Endocrine Physio 2 Nowadays there are receptors coupled with ions channels, or different enzyme, for example tyrosine

kinase, or other kinases named JAK (Just Another Kinase). Pituitary Gland: (Or hypophysis)

Very small gland, having the weight of 0.5 -1g, placed at the level of sellae turcica (sphenoid bone). It is made up of 2 components: Neurohypophysis(posterior), and Adenohypophysis(anterior). Neurohypophysis derives from diencephalon, while Adenohypophysis derives from Rathke s pouch. Both have anatomical and functional connection with hypothalamus. Adenohypophysis is made of pars tuberalis and pars distalis. Pars distalis is the anterior lobe. Neurohypophysis is made up of median eminence of hypothalamus , infudibular stem and infundibular process which is posterior. Besides these ant. and post. Lobe, there is also an intermediate lobe, which is very small, not very well developed in case of human beings, but very well developed in other inferior animals.

Pituitary gland secretes several hormones, namely : Growth hormone (or somatotrope hormone), prolactin, thyroid stimulating hormone (or thyrotropin), FSH, Luteinizing hormone, adrenocorticotrope hormone, melanocytes stimulating hormone, ADH (Vasopressin), and oxytocin. The activity of pituitary gland is under the controle of hypothalamus, supraoptic and paraventricular nuclei of hypothalamus which are magnocellular, they synthetize ADH and Oxytocin. The other hormones are synthetized by adenohypophysi s, but their synthesis and secretion is under the control of hypothalamus that secretes releasing hormones (Liberins), and also Inhibiting hormones (Statins). Example of inhibiting hormones: Dopamine (inhibiting hormone for prolactin), somatostatin.

Through circulation, the hormones go to their target cells. Adenohypophysis is made up of cords of cells, among them there are fenestrated capillaries, so the production of these cells is released directly into blood. From morphological point of view, there have been identified several types of cells: y Corticotrophs cells, they synthetize Adenocorticrotrope homone (ACTH) y Thyrotrophs, synthetize thyroid stimulating hormone y Somatotrophs: growth hormone y Lactotrophs: Prolactin y Gonadotrophs: gonadotrophins, namely FSH and LH TSH, is glycoprotein, having 31000Da, this hormone stimulates the secretion of thyroid hormones: Tyroxin(T4) and triodityronin (T3); it also stimulate the development (increase in size) of thyroid gland. FSH: 30 000Da, produced by gonadotrophs, this hormone is synthetized beginning with puberty, and there is a cyclical secretion of this hormone. It stimulates the development of follicle De Graaf in women. In man this hormone stimulates spermatogenesis. LH: also gonadotrope hormone, [tropism: to go toward something], in women stimulates ovulation, and in men it stimulates leydig cells that produce testosterone. TSH, FSH and LH are glycoproteins, they are made up of 2sub -units: alpha and beta. Alpha is common for all of them, while beta i s specific to each of them. Only when these two sub-units are together, these hormone are active. ACTH: made up of 39aa having the molecular weight around 4500Da, it is synthetoized by corticotroph cells, it stimulates the secretion of glucocorticoid hormones at the level of adrenal glands (namely the secretion of cortisol). Secretion of ACTH is highest in the morning and lowest in the evening, so there is a circadian variation in the secretion of this hormone. ACTH is synthetized as a pro-hormone named pro-opio-melanocortin (POMC), and this POMC is made up of several fragments: N-term fragment-ACTHbetalipotropin. [beta lipotropin stimulates the secretion of aldosterone, by its break down another two molecules are created: gamma lipotropin and beta endo rphin.

Beta lipotropin in animals produces lipolysis and mobilizes fatty acids from tissues. Breaking down of N-term fragment produces alpha melanocytes stimulating hormone.]

Prolactin: it is a polypeptide having the molecular weight of 26 000Da. It has a similar structure to growth hormone, it is synthetized by lactot rophs, and it stimulates the development of mammary gland and milk secretion. GH: It is polypeptide having the molkecular weight of 22 000Da, 90% of the Gh in circulation has this weight, and 10% has a molecular weight of 20 000Da. It is produced by somatotrophs, it is similar in structure with prolactin. GH stimulates the growth of body,a nd this action is due by stimulation of protein synthesiss, stimulation of production of nucleic acids, and stimulation of cell division. GH has two important effect: One is the stimulation of the growth of organism, and the other category of effect are metabolic effect. y Stimulation of growth by growth hormone: specially due in increasing in length of bones. At the level of different cells of the body there are receptors for gowth hormone, so when it reacts with its receptor, some substances are synthetized which are similar in structure with insulin, this is why they rae named insulin-like growth factors. It is accepted today that in liver chodronblasts, , have receptors for growth hormones, and GH stimulates the synthesis of insulin-like factors I and II. They are produced by liver, fibroblasts, muscles, cartlages. The se substances situlate the synthesis of collagen, and they also stimulate the introducing of sulfate group in the structure of cartilages.

Initially they were called somatomedins (a,b,c,d). But later it has been identified that somatomedinC is the same tha n Insulin-like growth factor I. Because insulin-like growth factors have some insulinic effect (produce hypoglycemia), insulin mediates its role in growth because of these insulin-like growth factor. Beside Gh, the synthesis sof Insulin-like growth factor is changed by other subtances, for instance Glucocorticoid hormone,s and hypoproteinemia and increase concentration of oestrogens inhibit the production of insulin-like growth factor I. ILGF stimulate the division of chondrocytes, the synthesis RNA and DNA, the formation of collagen favorising prolin into hydroxyl -prolin, and by this they stimulate the development of growth plate, and increase the increase in length of bone. The production of Gh is inhibited by an negative feedback of ILGF. At the level of hypothalamus, it also inhibits the release of GHreleasing factor. y Stimulation of metabolism by GH: GH increases the permeamibility of cell memb, for aa, also it stimulates the synthesis of nuclei acids (RNA, DNA, Ribosomal nuclei acid). Regarding lipid metabolism, growth stimulates glycolysis, and by this fatty acids are mobilized in circulation,a nd at the same time the oxidation of fatty acids is stimulated. GH is a ketogenic hormone, involved in the production of ketone body. GH has a diabetogenic effect, it produces hyperglycemia, and this is produced by increase of using of glucose by cells, also glucose is released from liver, somatotrope homone decreases the number of receptors for insulin, and inhibits the phosphorylation of glucose inside the c ells(=first step of glycolysis). So in disturbances of GH diabetes mellitus can occur. Regarding the metabolism of inorganic substances, Gh increase the intestinal absorption of Ca2+, and decreases renal excretion of sodium and potassium. Factors stimulating the secretion of growth hormone: It is not the same troughout the day, but there are several moments, 3 to 4 times a day, lasting about 20-30 minutes when growth hormone secretion is higher. The highest secretion is noted durong the sleep, specially a fter midnight, so between midneight and 4 o clock in the morning. The lowest value is reached in the afternoon, around 4 o clock. The blood concentration of Gh in adult is between 2 -3ng/mL. The secretion of growth hormone is stimulated by several factors : hypoglycemia (below 70mg/dL); increased concentration of amino acids arg,

leucine, tryptophane, ; another factor is stress; physical effort; sleep, specially the 3rd and the 4th phase of sleep. The secretion of Gh is decreased in obese persons. Physiology of growth: Growth of the organism is accelerated in the first 2 years of life, and at puberty. The growth is determined by genetical factors, external factors, environmental factors, and endocrine factors. Regarding genetical factors: the height of body is genetically pre -programmed. Regarding external factors: nutrition is one of them, it is recommended that animal proteins (specially in childhood). Some diseases during childhood: It has been noted that secretion of coryisol is secreted and cortisol stimulates the catabolism of proteins, and by this the growing is delayed. But after the disease is over, the growing is accelerated until the growth reaches a normal value. It is considered that strenous physical efforts during childhood inhibits growth. Regarding the endocrine factors: several hormones stimulate the growth (somatotrope hormone), thyroid hormones (T3-T4) they stimulate the calcification of cartilages, development of teeth, and the development of a normal aspect of face. Besides this, TSH stimulates the secretion of Gh. When there is a deficiency of thyroid hormone,s the organism is not developed properly, the person is very short, the body is not proportional and this is related with a mental retardation. Pituitary dwarfism is due to the lack of Gh. By comparison of pituitary dwarfism with thyroid dwarfism, in pituitary dwarfism, the person looks normal, and there is no mental retardation. Insulin which mediates its action because it can react with insulin -like growth factors, so in children suffering from diabetes mellitus, if they do not receive insulin, they remain shorter. Sexual hormones: Stimulate (androgen testosterone) secretion of ILGF I, the level of this hormone is very high during childhood, and the maximum is reached at the age of 13-17years. Oestrogens in redeuced concentration stimulate growth, while in high concentration, they inhibit the growth. Increased concentration of oestrogen inhibit secretion of insulin-like growth hormone.

Glucocorticoid hormones haves a negative impact on growth because the accemlarate the catabolism of proteins. Regulation of adeno-hypophyiss secretion: It is under the control of hypothalamus by means of some releasing hormones and some release inhibiting hormones. There are known several releasing hormones: y Corticotrope releasing hormone(CRH): for adenocorticotrope hormone, it has 41aa and it is produced by the neurosn from para -ventricular nuclei of hypothalamus (not the same producing oxytocin and ADH), these neurons are small and are named parvocellular cells. y Thyrotropin releasing hormone(TRH): it has 3aa, it stimulates the secretion of thyroid stimulating hormone. y GH releasing hormone(GHRH): made up of 44aa, stimulates the secretion of Gh. y Gonadotrope releasing hormone(GRH): stimulates the secretion of FSH and LH y Prolactin releasing hormone (PRH) It exist also PIRH, a prolactin inhibiting releasing hormone, it is in fact dopamine. Somatostatin, inhibiting hormone of GH, identified in gastric mucosa, intestinal mucosa, pancreas posterior horns of spinal cord and hypophysis. It inhibits the secretion of Gh and TSH, insulin, glucagon, gastrin, secretin, colecistocalin, vasoactive intestinal peptide. It increases gastric secretion and pancreatic secretion, it decreases the motility of stomach and biliary pathways. Therapeutically it is used for treatment of perons having pit uitary tumors that secrete growth hormones.

Neurohypophysis: It is not a gland, cause it do not secrete hormones, but hormones are stored and released at this level.

These hormones are synthetized by paraventricular and supra-optic nuclei of hypothalamus. These neurons are magnocellular cells. At their level ADH and oxytocin are secreted, together with neurophypophysin type I and type II. These hormones are synthetized as bigger hormones, ADH is synthetized together with neurhypophysin II and oxytocin with neurohypophysin I. During the axoplasmic transport, ADH is separated from neurohypophysin 2 ans same for oxytocin from neurohypophysin I. At the level of terminal nodes, there will be find vesicles with free ADH, free oxytocin, free Neurophyphysin 1 and free neurophysin II. y ADH: It is a polypeptide having 9aa, in human beings ADH is also called vasopressin or arginine vasopressin, while in other species lysine vasopressin in found. ADH acts on 2 types of receptors: RV1 and RV2. RV1 is found at level of smooth muscles cells of blood vessels, the action of ADH on this receptors I mediated by a G-rpotein and vasoconstriction is the result. In case of RV2 found in medial segment of collecting tubules of neph rons, its action is ont adenylate cyclase, AMPc is produced, and vesicles with aquaporines will be produced and these channels will be inserted on cell mb and water will be reabsorbed. Regulation of ADH secretion is done by sevral factors: When the osmotic pressure of blood (osmolarity of blood) is above 285mOsm/L, the secretion of ADH is stimulated together with the thirst sensation. The distention of atria and great vessels by increase of blood volume will inhibit the secretion of ADH. When the blood volume increases, there is more blood coming to atria, by this the wall of atria will extend, by a reflex mechanism, the secretion of ADH is inhibited. Baroreceptors influence the secretion of ADH, when blood pressure decreases, by a reflex mechanism, ADH secretion is stimulated. Exposure of the organism to cold, in this case, there is a peripheral vasoconstriction to prevent heat loss, this is associated with mobilization of blood toward intenral organs, increase of venous return, and by this atria are extended, and the same reflex mechanism inhibits the secretion of ADH. Angiotensin 2 : stimulates the secretion of ADH Stress, emotions, some drugs (morphine, nicotine, increases dosages of barbiturates) increase the secretion of ADH. Alcohol and other drugs inhibit the secretion of ADH. Decrease of blood volume stimulate secretion of ADH.

y Oxytocin: Molecular weight around 1 000Da, its named derives from greek oxus and Its goal is to produce the contraction of pregnant uterus during delivery when cervix is dilated, impulses are transmitted to nervous sytem and from there to hypothalamus, and secretion of oxytocin is stimulated. During labour the concentration of oxytocin increases sevral times, from 50microunits/mL until 150microunits/mL. Animals having removed pituitary gland, then the labour of the animal is prolonged. It is involved in fertilization (meeting of ovum with spermatozoa). During intercourse, oxytocin secretion is stimulated and it will produce contraction of uterus,a nd by this spermatozoa are helped to progress toward (where they meet) It stimulates the secretion of milk because it produces the contraction of myoepithelial cells of mammary gland. Disturbances of pituitary gland secretion: One of the disturbance is diabetes insipidus. It is the disease produced by decreased concentration of ADH. Water is not reabsorbed, so until 20liters of urine can be lost daily. Another pathological condition, it is secretion lack of secretion of Gh which leads to pituitary dwarfism. But and excessive secretion of Gh during childhood will produce another disease named gigantism. Acromegaly: hyper-secretion of Gh during adulthood, many times diabetes mellitus is associated, together with some neurological signs and ophtalmological signs.

Thyroid gland:
2lobes, ant and post, post release some hormones, while ant produces some hormones named trophic hormones that in their turn will go to other glands. Thyroid gland is bigger than pituitary, it has 25 -30g, it is anterior. The lobes are connected through the histmus. The structural and functional unit is thyroid follicle, there are around 300 billions of follicles, having the size between 100-500micrometers. These follicles are made up of a layer of cub oid cells, suroudned by a basement memb. Among these follicles there are fenestrated capillarie,s in which the product of secretion of thyroid gland is released. According to the state of activity of thyroid gland, the follicles may be smaller and the cells to become columnar or when the gland is inactive, the follicle are bigger and the cells are flattened.

Colloid contains thyroglobulin. Thyroglobulin is synthetized by the cells of follicles, and it is secreted in the inner part of the follicle. Outside of thse follicles, there is one more type of cells named parafolliclular cells or C-cells which synthetize calcitonin which is involved in calcium metabolism. The hormones synthetized are thyroxin (T4) and triiodothyronin (T3). Synthesis of thyroid hormones: The cells of follicle secrete thyroglobulin and 2 hormones T3 and T4, both T3 and T4 are organic compound containing iodine. Iodine is found in food and is absorbed as iodid. Daily intake 100-200micrograms, which is in balance with the amoun t of iodine which is secreted through urine. Thyroid gland takes up daily around 120micrograms and release in circulation around 80 micrograms of iodine under the form of thyroxin and triiodothyroin. The remainder amount of iodine diffuses in extra cellul ar space, and can be taken by other organs. The cells of follicle perform several acyions regarding the synthesis of thyroid hormone,s namely, they take iodin from blood, it is concentrated very much: 20x, producing a pool of iodin, after that iodin is ox idized under the acyion of a thyroid peroxidase which uses hydrogen peroxidase. By this iodin is transformed into oxidized iodin, and only this can react with residue of thyrosin producing mono-iode thyrosine and di-iode thyrosine. The reaction of iodine with the residue of tyrosin from the structure of thyroglobulin takes place at the level of apical mb of microvilli inside of colloid. Thyroglobulin is a protein containing sevral residue of tyrosin, around 123molecules of tyrosine.

Endocrine Physio 1 :
Endocrine system together with nervous system are the systems which are involved in regulation and coordination of the activity of all cells in the body. The action of nervous system is rapid, it is immediate, and it is of short duration. Usually it is localized. By comparison with the activity of the endocrine system which is more diffused, is delayed and has a longer duration. Endocrine system is made up of endocrine glands which by comparison with exocrine glands have the characteristics that follow: y No excretory channel y Secretion released in blood stream y One of the pus of the gland is in contact with capillary y The secretion is made of hormones, and hormones usually act at distance from the cells where they have been synthetized. y Hormones act on those cells who have receptors for them Hormones perform several effects:  Influence metabolic reactions  Involved in storage and catabolism of carbohydrates, lipids and proteins  Stimulate physical, mental and sexual development of the body  Participate to autonomic reactions (adrenaline synthetized by adrenal gland influence autonomic activity of different organs)  Act like enzymes  Chemically they can be peptides, amides, proteins, or steroids Regarding the mechanism of action of hormones:

 The action is exerted only after the hormone is bound by a specific receptors  The number of receptors on a cell is variable, from 2000 until 100 000 receptors per cell  When the concentration of a hormone in blood increases, the number of receptors expressed at the level of a cell decreases, this is named down-regulation  When the concentration in blood of a hormone decreases, the number of receptors expressed at the level of the cell increases, this is named up-regulation  According to the chemical nature of hormone,s the receptors are found at the level of cell mb, cytoplasma, of nucleus of the cell, so hormones that are hydrosoluble the receptors are at the level of cell membrane; liposoluble hormones (like steroid hormones and thyroid hormones) they have the receptor inside of the cell.

Hormones together with neuro-transmitters are named primary messengers. The effect of hormones will be due to some secondary messengers found inside of the cells(Ca2+, DAG, cAMP, IP3). There are some hormones who use cAMP as secondary messenger: Hormones which are polypeptides cannot penetrate inside of cells, so they have some receptors at the level of cell membrane. After the hormone is bound by its receptor, an enzyme is activated named adenyl cyclase and cyclic AMP is produced. The connection between the receptor and adenyl cyclase is made by a protein named protein G or hetero-trimerique GTP binding protein. It is made up of 3 sub-units: alpha, beta et gamma. It is considered that there are several types of G proteins, functionally they are stimulating G protein, or inhibitory G proteins: Gs or Gi. When protein G is inactive, it is coupled with GDP, alpha sub-unit binds it. When it becomes activated, GDP is replaced by GTP, this is due to the interaction of the hormone with its receptor. A complex made up of hormone and it s receptor can activate several molecules of protein G. After GDP is replaced by GTP, alpha sub-unit detaches from beta and gamma, and it activates adenylate cyclase. Alpha sub-unit has a GTP-ase activity, and hydrolysis GTP to GDP. Adenyl cyclase will convert ATP to cyclic AMP. Cyclic AMP is the secondary messenger that in it s turn will activate another protein: namely protein kinase A. Protein kinase A will phosphorylate other proteins and enzymes inside of cells and by this, the effect of hormone is produced. cAMP is broken down by another enzyme: phospho-diesterase, which converts cAMP into 5-AMP. Phosphodiesterase can be inhibited by different substances:  Coffee  Teophiline ADH acting on a receptor V2, parahormone produced by parathyroid glands, glucagon, adrenaline or epinephrine on beta receptors, thyreotrope hormone or thyroid stimulating hormone, adeno corticotrope hormone, luteinizing hormone, Folliculo stimulating hormone (FSH). Inositol Triphosphate and diacyl glycerol as secondary messenger: Phospholipase C is activated. After activation phosphatidyl inositol diphosphate (PIP2) is released from the mb is converted into inositol triphosphate and diacyl glycerol.

Inositol triphosphate diffuses inside of endoplasmic reticulum and opens calcium channels by which calcium will diffuse outside. Calcium together with aprotein named calmodulin will form a complex (4Ca2+ for 1 calmodulin) that will interact with different enzymes activating them. Diacyl glyceroml will activate protein kinase C and this protein will phosphorylate other proteins and enzymes, and by this process hormonal effect will be produced. There are some hormones that perfume their action this way: oxytocin, cathecolamines, anti-diuretic hormone on V1 receptors, cholecystokilin, adrenalin, noradrenalin.

The amount of calcium in organism : 1-2kg, 99% of it is found in bones, and only 1% is in other compartments. 0.3% in muscles, 0.1% is in extra cellular fluid, 0.01% is intra-cellular. [Ca2+] in circulation: 9.0-10.5mg%. 40% is bound to proteins, it is not diffusible calcium. 60% is diffusible(50% non ionized and 10% ionized). The absorption of Ca2+ at level of intestine, excretion of calcium at level of kidney, and amount of calcium mobilized from bone, these 3 factors influence the calcemia. Daily 500mg of calcium are mobilized, either stored or released from bones. Absorption of calcium: Daily intake of calcium is around 1g, but of this amount of calcium, only 1/3 is absorbed, the remainder is removed through stool. The amount which is absorbed, should be in balance with the amount which is excreted by the body. The absorption of calcium depends on the types of food taken up, there are some substance in food s that inhibite the absorption of calcium (phosphates, oxalates, found in vegetables), also a diet rich in fats decreases the absorption of calcium, a diet rich in proteins and lactose increases the absorption, of calcium. Duodenum and initial portion of jejunum and at the level of terminal ileum. At the level of initial portion of small intestine is done ba an active process that has a maximum absorption capacity, that means the the rest is absorbed at the level of terminal ileum. At the terminal ileum the absorption is done by diffusion, a passive transport. The absorption of calcium depends on vitamin D3. Vitamin D is found either in plants (VitaminD2 ergosterone) or in animals (from cholesterol from which 7-dehydrocholesterol and this substance in skin is transformed in vitamin D3 or cholecalciferon, inactive in this form). Vitamin D3 is taken from skin

At the level of intestine, the active vitamin D3 will stimulate the synthesis of the protein that is involved in the active transport of calcium, that protein is named calcium binding protein. The receptor for Vitamin D3 is at the level of nucleus, it belongs to the category of steroid hormones. Receptors for vitamin D3 are also found at the level of bones, liver, placenta, brain and parathyroid glands. At the level of bones, vitamin D3 in small concentrations stimulates the mineralization of bone because it activates the activity of alkaline phosphatase from osteoblasts. In high concentration, vitamin D3 stimulates bone resorption. In high concentration it inhibites the secretion of parathyroid hormone. (PS: at the level of kidney, the hydroxyle group at position 1 is introduced by a reaction catalyzed by an enzyme named 1alpha-hydroxylase, the activity of this enzyme is stimulated by parathyroid hormone). When the concentration of calcium in blood is higher, then the activity of this enzyme is inhibited, instead of being form 1alpha-hydroxylase, it is in the form of 24,25(OH)2dehydroxycolecalciferol which is inactive.

Because the metabolism of vitamin D are synthetized in different organs and then transported through blood to different organs , vitamin D3 can be considered as an hormone. Physiology of bones: 2/3 of bones are made up by mineral substances and 1/3 by organic substa nces. Mineral substances are represented by calcium and phosphates, bound together forming hydroxyapatite. Together with calcioum and phosphates, bone contain a lot of magnesium, carbonates, sodium. Bones can also take some radioactive substances like stronsium, plutonium. After exposition to radiations, malignant osteonoma can occur. Organic matrix is made up 95% by collagen fibers(type I collagen) and 5% is made up of ground substance(made up of proteoglycans specially). Organic matrix is called osteoid also, it is impregnated by hydroxyapatite cristals that give te bones a powerful structure, they are as strong as steel. At the level of bones 3 types of cells can be found, osteoblasts are very active metabolic cells having a diameter around 20micrometer, they have a rich endoplasmic reticulum and rich in ribosome, they are involved in secretion of collagen. Besides osteoblasts there are rich mineralization of bones. As long as osteoblast secrete the osteoid, and this osteoid becomes mineralized , then osteoblast slowly transform into osteocytes and they use their capacity then to produce organic matrix. Osteoblasts and osteocytes have some processes and these processes are found inside of some canalicules and by these they communicate with the surface of bones and by this they get nutritive substances and at the same time waste product of their metabolisms are taken. The role of osteocytes is not very clear, they are considered like matured osteoblasts, but osteocytes according to some authors have the role to resorb bone (like osteoclasts). The parat-hormone produces an enlargement of spaces surrounding osteocytes. Osteoclast is another type of cell, they are the macrophages of bone tissue, they derive from monocytes, they are multinucleated cells, having the role to erode the structure of bone, they contain acid phosphatase, and they release proteolytic enzymes by which osteoid is broken down, and also some acidic substances like citric acid and lactic acid by which calcium salts are removed from this structure, becoming soluble and calcium is released in circulation. In order that calcium and phosphate form hydroxyapatite, it is necessary that calcium and phosphate are in some concentration to become saturated and precipitate. Alkaline phosphatase released by osteoblast have the role to hydrolyze phosphoric esters and to supply the concentration of phosphates to the proximity of osteoblasts in order that calcium and phosphate to precipitate and to store as hydroxyapatite.

Parathyroid glands: 4 small glands placed on the posterior side of the thyroid gland. These glands are vital glands ad they weight together 120mg. Parathyroid glands are made up of 2 types of cells, namely principal cells having a clear cytoplasm, they are involved in secretion of Parathyroid hormone. Oxyphils cells are another type of cells, having many granules in their cytoplasma, but their function is not very well known. Parathyroid hormone is a polypeptide made up of 84aa, having a molecular weight of 9500Da. Parathyroid hormone have the receptor at the level of cell membrane, and it is coupled with G proteins, it mediates its activity by adenylate cyclase.

Parathyroid hormone have several effects, it stimulates the absorption of calcium at the level of small intestine indirectly because parathyroid hormone(PTH) stimulates the activity of one hydroxylase at the level of kidney. It is involved in the formation of active vitamin D3. PTH has a direct effect on bones, namely it stimulates the resorption of bones, it has been noted that if parathyroid gland tissue is transplanted into bones, then the activity of osteoblast is inhbited and the activity of osteoclast is stimulated. PTH inhibits the synthesis of collagen by osteoblast. Because it also stimulates the activity of osteoclast, PTH stimulates the resorption of bone and by this increases the urinary excretion of hydroxyl-proline. PTH by means of cyclic AMP stimulates the synthesis and release of lysosomal enzyme that contributes to dissolution/resorption of organic matrix. Daily are filtered around 10 000mg of calcium, 60% of this amount is reabsorbed in proximal convulated tubule, and till 98-99% is reabsorbed at the the level of thick ascending limb of loop of Henle and distal tubule. PTH stimulates the reabsorption of calcium at the level of thick ascending limb and distal tubule. The amount of calcium secreted daily is less than 1% of the amount which is filtered. At the same time PTH inhibits the reabsorption of phosphates at the level of proximal tubule. The secretion of PTH is not under the control of pituitary gland, when the concentration of calcium decreases below 9.5mg% then the secretion of PTH is stimulated, while the increase of calcium concentration inhibits the secretion of PTH. In some deseases when there is a chronical hypocalcimia (rickets disease in children)(p292 thieme) Calcitonin: Polypeptide containing 32aa, 3500Da, role is to reduce the concentration of calcium in blood, but it also reduces the concentration of phosphates, in fcat calcitonin acts by impeding the resoption of bone. Calcitonin also stimulates the activity of osteoblasts, and inhibits the activity of osteoclasts. It is considered that only at the level of osteoclasts there are receptors for calcitonin. The regulation of calcitonin secretion is not under the control of pituitary gland, but it is done by means of level of calcemia. The secretion of this hormone is stimulated when calcemia increases inbreases above 9.5mg%, the secretion is also stimulated by beta adrenergic substances(dopamine, epinephrine, norepinephrine, glucagon, cholecystokinin).

The concentration of calcitonin increases in pregnancy and by this it is considered that it protects the mother bones from being demineralized.

Disturbances of parathyroid gland: Hypofunction So PTH secretion lowered, the level of calcemia decreases, and the level of phosphate will ., when calcemia decreases below 7mg%, then spasmophilia or hypocalcemic tetania which is characterized by spontaneous contraction of muscles (squeletal muscles) and spasms at the level of larynx muscles. In this case there is an increased excitability, and this can be induced by placing the cuff of tensiometer on patients arm and it is pump by air until it is above the systolic pressure, we observe the Trousseau sign. Chwostek s sign. If calcium concentration decreases below 5mg% it is called tetany. Osteosclerosis is another disturbance, this disease is secondary with intoxication with Pb, ot to some bone tumors, and in this case there is an extra amount of bone tissue because osteoclast lost their capacity to resorb bone, and by this there is a decrease of bone cavities, and a decrease of bone marrow, and also a narrowing of orifices by which nerves penetrate bones. Osteoporosis: another disturbance in which there is a decrease of bone mass because bone matrix and inorganic substances are decreased in bone, the structure becomes more porous, more fragile, and there is an increased risk of fracture. Activity of osteoblasts is under the control of oestrogen, at menopause, the oestrogen secretion stops this can result in osteoporosis. Parathyroid hyperfunction: Bone resorption is increased and in bones can be formed some kyst (cavities), it is named fibrokistic osteo..tis or paget disease. X-ray will show the cavities and other areas with two much bone tissue on the other hand.

Endocrine pancreas: It is represented by Langerhans islets, they are the structural unit of endocrine pancreas. There are between 1-2 millions islets in pancreas. They represent 1-2% of the weight of pancreas, so around 2g, they have a size between 50-300micrometer, they are found in the tail and less in the head. Each islet is from a few hundreds to a few thousands of cells. There are 4 types of cells, producing 4 hormones. In the middle of these islets there are beta cells: 65-70% of the cells are beta cells, they produce insulin. 20% of cells are alpha cells producing glucagon, they are found at the periphery of the islets. Between 1-8% at the periphery, they are delta cells, producing somatostatin. Less than 1% are F cells, they produce pancreatic polypeptide.

Insulin: Discovered by a Romanian : Nicolae Paulescu. He called it Pancrein, he made several experiments on dogs, he noted that this substance decreases the value of glycemia, and it was named pancrein by Paulescu. The noble price was obtain by two Canadians: Banting and Best, they are considered to have discovered insulin. Secreted as a pre-pro-hormone at the level of beta cells. It is secreted at the level of endoplasmic reticulum. The genes for synthesis of insulin are localized on pair 11 of chromosome. After pre-pro-insulin enters the endoplasmic reticulum, it loses 23aa, becoming pro-insulin. Pro insulin is made of a peptide A having 20 amino acids, a peptide B made up of 31aa, and a connecting peptide between these two named peptide C made of 30aa. Peptide C is necessary for the petide A and B to have a certain position in space in order to form some sulfic bridges. Peptide C is removed under the action of an enzyme and is transformed in insulin. Insulin is after that packed in some membranes, some vesicles at the level of golgi apparatus and is stored in some granules at the level of the cell. Insulin is released from beta cell by exocytosis, which is a calcium dependant phenomena. In blood, insulin is secreted together with peptide C, but peptide C does not have a biological activity.

Also small amounts of pro-insulin are secreted in blood. Pro-insulin has only 5-10% of the activity of insulin. Peptide C is used in clinic in order to monitorize the secretory activity of endocrine pancreas in people suffering from diabetes who receive exogenous insulin.

Pancreas secretes daily, between 40-60units of insulin, but in pancreas there is a pool of 200units of insulin. So all insulin formed is not released in circulation, only 1/4th of it is. A unit of insulin represents the minimum amount of insulin able to decrease the value of glycemia from 120mg% until 45mg% in a rabbit of 2kg which was starved 24hours. After insulin is released in blood, it is taken by several organs having receptors for insulin, namely it is taken by liver, muscles, and fat tissue. Brain and RBCs do not uptake insulin, that means the penetration of glucose inside neurons and RBCs independently on insulin. The lifetime of insulin is 5 minutes, that is why it is continuously produced. Insulin is a protein, that s why it is broken down by digestive juices, that s why there is no insulin drug taken up orally. Effects of Insulin: The main effect is to decrease glycemia. Normal glycemia is 80-120mg/dL. Intravenous insulin decreases glycemia which reaches the lowest value within 30 minutes. If it is administrated subcutaneously, then the lowest value is reached in 2 to 4 hours. It has to react with its receptor, the receptor of insulin is made up of 2 alpha sub-units and 2 beta sub-units connected by sulfuric bridges. Alpha-subunits are more extra-cellular, and after reaction with alpha subunits, there is a conformational change and beta sub-units are activated. Beta subunits have the capacity of autophosphorylation, and osme tyrosine residue are activated, and after that a enzyme tyrosine kinase is activated,a nd this tyrosine belongs to the striucture of beta subunit. So beta subunits has a tyrosine kinase activity. The activation of this kinase will phosphorylate other proteins. The receptors for insulin on the cell is variable, when the concentration of insulin increases, the number of receptors on the cells decreases. In people suffering from obesity, they have a decreased number of receptors for insulin, and in this way is explained their resistance to insulin. During starvation, the number of receptors for insulin increases, because the concentration of insulin decreases. When there is an overfeeding, the secretion of insulin is stimulated continuously, so the number of receptors will decrease, and this process will produce a resistance to insulin.

Endocrine physio 5 : Insulin inside of beta cells, is packed in some granules and stored there. After Insulin is released it acts on some receptors and these receptors are enzyme-linked receptors. After contact with alpha sub-units, there is an activation of the enzyme.

Effects of Insulin: It performs several role in the organism, it is an anabolic hormone, its main role is to decrease the concentration of glucose in circulation. It is the only hormone that decreases yhe concentration of glucose in blood. Insulin performs this effect by several mechanisms. Insulin stimulates the uptake of glucose in different cells, specially in liver, muscle and adipose tissue. Most of the cells of the organism have receptors for insulin. Except a few cells where glucose can penetrate without insulin, these cells are neurons, RBCs, enterocytes, tubular cells, and beta cells of pancreas. After the ingestion of foods, glucose is absorbed and under the action of insulin, the penetration of glucose inside the hepatocytes is stimulated. Glucose is stored in hepatocytes as glycogen. In this way, a gradient of concentration for glucose is maintained in order that glucose continues penetrating inside of hepatocytes. Glucose can be stored as glycogen until glycogen reaches the value 5-6% of liver s mass. During inter-digestive periods, glycogen is broken down and glucose is released, so in this way is maintained a certain level of glycemia, even in the periods when the person does not eat (starvation period). A constantly supply of energy is assured. Under the action of insulin, glycogen synthesis is stimulated, this is glycogenesis, this is due because insulin inhibits the break-down of glycogen. Insulin inhibits glycogen phosphorylase, so glycogenolysis is inhibited, and gluco-kinase is activated, and glucose is phosphorylated, being transformed into glucose-6-phosphate. G6P is a product that cannot leave the hepatocytes. At the same time, other enzymes are stimulated by insulin: Phospho-fructo kinase, and glycogen synthase. The amount of glucose that cannot be stored in hepatocytes is transformed in fatty acid, and they will be transported and stored as triglycerides at the level of adipose tissue.

Muscles cannot take glucose in the absence of insulin, so in resting condition, they cannot uptake glucose. That s why in resting conditions, they use specially fatty acids as energetic substrates for the synthesis of ATP, but after a meal, when the secretion of insulin is stimulated, glucose can penetrate in striated muscles by facilitated diffusion. At the same time glucose can be stored in muscles as glycogen, but the amount stored in muscle is lesser than the amount stored in the liver. Glycogen can be stored till the level it reaches 1% of the muscle mass. Glycogen stored in muscle is used specially to supply energy in anaerobic conditions. In muscles being in activity, glucose can penetrate even without insulin, sor sarcolemma becomes more permeable to glucose during physical activity. Glucse is transformed in acetyl-coA, and acetyl-CoA in fatty acids. Fatty acids are transported as lipose proteins in fatty tissue and they form triglycerides which is stored in adipose tissue. Glucose can also penetrate in adipose tissue, but under the action of insulin in adipose cell, glucose is broken down by glycolysis, and by this process great amount of alpha-beta glycerol-phosphate are formed. Alpha-glycerophosphate reacts with fatty acids and triglycerides are formed. At the same time insulin at the level of adipose tissue inhbits a hormone dependant lipase and by this triglycerides are not broken down. Mobilisation of lipids from adipose tissue is inhibited. Insulin inhibits lipolysis, that s why in the absence of insulin, or decrease amount of insulin like in diabetes mellitus, these lipase will not be Inhibited, triglycerides will be broken down, fatty acids will be released, they will be taken by liver and at level of mitochondria in hepatocytes, these fatty acids will be oxidized forming acetyl-CoA. A certain amount of acetyl-CoA can be used by hepatocytes as energetic source, but most of acetylCoA condensates forming acid acetyl acetic that can pass into circulation. Cells can transform . In acetyl-CoA, so back. But when there is a deficit of insulin, this transformation is not produced, another one takes place: Namely acetyl acetic acid is transformed in beta hydroxylic acid and acetone. Their acculumation can lead to a state of acidosis, and even coma (the accvumulation of these acids). Insulin stimulates the transport of amino acids in cells, and at the same the synthesis of proteins in ribosomes, without insulin it is considered that ribosomes cannot work. So protein anabolism is stimulated. In diabetes when there is less insulin, catabolism of protein is stimulated which leads to a negative nitrogen balance, and diabetes because protein are not synthetized properly, also anti-bodies are not synthetized properly which explains the tendancy towards infection in people suffering form diabetes. At the same time because of high concentration of glucose in diabetes, the growing of germs is stimulated, because glucose from the fluids of the organism is a good medium for growth of bacteria. The growing is delayed because insulin is important for growing, and its important in synthesis of proteins. Insulin stimulates the transport of potassium, phosphate and calcium inside of cells. This is principally due to stimulation of the activity of sodium potassium ATPase. A side effect of high doses of insulin is hypo-potassemia. Regulation of insulin secretion: The main factor stimulating the secretion of insulin is the level of glycemia, anytime the concentration of glucose in blood increases, the secretion of insulin is stimulated. Secretion of insulin takes place in the following manner: Glucose penetrates inside of beta cells. There it is phosphorylated, later broken down and transformed in ATP. So by this the concentration of ATP in beta cells increases.

When it increases, some potassium channels are open, by being open these channels the depolarization of cells membrane is produced, and when it reaches a certain level, calcium voltage channels are open, calcium will penetrates inside of beta cells and this will stimulates the exocytosis of vesicles containing insulin. The secretion of insulin increases when the concentration of glucose is about 100mg%, and the latency is between 30-60 seconds. Increasing the concentration of some amino-acids stimulate the secretion of insulin: arginine, leucine, but also some substances like ketonic bodies. Adrenergic substances act on beta receptors, also glucagon stimulate the secretion of insulin. Parasynpathetic nervous system by means of acetyl choline also stimulates the secretion of insulin. Stimulation of sympathetic nervous system by means of alpha receptors will inhibit the secretion of insulin. (Alpha and beta adrenergic receptors are located on beta cells of Langerhans islets.) Cholecystokinin, secretin, gastric inhibitory peptide, enteroglucagon, stimulate directly the secretion of insulin, this is explains why the secretion of insulin is higher when the glucose is administrated orally by comparision with the concentration of insulin that is lower when glucose is administrated through a perfusion. (these substances are from the digestive tract) Other hormones like growth hormone stimulate the secretion of insulin, adreno-corticotrope hormone, and glucocorticoids by inducing hyperglycemia stimulate the secretion of insulin. Thyroid hormones by increasing the absorption of glucose at the level of digestive tract and by stimulating glycogenesis, induce hyperglycemia and induce secretion of insulin. Disturbance of insulin secretion: Diabetes mellitus: It can, be induced experimentally in animals by removing of pancreas or by administration of some drugs like ALOXAN or STREPTOZOTOCIN these trugs are pancreato-toxic, they will destroy the pancreas. Diabetes mellitus according to the needs of insulin, is classified in type I also called called insulindependant, and diabetes mellitus type II also called non insulin dependant. In case of type I, the pancreas is almost completely destroyed, it is supposed that 95% of pancreas is destroyed. It s considered to be an immune reaction that leads to that. In case of type II diabetes, they are mostly obese people, about 80%, in this case there is a decrease of secretion of insulin, and in this case it is considered that the decrease is the result of the overfeeding. In obese people the secretion of insulin is constantly stimulated, and at a certain moment the pancreas won t be ablme to provide enough insulin and its secretion will be reduced. In some cases of diabetes II some drugs stimulating the secretion of insulin is enough. The problem is that diabetes mellitus is a desease having an increased incidence, it is supposed that in 10 years the number of people suffering from diabetes will double, the cause is still not very well explain and known. In diabetes mellitus there is hyperglycemia, and also an increased concentration of lipids because glucose cannot penetrate in cells in absence of insulin, the person will have a constant desire to eat, that is named polyphagia, and also glucose is lost through urine. In normal condition, when glycemia is normal . Over 180mg% there is glucose found in urine, one of the sign is polyuria. (polydipsia?) Hyperinsulinism:

In this case insulin is secreted in higher amounts and this is due to some tumors at the level of pancreas. When glycemia decreases below 50mg%, that can induce hypoglycemic coma. When the level is between 50-70 mg% tremors, sweating, tachycardia, increased blood pressure, sweating, dizziness, speaking disturbances, the person looks like he/she s drunk due to all these symptoms. This is due to the lack of glucose at the level of neurons, these signs are due to stimulation of sympathetic nervous system. Glucagon: Peptide made up of 29 amino acids, 3500Da. It has the opposite effects to insulin, namely it induces hyperglycemia. The receptor for glucagon is coupled with G-protein and it induces its effects by stimulation of adenylate cyclase and increasing the concentration of AMPc. The AMPc will activate the enzyme involved in glycogenolysis and gluconeogenesis. Glucagon stimulates glycogenolysis in liver cells but not in muscle cells. Gluconeogenesis: main source amino acids, but inorder to be transformed into glucose they need to be deaminated, that s why this process is associated with increase or ureogenesis. At the level of adipose tissue, glucagon stimulates glycolysis, it has a catabolic role by the fact it stimulates the mobilization of fatty acids and amino acids. Glucagon stimulates the secretion of insulin, but also the secretion of growth hormone, somatostatin, and catecholamines. In higher concentration than normal, glucagon increases the force of contraction of heart. It also stimulates the biliary secretion and secretion of hydrochloric acid. Regulation of glucagon secretion is done by the level of glycemia, when level of glycemia decreases below 7mg%, then secretion of glucagon is stimulated. Stimulation of parasympathetic nervous system can also increase glucagon secretion. A diet rich in proteins and amino acids increases glucagon secretion. Cholecystokinin and gastrin stimulate glucagon secretion, while secretin decreases glucagon secretion. Somatostatin: It is produced by delta cells of pancreas, but it is also synthetized in hypothalamus and spinal cord, it is a polypeptide madeup of 14aa, somatostatin inhibits the secretion of insulin and glucagon. The secretion of pancreatic polypeptide is inhibited. Somatostatin inhibits the secretion of growth hormone at the level of pituitary gland. It decreases the motility of digestive tract, reduces gastric and biliary secretion, its secretion is inhibited by fatty acids. Pancreatic polypeptide: Made up of 36 aa, this hormone has a not well know role, it is supposed to reduce the exocrine secretion of pancreas, together with decrease of absorption of food. The secretion of this hormone has been noted after hypoglycemia, ingestion of proteins and starvation. While a decrease of its secretion has been noted after intra venous administration of glucose and by somatostatin. Endocrine pancreas is represented by Langerhans islets, there are several types of cells, the main hormones are insulin and glucagon having opposite effects on glycemia. Not well understood are somatostatin and pancreatic polypeptide.

Adrenal gland:
There are two adrenal glands, located on the superior poles of kidneys. These glands have a vital role because if they are removed, this will lead to collapse and death. The functional role of adrenal gland was described by Addison and Brown Sequar. Adrenal gland is made up of cortex and medulla. Cortex represents 70-901% of the gland, the remainder is medulla. At the level of cortex are described several layers: Zona glomerulosa, fasciculata, and reticullaris. The medulla secretes catcholamines. We ll talk for now only of the Cortex. The gland is surrounded by a capsule, and under the capsule the zona glomerulosa which synthesis some hormones named mineralo corticoids-M. Zone glomerulosa is above zone fasciculate which is made of cords of cells. Between these cord of cells there are fenestrated capillaries. Under there is zone retucularis made of a network of cells. Fasciculata and reticularis secrete androgens hormones and ..

Glomerulosa: mineralo-corticoids. Fasciculata and reticularis: Glucocorticoids and sexual hormones. The activity of adrenal gland is under the action of ACTH produced by pituitary glands, it stimulates the synthesis of adrenal gland hormones, and the normal functionnaing and the normal structure of the gland, it s a trophic.

Zona glomerulosa has a regenerative role, namely the other two zones can be regenerated by zone glomerulosa, but when zone glomerulosa is destroyed, then the structure of adrenal gland cannot be recovered. The activity of zone glomerulosa is not under the control of ACTH (or less influenced let s say). Synthesis of adrenal gland hormones: Adrenal hormones are synthetized from cholesterol, so these are steroids hormones, they are not hydrosoluble. Cholesterol is made of 3 rings of 6carbon atoms, and 1 ring of 5 carbon atoms. Most of cholesterol used comes from blood, it comes from LDL, and to a lesser level it is synthetized from acetate inside of adrenhal gland. At the level of cell mb, there are receptors for LDL. Adrenal gland synthetisis two types of steroids hormones: namely 21 steroids and 17 steroids C21 steroids are called in this way because there is attached a chain of carbon atoms, mineralocorticoids and gluco-corticoids are C21 steroid hormones. While the other category, C19 in this case, at the level of position 17 there is a ceto group or a hydroxyl group. And these C19 are sexual hormones. The hormones having a ceto in position 17 are also called ceto steroids. Adreno corticotrope hormones stimulates the penetration of cholesterol, inside cell cholesterol is esterified and stored inside of cytoplasma as some droplets of lipid.

Under the action of a hydrolase, from esterified cholesterol, free cholesterol is removed, and free cholesterol is used in mytochondria to produce pregnelonone, under the action of an en

Pregnenolone is transformed into progesterone under the Progesterone gives to aldosterone in zone glomerulosa, and cortisol and androgen hormones in zona fasciculata and zona reticularis.

The transformation of cholesterol in pregennolone is stimulated by ACTH, it mediates its action by mean of AMPc, AMPc will activate a protein kinase A which will phosphorylates different enzymes that become activated. Transport of adrenal hormones in circulation:

These hormones are not hydrosoluble, they are transported in plsma bound by proteins. Glycocorticoids hormones (Cortisol is the main) are transported 90% by an alpha2 globulin synthetized by liver and that is named transportin. The remainder is transported by albumin. The other glucocorticoid hormones: corticosterone, is also transported by transportin and albumin. The concentration of transportin increases in pregnancy, but in hepatic cirrhosis, nephrosis and multiple myeloma decreases, so in the second condition we have more free cortisol. In nephrosis protein are lost through urine, in cirrhosis, there is no production of protein, the tissue is replaced by fibrocytic tissue, and in myeloma that produces gamma globulins (antibodies). Bound hormones work as a pool from where free hormones are released. Anytime the concentration of free hormones decreases that will stimulate the synthesis of hormones and increases the secretion of corticotrope releasing hormone. Aldosterone which is the main mineralo-corticoid hormone, and deoxycorticosterone, they are mineralo-corticoid hormones which are produced by zona glomerulosa. They are transported by transportin and albumin. Endocrine physio 6 : They maintain the vascular tonus, and they increase the force of contraction of heart because they increase the response of smooth muscle cells to catecholamines. The effect of catecholamines on heart and smooth muscle cells of vessels is increased by cortisol. They also maintain plasmatic volume by increasing the flowing of fluid from interstitial space to the vessels. Regarding the effects of glucocorticoid on nervous system, during neonate period, cortisol inhibits the proliferation of cells in central nervous system, they decrease the mass of brain, the formation of synapses, they have an inhibitory role on the morphology and function of nervous system. In adult a hyper secretion of glucocorticoid hormones is associated with a emotional ability that can built until psychosis. The pattern EEG is changed under the action of cortisol, with predomination of some slow waves. There is an increase of taste and olfactory sensitivities, tiredness, and incapacity of concentration. Glucocorticoids have effect on other glands, for instance they inhibit the secretion of growth hormone, of TSH, the convertion of tyroxine into They stimulate the effects of glucagon, they stimulate the beta adrenergic effect of catecholamines. They inhibit the secretion of vasopressin. On gastro intestinal tract, glucocorticoid hormones stimulate the secretion of hydrochloric acid and pepsin, they inhibit the synthesis of prostaglandins, and by these two effects, they favorise the appearance of peptic ulcer. A side effect of treatment with synthetic glucocorticoid hormone: PREDNISON can produce petic ulcer or gastritis. ON blood cells, glucocorticoids have some effects: They decrease the number of eosinophils, basophils, and lymphocytes (eosinopenia, basopenia, lymphocytopenia), but they increase the number of neutrophils (neutrophilia), red blood cells, and of platelets. Glucocorticoids, because they stimulate the catabolism of proteins from lymphatic tissue, they decrease the size of lyph nodes in thymus, and they inhibit the division of lymphocytes, and by this the provoke lymphocytopenia. They inhibit the secretion of interleukin 2.( produced by helper T lymphocytes, this mediate the transformation of lymphocytes B in plasmocytes).

This explains the immunosuppressive role of glucocorticoids. Anti-inflammatory role is explained by inhibition of phospholipase A, by which is inhibited the relase of arachidonic acid from the phospholipids of cell membrane. Leukotrien and prostaglandines are pro-inflammatory molecules, produced from arachidonic acid. Cortisol inhibits the secretion of IL2, of gamma interferon, and the secretion of IL1 produced by macrop^hages during inflammatory reaction that goes to hypothalamus producing fever. Glucocorticoid hormones stabilizes the lysosomal membrane. By inhibition of degranulation of mast cells, histamine, heparine, serotonin, and other mediators are not released, and by this is explained the anti allergic effect of glucocorticoid. All this explains why glucocorticoids are used in treatment of inflammatory and immune disease. During stress, the secretion of adreno corticotrope hormone is stimulated. Corticotrope releasing hormone (from hypothalamus), stimulates release of ACTH from pituitary gland, that goes till adrenal glands. Due to the effect of cortisol on catecholamines, there is a vasoconstriction in skin, and a vasodilatation in muscle, so there is a certain distribution of bloo flow, specially oritented toward muscel which is necessary for muscle activity, and by this, the organism is held to go toward danger. This is named fight or flight. Regulation of glucocorticoid hormones secretion: The secretion of glucocorticoids is regulated adrenocorticotrope hormone synthetized by adrenohypophysis, it is a small peptide and it mediates its effect by means of G protein connected with adenine cyclase. Adrenococrticotrope hormone in its turn is released under the action of corticotrope releasing hormone from hypothalamus. The release of adrenocorticotrope hormone, and corticotrope releasing hormone has an oscilating profile, the highest peak is recorded in the morn ing before the person wakes up, and the lowst value is in the afternoon/evening. Adrenocorticotrope hormone is released in pulsatory way, the release lasts 10-20 minutes (the peaks) and after the secretion decreases. The secretion is higher with stress, when the concentration of cortisol decreases. Cortisol secretion is regulated by a negative feedback mechanism by ACTH. (check which hormone produces the negative feedback). Cortisol prolonged treatment, of another synthetic glucocorticoid hormones, will inhibit the secretion of Adreno corticotrope hormone, and can lead to atrophy of adrenal gland, and of hypophysis. Mineralocorticoids: They are represent,ted by aldosterone and by deoxycorticosterone. Aldosterone is synthetiozed by cells of zona glomerulosa, it stimulate the reabsorption of sodium at the level of distal tubule and collecting tubule, together with secretion of potassium or hydrogen. Being a steroid, its liposoluble and it has its receptors at the level of cytoplasm. The ligant receptor complex is transported till nucleus where it activates transcription of specific genes, so some proteins are synthetized. Because aldosterone mediates its effect by transcription of different genes, the effects takes place after 35-45 minutes. The reabsorption of sodium takes place also at the mlevel of salivary gland,s sweat glands, and at the level of gastro intestinal mucosa, all these things stimulated by aldosterone.

Aldosterone secretion is not under the controle of ACTH, it is stimulated by angiotensin 2, by increased potassium level and decreased sodium level in blood, and it can also be stimulated by adrenocorticotrope hormone, but only in very high doses. But deoxycorticosterone is under the control of ACTH. Increased potassemia only with with 0.1mEq/L wil stimulate the secretion of aldosterone (normal potassemia: 3.5-5mEq/L). Sodium has less effects, it is necessary that sodiumia do decrease below 20mEq/L under the normal level. Angiotensin 2 is formed by release of renin from juxtaglomerular cells. Angiotensin 2 will go to zona glomerulosa. The effects of angiotensin 2 is mediated by a receptor which is coupled with a G protein connected to phospholipase C, and that will transform . Renin is released from juxtaglomerular cells anytime the blood flow to kidnbey decreases, blood pressure decreases, when the amount of sodium chlorides at the level of macula densa decreases. Juxtaglomerular cells are localized around the afferent and less efferent arterioles. When renal blood flow decreases (chock dehydratation), decrease of blood pressure, decreased level of sodium chlorides. Cells of macula densa work as receptors. Stimulation of nervous system increases increase release of renin. Increase of potassium concentration will depolarize the cells from zona glomerulosa and by this calcium voltage gated channels will be open, calcium will enter the cells and again aldosterone secretion is stimulated. Aldosterone can have some effects on smooth muscle cells but not mediated by transcription of genes, this is not very clear yet. Androgens hormones secreted by adrenal gland: Adrenal glandsynthetises several sexual hormones, they are dehydroepiandrosteron, androstendion, oestrogen, testosterone. They are secreted by zone reticularis, the two first are not as potent as the two others, they have only 20% of the effect of testosterone. Their secretion is under the control of adrenocorticotrope hormone and not gonadotrope hormones like LH and FSH. These hormones are metabolized specially in liver, but it is considered that some other cells have the capacity to metabolize them. In liver cortisolo is conjugated with Glucoronic acid, also a certain amount of cortisol is transformed in liver in cortison c=which is also glucoconjugated. It besomes hydrosoluble, and released in blood from where it is transported to kidney and released through urine. In urine they are found as 17-hydroxysteroids, and their amount is 2-12mg per day secreted through urine. These values are for men. For women it s less. Around 10% of cortisol is transformed in liver in 17-ketosteroid which is also excreted though urine as a sulfoconjugated product. When the capacity of liver to metabolize or inactivate these hormones is decreased, these substances can accumulate in blood. Aldosterone is also glucoronoconjugated in liver. Adrenal androgens or sexual hormones are reverted 17-ketosteroid and they are also excreted into urine. Disturbances of adrenal gland secretion:

One of the disturbance is Cushing disease or syndrome. In this disease, there is a hyper secretion of cortisol, glucocorticoids, it is usually due to a tumor secreting ACTH at the level of pituitary gland. It can also be a tumor at the level of adrenal gland. Because of the high secretion of coritisol, protein metabolism will be increased specially at the level of muscle, skin and subcutaneous tissue. And because there is an incrased of this catabolism, the skin will become thinner, the elastic tissue gfrom skin will be catabolized and through which is thinner, it can get an aspect of stretch marks (vebix?), and though this can be seen better the vascularization because the synthesis of . Is inhibited. Lipids are mobilized from the areas where the are stored to other areas. Lipids are stored at the level of face, neck and superior part of trunk giving a peculiar aspect : buffalo neck. Because amino acids are mobilized toward liver, in cushing disease there is hypoglycemia, and diabetes mellitus. Also because cortisol decreases blood pressure due to effect of catecholamines, hyperblood pressure is common in cushing disease. Also osteoporosis. Because glucocorticoids have a certain mineralocorticoid effect, sodium and water are retained into the organism together with loss of potassium, and this explains increase of body weight, and astemia. Another aspect of cushing disease, it is the consequence of hydrogen hormones, acnea, and hirsutism. Primary hyperaldosteronism or Conn disease: hyper secretion of aldosterone, it is due to a tumor at the level of zona glomerulosa. Because of that there is a retention of sodium and high losses of potassium. Because potassium is lost in higher concentration, that can lead to a nephropathy which is named hypokalemia, in this case the kidney has a decrease capacity to concentrate urine, due to that polyuria occurs. Because of loss of calcium, some neuro muscular side effects can occur, asthemia, fatigue, weakness, paralysis in some cases. Secondary hyperaldosteronism is not the result f a tumor, but in this case, there is another condition by which the secretion of aldosterone is stimulated: dehydration shock, in people will cardiac failure(edema), or hepatic failure (ascitis). Addison disease, adrenal gland are partially or totally destroyed, sometimes this si an autoimmune disease, or it could be the result of tuberculosis, or tumors or bleeding. The effect is the same, the adrenal gland is destroyed, adrenal hormones are not produced, there will be deficiency of mineralocorticoid, and glucocorticoid, sodium will be lost, potassium kept, blood volume will decrease, hypoglycemia will be associated, the compensatory mechanism will be secretion of adrenocorticotrope hormone. Also because androgen hormones are secreted, the axia an dpubian will be lost. One aspect is hyperpigmentation in some areas, specially elbows, aureola mammaris, at the level of scars, at the level of oral mucosa and genital mucosa. ACTH is secreted as a pre-pro-hormone. From POMC, melanocytes secreting hormone is released, it has the role to stimulate the pigmentation of skin, that explains the hyperpigmentation of skin in some areas. Gonads: Reproduction function : Gametogenesis Endocrine role: synthesis of sex hormones (testosterone and progesterone and oestrogens). The reproductive function of the body starts at the puberty : 12years for girls, and 14 years for boys. The onset of puberty is accepted being normal until the age of 17 for girls, and 20 years for boys.

Until the age of puberty, gonads remain inactive but around puberty they express their function. The activation of gonads happens under the action of gonadotrope hormones produced by pituitary gland. Gonadoliberin produced by hypothalamus . In newborn there is a secretion of gonadoliberin (gonadotrope releasing hormone) in hypothalamus but this secretion is stopped at the age of 3-6 months. The synchronous and phasic activity is resumed at puberty. At the beginning of puberty, the activity of these hormones from hypothamalus is specially increased during the periods of sleep, but as long as puberty progresses, the secretion of gonadoliberin is also done during the day. It is not clear why the activity of these neurons is stoped until puberty, but it is supposed that at the level of hypothalamus there is a mechanism by which the secretion of gonadoliberin is inhibited until puberty. Testis: It has two function: produce spermatozoa which is gametogenetic function, and to synthetize testosterone which is the endocrine function. Spermatogenesis: It takes place at the level of seminiferous tubules, a testicle contains around 900 semineferous tubules having the length between 70-75cm. Spermatogenesis starts with some immature cells called spermatogonia that pass through different stages, they transform into primary spermatocytes, they will transform into secondary, then spermatids, and final from spermatid are formed spermatozoa. These spermatozoa that are form at the level of seminiferous tubules are not yet active cells, they need to pass though epidydyme, and other segments till they become mature and mobile. Sertoli cells contain glycogen, which is necessary for maturation of spertatozoa. Outside of seminiferous tubules, there are other cells: Leydig cells. There is a barrier between blood and seminiferous tubules, and due to this barrier, the penetration of different proteins and micromolecules from interstitial space into seminiferous tubules is impeded. Because of this spermatozoa are outside the immune system. This barrier is organized beginning with puberty, and because spermatozoa do not come in contact with immune system, spermatozoa work like some antigens from immune system.

It is described a type of infertilities in which antibodies against the own sperm are formed. Sertoli cells synthetize a protein named androgen binding protein (testosterone binding protein) by which testosterone is bound. Spermatogenesis is stimulated by folliculo stimulating hormone, FSH is a glycoprotein. Semineferous tubules are continued with epididyme at the level of epididyme, a spermatozoa become mobile, and here spermatozoa are stored between two ejaculations. The fluid existing in seminiferous tubule is the result of secretion of sertoli cells, and its composition is a little different from plasma, because it contains less proteins and glucose, but it contains more potassium, aspartic acid, glutamic acid, testosterone and oestrogens.

From epididyme spermatozoa pass into defferent duct, and they are stored in a portion more dilated of deferent duct which are seminal vesicles. Seminal vesicles contain much fructose which is necessary as a metabolic support for spermatozoa, but also prostaglandins, aspholic acid, fibrinogen. It is considered that prostaglandins from the secretion of seminal vesicles can induce the contraction of uterus and oviducts facilitating the progression of spermatozoa towards ovum. The next element through which spermatozoa pass, is prostate, at the level of prostate a milky substance is adde that is rich is phosphates and plasminogen, these substances from prostatic secretion are useful for neutralization of the acidic pH of vagina. The pH of vagina is between 3.5-4, it is acidic, but spermatozoa can survive only in an environment which more alkaline, 6-6.5, the lactic acid in vagina is responsible for the acidic pH there. The acidic pH of vagina has a protective role, it decreases the other bacteria, and preserves the normal flora. Because there are some factor of coagulation on this secretion, semen can coagulate, but also because of plasminogen. For the maturation of 1 spermatozoa needs 74 days. The volume of semen ejaculated once is normally is between 2-4mL. In every mL of semen, there will be between 60-100 millions of spermatozoa. When the number of spermatozoa decreases, becoming between 20 millions then more than 50% -50 of these people are sterile. When it s lower than 20millions, almost all these people are sterile. 20-50 millions: oligospermia. Lower than 20 milliion it is called aspermia. Often, the decrease of number is correlated to an abnormal structure of the spermatozoa. In order to have a normal spermatogenesis, it is necessary for the T of testis to be decreased, 32C, that the reason testis are found in scrotum, and regulates its position depending on the temperature due to contraction of cremasterian muscles.