Endocrine Glands PDF

The Endocrine system  Endocrine system !A distributed group of ductless glands that Secrete their hormones into blood & extracellular fluid. Together with the nervous system constitutes the control systems in the body.  Principal functions of the endocrine system  Maint...

The Endocrine system  Endocrine system !A distributed group of ductless glands that Secrete their hormones into blood & extracellular fluid. Together with the nervous system constitutes the control systems in the body.  Principal functions of the endocrine system  Maintenance of the internal environment (homeostasis).  Regulation of body metabolism.  Control of energy production, utilization & storage.  regulation of growth & development.  Control, & maintenance of sexual reproduction, body’s response to environmental stimuli.  Endocrine glands Include the following glands :  The pituitary  The thyroid  The parathyroid  The pancreas  The adrenal medulla & cortex  The gonads ( testes in males and ovaries in females )  Endocrine glands essential to life Without the hormones released from certain endocrine glands , death is expected in a short time These hormones should be replaced by therapy in patients suffering from deficiency of these hormones The essential glands include : The anterior pituitary (ACTH) The adrenal cortex (Cortisol ) The parathyroid glands (PTH)  Certain organs contain endocrine cells that synthesize and release hormones These includes: The hypothalamus The kidneys The heart The GIT The skin (releases vitamin D) The adipose tissue (releases leptin) The liver (releases IGF) The placenta (releases estrogens, progesterone, hCG, hCS )  Hormones? !A hormone is a chemical substance that is released by endocrine glands or organs to act on specific target cell to exert physiological effects.  Hormones acts through one or more of these types of signaling: 1/Endocrine action: the hormone is distributed in blood and binds to distant target cells. 2/Paracrine action: the hormone acts locally by diffusing from its source to target cells in the neighborhood. 3/Autocrine action: the hormone acts on the same cell that produced it.  A cell is a target because it has a specific receptor for the hormone Most hormones circulate in blood, coming into contact with essentially all cells. However, a given hormone usually affects only a limited number of cells, which are called target cells. A target cell responds to a hormone because it bears receptors for the hormone.  Types of hormones Hormones are categorized into four structural groups, with members of each group having many properties in common: – Amino acid derivatives – Peptides and proteins – Steroids – Fatty acid derivatives - Sites of catabolism : - The principal sites of hormonal destruction are: The liver (steroid hormones ). The kidney ( peptide hormones). Other tissues (e.g. adipose tissue) Half-life: The time required for half of a hormone to be metabolized or eliminated by the body. The half-life of peptide hormones is less than steroid & thyroid hormones. Glycoprotein hormones have longer half-life than other peptide hormones.  Hormones receptors Mostly protein in structure. Each target cell has  2000 – 100,000 receptors. Each receptor is highly specific for a single hormone.  Location of the receptors  Receptors for the water soluble hormones peptides & proteins are found on the surface of the target cell.  These types of receptors are coupled to various second messenger systems which mediate the action of the hormone in the target cell.  Exception is the thyroid hormones (have intracellular receptors )  Receptors for the lipid soluble hormones are found on the interior of the target cell (the nucleus or the cytoplasm ). Because these hormones can diffuse through the lipid bilayer of the plasma membrane, their receptors are located on the interior of the target cell  Hormones and their receptors Hormone Class of hormone Location Amine (epinephrine) Water-soluble Cell surface Amine (thyroid Intracellular hormone) Lipid soluble Peptide/protein Water solube Cell surface Steroids and Vitamin D Lipid Soluble Intracellular Mechanism of Action of hormones  Mechanism of Action: Peptides and Most Amines  They are water soluble (cannot pass through hydrophobic lipid bilayer). (with exception of the thyroid hormones )  Binds to receptor proteins on cell surface lead to activation of membrane-bound enzymes  This will lead to production of a second messenger inside the cell  e.g. cAMP  2nd messenger activates or deactivates various enzymes  By this the cell function will be altered  Second messenger systems  Receptors for the water soluble hormones are found on the surface of the target cell, on the plasma membrane. These types of receptors are coupled to various second messenger systems which mediate the action of the hormone in the target cell.  Second messenger systems a hormonal signal results in series of biochemical reactions within the cell carried by enzymes. The generation of second messengers and activation of specific protein kinases results in changes in the activity of the target cell. Second messengers include: 1/ cAMP (cyclic adenosine monophosphate): For ADH (V2 receptor), LH, FSH, TSH, ACTH, PTH, calcitonin, glucagon, catecholamines (β receptors). 2/ Tyrosine kinase : For oxytocin, growth hormone, prolactin, insulin &erythropoietin 3/Inositol-triphosphate (IP3), diacylglycerol (DAG) & calcium GnRH, TRH, catecholamines (α receptors), angiotesin II and ADH( V1 receptor). 4/cGMP (cyclic guanosine monophosphate): For atrial natriuretic peptide “ANP” (also for local signals like nitric oxide). Cell surface receptor action  Mechanism of Action: Steroids & Thyroid Hormones These are lipid soluble hormones binds to protein receptor in the cytoplasm or in the nucleus. The hormone/receptor complex enters the nucleus& binds to a specific gene on the DNA. It acts as a transcription factor that modulates gene expression (stimulating the transcription of messenger RNA). The messenger RNA is translated into protein. Modulates protein production & hence cell function.  Remember that ! ! Receptors are located intracellularly for :  Steroid hormones (fat soluble) receptors located in the cytoplasm.  Thyroid hormones (T4 & T3) receptors located in nucleus itself.  Thyroid hormone 5. Gene level - binds to chromatin - Influence DNA dependent RNA polymerase 4. Combine w receptor protein 3. Translocation to nucleus 1. Entry 2. Combine w protein  Control of Endocrine Activity Synthesis and secretion of hormones are the most highly regulated aspect of endocrine control. Such control is mediated by positive and negative feedback. Most hormones in the body are controlled by “a negative feedback mechanism.” Control of hormone secretion rate – Role of negative feedback Hormone + Endocrine cell Target cell - Too much function Negative Feedback Through negative feedback, when the amount of a particular hormone in the blood reaches a certain level, the endocrine system sends signals that stop the release of that hormone.  In other words, the hormone (or one of its products) has a negative feedback effect to prevent over secretion of the hormone or overactivity at the target tissue. Positive feedback mechanism Positive feedback occurs when the biological action of the hormone causes additional secretion of the hormone. The hormone stimulates its own release. Examples of positive feedback mechanism include : oxytocin, angiotensin II & LH in females (just before ovulation). Positive Feedback HYPOTHALAMUS-PITUITARY CONNECTIONS  Many endocrine glands (e.g. the thyroid, the adrenal cortex & the gonads) are controlled by the pituitary gland. Hormones of the pituitary are controlled by hormones released by the hypothalamus. This is known as “the hypothalamo-pituitary axis.” Certain factors (environmental, nutritional, ions …) act directly on the hypothalamus to stimulate or inhibit its hormones. Some glands are not controlled by the hypothalamo- pituitary axis (like the parathyroid gland, the pancreas and the adrenal medulla). The pituitary gland communicates with the hypothalamus to control many body activities.  Hypothalamus and Pituitary The hypothalamus-pituitary unit is the most dominant portion of the entire endocrine system. It is a form of neuro-endocrine relationship. The output of the hypothalamus-pituitary unit regulates the function of the thyroid, adrenal and reproductive glands and also controls growth, lactation, milk secretion and water metabolism.  The pituitary gland (hypophysis) The pituitary gland lies in a pocket of bone (sella tursica) at the base of the brain just below the hypothalamus. it is connected to hypothalamus by a stalk (infundibulum) containing nerve fibers and blood vessels.  The pituitary gland is a small gland (1g ) Divided into: Anterior pituitary (adenohypophysis) Posterior pituitary (neurohypophysis) Intermediate lobe ( found in animals not in humans ) Relationship of the hypothalamus to the anterior pituitary The portal hypophysial vessels form a direct vascular link between the hypothalamus and the anterior pituitary (Hypothalamo- hypophyseal portal vessels) Relationship of the hypothalamus to the anterior pituitary  Hypothalamus controls Anterior Pit hormones by releasing & inhibitory hormones.  Carried by portal vascular system to Anterior Pit  Anterior pituitary releases appropriate hormone into circulation  All Ant. Pit hormones have growth promoting effects on targets (called –trophic hormones).  Trophic hormones act on other endocrine glands to increase cellularity, vascularity and secretion of these glands.  Removal of trophic hormone causes atrophy of target.  Hypothalamic hormones Hypothalamic hormone Effect on pituitary Corticotropin releasing hormone Stimulates ACTH secretion (CRH) Thyrotropin releasing hormone Stimulates TSH secretion (TRH) Growth hormone releasing Stimulates GH secretion hormone (GHRH) Somatostatin Inhibits GH secretion Gonadotropin releasing hormone Stimulates LH and FSH secretion (GnRH) Prolactin releasing hormone (PRH) Stimulates PRL secretion Prolactin inhibiting hormone Inhibits PRL secretion (dopamine) Relationship of the hypothalamus to the posterior pituitary The connections between the hypothalamus and the posterior pituitary are neural. The posterior pituitary is a collection of nerve axons whose cell bodies are located in the hypothalamus and pass to the posterior pituitary via the hypothalamohpophysial neural tract.  The posterior pituitary secretes two peptide hormones ADH and oxytocin from the nerve terminal and their cell bodies are located in the supraoptic and paraventricular nuclei within the hypothalamus.  Remember that ! The anterior lobe synthesizes and release hormones that control activity other endocrine glands in the body. While the posterior lobe only stores and release hormones synthesized by the hypothalamus. Pituitary Gland The Pituitary Gland Hormones – Posterior Lobe: Antidiuretic hormone (ADH) Oxytocin – Anterior Lobe: Adrenocorticotropic (ACTH) Growth hormone (GH) Thyroid-stimulating hormone (TSH) Follicle-stimulating hormone (FSH) Luteinizing hormone (LH) Prolactin (PRL) Pituitary gland hormones  Remember that ! The anterior lobe synthesizes and release hormones that control activity other endocrine glands in the body. While the posterior lobe only stores and release hormones synthesized by the hypothalamus. HORMONES OF THE ANTERIOR PITUITARY Growth Hormone (GH) -Peptide hormone (191 aa ) -Half life : 20 min Effects of Growth hormone: 1/ Growth promotion in most tissues. Stimulate growth of bone & cartilage (chondrogenesis). 2/CHO met. : hyperglycemic. Increasing hepatic glucose output (gluconeogenesis & glycogenolysis) Antagonizing actions of insulin in muscles and adipose tissues.ie diabetogenic. Shifts the metabolism towards utilization of FFAs and sparing glucose as a source of energy for the brain. 3/ Protein metabolism : anabolic (+ve nitrogen & phosphorus balance). 4/ Fat metabolism. : lipolysis. Increases FFAs in plasma(ketogenic). 5/ Increase Ca++ & phosphate absorption. 6/ Reduced Na+, K+ excretion by the kidney. 7/ Lactogenic effect Control of GH secretion: From the hypothalamus by: Growth hormone releasing hormone (GHRH) Growth hormone inhibitory hormone (GHIH); somatostatin. Negative feedback mechanism by GH itself or by somatomedins (IGF). After adolescence, GH secretion decreases slowly with aging Control of secretion: Hypothalamus: ! Release Inhibition GHRH GHIH Control of GH Release Inhibition secretion: Non REM Growth sleep hormone Others: ! Stress REM sleep Hypoglycemia Cortisol FFAs, Exercise Glucose Somatomedins:I Arginine GF-1, IGF-2 Some hormones: ghrelin Medroxyprogesterone Glucagon, estrogens and androgens Somatomedins: - These are insulin like growth factors “IGF” produced by the liver and other tissues in response to GH. Insulin-like growth factor-I (IGF-I, or somatomedin C) Insulin-like growth factor II (IGF-II) -Functions of somatomedins: Mediate the effects of GH on skeletal tissues (stimulate growth of bone & cartilage) Stimulate protein synthesis. Exert some insulin like activity.  Abnormalities of GH Excess GH (due to pituitary tumors ) : Before puberty: causes gigantism (the size of viscera and the length of bones are increased because the abnormality occurred before closure of epiphyseal plate) After puberty: causes acromegaly (the size of viscera is increased but not the length of bones because the abnormality occurred after closure of epiphyseal plate) gigantism Acromegaly  Deficiency of GH (due to pituitary tumors or surgical removal ) Before puberty causes dwarfism ( short stature with intact mental function ) After puberty causes minor metabolic abnormalities  Prolactin (PRL ) -Peptide hormone (199 aa ) - Half life : 15 -20 min In addition to the anterior pituitary, it is also secreted by the endometrium & the placenta.  Effects 1/ Growth of breast ( during pregnancy ) 2/ Production of milk ( after delivery, this action is inhibited during pregnancy by estrogen & progesterone 3/Inhibition of gonadotrophins ( = loss of menstrual cycle during lactation ) Control of prolactin : From the hypothalamus by: Prolactin releasing hormone (PRLRH) Prolactin inhibitory hormone (PRLIH); also known as dopamine More dominant. Negative feedback mechanism by PRL. N.B Cutting the pituitary stalk increases release of PRL while decreasing release of other anterior pituitary hormones  Stimuli for prolactin release: Pregnancy & estrogen Suckling Sleep Stress Thyroid releasing hormone “TRH” (& hypothyroidism) Dopamine antagonists (e.g. phenothiazines Inhibitors : L dopa & dopamine agonists e.g. bromocriptine  Abnormalities Prolactin excess: (due to pituitary tumors ) Characterized by 1/ Infertility 2/ Amenorrhoea (stop of menstural cycle) 3/ Galactorrhoea (spontaneous flow of milk from breast not associated with child birth or nursing) 4/ Impotence & loss of lipido in males 5/ Osteoporosis in females (due to low estrogens resulting from the inhibition of gonadotropins).  ( ACTH ) corticotropin Adrenocorticotrophic hormone -Peptide hormone (39 aa ) - Half life : 5- 15 min Control of ACTH From the hypothalamus by corticotrophin releasing hormone (CRH). Negative feedback mechanism by: ACTH itself and cortisol. Diurnal (or circadian) rhythm: 75% released in the morning and decreased at evening (regulated by the suprachiasmatic nuclei of the hypothalamus ) -Stimuli for ACTH = all types of stress : Stressful stimuli acts on the hypothalamus stimulates release of CRH which induce ACTH release from the Anterior pitutary. Physical stress (exercise ) Emotional stress ( fear ) Hypoglycemia Cold exposure and pain Afferents from baroreceptors inhibits CRH release from the hypothalmus.  Effects of ACTH 1/Trophic effect : Increases cellularity & vascularity of adrenal cortex and increases cortisol secretion 2/ Increases the responsiveness of the adrenal cortex to subsequent doses of ACTH. 3/ pigmentation of the skin. ( MSH like effect)  Abnormalities of ACTH Excess ACTH: - Caused by: 1/ Pituitary tumors that secrete ACTH (= cortisol excess of secondary Cushing’s syndrome) 2/ Lung tumors that secrete ACTH (= cortisol excess of ectopic Cushing’s syndrome) 3/ Adrenal problems causing cortisol deficiency due to???................ called (= Primary Addison’s disease) Deficiency of ACTH: - Caused by: 1/ Pituitary tumors, which destroy the cells that secrete ACTH (= decreased cortisol secretion from the adrenal cortex = secondary Addison’s disease) 2/Diseases of the adrenal cortex that cause excessive cortisol secretion (= primary Cushing’s disease) are associated with low ACTH due to the negative feedback mechanism. Thyroid stimulating hormone (TSH ) -Glycoprotein Other glycoprotein hormones includes: FSH, LH and hCG (have similar alpha subunits) -Half life : 60 min Effects of TSH: Trophic effect: Increases cellularity & vascularity of thyroid gland and increases secretion of thyroid hormone.  Control of TSH secretion: From the hypothalamus by thyrotropin releasing hormone (TRH) Stimuli : cold Inhibitors : heat ,stress Glucocorticoids, dopamine and somatostatin (but not involved in its physiological control).  Abnormalities of TSH TSH excess : - Caused by: Pituitary tumors that secrete TSH (= high T3 & T4 = secondary hyperthyroidism) Thyroid diseases that decrease T3 & T4 secretion (= primary hypothyroidism) TSH deficiency : - Caused by: Pituitary tumors that decrease T3 & T4 secretion (= secondary hypothyroidism) Thyroid diseases that increase T3 & T4 secretion (= primary hyperthyroidism)  Follicle stimulating hormone (FSH ) & leutinizing hormone ( LH ) known as gonadotrophins. Glycoproteins. Half life : 1-3 hours Their release starts at puberty and continues throughout life  Effects of FSH & LH : 1/ Trophic effect : Increases cellularity & vascularity of the gonads & increases secretion of sex hormones 2/ Control of gonadal function : production of sperms in males and ovulation in females Control of FSH & LH: From the hypothalamus by (GnRH). Negative feedback mechanism by FSH and LH and by the sex hormones that are released from the gonads in response to them (estrogens, progesterone and testosterone). Inhibitors : Stress and Prolactin.  Abnormalities of FSH & LH Gonadotrophin excess : - Results in "precocious puberty" if occurred before puberty. Gonadotrophin deficiency : -Delays onset of puberty. - Results in infertility (if occurred after puberty).  HORMONES OF THE POSTERIOR PITUITARY  Antidiuretic hormone (ADH ) Also known as vasopressin Peptide (9 aa ) Half life : 18 min Synthesized in hypothalamus ( in the Supra-optic nucleus (SON) & Paraventricular nucleus (PVN). Stored and released by the posterior pituitary Vasopressin has two types of cell membrane receptors: V1 receptors : (in the blood vessels, liver & brain). V2 receptors: In the collecting ducts & distal part of the DCTs. Effects of ADH: 1/ ADH acts on the collecting ducts in the kidney causing water retention. 2/ Vasoconstriction. 3/ Other effects : Glycogenolysis in the liver. Neurotransmitter in the brain and spinal cord. Release of ACTH from the anterior pituitary.  Control of ADH Stimuli for ADH release : Hyperosmolarity (detected by osmoreceptors located at the hypothalamus and connected to the cell bodies of the SON & PVN through dendrites). Hypovolemia Hypotension Angiotensin ll Drugs : barbiturates, nicotine and morphine. Inhibitors of ADH include: Hypo-osmolarity Hypertension Hypervolemia Alcohol  Abnormalities of ADH Deficency of ADH: Causes polyuria and excessive thirst Urine volume may reach up to 23 L/day. this condition is known as diabetes insipidus (DI) could be: Neurogenic DI ( a problem in the hypothalamus) Nephrogenic DI (a problem in the kidney ) Excess ADH : Causes reduction in urine volume (oliguriua) , hypertension and edema due to water retention This condition known as syndrome of inappropriate ADH secretion (SIADH ) Oxytocin Peptide (9 aa ) Half life : 1-4 min Synthesized in hypothalamus mainly in the (PVN) and (SON) and stored in the posterior pituitary Effects of oxytocin : Ejection of milk during lactation. Contracts the uterus during labor. Other minor effects : Contraction of the uterus to facilitate movement of sperms. Contraction of the vas deferens to facilitate ejaculation. Control of oxytocin:.Positive feedback mechanism through neuro-endocrine reflexes stimulated by: Suckling Labor Other stimuli: Stress & coitus (genital stimulation). Inhibitors: Alcohol The Thyroid Gland  -The largest endocrine gland (20- 25 g )  -Found at the anterior aspect of the neck  -Moves with swallowing  -Consists of 2 lobes connected by the thyroid isthmus  -Synthesizes thyroid hormones and calcitonin (regulation of calcium )  Thyroid Hormones  -Two types : T3 ( Tri – iodothyronine ) & T4 (Thyroxin )  -Synthesized from : Tyrosine ( Two molecules ) and iodide (3 or 4 atoms )  -Half life : T3 = 1.5 day (Active hormone ) & T4 = 6-7 days ( Less active hormone )  THE THYROID GLAND -The largest endocrine gland (20- 25 g ) -Found at the anterior aspect of the neck -Moves of swallowing -Consists of 2 lobes connected by the thyroid isthmus -Synthesizes thyroid hormones (see below ) and calcitonin (see regulation of calcium ) Thyroid Hormones -Two types : T3 ( Tri – iodothyronine ) & T4 (Thyroxin ) -Synthesized from : Tyrosine ( Two molecules ) and iodide (3 or 4 atoms ) -Half life : T3 = 1.5 day (Active hormone ) & T4 = 6-7 days ( Less active hormone ) Anatomy of thyroid gland :- The gland is composed of large numbers of closed follicles These follicles are filled with a secretory substance called (colloid) and lined with cuboidal epithelial cells The major constituent of colloid is a large glycoprotein called --- thyroglobulin Synthesis and secretion of thyroid hormones:-  About 93% of metabolically active hormone secreted by thyroid gland are thyroxin. iAlmost all the thyroxin in the tissue is converted to tri iodothyronine. T3 is about 4 times as potent as thyroxin. But it present in blood in much smaller quantities and persist for shorter time than does thyroxin. odothyronine Iodine is required for formation of thyroxine About 1 mg/week Now to prevent deficiency iodized common table salt (1 part of Na iodide to every 100,000 parts of Nacl.  Transport of T4 and T3 Thyroid hormones bound to plasma proteins :- 1- thyroxine- binding globulin (TBG) 2-thyroxine- binding pre albumin (TBPA) 3-albumin Control of secretion  Effects of thyroid hormones  Increase oxygen consumption by tissues  Increase metabolism : Thyroid hormone increase the metabolic rate by 60% up to 100% above normal level. Increased thyroid level ,decrease the wt. Decreased thyroid level , increase the wt.. Protein catabolism ( in high levels ) and anabolism ( in low levels ) Mobilization of fats and decrease cholesterol levels Increase absorption of carbohydrates in the GIT  Increase growth Thyroid hormones are needed for normal growth promote the actions of growth hormone Hypothyroidism in children results in growth abnormalities  CVS : Increase heart rate and stroke volume Increase the cardiac output Increase the systolic B.P Decrease the diastolic B.P Increase the pulse pressure  GIT Increase appetite and increase motility  CNS : Increase development of the brain in children (cereberal cortex, basal ganglia and cochlea) Hypothyroidism in children causes mental retardation ,motor rigidity and deafness increase mentation in adults Increase rapidity of cerebration. So patients with hyperthyroidism ,suffer of extreme nervousness ,anxiety, extreme worry  Vitamins : Because of increase the metabolism by thyroid hormone , there is increase in need of vitamins.  The effect on respiratory increase the rate and depth of respiration.  Essential for normal menstruation and fertility  Abnormalities : Hyperthyroidism or ( thyrotoxicosis ) -Caused by toxic tumors , inflammation , drugs or auto antibodies. -Features : Increased metabolism = Increased heat production = intolerance to hot Increased heart rate , SV , COP, systolic B.P. and pulse pressure.And decreased diastolic B.P Irritability and nervousness Increased appetite Diarrhea Weight loss Fine tremor in fingers Eye signs ( lid lag , lid retraction and exophthalmos ) ; here the hyperthyroidism is also known as Graves’ disease  Hypothyroidism -Caused by congenital deficiency of thyroid enzymes involved in thyroid hormone synthesis , iodine deficiency , tumors , inflammation , surgical removal , autoantibodies or drugs -Features : Low metabolism = decreased heat production = intolerance to cold Easily fatigued  weight gain Hair changes ( becomes coarse coarse and sparse ) Skin changes ( becomes dry and yellow ) Voice changes ( becomes husky and slow ) CNS symptoms ( sleepy , slow memory ) Bradycardia Constipation  Cretinism -Hypothyroidism in children since birth -Features : Mental retardation Short stature Large protruded tongue Umbilical hernia Goiter -Swelling of the thyroid gland caused by increased TSH from the pituitary The End  The Adrenal Glands Lie on the superior border of each kidney Subdivided into two adrenal glands : – Superficial: adrenal cortex – Inner: adrenal medulla  Adrenal medulla Represents modified sympathetic ganglion that lost its postganglionic axons, it’s function resemble that of the sympathetic nervous system. Adrenal medulla synthesize : Epinephrine, norepinephrine and small amount of dopamine. The ratio of secreted epinephrine to norepinephrine is about 4:1. Effects of Epinephrine & Norepinephrine !Increase H.R. and B.P. !Vasoconstriction !Increase respiration !Increase metabolic rate !Increase glycogenolysis !Bronchodilation  Interesting that both are hormones when released by Adrenal gland, but neurotransmitters when released at synapses Catacholeamine Overproduction: Pheochromocytoma – Adrenal medullary tumor that secrete epinephrine and norepinephrine. Characterized by: High BP ,High metabolic rate, elevated temperature, high HR and high blood glucose levels  The adrenal cortex Secretes : gluco-corticoids and mineralo-corticoids (essential for life). Androgens. Adrenal cortical hormones are steroid hormones synthesized from cholesterol. Hormones secretion is under the control of (ACTH) especially gluco-corticoids and sex hormones. Mineralo-corticoids are released mainly in response to other stimuli. (eg. Angiotensin-II and hyperkalemia)  Adrenal cortex is divided into 3 zones : 1. Zona-glomerulosa: outer zone , secretes aldosterone , also replace the lost cells 2. Zona-fasiculata: middle zone , secretes gluco-corticoids. 3. Zona-reticularis: innermost zone , secretes sex hormones(Androgens). Slide 59 – Adrenal medulla  Zona fasiculata and zona reticulares depend on ACTH for growth , they undergo atrophy when ACTH is absent (eg: after hypophysectomy). Zona glomerulosa doesn’t undergo atrophy immediately because of angio-tensin-II activity , but later it does due to loss of potentiating factor from pituitary.  Adrenal Cortex Secretes the following hormones : Mineralocorticoids : mainly (Aldosterone) Glucocorticoids: mainly (Cortisol) Sex Hormones: (Androgens)  Glucocorticoids 1/ Cortisol (very potent, accounts for about 95 percent of all glucocorticoid activity) 2/ Corticosterone :much less potent than cortisol 3/Cortisone (physiologicaly insignificant ) can be formed in the body from cortisol by the enzyme 11β-Hydroxysteroid dehydrogenase (Type 1). Synthetic steroids: Cortisone (synthetic, almost as potent as cortisol) Prednisone, methylprednisone Dexamethasone 9α fluorocortisol  Cortisol The primary glucocorticoid Steroid hormone -Essential for life -Half life : 60-90 min -Released from the adrenal cortex in response ACTH from the anterior pituitary Cortisol transport 90 to 95 per cent of the cortisol in the plasma binds to plasma proteins: Cortisol-binding globulin or transcortin and, to a lesser extent, to albumin. Effects of cortisol 1/Metabolism of CHO: Cortisol causes hyperglycemia by : Anti-insulin action on the peripheral tissues ( with exception of the heart & brain) Increasing hepatic gluconeogensis; however it causes glycogenesis in the liver. The enhanced use of fatty acids for energy metabolism spares the blood glucose supply. 2/Protein catabolism Cortisol cause reduction of the protein stores in essentially all body cells except those of the liver. Increass the liver proteins & the plasma proteins. 3/Fat mobilization and stimulates formation of ketone bodies. In diabetics, glucocorticoids raises plasma lipid levels and increase ketone body formation, However, in normal individuals, counteracted by insulin. 4/ Permissive effect for catecholamines and glucagon: Cortisol is essential for glucagon and catecholamines to exert their calorigenic effects. For the effects of glucagon (e.g. lipolysis). For the effects of catecholamines (e.g. vasoconstriction( increases the vascular reactivity) & bronchodilation) Permissive effect: Small amounts of glucocorticoids must be present for a number of metabolic reactions to occur, although the glucocorticoids do not produce the reactions by themselves. 5/ Increases RBCs , platelets and neutrophils ; and decreases lymphocytes , basophils and eosinophils 6/Anti-stress effect (essential for life) It guards against stress; but the mechanism is unknown( may be due to the permissive action on catecholamines) glucocorticoid-deficient individuals receiving replacement therapy require larger doses of glucocorticoid to maintain their well-being during periods of stress 7/ The nervous system: -Cortisol deficiency: abnormal slowing of the EEG activity and personality changes (irritability apprehension and failure to concentrate). -Cortisol excess: rapid EEG rhythm, increased appetite, insomnia, euphoria, or frank psychosis). 8/Mineralocorticoid effect: Reabsorption of Na ⁺ & secretion of K ⁺ ( like aldosterone ) 9/ Cortisol increases the GFR and facilitates excretion of water load. Pharmacologic effects Anti-inflammatory effect: Excess Cortisol inhibits phospholipase A2 thus preventing formation of the inflammatory mediators: prostaglandins and leukotrienes. - Prevention of fibrous tissue formation Anti-allergic effect - Excess cortisol inhibits the release of histamine by mast cells. Anti-immunity effect - Excess cortisol decreases number of lymphocytes, decrease the release of lymphokines like IL-2& decreases the size of lymphatic organs. Other effects: Cortisol accelerates surfactant production during fetal life. Excess cortisol decreases growth hormone and TSH secretion. Induce epinephrin synthesis by increasing PNMT Inhibition of bone formation & decrease intestinal Ca2+ absorption.  Effects of cortisol : Hyperglycemia (antagonizes insulin ) Protein catabolism Fat mobilization Increases RBCs , platelets and neutrophils ; and decreases lymphocytes , basophils and eosinophils Reabsorption of Na ⁺ & secretion of K ⁺ ( like aldosterone ) Anti-inflammatory effect Anti-allergic effect Anti-immunity effect Anti-stress effect Control of cortisol : 1/ Hypothalamo-pituitary axis CRH from the hypothalamus stimulates the anterior pituitary to releases ACTH, which increases the secretion of glucocorticoids by the adrenal cortex. 2/ Negative feedback mechanism 3/Circadian rhythm ( high in the morning and low at night ) Stimuli : All types of stress. Control of secretion Negative feedback effects of cortisol  Abnormalities of cortisol Cortisol excess: Cushing’s syndrome causes. 1/ACTH independent causes ( low ACTH) include: Adrenal tumor or hyperplasia secreting cortisol (primary Cushing’s). Prolonged use of drugs with cortisol activity (e.g. prednisolone in asthma). 2/ ACTH dependent causes (High ACTH) include: Pituitary tumor secreting ACTH (secondary Cushing’s or Cushing’s disease). Lung tumor secreting ACTH or CRH (ectopic Cushing’s). Cushing’s syndrome characterized by: 1/ redistribution of fat in the face, neck & trunk. Central obesity and thin limbs ,rounded moon face, Buffalo hump 2/Thin hair& skin and weak muscles resulting in: poor healing of wounds and easy bruising and ecchymoses. 3/Purpule striae (appear in the skin of the abdomen because it is thin and stretched by the fat deposition). 4/Plethora. 5/hypokalemia 6/ Hypertension due to: Salt and water retention by cortisol or deoxycorticosterone. The permissive effect of cortisol on blood vessels Increased secretion of angiotensinogen 7/Diabetes mellitus (hyperglycemia, hyperlipemia and ketosis). 8/ Osteoporosis (loss of bone mass) and fractures. 9/ Increased facial hair “hirsutism” and acne (due to associated androgen secretion). 10/ CNS changes and personality changes (rapid EEG rhythm, increased appetite, insomnia, euphoria, or frank psychosis Cortisol deficiency ( Addison's disease ) - Primary adrenal insufficiency “Addison's disease” is caused by destruction of the adrenal cortex (by tuberculosis or autoantibodies). - Secondary adrenal insufficiency is caused by pituitary disorders (decrease ACTH release). - Tertiary adrenal insufficiency caused by hypothalamic disorders (decrease CRH release). Adrenal insufficiency is characterized by: 1/ Hyponatremia 2/ Hypotension 3/ Hyperkalemia 4/ Hyperpigmentation of gums, palmer creases,etc (only in the primary type. why??? 5/ Acidosis 6/ Weight loss 7/ Muscle weakness (due to hyperkalemia) 8/Small heart. Why? 9/GI upset, nausia ,vomiting &anorexia o Risk of death in Adrenal insufficiency is due to: Addisonian crisis (caused by stress and characterized by circulatory collapse) Fasting (causes fatal hypoglycemia) Water intoxication (failure to excrete water) ADH is high in Addison’s disease.  Mineralocorticoids Aldosterone (very potent, accounts for about 90 per cent of all mineralocorticoid activity) Desoxycorticosterone ( 3% as potent as aldosterone, but very small quantities secreted) Corticosterone is a glucocorticoid with a slight mineralocorticoid activity) Fluorocortisol (synthetic , slightly more potent than aldosterone and has 10 times cortisol activity )  Aldosterone Steroid hormone Essential for life Is the main mineralocorticoid. Formed only in the zona glomerulosa -Half life : 20 min ( because less bound to protein about 60% bound)  Effects of Aldosterone : Reabsorption of Na⁺ & secretion of K ⁺ in : The DCT and CDs in the kidneys ( prinicipal cells) N.B (Reabsorption of Na+ is coupled to H+ secretion in the intercalated cells) alkalosis. GIT (salivary ducts and colon) Sweat glands  Aldosterone actions either rapid or late: Rapid effects (within 10-30 min) include: Activation of pre-existing epithelial sodium channels (ENaCs); thus increasing the permeability of the luminal membrane to sodium. Activation of pre-existing Na+-K+ pumps later effects include: Increased number of ENaCs Increased number of Na+-K+ pumps  Control of aldosterone Not under the control of the hypothalamo-pituitary axis. The direct Stimuli of aldosterone secretion : 1/Hyperkalemia. 2/The rennin –angiotensin – aldosterons system. Rennin enzyme which is produced by the Juxta – glomerular apparatus in the kidney results in activation of angiotensinogen to “angiotensin I.” Then the angiotensin converting enzyme in the pulmonary circulation converts “angiotensin I” to “angiotensin II”. Angiotensin ll stimulates aldosterone secretion from the adrenal cortex. 3/ High level of ACTH ACTH levels higher than that which stimulate maximal cortisol secretion, can also stimulate aldosterone secretion. Indirect Stimuli of aldosterone secretion : Are the stimuli that stimulates release renin these include: 1/ Hyponatremia 2/ Renal ischemia (caused by hypotension, standing, hypovolemia or renal artery stenosis) 3/Sympathetic stimulation (associated with stressful stimuli, here cortisol secretion is also stimulated). Inhibitors of aldosterone secretion ANP decreases aldosterone secretion by inhibiting renin secretion and decreasing the effects of angiotensin II on zona glomerulosa. High sodium ion concentration in the extracellular fluid very slightly decreases aldosterone secretion. Abnormalities of aldosterone: Primary hyperaldosteronism or Conn’s syndrome: Caused by an aldosterone-secreting tumor. Characterized by : increased ECF volume (due to increased Na+ reabsorption). High blood pressure Hypoklemia Metabolic alkalosis (due to increased H+ secretion) Muscle weakness (due to low K+) Tetany due to ??? low Ca++ ions secondary to the alkalosis Renin levels will be ?? Decreased because the increased ECF volume N.B: Excess Aldosterone Increases Extracellular Fluid Volume and Arterial Pressure but Has Only a Small Effect on Plasma Sodium Concentration. NO Edema in primary hyperaldosteronism This is due to aldosterone escape phenomenon caused by ANP. The primary reason for the escape is the pressure natriuresis and diuresis that occur when the arterial pressure rises Secondary hyperaldosteronism Associated with congestive heart failure , liver cirrhosis and renal failure. Characterized by high renin secretion and development of edema. Al dosterone deficiency : could be due to : Destruction of adrenal cortex Hyporeninemic hypoaldosteronism Pseudo-hypoaldosteronism: occurs due receptor defects. -These disorders are characterized by; Salt loss, hypotension, hyperkalemia and acidosis.  Adrenal Androgens Androgens secreted by the adrenal cortex are: Dehydroepiandrosterone Androstenedione They are moderately active male sex hormones Released mainly from Zona-reticlaris and small amount from Zona-fasiculata. Controlled by ACTH not by Gonadotrophins N.B both layers also secrets very small amount of estrogens  Adrenal androgens Have only weak effects in humans: Early development of the male sex organs. Proteins anabolism and promotes growth Mild effects in the female, growth of the pubic and axillary hair. In extra-adrenal tissues, some of the adrenal androgens are converted to testosterone, the primary male sex Hormone and some converted to estrogens  N.B Progesterone and estrogens, which are female sex hormones, are secreted in minute quantities by the adrenal cortex. Adrenogenital Syndrome: Caused by adrenocortical tumor secretes excessive quantities of androgens or congenital deficiency of an enzyme of steroid hormones biosynthesis. This cause intense masculinizing effects throughout the body. In female: she develops virile characteristics, including growth of a beard, a much deeper voice and deposition of proteins in the skin and especially in the muscles. In a female child : Pseudohermaphroditism In prepubertal male: Rapid development of the male sexual organs but no testicular growth. Precocious pseudo-puberty. In adult male: the virilizing characteristics of adrenogenital syndrome are usually obscured by the normal virilizing characteristics of the testosterone secreted by the testes.  THE PANCREAS -Has both types of glands: Endocrine ( lslets of langerhans = (2%) ) & Exocrine = (98% ) -Types of cells in islets of Langerhans : Type A cells secrete Glucagon Type B cells secrete Insulin Type D cells secrete Somatostatin Type F cells secrete Pancreatic poly peptide -All these hormones are polypeptides -They control glucose concentration in the blood Fig 11.30  Insulin - polypeptide hormone Consist of two chains ( A & B ) Synthesized in the rough endoplasmic reticulum of the beta cells of the pancreas then packed into secretory vesicles or granules in golgi apparatus as follows Insulin Synthesis  Control of secretion Not by the hypothalamo-pituitary axis Stimuli : Hyperglycemia Amino acids Keto acids GIT hormones especially GIP Parasympathetic stimulation Drugs (sulphonylureas ,theophilline, B adrenergic agonists) Inhibited by : 2 deoxyglucose somatostatin catecholamines Insulin Drugs (alpha adrenergic agonists, beta adrenergic blockers ,thiazide diruetics,phenytoin…) Regulation of Insulin Secretion  Insulin is secreted in a rate of 1 unit per hour but after meals up to 5-10 units ,so the average is about 40 units per day. Mechanism of Insulin release by glucose  Insulin detected by high [glucose] stims insulin secretion by s in blood  cells - bloodstream neg feedback stims glucose facilitated lowers [glucose] transport into muscle & fat in blood Glucose is the primary stimulator of insulin secretion Feedback control of insulin by glucose concentrations  Effects of Insulins of Insulin Insulin is an anabolic hormone with growth promotions effects It acts on membrane receptors physiologic effects of insulin are divided into rapid, intermediate, and delayed actions, The best known is the hypoglycemic effect, there are other effects on amino acid and electrolyte transport, many enzymes, and growth.  Rapid effects Rapid (seconds) Increased transport of glucose, amino acids, and K into insulin-sensitive cells (muscle,fat,liver cells)  Intermediate (minutes) Increases synthesis and decreases catabolism of (glycogen,fat and protein) Inhibits gluconeogenesis  Delayed effects (hours) : Increases mRNAs for the enzymes involved in anabolism (ie promotion of growth)  Insulin action (summary): Dominates in Fed State Metabolism  glucose uptake in insulin sensitive cells  glucose use & storage  protein synthesis  fat synthesis Insulin: Summary  Abnormalities Insulin excess : Causes hypoglycemia It may be caused by insulinoma or insulin injections Symptoms include sweating , tremors , hunger , palpitations , irritability , convulsion comas Permanent brain damage and death  Insulin deficiency : Causes Diadetes Mellitus (DM) DM is 2 types : IDDM (insulin dependent DM ) or ( type 1 ) : appears early due to insulin deficiency due to destruction of beta cells , treated with insulin NIDDM (non insulin dependent DM ) or (type 2 ) : appears late due to relative insulin deficiency caused by insulin resistance; , treated by oral hypoglycemic drugs -Symptoms of diabetes mellitus include fatigability , polyuria , thirst , hunger and weight loss -DM should be controlled tightly to avoid complications  Diabetes Mellitus Two types: Type-I (Insulin-dependent, juvenile-onset) – Degeneration of -cells – no endogenous insulin – Must give exogenous insulin Type-II (non-insulin dependent, adult-onset) – Cells desensitized (tolerant) of diabetes – Often due to obesity – controlled by regulating dietary glucose  Metabolic abnormalities  Hyperglycemia : entry of glucose in cells output of glucose from liver  entry of amino acids into cells , protein synthesis.  FFAs and cholesterol  ketosis  dehydration and decreased Na and K  Signs and symptoms of Diabetes  Polyuria  Polydepsia  Fatigue  Hyperphagia  Weight loss  Coma (DKA,non ketotic hyperosmolar coma, lactic acidosis) hypoglycemic coma  On investigation High blood glucose Glycosuria Ketosis and ketonuria Acidosis High Hb A1c  Possible complications DKA Hyperosmolar non ketotic coma Atherosclerosis Diabetic nephropathy and retinopathy Peripheral neuropathy Increased susceptibility to infections  Glucagon Peptide hormone Hyperglycemic Stimulated by hypoglycemia  Glucagon Peptide hormone Hyperglycemic Stimulated by hypoglycemia – Released by alpha cells – Mobilizes energy reserves Affects target cells: – Stimulates breakdown of glycogen in skeletal muscle and liver tissue – Stimulates breakdown of triglycerides in adipose tissue – Stimulates production of glucose in liver  Glucagon detected by low [glucose] increases glucagon secretion in blood  cells by s - raises [glucose] bloodstream in blood glucose Liver activates stimulates membrane receptors in liver via 2nd messenger enzymes system liver glycogen  Pancreatic polypeptide Pancreatic polypeptide Peptide hormone Also stimulated by hypoglycemia Its function is unknown  Somatostatin Peptide hormone Released from other sites in the body (e.g. Stomach and hypothalamus ) It inhibits release of the pancreatic hormones (insulin,glucagon and pancreatic polypeptide) It also inhibits growth hormone ,thyroid stimulating hormone and gastrin.  Regulation of calcium Total body calcium in adults is about one kg. About 99%of this amount is found in bone The level of calcium in plasma = 10mg/dl or 2.5mmol/L Dietary sources of calcium include milk and milk products, other animal products and some plants  About 30-80% of ingested calcium is absorbed at the duodenum or ileum Absorption is by active transport (regulated by vit D) and by passive diffusion Vit D and proteins increase its absorption while phosphate ,oxalate ,caffeine decreases it.  Excretion : Stool (mainly) Some amount in urine Renal handling : 98% of filtered calcium is reabsorped Reabsorption is mainly in PCT (60%) , loop of henle , DCT (regulated by PTH)  PLASMA CALCIUM  Diffusible (50%) Ca2+ ionized (10%) combined with anions (citrate, phosphate) – non- dissociated  Nondiffusible (40%) combined with plasma proteins Plasma calcium level is affected by :  Plasma proteins levels  PH ( plasma proteins are more ionized when there is high PH providing more protein anions to bind calcium)  Functions of calcium Formation of bone and teeth Contraction of muscles Conduction in nerves Intracellular second messenger Hemostasis (a clotting factor ) Releasing of transmitters from synapses  The main hormones that regulate calcium level in blood are : Parathyroid hormone from the parathyroid gland Vitamin D from the skin and food Calcitonin from the thyroid gland  The parathyroid gland Small gland (3x6x2mm)..20-25 mg usually 4 in number. Found in the posterior surface of the thyroid gland. Contain 2 types of cells: Chief cells: the main cells secrete PTH Oxyphil cells : of unknown function  The parathyroid hormone Polypeptide hormone (84aa) Produced by chief cells in the parathyroid glands Half life is about 10 mins  Stimulating factors: Decreased calcium ions in the blood Low magnesium ions in the blood High phosphate ions in the blood Stimulation of beta 2 receptors  Effects: Regulates calcium and phosphate level in plasma Increases calcium Decreases phosphate  Parathyroid hormone action on the kidneys and bone is direct while in the intestine its indirect Kidney : calcium reabsorption in DCT & CDs phosphate reabsorption in PCT Bone : activity of osteoclast release of calcium from bone Intestine : activity of vit D , thus calcium absorption.  Abnormalities : Primary hyperparathyroidism: Increased production of PTH due to a tumor in the parathyroid gland or sometimes lung tumor. Results in removal of calcium from bone and hypercalcemia (which causes polyuria , renal stones and calcification in tissues)  hypoparathyroidism Decreased production of PTH due to damage to the parathyroid gland by a tumor, autoantibodies, or surgical removal. Results in hyper excitability in nerves characterized by convulsions and tetany. Tetany is charcterized by carpal spasm and may cause death by causing laryngeal spasm  Negative feed back loops Calcitonin plays a role in skeletal integrity in pregnancy or breast feeding Gastrointestinal hormones  Vitamin D Fat soluble vitamin Synthesized in the skin by the action of sun light on cholesterol to form D3 or cholecaalciferol Cholicalciferol is activated in the liver and then in the kidney to form 1.25(OH2)D3 Vitamin D is also found in food and can be stored in the liver  Stimuli : Hypocalcaemia Hypophosphatemia  Effects : Regulation of plasma calcium and phosphate -increase calcium level -increases phosphate level Site of action : Bone : stimulates osteoblasts for bone mineralization Kidney : increases calcium reabsorption and phosphate reabsorption Intestine : increases calcium absorption and phosphate absorption  Abnormalities : Rickets : Occurs due to deficiency of vitamin D in children It is characterized by hypocalcaemia and weakness and bowing of bones. Ostemalacia: Deficiency of vitamin D in adults Characterized by weak and easily fractured bone in adults  calcitonin Polypeptide hormone (32aa) Produced by the thyroid gland Half life : less than 10 mins Stimuli : Hypercalcaemia GIT hormones e.g. gastrin  Effects : Lower calcium and phosphate levels Inhibits bone resorption by inhibiting osteoclasts Increases calcium excretion in urine  Calcitonin The major stimulus of calcitonin secretion is a rise in plasma Ca++ levels Calcitonin is a physiological antagonist to PTH with regard to Ca++ homeostasis  abnormalities Calcitonin excess: Occurs due to certain thyroid tumors Not associated with symptoms related to calcitonin Calcitonin deficiency : Not reported syndrome Other organs which produce hormones GI tract Stomach - gastrin and serotonin – in stomach release of HCl and contraction Duodenum - secretin and cholecyctokinin – in pancreas release of bicarbonate and enzymes Kidney- erythropoetin – production of RBCs in bone marrow Other organs which produce hormones Skin- cholecalciferol – from vitamin D activated in the kidneys to calcitirol promotes Ca++ absorption Heart - atrial natriuretic factor ( ANF) – in kidneys inhibits Na+ reabsoption and renin release and inhibits secretion of aldosterone by the adrenal cortex Placenta- a bunch of hormones including progesterone and estrogen , human chorionic gonadotropin and others End 