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Endocrine System for Dental Student

Endocrine System for Dental Student

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THE ENDOCRINE SYSTEM

Dr. Yaser Ashour

THE ENDOCRINE SYSTEM
By

Dr. Yaser Mohamed Ashour Prof. of Physiology Al Azhar Faculty of Medicine (Assuit)

Dr. Yaser Ashour

• The body functions are regulated by nervous and endocrine systems aiming for homeostasis. • Both systems represent two parts of continuum of control systems. • The difference between the two systems is in their speed and time needed to exert their action. • The nervous system responds within a fraction of seconds whereas the endocrine system responds from a fraction of second up to over cycles of days, month or even years.
Dr. Yaser Ashour

Introduction

• The difference in time factor because the nervous system depends upon an action potential as a conductor of its signal, which travel along the nerve fibers within a fraction of seconds while the endocrine system depends upon a chemical substance called hormone which travel allover the body with blood to exert the signal which it carries.
Dr. Yaser Ashour

• Both systems are integrated to control homeostasis and this principle is clearly seen in the hypothalamus and pituitary gland where the two systems are linked
Dr. Yaser Ashour

• (1) The

nervous system mediate its activity through nerves that directly innervate the cells being controlled, by releasing regulatory molecules known as neurotransmitters to achieve the desired
Dr. Yaser Ashour

• (2) Both systems enable the body to respond to a wide range of internal and external stimuli by electing appropriate responses to these stimuli that ensure that the physiological functioning of the body is done to achieve homeostasis. HOMEOSTASIS keeping the parameters of the body in a steady, same state.
Dr. Yaser Ashour

The endocrine system consists of glands, which secrete hormones directly into blood stream. Major Endocrine Glands
• • • • • • Hypothalamus Anterior pituitary Posterior pituitary Pineal Thyroid Parathyroids • • • • • • Adrenal medulla Adrenal cortex Pancreas Ovaries Testes Placenta

Dr. Yaser Ashour

Dr. Yaser Ashour

THE HORMONES

Dr. Yaser Ashour

• The endocrine gland secrete a chemical substance called hormone • Hormone is a chemical transmitter (messenger) synthesized by specialized cells (glandular cells) and carried by bloodstream after its secretion in response to a specific stimulus to exert its physiological control on other distant target cells.
Dr. Yaser Ashour

Dr. Yaser Ashour

Hormones are grouped into three classes:

• Steroids: These are derivatives of cholesterol e.g. testosterone, estrogen, cortisol, and Aldosterone. • Peptides: These are short chains of amino acids e.g. growth hormone, insulin, and ADH. • Amines: These are formed of amino acid as T3 – T4 and adrenaline.
Dr. Yaser Ashour

Properties of Hormones

1- Hormones are synthesized continuously. 2- Hormones may be stored within the cytoplasm of the cells as inactive granule e.g. pituitary hormones or in the form of colloid mass as in thyroid acini. 3- Some hormones are secreted by more than one gland e.g. estrogenic hormones are secreted by (ovary, placenta and adrenal cortex). 4 -Most hormones are released from their glands in short burst (pulses) that maintain basal Dr. for Ashour definite level Yaser each hormone in blood.

5- The hormone secretion show diurnal variation (circadian rhythm) e.g. growth hormone secretion is markedly increased in early hours of sleep, while plasma cortisol rise in early morning. 6- Reciprocal chemical regulation: The stimuli which produce secretion of one hormone inhibits the release of its antagonistic e.g. fall in plasma calcium stimulate secretion of parathormone and inhibit the secretion of thyrocalcitonin hormone. 7- Hormones produce their physiological effect by a very low concentration in blood.
Dr. Yaser Ashour

8- Hormones act on a very specific receptors. 9- Hormones act as trigger substances, which initiate biochemical reactions that persist after disappearance of hormone from blood. 10- Hormones may affect many cells of the body e.g. insulin & thyroxine. 11- Hormones may produce specific action e.g. insulin lowers blood glucose.
Dr. Yaser Ashour

12- Hormones can be classified into local and general hormones:- Local hormones → which have specific local effects at or near their site of release e.g. G.I.T. hormones. - General hormones → which have generalized effects away from its site of release e.g. pituitary hormone. 13- Antigenic property: protein and peptide hormones stimulate the formation of antihormone when injected to another species due to difference in the arrangement of amino acids at Dr. Yaser Ashour parts of molecule.

1. STEROID HORMONES (LIPID SOLUBLE)

-Pass through the cell membrane to a receptor in the nucleus . -Activates genes that cause the production

Dr. Yaser Ashour

PEPTIDE (PROTEIN) HORMONESwater soluble

-Bind to cell membrane receptor. -series of reactions that alter cell activity.

Dr. Yaser Ashour

The Mechanisms of Hormones Action

• The chemical nature of a hormone has implications for its transport in blood and its mechanism of action at the target cell. The hormones are classified as fallow:• Hydrophilic hormones: (water soluble hormones), which include peptide and adrenaline. • Lipophilic hormones: (Lipid soluble hormones), which include the steroid and T3, T4.
Dr. Yaser Ashour

• The hormone action starts by binding of the hormone to the receptor, which they are located either on the cell membrane, cytoplasm or nucleus of the cell. • The binding of a hormone molecule with a specific receptor leads to the formation of a receptor hormone complex. • Receptors on target cell membranes bind only to one type of hormone. • More than fifty human hormones have been identified. • All act by binding to receptor molecules. • The binding hormone changes the shape of the receptor causing the response to the hormone.
Dr. Yaser Ashour

The mechanism of hydrophilic hormone action (water soluble).

• Hydrophilic hormones bind to external receptors found in the cell membrane of the target cells. • Binding of the hormone to the receptor activates the receptor which leads to one of the following reactions:-

Dr. Yaser Ashour

Cell surface receptors
• Peptide hormones and catecholamines bind to cell surface receptors • Receptors have extracellular, transmembrane and intracellular domains • Extracellular domain contains ligand (hormone) binding site

Dr. Yaser Ashour

Cell surface receptors

Dr. Yaser Ashour

G protein –linked receptors

Dr. Yaser Ashour

Non-G linked receptors
• Cell surface receptors with intracellular domains with intrinsic enzymatic activity
– Protein kinase (serine or tyrosine kinases)

• Or intracellular domains that link closely to other enzymes

Dr. Yaser Ashour

Non-G protein Receptors

Dr. Yaser Ashour

Second messengers
• Binding to cell surface receptors releases second messenger molecules inside cell • Second messengers include
– cAMP or cGMP – phopholipids diacylglycerol and inositol triphosphate (DAG and IP3) – calcium

Dr. Yaser Ashour

cAMP as second messenger

Dr. Yaser Ashour

Phospholipids as Second Messengers

Dr. Yaser Ashour

Biological effects
• Second messengers create phenotypic changes in target cells
– Alter phosphorylation (activity) of proteins – Alter permeability of membranes – Indirectly influence gene expression

Dr. Yaser Ashour

Receptor Down-regulation
• After hormone binding receptors may be internalized (coated pits) • Leads to reduced responsiveness of target cell (usually temporary) • Receptor may be recycled to cell surface or degraded

Dr. Yaser Ashour

Intracellular Receptors
• Steroid and thyroid hormones act via intracellular receptors • Hormone-receptor complex interacts directly with DNA in chromatin fiber at the promoter of specific genes • H-R complex acts as a transcription factor to enhance (or decrease) rate of transcription

Dr. Yaser Ashour

Intracellular Receptors

Dr. Yaser Ashour

Steroid Receptor Domains

Steroid receptors interact with the grooves in DNA double-helix via ‘zinc fingers’ formed as loops in the receptor
Dr. Yaser Ashour

Response Elements in Genes
• Steroid hormone receptors recognize specific DNA elements in genes • Short elements are steroid specific

Dr. Yaser Ashour

Endocrine Dysfunction
• At level of endocrine gland
– Structure, secretion, stability, elimination of hormone – Primary problems in gland of origin – Secondary due to signals from Hypo-Pit – Presence of other agonists / antagonists

• At level of target cell
– Structure, stability of receptor – Downregulation reduces sensitivity – Post-receptor signal transduction defects
• Second messengers • Gene expression • HRE

Dr. Yaser Ashour

Regulation of endocrine system
Direct negative feedback: • There is direct interaction between the controlling hormone and the controlled metabolite: - e.g.:- Plasma calcium level. • E.g. In case of decreased plasma calcium level → this is detected directly by parathyroid cells lead to synthesis of parathormone hormone leads to increase calcium level by increased secretion.
Dr. Yaser Ashour

Indirect negative Feedback: • Some peripheral endocrine glands (thyroid, adrenal cortex and gonads) are dependent on the regulation provided by hormones released from the anterior pituitary, whose release is in turn dependent on the endocrine activity of hypothalamus. • In this situation, the hypothalamic neuroendocrine cells are frequently integrating information from a variety of sources, including the circulating levels of the hormone secreted by the peripheral endocrine gland.
Dr. Yaser Ashour

Negative Feedback: A self-correcting system
Upper limit Bl glu
normal

Lower limit

Dr. Yaser Ashour

A Negative Feedback System

Dr. Yaser Ashour

Positive Feedback:
• Positive feedback exists when a hormone is able to stimulate its own production. • Such situations are rare and the only example that is well documented, relates to ovulation and 17 boestrdiol, which achieves positive feedback by stimulating the release of hypothalamic GnRH; this causes the release of pituitary FSH and LH, which in turn stimulates the production of more 17 b-oestradiol by the ovary.
Dr. Yaser Ashour

Positive Feedback?

This is a NON-correcting system. A little becomes more. Less becomes a lot less. Examples: Oxytocin and Prolactin hormones .
Dr. Yaser Ashour

Hypothalamus and Pituitary

Hypothalamus and Pituitary
• The hypothalamus-pituitary unit is the most dominant portion of the entire endocrine system. • The output of the hypothalamus-pituitary unit regulates the function of the thyroid, adrenal and reproductive glands and also controls somatic growth, lactation, milk secretion and water metabolism.
Dr. Yaser Ashour

Hypothalamus and pituitary gland

Dr. Yaser Ashour

Hypothalamus and pituitary gland

Dr. Yaser Ashour

Hypothalamus and Pituitary
• Pituitary function depends on the hypothalamus and the anatomical organization of the hypothalamus-pituitary unit reflects this relationship. • The pituitary gland lies in a pocket of bone at the base of the brain, just below the hypothalamus to which it is connected by a stalk containing nerve fibers and blood vessels. The pituitary is composed to two lobes-- anterior and posterior
Dr. Yaser Ashour

Posterior Pituitary: neurohypophysis
• Posterior pituitary: an outgrowth of the hypothalamus composed of neural tissue. • Hypothalamic neurons pass through the neural stalk and end in the posterior pituitary. • The upper portion of the neural stalk extends into the hypothalamus and is called the median eminence.
Dr. Yaser Ashour

Hypothalamus and posterior pituitary
Midsagital view illustrates that magnocellular neurons paraventricular and supraoptic nuclei secrete oxytocin and vasopressin directly into capillaries in the posterior lobe

Dr. Yaser Ashour

ADH = ANTIDIURETIC HORMONE
 1.

low water concentration of blood (causes  of   dehydration?) 2. hypothalamus osmoreceptors fire  3. posterior pituitary secretes ADH and  increases  thirst.  4.     ADH ­ increases permeability of kidney  tubules to water, increasing  reabsorption of  water from urine into  blood.. (stealing water from  the urine)  5.      High water concentration of blood
Dr. Yaser Ashour

  ­DIURETICS (caffeine, alcohol) interfere with ADH,  so water remains in urine and is not returned to  blood.  Results in dehydration.    ­DIABETES INSIPIDUS –very little ADH is made, so  water is not reabsorbed from urine.   Symptoms:  excessive urination (12L) thirst, copious  dilute urine.  ­Bedwetting:  due to low ADH? Nosespray? ­What medical conditions could be treated  with  diuretics? -Why are athletes advised against cola and coffee? Dr. Yaser Ashour

Anterior pituitary: adenohypophysis
• Anterior pituitary: connected to the hypothalamus by the superior hypophyseal artery. • The antererior pituitary is an amalgam of hormone producing glandular cells. • The anterior pituitary produces six peptide hormones: prolactin, growth hormone (GH), thyroid stimulating hormone (TSH), adrenocorticotropic hormone (ACTH), follicle-stimulating hormone (FSH), and luteinizing hormone (LH).
Dr. Yaser Ashour

Hypothalamus and anterior pituitary
Midsagital view illustrates parvicellular neurosecretory cells secrete releasing factors into capillaries of the pituitary portal system at the median eminence which are then transported to the anterior pituitary gland to regulate

Dr. Yaser Ashour

neocortex Reituclar activating substance Sleep/ wake Heat regulation (temperature) Thalamus

Limbic system Emotion, fright, rage, smell

Optical system vision

pain

Energy regulation (hunger, BMI)

Autonomic regulation (blood pressure etc)

Water balance (blood volume, intake--thirst, output—urine volume)

Metabolic rate, stress response, growth, reproduction, lactation)

Regulation of Hypothalamus

posterior pituitary hormones

Anterior pituitary hormones

Dr. Yaser Ashour

Hypothalamus/Pituitary Axis

Dr. Yaser Ashour

Hypothalamic releasing factors for anterior pituitary hormones
 Travel to adenohypophysis via hypophysealportal circulation  Travel to specific cells in anterior pituitary to stimulate synthesis and secretion of trophic hormones

Dr. Yaser Ashour

Hypothalamic releasing hormones
Hypothalamic releasing hormone Corticotropin releasing hormone (CRH) Thyrotropin releasing hormone (TRH) Growth hormone releasing hormone (GHRH) Somatostatin Gonadotropin releasing hormone (GnRH) a.k.a LHRH Prolactin releasing hormone (PRH) Prolactin inhibiting hormone (dopamine) Effect on pituitary Stimulates ACTH secretion Stimulates TSH and Prolactin secretion Stimulates GH secretion Inhibits GH (and other hormone) secretion Stimulates LH and FSH secretion Stimulates PRL secretion Inhibits PRL secretion

Dr. Yaser Ashour

Characteristics of hypothalamic releasing hormones
• • • • • • Secretion in pulses Act on specific membrane receptors Transduce signals via second messengers Stimulate release of stored pituitary hormones Stimulate synthesis of pituitary hormones Stimulates hyperplasia and hypertophy of target cells • Regulates its own receptor
Dr. Yaser Ashour

Hypothalamus and anterior pituitary

Dr. Yaser Ashour

Anterior pituitary
• Anterior pituitary: connected to the hypothalamus by hypothalmoanterior pituitary portal vessels. • The anterior pituitary produces six peptide hormones:
– – – – – – Prolactin. Growth hormone (GH), thyroid stimulating hormone (TSH), adrenocorticotropic hormone (ACTH), follicle-stimulating hormone (FSH), luteinizing hormone (LH).
Dr. Yaser Ashour

Anterior pituitary cells and hormones
Cell type Pituitary populatio n 15-20% Product Target

Corticotroph

Thyrotroph Gonadotroph Somatotroph Lactotroph

3-5% 10-15% 40-50% 10-15%

ACTH βlipotropin TSH LH, FSH GH PRL

Adrenal gland Adipocytes Melanocytes Thyroid gland Gonads All tissues, liver
Breasts gonads

Dr. Yaser Ashour

Anterior pituitary hormones

Dr. Yaser Ashour

THYROXIN
-Produced by the thyroid gland -increases rate of metabolism (cell respiration) -provides more energy, uses up glucose and oxygen, produces heat.
Dr. Yaser Ashour

1. 

low metabolic rate-

2. hypothalamus secretes TSHR 3.      ant. Pit secretes TSH 4.      thyroid secretes thyroxine

Control of thyroxin secretion

TSHRF – Thyroid stimulating hormone releasing factor 5.      increase in metabolic rate 6.      too high metabolic rateTSH – Thyroid stimulating hormone 7.      hypoth. decreases TSHRF 8.      ant pit decreases TSH 9.      thyroid gland decreases Dr. Yaser Ashour

 hypothyroidism – low thyroxine
­Symptoms: fatigue, weight gain in  adults, cold, slow thought, possible  goiter. ­called Cretinism in kids.  Retarded  and small. Goiter: Results from low dietary  Iodine.  Thyroid needs lots of Iodine to   make thyroxine. With no iodine,  high TSHRF and TSH continue to  stimulate thyroid making it large  and over­worked. Dr. Yaser Ashour

Hyperthyroidism = high thyroxin
Symptoms: 
High energy, weight  loss, hunger,  very alert and unable  to sleep. Exophthalmos
Dr. Yaser Ashour

Exophthalmos due to hyperthyroidism

THE PARATHYROID GLANDS AND CALCIUM HOMEOSTASIS Plasma calcium levels are maintained within very narrow limits in order to support the many physiological functions in which calcium is involved: • Calcium ions play an essential role in the regulation of membrane permeability, and hence influence neuromuscular excitability. • They participate in the release of neurotransmitters, and are a vital component in the excitation – contraction process in muscle cells.
Dr. Yaser Ashour

• They are also involved in many intracellular metabolic pathways where they act as coenzymes and regulators, and in both endocrine and exocrine cells they are often implicated in excitation-secretions pathways. • Blood coagulation is dependent on normal levels of calcium, as are bone & teeth formation and milk production. • More than 99% of total body calcium is contained in bone and, although it provides the principle store of calcium most is incorporated into a complex crystal structure called hydroxyapatite, which means that it cannot be released quickly when required.
Dr. Yaser Ashour

• The remaining 1% of the calcium in bone can be readily exchanged, being in the form of calcium phosphate salts that are in equilibrium with plasma calcium and hence provide a convenient buffer to sudden changes in calcium levels. • Normally, plasma calcium is maintained at 2.32.6 m mol/L and is present in three forms:• Diffusible ionized= ionic Ca++= 50%= 1.2 m mol/L* non diffusible= protein bound= 41%= 1.0 m mol/LDiffusible= combined with citrate/phosphate= 9%= 0.2 m mol/LTotal= 2.4 m mol/L
Dr. Yaser Ashour

• The daily loss of calcium from the body in nails, dead cells and hair, is added to daily flux of calcium across the gastrointestinal and kidney epithelia. • The net result is daily loss of 1000 mg of calcium which needs to be replaced in the diet.

Dr. Yaser Ashour

Regulation of plasma calcium depends upon:• • • • • • Parathormone (PTH) → ↑ plasma Ca++ level. Calcitonin → ↓ plasma Ca++ level. 1, 25 dihydrocholecalciferol → ↑ plasma Ca++ level. Adrenal glucocorticoids → ↓ plasma Ca++ level act as anti vitamin D. Growth hormone → ↑ plasma Ca++ level by ↑ Ca++ excretion & ↑ Ca++ absorption. Thyroid hormone → ↑ plasma Ca++ level.
Dr. Yaser Ashour

Parathormone Hormone:
• This hormone is secreted by the parathyroid glands. • The parathyroid glands are four, and they are embedded in the posterior surface of thyroid gland. Two in each lobe. • There are two cells in the parathyroid gland: • Chief cells → producing parathormone hormone. • Oxyphilic cells → whose function is not yet clear.
Dr. Yaser Ashour

Action of the parathormone:
• The parathormone is a major regulating factor for both calcium (Ca++) and phosphate (PO4--) concentrations in body fluids. • Normally, the plasma PO4—concentration is inversely related to the Ca++ concentration Ca++ 1/a PO4--. • Ca++ X PO4 = constant = solubility product.
Dr. Yaser Ashour

• The main function of PTH is to increase the plasma Ca++ level and decrease the plasma PO4-- level. • A reciprocal relationship exists between plasma calcium and phosphate, such that a decrease in one results in an elevation of the other, and vice versa.

Dr. Yaser Ashour

PTH exerts its actions by working on (kidney, bone & intestine).

Kidney: • More than 95% of the filtered calcium load is reabsorbed via a number of active and passive transport mechanisms. • PTH: inhibits reabsorption of calcium in the proximal tubule & stimulate reabsorption in the distal nephron → there is overall effect of increased reabsorption and increased plasma calcium concentration. • PTH inhibit phosphate reabsorption by the proximal convoluted tubules → this lead to:Dr. Yaser Ashour

∀ ↑ Phosphate excretion in urine. ∀ ↓ Phosphate level in plasma. ∀ ↑ Calcium level in plasma to maintain the solubility product constant i.e. Ca++ X PO-- = constant. • PTH activates renal 1-hydroxylase which converts 25-hydroxycholecalciferol to active 1, 25 dihydroxycholecalciferol. • PTH increase Mg++ and H+ reabsorption by renal tubules.

Dr. Yaser Ashour

Gastrointestinal tract (intestine):
• PTH has no direct effect on the intestine. • PTH has an indirect effect on the intestine through its stimulation of kidney to form 1, 25 dihydroxycholecalciferol which in turn stimulate Ca++ & PO4-- absorption from upper small intestine.

Dr. Yaser Ashour

Bone:
• 99% of the body’s calcium is in bone, and 99% of this calcium is contained in a complex mineralized matrix of hydroxyapatite crystals from which calcium ions cannot readily be removed. • However, a small proportion of bone is constantly remodeled throughout life, which is why bones are able to heal following a fracture. • This remodeling is a dynamic equilibrium in which bone resorption roughly equals bone formation. • PTH is able to influence the buffering capability provided by the calcium phosphate salts present in this readily exchangeable bone.
Dr. Yaser Ashour

Control of parathormone secretion: PTH is regulated by:(1) Ca++ ions level in plasma: ∀ ↓ Ca++ level by 0.5 mg % → stimulate PTH secretion. ∀ ↑ Ca++ level → inhibit PTH secretion. (2) PO4-- Level in plasma: ∀ ↑ PO4—plasma level → stimulates PTH secretion. (3) Mg++ level in plasma: ∀ ↓ Mg++ level → stimulate PTH secretion. ∀ ↑ Mg++ level → inhibit PTH secretion.
Dr. Yaser Ashour

Calcitonin:
• Calcitonin (CT) is a calcium lowering hormone. • It is a polypeptide secreted from the Parafollicular cells of the thyroid gland. • It was found that (CT) also found in the brain, pituitary, thymus, lung, liver and gut. • The plasma level of CT is 2-4 mg %. • Its half life in circulation is less than 10 minutes.
Dr. Yaser Ashour

Actions of calcitonin:
(1) Effect on Bone: • Inhibits bone resorption by: • Inhibit the permeability of osteoclasts and osteocytes to calcium i.e. decrease mobilization of calcium from both. ∀ ↓ The activity and numbers of osteoclast. (2) Effect on G.I.I.: • Inhibit intestinal absorption of Ca++ & PO4--. ∀ ↓ Gastric acid secretion. (3) Effect on kidney: ∀ ↑ Urinary excretion of PO4--, Ca++ and Na+, Cl-. • Inhibit renal 1 a-hydroxylase activity.
Dr. Yaser Ashour

Vitamin D
• Vitamin D → It is word refer to a group of a closely related sterols, the commonest of which are vitamin D2 (calciferol) and vitamin D3 (cholecalciferol). • Vitamin D3: is formed in the skin by the effect of ultraviolet rays of the sun, also it is taken in the diet (e.g. cod liver oil and egg yolk). • Vitamin D2: is taken in food and it has the metabolism as VD3.
Dr. Yaser Ashour

Action of Vitamin D3:
It increases absorption of both Ca++ & PO4—from intestine. It mobilizes both Ca++ & PO4—from bone. It facilitates Ca++ reabsorption in the kidneys. It helps development of normal bone and teeth. It stimulates differentiation of immune Dr. keratinocytes in the skin. cells and Yaser Ashour

Other hormones affecting calcium metabolism: • Glucocorticoids → ↓ Ca++ level. • Growth hormone → ↑ Ca++ level. • Thyroxine → hypercalcaemia – hypercalciuria & osteoprosis. • Sex hormones → Androgen → * calcium retention • Oestrogen → * ↓ plasma Ca++ level. * prevent osteoprosis.

Dr. Yaser Ashour

Control of Ca++ blood concentration is by PTH and Calcitonin.

-Calcium can move between the blood
and the storage pools in bones and teeth depending on the body’s needs. ……..What Dr. Yaser Ashour needed for? is calcium

PARATHYROID HORMONE
-Produced by parathyroid glands when blood calcium is low. PTH increases blood calcium by 1. Dissolving Ca from bones and teeth into blood. 2. Causing increased absorption of Ca from the gut into the blood When would you expect PTH blood concentrations to be high?
Dr. Yaser Ashour

OSTEOPOROSI S is Calcium loss from bone. If your diet and thus your blood is low in calcium then PTH will be dissolving your bones resulting in osteoporosis. Low estrogen

Dr. Yaser Ashour

CALCITONIN HORMONE
Produced by thyroid gland when blood Ca levels are high. Calcitonin decreases blood Ca by: 1. Increasing Ca deposition in bones and teeth. 4. Reducing Ca absorption from the gut into the blood. When would you expect Calcitonin blood concentrations to be high? Dr. Yaser Ashour

Where is calcitonin and PTH released?
A
Blood calciu m

B
Dr. Yaser Ashour

Disorders of Calcium Homeostasis

Hypovitaminosis D: • Vitamin D deficiency causes Rickets in children and osteomalacia in adults. Causes: • Inadequate intake of vitamin D in diet. • Inadequate exposure to ultraviolet rays. • Inadequate absorption in the intestine e.g. celiac disease or obstructive jaundice.

Dr. Yaser Ashour

• Renal failure → there is failure of hydroxylase 25 – hydroxycholcalciferol to calcitrol. Manifestations:

• Lack of vit D → decrease Ca++ absorption from the intestine → hypocalcaemia → failure of mineralization of new bone and more secretion PTH lead to more bone demineralization and mobilization of Ca++ from bone lead to Rickets in children and osteomalacia in adult
Dr. Yaser Ashour

Rickets: • This is a common disease in poor community due to malnutrition. Characteristic of Rickets: • Growth retardation or stoppage. • Swelling near the joints (due to continuous growth of epiphyseal plates). • Bone deformities: * Bowing of leg. * Pelvis deformity.
Dr. Yaser Ashour

Osteomalacia:

• This is a disease which occurs in adult due to hypocalcaemia and usually it occurs in multipart ladies, and their bones become brittle, tender and painful.

Dr. Yaser Ashour

Hypervitaminosis D: Prolonged administration of large doses of vitamin D produce:• Hypercalcaemia and deposition of calcium in soft tissues. ∀ ↑ Calcium and phosphate excretion in urine → polyuria + polydipsia. • Renal ischemia → due to deposition of calcium in renal blood vessel → hypertension. • Renal failure → due to calcium deposition in renal tubules. • Other symptoms (anorexia, nausea, vomiting, headache, drowsiness). • Bone resorption → osteoporosis.
Dr. Yaser Ashour

Hyperparathyroidism:
• Hyperfunction of parathyroid gland is produced by parathyroid hyperplasia or adenoma with excess PTH secretion. Manifestations: * Urine & blood changes: ∀ ↑ Phosphate excretion in urine (hyperphosphaturia). ∀ ↓ Plasma phosphate (hypophosphatatemia). ∀ ↑ Plasma calcium (Hypercalcaemia). ∀ ↑ Calcium excretion in urine (hypercalciuria). ∀ ↑ Plasma alkaline phosphatase. • * ↑↑ bone resorption → ↑ decalcification of bones: • Bone becomes fragile bone show multiple cysts (ostitis fibrosa cystica). Dr. Yaser Ashour

∀ ↓↓ Neuromuscular excitability → (due to hypercalcaemia). • Mental retardation. • Depression of reflexes. • Muscle weakness. • Constipation. • * Renal changes: • Polyuria. • Renal stones. • Renal failure.
Dr. Yaser Ashour

Hypoparathyroidism This is due to faulty removal of parathyroid during thyroidectomy. Manifestations: • * Urine and blood changes: ∀ ↓ phosphate excretion in urine. ∀ ↑ phosphate level in plasma. ∀ ↓ calcium level in plasma. ∀ ↓ calcium excretion in urine. • * ↓ ionized Ca++ level in plasma:
Dr. Yaser Ashour

• Tetany. ∀ ↑ H.R., cardiac arrhythmia, prolongation of S-T segment, and prolongation of Q-T interval. • Intestinal and biliary colic. • Opacity of eye lens (cataract). • Hair falls & brittle nails.

Dr. Yaser Ashour

TETANY • It is a disease characterized by increased neuromuscular excitability due to ↓ ionized calcium level in plasma. • It is characterized by attacks of spasmodic contractions which may involve the laryngeal and respiratory muscles. Causes of tetany: • Hypocalcaemia: → ↓ calcium level in blood due to:- Hypoparathyroidism. - ↓ calcium intake. - Calcium need (pregnancy & lactation). - ↓ absorption of calcium as in:- steatorrhea (fatty diarrhea) → due to combination of fat with Yaser Ashour Dr. calcium forming calcium soaps.

• Deficiency of vitamin D. ∀ ↑ alkalinity of intestinal content which precipitates calcium. • Administration of oxalate or citrate • Oxalate → precipitate calcium. • Citrate → form unionized calcicitrate. Types of Tetany • Upon the calcium level in the blood there are two types of tetany:1- Manifest tetany → when the calcium level is below 7 mg %. 2- Latent tetany → when the calcium level drops between 9 mg % → 7 mg%.
Dr. Yaser Ashour

Manifest tetany: Manifestations: 1- Fibrillary twitches of skeletal muscles and attacks of clonic & tonic contractions. • These tonic contractions may lead to generalized convulsions. • Spasmodic contraction of laryngeal muscles leads to respiratory distress and cyanosis. • If this spasmodic contraction prolonged it leads to death as a result of asphyxia (laryngeal stridor).
Dr. Yaser Ashour

2- Carpopedal spasm = obstetrician hand = Accoche’s hand.= carpal spasm = stiffness of hand muscles. There is flexion of wrist Flexion of metacorpo-phalngeal joints. Extension of interphalngeal joints. Adduction of thumb into hand Pedal spasm = dorsiflexion of foot toes are planter flexed.

Dr. Yaser Ashour

carpopedal spasm

Dr. Yaser Ashour

Latent tetany:

• Plasma calcium level is above 7 mg % and ↓ 9 mg %. • Manifestations of tetany are absent at rest. • These manifestations appear when there is an increase of body need to calcium. • Or there is exposure to stress e.g. pregnancy, lactation, emotion and hyperventilation.
Dr. Yaser Ashour

Diagnosis of latent tetany: 1- Determination of ionized calcium level in plasma. Trousseau’s sign: on application of occlusion of blood supply to the arm by sphygmomanometer cuff → Trousseau’s sign. Chvostek’s sign: Tapping the facial nerve in front of the ear results in twitch of facial muscles especially the upper lip due to increased excitability to mechanical stimuli.
Dr. Yaser Ashour

Erb’s sign: ↑ excitability of motor nerves to galvanic current. • On application of a signal electric stimulus of any superficial motor nerve → produce prolonged spasmodic contraction in the supplied muscles in positive cases. Treatment: * Acute tetanic attacks → are treated by slow I.V. calcium chloride injection. * After attack: – * Vitamin D. – * Diet rich in calcium. – * Ammonium chloride. – * PTH injection.* A.T.10
Dr. Yaser Ashour

GLUCAGON
• Alpha cells secrete glucagon peptide of 29 amino acids.
– Stimulus for release is decrease in blood glucose levels – Synthesized as a larger proglucagon molecule and then clipped down by enzymes – Potent hyperglycemic agent - major target organ is the liver – Stimulates glycogenolysis and lipolysis
Dr. Yaser Ashour

INSULIN • Beta cells secrete insulin - peptide of 51 amino acids.
– Synthesized as a larger proinsulin molecule and then clipped down by enzymes. – Lowers blood glucose by enhancing membrane transport of glucose into body cells (especially muscle and fat cells). The brain, kidney and liver have easy access to glucose and do not require insulin. – Inhibits glycogenolysis and gluconeogenesis
Dr. Yaser Ashour

INSULIN
• After glucose enters a target cell, insulin binding triggers enzymatic activity that:
– Catalyze the oxidation of glucose for ATP production – Join glucose molecules together to form glycogen – Convert excess glucose to fat

Dr. Yaser Ashour

INSULIN
• Diabetes mellitus results from hyposecretion of insulin or hypoactivity of insulin. • When insulin is absent or deficient, blood sugar levels remain high after a meal because glucose is unable to enter most tissue cells.
Dr. Yaser Ashour

DIABETES
• Type I diabetes mellitus (insulindependent) afflicts 750, 000 Americans.
– Autoimmune disease (beta cells are attacked by immune cells). May be due to a virus entering the body and mimicking beta cell antigens. – Insulin is not produced or secreted, requiring regular insulin injections.

Dr. Yaser Ashour

DIABETES • Type II diabetes mellitis (non-insulindependent) afflicts 7.5 million Americans.
– Insulin resistance - Insulin is usually produced but the receptors do not respond. – The membrane protein PC-1 may be a culprit – it has been shown to inhibit the tyrosine kinase receptor, but its mechanisms of action are unknown.
Dr. Yaser Ashour

DIABETES
Heredity plays a role - an estimated 30% of poples carry a gene that predisposes them to Type II diabetes. Lifestyle play a role - Type II diabetics are almost always obese and sedentary. Adipose tissue produces a hormone-like chemical called tumor necrosis factoralpha, which depresses synthesis the cellular glucose transporter (glut-4). Cells cannot take up glucose in the absence of Dr. Yaser Ashour glut-4.

ANTAGONISTIC HORMONE PAIRS
work together to keep a parameter from becoming too high or too low. Eg. Insulin decreases blood glucose Glucagon increases blood glucose Eg. PTH increases blood Ca++ CalcitoninDr. Yaser Ashour decreases blood
Dr. Yaser Ashour

CONTROL OF BLOOD GLUCOSE - Where are insulin and glucagon secreted from? The islets of Langerhans in the pancreas.

Alpha islet cells secrete glucagon. Dr. Yaser Ashour Beta islet cells secrete insulin.

WHEN BL. GLUCOSE IS HIGH, INSULIN DECREASES IT BY:
1.
GLUCOSE GGGGGG

Increasing glucose permeability of cell (open glucose gates on cell membranes).

CELL LIVER

2

Causes liver to remove excess glucose from the blood and store it as liver glycogen and fat.

Dr. Yaser Ashour

INSULIN UNLOCKS THE GLUCOSE GATES ON THE CELL SO GLUCOSE CAN ENTER THE CELL FROM THE BLOODSTREAM. If there is no insulin, glucose remains in the blood (high bl. Glu) and the cell starves, producing no energy. The victim becomes Dr. Yaser Ashour

WHEN GLUCOSE IS LOW, GLUCAGON INCREASES IT BY:

1. Decreasing permeability of cells to glucose (close glucose gates on cells).
GGGGGGGGG cell

2. Releasing stored glucose from the liver into the blood.
Dr. Yaser Ashour

liver

When are insulin and glucagon released?

A
Blood glucose

B
Dr. Yaser Ashour

What happens when insulin isn’t secreted or cells become insulin resistant? Disease DIABETES MELLITUS
Type I: juvenile – due to lack of insulin Type II: adult onset – due to insulin resistance (Associated with obesity). Symptoms: • High blood glucose, fatigue, high glu in  urine, high urine volume, weight loss.
Dr. Yaser Ashour

What’s the physiology behind these symptoms? High blood glucose Fatigue High glu in urine High urine volume Dry, itchy skin Thirst
Dr. Weight loss. Yaser Ashour

High blood glucose – glucose from food can not enter cells so it remains in blood.

Fatigue – cells lack glucose for cell respiration so no ATP energy is made. High glu in urine – XS glu spills into urine and is not returned completely to blood by active transport. High urine volume – Normally water from the urine follows glucose back into the blood by osmosis, but because some glu remains in the urine, the water remains with it. Dry, itchy skin – The increased loss of water in urine dehydrates the blood stream. Thirst – Same as above Weight loss – The glucose lost in the urine is from Dr. Yaser Ashour your meals.

• Treatment
    Injection of insulin, oral hypoglycemic pills, control of exercise, diet, weight reduction. Continuous Blood Glucose monitoring .

Insulin Pump automa t-ically injects insulin into Dr. Yaser Ashour the

DIABETES TECHNOLOGIES
• Recombinant DNA technology: Human insulin gene transfered into bacteria?
http://www.angelfire.com/dc/apgenetics/rec.dna.plasmid.gif

• Transplanting normal human islet cells into liver of diabetic patient?
http://www.ianblumer.com/islet_cell_transplants.htm

• Gene Therapy: Transplanting insulin genes into embryos or fetuses?
Dr. Yaser Ashour

The Edmonto n Protocol

Dr. Yaser Ashour

What happens if you can’t make Glucagon ? HYPOGLYCAEMIA:
Blood glucose can’t be raisedit stays low.
Symptoms: ·       Low blood glucose, fatigue, passing out.  Treatment?
Dr. Yaser Ashour

Hormones
• Regulatory molecules secreted into the blood or lymph by endocrine glands. “Ductless”
– Lack ducts. – Derived from epithelium but lose connection with surface.

• Carry hormone to target tissue where it produces its effects.

Dr. Yaser Ashour

Chemical Classification of Hormones
• • • • Amines Polypeptides Glycoproteins Steroids

Dr. Yaser Ashour

Amines
• Hormones derived from tyrosine and tryptophan. • Include hormones secreted by adrenal medulla, thyroid, and pineal glands.

Dr. Yaser Ashour

Polypeptides
• Chains of amino acids (< 100 amino acids in length).
– ADH – Insulin

Dr. Yaser Ashour

Glycoproteins
• Long polypeptides (>100) bound to one or more carbohydrate (CHO) groups.
– FSH – LH

Dr. Yaser Ashour

Steroids
• Lipids derived from cholesterol. • Are lipophilic hormones.
– Testosterone – Estradiol – Cortisol – Progesterone

Dr. Yaser Ashour

Thyroid Hormones
• Tyrosine derivatives bound together. • Contain 4 iodine atoms (T4). • Contain 3 iodine atoms (T3). • Small, non-polar molecules.
– Soluble in plasma membranes.
Dr. Yaser Ashour

Hormonal Interactions
• Synergism:
• Two hormones work together to produce a result.
– Additive:
• Each hormone separately produces response, together at same concentrations stimulate even greater effect.
– Epinephrine and norepinephrine.

– Complementary:
• Each hormone stimulates different step in the process.
– FSH and testosterone.

Dr. Yaser Ashour

Hormonal Interactions
• Permissive effects:
– Hormone enhances the responsiveness of a target organ to second hormone. – Increases the activity of a second hormone.
• Prior exposure of uterus to estrogen induces formation of receptors for progesterone.

Dr. Yaser Ashour

Hormonal Interactions
• Antagonistic effects: • Action of one hormone antagonizes the effects of another. – Insulin and glucagon.

Dr. Yaser Ashour

Effects of Hormone Concentration
• Concentration of hormones in blood reflects the rate of secretion. • Half-life:
– Time required for the plasma concentration is reduced to ½ reference level.

• Physiological range of concentration produces normal tissue response.

Dr. Yaser Ashour

Effects of Hormone Concentration
• Varying hormone concentration within normal, physiological range can affect the responsiveness of target cells. • Priming effects (upregulation)
– Increase number of receptors formed on target cells. – Greater response by the target cell.

Dr. Yaser Ashour

Effects of Hormone Concentration
• Desensitization (downregulation):
– Decrease in number of receptors on target cells. – Produces less of a target cell response.
• Insulin in adipose cells.

• Pulsatile secretion may prevent downregulation.
– GnRH and LH.
Dr. Yaser Ashour

• Hormones of same chemical class have similar mechanisms of action.
– Location of cellular receptor proteins.

Mechanisms of Hormone Action

• Target cell must have specific receptors for that hormone (specificity). • Hormones bind to receptors with high bond strength (affinity). • Low capacity of receptors (saturation).

Dr. Yaser Ashour

Hormones That Bind to Nuclear Receptor Proteins
• Lipophilic steroid and thyroid hormones bound to plasma carrier proteins. • Hormones dissociate from carrier proteins to pass through lipid component of the target cell membrane. • Receptors for the lipophilic hormones are known as nuclear hormone receptors.

Dr. Yaser Ashour

Nuclear Hormone Receptors
• Function within cell to activate genetic transcription. • mRNA directs synthesis of specific enzyme proteins that change metabolism. • Receptor must be activated by binding to hormone before binding to specific region of DNA called HRE (hormone responsive element).
– Located adjacent to gene that will be transcribed.

Dr. Yaser Ashour

Mechanisms of Steroid Hormone Action
• Steroid receptors located in cytoplasm. • Bind to steroid hormone. • Translocates to nucleus. • DNA-binding domain binds to specific HRE of the DNA. • Dimerization occurs. • Stimulates Dr. Yaser Ashour transcription.

Dr. Yaser Ashour

Dr. Yaser Ashour

Hormones That Use 2nd Messengers
• Cannot pass through plasma membrane. • Catecholamines, polypeptides, and glycoproteins bind to receptor proteins on the target cell membrane. • Actions are mediated by 2nd messengers (signal-transduction mechanisms).
– Extracellular hormones are transduced into intracellular second messengers.

Dr. Yaser Ashour

Dr. Yaser Ashour

Dr. Yaser Ashour

Dr. Yaser Ashour

Endocrine Glands

Dr. Yaser Ashour

Dr. Yaser Ashour Anterior and posterior pituitary glands.

Posterior Pituitary
• Also called the neurohypophysis. • Formed by downgrowth of the brain during fetal development. • Is in contact with the infundibulum. • Nerve fibers extend through the infundibulum.

Dr. Yaser Ashour

Hypothalamic Control of Posterior Pituitary
• Hypothalamus produces:
– ADH: paraventricular nucleus – Oxytocin: supraoptic nucleus

• Hormones transported along the hypothalamohypophyseal tract. • Stored in posterior pituitary. • Release controlled by neuroendocrine reflexes. Yaser Ashour Dr.

Anterior Pituitary
• Master gland (also called adenohypophysis). • Derived from a pouch of epithelial tissue that migrates upward from the mouth. • Consists of 2 parts: • Pars distalis: anterior pituitary. • Pars tuberalis: thin extension in contact with the infundibulum.
Dr. Yaser Ashour

Anterior Pituitary
• Trophic effects:
– Health of the target glands, depends upon stimulation by anterior pituitary for growth. – High plasma hormone concentration causes target organ to hypertrophy. – Low plasma hormone concentration causes target organ to atrophy.
Dr. Yaser Ashour

Dr. Yaser Ashour

Hypothalamic Control of the Anterior Pituitary
• Hormonal control rather than neural. • Hypothalamus synthesizes releasing hormones and inhibiting hormones. • Hormones are transported to axon endings of median eminence.
– Delivers blood and hormones to anterior pituitary via portal system.

Dr. Yaser Ashour

Feedback Control of the Anterior Pituitary
• Anterior pituitary and hypothalamic secretions are controlled by the target organs they regulate. • Negative feedback inhibition by target gland hormones.

Dr. Yaser Ashour

Feedback Control of the Anterior Pituitary
• Negative feedback at 2 levels:
– The target gland hormone can act on the hypothalamus and inhibit releasing hormones. – The target gland hormone can act on the anterior pituitary and inhibit response to the releasing hormone.

Dr. Yaser Ashour

Dr. Yaser Ashour

Dr. Yaser Ashour

Adrenal Glands
• Paired organs that cap the kidneys. • Each gland consists of an outer cortex and inner medulla. • Adrenal medulla: – Derived from embryonic neural crest ectoderm (sympathetic ganglia).
– Synthesizes and secretes:
• Catecholamines (mainly epinephrine but some norepinephrine).

Dr. Yaser Ashour

Dr. Yaser Ashour

Adrenal Medulla
• Innervated by sympathetic nerve fibers.
– Increase respiratory rate. – Increase heart rate, cardiac output; and vasoconstrict blood vessels, thus increasing venous return. – Stimulate glycogenolysis. – Stimulate lipolysis.

Dr. Yaser Ashour

Dr. Yaser Ashour

Dr. Yaser Ashour

Thyroid Hormones
• Thyroid gland located just below the larynx. • Thyroid is the largest of the pure endocrine glands. • Follicular cells secrete thyroxine. • Parafollicular cells secrete calcitonin.

Dr. Yaser Ashour

Production of Thyroid Hormones
• I- (iodide) actively transported into the follicle and secreted into the colloid. • Oxidized to (Io) iodine. • Iodine attached to tyrosine.
– Attachment of 1 iodine produces monoiodotyrosine (MIT). – Attachment of 2 iodines produces diiodotyrosine (DIT).

• MIT and DIT or 2 DIT molecules coupled. Dr. Yaser Ashour

Production of Thyroid Hormones
• T3 and T4 produced. • TSH stimulates pinocytosis into the follicular cell.
– Enzymes hydrolyze to T3 and T4 from thyroglobulin.

• Attached to thyroid-binding protein and released into blood.

Dr. Yaser Ashour

T3 Effects
• Stimulates cellular respiration by:
– Production of uncoupling proteins. – Stimulate active transport Na+/ K+ pumps. – Lower cellular [ATP].

• Increases metabolic heat. • Increases metabolic rate.
– Stimulates increased consumption of glucose, fatty acids and other molecules.
Dr. Yaser Ashour

Dr. Yaser Ashour

Parathyroid Hormone
• Parathyroid glands embedded in the lateral lobes of the thyroid gland. • Only hormone secreted by the parathyroid glands. • Single most important hormone in the control of plasma Ca++ concentration. • Stimulated by decreased plasma Ca++ concentration.
Dr. Yaser Ashour

Dr. Yaser Ashour

Dr. Yaser Ashour

Dr. Yaser Ashour

Pancreas
• Endocrine portion consists of islets of Langerhans. • Beta cells secrete insulin
– Stimulus is increase in plasma glucose concentrations – Promotes entry of glucose into cells

• Alpha cells secrete glucagon
– Stimulus is decrease in plasma glucose concentrations – Stimulates lipolysis.
Dr. Yaser Ashour

Dr. Yaser Ashour

Pineal Gland
• Melatonin:
– Production stimulated by the suparchiasmatic nucleus (SCN) in hypothalamus. – SCN is primary center for circadian rhythms.

• May inhibit GnRH.

Dr. Yaser Ashour

Dr. Yaser Ashour

Thymus
• Site of production of T cells (thymusdependent cells), which are lymphocytes.

Dr. Yaser Ashour

Gonads and Placenta
• Gonads (testes and ovaries):
– Secrete sex hormones.
• Testosterone. • Estradiol. • Progesterone.

• Placenta:
– Secretes large amounts of estrogen and progesterone.

Dr. Yaser Ashour

Prostaglandins
• Most diverse group of autocrine regulators. • Produced in almost every organ. • Wide variety of functions.
– Immune system:
• Promote inflammatory process.

– Reproductive system:
• Play role in ovulation.

– Digestive system:
• Inhibit gastric secretion.

Dr. Yaser Ashour

Prostaglandins
– Respiratory system:
• May bronchoconstrict or bronchodilate.

– Circulatory system:
• Vasoconstrictors or vasodilators.

– Urinary system:
• Vasodilation.

Dr. Yaser Ashour

Dr. Yaser Ashour

Good Luck ya 2ooroood

Dr. Yaser Ashour

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