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

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

CHAPTER 24. HORMONAL REGULATION OF METABOLISM AND CELLULAR BIOLOGICAL FUNCTIONS. II. PEPTIDE AND AMINO ACID-DERIVED HORMONES

Protein-Peptide Hormones are a large group of physiologically active compounds with hormonal and neurotransmitter properties that are produced in various Organs and Tissues and are chemically Polypeptides (simple Proteins, Glycoproteins, low-molecular-weight Peptides).

The main classes of protein-peptide hormones synthesized in the Endocrine System include pituitary, hypothalamic, and Pancreatic Hormones. Close in their Mechanisms of action to protein-peptide hormones are BIOREGULATORS — Amino Acid Derivatives (biogenic amines) — catecholamines, serotonin, histamine, and melatonin.

Simple peptides also include bioregulators belonging to histohormones:

- Brain opioid peptides;

- gastrointestinal system peptides;

- Components of the kinin and renin-angiotensin systems;

- hormones and mediators of The Immune System, and functionally similar peptide growth factors, and cytomedins;

- cardiac and brain natriuretic peptides, etc.

24.1. HYPOTHALAMIC-PITUITARY SYSTEM

The central endocrine gland of humans and higher animals is the Pituitary Gland, an organ that controls the endocrine activity of most subordinate (peripheral) Endocrine glands. In turn, the functional activity of the pituitary gland is regulated by neuroendocrine Cells of specialized hypothalamic nuclei. Hormones and/or Neurotransmitters (or modulatory Neuropeptides) of the hypothalamic and other subcortical brain nuclei control the secretion (and in some cases, Biosynthesis and production) of Pituitary Hormones.

A. Hypothalamic hormones

The Hypothalamus is an area of the brain that regulates The activity of the pituitary gland and peripheral endocrine glands through The production of specific hypothalamic hypophysiotropic hormones in neurosecretory cells and the action of neurotransmitters that control the Functions of subordinate endocrine glands via the sympathetic and parasympathetic nervous systems.

According to the recommendations of the Commission on Biochemical Nomenclature of the International Union of Biochemistry (1974), hypothalamic hormones that promote the release of certain pituitary hormones are designated as "releasing hormones" (releasing factors, or liberins), while bioregulators that inhibit the release of pituitary hormones are termed "inhibiting hormones" (or statins).

Currently, the Synthesis and Secretion of the following peptide hypophysiotropic hormones have been established in the hypothalamus:

Somatoliberin (Growth Hormone-releasing hormone, GHRH) — stimulates the production and release of growth hormone in the pituitary gland.

Somatostatin (SS; growth hormone-inhibiting hormone) — a hormone that inhibits the production and release of growth hormone; In addition to the hypothalamus, somatostatin is also synthesized in the pancreatic islets and other Cell formations of the gastrointestinal tract, where it performs specific physiological functions.

Prolactostatin (prolactin-inhibiting hormone, PIH) — a peptide that inhibits prolactin production and exhibits gonadoliberin activity.

Thyroliberin (thyrotropin-releasing hormone; TRH) — a hormone that stimulates the production and release of pituitary thyrotropic hormone.

Gonadoliberin (gonadotropin-releasing hormone; GnRH; luliberin) — stimulates the synthesis and release of the gonadotropic hormones FSH and LH.

Corticoliberin (corticotropin-releasing hormone) — a hormone that stimulates the release of corticotropin.

Chemically, liberins and statins are polypeptides secreted by specific hypothalamic Neurons. Upon reaching the adenohypophysis via the portal Circulation system or neuronal axons—along with biogenic amines (dopamine, serotonin, norepinephrine) and other neurotransmitters—they regulate its specific hormonal functions. The production of hypothalamic hormones is subject to complex regulation by the Central Nervous system, whose neurotransmitters (biogenic amines, neuropeptides, mediator Amino Acids) exert a modulating effect on the functional activity of the hypothalamic nuclei.

B. Hormones of the anterior pituitary

The anterior pituitary gland (adenohypophysis) produces a significant amount of hormones that stimulate PHYSIOLOGICAL AND BIOCHEMICAL processes in various target tissues, including activating the action of other endocrine glands (the trophic function of pituitary hormones). Based on Molecular Genetics, biosynthesis, and structural-functional properties, the hormones of the adenohypophysis are divided into three groups:

Group I — "growth hormone-prolactin-chorionic somatomammotropin";

Group II — glycoproteins — "pituitary trophic hormones";

Group III — derivatives of "proopiomelanocortin".

I. The Growth Hormone Group is a biochemical cluster ("family") of protein hormones that share significant Homology in their Primary Structure (Amino acid sequences) and close functional-biochemical effects. In most animal species, these hormones consist of 190–199 amino acid residues and exhibit growth-promoting and lactogenic activities.

1. Growth hormone (somatotropin, somatotropic hormone, STH) is a simple protein consisting of a single polypeptide chain (191 amino acid residues; molecular mass ~21.5 kDa) with two intramolecular Disulfide Bonds. The hormone is synthesized in somatotroph cells, which make up about 50% of the cells in the adenohypophysis. The Gene controlling STH expression is located on the 17th chromosome of the Human Karyotype. STH is synthesized as several prohormones, which accounts for a certain molecular heterogeneity of growth hormone.

Biological Properties of STH

The main function of STH is The stimulation of postnatal somatic growth; this complex biological function is realized through a diverse spectrum of hormone effects on METABOLISM/35.html">Protein Biosynthesis, carbohydrate, and Lipid Metabolism:

a) effect on protein biosynthesis — characterized by an anabolic orientation: STH stimulates the Transport of Amino acids into cells and the processes of Transcription and Translation in hormone-sensitive tissues (primarily in Muscles, Cartilage, bones, Liver, Connective Tissue, etc.); overall, The Effect of STH on the body leads to a positive nitrogen balance, meaning the predominance of synthesis processes over the Catabolism of PROTEINS AND AMINO acids;

b) effect on carbohydrate and lipid metabolism — determined by the "counter-Insulin effects" of the hormone: administration of STH is accompanied by hyperglycemia (hyperglucosemia), which results from both decreased cellular glucose utilization (inhibition of glucose Transport from the extracellular space and inhibition of its glycolytic oxidation) and activation of its production via Gluconeogenesis; in adipocytes of adipose tissue, STH activates lipolysis reactions, leading to the stimulation of NEFA and glycerol release into Blood Plasma.

The lactogenic properties of STH are related to its ability to interact with lactogenic receptors of the mammary gland; in a healthy body, these effects of STH are not of major significance and manifest under conditions of pituitary pathology.

Somatomedins

A characteristic feature of the biological action of STH is that it is mediated through the hepatic synthesis and BIOLOGICAL EFFECTS OF two Polypeptide Growth Factors (somatomedins) — IGF-1 and IGF-2 ("Insulin-like Growth Factors 1 and 2", which are peptides consisting of 70 and 67 amino acid residues, respectively).

The Introduction/19.html">Primary structure of somatomedins resembles that of the proinsulin molecule. The gene encoding IGF-1 synthesis is localized on the 12th human chromosome, and the IGF-2 gene on the 11th chromosome, in close proximity to the insulin gene. Both growth factors stimulate DNA Replication, manifested by enhanced thymidine incorporation into DNA, as well as transcription and translation in STH target tissues.

The stimulation of tissue growth by somatomedins is 50–100 times stronger compared to insulin, while the growth-promoting properties of STH correlate most closely with the effects of IGF-1: individuals with a deficiency of this somatomedin lack the capacity for normal growth. The effects of IGFs are realized via receptors localized on the Plasma Membranes of target cells — type 1 receptors, which possess Tyrosine kinase activity, and type 2 receptors, whose activation leads to the engagement of cellular effector systems via G-proteins.

Regulation of STH Secretion

The production and secretion of growth hormone are under positive and negative neurohumoral control: the release of STH from the pituitary is stimulated by somatoliberin and inhibited by somatostatin. In addition, the release of STH by the pituitary is activated by such physiologically active compounds as dopamine, serotonin, vasopressin, estrogens, agonists of γ-adrenergic receptors, and γ-aminobutyric acid.

The release of STH (similar to Other Hormones of the hypothalamo-pituitary system) occurs in a pulsatile manner — maximum hormone synthesis is observed 60–90 minutes after the onset of Sleep (Cytology/cytology/16.html">Early stages of deep, "slow-wave" sleep); the sleep process is considered a physiological stimulator of somatotropin secretion ("Children grow in their sleep!").

Pathologies Associated with Growth Hormone

acromegaly — a disorder caused by increased production of growth hormone in adults; it is characterized by a pathologically disproportionate enlargement of skeletal bones (especially the extremities, jaws, and Other components of the Skull), soft tissues, and Internal Organs; in young women, the condition manifests as galactorrhea caused by increased prolactin production or the intrinsic lactogenic activity of STH. The Etiology of the disease is associated with the presence of a tumor — a pituitary adenoma (somatotropinoma);

gigantism — a manifestation of excessive growth hormone secretion in childhood and adolescence, leading to excessive height (conventionally above 190 cm); the prolongation of abnormally high STH production into adulthood leads to The Development of acromegaly in such patients;

dwarfism (nanism) — growth retardation (in men — below 130 cm, in women — below 120 cm) caused by heterogeneous factors associated both with decreased synthesis of STH and, consequently, IGF-1 ("STH-deficient dwarfs"), and with impaired tissue reactivity to the hormone: "Laron dwarfs" — individuals lacking hepatic STH receptors, and pygmies, who exhibit molecular pathology in the post-receptor Transduction of the hormonal signal.

2. Prolactin (lactogenic hormone, mammotropin, luteotropic hormone) is a simple protein consisting of a single polypeptide chain (molecular mass ~23 kDa). The hormone is produced in acidophilic Cells of the adenohypophysis — lactotrophs, whose number and size increase during Pregnancy.

Prolactin is involved in the initiation and stimulation of Lactation in women, with the hormone's action manifesting only against the Background of sensitization of mammary gland cells by Female Sex Hormones.

Tumors consisting of prolactin-producing pituitary cells lead to Amenorrhea and galactorrhea in women, and to certain types of Infertility in men.

The synthesis and secretion of prolactin are inhibited by dopamine and a specific hypothalamic inhibitory neuropeptide known as prolaktostatin, which also exhibits gonadotropin-releasing hormone activity (gonadotropin-releasing hormone-associated peptide, GAP).

3. Chorionic somatomammotropin (CS; placental lactogen) is a hormone that exhibits lactogenic and luteotropic activities, while its metabolic effects are similar to those of somatotropin. The true Physiological Role of CS in The Human Body remains unclear.

II. The group of pituitary tropic hormones comprises glycoprotein compounds: thyroid-stimulating hormone, and the pituitary and placental gonadotropins (follicle-stimulating hormone, luteinizing hormone, chorionic gonadotropin).

Each hormone in this group is a dimer consisting of two subunits, α and β, linked together by non-covalent bonds. The Molecular Weight of these hormones is approximately 30 kDa, with carbohydrate (oligosaccharide) groups accounting for 15-30% of the molecular mass. The oligosaccharide radicals include residues of galactose, mannose, fucose, galactosamine, glucosamine, and sialic acid.

The α-subunits are identical across all four glycoprotein hormones, whereas the β-subunits differ and determine the biological Specificity of each hormone. The α-subunits are shorter (containing 89-96 amino acid residues) and linked to 2 carbohydrate radicals, while the β-subunits are longer and compositionally variable (containing 113-119 amino acid residues and several carbohydrate radicals):

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Structural diagram of glycoprotein hormones (carbohydrate residues are indicated by bold dots).

The genes encoding the α- and β-subunits of glycoprotein hormones are located on different Chromosomes, specifically chromosome 6 and chromosome 1, respectively.

Thyroid-stimulating hormone (TSH; thyrotropin), similar to other pituitary glycoprotein hormones, is an αβ-type dimer (molecular weight approx. 30 kDa). The hormone is synthesized by basophilic cells of the anterior pituitary lobe, known as thyrotrophs, which make up 3-5% of The Cell population in the adenohypophysis.

The primary biological function of TSH is to maintain the structural integrity and functional activity of The Thyroid Gland (the synthesis of THYROID HORMONES). The effects of TSH on thyrocytes are mediated through a membrane mechanism: the interaction of the hormone with Membrane Receptors via various G-proteins leads to the activation of adenylate cyclase and phospholipase C. Thus, the TSH-induced activation of the hormone-producing function of the thyroid gland is achieved through several secondary messengers: cAMP, Inositol 1,4,5-trisphosphate, and diacylglycerol.

The release of TSH by the pituitary gland is positively modulated by the specific hypothalamic hormone thyrotropin-releasing hormone (TRH). Conversely, the thyroid hormones thyroxine and triiodothyronine inhibit the thyrotropic function of the pituitary by suppressing the hypothalamic secretion of TRH.

Pathological production of TSH can occur in the presence of thyrotropin-secreting pituitary adenomas, manifesting as symptoms of thyrotoxicosis (see below).

Gonadotropic hormones

Gonadotropins are hormones that ensure normal gametogenesis and the production of corresponding sex hormones in both male and female organisms. Structurally, these glycoproteins are also αβ-type dimers. Gonadotropins are synthesized in basophilic pituitary cells called gonadotrophs, which account for 10-15% of the total adenohypophyseal cell population. During pregnancy, physiological hyperplasia of gonadotrophs occurs.

1. Follicle-stimulating hormone (FSH; follitropin) is a protein with a molecular weight of 33 kDa. The target cells for FSH are ovarian follicular cells and Sertoli cells of the Testes. The chemical signal transmission upon FSH action is mediated by the activation of adenylate cyclase.

2. Luteinizing hormone (LH; lutropin; interstitial cell-stimulating hormone — ICSH) is a protein with a molecular weight of 29 kDa. Receptors for LH are localized on the plasma membranes of ovarian cells (in females) and testicular Leydig cells (in males). As with FSH, cAMP serves as The secondary messenger mediating the action of LH on cellular effector systems.

3. Chorionic gonadotropin (CG) is a protein with a molecular weight of approximately 37 kDa, synthesized by the placental trophoblast.

The Biological Role of gonadotropins consists in regulating the Functions of the human Reproductive System during the prepubertal and pubertal periods, as well as in adults, controlling both gametogenesis and sex hormone production.

In females, FSH and LH control the Menstrual cycle (see Chapter 25) by stimulating follicular growth, estrogen synthesis within follicles (predominantly mediated by FSH), ovulation and corpus luteum formation (FSH action in the presence of LH), as well as corpus luteum persistence and progesterone production (mediated by LH and/or CG during pregnancy).

In males, FSH promotes Spermatogenesis by inducing the proliferation of Sertoli cells and the spermatogenic epithelium, and by increasing the sensitivity of Leydig cells to LH (by upregulating LH-sensitive receptors). The target for LH (ICSH) is the interstitial Leydig cells, in which the hormone stimulates The biosynthesis of testosterone—the primary male sex hormone—from Cholesterol.

The secretion of gonadotropic hormones is regulated by the hypothalamus through the release of gonadotropin-releasing hormone (GnRH), which stimulates the adenohypophysis to synthesize and secrete both FSH and LH. Prolaktostatin (gonadotropin-releasing hormone-associated peptide, GAP) also exhibits GnRH-like properties. Similar to other adenohypophyseal tropic hormones, the production of FSH and LSH is controlled via negative feedback by sex hormone concentrations: elevated blood levels of estrogens and androgens inhibit LH release, whereas FSH secretion is suppressed by progesterone. A decline in gonadal functional activity (menopause, surgical or radiation castration) is accompanied by stimulated gonadotropin secretion.

Impairments in the synthesis, secretion, and/or reception of gonadotropins are observed in numerous hereditary and acquired disorders that can lead to various Clinical forms of reproductive dysfunction in humans.

III. The pro-opiomelanocortin group — the hormones belonging to this family are products of the post-translational Processing of a biological precursor, the prohormone pro-opiomelanocortin (POMC).

Generation of physiologically active peptides from pro-opiomelanocortin.

POMC is synthesized in the basophilic cells of the pituitary gland; it is a glycoprotein consisting of 239 amino acid residues (molecular weight of approximately 30 kDa) and serves as a precursor for numerous physiologically active peptides with hormonal and neurotransmitter actions, which are formed from POMC via Limited proteolysis and covalent modification reactions (glycosylation, Acetylation).

POMC processing occurs in the anterior and intermediate lobes of the pituitary gland (the intermediate lobe is active only during the Embryonic period and in women during late pregnancy) and in certain peripheral tissues, such as the Placenta, intestines, and male reproductive tract. The main products of this processing are:

- adrenocorticotropic hormone (ACTH), which in turn serves as a precursor for melanocyte-stimulating hormone (α-MSH) and the corticotropin-like intermediate lobe peptide (CLIP);

- β-lipotropic hormone (β-LPH), which serves as a precursor for γ-lipotropin (γ-LPH), β-MSH, and endorphins (β, γ, α).

1. Adrenocorticotropic hormone (ACTH; corticotropin) is a single-chain peptide consisting of 39 amino acid residues (molecular weight of 4.5 kDa).

Primary structure of human ACTH.

The primary targets of ACTH are the cells of the adrenal cortex, upon which the hormone exerts Two Types of biological activity: stimulation of steroidogenesis and maintenance of Adrenal gland mass.

(1) The effect of ACTH on the Biosynthesis of Adrenal hormones is driven by the activation of cAMP-dependent protein Kinases, which catalyze key reactions in The conversion of cholesterol to pregnenolone—the precursor of C₂₁-steroid corticosteroids. The primary effect of this action is the stimulation of glucocorticoid synthesis (mainly cortisol); however, under conditions of prolonged stimulation of the adrenal cortex by corticotropin (Cushing's Disease, administration of pharmacological ACTH preparations), the synthesis of mineralocorticoids and androgens is also activated.

(2) The increase in adrenal cortical mass induced by ACTH (primarily in the zona reticularis and zona fasciculata) is likewise mediated through the stimulation of cAMP-dependent protein kinases, which phosphorylate specific ribosomal proteins and stimulate the DNA and RNA Synthesis necessary for the generation of new cells.

The extra-adrenal effects of ACTH include the stimulation of lipolysis in adipose tissue and the activation of Amino Acid and glucose uptake by muscles. ACTH also exhibits a certain melanocyte-stimulating effect (increased Skin pigmentation), which is attributed to the presence in its primary structure of a tetrapeptide sequence shared with MSH (see below).

The pituitary release of ACTH is subject to complex neurohumoral control involving both positive and negative feedback loops: the positive regulators include the hypothalamic hormone corticotropin-releasing hormone, as well as vasopressin, adrenaline, and angiotensin II, while the negative regulator is the glucocorticoid cortisol.

2. Lipotropic hormone (LPH; lipotropin) is a group of peptides possessing The ability to activate lipolysis in adipose tissue adipocytes and the mobilization of Fatty acids.

Both β- and γ-lipotropins have been found in the human pituitary gland; given that the specific lipolytic activity of these peptides is negligible compared to that of other HORMONES AND BIOREGULATORS, it is widely believed that their primary physiological significance lies in the production of endorphins.

3. Endorphins are members of the opioid neuropeptide family (α-, β-, γ-, and δ-endorphins) that function as neurotransmitters, endogenous analgesics, and modulators of key psychophysiological processes within peptidergic brain structures (Chapter 33).

4. Melanocyte-stimulating hormone (MSH) is a group of peptides (α-, β-, γ-MSH) produced in the intermediate lobe of the pituitary gland that stimulate the functional activity of skin melanocytes, thereby increasing skin pigmentation. The Biochemical Mechanisms of MSH action involve increasing the activity of tyrosinase, an enzyme involved in the conversion of tyrosine into melanin pigments. This specific biological activity of various MSH peptides is due to the presence of a characteristic tetrapeptide sequence, -His-Phe-Arg-Trp-, in the hormone's primary structure, which is also present in the ACTH molecule.

Various types of MSH are present in mammalian pituitary glands; however, the physiological function of the hormone in humans remains insufficiently understood due to the regression of the pituitary intermediate lobe in adults—α-MSH is detected in humans exclusively in fetal pituitary glands, in cases of pituitary tumors, and occasionally during pregnancy.

B. Hormones of the posterior pituitary

The hormones of the posterior pituitary are vasopressin and oxytocin. These are neurohypophyseal hormones, as the posterior pituitary merely serves as a storage site for them, whereas their biosynthesis takes place in the supraoptic and paraventricular nuclei of the hypothalamus. Synthesized within hypothalamic neurosecretory cells, the hormones are transported to the posterior pituitary along the axons of the hypothalamo-neurohypophyseal tract; they are transported in the form of granules complexed with a carrier protein called neurophysin.

Vasopressin and oxytocin are cyclic peptides consisting of 9 amino acid residues (nonapeptides); the primary structures of the two hormones differ solely in The amino acid residues occupying the 3rd and 8th positions.

(1) Vasopressin

The BIOLOGICAL FUNCTIONS OF vasopressin (antidiuretic hormone, ADH) are associated with The regulation of osmolarity and the Osmotic Pressure of Body Fluids.

The BIOCHEMICAL BASIS OF vasopressin's physiological effects lies in the stimulation of Water reabsorption in the distal renal tubules. Additionally, the hormone helps maintain blood pressure through a direct effect on the vascular wall, enhances Glycogenolysis in The Liver and muscles, and induces platelet aggregation and the release of coagulation factors.

The MOLECULAR MECHANISMS OF vasopressin action rely on the presence of two receptor types for this active peptide:

V₁ receptors (located on the membranes of hepatocytes, vascular smooth Muscle, and platelets), which are coupled to phospholipase C, whose activation triggers the phosphoinositide cycle (producing IP₃ and DAG) and increases intracellular Ca²⁺ ion concentration;

V₂ receptors (located on the membranes of epithelial cells in the renal tubules and loops of Henle), which are coupled to adenylate cyclase activation and cAMP generation; the sequential action of this biochemical cascade leads to an increase in the water permeability of target cell membranes.

Impairments in the synthesis, transport, and release of vasopressin in the hypothalamus, or decreased sensitivity of nephron receptors to the hormone, lead to a severe condition known as diabetes insipidus. Its clinical manifestations include The excretion of large volumes of urine (several liters per day) with a low specific gravity, accompanied by constant thirst.

(2) Oxytocin

The physiological action of oxytocin involves stimulating uterine smooth muscle contractions (inducing labor) and contracting the myoepithelial cells surrounding the alveoli of the Mammary Glands (facilitating milk ejection from the alveoli into the lactiferous ducts during lactation). The hormone's effects on target cells are mediated via the adenylate cyclase system with the obligatory participation of Ca²⁺ ions.