GENERAL PRINCIPLES OF METABOLISM REGULATION. HORMONES.

Levels of the homeostasis regulation Highest level – nervous system Intermediate - hormonal regulation Intracellular (enzymes)

Hormones – organic biologically active compounds of different chemical nature that are produced by the endocrine glands, enter directly into blood and accomplish humoral regulation of the metabolism of compounds and functions on the organism level. Hormonoids (tissue hormones) – compounds that are produced not in glands but in different tissues and regulate metabolic processes on the local level, but some of them (serotonin, acetylcholine) enter blood and regulate processes on the organism level.

Specific stimulus for hormones secretion is: nervous impulse concentration of the certain compound in blood passing through the endocrine gland

Endocrine glands: 1. Hypothalamus 2. Pituitary 3. Epiphysis 4. Thymus 5. Thyroid gland 6. Parathyroid glands 7. Langergans’ islands of pancreas 8. Epinephrine glands 9. Sex glands

Classification of hormones according to chemical nature Proteins: hormones of anterior pituitary (except ACTH), insulin, parathyroid hormone. Peptides: ACTH, calcitonin, glucagon, vasopressin, oxytocin, hormones of hypothalamus (releasing factors and statins). Derivatives of amino acids: catecholamins (epinephrine and norepinephrine), thyroxin, triiodthyronin, hormones of epiphysis. Steroid (derivatives of cholesterol): hormones of the cortex of epinephrine lands, sex hormones. Derivatives of polyunsaturated fatty (arachidonic) acids: prostaglandins.

Fate of hormones in the organism Are secreted directly into the blood Peptide and protein hormones are secreted by exocytosis Steroid (lipophilic) hormones continuously penetrate the membrane (they are not accumulated in cells, their concentration in blood is determined by the speed of synthesis)

Transport of hormones in blood Protein and peptide nature – in free state Steroid hormones and hormones of thyroid gland – bound with alpha-globulins or albumins Catecholamines – in free state or bound with albumins, sulphates or glucuronic acid Reach the target organs Cells have the specific receptors to certain hormone

Receptors of hormones Two groups: placed on the surface of membrane – peptide and protein hormones, prostaglandins; placed inside the cells (cytoplasm, nucleus) – steroid and thyroid hormones

Model of the insulin receptor ( Jacobs, Cautrecasas, 1982)                                                                                                    Model of the insulin receptor ( Jacobs, Cautrecasas, 1982)  

Inactivation of hormones After biochemical effect hormones are released and metabolized Hormones are inactivated mainly in liver Inactive metabolites are excreted mainly with urine Half-time life from several min to 20 min – for the majority of hormones till 1 h – for steroid hormones till 1 week – for thyroid hormones

THE FINAL EFFECTS OF HORMONES ACTION Change the permeability of cell membrane, accelerate the penetration of substrates, enzymes, coenzymes into the cell and out of cell. Acting on the allosteric centers affect the activity of enzymes (Hormones penetrating membranes). Affect the activity of enzymes through the messengers (cAMP). (Hormones that can not penetrate the membrane). Act on the genetic apparatus of the cell (nucleus, DNA) and promote the synthesis of enzymes (Steroid and thyroid hormones).

HYPOTHALAMUS It is located in the base of forebrain between thalamus and pituitary gland. Has wide anatomical bonds and collects information from another structures of brain. Collect information from blood flowing through hypothalamus.

Tight anatomical bonds with pituitary gland Two groups of hormones related to anterior and posterior lobes of pituitary

Hypothalamus and posterior lobe of pituitary 3 peptides are synthesized Migrate along axons into posterior lobe of pituitary Antidiuretic hormone (vasopressin) Oxytocin Neurophysin (promotes transport of vasopressina and oxytocin into pituitary gland)

Hypothalamus and anterior pituitary Bound with anterior pituitary by the capillary net – hypothalamic portal system Releasing factors and statins rich the anterior pituitary via this system

Secretion of liberins and statins by hypothalamus is carried out under the effect of nervous impulses and as result of the change of concentrations of certain hormones in blood (feedback regulation). Releasing factors (liberins) stimulate secretion of pituitary hormones; statins - inhibit. somatoliberin, thyroliberin, corticoliberin, foliliberin, prolactoliberin, luteinising-hormone liberin, melanoliberin somatostatin, prolactostatin, melanostatin

HYPOPHISIS - “conductor of the hormonal orchestra of the organism” There are hormones of anterior, posterior and intermediate lobes of pituitary gland. The most important – anterior lobe (secrets tropic hormones) Tropic – because stimulate functions of peripheral endocrine glands

TROPIC HORMONES OF PITUITARY Somatotropic hormone (growth hormone) Chemical nature – simple protein It is secreted continuously during the whole life Secretion is stimulated by somatoliberin, is inhibited by somatostatin Main function – stimulates somatic growth of organs and tissues, particularly bones, cartilages, muscles.

Acts both directly and through the stimulation of the formation of polypeptides somatomedins (insulin-like growth factors). ILGF are synthesized in liver

The effect of STH on the protein metabolism Promotes the entrance of AA into cells, Inhibits catabolism of proteins and AA Activates the synthesis of proteins, DNA, RNA. The effect of STH on the carbohydrate metabolism Antiinsulin hormone – activates insulinase of liver Activates the exit of glucose from liver Inhibits the conversion of glucose into fat The effect of STH on lipid metabolism Stimulates the decomposition of lipids (lipolisis) Stimulates the oxidation of fatty acids.

In the inherited hypoplasia of pituatary gland dwarfism is developed. For the treatment GH is used.

Yao Defen, the tallest women in the life, 2.36 м Hyperproduction of GH before puberty and before the completion of ossification results in gigantism Yao Defen, the tallest women in the life, 2.36 м

Hyperfunction of pituitary inadults results in acromegaly – unproportionally intensive growth of particular body parts (fingers, nose, lower jaw, tongue, inner organs). Cause – tumor of anterior pituitary

Adrenocorticotropic hormone (АCTH) Chemical nature – polipeptide Secretion is stimulated by corticoliberin Feedback regulation of the speed of secretion depending on the cortisol level Controls the cortex of epinephrine gland where cortisol is produced: promotes the increase of cholesterol content in epinephrine glands cortex and its conversion into corticosteroids; activates the passing of glucose into epinephrine glands and pentose phosphate cycle (NADPH synthesis) has melanocyte stimulating activity

Cushing’s disease Cushing's disease – hyperproduction of ACTH (adenoma in a pituitary gland) which in turn elevates cortisol. Obesity, particularly of the trunk and face (“moon face“) with sparing of the limbs; striae (stretches of the skin) Proximal muscle weakness Hirsutism (facial male-pattern hair growth) Insomnia, impotence, amenorrhoea, infertility Heart diseases, hypertension Polyuria, hypokalemia hyperglycemia, glucosuria (steroid diabetes) Kidney bones Depression, anxiety Hyperpigmentation

Thyrotropic hormone (ТТH) Chemical structure – protein (glycoprotein) Secretion is stimulated by thyroliberin The speed of secretion is regulated according to the feedback regulation by thyroid hormones It is necessary for the normal functioning of thyroid gland: promotes the accumulation of iodine in thyroid gland and its insertion into tyrosine; stimulates the synthesis of try- and tetraiodthyronin

Gonadotropic hormones Follicle-stimulating гормон Chemical nature – protein (glycoprotein) Secretion is stimulated by foliliberin Function: stimulates the function of follicles in women and spermatogenesis in men Luteinizing hormone Chemical nature – protein (glycoprotein) Secretion is stimulated by luliberin Function: stimulates the follicular growth and conversion of the follicle into a corpus luteum n women and secretion of testosterone in men

Prolactin Chemical nature – protein Secretion is stimulated by prolactoliberin Functions: -stimulates the function of mammary glands (lactation); -provides the body with sexual gratification after sexual acts -stimulates the function of corpus luteum (progesterone secretion); -stimulates the growth of tissue of prostatic gland in men; -responsible for the mother instinct

Lipotropic hormones Chemical nature – simple proteins Functions: -mobilization of lipids from depot; -melanocyte stimulating function; -decrease Ca in blood

THE INTERMEDIATE LOBE OF PITUITARY Melanocyte stimulating hormone (melanotropin) Chemical nature – peptide Functions: -stimulates melaninogenesis; -adaptation of vision in darkness

POSTERIOR LOBE OF PITUITARY Vasopressin (antidiuretic hormone) Chemical nature – peptide

Functions: -activates hyaluronidase which decomposes hyaluronic acid in the membranes of kidney canaliculi – increases the reabsorption of water in kidneys; -contractions arterioles and capillaries – increases blood pressure Insufficiency – diabetes insipidus (polyuria, low density of urine, dehydratation)

Oxytocin Chemical nature – peptide

Functions: -stimulates the contraction of smooth muscles (of uterus during labor) stimulates milk secretion (contraction of muscle fibers around mammary alveoli) Using: -for labor stimulation; -to stop after labor hemorrhage; -for stimulation of milk secretion

EPIPHYSIS (PINEAL GLAND) Produces: Мelatonin from serotonin (regulates the pigment metabolism) Adrenoglomerulotro-pin – stimulates secretion of mineralocorticoids in the epinephrine glands cortex. Inhibitor of gonadotropin – inhibits the synthesis of prolactin, cholesterol

PANCREAS Exocrine and endocrine parts Endocrine – Langerhans islets (alpha-, beta- and delta-cells)

Alpha-cells: glucagon Beta-cells: insulin Delta-cells: somatostatin Epithelium of ducts: lipocain

Insulin Nature – protein (51 АA) Is formed from proinsulin by proteolisis Contains zinc

Regulation of the synthesis: Glucose concentration in blood Other hormones (somatostatin) Sympathetic and parasympathetic nervous system It is destroyed by insulinase (enzyme of liver) Target cells: Hepatocytes Myocytes Adipocytes In the unsufficiency – diabetes mellitus

The effect on carbohydrate metabolism Increases the permeability of membranes for glucose Activates glucokinase (hexokinase) in glycolysis Activates TAC (citrate synthase) Activates PPC (G-6-PDH) Activates glycogen synthase Activates pyruvate- and alpha-кetoglutarate dehydrogenase Inhibits gluconeogenesis Inhibits the decomposition of glycogen (glucose-6-phosphatase)

Effect on the protein metabolism Increases the permeability of membranes for AA Activates synthesis of proteins and nucleic acids Inhibits gluconeogenesis Effect on the lipid metabolism Activates of the lipids synthesis Promotes the saving of fats activating the decomposition of carbohydrates Effect on the mineral metabolism Activates Na/K-АТP-аse

Glucagon Nature – polypeptide Antagonist of insulin Synthesis is activated in fasting

Functions Activates the decomposition of glycogen in liver Activates gluconeogenesis Inhibits glycolysis Activates lipolysis

Somatostatin Nature – peptide Functions: Inhibits secretion of insulin and glucagon Inhibits secretion of STH and TTH Inhibits secretion of local hormones of intestine

Lipocain Functions: Activates the synthesis of phospholipids in liver Stimulates the action of lipotropic factors Activates the oxidation of fatty acids in liver

THYROID GLAND Hormones of two types: 1. Iodine containing : thyroxin (tetraiodthyronin) and triiodthyronin – derivatives of tyrosine; 2. Calcitonin - peptide 48

Synthesis of iodine containing hormones is regulated by thyrotropic hormone, which in turn is stimulated by thyroliberin 49

Functions of iodine containing hormones Necessary for normal growth, differentiation, sex and mental development Regulate the speed of metabolism 50

Effect on protein metabolism Effect on carbohydrate metabolism In physiological concentration stimulate synthesis of proteins, nucleic acids. In the increased concentration activate the protein decomposition. Effect on carbohydrate metabolism Accelerate the absorption of carbohydrates in the intestine Activate the decomposition of glycogen. 51

Effect on lipid metabolism Effect on energetic metabolism Activate the exit of lipids from depot, its decomposition and oxidation Effect on energetic metabolism In excess thyroxin uncouples respiration and phosphorilation, decreases the ATP formation and increases the heat formation 52

Hyperfunction of gland – diffuse toxic goiter (thyrotoxicosis, Graves disease) Goiter – hyperplasia of gland Hypermetabolism Increase of body temperature Sweating, muscle weakness Weight loss with good appetite Tremor, emotional lability, insomnia Exophtalm 53

Hypofunction of gland (occurs in the deficit of iodine in water, soil, air) Decrease of metabolism Decrease of body temperature Hypofunction in childhood - cretinism Growth inhibition Unproportional body development Disorders of mental development Hypofunction in adults – mixedema Edema of mucosa mixedema cretinism 54

Endemic goiter (occurs in the deficit of iodine in water, soil and air) Connective tissue is enlarged in gland and it is increased in size markedly 55

Calcitonin Is synthesized by parafollicular cells of thyroid gland Affects the metabolism of Са and Р Promotes the transferring of Са2+ from blood into bones Inhibits reabsorption of Р in kidneys (decreases the content of Р in blood due to its excretion with urine) 56

Increase of calcitonin hypocalciemia hypophosphatemia hyperphosphaturia Decrease of calcitonin - hypercalciemia hyperphosphatemia hypophosphaturia 57

PARATHYROID GLANDS Parathyroid hormone - protein Affects the metabolism of Са and Р Promotes moving of Са2+ from bones into blood Inhibits reabsorption of Р in kidneys (decreases the content of Р in blood due to its excretion with urine) Stimulates the absorption of Ca in the intestine Дія зв’язана з вітаміном D (утворює активну форму вітаміну D в нирках) 58

Hyperfunction (Recklinghausen’s disease) Hypofunction hypocalciemia hyperphosphatemia hypophosphaturia tetanus Hyperfunction (Recklinghausen’s disease) hypercalciemia hypophosphatemia hyperphosphaturia osteoporosis Accumulation of Са in tissues 59

EPINEPHRINE GLANDS Two parts: -cortex -medulla 60

Hormones of medulla - catecholamines Epinephrine, norepinephrine and DOPA Nature – derivatives of tyrosine Excretion is regulated by sympathetic nervous system and brain cortex 61

Functions: Stress hormones. Contraction of vessels, increase the blood pressure, accelerate pulse. Contraction of uterus muscles. Epinephrine relaxes the muscles of bronchi and intestine. On carbohydrate metabolism: -activates the decomposition of glycogen in liver and muscles -activates glycolysis, PPC, TAC and tissue respiration On protein metabolism -accelerate the decomposition of proteins On lipid metabolism -activates lipase, mobilization of lipids and their oxidation 62

Hormones of cortex - corticosteroids There are more than 50 corticosteroids Nature – steroids Are synthesized from cholesterol Two groups -glucocorticoids (protein, carbohydrate and lipid metabolism) -mineralocorticoids (mineral metabolism) 63

Glucocorticoids Most important: corticosteron, cortison, hydrocortison Synthesis is regulated by ACTH Are transported combined with proteins Half-life time – till 1 hour In the decomposition17-ketosteroids are formed (excretion with urine). Diagnostic significance – index of the function of cortex of epinephrine glands and testis 64

65

Functions Antiinflammatory, antiallergic, antiimmune Adaptive effect Maintain the blood pressure Maintain the volume of extracellular liquid 66

Effect on protein metabolism Stimulate catabolic processes in connective, lymphoid and muscle tissues Activate protein synthesis in liver Stimulate amino transferases Stimulate the urine biosynthesis 67

Effect on the carbohydrate metabolism Effect on the lipid metabolism Increase the glucose level Activate gluconeogenesis Inhibit hexokinase (glycolisis) Effect on the lipid metabolism Activate lipolysis Activate the conversion of FA into carbs 68

Mineralocorticoids Functions: The most important hormone: aldosteron Excretion is controlled by rhenin-angiothensin system Functions: -activate the reabsorption of Na, water and Cl in kidney canaliculi - Promotes the excretion of К ions via the kidneys, skin and saliva 69

Disorders of the function of epinephrine gland cortex Insufficiency: Addison disease (bronze disease) Causes: -injury of epinephrine gland cortex -insufficient production of ACTH Blood pressure decrease, loss of weight, weakness, anorexia. Hyperpigmentation - bronze skin 70

Hyperproduction: Kushing syndrom Causes: hypeplasia or tumor of epinephrine gland cortex Obesity, particularly of the trunk and face (“moon face“) with sparing of the limbs; striae (stretches of the skin) Proximal muscle weakness Hirsutism (facial male-pattern hair growth) Insomnia, impotence, amenorrhoea, infertility Heart diseases, hypertension Polyuria, hypokalemia hyperglycemia, glucosuria (steroid diabetes) Kidney bones Depression, anxiety Hyperpigmentation 71

Aldosterone hyperproduction Causes: -aldosteroma Symptoms: -hypokaliemia -hypernatriemia -hyperchloremia -hypervolemia -edema, hypertension 72

Sex hormones Are synthesized in: -sex glands -placenta -cortex of epinephrine glands A little amount of female sex hormones is formed in male organism and vice versa. Female – estrogens, progesteron. Male – androgens. 73

Estrogens Nature: steroids Estradiol – is formed in follicles of ovarium Estron and estriol – are formed in liver and placenta in the metabolism of estradiol естріол eстрадіол 74

Functions of estrogens Biochemical functions of estrogens Development of the female reproductive system organs Ability to fertility in reproductive period Biochemical functions of estrogens Anabolic action on the tissues of reproductive organs Inhibit the exit of Ca from bones (osteoporosis in menopause) 75

Progesteron Nature: steroid Is formed in corpus luteum, placenta and epinephrine glands 76

Functions of progesteron Prepares the endometrium of uterus to implantation of ovum Inhibits the uterus contraction during pregnancy Stimulates the growth of mammary glands 77

Androgens Testosteron Nature: steroid Is formed in the interstitial cells of testis Is excreted as 17-кetosteroids 78

Functions of testosterone Biochemical functions of testosterone Development of the primary sex features Development of the secondary sex features Stimulates spermatogenesis Biochemical functions of testosterone Strong anabolic action (stimulates the synthesis of NA, proteins, phospholipids) – increases the mass of muscles Keeps the Ca and P in organism 79

Derivatives of androgens – active anabolics 80