The Endocrine System إتجاهات عروض علم وظائف الأعضاء PDF

10 Baraah Habahbeh Leen Qasim Fatima Daoud THE ENDOCRINE SYSTEM First, our body is under control by two systems: 1- nervous system. 2– endocrine system ‫الشيت سهل واخذناه من قبل‬ enjoy !!! The nervous and endocrine systems coordinate all the body systems. The nervous system does so through the actio...

10 Baraah Habahbeh Leen Qasim Fatima Daoud THE ENDOCRINE SYSTEM First, our body is under control by two systems: 1- nervous system. 2– endocrine system ‫الشيت سهل واخذناه من قبل‬ enjoy !!! The nervous and endocrine systems coordinate all the body systems. The nervous system does so through the action of neurons, and the neurotransmitters. The endocrine system uses hormones to produce their effects. However, the kind of regulation varies a little bit between the endocrine & the nervous system, the major differences are: 1)speed of response. The nervous system controls homeostasis through nerve impulses and neurotransmitters, which act locally and quickly. While the endocrine system uses hormones, which act more slowly in distant parts of the body. So, if we want a slow action for a longer regulation of time we will need the endocrine system. 2) site of function. The nervous system controls neurons, muscle cells, and glandular cells. The endocrine system regulates virtually all body cells. -Functions of endocrine system: The endocrine system primarily controls processes that require duration rather than speed, most of which are aimed at maintaining homeostasis, such as regulating nutrient metabolism and water and electrolyte balance; promoting growth; and facilitating reproductive capacity. Furthermore, the endocrine system works along with the autonomic nervous system to control and integrate activities of both the circulatory and the digestive systems. -We need to classify the hormones according to their site of action: 1) endocrine hormones: secreted into interstitial fluid and then absorbed into the bloodstream. Although a given hormone travels throughout the body in the blood, it affects only specific target cells, since only the target cells for a given hormone have receptors that bind and recognize that hormone. down-regulation (less sensitive) , up-regulation (more sensitive) 2) Autocrine hormones: are local hormones that are secreted and bind to the same cell. (The same cell that secret the hormone has its receptor) Ex, interleukin- 2 (IL-2), which is released by helper T cells. 3) Paracrine hormones: are local hormones that are secreted into interstitial fluid and act on nearby cells ex: nitric oxide (NO) in cardiovascular system, its receptors are usually present on smooth muscle cells. -CHEMICAL CLASSES OF HORMONES Hormones can be divided into two broad chemical classes: 1) Water soluble hormones (hydrophilic) 2) Lipid soluble hormones (Lipophilic or hydrophobic) 1)Water soluble hormones: a) amino hormones: -are synthesized by modifying certain amino acids. -The catecholamines: epinephrine, norepinephrine, and Dopamine. They are synthesized by modifying the amino acid tyrosine. -Histamine is synthesized from the amino acid histidine. -Serotonin and melatonin are derived from tryptophan. b) peptide hormones and protein: -The smaller peptide hormones consist of chains of 3 to 49 amino acids -The larger protein hormones include 50 to 200 amino acids. - Peptide hormones are antidiuretic hormones (ADH) and oxytocin. -Protein hormones include growth hormones and insulin. Several of the protein hormones, such as thyroid-stimulating hormone (TSH), have attached carbohydrate groups and thus are glycoprotein hormones. Water soluble hormones action: -Water soluble hormones are easy to transport in the watery blood (because the plasma consists 92% of water). -The plasma membrane of target cells, However, is impermeable to them. -Hydrophilic hormones on binding with Surface membrane receptors primarily act through second-messenger systems to alter the activity of preexisting proteins, such as enzymes, within the target cell to produce their physiologic response. they work on activation or inactivation for Certain pathways so they are faster than lipid soluble hormones 2)The lipid soluble hormones: a) Steroid hormones are derived from cholesterol. Each steroid hormone is unique due to the presence of different chemical groups attached at various sites on the four rings at the core of its structure. b) Thyroid hormones (T3 and T4) are synthesized by attaching iodine to the amino acid tyrosine. The presence of benzene ring within a T3 or T4 molecule makes these molecules very lipid soluble. Lipid soluble hormones action: -lipophilic hormones are largely bound to plasma protein -Lipophilic steroid hormones and thyroid hormones, by contrast, activate genes on binding with receptors inside the cell, thus bringing about formation of new proteins in the target cell that carry out the desired response. -As we can see in this pic, the lipid soluble hormone needs a transport protein to be carried throughout the plasma. Then they can diffuse into the cell, then usually bind to a receptor in the nucleus. which makes an alert for gene expression (DNA to mRNA to synthesis a new protein or inhibition of synthesis of a certain protein) -Tropic hormones A hormone that has as its primary function in the regulation of hormone secretion of another endocrine gland is classified functionally as a tropic hormone. (a gland effects on a gland) ▪ Tropic means “nourishing” It means that hormones not only stimulate the secretion but also maintain the structure of their endocrine target tissues. ▪ A tropic hormone’s actions aimed at maintaining the structural integrity of its target gland are specifically known as trophic (growth promoting) actions. ▪ For example, thyroid-stimulating hormone (TSH), a tropic hormone stimulates thyroid hormone secretion by the thyroid gland and maintains the structural integrity of this gland. In the absence of TSH, the thyroid gland atrophies (shrinks) and produces very low levels of its hormones. (In any absence of a tropic hormone the second gland shrinks ) The effective plasma concentration of a hormone is normally regulated by changes in the rate of its secretion. -Control of hormones (Most hormonal regulatory systems work via negative feedback, but a few operate via positive feedback.) -Negative feedback -positive feedback The final hormone or product The final hormone or. product will Exert an inhibition. will Exert an activation on its production. on its production ex:(CA/PTH) ex(oxytocin/childbirth) We will start with the “central glands" located in the CNS. HYPOTHALAMUS: ▪ The hypothalamus is the major link Between the nervous and the endocrine systems, it’s an actual part of the nervous system, our hormones are affected by our emotions, you will notice that some hormones affected by our mental health or psychological states (hypothalamus is responsible for that) Pituitary gland: The pituitary gland, or hypophysis, is a small endocrine gland located in a bony cavity (hypophyseal fossa and that’s why we call it “hypophysis") at the base of the brain just below the hypothalamus. The pituitary is connected to the hypothalamus by a thin connecting stalk. (infundibulum) The pituitary has two anatomically and functionally distinct lobes: the posterior pituitary, and the anterior pituitary. -The posterior pituitary is composed of nervous tissue and thus is also termed the neurohypophysis. -The anterior pituitary consists of glandular epithelial tissue and accordingly is also called adenohypophysis. -The posterior and anterior pituitary lobes have only their location in common. -They arise from different tissues embryonically, serve different functions, and are subject to different control mechanisms -Let’s talk about the posterior one (neurohypophysis): The hypothalamus and posterior pituitary form a neuroendocrine system that consists of a population of neurosecretory neurons whose cell bodies lie in two well-defined clusters in the hypothalamus, the supraoptic nucleus and the paraventricular nucleus. The axons of these neurons pass down through the connecting stalk to terminate on capillaries in the posterior pituitary. -The posterior pituitary consists of these neuronal terminals plus supporting cells. -The posterior pituitary does not actually produce any hormones. It simply stores and, on appropriate stimulation, releases into the blood two small peptide hormones, vasopressin, and oxytocin, which are synthesized by the neuronal cell bodies in the hypothalamus. -These hydrophilic peptides are made in both the supraoptic and paraventricular nuclei, but a single neuron can produce only one of these hormones. What is the connection between the post. Pit and the hypothalamus? Answer: the hypothalamic -hypophyseal tract (axons of neurosecretory cells) The cell bodies of the neurosecretory cells are in the paraventricular and supraoptic nuclei of the hypothalamus; their axons form the hypothalamic-hypophyseal tract. This tract begins in the hypothalamus and ends (axon terminals) near blood capillaries in the posterior pituitary. What do we call this structure? Optic chiasm, it’s were the crossing Optic nerve occurs & when the pituitary gland get tumor or adenoma it will exert pressure on the optic chaism which makes a certain kind of visual loss or blindness Paraventricular nucleus synthesis: Oxytocin Supraoptic nucleus synthesis: ADH (Antidiuretic hormone) or vasopressin Note: oxytocin & ADH = peptide hormones oxytocin & ADH structures are similar (they differs only in 2 amino acid sequence) (Certain proteins carry these hormones from hypothalamus to the terminals in post.pit and under certain Stimuli they will be released into the blood circulation) ADH/vasopressin: 1.Targets the collecting ducts in the kidney to minimize water loss. 2. Causes contraction of arteriolar smooth muscle (a vessel pressor effect). ▪ The major control for hypothalamic-induced release of vasopressin is input from hypothalamic osmoreceptors, which increases vasopressin secretion in response to a rise in plasma osmolarity. ▪A less powerful input from the left atrial volume receptors increases vasopressin secretion in response to a fall in ECF volume and arterial blood pressure. Oxytocin: “love hormone" ▪ Targets smooth muscle in the uterus (delivers the baby) and breasts. -In the uterus, oxytocin stimulates uterine contractions, and in response to the sucking from an infant. Also, oxytocin stimulates “milk letdown” in the breasts. ▪ Appropriately, oxytocin secretion is increased by reflexes that originate within the birth canal during childbirth and by reflexes that are triggered when the infant suckles the breast. ▪ Oxytocin influences a variety of behaviors (bonding, or attachment). ‫هرمون التعلق يعني بعمل رابطه تعلق بين األم وابنها‬ Note: oxytocin is only responsible for delivering the milk to the baby & have no relation in producing it Anterior pituitary (adenohypophysis) Is anatomically and functionally connected to the hypothalamus by blood vessels that form a portal system called the hypophyseal portal system. -In a portal system, blood flows from one capillary network into a portal vein, and then into a second capillary network before returning to the heart. -The name of the portal system indicates the location of the second capillary network. In the hypophyseal portal system, blood flows from capillaries in the hypothalamus into portal veins that carry blood to capillaries of the anterior pituitary. - The two most important factors that regulate anterior pituitary hormone secretion are hypothalamic hormones and feedback by target-gland hormones. The presence of the portal system is to deliver the hormones with no change on the concentration & form a private way. The way they communicate is through endocrine hormones. ‫يعني لوال وجوده كان لف الهرمون كل الدوره الدمويه بعدين وصل وهاد يؤدي إلى‬ ‫انه يقل تركيزه‬ As a result, almost all blood supplied to the anterior pituitary must first pass through the hypothalamus. Because materials can be exchanged between blood and surrounding tissue only at the capillary level, the hypothalamic–hypophyseal portal system provides a “private” route through which releasing and inhibiting hormones can be picked up at the hypothalamus and delivered immediately and directly to the anterior pituitary at relatively high concentrations, bypassing the general circulation. If the portal system did not exist, once the hypophysiotropic hormones were picked up in the hypothalamus, they would be returned to the heart through the systemic veins, pumped through the pulmonary circulation, then returned to the heart and finally be pumped into the systemic arteries for delivery throughout the body, including the anterior pituitary. Not only would this process take much longer, but the hypophysiotropic hormones would be considerably diluted before arriving at the anterior pituitary. 5 types of anterior pituitary cells secrete seven hormones. ▪ Most anterior pituitary hormones are tropic + there name is According to the hormone they secret 1 – Somatotroph or (somatotropis)(GH) 2- thyrotroph (TSH) 3- Gonadotroph (FSH & LH). 4- Lactotroph (prolactin) 5 – corticotroph  (ACTH) Hypothalamus Controls Pituitary Secretion: Almost all secretion by the pituitary is controlled by either hormonal or nervous signals from the hypothalamus. The hypothalamus receives signals from many sources in the nervous system. Pain, depressing or exciting thoughts, olfactory stimuli, concentrations of nutrients, electrolytes, water. ** GH, TSH, ACTH, FSH, and LH are all tropic hormones because they each regulate secretion of another specific endocrine gland. ** FSH and LH are collectively referred to as gonadotropins because they control secretion of the sex hormones by the gonads Among the anterior pituitary hormones, PRL is the only one that does not stimulate secretion of another hormone. It acts directly on nonendocrine tissue to exert its effects. ** Of the tropic hormones, FSH, LH, and GH exert effects on nonendocrine target cells in addition to stimulating secretion of other hormones. Number of aa isn't required .‫الجداول الدكتوره ذكرت انه اقرأوهم ف مطلوبين‬ ** For most of the anterior pituitary hormones, it is the releasing hormones that are important, but for prolactin, a hypothalamic inhibitory hormone probably exerts more control. ‫ويشاء ربك ان يناولك القمر‬ ‫وتشاء أنت من األماني نجمه‬ THE END OF SHEET #10 ‫ال تنسوا الدعاء ألهل غزه وادعولنا‬ Ashar Ahmad Abdullah Alrawashdeh Dr. Fatima Daoud Growth Hormone. Remember from last lecture: *Hormones that are secreted from Hypothalamus pituitary(neurohypophysis) through axons are the : 1-Oxytocin (smooth muscle of uterus & mammary gland). 2- ADH -Vasopressin- (blood vessels & kidney). and released to posterior * Hormones of Anterior pituitary (adenohypophysis) are from 5 types of cells: 1- Somatotroph; Growth hormone (our topic of today) 2- Thyrotroph; Thyroid stimulating hormone 3- Gonadotroph; follicular stimulating hormone (FSH) & Luteinizing hormone (LH) 4- Corticotroph; Adrenocorticotropic hormone (ACTH) 5- Lactotroph; Prolactin (PRL). All are tropic hormone that control the secretion of other hormone from another gland (except for PRL), so they have a three-hormone sequence called an endocrine axis; Hypothalamus – pituitary – target gland. - There are 2 Ways that affect the secretion of these hormones: 1- Negative feedback; from the final target at the level of Ant.pituitary also at level of Hypothalamus, most common way to regulate endocrine hormones. The secretory activity of three types of anterior pituitary cells (thyrotrophs, corticotrophs, and gonadotrophs) decreases when blood levels of their target gland hormones rise. 2- Certain Hormones secreted through Hypothalamus, releasing H. & inhibitory H. However, most of Ant.pituitary are under the control of releasing H. Growth H. has a releasing & inhibitory H. (Somatostatin) Prolactin Always under inhibition of Hypothalamus (through Dopamine -which is neurotransmitter in CNS and always exist in the blood and suppress PRL). So, experimentally if we remove Ant.pituitary and transplant it in another part in the body, Secretion of all six hormones of it will decrease to very low level Except for sure PRL bcz there is no more inhibition from Dopamine. But what about GH? Why its secretion decreases? because it has a releasing hormone that has a greater influence than the inhibitory. What about removing Pos.pituitary? Sure, its Hormones won’t be affected because their factory (Hypothalamus) stays normal and secretes these Hormones regardless of presence of pos. pituitary. Synthesis and directly secretion without Storage. ،،، ‫ تنقط الهرمونات‬Hypothalamus ‫يعني كأنك قطعت الحنفية اللي بتخزنهم و بتنزلهم و بتصير ال‬ Hypothalamus controls pituitary secretion *almost all secretion by the pituitary is controlled by either hormonal or nervous signals from hypothalamus. * Hypothalamus receives signals from many sources in the nervous system. Hypothalamus collect information from all over the body by having for e.g osmoreceptors for electrolytes , info. About glucose ,emotions ( so we’ll see many endocrine hormones affected by emotional state like depress , anxiety , exciting thoughts), concentration of nutrient , satiety , and olfactory stimuli. Now... let’s start with GROWTH HORMONE. Main ideas from the lectures collected here and discussed below.. 1- GH affect on most tissues that capable of growth. 2- It increases rate of protein synthesis (decreases the amount of Amino Acids in plasma) (this point is the only one related to growth) 3- Increased mobilization of fatty acids from adipose tissue (increase free f.a in blood & increased use of fatty acid in energy). 4- Decreased rate of glucose utilization in the body (result in hyperglycemia and increasing in insulin levels ) 5- Under the control of GH the body switch the source of energy to be the fats instead of glucose and proteins. As the name suggest it is a hormone that is important for growing, but also it has metabolic activities, so we as an adult that stopped growing, also we have continuous secretion at certain rhythm of this hormone, but not as much as children, and in adolescence and around puberty is in higher level. -Slides info. : *In growing children, continuous net protein synthesis occurs under the influence of growth hormone (GH) as the body steadily gets larger. *Weight gain alone is not synonymous with growth because weight gain may occur from retaining excess water or storing fat without true structural growth of tissues. * Growth requires net synthesis of proteins and includes lengthening of the long bones (the bones of the extremities) and increases in the size and number of cells in the soft tissues. * GH in contrast of other hormone it doesn’t function through a target gland but exert its effect directly on all or almost tissues of the body. *It causes growth of almost all tissues of the body that are capable of growing * GH is the most abundant hormone produced by the anterior pituitary, even in adults in whom growth has already ceased, although GH secretion typically starts to decline after middle age. The continued high secretion of GH beyond the growing period implies that this hormone has important influences beyond its influence on growth, such as metabolic effects. Growth Hormone has several metabolic effects. Proteins: - Increase in protein amount (balance between production and destruction). - So, the synthesis of proteins increases and catabolism -destruction- decrease under the influence of growth hormone. But How!! 1- Enhancement of Amino Acid Transport Through the Cell Membranes... ( increase uptake of a.a which is requirement of translation) 2- Enhancement of transcription& Enhancement of RNA Translation to Cause Protein Synthesis by the Ribosomes. (Most imp role). ** by the first two steps I increase “synthesis”. 3- Decreased Catabolism of Protein and Amino Acids. So, all of that will cause Growth of cells by increasing cell size (i.e Hypertrophy) via increasing the amount of proteins in the cells (e.g muscles). To conclude : “GH Promotes Protein Deposition in Tissues”. Fats: -GH increases lean body mass ; by increasing muscles and decreases body fat and adipose tissue. So adipose tissue will undergo lipolysis (break down by GH) and free fatty acid (will increase in plasma) and used for energy in muscles, so here we’re sparing carbs and proteins (proof that GH decrease the destruction of proteins) To remember that : the builders abuse Growth hormone to increase lean body mass Lean body mass: your overall weight minus your weight from body fat. Slides: * GH decreases breakdown of cell protein, probable reason for this decrease is that GH also mobilizes large quantities of free fatty acids from the adipose tissue, and these are used to supply most of the energy for the body’s cells, thus acting as a potent “protein sparer.” *Growth hormones increases mobilization of fatty acids from adipose tissue. *GH increases free fatty acids in the blood. *GH increases use of fatty acids for energy. * The ability of GH to promote fat utilization, together with its protein anabolic effect, causes an increase in lean body mass. Carbs : Net effect : decreases carbs catabolism and utilization , also it increases sparing of carbs. So glucose level will Increase in blood-plasma- (Hyperglycemia) , but why when high levels of growth hormone the body switch the usage of fats as a source of energy instead of carbs ? – because it leaves the carbs for the brain(glucose dependent tissue). - Also, it decreases the uptake of glucose by muscles and fat. - Increase the production of glucose by liver in a process called Gluconeogenesis - While the glucose level increases in blood also Insulin secretion will be high… (diabetes type 2 and represent also insulin resistance). Slides : * Each of these changes results from growth hormone–induced “insulin resistance,” which attenuates insulin’s actions to stimulate the uptake and utilization of glucose in skeletal muscle and adipose tissue and to inhibit gluconeogenesis (glucose production) by the liver; this leads to increased blood glucose concentration and a compensatory increase in insulin secretion. For these reasons, growth hormone’s effects are called diabetogenic, and excess secretion of growth hormone can produce metabolic disturbances similar to those found in patients with type II (non-insulin-dependent) diabetes, who are also resistant to the metabolic effects of insulin. *We do not know the precise mechanism by which growth hormone causes insulin resistance and decreased glucose utilization by the cells. However, growth hormone–induced increases in blood concentrations of fatty acids likely contribute to impairment of insulin’s actions on tissue glucose utilization. Experimental studies indicate that raising blood levels of fatty acids above normal rapidly decreases the sensitivity of the liver and skeletal muscle to insulin’s effects on carbohydrate metabolism. “GH Decreases Carbohydrate Utilization” Quick summary : GH… Increases Glucose level in blood , decreases its uptake by cells, gluconeogenisis by liver… hyperglycemia Increase free fatty acid in plasma (lipolysis and releasing them from adipose to plasma) to be used as a source of energy. Decrease amino acid level in Plasma; increases the Amino acids uptake by cells to form proteins. Slides: Thus, the overall metabolic effect of GH is to mobilize fat stores as a major energy source while sparing glucose for glucose-dependent tissues such as the brain. The brain can use only glucose as its metabolic fuel, yet nervous tissue cannot store glycogen (stored glucose) to any extent. This metabolic pattern induced by GH is suitable for maintaining the body during prolonged fasting or other situations when the body’s energy needs exceed available glucose stores. Regulators of growth hormone secretion: - Hormonal & metabolic regulator. Remember : endocrine hormone under regulation of negative feedback ( by hormones usually but here is metabolic ) … For e.g if glucose level decreases what will happen to GH? (increase) Hyperglycemia ? (GH decrease) Decrease fatty acid ? it increase … and so on… All of these effects are indirectly related to growth by (increase protein synthesis). In term of growth: Growth Not necessarily equal to weight gain. But increasing size (hypertrophy) and/or number of cells (hyperplasia) , this for soft tissue. Promote growth by lengthening of bones. Slides : ** growth-promoting effects: GH stimulates growth of both the soft tissues and the skeleton. ** GH promotes growth of soft tissues by (1) increasing the size of cells (hypertrophy) and (2) increasing the number of cells (hyperplasia). ** GH increases the size of cells by favoring synthesis of proteins. Growth Hormone Stimulates Cartilage and Bone Growth The effects on bone depend on its type; For long bone.. As the epiphyseal plate present GH will stimulate chondrocyte to proliferate and then ossified causing increase in bone length. Epiphyseal plate disappears at age of 18-25 so even if GH is existed, we won’t become taller. For Flat -membranous- bone.. Vertebra, scapula, skull.. -they have two types of cells Osteoblast (deposition and thickening of the bone) & Osteoclasts (bone resorption/degradation), so GH indeed stimulates osteoblasts and this increases thickness of bone. Slides: **This growth first causes deposition of new cartilage, followed by its conversion into new bone, thus elongating the shaft and pushing the epiphyses farther and farther apart. At the same time, the epiphyseal cartilage itself is progressively used up, so by late adolescence, no additional epiphyseal cartilage remains to provide for further long bone growth. At this time, bony fusion occurs between the shaft and the epiphysis at each end, so no further lengthening of the long bone can occur. ** Second, osteoblasts in the bone periosteum and in some bone cavities deposit new bone on the surfaces of older bone. Simultaneously, osteoclasts in the bone remove old bone. When the rate of deposition is greater than that of resorption, the thickness of the bone increases. Growth hormone strongly stimulates osteoblasts. Therefore, the bones can continue to become thicker throughout life under the influence of growth hormone; this is especially true for the membranous bones. For instance, the jaw bones can be stimulated to grow even after adolescence, causing forward protrusion of the chin and lower teeth. Likewise, the bones of the skull can grow in thickness and give rise to bony protrusions over the eyes. African Pygmy. They have short stature but by testing GH level they found it either normal or high, they also test thyroid hormone (it has an effect on length) also found normal; but they found a deficiency in a mediator called somatomedian C (insulin like growth factor – IGF1) … *The rate of growth hormone secretion is normal or high, but there is a hereditary inability to form somatomedin C (IGF-I.) Remember: cells that release GH called somatotroph and the hormone has another name of (somatotropin) and the inhibitory of it is Somatostatin.. the mediator Somatomedian. So, they found that GH exert most of its effect especially on bone through intermediate (IGF1- it has a structure similar to insulin and types of enzymes the activates also similar to enzymes. *Synthesized by liver (endocrine effect) and Locally (imp) by the stimulation of growth factor then released to blood stream … but they found also that other tissues like chondrocyte can produce its own IGF under stimulation of growth factor (para or autocrine effect without releasing it). Slides: *Potent effect of increasing all aspects of bone growth. **It has been postulated that most, if not all, of the growth effects of growth hormone result from somatomedin C and other somatomedins, rather than from direct effects of growth hormone on the bones and other peripheral tissues. ** The major source of circulating IGF-I is the liver, which releases this peptide product into the blood in response to GH stimulation. IGF-I is also produced by most other tissues, although they do not release it into the blood to any extent. Regulation of growth hormone secretion. How we can control the secretion of GH ?! GH doesn’t have a steady state ; it has a pulsatile pattern of secretion and the highest (peak) release of the hormone is after 2hrs of Deep sleep. And as one become older there is no more efficient sleep this proof why older people have less GH than children and also will decrease with age, as the efficiency of the sleeping cycle decreases 2nd thing that boosts GH is Exercise Slides: * After adolescence, GH secretion decreases slowly with aging, finally falling to about 25% of the adolescent level in very old age. ** ghrelin)‫(هرمون الجوع‬, a hormone secreted by the stomach before meals during fasting for example. What about testosterone & estrogen why they increases GH ? Because just before puberty they stimulate releasing GH and this results in increasing in length. Some men in order to increase their exercise and bone capacity, tend towards the exogenous GH ( GH’s substances and processes that are originated from outside of an organism ), without the acknowledgment of its affect, which is a great suppression of the endogenous one , that’s why we consider it as an “ inhibition effect “. Starving and Fasting.. This will decrease glucose level but if long run(for a long time) will cause protein deficiency. Here regulation of GH depend on timing… Now to understand let’s consider a patient expected to have GH deficiency if we give them insulin they will have Hypoglycemia and in Normal condition GH will increase , so if it doesn’t increase the patient is suffering from Growth hormone deficiency. **So, under acute conditions, hypoglycemia is a far more potent stimulator of GH secretion than is an acute decrease in protein intake. In the next page you will know what is the main stimulator in chronic -long time- conditions … Physiological Functions of Growth Hormone. Kwashiorkor: People with severe protein deficiency. Decreasing in protein concentration will increase GH levels... and that what is found in these people. They start giving them carbs, but the level of GH stays the same until they give them protein. So, in longer duration of GH regulation amount of protein more important than glucose amount. ** in chronic conditions, GH secretion seems to correlate more with the degree of cellular protein depletion than with the degree of glucose insufficiency. For example, the extremely high levels of GH that occur during starvation are closely related to the amount of protein depletion. Pay attention that in acute condition ( like fasting for just hours) glucose is the regulator of GH secretion ; but in chronic condition (starvation for a long time so the body starts to break down Proteins) protein amount is the main regulator of GH secretion. Slides : ** this slide demonstrates the effect of protein deficiency on plasma GH and then the effect of adding protein to the diet. The first column shows very high levels of GH in children with extreme protein deficiency during the protein malnutrition condition called kwashiorkor; the second column shows the levels in the same children after 3 days of treatment with more than adequate quantities of carbohydrates in their diets, demonstrating that the carbohydrates did not lower the plasma GH concentration. The third and fourth columns show the levels after treatment with protein supplements for 3 and 25 days, respectively, with a concomitant decrease in the hormone. ** These results demonstrate that under severe conditions of protein malnutrition, adequate calories alone are not sufficient to correct the excess production of GH. The protein deficiency must also be corrected before the GH concentration will return to normal. At the end the axis is : Hypothalamus – Anterior pituitary – liver which will produce IGF that will exert negative feedback on Ant.pituitary & Hypothalamus. Slides: When GH is administered directly into the blood of an animal over several hours, the rate of endogenous GH secretion decreases. This decrease demonstrates that GH secretion is subject to typical negative feedback control, as is true for essentially all hormones. The nature of this feedback mechanism and whether it is mediated mainly through inhibition of GHRH or enhancement of somatostatin, which inhibits growth hormone secretion, are uncertain. Abnormalities of Growth Hormone Secretion. 1) Panhypopituitarism in the Adult: A deficiency in all Anterior pituitary hormones including growth hormone. Causes : a) tumor that compress on or destroy anterior pituitary b) circulatory shock that decrease the blood supply to the gland. The hormones that will be affected: Decrease in TSH: decrease in thyroid hormone (hypothyroidism) Decrease in ACTH : decrease in adrenal corticoid hormones (depressed production of glucocorticoids) Decrease in FSH & LH: decrease in testosterone & estrogen in gonad hormones. (Suppressed secretion of the gonadotropic hormones…. non active sexually) Treatment : Except for the abnormal sexual functions, the patient can usually be treated satisfactorily by administering adrenocortical and thyroid hormones. 2) Dwarfism : Short stature due to deficiency in growth hormone. Two expected causes : either because of Panhypopituitarism during childhood OR deficiency of IGF-1 (African Pygmy) In comparison with Panhypopituitarism , African Pygmy can be sexually active -they can reproducebecause they have a deficiency in IGF-1. Another type of dwarfism : Laron dwarfs : that have a deficiency in receptors of the hormone not the hormone itself nor IGF. Slides : *Panhypopituitarism first occurring in adulthood generally results from one of three abnormalities: Two tumorous conditions that may compress the pituitary gland until the functioning anterior pituitary cells are totally or almost totally destroyed. The third cause occurs when a new mother experiences circulatory shock after the birth of her baby. Slides : Dwarfism: *All the physical parts of the body develop in appropriate proportion to one another, but the rate of development is greatly decreased. * A person with panhypopituitary dwarfism does not pass through puberty and never secretes sufficient quantities of gonadotropic hormones to develop adult sexual functions. * In Laron dwarfs and African pygmies, the rate of GH secretion is normal or high, but responsiveness to GH is impaired due to mutations of the GH receptor or a hereditary inability to form IGF-1, a key step for the promotion of growth by GH. Gigantism and Acromegaly: Both have Increase in GH. Gigantism : -before puberty when epiphyseal plate is present so growth hormone will increase the length of the bone like the man in the picture is very very tall. *epiphyseal plate undergo closure under the control of testosterone and estrogen. Slides : Excess growth hormone before adolescence. All body tissues grow rapidly, including the bones. Hyperglycemia  degeneration of B cells (pancreatic cells because of excessive secretion of insulin)  10 percent will develop full-blown diabetes mellitus. Panhypopituitarism  general deficiency of pituitary hormones usually causes death in early adulthood. Treatment: microsurgical removal of the tumor or by irradiation of the pituitary gland If the cause is a tumor in somatotrophs this will affect other cells so they will suffer also from deficiency in other hormones. Acromegaly : -After puberty and closure of epiphyseal plate so GH will affect on soft tissue causing Hyperplasia and Hypertrophy. So, each tissue able to grow it will grow (hand, feet, protruded jaw, protruded forehead, nose, tongue and kidneys enlargement) but no chance in length. Slides: Excess growth hormone after adolescence. Enlargement in the bones of the hands and feet and in the membranous bones, including the cranium, nose, bosses on the forehead, supraorbital ridges, lower jawbone, and portions of the vertebrae. the lower jaw protrudes forward the forehead slants forward the nose increases to as much as twice normal size the feet and hands are almost twice normal size. kyphosis. the tongue, the liver, and especially the kidneys, become greatly enlarged. Question.. A boy 18 years of age is brought with progressively increasing height and increase in shoe size. The parents feel that the child should have stopped growing fast by now as his siblings are much shorter than him though they are older. You would not expect to see: A) Increased IGF B) A macroadenoma of the pituitary C) Bilateral hemianopia (loss of vision) D) Hypoglycaemia Summary : The End Of Sheet 11. 12 Malak Amro Dania tareq Fatima daoud Thyroid gland    The thyroid gland is located directly below the larynx and can extend to the anterior side of the trachea. It is composed of two lobes (right lobe, left lobe) the lobes are connected through the isthmus is one of the largest of the endocrine glands, normally weighing 15 to 20 grams in adults. Structure of the thyroid gland:      The histology of the thyroid gland is made of follicles. The cellular epithelium surrounds this follicle, you can also see the capillaries around it. The follicles are filled with the colloid (colloid: is a sticky fluid , composed of a large glycoprotein called thyroglobulin MW=335,000) Around each follicle we find follicular cells, they are the cells responsible for producing the thyroid hormones (T3, T4). There is another type of cell with a lower quantity called the para follicular cells or C cells they produce calcitonin. Synthesis of thyroid hormone: basal membrane apical membrane  now since the colloid is filled with the thyroglobulin protein (secretory protein) so, after the transcription &translation of the thyroglobulin ( TG ) in the nucleus it must go to the (ER, Golgi apparatus) so I can secret it to the colloid. ((TG: is made of around 70 tyrosine amino acid.))  The most important ion in the synthesis of Tg is the iodide ion (we can take iodine from fish & table salt (it is supplemented with iodine)).  The first stage in the formation of thyroid hormones is transport of iodides from the blood into the thyroid glandular cells and follicles. The basal membrane of the thyroid cell has the specific ability to pump the iodide actively to the interior of the cell. This is achieved by the action of a sodium-iodide symporter (NIS), which co-transports one iodide ion along with two sodium ions across the basolateral (plasma) membrane into the cell.  The energy for transporting iodide against a concentration gradient comes from the sodium-potassium ATPase pump, which pumps sodium out of the cell, thereby establishing a low intracellular sodium concentration and a gradient for facilitated diffusion of sodium into the cell.  It is an active transport since it used the Na+ gradient which is made by the Na+ /K+ pump (which directly uses ATP)).  Once I let the iodide into the cells this is called Iodide trapping (increasing the concentration of iodide inside the cell.  Iodide is transported out of the thyroid cells across the apical membrane into the colloid by (a chloride-iodide ion counter-transporter) molecule called pendrin.  Once the iodide leaves the cell it is directly oxidized to iodine through the peroxidase enzyme and this is the first essential step for the formation of the thyroid hormones. when the peroxidase system is blocked or when it is hereditarily absent from the cells , the rate of formation of thyroid hormones falls to zero.  The thyroid epithelial cells also secrete thyroglobulin protein into the colloid. Once the iodide is oxidized to iodine it directly gets (added, coupled) to the thyroglobulin (on the tyrosine AA) this step is called - “organification” of thyroglobulin. They are still within the thyroglobulin molecule.      Tyrosine is first iodized to monoiodotyrosine and then to diiodotyrosine. Then, during the next few minutes, hours, and even days, more and more of the iodotyrosine residues become coupled with one another forming Triiodothyronin (T3) which represents about one-fifteenth of the final hormones But the major hormonal product of the coupling reaction is the molecule thyroxine (T4) which is formed when two molecules of diiodotyrosine are joined together. When we say thyroid hormones we mean (T3, T4)they are still part of the thyroglobulin complex that is inside the colloid. this gives the thyroid gland a very unique characteristics which is that it can store the hormone not just synthesize it. So, The thyroid gland is unusual among the endocrine glands in its ability to store large amounts of hormone. Each thyroglobulin molecule contains up to 30 thyroxine molecules and a few triiodothyronine molecules. This stored amount can supply the body with its normal requirements of thyroid hormones for 2 to 3 months. Therefore, when synthesis of thyroid hormone ceases, the physiologic effects of deficiency are not observed for several months. SECRETION OF THE THYROID HORMONES  Now under certain stimulation I need the (T3, T4) to be secreted into the blood circulation. The most important stimulus is the TSH (thyroid stimulating hormone).  The apical surface of thyroid cells sends out pseudopod extensions that close around small portions of the colloid to form pinocytic vesicles that enter the apex of the thyroid cell and contain MIT, DIT, T3, T4, RT3 and colloid so it also called colloid droplet. Then lysosomes in the cell cytoplasm immediately fuse with these vesicles to form digestive vesicles containing digestive enzymes from the lysosomes mixed with the colloid. Multiple proteases among the enzymes digest the thyroglobulin molecules and release thyroxine (T4) and triiodothyronine (T3) in free form, which then diffuse through the base of the thyroid cell into the surrounding capillaries. Thus, the thyroid hormones are released into the blood.  At the same time, we have: 1. The secretion of (T3, T4) in free form. 2. Recycling of (MIT, DIT), by breaking it down to the basic unit (tyrosine) so it could be used again in the thyroglobulin synthesis. 3. Recycling of the IODINE through an enzyme called (Deiodinase) Deiodinase: enzyme that makes virtually all this iodine available again for recycling within the gland for forming additional thyroid hormones The Deiodinase is very important, people with deficiency of this enzyme they need to increase their uptake. Pinocytosis of thyroglobulin   Proteases cleavage Recycling of MIT, DIT (Deiodinase) Secretion of T3, T4 bound to thyroxinebinding globulin As we said in the previous sheet the Thyroid hormones are lipid soluble hormones (due to the presence of the benzyne ring), so they need a transporter. The transporters are the thyroxine-binding globulin.  The thyroid gland usually produces (93% thyroxine, and 7% triiodothyronine), however in the circulation when they get to the liver all the thyroxineT 4 is converted to triiodothyronineT3. by the deiodinase enzyme. This primarily happens in the liver and kidneys.  Triiodothyronine is about four times as potent as thyroxine, but it is present in the blood in much smaller quantities and persists for a much shorter time than does thyroxine. In this experiment scientists studied the effect of injecting an animal with thyroxine on the basal metabolic rate. Basal metabolic rate: the smallest metabolic is needed to survive (at rest without any metabolic or exercise)  One of the effects of the thyroid hormone is increasing the basal metabolic rate (basal metabolic rate: the amount of energy that I need to only stay alive, without any activities.)  On the first day: there is no increase at all but in 2 or 3 days we will notice a high increase in the metabolic rate. until it reaches the peak in about 10-12 days. (for T4)  This effect can persist for about 6 weeks or months.  (As we said the T3 is more potent than T4 so generally speaking the curve will be much faster. (start to increase 12 h-1 day /the peak might be in 4 days))  Now these 2-3 days delay in the activity of T4 is called the latent period. This long latent period could be explained by: 1. That still needs to be changed into T3. 2. It needs a transporter. (As long it is bounded it is active other ways it is not). 3. When it reaches the targeted cell, it still needs to affect the gene transcription &translation. This also takes time since it synthesis a new protein. So, most of the latency and prolonged period of action of these hormones are probably caused by their binding with proteins both in the plasma and in the tissue cells, followed by their slow release. However, we shall see in subsequent discussions that part of the latent period also results from the way these hormones perform their functions in the cells themselves. (as explained in the 3 previous points)  Physiological Functions of the Thyroid Hormones: 1. Increase the Transcription of Large Numbers of Genes. (explained above)  The rate of utilization of foods for energy is greatly accelerated.  Although the rate of protein synthesis is increased, at the same time the rate of Protein catabolism is also increased.  The growth rate of young people is greatly accelerated.  The mental processes are excited, and the activities of most of the other Endocrine glands are increased. 2. Increase Cellular Metabolic Activity which means:  Increase the number and activity of mitochondria (increased ATP production which leads to increase in the production of heat.  Increase active transport of ions through cell membranes (Na-K-ATPase).  Increase basal metabolic rate  This increase in the ATP production means an excessive quantities of the hormone can occasionally increase the basal metabolic rate by 60% to 100% above normal. Conversely, when no thyroid hormone is produced, the basal metabolic rate falls to almost one-half of normal. THYROID HORMONES ARE IMPORTANT IN TEMPRETURE HOMEASTASIS& BOOSTS THE WHOLE CELLULAR ACTIVITY.  Hyperthyroidism (basal metabolic rate) is higher than normal with almost 60%-100%  Hypothyroidism (basal metabolic rate) is being lower than normal up to 50%. 3. Sympathomimetic Effect  Thyroid hormone increases target-cell responsiveness to catecholamines.  Thyroid hormone accomplishes this permissive effect on the catecholamines by causing a proliferation of catecholamine target-cell receptors. (they found out that Epinephrine and norepinephrine need the presence of the thyroid hormone so their function would be very efficient) They also have a huge effect on GH.  Thyroid hormone not only stimulates GH secretion but increases production of IGF-I by the liver.  Promotes the effects of GH and IGF-I on the synthesis of new protein and on bone growth.  So, o children with Hypothyroidism are short bcz thyroid H stimulate GH &IGF-1 which effect on growth (Promotes the effects of GH and IGF-I on the synthesis of new structural proteins and on bone growth.) o In children with hyperthyroidism, excessive skeletal growth often occurs, causing the child to become considerably taller at an earlier age. However, the bones also mature more rapidly and the epiphyses close at an early age, so the duration of growth and the eventual height of the adult may be shortened.  Thyroid hormone plays a crucial role in development of the nervous system in children: An important effect of thyroid hormone is to promote growth and development of the brain during fetal life and for the first few years of postnatal life. If the fetus does not secrete enough thyroid hormone, growth and maturation of the brain both before birth and afterward are greatly retarded and the brain remains smaller than normal. Without specific thyroid therapy within days or weeks after birth, the child without a thyroid gland will remain mentally deficient throughout life.  Thyroid hormone is also essential for normal CNS activity in adults. Hypothyroidism doesn’t cause them any brain damage but will affect his thinking skills etc.…  Thyroid Hormones Increase Cellular Metabolic Activity.  Stimulation of carbohydrate metabolism.  Stimulation of fat metabolism (decreases the fat stores) and increase amount of lipolysis this will increase the amount of free fatty acids in the plasma which will enhance the utilization of FA as a source of energy.  Decreases the concentrations of cholesterol, phospholipids, and triglycerides in the plasma, even though it increases the free fatty acids in the plasma.  Thyroid hormone increases heart rate and force of contraction, thus increasing cardiac output.  Increase respiration.  Increase gastrointestinal motility.  Increase the muscle activity (vigorous, tremor (‫ )الرعشة‬with a hyperthyroidism patient.  Increase excitability of the brain  Increases the rates of secretion of several other endocrine glands, but it also increases the need of the tissues for the hormones. (Pancreases, ant. pituitary, parathyroid) The doctor said to focus on the other points.  Regulation of Thyroid Hormone Secretion:  TSH as said before is a Tropic hormone as it doesn’t only control the secretion it also effects the size of the thyroid gland.  Negative feedback systems are used as a way of controlling the secretion (too much T3, T4 will affect both the hypothalamus and the ant pituitary to control the secretion).  The most important early effect after administration of TSH is to initiate proteolysis of the thyroglobulin, which causes release of thyroxine and triiodothyronine into the blood within 30 minutes. The other effects require hours or even days and weeks to develop fully.  (it also increases the iodine trapping, organification).  It also increases the cells size (hypertrophy)  It also increases the cells number (hyperplasia)  TSH is controlled by the TRH which is directly controlled by the hypothalamus through collecting information (using the thermoreceptors in the hypothalamus)  So, TRH increases when there is a decrease in temperature. increase in TRH, TSH, T3, T4, so increase in ATP production, increase in heat production). Actually one of the best-known stimuli for increasing the rate of TRH secretion by the hypothalamus, and therefore TSH secretion by the anterior pituitary gland, is exposure of an animal to cold.    Also, when you eat a meal rich with fat which will increase the concentration of leptin hormone in the blood. As a result, it will increase TRH production. )‫(ألنه هلء اكلت يعني الزم احرق االكل والعكس صحيح في حالة الصيام‬ Prolonged fasting reduces plasma leptin levels which, in turn, inhibits TRH. Excitement and anxiety—conditions that greatly stimulate the sympathetic nervous system—cause an acute decrease in secretion of TSH, perhaps because these states increase the metabolic rate and body heat and therefore exert an inverse effect on the heat control center.  Why do patients with Hypothyroidism have atherosclerosis? Because the thyroid hormone decreases the cholesterol levels in plasma. But these patients don’t have thyroid hormone so they have high concentration of cholesterol so they will suffer from atherosclerosis. End of sheet 12 Mera Masalmeh Orjwan Al Amaireh Fatima Daoud 1) Mechanism of Action: Cortisol exerts its anti-inflammatory effects by interfering with several key steps in the inflammation process: Suppression of neutrophil migration to the site of injury and inhibition of their phagocytic activity. Suppression of inflammatory cytokine production. Interference with antibody production by lymphocytes. 2) Role in Stress-Induced Inflammation: When stress is accompanied by tissue injury, inflammatory and immune responses accompany the stress response. Cortisol exerts anti-inflammatory and immunosuppressive effects to help hold these immune system responses in a check-andbalance fashion. 3) Disease Treatment: Treatment for all these diseases are characterized by severe local inflammation, and the harmful effects on the body are caused mainly by the inflammation itself and not by other aspects of the disease: rheumatoid arthritis, rheumatic fever, and acute glomerulonephritis 4) Application in Allergic Disorders and Organ Transplant Rejections: Cortisol is also used in treating allergic disorders and preventing organ transplant rejections. In both cases, its immunosuppressive effects helps in mitigation of immune responses that lead to inflammation, contributing to better management of these conditions. 5) Potential Risks of Prolonged Suppression: Prolonged suppression of this axis can lead to irreversible atrophy (shrinkage) of the cortisol-secreting cells of the adrenal gland and thus to permanent inability of the body to produce its own cortisol. In summary, cortisol's anti-inflammatory effects are achieved through multiple mechanisms, making it a valuable component in managing inflammatory conditions and immune-related disorders. However, long-term use or excessive levels of cortisol require careful monitoring to avoid adverse effects on adrenal function.. Note: cortisol related to chronic conditions / diseases. Regulation Pathway: Cortisol secretion is intricately regulated by the hypothalamus-pituitary-adrenal (HPA) axis, which plays a crucial role in responding to chronic conditions and diseases. The process starts with the hypothalamus, which signals the anterior pituitary gland. The anterior pituitary then releases adrenocorticotropic hormone (ACTH). ACTH stimulates the adrenal cortex, specifically the zona fasciculata and zona reticularis, to produce and release cortisol, along with adrenal androgens. ❖ Negative Feedback Control: The negative-feedback system for cortisol maintains the level of cortisol secretion relatively constant around the set point. Superimposed on the basic negative-feedback control system are two additional factors that influence plasma cortisol concentrations by changing the set point (could be altered): diurnal rhythm and stress, both of which act on the hypothalamus to vary the secretion rate of CRH. This regulated pathway ensures that cortisol levels remain within a physiological range, but factors like diurnal rhythm and stress can modulate cortisol secretion accordingly. Diurnal rhythm: There's a natural fluctuation in cortisol levels throughout the day, with higher levels in the morning and lower levels at night. Stress: Stressful situations trigger the hypothalamus to increase the secretion rate of corticotropinreleasing hormone (CRH), which in turn stimulates ACTH release, leading to elevated cortisol levels Circadian Rhythm of Glucocorticoid Secretion The secretory rates of ACTH and cortisol are high in the early morning but low in the late evening. Surge an hour or so after awaking in the morning. Therefore, measurements of blood cortisol levels are meaningful only when expressed in terms of the time in the cycle at which the measurements are made. If you administer cortisol to inhibit inflammation in a patient with rheumatoid arthritis, several physiological effects will occur: The introduction of exogenous cortisol will trigger a negative feedback response on both the anterior pituitary gland and the hypothalamus. This negative feedback loop will signal a decrease in the production of adrenocorticotropic hormone (ACTH) from the anterior pituitary. As a tropic hormone, ACTH plays a crucial role in controlling the secretion of cortisol from the adrenal cortex also influences the structural size. Prolonged inhibition of ACTH, as seen with continuous cortisol administration, can lead to adrenal cortex shrinkage over time. →If a patient has been receiving cortisol for an extended period, it's essential to taper off the medication gradually rather than stopping it abruptly. This gradual tapering allows the adrenal glands to gradually resume their natural cortisol production without causing adverse effects associated with sudden cessation of cortisol administration. The adrenal cortex secretes both male and female sex hormones in both sexes under control of ACTH. Adrenal glands produce androgens (zona reticularis), including Note: Testosterone exerts about 100 times greater weaker ones like DeHydroEpiAndrosterone (DHEA), and more “androgenicity” than DHEA potent ones like testosterone. The testes' primary androgen product is potent testosterone, while the most abundant adrenal androgen is weaker DHEA. Females do not have a major site for testosterone production; instead, DHEA is more significant in females. DHEA has a prominent effect on females, governing processes such as growth of pubic and axillary hair, enhancing the pubertal growth spurt, and developing/maintaining the female sex drive. Adrenal androgens are continually secreted, especially during fetal life, and are part of the early development of male sex organs during childhood. Adrenal androgens play a role in the development of male characteristics. Adrenal androgens feedback outside the hypothalamus-pituitary-adrenal axis by inhibiting gonadotropin-releasing hormone (GnRH), similar to testicular androgens: DHEA inhibits GnRH, leading to a negative feedback loop that affects luteinizing hormone (LH) and follicle-stimulating hormone (FSH) secretion. Adrenocorticotropic hormone (ACTH) regulates the production of adrenal androgens, including DHEA. ACTH controls the initial conversion of cholesterol to pregnenolone. This initial conversion is the “rate-limiting” step for all the adrenocortical hormones, which explains why ACTH is normally necessary for any adrenocortical hormones to be formed. Long-term stimulation of the adrenal cortex by ACTH not only increases secretory activity but also causes hypertrophy and proliferation of the adrenocortical cells, especially in the zona fasciculata and zona reticularis, where cortisol and the androgens are secreted. ❖ Signs and Symptoms: Increased blood glucose concentration. Deposition of fat in certain area. Increased Protein catabolism → loss protein from muscles → weakness. The loss of protein synthesis in the lymphoid tissues → suppressed immune system Decreased collagen fibers in the subcutaneous tissue →subcutaneous tissues tear easily, resulting in development of large purplish striae where they have torn apart based on it stretch mark produced. Decreased protein deposition in the bones →osteoporosis with consequent weakness of the bones. Mobilization of fat from the lower part of the body, with concomitant extra deposition of fat in the thoracic and upper abdominal regions, giving rise to a buffalo torso. The excess secretion of steroids also leads to an edematous appearance of the face, and the androgenic potency of some of the hormones sometimes causes acne and hirsutism (excess growth of facial hair) “moon face”. 80% of patients have hypertension. In Hirsutism → cortisol acts like androgen In hypertension → it acts like aldosterone Ok, further explanation: Androgen, aldosterone and cortisol all made from cholesterol (they have similar structures) Aldosterone is the most popular minral corticoid and cortisol is the most popular glucocorticoid but it has tiny amount of minral corticoid effect (this effect appears at high concentration of cortisol) Its origin differ from adrenal cortex The adrenal medulla consists of modified postganglionic sympathetic neurons called chromaffin cells because of their staining. Unlike ordinary postganglionic sympathetic neurons, chromaffin cells do not have axonal fibers that terminate on effector organs. On stimulation by the preganglionic fiber the chromaffin cells release their chemical transmitter directly into the blood. Adrenomedullary catecholamine output, epinephrine accounts for 80% and norepinephrine for 20% Calcium Homeostasis There are 3 hormone control ca it Parathyroid Hormone, Calcitonin (the least effect) and vitamin D. 99%: crystalline form within the skeleton and teeth. 0.9% : intracellularly within the soft tissues less than 0.1%: is present in the ECF Approximately half of the ECF Ca is bound to plasma proteins (mainly albumin) or is complexed with phosphate The other half of the ECF Ca is freely diffusible and can readily pass from the plasma into the interstitial fluid and interact with the cells. Only this free ECF Ca is biologically active and subject to regulation; it constitutes less than one thousandth of the total Ca in the body. The ionic calcium- free form- is the form that is important for most body functions of calcium (highly regulated) Calcium physiological roles Ca will work on contraction of our muscle, If we used it in skeletal muscle it will be intracellular calcium (from sarcoplasmic reticulum), If it is smooth muscle or cardiac it will be intra and extracellular Ca. 1) Neuromuscular excitability: Hypocalcemia causes the nervous and muscular system to become progressively more excitable. If Ca level decrease (hypocalcemia) the neuron will be more excitable→ By increasing neuronal membrane permeability to sodium ions, allowing easy initiation of action potentials→ Spontaneous nerve impulses → skeletal muscles (tetany), brain (seizures). →Conversely, a rise in free Ca depresses neuromuscular excitability. Hypercalcemia: cardiac arrhythmias and generalized depression of neuromuscular excitability. Tetany ordinarily occurs when the blood concentration of calcium falls from its normal level of 9.4 mg/dl to about 6 mg/dl, (35%) below the normal, and it is usually lethal at about 4 mg/dl. 2) Stimulus–secretion coupling. The entry of Ca into secretory cells in response to appropriate stimulation, triggers the release of the secretory product by exocytosis. 3) Clotting of blood. Calcium serves as a cofactor in several steps of the cascade of reactions that leads to clot formation. Regulation of Ca metabolism depends on hormonal control of exchanges between the ECF and three other compartments: bone, kidneys, and intestine. Bone resorption is the process by which specialized cells called osteoclasts break down and remove old or damaged bone tissue. →In hypocalcemia: ✓ Immediate adjustments required to maintain a constant free plasma Ca concentration on a minute-to-minute basis. → This is largely accomplished by rapid exchanges between bone and ECF and to a lesser extent by modifications in urinary excretion of Ca. ✓ Regulation of calcium balance involves the more slowly responding adjustments required to maintain a constant total amount of Ca in the body. ✓ Calcium balance is maintained by adjusting the extent of intestinal Ca absorption and urinary Ca excretion. Parathyroid Hormone →Parathyroid hormone raises free plasma Ca, a life-saving effect. - Parathyroid hormone (PTH) is a peptide hormone secreted by the parathyroid glands, four rice grain–sized glands located on the back surface of the thyroid gland, one in each corner. - The overall effect of PTH is to increase the Ca concentration of plasma (Its stimulus by hypocalcemia) - Also lowers plasma phosphate concentration - Like aldosterone, PTH is essential for life. - If any deficiency in PTH consider lethal. ❖ PTH functions: → The main effects of increased PTH secretion in response to decreased extracellular fluid calcium ion concentration: (1) PTH stimulates bone resorption, causing release of calcium into the extracellular fluid (2) PTH increases reabsorption of calcium and decreases phosphate reabsorption by the renal tubules, leading to decreased excretion of calcium and increased excretion of High concentration of free Ca inhibits PTH phosphate; and (3) PTH is necessary for conversion of 25-hydroxycholecalciferol to 1,25 dihydroxycholecalciferol (active form of vit D), which, in turn, increases calcium and phosphate absorption by the intestines. These actions together provide a powerful means of regulating extracellular fluid calcium concentration. ❖ PTH regulation: → The primary regulator of PTH secretion is plasma concentration of free Ca. → Appropriately, PTH secretion increases when plasma Ca falls and decreases when plasma Ca rises. Calcitonin secretion from thyroid gland upon stimulation by hypercalcemia. A peptide hormone secreted from parafollicular cells, or C cells in the thyroid gland. Function: Remember: Decrease plasma calcium concentration. Thyroid follicles produce thyroid hormones Parafollicular cells or C cells produce calcitonin →Two effects on bone: 1) Short term, calcitonin decreases Ca movement from the bone fluid into the plasma. 2) Long term, calcitonin decreases bone resorption. # opposite to PTH effect. →Inhibits Ca and phosphate reabsorption from the kidney tubules. Calcitonin has no effect on the intestine or on vitamin D. However, the quantitative role of calcitonin in humans is far less than that of PTH in regulating calcium ion concentration. The primary stimulus for calcitonin secretion is increased extracellular fluid calcium ion concentration. Vitamin D and PTH more important than Calcitonin. It's a steroid hormone which works on gene expression, carried in plasma by It is both steroid hormone and vitamin carrier (vitamin D carrying protein) it was originally discovered and isolated from a dietary source and tagged as a vitamin (we can get it from diet) The skin would be an adequate source of vitamin D if it were exposed to sufficient sun (Inactive form). Keratinocytes can produce cholecalciferol (vit D) from a precursor related to cholesterol (7 -dehydrocholesterol) on exposure to sunlight. Activation of Vitamin: vitamin D is biologically inactive when it first enters the blood from either the skin or the digestive tract. It must be activated by two sequential biochemical alterations that involve the addition of two hydroxyl (—OH) groups. The first of these reactions occurs in the liver, and the second takes place in the kidneys. PTH stimulates the kidney enzymes involved in the second step of vitamin D activation in response to a fall in plasma Ca. To a lesser extent, a fall in plasma phosphate also enhances the activation process. The end result is production of the active form of vitamin D, 1,25-(OH)2-vitamin D3, also known as calcitriol. Vitamin D in its various forms circulates in the blood primarily bound to vitamin D– binding protein. PTH stimulates the kidney enzymes involved in the second step of vitamin D activation. →Vitamin D Functions: *Increase calcium absorption from the intestinal tract. By increasing, over a period of about 2 days, formation of calbindin, calcium-binding proteins in the intestinal epithelial cells. *Vitamin D promotes phosphate absorption by the intestines. *Vitamin D decreases renal calcium and phosphate excretion. *Vitamin D plays important roles in both bone absorption and bone deposition. → Vitamin D plays important roles in bone resorption and bone deposition. Administration of extreme quantities of vitamin D causes resorption of bone. → Vitamin D in smaller quantities promotes bone calcification. One of the ways it promotes this calcification is to increase calcium and phosphate absorption from the intestines. However, even in the absence of such an increase, it enhances the mineralization of bone. Here again, the mechanism of the effect is unclear. → so, it is complex... it can do both... depends on the dose Study this picture very well: PTH is principally responsible for controlling Ca homeostasis because the actions of vitamin D are too sluggish for it to contribute substantially to the minute-to-minute regulation of plasma Ca21 concentration. However, both PTH and vitamin D are essential to Ca balance, the process ensuring that, over the long term, dietary Ca input into the body is equivalent to Ca output in the urine. When dietary Ca21 intake is reduced, the resultant transient fall in plasma Ca level stimulates PTH secretion. The increased PTH has two effects important for maintaining Ca balance: (1) It stimulates Ca reabsorption by the kidneys, thereby decreasing Ca output; (2) it activates vitamin D, which increases the efficiency of uptake of ingested Ca. Because PTH also promotes bone resorption, a substantial loss of bone minerals occurs if Ca intake is reduced for a prolonged period, even though bone is not directly involved in maintaining Ca input and output in balance. The major consequence of vitamin D deficiency is impaired intestinal absorption of calcium→hypocalcemia → stimulation to parathyroid hormone → PTH effected go to the bone → get Ca. PTH maintains the plasma Ca level at the expense of the bones. As a result, the bone matrix is not properly mineralized. The demineralized bones become soft and deformed, bowing under the pressures of weight bearing, especially in children. This condition is known as rickets in children and osteomalacia in adults. The plasma calcium concentration in rickets is only slightly depressed, but the level of phosphate is greatly depressed. Why? This is because the parathyroid glands prevent the calcium level from falling by promoting bone absorption every time the calcium level begins to fall. However, there is no good regulatory system for preventing a falling level of phosphate, and the increased parathyroid activity actually increases the excretion of phosphates in the urine. ‫اليأس يو ِهنُها قواها‬ ‫وصار‬ ‫للنفس إنْ فقدَتْ رجاها‬ ‫وقل‬ ِ َ ُ ‫مِ ن الدنيا وخالقُها كفاه‬ ‫ كم خافتْ نفوس‬،ِ‫ثقي باهلل‬ 13 Omar wawi Ruba shkokani Fatima daoud In our previous lecture, we discussed the thyroid gland—its structure, hormones, functions, and how it’s regulated. Today, we’ll go deeper into the various Thyroid Gland Disorders. Thyroid Gland Disorders General definitions: Hyperthyroidism: A disease associated with elevated levels of thyroid hormones compared to normal levels. Hypothyroidism: A disease associated with reduced levels of thyroid hormones compared to normal levels. Signs and symptoms: Hyperthyroidism Goiter(1) Tachycardia(2) Diarrhea(3) Weight loss despite increase in appetite Heat intolerance(4) Anxiety, irritability(5) Fast, fine tremor (muscles) Hypothyroidism Goiter(1) Bradycardia(2) Constipation(3) Weight gain Cold intolerance(4) Mental impairment, depression, lethargy(5) Atherosclerosis(6) discussing some signs and symptoms: (1)-Goiter: refers to an enlargement of the thyroid gland that is visible to the eye (often resulting in a visibly enlarged neck). -It is not exclusively associated with hyperthyroidism; it can also occur in cases of hypothyroidism. (2)-Tachycardia (in hyperthyroidism) and bradycardia (in hypothyroidism): Thyroid hormones have two distinct effects on cardiac cells: -Sympathomimetic effect: They mimic the action of the sympathetic nervous system, leading to increased heart rate (tachycardia). -Permissive effect: means the presence of one hormone is essential for another hormone to fully exert its effects on a target cell. -Thyroid hormones enhance the responsiveness of cardiac cells to catecholamines (such as epinephrine and norepinephrine) by increasing their receptors (Permissive effect). (3)-diarrhea and constipation: (4)-heat intolerance and cold intolerance: in hyperthyroidism there will be a vey high metabolic processes and high production of energy and heat which cause heat intolerance and vice versa in cold intolerance in hypothyroidism. (5)- Anxiety, irritability and Mental impairment, depression, lethargy: represent effects of thyroid hormones on CNS -Thyroid hormone have two main roles on CNS: A-In children for neural development. B-In adults to maintain function of neural activity. (6)-atherosclerosis (in hypothyroidism): decreased thyroid secretion greatly increases the plasma concentrations of cholesterol, phospholipids, and triglycerides and almost always causes excessive deposition of fat in the liver as well. The large increase in circulating plasma cholesterol in prolonged hypothyroidism is often associated with severe atherosclerosis. Hyperthyroidism -Graves’ disease, ( is an autoimmune disease: our immune system doesn’t recognize our self-antigen ),is the most common form of hyperthyroidism, in which antibodies called Thyroid-Stimulating Immunoglobulins (TSIs) form against the TSH receptors in the thyroid gland and These TSIs mimic the action of TSH by binding to the same membrane receptors ,As a result, the thyroid gland is continuously activated, leading to excessive production of thyroid hormones (T3 and T4). - T3 and T4 levels increase due to the TSI activity. - TSH levels decrease as a negative feedback mechanism, as the elevated thyroid hormones signal the pituitary gland to reduce TSH production. The symptoms of hyperthyroidism are obvious from the preceding discussion of the physiology of the thyroid hormones: (1) a high state of excitability, (2) intolerance to heat, (3) increased sweating, (4) mild to extreme weight loss (sometimes as much as 100 pounds), (5) varying degrees of diarrhea, (6) muscle weakness, (7) nervousness or other psychic disorders, (8) extreme fatigue but inability to sleep, and (9) tremor of the hands (the doctor said not to care about the treatment 😊) -treatment: may include surgical removal of part or all of the thyroid gland (thyroidectomy), or the use of radioactive iodine (131l) to selectively destroy thyroid tissue, and the use of antithyroid drugs to block synthesis of thyroid hormones Hypothyroidism -Hashimoto disease, the most common form of hypothyroidism (also autoimmune disease) in which Thyroid peroxidase antibody and the anti-thyroglobulin antibody encounter peroxidase and thyroglobulin within the thyroid gland, and these antibodies are commonly used to detect the presence of Hashimoto's thyroiditis. -T3 and T4 levels decrease due to the autoimmune attack on the thyroid gland. -TSH levels increase as a negative feedback mechanism, as the pituitary gland tries to stimulate the thyroid to produce more hormones. The symptoms of Hypothyroidism: They include fatigue and extreme somnolence, with persons sleeping up to 12 to 14 hours a day, extreme muscular sluggishness, a slowed heart rate, decreased cardiac output, decreased blood volume, sometimes increased body weight, constipation, mental sluggishness, failure of many trophic functions in the body as evidenced by depressed growth of hair and scaliness of the skin, development of a froglike, husky voice, and, in severe cases, development of an edematous appearance throughout the body called myxedema. -treatment: thyroxine(T4) Endemic Colloid Goiter Caused by: Dietary Iodide Deficiency The thyroid gland produces thyroid hormones in the presence of iodine so :  Lack of iodine prevents production of both thyroxine and triiodothyronine by the thyroid gland  As a result, no hormone is available to inhibit production of TSH by the anterior pituitary.  This causes the pituitary to secrete excessively large quantities of TSH.  The TSH (tropic hormone) then stimulates the thyroid cells to secrete tremendous amounts of thyroglobulin colloid into the follicles, and the gland grows larger and larger.  But because of lack of iodine, thyroxine and triiodothyronine production does not occur in the thyroglobulin molecule and therefore does not cause the normal suppression of TSH production by the anterior pituitary.  The follicles become tremendous in size, and the thyroid gland may increase to 10 to 20 times’ normal size  Treatment: iodide supplement Cretinism Extreme hypothyroidism during fetal life, infancy, or childhood. Characterized by failure of body growth and by mental retardation. Thyroid hormone is essential for growth but is not itself directly responsible for promoting growth. It plays a permissive role in skeletal growth; the actions of GH fully manifest only when enough thyroid hormone is present. As a result, growth is severely stunted in hypothyroid children, but hypersecretion of thyroid hormone does not cause excessive growth. It results from congenital lack of a thyroid gland (congenital cretinism), from failure of the thyroid gland to produce thyroid hormone because of a genetic defect of the gland, or from iodine lack in the diet (endemic cretinism). The neonate’s movements become sluggish and both physical and mental growth begin to be greatly retarded. Obese, stocky, and short appearance. Occasionally the tongue becomes so large in relation to the skeletal growth that it obstructs swallowing and breathing, inducing a characteristic guttural breathing that sometimes chokes the child. Treatment of the neonate with cretinism at any time with adequate iodine or thyroxine usually causes normal return of physical growth, but unless the cretinism is treated within a few weeks after birth, mental growth remains permanently retarded Adrenal Glands Ad=supra, Renal=kidney so it’s located superior to the kidney During embryonic development, the adrenal glands differentiate into two structurally and functionally distinct regions: a large, peripherally located adrenal cortex, and a small, centrally located adrenal medulla (The adrenal medulla produces three catecholamine hormones— norepinephrine, epinephrine, and a small amount of dopamine) -It is covered by connective tissue capsule 1-adrenal cortex(outer) 2- adrenal medulla (inner) 1- Adrenal cortex: peripherally located, comprising 80–90% of the gland, produces steroid hormones that are essential for life. Complete loss of adrenocortical hormones leads to death due to dehydration and electrolyte imbalances in a few days to a week, unless hormone replacement therapy begins promptly. its subdivided to three zones and they are responsible of producing adrenocortical hormones: (all synthesized from the steroid cholesterol) A-the zona glomerulosa, 15%–> The outer zone  mineralocorticoids  affect mineral homeostasis. (the most common is aldosterone) B-the zona fasciculata, 75% The middle zone (widest)  glucocorticoidsaffect glucose homeostasis. (the most common is cortisol) C-and the zona reticularis, 10% the inner zone adrenal androgens  steroid hormones that have masculinizing effects. D- medulla is responsible for production of epinephrine (mainly) and a little bit of norepinephrine. - they are all called corticoids because they are all steroids (lipid soluble), mineralocorticoids (ex: aldosterone ) is responsible for minerals(mainly Na + and K ) , glucocorticoids (ex: cortisol) will control glucose activity. -Some of these hormones have both glucocorticoid and mineralocorticoid activities due to their structural similarities. For example, cortisol, which primarily has glucocorticoid activity, also has some weak mineralocorticoid activity (because its structure similar to aldosterone). This is significant because some syndromes of excess cortisol secretion can cause significant mineralocorticoid effects, along with its much more potent glucocorticoid effects, Aldosterone’s mineralocorticoid activity is about 3000 times greater than that of cortisol All of the adrenocortical hormones synthesized from the steroid cholesterol and they are lipid soluble. All steroidogenic tissues first convert cholesterol to pregnenolone(intermediate), then modify this common core molecule by stepwise enzymatic reactions to produce active steroid hormones. -Each steroidogenic tissue has a complement of enzymes to produce one or several but not all steroid hormones. -Slight variations in structure confer different functional capabilities on the various adrenocortical hormones. -Because the adrenocortical hormones are all lipophilic and immediately diffuse through the plasma membrane of the steroidogenic cell into the blood after being synthesized, controlling the rate of synthesis regulates the rate of secretion. -Being lipophilic, the adrenocortical hormones are all carried in the blood extensively bound to plasma proteins. Cortisol is bound mostly to a plasma protein specific for it called corticosteroid-binding globulin (transcortin), whereas aldosterone and dehydroepiandrosterone are largely bound to albumin. Aldosterone(mineralocorticoid) -Produced from Zona glomerulosa - from mineralocorticoids family 1-The principal site of aldosterone action is on the distal and collecting tubules of the kidney, where it promotes Na retention and enhances K elimination (Regulates homeostasis). The promotion of Na retention by aldosterone then induces osmotic retention of H2O, expanding(increasing) the ECF volume (including the plasma volume) and blood pressure, which is important in the long-term regulation of blood pressure. 2-Promotes excretion of H+ in the urine; this removal of acids from the body can help prevent acidosis. 3- Mineralocorticoids are essential for life. Without aldosterone, a person rapidly dies from circulatory shock because of the marked fall in plasma volume caused by excessive losses of H2O-holding Na. Renin–Angiotensin–Aldosterone (RAA) 1- Stimuli that initiate the renin–angiotensin–aldosterone pathway include dehydration, Na+ deficiency, or hemorrhage. 2- These conditions cause a decrease in blood volume. 3- Decreased blood volume leads to decreased blood pressure. 4- Lowered blood pressure stimulates certain cells of the kidneys, called juxtaglomerular cells, to secrete the enzyme renin. 5- The level of renin in the blood increases. 6- Renin converts angiotensinogen, a plasma protein produced by the liver, into angiotensin I. 7- Blood containing increased levels of angiotensin I circulates in the body. 8- As blood flows through capillaries, particularly those of the lungs, the enzyme angiotensin-converting enzyme (ACE) converts angiotensin I into the hormone angiotensin II. 9- Blood level of angiotensin II increases. 10- Angiotensin II stimulates the adrenal cortex to secrete aldosterone. 11- Blood containing increased levels of aldosterone circulates to the kidneys. 12- In the kidneys, aldosterone increases the reabsorption of Na+, which in turn causes the reabsorption of water by osmosis (in the principal cells of the collecting tubules). As a result, less water is lost in the urine. Aldosterone also stimulates the kidneys to increase the secretion of K+ and H+ into the urine. 13- With increased water reabsorption by the kidneys, blood volume increases. 14- As blood volume increases, blood pressure increases to normal. 15- Angiotensin II also stimulates the contraction of smooth muscle in the walls of arterioles. The resulting vasoconstriction of the arterioles helps raise the blood pressure to normal. 16- Besides angiotensin II, an increase in the K+ concentration of blood (or interstitial fluid) is a second stimulator of aldosterone secretion Regulation of Aldosterone Secretion 1. An increase in the concentration of potassium ions in the extracellular fluid greatly enhances the secretion of aldosterone. 2. Similarly, an increase in the concentration of angiotensin II in the extracellular fluid also greatly enhances aldosterone secretion. 3. Conversely, an increase in the concentration of sodium ions in the extracellular fluid slightly reduces aldosterone secretion. 4. ACTH from the anterior pituitary gland is necessary for aldosterone secretion but has little effect in controlling the rate of secretion in most physiological condition -Of these factors, potassium ion concentration and the renin-angiotensin system(angiotensin II particularly ) are by far the most potent in regulating aldosterone secretion -In the case of ACTH, if even a small amount is secreted by the anterior pituitary gland, it is usually enough to permit the adrenal glands to secrete whatever amount of aldosterone is required, but total absence of ACTH can significantly reduce aldosterone secretion. Therefore, ACTH appears to play a “permissive” role(by stimulates growing and blood supply to adrenal gland) in regulation of aldosterone secretion. At all it has slight effect. )‫(يعني وجوده مهم جدا بس زيادته او نقصانه ما بأثر كثير‬ Cortisol(glucocorticoid) -Produced from Zona fasciculata Metabolic effects of cortisol: The overall effect of cortisol’s metabolic actions is to increase the concentration of blood glucose at the expense of protein and fat stores General effects: 1-increase blood glucose(same as GH) 2-increase blood fatty acids(same as GH) 3-increase blood amino acids(opposite to GH) Cortisol is considered one of the stress hormones. If the body doesn’t receive food (no carbs), there will be an increase in the level of cortisol to spare glucose for the brain(only uses carbs). This leads to an increase in the concentration of blood glucose at the expense of protein and fat stores, once we eat, the metabolism returns to normal. We conclude that cortisol shift away from protein and fat stores in favor of expanded carbohydrate stores and increased availability of blood glucose to protect the brain from malnutrition during the imposed fasting period. Lets discuss cortisol effects on each macromolecule: Carbohydrates -Stimulation of gluconeogenesis by the Liver using non carbohydrates substrates. (we need carbs so we don’t use it in glucose synthesis :) - It inhibits glucose uptake and use by many tissues, except the brain, thus sparing glucose for use by the brain. This is because the brain uses only carbohydrates for its metabolic processes (Decreased glucose utilization by all cells except brain). -As a result, elevated blood glucose concentration and named by “adrenal diabetes”. FATS -Promotes mobilization of fatty acids from adipose tissue(lipolysis). -This increases the concentration of free fatty acids in the plasma. -Increases utilization of fat for energy. -Important for long-term conservation of body glucose and glycogen. -When cortisol levels are excessively high, lipolysis occurs in some tissues. Simultaneously, and for unknown reason, fat is deposited in unusual areas such as the face, shoulders, and it can lead to central obesity(in abdomen). Protein -Reduction of the protein stores in essentially all body cells except those of the liver -Decreased protein synthesis, especially in (muscles and lymphoid tissues) and Increased catabolism of protein. -this result in Increased blood amino acids(part of it used for gluconeogenesis) -Diminished transport of amino acids into extrahepatic cells, and enhanced transport into hepatic cells(Liver), increases plasma proteins synthesis by the liver. -cortisol affects proteins by both promoting gluconeogenesis and stimulating the synthesis of plasma proteins simultaneously. -In the presence of great excesses of cortisol, the muscles can become so weak that the person cannot rise from the squatting position. And the immunity functions of the lymphoid tissue can be decreased to a small fraction of normal. Result: It stimulates protein degradation in many tissues, especially muscle. By breaking down a portion of muscle proteins into their constituent amino acids, cortisol increases the blood amino acid concentration. These mobilized amino acids are available for use in gluconeogenesis or wherever else they are needed, such as for repair of damaged tissue or synthesis of new cellular structures. Cortisol Is Important in Stress adaptation -stress could be mental, physical, or due to trauma , surgery etc. - Upon experiencing a stressor such as a fracture of the tibia and fibula, a rat’s adrenal cortex reacts rapidly. This reaction triggers an increasing in cortisol levels, which can increase up to six-fold within a span of 4 to 20 minutes. The rise in cortisol levels during stressful situations is a survival mechanism. It helps the body prioritize essential functions, such as maintaining glucose supply for the brain, degradation of proteins in muscles and using their amino acids for build proteins in site of injury which is crucial for the rat’s survival in dangerous situations.  A cortisol-induced shift away from protein and fat stores in favor of expanded carbohydrate stores and increased availability of blood glucose would help protect the brain from malnutrition during the imposed fasting period. Also, the amino acids liberated by protein degradation would provide a supply of building blocks for tissue repair if physical injury occurred ‫الـقدس مـعركة وتـلك بـشـائر‬ ‫فـي‬ ِ ‫ــنـصـر جــنــدهُ الــدي َّــا ُن‬ ‫بــالـعـز ي‬ ِ ُ. ‫فـجـرا غـاضبًا‬ ‫طـوفـانُ غــزة جــاء‬ ً ‫ وزُلـزلـت أركــا ُن‬،ُ‫ســقـط الـقـنـاع‬. ً ‫الـتـحرير تـصـه ُل بـهـجة‬ ‫ق‬ ُ ‫وبــنـاد‬ ِ ‫رس حــيـن ت ُـقيمه الـفرسا ُن‬ ِ ُ ‫بـالـع‬. ‫ـغير بـطـولـة‬ ُ ِ ‫األرض تــشـهـد ُ لـلـ ُم‬ ‫مـهـرهـا اإليــمـا ُن‬ ‫الــشـهـادة‬ ‫إن‬ ُ ‫سبحان هللا العظيم‬ ‫سبحان هللا وبحمده‬ THE END OF SHEET #13 15 Amer abuissa Dental student Dr. Fatima Daoud The last part of endocrine system, which is about glucose homeostasis, when we talk about glucose homeostasis we mainly talk about insulin and glucagon (acute regulation). ❖ Insulin, Glucagon, and Diabetes Mellitus So we have to zoom in to the pancreas which is composed of Endocrine(1-2%)+ exocrine. (99%). Scattered among the exocrine acini are 1–2 million tiny clusters of endocrine tissue called pancreatic islet or islets of Langerhans. Abundant capillaries serve both the exocrine and endocrine portions of the pancreas. The islets make up about 1% to 2% of the total pancreatic mass.. The islets of langerhans consist of different types of cells mainly: ▪ beta cells (60%)—> which is responsible for secretion of insulin. ▪ alpha cells (25%)—>which secrete glucagon. ▪ delta cells (10%) —> which secrete somatostatin. ▪ and the least percentage gamma or F cells—> secrete pancreatic polypeptide. o pancreatic polypeptide: a hormone that plays a possible role in reducing appetite and food intake. Remember: the somatostatin is GH inhibiting hormone from hypothalamus, this hormone has different site of production (in the pancreas), it mainly controls of the GI. ❖ Insulin Is a Hormone Associated with Energy Abundance The insulin usually secreted after the absorption( in the absorptive phase) , for example : after you eat, your body secretes insulin so it’s usually associated with energy abundance (high level of energy). ▪︎ The main effects of insulin are: has important effects on carbohydrate, fat, and protein metabolism. It lowers the blood levels of glucose, fatty acids, and amino acids and promotes their storage. As these nutrient molecules enter the blood during the absorptive state, insulin promotes their cellular uptake and conversion into glycogen, triglycerides, and protein, respectively. Excess carbohydrates will be stored as glycogen mainly in the liver and muscles. Excess carbohydrates are converted under the stimulus of insulin into fats and stored in the adipose tissue. Promotes amino acid uptake by cells and conversion of these amino acids into protein and Inhibits the breakdown of the proteins that are already in the cells. Insulin exerts its many effects by altering either transport of specific blood-borne nutrients into cells or activity of the enzymes involved in specific metabolic pathways. To accomplish its effects, in some instances insulin increases the activity of an enzyme, for example glycogen synthase, the enzyme that synthesizes glycogen from glucose molecules. In other cases, however, insulin decreases the activity of an enzyme, for example by inhibiting hormone-sensitive lipase, the enzyme that catalyses the breakdown of stored triglycerides back to free fatty acids and glycerol. Again... ❖ Metabolic effect of insulin ▪︎ The arrow number 1 —> increase the glucose uptake by muscle and adipose tissue, the adipose tissue would convert it to Fat and the muscles store it as glycogen. ○ What happens to the glucose level in plasma? Decrease. ▪︎ When you eat a meal which contain a fatty acid what happen to these fatty acids? In liver, utilization of energy which eventually give ketones, FA can be stored and converted to adipose tissue which decrease their level in the plasma. ▪︎ Uptake of the amino acids used to build up protein which also decrease their level in the plasma. The inhibition arrow of AA to the liver means inhibition of gluconeogenesis. The inhibition arrow of AA to leave the muscle is inhibition the degradation of proteins. ✓ When you eat a good meal , the body in a good well fed situation not a stress situation , so now you can use the sugar (glucose) as you wish , unlike GH or Cortisol which use the fat and spare the glucose for the brain , in the presence of insulin I have abundance of AA and of Free FA , but the glucose is used as the source of energy ,As we know the glucose should be maintained within a certain range so If we found a excess of glucose What should do about it ? Storage as glycogen in the liver or skeletal muscle or convert it to fat and store it in adipose tissue, If the meal contain fatty acids would I use them as a source of energy? No, I store them again in the adipose tissue, what about AA? We don’t need to use them as a source of energy, so these AA used to build up the protein, ✓ when the hormone builds up protein: Anabolic hormone (help in growth), so the GH and Insulin integrate in the growth process. ✓ Absorption of glucose in the digestive tract is rarely controlled by hormone. But what are the sources of glucose? ▪ Absorption of the digested glucose, No control over this process ▪ Gluconeogeneses. ▪ Glycogenlysis (breakdown of glycogen) Normally, no glucose is excreted with the urine, but for example in diabetes, and in case of hyperglycemia, the glucose level in the blood increase above certain limit, above the threshold of reabsorption it is filtered away with the urine this case is called (glucoseuria) which is a sign of diabetes. ▪︎The 2 yellow boxes can be controlled and regulated by hormones, the other 2 boxes can’t be controlled. ▪ only utilization or/and production which can be controlled. ❖ Effect of insulin on carbohydrate metabolis If I had a certain amount of glucose and its concentration is increasing the insulin level will increase dramatically which will: 1. increase the glucose uptake for storage and utilization as source of energy 2. increases glycogen storage in skeletal muscles and liver. 3. insulin inhibits glycogenolysis and gluconeogenesis. ✓ How does insulin increase the glucose uptake? By increasing the concentration of GLUT4 on the plasma membrane. ✓ GLUT’s: glucose transporter in body which are numbered from 1 to 14, the most important one is insulin dependent GLUT4. ✓ The GLUT4 is stored in vesicles intracellularly, upon the stimulation of insulin, GLUT4 is secreted by exocytosis, then the glucose can easily diffuse through these channels (from the extracellular to intracellular), GLUT4 is not always expressed on the cell membrane, only in the presence insulin where it exit from intracellular compartment to the cell membrane—>which increase the uptake of glucose. The GLUT4 exist in most of the tissues, but higher amounts in (Adipose tissue +muscles), to increase the uptake and storage. (This process is considered one of the mechanisms of glucose regulating the Carbohydrate metabolism by increasing the number of transporters, specially GLUT4) The 1. And 2. is done by increasing the GLUT4. ▪ Insulin exerts its many effects by altering either transport of specific blood-borne nutrients into cells or activity of the enzymes involved in specific metabolic pathways. 1. Insulin causes enhanced uptake of glucose from the blood by the liver cells. It does this by increasing the activity of the enzyme glucokinase, which is one of the enzymes that causes the initial phosphorylation of glucose after it diffuses into the liver cells. Once phosphorylated, the glucose is temporarily trapped inside the liver cells because phosphorylated glucose cannot diffuse back through the cell membrane. 4. Insulin also increases the activities of the enzymes that promote glycogen synthesis, including especially glycogen synthase, which is responsible for polymerisation of the monosaccharide units to form the glycogen molecules. 3. Insulin inactivates liver phosphorylase, the principal enzyme that causes liver glycogen to split into glucose. This prevents breakdown of the glycogen that has been stored in the liver cells. ✓ The insulin Increase the activity of glucokinase in the liver, which catalyze the phosphorylation of glucose to glucose-6-phosphate ( step 1 in the graph) which cause glucose Trapping )‫ (ما بقدر يطلع‬and at the same time the GLUT’s transport glucose into the cell for glucokinase to add the phosphate group which decrease the level of glucose and increase the level of glucose-6-phosphate intracellularly which form a gradient to keep the reaction going. ✓ The most important effect of insulin in the liver is to increase the glucokinase activity for phosphorylation. ✓ generally speaking if you want to summarize the mechanism of the insulin, think about the transporters and the process of inhibition or activation of a certain enzymes. ❖ Effect of insulin in fat metabolism Actions on Fat Insulin exerts multiple effects to lower blood fatty acids and promote triglyceride storage: 1. It enhances entry of fatty acids from the blood into adipose tissue cells. 2. It increases transport of glucose into adipose tissue cells by means of GLUT-4 recruitment. Glucose serves as a precursor for formation of fatty acids and glycerol, which are the raw materials for triglyceride synthesis (lipogenesis). 3. It inhibits lipolysis by inhibiting hormone-sensitive lipase. ❖ Effect of insulin on protein metabolism and on growth: Increase the protein (Anabolic) —> decrease the level of AA in plasma and this is why the insulin essential for the normal growth. -insulin promotes protein synthesis and storage. 1. insulin stimulates transport of many of the amino acids into the cells. 2. insulin increases the translation of messenger RNA, thus forming new proteins. 3. insulin also increases the rate of transcription of selected DNA genetic sequences. 4. insulin inhibits the catabolism of proteins. 5. in the liver, insulin depresses the rate of gluconeogenesis (no usage of amino acids) ▪ The collective result of these actions is a protein anabolic effect. For this reason, insulin is essential for normal growth. -The insulin work fast enough in AA uptake, but in building up of protein the mechanism is slow. Insulin and growth hormone interact synergistically to promote growth: In this graph we have an animal that has neither pancreas nor AP. Therefore, no GH no insulin. administration of GH alone will cause slight increase in Growth. Administration of insulin alone will cause slight increase in the Growth in comparison to the base line. Together—> dramatic increase in growt