GENERAL PRINCIPLES OF THE METABOLIC PROCESSES REGULATION IN THE HUMAN ORGANISM

General principles of the metabolic processes regulation in the human organism. Hormones: general characteristics, classification. Hormones of a pituitary gland. Hormones of thyroid, parathyroid, pancreatic, adrenal and sex glands.

 

The survival of multicellular organisms depends on their ability to adapt to a constantly changing environment. Intercellular communication mechanisms are necessary requirements for this adaptation. The nervous system and the endocrine system provide this intercellular, organism- wide communication. The nervous system was originally viewed as providing a fixed communication system, whereas the endocrine system supplied hormones, which are mobile messages. In fact, there is a remarkable convergence of these regulatory systems. For example, neural regulation of the endocrine system is important in the production and secretion of some hormones; many neurotransmitters resemble hormones in their synthesis, transport, and mechanism of action; and many hormones are synthesized in the nervous system.

Hormones are chemical signaling substances. They are synthesized in specialized cells that are often associated to form endocrine glands. Hormones are released into the blood and transported with the blood to their effector organs. In the organs, the hormones carry out physiological and biochemical regulatory functions. In contrast to endocrine hormones, tissue hormones are only active in the immediate vicinity of the cells that secrete them. The distinctions between hormones and other signaling substances (mediators, neurotransmitters, and growth factors) are fluid. Mediators is the term used for signaling substances that do not derive from special hormone- forming cells, but are formbymany cell types. They have hormone-like effects in their immediate surroundings. Histamine and prostaglandins are important examples of these substances. Neurohormones and neurotransmitters are signaling substances that are produced and released by nerve cells.

Endocrine glands: hypothalamus, pituitary, epiphysis, thyroid, parathyroid, thymus, pancreas, adrenal glands, sex glands

Hormonoids (tissue hormones, histohormones) - organic trace substances produced by different cells of different tissues (not by specific glands) that regulate metabolism on the local level (some hormonoids  are produced in the blood too (serotonin, acetylcholine).

Hormones regulate the following processes:

Growth and differentiation of cells, tissues, and organs These processes include cell proliferation, embryonic development, and sexual differentiation— i. e., processes that require a prolonged time period and involve proteins de novo synthesis. For this reason, mainly steroid hormones which function via transcription regulation are active in this field

Metabolic pathways Metabolic regulation requires rapidly acting mechanisms. Many of the hormones involved therefore regulate interconversion of enzymes. Themain processes subject to hormonal regulation are the uptake and degradation of storage substances (glycogen, fat), metabolic pathways for biosynthesis and degradation of central metabolites (glucose, fatty acids, etc.), and the supply of metabolic energy.

Digestive processes  Digestive processes are usually regulated by locally acting peptides (paracrine), but mediators, biogenic amines, and neuropeptides are also involved.

Maintenance of ion concentrations (homeostasis) Concentrations of Na+, K+, and Cl– in body fluids, and the physiological variables dependent on these (e. g. blood pressure), are subject to strict regulation. The principal site of action of the hormones involved is the kidneys, where hormones increase or reduce the resorption of ions and recovery of water. The concentrations of Ca2+ and phosphate, which form the mineral substance of bone and teeth, are also precisely regulated. Many hormones influence the above processes only indirectly by regulating the synthesis and release of other hormones (hormonal hierarchy).

Endocrine, paracrine, and autocrine hormone effects.

Hormones transfer signals by migrating from heir site of synthesis to their site of action. They are usually transported in the blood. In this case, they are said to have an endocrine effect (example: insulin). By contrast, tissue hormones, the target cells for which are in the immediate vicinity of the glandular cells that produce them, are said to have a paracrine effect (example: gastrointestinal tract hormones). When signal substances also pass effects back to the cells that synthesize them, they are said to have an autocrine effect (example: prostaglandins). Autocrine effects are often found in tumor cells, which stimulate their own proliferation in this way. Insulin,which is formed in the B cells of the pancreas, has both endocrine and paracrine effects. As a hormone with endocrine effects, it regulates glucose and fat metabolism. Via a paracrinemechanism, it inhibits the synthesis and release of glucagon from the neighboring A cells.

Classification of hormones.

The animal organism contains more than 100 hormones and hormone-like substances, which can be classified either according to their structure or according to their function. In chemical terms, most hormones are:

Ø     hormones of protein structure: all hormones of anterior pituitary (except ACTH), insulin, parathyroid hormone;

Ø      hormones of peptide structure: ACTH, calcitonin, glucagon,hormones of posterior pituitary, factors of hypothalamus, thymozin;

Ø      steroid hormones: adrenal cortical steroids, sex hormones;

Ø     hormones - derivatives of amino acid: thyroid hormones, adrenal medulla hormones, epiphysis hormones;

Ø     .hormones derivatives of unsaturated fatty acid: prostaglandins.

 Mechanism of action

A.   Mechanism of action of lipophilic hormones

Lipophilic signaling substances include the steroid hormones, calcitriol, the iodothyronines (T3 and T4), and retinoic acid. These hormones mainly act in the nucleus of the target cells, where they regulate gene transcription in collaboration with their receptors and with the support of additional proteins (known as coactivators and mediators). There are several effects of steroid hormones that are notmediated by transcription control. These alternative pathways for steroid effects have not yet been fully explained. In the blood, there are a number of transport proteins for lipophilic hormones. Only the free hormone is able to penetrate the membrane and enter the cell. The hormone encounters its receptor in the nucleus (and sometimes also in the cytoplasm). The receptors for lipophilic hormones are rare proteins. They occur in small numbers (103–104 molecules per cell) and show marked specificity and high affinity for the hormone (Kd = 10–8–10–10 M). After binding to the hormone, the steroid receptors are able to bind as homodimers or heterodimers to control elements in the promoters of specific genes, from where they can influence the transcription of the affected genes—i. e., they act as transcription factors. The illustration shows the particularly well-investigated mechanism of action for cortisol, which is unusual to the extent that the hormone–receptor complex already arises in the cytoplasm. The free receptor is present in the cytoplasm as a monomer in complex with the chaperone hsp90. Binding of cortisol to the complex leads to an allosteric conformational change in the receptor, which is then released from the hsp90 and becomes capable of DNA binding as a result of dimerization. In the nucleus, the hormone–receptor complex binds to nucleotide sequences known as hormone response elements (HREs). These are short palindromic DNA segments that usually promote transcription as enhancer elements. The illustration shows the HRE for glucocorticoids (GRE; “n” stands for any nucleotide). Each hormone receptor only recognizes its “own” HRE and therefore only influences the transcription of genes containing that HRE. Recognition between the receptor and HRE is based on interaction between the amino acid residues in the DNA-binding domain (B) and the relevant bases in the HRE (emphasized in color in the structure illustrated). As discussed on p. 244, the hormone receptor does not interact directly with the RNA polymerase, but rather—along with other transcription factors—with a coactivator/mediator complex that processes all of the signals and passes them on to the polymerase. In this way, hormonal effects lead within a period of minutes to hours to altered levels ofmRNAs for key proteins in cellular processes (“cellular response”).

b.   Mechanism of action of hydrophilic hormones

The messages transmitted by hydrophilic signaling substances are sent to the interior of the cell by membrane receptors. These bind the hormone on the outside of the cell and trigger a new second signal on the inside by altering their conformation. In the interior of the cell, this secondary signal influences the activity of enzymes or ion channels. Via further steps, switching of the metabolism, changes in the cytoskeleton, and activation or inhibition of transcription factors can occur (“signal transduction”) can occur.

 Hormones of hypothalamus (releasing and inhibitory factors), structure, mechanism of action.

Hypothalamus has the wide anatomic links with other parts of the brain. Therefore in different mental disorders there is the change of secretion of hypothalamus hormones.

Two groups of hormones are produced by hypothalamus corresponding to the anterior and posterior pituitary.

Hypothalamus and posterior pituitary. 3 peptides are synthesized in the hypothalamus that pass to the posterior pituitary along axons where they are accumulated: oxytocin, vasopressin (antidiuretic hormone) and neurophysin. The later binds the oxytocin and vasopressin and promotes their transportation to the pituitary.

Hypothalamus and anterior pituitary. Hypothalamus is connected with the anterior pituitary by the net of blood capillaries, so called hypothalamic portal system. Hypothalamus produces very active peptide compounds that pass via this portal system to anterior pituitary and stimulate or oppress the secretion of tropic hormones. Compounds stimulating the secretion are called releasing factors. 7 releasing factors are known according to the amount of tropic hormones of anterior pituitary:

- corticotropin-releasing factor

- thyrotropin-releasing factors

- somatotropin-releasing factors

- follicletropin-releasing factor

- luteotropin-releasing factor

- prolactotropin-releasing factor

- melanotropin-releasing factor.

Hypothalamus also secretes substances called inhibitory factors or statins, which can inhibit release of the some pituitary hormones. 3 inhibitory factors are known today:

- somatostatin

- prolactostatin

- melanostatin.

Releasing and inhibitory factors are produced in only minute amounts.

 Hormones of pituitury, structure, mechanism of action.

Tropic hormones are produced by the anterior pituitary. Usually tropic hormones not directly regulate the metabolism but act on the peripheral endocrine glands.

Somatotropic hormone (STH, growth hormone).

The main function of somatotropic hormone - stimulation of growth. Hormone is necessary for the bone tissue formation, for the muscle tissue growth, for the formation of peculiarities of men and women body.

Somatotropic hormone can act both directly on the metabolism and indirectly stimulating the synthesis of somatomedines (specific protein growth factors which are synthesized in liver).

The deficiency of somatotropic hormone in children age causes nanism. Nanism - proportional underdevelopment of all body.

The deficiency of somatotropic hormone in adult persons hasn’t clinical symptoms.

The excess of somatotropic hormone in children age causes gigantism.

The excess of somatotropic hormone in adult persons causes acromegalia (disproportional development of the separate body parts).

Thyrotropic hormone (TTH).

Thyrotropic hormone promotes:-      accumulation of iodine in thyroid;-  including of iodine into the tyrosine;-        synthesis of thyroxine and triiodothyronine.

Adrenocorticotropic hormone (ACTH).

This hormone is necessary for the normal functions of adrenal cortex. It enhances the formation of steroid hormones and their secretion into the blood.

ACTH has also the melanocyte-stimulating activity.Excessive secretion of ACTH causes the Icenko-Kushing disease (symptoms of hypercorticism, hyperpigmentation).

Gonadotropic hormones.

Follicle stimulating hormone (FSH). Function: stimulates the function of follicles (oogenesis) in women and spermatogenesis in men.

Luteinizing hormone (LH).

Chemical. Function: stimulates the formation of yellow body in women and testosterone secretion in men.

Prolactin (PRL).Functions: - stimulates lactation;-       stimulates function of yellow body (secretion of progesterone);-   promotes formation of mother instinct;-   stimulates the formation of prostate glandular tissue in men.

Lipotropic hormone.Functions: - stimulates the mobilization of lipids from depot;          decreases the Ca amount in blood;   has the melanocyte-stimulating activity.

Posterior pituitary.

Vasopressin. Functions: - activates the hyaluronidase. This enzyme splits the hyaluronic acid. The permeability of membranes is increased and reabsorption of water in kidneys is increased too. As result the day diuresis is decreased; -        narrows arterioles and capillaries and increases the blood pressure.

The deficiency of vasopressin in organism causes diabetes insipidus. Clinical symptoms - poliuria, dehydration of the organism, low density of the urine.

Oxytocin.  Functions: stimulates the contraction of smooth muscles, especially the muscles of uterus and muscle fibres of alveoluses of mammas.

Oxytocin is used for delivery stimulation, for stop of bleeding after delivery, for stimulation of lactation.

Thyrotropin (thyroid-stimulating hormone, TSH) and the related hormones lutropin (luteinizing hormone, LH) and follitropin (follicle-stimulating hormone, FSH) originate in the adenohypophysis. They are all dimeric glycoproteins with masses of around 28 kDa. Thyrotropin stimulates the synthesis and secretion of thyroxin by the thyroid gland.

 

Insulin is produced and released by the B cells of the pancreas and is released when the glucose level rises. Insulin reduces the blood sugar level by promoting processes that consume glucose— e. g., glycolysis, glycogen synthesis, and conversion of glucose into fatty acids. By contrast, it inhibits gluconeogenesis and glycogen degradation.

Glucagon, a peptide of 29 amino acids, is a product of the A cells of the pancreas. It is the antagonist of insulin and, like insulin, mainly influences carbohydrate and lipid metabolism. Its effects are each opposite to those of insulin. Glucagon mainly acts via the second messenger cAMP

Hormones of adrenal glands.

Adrenal glands consist of two parts: external - cortex, internal - medulla.

Hormones of adrenal medulla – catecholamines (epinephrine, norepinephrine, dopamine). Chemical structure - these hormones are derivatives of amino acid tyrosine. Functions: causes very potent contraction of vessels and increase the blood pressure, increase a pulse rate. Epinephrine relaxes the smooth muscles of bronchi, intestine, promote the contraction of uterus smooth muscle. Epinephrine play a great role in stress reactions.

Hormones of thyroid and parathyroid, structure, mechanism of action.

Thyroid synthesizes two kinds of hormones: iodine containing hormones and calcitonin.Iodine containing hormones - thyroxine and triiodthyronine. Thyroxine and triiodthyronine are iodinated derivatives of amino acid tyrosine. Functions: these hormones are necessary for growth of organism, mental, physical and sex development, they regulate the rate of basal metabolism.

Effect of thyroxine and triiodthyronine on the protein metabolism:

1.     in normal concentration stimulate the synthesis of proteins and nucleic acids;

2.     in excessive concentration activate the catabolic processes.

Effect of thyroxine and triiodthyronine on the carbohydrate metabolism:

1.     promote the absorption of carbohydrates in the intestine;

2.     activates the decomposition of glycogen.

Effect of thyroxine and triiodthyronine on the lipid metabolism:

-         activate the lipid oxidation and mobilization.

Effect of thyroxine and triiodthyronine on the energy metabolism:

1.     activates dehydrogenases of mitochondria;

2.     in excessive amount of these hormones the disconnection of tissue respirstion and oxidative phosphorylation takes place. As result the formation of ATP is decreased and the temperature of the organism is increased.

Excessive secretion of thyroid hormones, called hyperthyroidism, is responsible for Graves' disease, or exophthalmic goiter, while deficiency in thyroid hormones, hypothyroidism, is characteristic of the disease myxedema.

Calcitonin. Calcitonin is synthesized by the parafollicle cells of thyroid. Functions: - promotes the transition of calcium from blood in bones;    inhibits the reabsorption of phosphorus in kidneys.Thus, calcitonin decreases the Ca and P contents in blood.

 Parathyroid glands. Parathyroid hormone. Functions:  promotes the transition of calcium from bones to blood; promotes the absorption of Ca in the intestine;   inhibits the reabsorption of phosphorus in kidneys.Thus, parathyroid hormone increases the Ca amount in blood and decreases the P amount in blood.

Hormones of adrenal cortex.

Adrenal glands consist of two parts: external - cortex, internal - medulla.Each part secrets specific hormones.Hormones synthesized in adrenal cortex are named corticosteroids. Corticosteroids have potent regulatory effect on all kinds of metabolism. Cholesterol is the precursor of corticosteroids. According to the biological effect corticosteroids are divided on two groups: glucocorticoids and mineralocorticoids. Glucocorticoids regulate the protein, lipid and carbohydrate metabolism, mineralocorticoids - metabolism of water and mineral salt.       

The most important glucocorticoids: corticosterone, hydrocortisone, cortisol. The most important mineralocorticoid: aldosterone. The synthesis of corticosteroids is regulated by ACTH.

Functions of glucocorticoids.

Glucocorticoids have antiinflammatory, antiallergic, antiimmune  effect. They support the blood pressure and constancy of the extracellular liquids.

The effect of glucocorticoids on protein metabolism:

1.     stimulate the catabolic processes (protein decomposition) in connective, lymphoid and muscle tissues and activate the processes of protein synthesis in liver;

2.     stimulate the activity of aminotransferases;

3.     activate the synthesis of urea.

 The effect of glucocorticoids on carbohydrate metabolism:

1.     activate the gluconeogenesis;

2.     inhibit the activity of hexokinase;

3.     activate the glycogen synthesis in liver.

Glucocorticoids causes the hyperglycemia.

The effect of glucocorticoids on lipid metabolism:

1.     promote the absorption of lipids in intestine;

2.     activate lipolisis;

3.     activate the conversion of fatty acids in carbohydrates.

 

Functions of mineralocorticoids.

Secretion of mineralocorticoids is regulated by renin-angiotensine system

-         activates the reabsorption of Na+, Cl- and water in kidney canaliculuses;

-         promote the excretion of K+ by kidneys, skin and saliva.

 

Deficiency of corticosteroids causes Addison's disease. For this disease the hyperpigmentation is typical because the deficiency of corticosteroids results in the excessive synthesis of ACTH. Hyperfunction of adrenal cortex causes Icenko-Cushing syndrome. This state is called steroid diabetes. Symptoms: hyperglycemia, glucosuria, hypercholesterolemia, hypernatriemia, hyperchloremia, hypokaliemia.

 

Sex hormones are synthesized in testes, ovaries. Smaller amount of sex hormones are produced in adrenal cortex and placenta. Small amount of male sex hormones are produced in ovaries and female sex hormones - in testes.

Chemical structure - steroids.

Synthesis and secretion of the sex hormones are controlled by the pituitary honadotropic hormones. Sex hormones act by means of the activation of gene apparatus of cells. Catabolism of sex hormones takes place in liver. The time half-life is 70-90 min.

The main estrogens: estradiol, estrole, estriole (are produced by follicles) and progesterone (is produced by yellow body and placenta). The main biological role of estrogens - conditioning for the reproductive female function (possibility of ovum fertilization). Estradiol results in the proliferation of endometrium and progesterone stimulates the conversion of endometrium in decidual tissue which is ready for ovum implantation. Estrogens also cause the development of secondary sexual features.

The main androgen is testosterone. Its synthesis is regulated by the luteinizing hormone. Testosterone forms the secondary sexual features in males.

Effect of sex hormones on protein metabolism:

1.     stimulate the processes of protein, DNA, RNA synthesis;

2.     cause the positive nitrogenous equilibrium.

 Effect of sex hormones on carbohydrate metabolism:

1.     activate the Krebs cycle;

2.     activate the synthesis of glycogen in liver.

 

Effect of sex hormones on lipid metabolism:

1.     enhance the oxidation of lipids;

2.     inhibit the synthesis of cholesterol.

Effect of sex hormones on energy metabolism:

-         stimulate the Krebs cycle, tissue respiration and ATP production.

Sex hormones are used for treatment of variety diseases. For example, testosterone and its analogs are used as anabolic remedies; male sex hormones are used for the treatment of malignant tumor of female sex organs and vice versa.

 Tissue hormones.

Prostaglandins. The precursor of prostaglandins is arachidonic acid. Time half-life - 30 s. There are different prostaglandins and they have a lot of physiological and pharmacological effects and different prostaglandins have different effects.

Prostaglandins: - decrease the activity of lipid tissue lipase;

-         regulate the calcium metabolism in muscle tissue and as result effect on the contraction and relaxation of muscles;

-         inhibit the gastric secretion;

-         stimulate the formation of steroids.

Kallicrein-kinin system. Kinins - group of peptides with similar structure and biological properties. The main kinins - bradykinin and kallidine.

Kinins are formed from their precursors kininogens that are synthesized in liver owing to acting of kallicreins. Kallicreins are also formed from inactive precursors prekallicreins by means of proteolysis.

Functions: - kinins relax the smooth muscles of blood vessels and decrease the blood pressure;

-         increase the capillaries permeability;

-         takes part in the inflammatory processes.

 Renin-angiotensin system.  Renin - enzyme that is synthesized in special cells located near the renal glomerules.

Renin acts on angiotensinogen. As result angiotensin-I is formed. Under the effect of peptidase angiotensin-I is converted to angiotensin-II. Angiotensin-II causes 2 effects:

-         narrows the vessels and increases the blood pressure;

-         stimulates the secretion of aldosterone.

The decrease of renal blood stream is the specific stimulant for renin secretion.