Fundamentals of Biochemistry - A. A. Anisimov 1986

Integration and Regulation of Metabolism
Human and Animal Hormones

12.6.1. Cytology/cytology/25.html">General characteristics and Mechanisms of action. Hormones (from the Greek hormao, meaning to set in motion or urge on) are Organic compounds produced by Endocrine glands (ductless glands), which are transported by the Blood to target Cells and actively influence metabolic, morphogenetic, and physiological processes. However, certain hormones are synthesized not only by endocrine glands but also within the cells of other Organs and Tissues. For instance, pancreatic hormones (Insulin and Glucagon) are also generated in intestinal cells, while catecholamines (Adrenal hormones) are synthesized within nerve endings.

A crucial distinguishing feature of hormones from other BIOLOGICALLY ACTIVE SUBSTANCES is the specialization of the cells that synthesize them. Endocrine glands lack excretory ducts; their cells are entwined with an abundant network of Blood and Lymphatic capillaries, releasing their metabolic products directly into the lumens of these vessels. This is what differentiates endocrine glands from exocrine glands, which secrete their products through dedicated ducts.

The effects of hormones on organs and tissues are characterized by several key features.

1. High biological activity, manifesting as the ability of hormones to exert physiological effects at extremely low concentrations.

2. Action Specificity: hormones elicit strictly specific response reactions in organs and tissues.

3. Distant action: hormones are typically transported via the bloodstream far from their site of origin and affect specific target organs or target cells sensitive to them (though exceptions to this rule have been discovered recently, with some hormones acting locally at their site of synthesis).

4. A relatively short half-life, usually under 1 hour; As a result, effective hormonal functioning requires continuous Synthesis and Secretion throughout the entire duration demanded by the body's current physiological state.

Endocrine glands emerged in Arthropods and vertebrates as a core component of the neuroendocrine regulatory system designed to maintain Homeostasis. In the past decade, hormones or substances with similar modes of action have also been discovered in worms.

Based on their chemical Structure, mammalian hormones can be divided into three major groups: 1) Proteins AND Peptides, 2) Amino Acid Derivatives, and 3) Steroids.

A special group is typically reserved for so-called tissue hormones, or humoral factors, which are produced not in endocrine glands but in numerous tissues throughout the body (such as histamine, Prostaglandins, etc.).

Several polypeptide hormones are synthesized by endocrine glands as larger precursor molecules known as prohormones, while in some cases, products of ribosomal synthesis represent even larger proteins called preprohormones. In addition to the inhibitory peptide found in all prohormones, the latter contain an additional peptide that governs The transport of the hormone across the membrane during its secretion by the gland.

Two main Mechanisms of Hormone action are currently recognized (for steroid and non-Steroid Hormones). Hormone specificity toward target cells is mediated by protein receptors. The receptors for most hormones (namely Polypeptides and amino acid derivatives, i.e., non-steroid hormones) are located in Cell/30.html">The Plasma Membrane of the cells. A response is triggered upon the binding of the hormone to the receptor. Since these receptors are Glycoproteins, their specificity is determined by their carbohydrate component. Carbohydrate fragments of gangliosides located within The Lipid Bilayer of the plasma membrane also play a definite role in this process.

The Interaction of a non-steroid hormone with its receptor activates adenylate cyclase, leading to an elevated intracellular concentration of cAMP and, consequently, the phosphorylation of various proteins—enzymatic, membrane, ribosomal, and Chromatin—by protein Kinases. This cascade can trigger A wide variety of changes in cellular METABOLISM. The phosphorylation of chromatin proteins affects Gene Transcription, thereby regulating The rate of synthesis of Enzymes and other proteins. Exceptions within the group of polypeptide and amino acid-derived hormones include insulin and THYROID HORMONES. The receptors for the latter are intranuclear proteins that form part of chromatin. This reception leads to enhanced RNA Synthesis within cells, activation of RNA polymerase, and an increased rate of Protein Synthesis. Thyroid hormones apparently stimulate the latter at the transcriptional stage, which underlies their effects on cell growth, development, and differentiation. Furthermore, thyroid hormones possess receptors in the mitochondrial membrane, thereby influencing Energy Metabolism.

Insulin receptors are localized On the surface of target cells, and the hormone exerts its effects without penetrating The Cell interior. However, most of insulin's effects (such as The regulation of lipolysis, Glycogen synthesis, etc.) run counter to the action of cAMP. Consequently, insulin does not share this similarity with other polypeptide hormones, as it does not stimulate adenylate cyclase activity. In addition, specific insulin-binding receptors have been discovered in the nuclei of certain cells, though their precise role remains insufficiently understood. The binding of insulin to target cells leads to an increased rate of synthesis and accumulation of proteins, glycogen, and Lipids (i.e., energy storage).

Steroid hormones penetrate the Cytoplasm of target cells and bind to specific cytoplasmic receptor proteins. The resulting complexes migrate into the cell nuclei and attach to chromatin. By altering the transcriptional accessibility of specific DNA segments, steroid hormones influence mRNA synthesis, thereby acting at The Genome level.

Thus, the Mechanism of hormone Action is directed primarily at proteins: affecting their synthesis rate, activation, and the modification of already synthesized proteins. Steroid and thyroid hormones exert their regulatory function via the first pathway, influencing protein synthesis at the transcriptional stage. Protein hormones, peptides, and amino acid derivatives (excluding thyroid hormones) affect metabolism primarily through the activation and modification of proteins via protein kinase-mediated phosphorylation (the second pathway). In some cases, as a result of the phosphorylation of chromatin and ribosomal proteins, non-steroid hormones can also indirectly influence protein synthesis itself.

Complex interactions are established among endocrine glands. This is due to the facts that: 1) the function of each organ is influenced by multiple hormones simultaneously; and 2) hormones produced by certain glands affect the function of other endocrine glands. Three primary types of interaction between endocrine glands are distinguished.

1. Interaction based on THE PRINCIPLE OF positive feed-forward or negative feedback. For instance, the anterior Pituitary Gland produces thyrotropin (thyroid-stimulating hormone), which stimulates The formation of thyroid hormones—a positive feed-forward mechanism. Conversely, an elevation of thyroid hormone levels above normal inhibits The production of pituitary thyrotropin—a negative feedback mechanism.

2. Synergism of Hormonal Influences. For example, both adrenaline (a hormone of The adrenal medulla) and glucagon (produced by the alpha Cells of the pancreatic islets) activate The breakdown of Liver glycogen into glucose, causing an elevation in blood glucose levels.

3. Antagonism of hormonal influences. A classic example is provided by Female Sex Hormones: estrogens and progesterone. The former enhance the contractile function of the Uterus, whereas the latter inhibits it.

A well-defined connection exists between the endocrine and nervous systems. Specialized secretory cells in the Hypothalamus (a region of the Brain) produce hormones known as low-molecular-weight polypeptides, termed releasing factors or regulatory factors. Their target organ is the adenohypophysis (anterior pituitary). According to one of the leading Soviet endocrinologists, N. A. Yudaev (1976), hypothalamic releasing factors can be regarded as universal chemical signals through which neural impulses are transmitted to the Endocrine System.

Neural stimuli originating from the Thalamus and Cerebral cortex influence the release rate of hypothalamic regulatory hormones, which reach the adenohypophysis via the hypothalamo-hypophysial portal Blood Circulation system and trigger the secretion of specific adenohypophysial hormones. Thus, via these Neural Pathways, rapid regulation of adenohypophysial secretion is executed in response to various environmental stressors (such as cold, Hypoxia, trauma, toxins) or specific physiological states (fear, anxiety).

The Commission on Biochemical Nomenclature of IUPAC-IUBMB (International Union of Biochemistry) proposed that the names of hypothalamic releasing factors that promote the formation of Pituitary Hormones should end in the suffix -liberin, while inhibitory factors should end in -statin (e.g., corticoliberin, prolostatin).

The hypothalamus is also directly linked (both anatomically and functionally) to the neurohypophysis (posterior pituitary). The hormones secreted by the neurohypophysis (in response to specific neural stimuli) are synthesized in the hypothalamus, migrate in the form of granules along nerve fibers, and accumulate at their nerve endings within the neurohypophysis. All of the above demonstrates that the "hypothalamo-hypophysial axis" serves as the anatomical and biochemical foundation for the Integration of the nervous and endocrine systems.

In turn, hormones exert an influence on The Nervous system. This process involves alterations in the metabolism of brain tissue Neurons—specifically electrolyte and Amino Acid Turnover, as well as the processes of Ammonia Formation and binding. The impact of hormones on neuronal Functions within brain structures leads to their involvement in the regulatory and corrective Influence of the Central Nervous System over various organs. Hormones also exert effects at the receptor level, particularly on chemoreceptors located within blood vessel walls.

12.6.2. Thyroid Gland. It secretes thyroxine and triiodothyronine, as well as Calcitonin (produced by specialized parafollicular cells). The initial precursors for the Synthesis of the first two hormones are Tyrosine and inorganic iodine.

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The synthesis of thyroxine and triiodothyronine is catalyzed by thyroid peroxidase through the Iodination of tyrosine residues within the thyroglobulin protein molecule. Thyroglobulin itself has no hormonal activity; this property is exclusive to the iodothyronines released during its proteolysis by intracellular epithelial cell proteinases. Both synthesis and proteolysis of thyroglobulin occur continuously.

In Blood Plasma, thyroxine binds to carrier proteins: thyroxine-binding globulin, prealbumin, and albumin.

Hypofunction of The Thyroid Gland (hypothyroidism) leads to a decrease in basal metabolic rate and body Temperature, accompanied by mucinous edema, a condition known as Myxedema. When hypothyroidism occurs in children, it results in cretinism, which involves delayed physical growth and mental development. Hyperfunctioning of the thyroid gland is characterized by a sharp acceleration of metabolism, tachycardia, hand tremors, and exophthalmos. This clinical syndrome is known as Graves' disease.

Calcitonin is a linear polypeptide composed of 32 amino acid residues. All 32 residues are essential for its biological activity. The Introduction/19.html">Primary Structure of calcitonin varies among animal species, though it remains quite similar; for instance, cod calcitonin differs from that of higher vertebrates by only nine amino acid residues. The primary Physiological Role of calcitonin is to prevent a potential rise in blood Ca²⁺ levels by inhibiting the release of Ca²⁺ from bones.

12.6.3. Parathyroid glands. They secrete parathyroid hormone (parathormone), a protein (M 9500) that exists within the parathyroid glands as a prohormone containing an additional hexapeptide at the N-terminus. It is believed that the Cleavage of this hexapeptide triggers biological activity.

The main function of parathormone is the Regulation of Blood Ca ion concentration by increasing it when levels drop for any reason. The primary target organs for parathormone are the Kidneys and skeletal bones.

12.6.4. Gonads. The Testes secrete testosterone and dihydrotestosterone (androgens) at a rate of 5–7 mg/day.

The Biosynthesis of these hormones originates from Cholesterol. Androgens drive the normal growth of Male reproductive organs and The Development of secondary male sex characteristics. A deficiency in testosterone slows down Protein Biosynthesis, leads to obesity, and causes Hair loss. Androgens also exert a pronounced anabolic effect on nitrogen and calcium metabolism.

Female sex hormones (estrogens) are synthesized primarily in the Ovaries. Ovarian follicles secrete the most potent estrogen, ß-estradiol, at a rate of 1 mg/day.

It governs the Development of the reproductive organs and secondary sex characteristics. Estetrol (or estradiol) deficiency disrupts menstrual cycles, leads to spontaneous miscarriages, and causes obesity. Estrogens exert a significant influence on the synthesis of proteins and Nucleic Acids, as well as Lipid Metabolism.

12.6.5. Corpus Luteum. It produces progesterone and relaxin. Progesterone is synthesized during the second half of the Menstrual cycle and is produced in particularly large amounts during Pregnancy. Because it acts on the hyaluronidase–hyaluronic acid system, progesterone is essential for preparing the uterine mucosa for the implantation of a fertilized egg. Progesterone also affects the permeability of cellular and mitochondrial membranes, Oxidative Phosphorylation, and mRNA formation.

Relaxin is a polypeptide (M 6000) consisting of two non-identical chains linked by disulfide bridges, bearing a strong structural resemblance to insulin. Relaxin prepares the uterus and pelvic joints for childbirth.

12.6.6. Adrenal Glands. They consist of the medulla and the cortex. The Hormones of the medulla are adrenaline (epinephrine) and noradrenaline (norepinephrine). These hormones, along with closely related amines containing a catechol group in their structure, are termed catecholamines. The Role of adrenaline and its metabolic products in the Organism was thoroughly investigated in the works of A. M. Utevsky (1950).

The principal pathway for catecholamine synthesis is: tyrosine → dihydroxyphenylalanine (DOPA) → dihydroxyphenylethylamine (DOPAMINE) → noradrenaline → adrenaline.

By stimulating adenylate cyclase in target organs, adrenaline and noradrenaline activate glycogen phosphorolysis in The Liver and skeletal Muscles, dramatically elevating blood glucose levels, while also increasing the force of Heart contractions and the secretion of salivary amylase. Catecholamines possess potent lipid-mobilizing activity.

The Physiological effects of adrenaline and noradrenaline closely mimic The Influence of the sympathetic nervous system (such as increasing blood pressure). Because excitation of these nerves triggers the secretion of these hormones, they are referred to as sympathomimetic amines. Given that they function as both hormones and Neurotransmitters, these amines can be synthesized in the nervous system from tyrosine via the same pathway as in the adrenal glands. Under resting conditions, the blood of animals and humans contains very little adrenaline. However, acute emotional excitement, pain, physical exertion, and cold exposure lead to a significant spike in its blood concentration, as it acts as a trigger for the body's mobilization readiness.

Overall, the entire sympathoadrenal system (the adrenal medulla and the Sympathetic division of the nervous system) prepares the body for defensive reactions that require active physical exertion. This readiness manifests as enhanced cardiovascular function, an elevated Energy balance, suppression of gastrointestinal activity, and increased Blood supply to skeletal muscles. Consequently, adrenaline is often called the "fight-or-flight hormone." For animals, the sympathoadrenal system is of paramount importance in the struggle for survival. In humans, it also plays a crucial role in preparing the body to handle increased physical demands, such as when athletes train for competitions,

There are certain differences between the actions of adrenaline and noradrenaline. For instance, unlike adrenaline, noradrenaline causes only a minimal increase in blood glucose levels and O₂ consumption.

Under normal conditions, the adrenal cortex secretes adrenocorticosteroids: cortisol (hydrocortisone), corticosterone, and aldosterone. Cholesterol serves as the precursor for all adrenocorticosteroids.

In humans, cortisol is secreted at 10–30 mg/day, corticosterone at 2–4 mg, and aldosterone at 300–400 mcg. Cortisol and corticosterone are transported by the globulin transcortin, whereas aldosterone is bound to albumin. Corticosteroids influence the following metabolic and physiological processes: 1) they promote Glycogenesis, increasing glycogen levels in the liver and glucose in the blood; 2) they strongly inhibit Protein synthesis in muscles and various other tissues while activating the formation of specific liver proteins; 3) they enhance the mobilization of lipids from fat depots; 4) they regulate Water-salt balance; 5) they stimulate erythropoiesis while decreasing lymphocyte counts; 6) they increase the secretion of HCl and pepsinogen; 7) they prevent and slow down the development of inflammatory and allergic reactions; 8) they help maintain homeostasis under the action of damaging factors (trauma, infectious agents, harmful chemicals, etc.).

12.6.7. Pancreas. It synthesizes insulin, glucagon (see sec. 6.8), Somatostatin, secretin, and avian Pancreatic Polypeptide (APP, from Lat. avis — bird).

Somatostatin inhibits the release of somatotropin by the pituitary gland, insulin and glucagon by the pancreas, and gastrin by the gastric mucosa. Consequently, somatostatin regulates Growth Hormone secretion, exerts an antihyperglycemic effect, and promotes the release of lipids from adipose tissue. The presence of somatostatin has been demonstrated not only in the hypothalamus—its primary site of secretion—but also in the pancreas, gastric mucosa, and intestines. Structurally, somatostatin is a fourteen-membered peptide containing a single disulfide bond.

Secretin contains 27 amino acid residues; it stimulates the secretion of Pancreatic juice and, to a lesser extent, Bile and intestinal juice, while suppressing gastrin production. In animals and humans, apart from gastrin and secretin, other Peptide Hormones regulating gastrointestinal activity are also produced, such as cholecystokinin (which stimulates Gallbladder contraction), vasoactive intestinal peptide, gastric inhibitory peptide, etc.

Pancreatic polypeptide contains 36 Amino Acids. It increases the secretion of gastric and pancreatic enzymes, relaxes the gallbladder, and decreases intestinal motility.

12.6.8. Thymus. It synthesizes and secretes hormones that influence the rate of development and maturation of specific lymphoid cell populations. These hormones include thymosin, thymopoietins I and II, thymic humoral factor, and homeostatic thymic hormone. Because lymphoid cells are of paramount importance for Immunity, the role of thymic hormones in this regard is likewise crucial.

12.6.9. Pituitary gland (hypophysis). An appendage of the brain consisting of the anterior (adenohypophysis), posterior (neurohypophysis), and intermediate lobes. The International Commission on Anatomical Nomenclature divides the pituitary into the neurohypophysis and adenohypophysis, with the latter including both the anterior and intermediate (middle) lobes.

The mammalian neurohypophysis secretes: vasopressin, oxytocin, alpha- and beta-melanocyte-stimulating hormones, and koherin.

Oxytocin and vasopressin are cyclic nonapeptides. Because two Cysteine residues close the peptide into a ring to form a single cystine molecule, these hormones are sometimes referred to as octapeptides.

Human Vasopressin and Oxytocin differ by only two amino acid residues. Studies of vasopressin structure in various higher animals have demonstrated species specificity in its makeup. For example, porcine vasopressin differs from human vasopressin by the substitution of an Arg residue with Lys.

Oxytocin stimulates uterine smooth Muscle contraction and promotes Lactation. Vasopressin enhances the contraction of blood vessel smooth muscles, leading to increased blood pressure. Furthermore, vasopressin participates in regulating plasma osmotic pressure and water balance (exhibiting antidiuretic properties, i.e., inhibiting urine output).

Koherin is a peptide synthesized in the neurohypophysis that induces coordinated intestinal contractions.

Melanocyte-stimulating hormone (melanotropin, MSH) has The ability to increase the number of melanocytes—cells containing the dark pigment melanin. In vertebrates, this ability is shared by two peptides: alpha-MSH and beta-MSH. Their Amino Acid Composition shows some variation across individual vertebrate species.

The ability of MSH to cause Skin darkening in amphibians by dispersing melanin concentrated in the center of melanocytes is well established. In humans and higher animals, MSH increases thyroid activity, stimulates sebaceous gland secretion, decreases dark adaptation of the eyes, enhances light sensitivity, and participates in regulating the movement of cells in the retinal pigment epithelium.

Neurohormones appeared at very Early stages of phylogeny. In all vertebrates except mammals, vasotocin is secreted, differing from vasopressin solely by the substitution of a Phe residue with Ile. This hormone is produced even in ancient fish and cyclostomes. Oxytocin is likewise the product of a long evolutionary process. In ancient fish, the analog of this hormone is glumitocin (differing from oxytocin by two amino acid residues at positions 4 and 8); in teleost fish, it is isotocin (also differing by Two amino acids); and in birds, reptiles, and amphibians, it is mesotocin (differing from oxytocin only by the substitution of the Leu residue at position 8 with Ile).

Over the course of evolution, changes also occurred in the Functional Significance of neurohypophyseal hormones. For instance, vasotocin extracted from the pituitary glands of fish exerts a strong antidiuretic effect when administered to amphibians and mammals, yet it does not affect fish in this manner. Apparently, in fish, vasotocin does not regulate water balance but instead performs some other function.

The adenohypophysis secretes thyrotropin, adrenocorticotropin, luteinizing and follicle-stimulating hormones, prolactin, somatotropin, and lipotropins.

Thyrotropin is a glycoprotein consisting of two subunits (M_r 13,600 and 14,700); it belongs to the class of sulfur-rich proteins. It influences the rate of iodine uptake from the blood by the thyroid gland, the incorporation of iodine into thyroid hormones, and the secretion of the latter.

Adrenocorticotropic hormone (adrenocorticotropin, corticotropin, ACTH) is a peptide composed of 39 amino acid residues. The primary structure of ACTH has been established for humans and several higher animals (sheep, pig, cattle, etc.). Species differences have been identified: the most variable Amino acids are located at positions 25–32. ACTH participates in regulating the biosynthesis of corticosteroids by the adrenal glands, stimulates adrenal cortex growth, and plays a role in mobilizing lipids from adipose tissue.

Follicle-stimulating hormone, luteinizing hormone, and prolactin are collectively known as gonadotropic hormones. These are glycoproteins consisting of alpha and beta subunits. In females, follicle-stimulating hormone induces the development of numerous follicles and an increase in ovarian mass. Luteinizing hormone promotes the final maturation of ovarian follicles, follicular rupture, and their conversion into the corpus luteum. Prolactin is essential for milk production in female mammals upon parturition.

Somatotropin is a hormone that accelerates growth and increases body mass. It is a protein with a Molecular Weight of 21,000.

Lipotropins are alpha- and beta-polypeptides that stimulate the release of Fatty acids from adipose tissue. Beta-lipotropin consists of 91 amino acid residues and serves as a precursor to endorphins (see sec. 2.5.1). Additionally, The amino acid chain of beta-lipotropin contains sequences corresponding to ACTH and beta-melanocyte-stimulating hormone.

12.6.10. Other mammalian hormones. Certain hormones are synthesized in cells not belonging to the endocrine system. For instance, the gastric mucosa produces a group of hormones termed gastrins. Their primary function is to stimulate the secretion of gastric juice and Hydrochloric acid. Furthermore, they enhance the tone and contraction of the Muscles of the Stomach and Small Intestine, and stimulate the secretion of glucagon and insulin by the pancreas. The presence of four gastrins in the gastric mucosa has been demonstrated; one of them has a molecular weight of 20,000 and is classified as a protein, while the other three are peptides.

12.6.11. Insect Hormones. Invertebrates possess a neuroendocrine system that shares A number of common features with that of mammals. Insects synthesize an activation hormone that regulates the secretory function of paired glands. These paired glands produce juvenile hormone in insect larvae.

The prothoracic gland of insects secretes ecdysone, which belongs to the class of steroid hormones. This hormone is essential for the periodic shedding of the larval exoskeleton, hence its alternative name, the molting hormone. Various types of ecdysones have been identified, and it is believed they may influence different stages of insect development. Ecdysone stimulates RNA synthesis in tissues and, much like mammalian steroid hormones, appears to directly control the transcription process.