from disorders in the synthesis, secretion, and functions of iodothyronines are among the most common endocrine disorders.

1. Biosynthesis of iodothyronines

Iodothyronines are synthesized as part of the thyroglobulin (Tg) protein (Fig. 11-18) within follicles, which represent the morphological and functional unit of the thyroid gland.

Thyroglobulin is a glycoprotein with a molecular weight of 660 kD containing 115 tyrosine residues. CARBOHYDRATES account for 8–10% of thyroglobulin mass. The iodide content in the body ranges from 0.2 to 1%.

Thyroglobulin is synthesized on the Ribosomes of the rough ER as prethyroglobulin, then transferred to the cisternae of the ER, where secondary and tertiary structures are formed, including glycosylation processes. From the ER cisternae, thyroglobulin enters the Golgi apparatus, is incorporated into secretory granules, and is secreted into the extracellular colloid, where Iodination of tyrosine residues and the formation of iodothyronines take place.

Thyroglobulin iodination and iodothyronine formation are carried out in several stages (Fig. 11-18).

Fig. 11-18. Scheme of iodothyronine synthesis. Thyroglobulin is synthesized on ribosomes, then enters the Golgi apparatus, and subsequently the extracellular colloid, where it is stored and where tyrosine residues are iodinated. The formation of iodothyronines occurs in several stages: transport of iodine into thyroid cells; oxidation of iodine; iodination of tyrosine residues; formation of iodothyronines; transport of iodothyronines into the blood. ER — Endoplasmic reticulum; DIT — diiodotyrosine; Tg — thyroglobulin; T₃ — triiodothyronine, T₄ — thyroxine.

Transport of iodine into thyroid cells. Iodine in the form of organic and Inorganic Compounds enters the gastrointestinal tract with food and drinking water. The daily iodine requirement is 150–200 mcg. Of this amount, 25–30% of iodides are captured by the thyroid gland. Iodide transport into thyroid cells is an energy-dependent process and occurs via a specialized transport protein against an electrochemical gradient (the normal ratio of intracellular I^- concentration in the gland to serum I^- concentration is 25:1). The operation of this iodide-transporting protein is coupled with Na⁺, K⁺-ATPase.

Oxidation of iodine. The oxidation of I^- to I⁺ occurs with the participation of heme-containing thyroperoxidase and H₂O₂ as an oxidizing agent.

Tyrosine iodination. Oxidized iodine interacts with tyrosine residues within the thyroglobulin molecule. This reaction is also catalyzed by thyroperoxidase.

Formation of iodothyronines. Under the action of thyroperoxidase, oxidized iodine reacts with tyrosine residues to form monoiodotyrosines (MIT) and diiodotyrosines (DIT). Two DIT molecules condense to form the iodothyronine T₄, while MIT and DIT condense to form the iodothyronine T₃. Iodothyroglobulin is transported from the colloid into the follicular cell via endocytosis and is hydrolyzed by lysosomal enzymes, releasing T₃ and T₄. Under normal conditions, the thyroid gland secretes 80–100 mcg of T₄ and 5 mcg of T₃ per day. An additional 22–25 mcg of T₃ is produced as a result of T₄ deiodination in peripheral tissues at the 5'-carbon atom.

Transport and Metabolism of iodothyronines. From half to two-thirds of T₃ and T₄ reside outside the thyroid gland within the body. The majority of these hormones circulate in the blood in a protein-bound form, complexed with thyroxine-binding globulin (TBG) and thyroxine-binding prealbumin (TBPA). TBG serves as the primary transport protein for iodothyronines and also acts as their storage depot. It exhibits a higher affinity for T₃ and T₄ and under normal conditions binds almost the entirety of these hormones. Only 0.03% of T₄ and 0.3% of T₃ circulate in the free form.

The half-life (T_1/2) of T₄ in plasma is 4–5 times longer than that of T₃. For T₄, this period is approximately 7 days, whereas for T₃ it is 1–1.5 days. The biological activity of iodothyronines is determined by their unbound fraction. T₃ is the principal biologically active form of iodothyronines; its affinity for target cell receptors is 10 times greater than that of T₄. In peripheral tissues, deiodination of a portion of T₄ at the fifth carbon atom yields the so-called "reverse" form of T₃, which is almost completely devoid of biological activity.

Alternative pathways of iodothyronine metabolism include complete deiodination, deamination, or decarboxylation. Iodinated catabolites of iodothyronines are conjugated in the liver with glucuronic or sulfuric acid (see Section 12), secreted into the bile, reabsorbed in the intestine, deiodinated in the kidneys, and excreted in the urine.

2. Regulation of Iodothyronine Synthesis and Secretion

The rate of iodothyronine synthesis and secretion is regulated by the hypothalamic-pituitary system via a feedback mechanism (Fig. 11-19).

Fig. 11-19. Regulation of iodothyronine synthesis and secretion. 1 — thyrotropin-releasing hormone stimulates TSH release; 2 — TSH stimulates the synthesis and secretion of iodothyronines; 3, 4 — iodothyronines inhibit the synthesis and secretion of TSH and thyrotropin-releasing hormone.

A decrease in blood iodothyronine concentrations serves as the stimulus for increased secretion of thyrotropin-releasing hormone and thyrotropin.

3. Mechanism of Action and Biological Functions of Iodothyronines

Target cells for iodothyronines possess two types of receptors for these hormones. The primary effects of iodothyronines result from their interaction with high-Specificity receptors that, complexed with the hormones, reside permanently in The Nucleus and interact with specific DNA sequences, thereby participating in the regulation of Gene Expression.

Other receptors are located in the plasma membrane of cells, though these are distinct proteins from those in the nucleus. They exhibit a lower affinity for iodothyronines and presumably serve to bind the hormones, keeping them in the immediate vicinity of the cell.

At physiological concentrations, iodothyronines act to accelerate protein synthesis, stimulate growth processes, and promote cellular differentiation. In this regard, iodothyronines act synergistically with growth hormone. Furthermore, T₃ accelerates the transcription of the growth hormone gene. In animals with a T₃ deficiency, pituitary cells lose their ability to synthesize growth hormone.

Very high concentrations of T₃ inhibit PROTEIN SYNTHESIS AND stimulate catabolic processes, as indicated by a negative nitrogen balance.

The metabolic effects of iodothyronines are primarily related to Energy Metabolism, manifested as an increase in cellular oxygen consumption. This effect occurs in all organs except the brain, the reticuloendothelial system, and the gonads.

In various cells, T₃ stimulates Na⁺, K⁺-ATPase activity, which consumes a significant portion of the energy utilized by the cell.

In the liver, iodothyronines accelerate Glycolysis, cholesterol synthesis, and bile acid synthesis. In The Liver and adipose tissue, T₃ increases cellular sensitivity to adrenaline and indirectly stimulates lipolysis in adipose tissue and Glycogen mobilization in the liver. At physiological concentrations, T₃ enhances glucose uptake in muscles, stimulates protein synthesis and muscle mass growth, and increases the sensitivity of muscle cells to adrenaline.

Iodothyronines also participate in the adaptive response to cold exposure by increasing heat production, enhancing the sensitivity of the sympathetic nervous system to noradrenaline, and stimulating noradrenaline secretion (see Section 6).

4. Thyroid Disorders

Thyroid hormones are essential for normal Human Development.

Congenital hypothyroidism leads to The Development of cretinism, which manifests as multiple congenital anomalies and severe, irreversible intellectual disability.

Hypothyroidism develops as a result of iodothyronine deficiency. Typically, hypothyroidism is associated with impaired thyroid function, but it can also arise from pituitary and hypothalamic disorders.

The most severe forms of hypothyroidism, accompanied by mucinous edema of the Skin and subcutaneous tissue, are termed "Myxedema" (from Greek *myxa* — mucus, *oedema* — Swelling). This swelling is caused by the excessive accumulation of glycosaminoglycans and water. Glucuronic acid and, to a lesser extent, chondroitin sulfate accumulate in the subcutaneous tissue. An excess of glycosaminoglycans alters the colloidal STRUCTURE OF THE Extracellular matrix, increases its hydrophilicity, and binds sodium ions, leading to water retention.

Characteristic clinical manifestations include bradycardia, lethargy, drowsiness, cold intolerance, and dry skin. These symptoms develop as a result of a decreased basal metabolic rate, reduced rates of glycolysis, glycogen and fat mobilization, and muscular glucose consumption, alongside diminished muscle mass and lowered heat production. When hypothyroidism occurs in older children, growth retardation is observed without intellectual disability.

Currently, chronic autoimmune thyroiditis, which impairs iodothyronine synthesis, is a frequent cause of hypothyroidism in adults (Hashimoto's thyroiditis).

Hypothyroidism can also result from insufficient dietary iodine intake, known as endemic goiter. Endemic goiter (nontoxic goiter) is common among populations living in regions where the iodine content in water and soil is deficient. If iodine intake drops (below 100 µg/day), iodothyronine production decreases, leading to elevated TSH secretion (due to the attenuation of the negative feedback effect of iodothyronines on the pituitary). This hormonal response triggers a compensatory enlargement of the thyroid gland (hyperplasia), though iodothyronine production remains unrestored.

Hyperthyroidism occurs as a result of increased production of iodothyronines. DIFFUSE TOXIC GOITER (Basedow's disease, Graves' disease) is the most common thyroid disorder. This condition is characterized by enlargement of the thyroid gland (goiter), a 2- to 5-fold increase in the concentration of iodothyronines, and the development of thyrotoxicosis.

Characteristic signs of thyrotoxicosis include an elevated basal metabolic rate, tachycardia, muscle weakness, weight loss (despite an increased appetite), excessive sweating, elevated body Temperature, tremor, and exophthalmos (protruding eyes). These symptoms reflect the simultaneous stimulation by iodothyronines of both anabolic (tissue growth and differentiation) and catabolic (carbohydrate, lipid, and Protein Catabolism) processes. Catabolic processes predominate, as evidenced by a negative nitrogen balance.

Hyperthyroidism can be triggered by various factors: tumor development, thyroiditis, excessive intake of iodine and iodine-containing drugs, and autoimmune reactions.

Graves' disease develops due to the production of antibodies against thyroid Antigens. One of these, an immunoglobulin (IgG), mimics the action of thyrotropin by binding to thyrotropin receptors on the thyroid cell membrane. This leads to diffuse enlargement of the thyroid gland and excessive, uncontrolled production of T₃ and T₄, since IgG synthesis is not regulated by negative feedback. TSH levels in this condition are decreased due to the suppression of pituitary function by high concentrations of iodothyronines.

D. Hormones of the Adrenal Cortex (Corticosteroids)

The adrenal cortex synthesizes more than 40 different Steroids that vary in structure and biological activity. Biologically active corticosteroids are grouped into 3 main classes based on their predominant physiological effects.

Glucocorticoids, C₂₁-steroids, play a crucial role in the adaptation to stress. They exert diverse effects, the most important of which is the stimulation of gluconeogenesis (see Section 7). The primary human glucocorticoid is cortisol.

Mineralocorticoids, C₂₁-steroids, are essential for maintaining Na⁺ and K⁺ Homeostasis. The most active hormone in this class is aldosterone (see Subsection VI below).

Androgens — C₁₉-steroids. The adrenal cortex produces androgen precursors, the most active of which is dehydroepiandrosterone (DHEA), along with a weaker one, androstenedione. Testosterone, the most potent adrenal androgen, is synthesized in the adrenal glands in small amounts. These steroids are converted into more potent androgens outside the adrenals. Testosterone can be converted in trace amounts into estradiol within the adrenal glands. However, under normal conditions, the adrenal production of these hormones does not play a significant physiological role.

1. Biosynthesis and Metabolism of Corticosteroids

Cholesterol serves as the common precursor for corticosteroids (Fig. 11-20).

Fig. 11-20. Structure and Main stages of corticosteroid synthesis. 1 — conversion of cholesterol to pregnenolone (side-chain cleavage hydroxylase); 2 — formation of progesterone (3-β-hydroxysteroid dehydrogenase); 3, 4, 5 — cortisol synthesis reactions (3 — 17-hydroxylase, 4 — 21-hydroxylase, 5 — 11-hydroxylase); 6, 7, 8 — aldosterone synthesis pathway (6 — 21-hydroxylase, 7 — 11-hydroxylase, 8 — 18-hydroxylase, 18-hydroxydehydrogenase); 9, 10, 11 — testosterone synthesis pathway (9 — 17-hydroxylase, 10 — 17,20-lyase, 11 — dehydrogenase).

In the Mitochondria, cholesterol is converted into pregnenolone with the participation of a hydroxylase belonging to the cytochrome P₄₅₀ family. The side-chain cleavage cytochrome P₄₅₀ is localized in The inner mitochondrial membrane. The cleavage of the cholesterol side chain involves two hydroxylation reactions: one at the C₂₂ atom and the other at C₂₀. Subsequent cleavage of the six-carbon fragment yields the C₂₁-steroid pregnenolone. Further transformation of pregnenolone occurs under the action of various hydroxylases utilizing molecular oxygen and NADPH, as well as dehydrogenases, isomerases, and lyases. These enzymes have distinct intra- and intercellular localizations. The adrenal cortex comprises 3 distinct cell types forming 3 layers, or zones: the zona glomerulosa, zona fasciculata, and zona reticularis. The final steroid product depends on the specific enzymatic Complement of the cell and The sequence of hydroxylation reactions. For instance, the enzymes required for aldosterone synthesis are present exclusively in the cells of the zona glomerulosa, whereas the enzymes for glucocorticoid and androgen synthesis are localized in the zona fasciculata and zona reticularis.

Pathway of cortisol biosynthesis. Cortisol is synthesized from cholesterol, which is mainly supplied by the blood as LDL or synthesized de novo within the cells from acetyl-CoA. A significant amount of cholesterol esters is stored in the cell cytosol within lipid droplets. ACTH stimulates a specific esterase, and free cholesterol is subsequently transported into the mitochondria (Fig. 11-21).

Fig. 11-21. Intracellular Localization of cortisol synthesis. 1 — adenylate cyclase complex; 2 — cholesterol esterase; 3 — protein kinase A; 4 — cholesterol desmolase cleaves the cholesterol side chain. Ch — cholesterol; CE — cholesterol esters.

The synthesis of cortisol begins with the conversion of pregnenolone to progesterone. This reaction takes place in the cytosol of cells in the zona fasciculata of the adrenal cortex, where pregnenolone is transported from the mitochondria. The reaction is catalyzed by 3-β-hydroxysteroid dehydrogenase.

In The endoplasmic reticulum (ER) membranes, 17-α-hydroxylase mediates the hydroxylation of progesterone at the C₁₇ position to form 17-hydroxyprogesterone. The same enzyme catalyzes the conversion of pregnenolone to 17-hydroxypregnenolone, from which a two-carbon side chain can subsequently be cleaved by 17,20-lyase to yield the C₁₉-steroid dehydroepiandrosterone. 17-Hydroxyprogesterone serves as the precursor for cortisol, whereas dehydroepiandrosterone acts as the precursor for androgens. Next, 17-OH-progesterone is hydroxylated by 21-hydroxylase (P_450-C21), localized in the ER membrane, and converted into 11-deoxycortisol. This intermediate is then transported to the inner mitochondrial membrane, where it undergoes hydroxylation by cytochrome P_450-c11 to form cortisol.

The rate of cortisol synthesis and secretion is stimulated in response to stress, trauma, infection, and decreased blood glucose levels. An elevated cortisol concentration suppresses the synthesis of corticotropin-releasing hormone (CRH) and ACTH via a negative feedback mechanism.

Synthesis of mineralocorticoids in the cells of the zona glomerulosa of the adrenal cortex likewise begins with the conversion of cholesterol to pregnenolone and subsequently to progesterone. Progesterone is first hydroxylated at the C₂₁ position to yield 11-deoxycorticosterone. The next hydroxylation occurs at the C₁₁ position, resulting in the formation of corticosterone, which exhibits weak glucocorticoid and mineralocorticoid activity.

The cells of the zona glomerulosa lack 17-α-hydroxylase but contain mitochondrial 18-hydroxylase, which hydroxylates corticosterone. This is followed by dehydrogenation to form an aldehyde group at the C₁₈ position.

The primary stimulus for aldosterone synthesis is angiotensin II (see Subsection V below).

Transport of corticosteroids. In blood plasma, cortisol is bound to the α-globulin transcortin (corticosteroid-binding globulin), with a small fraction remaining in the free state. Transcortin synthesis occurs in the liver and is stimulated by estrogens.

The half-life (T_1/2) of cortisol is 1.5 — 2 hours. Unbound, or free, cortisol accounts for about 8% of the total hormone in plasma and represents the biologically active fraction.

Aldosterone does not have a specific transport protein, but forms weak bonds with albumin.

Catabolism of Adrenocortical Hormones occurs primarily in the liver. Hydroxylation, oxidation, and reduction Reactions of the hormones take place here. The catabolites of corticosteroids (except for corticosterone and aldosterone) are excreted in the urine as 17-ketosteroids, which are formed by the cleavage of the side chain. These metabolites are excreted predominantly as conjugates with glucuronic and sulfuric acids. 17-Hydroxy- and 17-ketosteroids are also formed during the catabolism of Sex Hormones that contain hydroxyl or keto groups at C₁₇. In men, 2/3 of ketosteroids are derived from corticosteroids and 1/3 from testosterone (totaling 12–17 mg/day). In women, 17-ketosteroids are formed mainly from corticosteroids (7–12 mg/day). The determination of urinary 17-ketosteroids allows for the assessment of both The amount of glucocorticoids secreted by the adrenal cortex and overall adrenal function.

2. Biological functions of corticosteroids encompass a wide range of effects on metabolic processes and are discussed in detail in the relevant sections.

A crucial factor in The Mechanism of action of corticosteroids is their interaction with specific receptors located in the cell cytosol or nucleus. The regulation of intracellular processes by corticosteroid hormones manifests as changes in

the amounts of proteins—typically key metabolic enzymes—via the regulation of gene transcription in target cells.

The Effect of glucocorticoids on Intermediary Metabolism is associated with their ability to exert coordinated actions on various tissues and diverse processes, both anabolic and catabolic.

Cortisol stimulates glucose production in the liver by enhancing gluconeogenesis while simultaneously increasing the release rate of amino acids, which serve as gluconeogenic substrates from peripheral tissues. In the liver, cortisol induces the synthesis of Amino Acid Catabolism enzymes (Alanine aminotransferase, Tryptophan pyrrolase, and tyrosine aminotransferase) as well as the key gluconeogenic enzyme phosphoenolpyruvate carboxykinase. Additionally, cortisol stimulates hepatic glycogen synthesis and inhibits glucose utilization by peripheral tissues. This effect of cortisol is primarily evident during fasting and insulin deficiency (see subsection V below). In healthy individuals, these effects of cortisol are counterbalanced by insulin.

Excessive amounts of cortisol stimulate lipolysis in the extremities and lipogenesis in other PARTS OF THE body (face and torso). Furthermore, glucocorticoids potentiate the lipolytic action of catecholamines and growth hormone.

The influence of glucocorticoids on protein and NUCLEIC ACID METABOLISM is twofold: in the liver, cortisol predominantly exerts an anabolic effect (stimulating the synthesis of proteins and Nucleic Acids). In muscle, lymphoid and adipose tissue, skin, and bones, cortisol inhibits the synthesis of proteins, RNA, and DNA, while stimulating the degradation of RNA and proteins.

At high concentrations, glucocorticoids suppress immune responses by inducing lymphocyte apoptosis and the involution of lymphoid tissue; they inhibit inflammatory responses by decreasing the number of circulating leukocytes and inducing the synthesis of lipocortins, which inhibit phospholipase A₂, thereby reducing the synthesis of inflammatory mediators such as Prostaglandins and Leukotrienes (see Section 8).

High concentrations of glucocorticoids inhibit fibroblast growth and division, as well as the synthesis of Collagen and Fibronectin (see Section 15). Glucocorticoid hypersecretion is typically characterized by skin thinning, impaired wound healing, muscle weakness, and muscle atrophy.

Glucocorticoids participate in the physiological response to stress associated with trauma, infection, or surgery. Catecholamines play the primary role in this response, but in many cases, the action of glucocorticoids is required for their maximal activity.

Mineralocorticoids stimulate Na⁺ reabsorption in the distal convoluted tubules and collecting ducts of the kidneys. In addition, they promote The excretion of K⁺ and NH₄⁺ in the kidneys and other Epithelial Tissues, such as Sweat Glands, the intestinal mucosa, and Salivary Glands. In The Human Body, aldosterone is the most potent mineralocorticoid.

The mechanism of action and biological effects of aldosterone are discussed in detail in subsection VI of this section.

3. Metabolic alterations in hypo- and Hyperfunction of the adrenal cortex

Adrenocortical disorders can manifest with symptoms of either hormone hypoproduction or hyperproduction.

Most clinical manifestations of adrenal insufficiency are caused by a deficiency of glucocorticoids and mineralocorticoids.

Acute adrenal crisis is a major life-threatening condition as it is accompanied by the decompensation of all Types of Metabolism and adaptive processes. It manifests as vascular collapse, severe adynamia, and loss of consciousness. This condition arises from electrolyte disturbances that lead to the renal loss of Na⁺ and Cl^- ions, dehydration due to extracellular fluid loss, and elevated K⁺ levels in blood serum, intercellular fluid, and cells, which can impair myocardial contractility. Alterations in carbohydrate metabolism present as decreased blood sugar levels and depleted glycogen reserves in the liver and skeletal muscles.

Acute adrenocortical insufficiency may result from the decompensation of chronic diseases and can also develop in patients undergoing long-term glucocorticoid therapy for non-endocrine conditions, such as infectious-allergic diseases.

Prolonged glucocorticoid administration suppresses the function of the hypothalamic-pituitary-adrenal axis, leading to the atrophy of adrenocortical cells. Abrupt discontinuation of hormonal medications can trigger acute adrenal insufficiency (the so-called withdrawal syndrome).

Primary adrenal insufficiency (Addison's disease) develops as a result of destruction of the adrenal cortex by tuberculosis or autoimmune processes. The MAIN CLINICAL MANIFESTATIONS include weight loss, generalized weakness, anorexia, nausea, vomiting, hypotension, and the hyperpigmentation of the skin characteristic of primary adrenal insufficiency ("bronze disease"). The cause of hyperpigmentation is increased production of POMC, the precursor to ACTH and melanocyte-stimulating hormone.

Secondary adrenal insufficiency can develop due to ACTH deficiency, which in turn may result from a pituitary tumor or infection. Unlike Addison's disease, secondary adrenal insufficiency is not accompanied by hyperpigmentation.

In congenital adrenal hyperplasia, cortisol synthesis is impaired. In 95% of cases, this pathology is caused by a 21-hydroxylase deficiency (less commonly, 11-hydroxylase deficiency). Reduced cortisol production is accompanied by increased ACTH secretion and the accumulation of intermediate products of corticosteroid synthesis, particularly androgen precursors.

Excess androgens lead to accelerated somatic growth, precocious Puberty in boys, and the development of male secondary sex characteristics in girls (adrenogenital syndrome).

In partial 21-hydroxylase deficiency, women may experience menstrual irregularities.

Overproduction of glucocorticoids (hypercorticism) can result from elevated ACTH levels due to pituitary tumors (Cushing's Disease) and tumors of other cells (Bronchi, Thymus, pancreas) that secrete corticotropin-like substances, or from excessive cortisol synthesis caused by hormonally active tumors of the adrenal cortex (Cushing's syndrome).

Hypercorticism is characterized by hyperglycemia and decreased glucose tolerance caused by the stimulation of gluconeogenesis ("steroid diabetes"), increased protein catabolism, muscle wasting, skin thinning, Osteoporosis, and the involution of lymphoid tissue. A distinctive redistribution of body fat ("moon facies", protruding abdomen) is also typical. Hypernatremia, Hypertension, and hypokalemia are caused by the mild mineralocorticoid activity of cortisol, which manifests when it is present in excess.

To identify the primary cause of hypercorticism, in addition to measuring plasma ACTH concentration, high-dose tests using the synthetic glucocorticoid dexamethasone (a structural analogue of cortisol) are employed. Dexamethasone suppresses ACTH secretion via a negative feedback mechanism.

Cushing's disease is characterized by a decrease in cortisol concentration of more than 50% following dexamethasone administration. A lack of response to dexamethasone may indicate the presence of an adrenal tumor or extra-pituitary ACTH secretion.

E. Hormones of The adrenal medulla

Like the posterior pituitary, the adrenal medulla is derived from neural tissue. It can be viewed as an extension of the sympathetic nervous system, since preganglionic fibers of the splanchnic nerve terminate on the chromaffin cells of the adrenal medulla.

These cells got their name because they contain granules that stain red with potassium dichromate. Such cells are also found in The Heart, liver, kidneys, gonads, postganglionic neurons of the sympathetic nervous system, and the central nervous system.

Upon stimulation of the preganglionic neuron, chromaffin cells produce catecholamines—dopamine, epinephrine, and norepinephrine.

In most animal species, chromaffin cells secrete primarily epinephrine (~ 80%) and, to a lesser extent, norepinephrine.

In terms of chemical structure, catecholamines are 3,4-dihydroxy derivatives of phenylethylamine. Tyrosine serves as the direct precursor to these hormones (see Section 9).

1. Synthesis and Secretion of Catecholamines

The synthesis of catecholamines occurs in the Cytoplasm and granules of adrenal medullary cells (Fig. 11-22). The storage of catecholamines also takes place within the granules.

Catecholamines enter the granules via ATP-dependent transport and are stored within them in a complex with ATP at a ratio of 4:1 (hormone-ATP). Different granules contain different catecholamines: some contain only epinephrine, others norepinephrine, and still others both hormones.

Fig. 11-22. Synthesis and secretion of catecholamines. The Biosynthesis of Catecholamines occurs in the cytoplasm and granules of adrenal medullary cells. Some granules contain epinephrine, others norepinephrine, and some both hormones. Upon stimulation, the Contents of the granules are released into the extracellular fluid. E — epinephrine; NE — norepinephrine.

Hormone secretion from the granules occurs via exocytosis. Catecholamines and ATP are released from the granules in the same ratio in which they are stored. Unlike sympathetic nerves, cells of the adrenal medulla lack a reuptake mechanism for the released catecholamines.

In blood plasma, catecholamines form a loose complex with albumin. Epinephrine is transported primarily to the liver and skeletal muscles. Norepinephrine is produced mainly in organs innervated by sympathetic nerves (80% of the total amount). Only negligible amounts of norepinephrine reach peripheral tissues. T_1/2 of catecholamines is 10-30 s. The bulk of catecholamines is rapidly metabolized in various tissues by specific enzymes (see Section 9). Only a small fraction of epinephrine (~ 5%) is excreted in the urine.

2. Mechanism of Action and Biological Functions of Catecholamines

Catecholamines act on target cells via receptors localized in the plasma membrane. There are two main classes of such receptors: α-adrenergic and β-adrenergic. All catecholamine receptors are glycoproteins that are products of different genes, differ in their affinity for Agonists and Antagonists, and transmit signals into cells using different second messengers. This determines The Nature of their effect on target cell metabolism.

Epinephrine interacts with both α- and β-receptors; norepinephrine at physiological concentrations interacts primarily with α-receptors.

The interaction of the hormone with β-receptors activates adenylate cyclase, whereas binding to the α₂-receptor inhibits it. The interaction of the hormone with the α₁-receptor activates phospholipase C and stimulates the inositol phosphate signal transduction pathway (see Section 5).

The biological effects of epinephrine and norepinephrine affect virtually all body functions and are discussed in the relevant sections. What is common to all these effects is the stimulation of processes necessary for the body to cope with emergency situations.

3. Pathology of the Adrenal Medulla

The primary pathology of the adrenal medulla is pheochromocytoma, a tumor formed by chromaffin cells that produces catecholamines. Clinically, pheochromocytoma manifests as recurring episodes of headache, palpitations, sweating, and elevated blood pressure, accompanied by characteristic metabolic changes (see Sections 7, 8).

F. Hormones of the Pancreas and Gastrointestinal Tract

The pancreas performs two critical functions in the body: exocrine and endocrine. The exocrine function ensures the synthesis and secretion of enzymes and ions required for digestive processes. The endocrine function is carried out by the cells of the pancreatic islet apparatus, which secrete hormones involved in regulating many bodily processes.

Within the islet tissue of the pancreas (islets of Langerhans), four cell types are distinguished that secrete different hormones: A (or α) cells secrete glucagon, B (or β) cells secrete insulin, D (or δ) cells secrete somatostatin, and F cells secrete Pancreatic Polypeptide.

1. Insulin. Structure, Synthesis, and Secretion

Insulin is a polypeptide consisting of two polypeptide chains. Chain A contains 21 amino acid residues, and chain B contains 30 amino acid residues. Both chains are interconnected by two disulfide bridges (Fig. 11-23). Insulin can exist in several forms: monomer, dimer, and hexamer. The hexameric structure of insulin is stabilized by zinc ions, which bind to the His residues at position 10 of the B-chain in all 6 subunits.

Fig. 11-23. Structure of human insulin. A. Primary structure of insulin. B. Model of the Tertiary Structure of insulin (monomer): 1 — A-chain; 2 — B-chain; 3 — receptor-binding site.

The insulin molecule also contains an intramolecular disulfide bridge connecting the sixth and eleventh residues in the A-chain. The insulins of certain animals show significant primary structure similarity to human insulin.

Bovine insulin differs from human insulin by three amino acid residues, whereas porcine insulin differs by only a single amino acid, which is alanine instead of Threonine at the carboxy-terminal end of the B-chain.

In both chains, substitutions that do not affect the biological activity of the hormone occur at many positions. These substitutions are most frequently found at positions 8, 9, and 10 of the A-chain.

At the same time, substitutions are extremely rare at the positions of disulfide bonds, hydrophobic amino acid residues in the C-terminal regions of the B-chain, and the C- and N-terminal residues of the A-chain, indicating the crucial importance of these regions for insulin's biological activity. The Use of chemical modifications and Amino Acid Substitutions in these regions has helped establish the structure of insulin's active center, the formation of which involves the B-chain phenylalanine residues at positions 24 and 25, as well as the N- and C-terminal residues of the A-chain.

Biosynthesis of insulin involves the formation of two inactive precursors, preproinsulin and proinsulin, which are converted into the active hormone through sequential proteolysis. The biosynthesis of preproinsulin begins with the formation of a signal peptide on polyribosomes bound to the ER. The signal peptide penetrates the ER lumen and directs The entry of the growing polypeptide chain into the ER lumen. Upon completion of preproinsulin synthesis, the signal peptide, comprising 24 amino acid residues, is cleaved off (Fig. 11-24).

Fig. 11-24. Diagram of insulin biosynthesis in the β-cells of the islets of Langerhans. ER — endoplasmic reticulum. 1 — Formation of the signal peptide; 2 — synthesis of preproinsulin; 3 — cleavage of the signal peptide; 4 — transport of proinsulin to the Golgi apparatus; 5 — conversion of proinsulin to insulin and C-peptide and incorporation of insulin and C-peptide into secretory granules; 6 — secretion of insulin and C-peptide.

Proinsulin (86 amino acid residues) enters the Golgi apparatus, where it is cleaved at several sites by specific proteases to yield insulin (51 amino acid residues) and the C-peptide, which consists of 31 amino acid residues.

Insulin and the C-peptide are incorporated into secretory granules in equimolar amounts. Within the granules, insulin binds with zinc to form dimers and hexamers. Mature granules fuse with the plasma membrane, and insulin and the C-peptide are secreted into the extracellular fluid via exocytosis. Following secretion into the blood, insulin oligomers dissociate. The T1_/2 of insulin in blood plasma is 3–10 min, and that of the C-peptide is about 30 min.

The degradation of insulin is mediated by the enzyme insulinase, primarily in the liver and to a lesser extent in the kidneys.

Regulation of Insulin synthesis and secretion. Glucose is the primary regulator of insulin secretion, and β-cells are the most important glucose-sensing cells in the body. Glucose regulates the expression of the insulin gene as well as The genes of other proteins involved in major energy metabolism. The effect of glucose on the rate of gene expression can be direct, when glucose interacts directly with transcription factors, or secondary, via its influence on insulin and glucagon secretion. Upon glucose stimulation, insulin is rapidly released from secretory granules, a process accompanied by the transcriptional activation of insulin mRNA.

Insulin synthesis and secretion are not strictly coupled processes. Hormone synthesis is stimulated by glucose, whereas its secretion is a Ca²⁺-dependent process and decreases in the event of Ca²⁺ deficiency, even under conditions of high glucose concentrations that stimulate insulin synthesis.

Glucose uptake by β-cells occurs primarily with the participation of GLUT-1 and GLUT-2, and the intracellular glucose concentration rapidly equilibrates with the blood glucose concentration. In β-cells, glucose is converted to glucose-6-phosphate by glucokinase, which has a high Km, resulting in a phosphorylation rate that depends almost linearly on blood glucose concentration. The enzyme glucokinase is one of the most vital Components of the glucose-sensing apparatus of β-cells, which likely also includes, alongside glucose, intermediates of glucose metabolism, the citrate cycle, and possibly ATP. Mutations in glucokinase lead to the development of a specific form of Diabetes Mellitus.

Insulin secretion is influenced by other hormones. Epinephrine via α₂-receptors inhibits insulin secretion even against the Background of glucose stimulation, whereas β-adrenergic agonists stimulate it, likely as a result of elevated cAMP concentrations. This mechanism is thought to underlie the action of Gastrointestinal Hormones such as secretin, cholecystokinin, and gastric inhibitory polypeptide (GIP), which enhance insulin secretion. High concentrations of growth hormone, cortisol, and estrogens also stimulate insulin secretion.

2. Biological Functions of Insulin

Insulin is the primary anabolic hormone. It participates in the REGULATION OF METABOLISM, The transport of glucose, amino acids, and ions, and protein synthesis. Insulin also affects Replication and transcription processes, thereby participating in the regulation of Cell Differentiation, proliferation, and transformation. The Role of insulin in Metabolic Regulation is discussed in the relevant sections (see sections 7, 8, and 9). The effects of insulin on key metabolic enzymes are presented in Table 11-7.

Table 11-7. Effects of insulin on key metabolic enzymes

Glucose transport into cells occurs with the involvement of specialized carrier proteins (see section 7). The insulin-regulated transporter (GLUT-4) is found exclusively in muscle and adipose tissue (insulin-dependent tissues). In the absence of insulin, GLUT-4 resides in cytosolic vesicles. Upon insulin stimulation, these vesicles translocate to the plasma membrane; when the hormone concentration declines, the glucose transporters return to the cytosol, and glucose transport ceases.

In liver cells, insulin induces the synthesis of glucokinase. As a result of phosphorylation, the concentration of free glucose inside the cells is kept low, which facilitates its Transport from the blood along a concentration gradient.

Effect of insulin on glucose metabolism. Insulin stimulates glucose utilization in cells through various pathways. About 50% of glucose is used in glycolysis, 30–40% is converted into fats, and approximately 10% is stored as glycogen. The overall result of stimulating these processes is a decrease in blood glucose concentration.

Insulin exerts its effects on glucose metabolism by increasing the activity and amount of key glycolytic enzymes: glucokinase, phosphofructokinase, and pyruvate kinase (see Section 7). In muscles, insulin activates hexokinase II. In the liver and muscles, insulin decreases the intracellular concentration of cAMP by activating phosphodiesterase. Furthermore, insulin activates Phosphatases that dephosphorylate glycogen synthase, thereby promoting glycogen synthesis and inhibiting its breakdown.

The effects of insulin mediated by the phosphorylation and dephosphorylation of enzymes develop very rapidly, within seconds to minutes. Concurrently with the activation of glycolytic enzymes, insulin inhibits gluconeogenesis by repressing the synthesis of its key enzyme, phosphoenolpyruvate carboxykinase (PEPCK).

Effect of insulin on Lipid Metabolism. In the liver and adipose tissue, insulin stimulates lipogenesis by providing the necessary substrates for this process (acetyl-CoA, α-glycerophosphate, and NADPH) derived from glucose. In adipocytes, insulin activates acetyl-CoA carboxylase and lipoprotein lipase, and induces the synthesis of fatty acid synthase, acetyl-CoA carboxylase, and lipoprotein lipase (see Section 8 and Table 11-7). In adipose tissue, insulin inhibits lipid mobilization. It activates a phosphatase that dephosphorylates and thereby inactivates hormone-sensitive triacylglycerol lipase (TAG lipase). Thus, insulin lowers the concentration of circulating free Fatty acids in the blood (see Section 8). Insulin also stimulates the uptake of neutral amino acids in muscles and Protein synthesis in the liver, muscles, and heart.

Insulin stimulates the proliferation of numerous cells in tissue culture and is also likely involved in regulating growth in vivo. Fibroblast cultures are most commonly used to study growth regulation. In such cells, insulin enhances the ability of fibroblast growth factor (FGF), platelet-derived growth factor (PDGF), epidermal growth factor (EGF), prostaglandin (PGF₂α), vasopressin, and cAMP analogs to stimulate the proliferation of cells arrested in the G phase.

3. Mechanism of Insulin Action

The Action of Insulin begins with its binding to a specific glycoprotein receptor On the surface of the target cell (see Section 5). Insulin receptors are found in almost all cell types, but they are most abundant in hepatocytes and adipose tissue cells. Since the concentration of insulin in the blood is ~10^-10 M, the number of insulin-bound receptors depends on their total density on The cell membrane. Cells with varying receptor densities respond differently to the same hormone concentration.

The insulin receptor (IR) undergoes continuous Synthesis and degradation, with a half-life ($T_{1/2}$) of 7–12 hours. High plasma insulin concentrations, such as those observed in obesity, can lead to a downregulation of insulin receptors, rendering target cells less sensitive to insulin—a factor that may contribute to the development of type 2 diabetes mellitus (see Subsection V below).

The reduction in cellular sensitivity to the hormone (desensitization) is mediated by two mechanisms. The first involves receptor loss through internalization: the insulin-receptor complex is engulfed into the cell via endocytosis. Following internalization, a fraction of the receptors is degraded in Lysosomes, while another fraction is recycled back to the plasma membrane. The second desensitization mechanism is Covalent Modification of the receptor via phosphorylation. For instance, phosphorylation of the IR at Serine and threonine residues decreases its affinity for insulin.

The insulin receptor belongs to the family of receptors possessing intrinsic tyrosine kinase activity (see Section 5). Insulin-stimulated autophosphorylation of the IR β-subunit at tyrosine residues leads to the phosphorylation of other intracellular proteins known as insulin receptor substrates (IRS). Several such substrates have been identified, including IRS-1, IRS-2, and certain members of the STAT protein family.

IRS-1 plays a major role in mediating the cellular response to the insulin signal. IRS-1 is a phosphoprotein consisting of more than 1,200 amino acid residues, with a proportion of its serine, tyrosine, and threonine residues being phosphorylated. Upon insulin stimulation, the degree of IRS-1 phosphorylation increases, enabling it to associate with other cytosolic proteins. This triggers the activation of multiple signaling pathways that constitute a cascade of specific protein kinase activations. Consequently, the activated protein kinases phosphorylate target enzymes and transcription factors, which underlies the diverse metabolic effects of insulin.

Insulin activation of the Ras signaling pathway. The Ras protein belongs to the family of small GTP-binding proteins. In its inactive state, the Ras protein is anchored to the inner leaflet of the plasma membrane and bound to GDP. Insulin stimulation leads to the formation of the active, GTP-bound form of Ras (Fig. 11-25).

Fig. 11-25. Activation of the Ras pathway by insulin. 1 — GRB-2/mSOS, a cytosolic protein, non-covalently binds to the phosphorylated insulin receptor with the participation of an insulin receptor substrate, Shc; 2 — the resulting complex interacts with the Ras protein, recruiting proteins that facilitate the release of GDP from Ras and the binding of GTP; 3 — activated Ras binds to the Raf-1 protein kinase, resulting in the activation of Raf-1 kinase; 4, 5 — activated Raf-1 kinase stimulates a cascade of phosphorylation reactions and activates other protein kinases, specifically MEKK and MAPK. MAPKs phosphorylate numerous cytoplasmic proteins and transcription factors. MAPK stands for mitogen-activated protein kinase.

The Conversion of the Ras protein into its active form proceeds with the involvement of a family of proteins that act as protein kinase activators and protein kinases themselves, and—like Ras—derived their names from oncogenes (see Section 16). One of the insulin receptor substrates, Shc, participates in forming a complex with the small cytosolic protein Grb. The resulting complex interacts with the Ras protein. This complex also incorporates other proteins: GAP (GTPase-activating protein), GEF (guanine nucleotide exchange factor), and SOS (son of sevenless, named after a mutant gene in Drosophila). The latter two proteins promote the dissociation of GDP from Ras and the binding of GTP. Activated Ras then binds to the Raf-1 protein kinase. In its inactive state, Raf-1 resides in the cytosol bound to molecular chaperones. Raf-1 activation is a multi-step process involving membrane translocation, phosphorylation, and interaction with the insulin receptor. Activated Raf kinase stimulates a cascade of phosphorylation reactions leading to the activation of downstream protein kinases, notably mitogen-activated protein kinases (MAPKs). Via Raf-1, MAPK kinase (MAPKK) is first phosphorylated and activated, which in turn phosphorylates MAPK.

MAPK phosphorylates numerous cytoplasmic proteins, including the pp90S6 protein kinase, ribosomal proteins, phospholipase A₂, and transcription factors (such as TC F). The Ras pathway is activated not only by insulin but also by many other hormones and growth factors. Many components of this pathway are proto-oncogene products whose mutations lead to malignant cellular transformation (see Section 16).

Insulin effects can manifest within seconds to minutes (nutrient transport, protein phosphorylation and dephosphorylation, enzyme Activation and inhibition, RNA Synthesis) or over several hours (DNA and protein synthesis, cell growth).

Activation of phosphoinositide 3-kinase (PI3K). This enzyme catalyzes the phosphorylation of phosphatidylinositol (PI), PI-4-phosphate, and PI-4,5-bisphosphate at the D-3 position to generate polyphosphoinositides: PI-3-phosphate, PI-3,4-bisphosphate, and PI-3,4,5-trisphosphate. In various cell types, these second messengers stimulate Ca²⁺ mobilization and the activation of specific protein kinases (see Section 5). PI3K activation promotes the translocation of GLUT-4 to the plasma membrane, thereby accelerating transmembrane glucose uptake in adipose and Muscle Tissues. In adipose tissue, PI3K activation leads to the inhibition of lipolysis. The reduction in lipolysis rate occurs via the activation of phosphodiesterase and a decrease in intracellular cAMP concentration (Fig. 11-26).

Fig. 11-26. Activation of adipocyte phosphodiesterase by insulin. 1 — the phosphorylated insulin receptor phosphorylates insulin receptor substrates; 2 — formation of a complex between phosphoinositide 3-kinase (PI3K) and activated insulin receptor substrates; 3 — activation of protein kinase B (PKB); 4 — protein kinase B activates phosphodiesterase (PDE) via phosphorylation; 5 — PDE catalyzes the conversion of cAMP to AMP.

Activation of glycogen synthase by insulin. One of the protein kinases activated via the Ras pathway is protein kinase pp90S6. This enzyme phosphorylates protein phosphatase associated with glycogen granules. Upon phosphorylation, the protein phosphatase becomes active and dephosphorylates phosphorylase kinase, glycogen phosphorylase, and glycogen synthase. The dephosphorylated forms of phosphorylase kinase and glycogen phosphorylase are inactive, which slows down glycogen mobilization. Conversely, Glycogen synthase is activated, and glycogen synthesis is accelerated (Fig. 11-27).

Fig. 11-27. Activation of glycogen synthase by insulin. 1 — activation of the Ras pathway; 2 — protein kinase pp90S6, activated by insulin via the Ras pathway (Fig. 11-25), phosphorylates glycogen granule-associated protein phosphatase, which triggers a cascade of dephosphorylation reactions; 3 — inactivation of phosphorylase kinase and glycogen phosphorylase; 4 — inhibition of glycogen mobilization; 5 — activation of glycogen synthase; 6 — stimulation of glycogen synthesis.

Insulin influences the transcription rate of more than 100 specific mRNAs in the liver, adipose tissue, skeletal muscle, and heart. The effect of insulin on gene transcription was first demonstrated using phosphoenolpyruvate carboxykinase—a key gluconeogenic enzyme whose rate of synthesis in hepatoma cell cultures decreased within minutes.

4. Glucagon

Glucagon is a single-chain polypeptide consisting of 29 amino acid residues. Its biosynthesis takes place in the α-cells of the islets of Langerhans, enteroendocrine cells, and certain regions of the central nervous system. The inactive precursor proglucagon undergoes partial proteolysis to yield several peptides. In pancreatic cells, the primary peptide is glucagon, whereas intestinal cells produce glucagon-like peptides (GLP-1, GLP-2), glicentin, and others. GLP-1 inhibits glucagon secretion while stimulating insulin synthesis and secretion. The secretion of GLP-1 is stimulated by another hormone, gastric inhibitory polypeptide (GIP), which is synthesized in the mucosal cells of the upper Small Intestine. GIP secretion is stimulated by food intake, with glucose acting as the most potent secretagogue. Glucagon secretion is also influenced by various Other Compounds, including amino acids, fatty acids, Ketone Bodies, and Neurotransmitters. Carbohydrate-rich meals suppress glucagon secretion. Protein-rich foods stimulate the secretion of both insulin and glucagon; however, Certain amino acids exert a greater effect on the secretion of one over the other. For instance, alanine stimulates glucagon secretion but does not affect insulin.

In blood plasma, glucagon is not bound to any carrier protein. The half-life (T_1/2) of the hormone is approximately 5 min. In the liver, glucagon is rapidly degraded by specific proteases.

The effects of glucagon are largely opposite to those of insulin. The primary target cells for glucagon are the liver and adipose tissue. Upon binding to receptors on the plasma membrane of target cells, glucagon increases intracellular cAMP levels (see Section 5). In hepatocytes, this leads to the activation of glycogen phosphorylase and a decrease in glycogen synthase activity, thereby accelerating glycogen mobilization. The phosphorylation of pyruvate kinase and PFK-2 inhibits glycolysis while accelerating gluconeogenesis. Furthermore, glucagon stimulates gluconeogenesis by inducing the synthesis of Key Enzymes: glucose-6-phosphatase, phosphoenolpyruvate carboxykinase, and fructose-1,6-bisphosphatase (see Section 7). In adipose tissue, glucagon activates hormone-sensitive triacylglycerol lipase via the adenylate cyclase cascade, thereby stimulating lipolysis (see Section 8). Thus, in contrast to insulin, glucagon promotes the mobilization of major energy substrates—carbohydrates and fats.

5. Other Gastrointestinal Hormones

More than 10 biologically active peptides have been isolated from gastrointestinal tissues. Many of these function as true hormones with systemic endocrine effects, including gastrin, secretin, GIP, cholecystokinin, motilin, pancreatic polypeptide, and enteroglucagon. Other Gastrointestinal Peptides exert paracrine or neuroendocrine effects, such as vasoactive intestinal peptide (VIP) and somatostatin.

A distinctive feature of the gastrointestinal Endocrine System is that its cells are diffusely scattered throughout various regions rather than aggregated into a single discrete organ. Many gastrointestinal peptides are also found within enteric nerves and central nervous system cells. Additionally, these peptides frequently exist in multiple Structural and functional isoforms, which complicates The Study of their structures and functions. Among the major gastrointestinal hormones, only secretin exists as a single molecular form. Based on primary Structure and Functional homology, most gastrointestinal hormones can be classified into two families.

The gastrin family comprises gastrin and cholecystokinin.

The Secretin Family comprises secretin, glucagon, GIP, VIP, and glicentin.

Relatively little is known about the precise Mechanisms of action of gastrointestinal hormones. Six distinct classes of receptors have been identified on pancreatic acinar cells: one class belonging to the gastrin family functions via the inositol phosphate signaling pathway, whereas secretin and VIP receptors are components of the adenylate cyclase system. The physiological roles of the major gastrointestinal hormones are discussed in detail in human physiology courses and in Section 9.