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The endocrine system Chapter Readings Chapters 74-77; Chapter 79 pgs 979-980; 985-992 Lecture outline I. Overview of basic hormone action A. Receptors B. Fate of hormones II. Hormone classification A. Steroid 1. Characteristics 2. Mode of action B. Protein/peptide/amines 1. Characteristics 2. Examples of amines 3. Mode of action 2 “Trigger” mechanisms for hormone release A. Neural B. Humoral C. Hormonal –H-P-X axis 1. Review of H-P relationship a. Hormones of anterior pituitary b. Hormones “from” the posterior pituitary c. Hypothalamic-hypophyseal connections IV. H-P-T axis A. Negative Feedback mechanisms B. Negative feedback at ALL levels C. Disruption of pathway—what happens to hormone levels? III. 3 V. Thyroid Gland A. Microscopic structure/follicles B. Synthesis of TH C. Actions of TH D. Disorders of the thyroid gland 1.Diagnosing the problem 2. Hyperthyroidism 3. Hypothyroidism E. Review of thyroid pathology 4 VI. VII. VIII. Adrenal glands- H-P-A- axis A. Anatomical review B. Adrenal cortex 1. Glucocorticoids 2. Mineralcorticoids a. Aldosterone (TBC- unit 4) C. Corticosterone follows HPA axis neg. feedback control D. Effects of corticosterone E. Pathophysiology of HPA 1. Deficiencies a. Addison’s- primary adrenal insufficiency b. Secondary adrenal insufficiency (pit. problem) 2. Excess a. Cushing’s disease (Pit is problem) b. Cushing’s syndrome (ectopic tumor/iatrogenic) i. Primary hyperadrenalism (tumor on adrenal glands) 3. CAH- excess and deficiency Growth Hormone Parathyroid Hormone/ calcium regulation 5 • The endocrine system is a series of glands that release a hormone into the plasma, where it is dissolved and transported throughout entire body within 60 seconds. Every cell is exposed to the hormone, but not every cell responds to it. The cell must have a functional hormone receptor. A cell that responds will do so in various ways. The cells in the heart, pancreas, and brain respond to epinephrine differently. One thing that always happens is that a cell will change its physiology in response to a hormone. It will do something different, depending on the genes of the cell in that organ. 6 • Hormones can be synergistic; aldosterone and ADH both help increase volume of fluid in body. Some hormones are antagonists; Atrial natriuretic peptide (ANP, produced by heart cells) is the opposite of ADH, and makes you urinate more. Some hormones are permissive; you need one around in order for a second to do its job well. Thyroid hormone is permissive for growth hormone. Not enough thyroid hormone can cause stunted growth, even if enough growth hormone is present. 7 Basic hormone action – Made by the gland’s cells, possibly stored, then released – Circulate throughout the body vasculature, fluids • Basic hormone action – Influences only specific tissues: –target Circulate throughout the body cells that have receptor for in blood vessels hormone only specific tissues – –A Influences hormone can have different effects on different target cells: – target cells that have depends onfor thehormone receptor receptor – –Effects dependcan on the A hormone have different preprogrammed response the effects on different targetofcells target cells- hormones are merely –molecular Effects depend on the “triggers” preprogrammed of – Some hormones areresponse “permissive” cellshormones forthe thetarget actions of another (T3 forare GH) molecular “triggers” Ultimatemerely goal: alter cell activity by altering protein activity through gene expression or through altering phosphorylation Hormones What would happen if there was a defect in the gene code for a particular hormone, or a defect in the cell’s machinery to make the hormone? http://www.megalo-media.com/art/ccolor3.html • 8 • A target cell is only a target cell if it is has a functional receptor (a protein). At home, you may watch TV with either a cable or satellite dish. Satellite waves are exposed to those homes with cable, but only those with dishes receive the signal. The target cell’s receptor serves to transduce (convert) the signal into a response. Receptors are proteins, which can be inside the cell or on its membrane. What would happen if there were a gene defect in the DNA code for a receptor? The receptor becomes faulty. The receptor will also not function properly if the cell is exposed to excess salt, heat, or pH. 9 What is a “receptor”? • It is a protein made by the target cell (protein synthesis, gene expression) • Inserted into plasma membrane, or found in cytoplasm or nucleoplasm • Active site “fits” the hormone • Acts to convert or “transduce” the signal into a response What would happen if there were a gene defect in the DNA code for a receptor? What would happen if the receptor protein was denatured? 10 • Endocrine glands secrete hormones into the plasma. Then, several different events could occur. It could bind to its receptor on the target cell, causing a change. Or, it could be destroyed by enzymes in the plasma. It could land in the kidneys and be filtered out before reaching its target. 11 What happens to a hormone once it’s secreted? Carrier-bound hormone Endocrine cell • • • • Degraded in bloodstream May be activated (e.g. T4) May be excreted by kidneys/ liver May reach a target cell and cause a cell response • May need carrier to reach target cell Free Hormone Hormone Degradation or removal Hormone receptor Biological effects 12 Classes of Hormone • • • • • • • Steroids (the only one that is hydrophobic) Amino Acid Derived Peptides (<100 AA) Proteins (>100 AA) The smallest categories are the AA derived and steroids. The largest categories are the peptides and proteins. Study Tip: You don’t have to memorize which hormones are in which category, just memorize those in the smallest category, and the rest are peptides and proteins. “DENTONE” stands for those in the short categories: DENT stands for the AA derived hormones: Dopamine, Epinephrine, Norepinephrine, and Thyroid hormone . “ONE” stands for hormones that end in “one”, such as testosterone, progesterone. They are all steroid derived. The only steroid hormone that does not end in “one” is estrogen. 13 Steroid hormones are synthesized from cholesterol, are lipids Hydrophobic, lipophilic Require a transport protein to be carried in bloodstream • Long lasting effects: dissolve in body fat stores, long “half life” • Can “go all the way” across cell and nuclear membranes to bind receptor • Act directly on gene transcription 14 Steroid Hormones • Steroid hormones are synthesized from cholesterol, are hydrophobic, and require a transport protein in plasma. They all have rings, which make it lipophylic (hydrophobic). Examples of steroid hormones are cortisol, aldosterone, testosterone, and estradiol. Steroid hormones have long-lasting effects, dissolve in body fat stores, and a long half life. Their receptor will be inside of cell since they are the only class of hormone that can get through cell membranes by themselves. A steroid receptor is usually all the way in the nucleus, although it may have a receptor in the cytoplasm, in which case, it will then continue on into the nucleus. How does it change the physiology of the cell? Steroid 15 hormones act directly on DNA (gene) transcription. • There is one other hormone (Thyroid hormone) that has its receptor all the way in the nucleus, yet it is not a steroid. Thyroid hormone is AA derived, but its side chain has a hydrophobic ring made out of two Tyrosine amino acids, making thyroid hormone hydrophobic as well. Thyroid hormone also effects DNA (gene) transcription. Thyroid hormone is AA derived, but it behaves like a steroid. Steroids effect the genes. 16 Figure 74-6; Guyton & Hall Steroid hormones and Thyroid Hormone • These use intracellular receptors • Steroid hormones enter cells, bind to cytoplasmic receptor and together, these enter nucleus to have direct effects on DNA transcription. Result: new cell proteins are made. • Thyroid hormone “goes all the way” to the nucleus, binds to nuclear receptor, and has direct effects on DNA transcription. Result: new cell proteins are made. 17 Protein/Peptide/AA-Derived Hormones (except Thyroid hormone) • Hydrophilic, don’t need a plasma protein carrier. Their receptors are not inside of cells, they are an integral protein that goes through the cell membrane. The hormone binds to the outside, signal is sent into the cell. A series of second messengers are involved in this signal transmission. Second messer systems are not the first chemical messenger (that is the hormone). There are three common ones: Cyclic ATP, IP3-DAG, and Enzyme-linked type. You will learn the details of these in the second unit. 18 • Second messengers change the physiology of a cell by this: a protein called a kinase is activated. The kinase adds phosphate groups onto the protein. This alters the protein’s activity, usually by supercharging it, like drinking 6-pack of Red Bull. Very efficient. Not all of them become supercharged, sometimes they are suppressed. When a protein is phosphorilated, its activity is changed. The cells activity will then change. All hormones have the same end result, it alters the physiology of the cell. 19 Protein/peptide/ Amine -based hormones • Hydrophilic/ lipophobic • May not require a transport protein, soluble in water (usually). • Must bind receptor on the target cell membrane and trigger second messengers to change physiology of target cell. • Exception is TH! Behaves like a steroid..... Figure 74-2; Guyton & Hall 20 Synthesis of Amine Hormones • Tyrosine can be turned into Dopamine, norepinephrine, epiniephron, and thyroid hormone. Norepi is primarily used as a neurotransmitter. It is also used as a hormone. Epi is primarily used as a hormone, but it can be used as a neurotransmitter. The diff between the two is a methyl group. They are similar in effect on a target cell. 21 Synthesis of Amine Hormones tyrosine hydroxylase Tyrosine L-Dopa dopa decarboxylase Dopaminergic Dopamine Neurons In hypothalamus dopamine hydroxylase Adrenergic Neurons in adrenal medulla Norepinephrine phenylethanolamineN-methyltransferase Epinephrine Adrenal Glands Thyroid Hormones Thyroid Gland 22 Signal Transduction systemsgive amplification These are just some examples! Scientists continue to discover more pathways 23 What triggers hormones to be released? HUMORAL NEURAL HORMONALH-P-X acis Insulin and glucagon 24 What triggers hormone release? There are three different mechanisms • Neuronal Trigger • The hormone is made in a neuron, is transported down the axon and stored in the synaptic knob. It is released from there into the bloodstream, where it is carried to the target cell. Examples are oxytocin, ADH, Epinephrine. 25 • Humoral Trigger • Something in the blood is being monitors, stimulates the relese of the hormone. Insulin, glucagon, parathyroid hormone. When you eat, glucose gets high, releases insulin. Glucose is low, glucagon released. Low calcium in blood for parathyroid gland, targets intestinal cells to absorb more calcium, and kidneys to reabsorb more ca, and stimulates osteoclasts to degrade bone matrix and ca goes into blood. 26 • Hormonal Trigger • One endocrine gland releases a hormone that stimulates another endocrine gland to release its hormone. 27 • • The hypothalamus is like a mom, her small child is like the pituitary gland, her older child doing homework is like the thyroid gland. None can move, only their messengers can take their message from one to the other. Mom sends the young child to tell the older one to get his homework done. She hears the young child passing the message, but after a while, the homework is not presented to her, so tension builds up in her, and she sends the messages more loudly until she is presented with the finished homework. 28 • This is what happens in the body. • Hypothalamus makes TSH-RH (thyroid stimulating hormone releasing hormone) • Pituitary makes TSH (thyroid stimulating hormone) • Thyroid gland makes TH (thyroid hormone) 29 • The hypothalamus releases its hormone (TSH-RH) to the pituitary, telling the pituitary to release its hormone (TSH), which tells the thyroid gland to release thyroid hormone (TH). When thyroid hormone is released, some of it will bind to receptors in the hypothalamus, and the hypothalamus will stop releasing TSH-RH. Until the receptors in the hypothalamus are bound with the resulting thyroid hormone, the hypothalamus is not satisfied that there is enough thyroid hormone present. The pituitary tells the hypothalamus that it sent its signal to the thyroid gland, so they hypothalamus is appeased for a while. But, until the target cell (thyroid gland) changes its physiology (releases thyroid hormone), the hypothalamus will continue to release its signal (TSH-RH). When Thyroid levels are high enough, it will turn off its signal. 30 Hypothalamic Control of Hormone Secretion Neural and hormonal control ACTH adrenocorticotropic H TSH thyroid-stimulating H GH growth hormone PRL prolactin FSH follicle-stimulating H LH luteinizing H MSH melanocyte-stimulating H Neural control hormonal 31 Hypothalamic Control of Hormone Secretion from the Adenohypophysis • • • Hypothalamus regulates secretion of hormones Almost always controlled by negative feedback loops – Blood concentration declines below a minimum • More hormone is secreted – Blood concentration exceeds maximum • Hormone production is halted Secreted like neurotransmitters from axon terminals – Secretes releasing factors to release hormones – Can also secrete inhibiting hormones to turn off secretion of hormones 32 What if the hypothalamus released its signal and the thyroid released too much hormone? • The hypothalamus will stop releasing its hormone. This is a negative feedback signal. • When very few TH receptors are bound on the hypothalamus, it will keep releasing its hormone. When its thyroid receptors are saturated, will stop. 33 • All cells respond to thyroid hormone, increasing their metabolic rate (more gene expression, heart speeds up, beats with greater force, etc). Too much thyroid hormone is hyperthyroidism; these people are thin and active. When levels of TH are too low, it is called hypothyroidism; these people are overweight, move slowly, have no energy. 34 • The posterior pituitary is an extension of the hypothalamus. The cell bodies of some neurons are in the hypothalamus, while their axons are within the posterior pituitary. • The adrenal gland releases epinephrine and some norepinephrine. The anterior pituitary makes 7 hormones that can be released after a signal by the hypothalamus. 35 Study Tip to remember the hormones secreted by the pituitary gland • “Melons grow and produce through late fall” stands for the hormones made in the anterior pituitary. • Melanocyte stimulating hormone (MSH) • MSH is created by a larger protein precursor, which also makes ACTH • Growth Hormone (GH). • Adrenal corticotropic Hormone (ACTH). • Prolactin (stimulates the production of breast milk) • Thyroid stimulating hormone (TSH) • Luteinizing Hormone (LH) • Follicle stimulating Hormone (FSH) 36 • For the anterior pituitary to release a hormone, it needs a hormone from the hypothalamus. If the hypothalamus releases GH-RH, then the pituitary will release GH. Some of the cells in the pituitary are somatotrops, some are corticotrops, some are thyrotrops. The somatotrops have receptors only for GH. They only respond to the one receptor they have. GN-RH is gonadotropic releasing hormone, which stimulated luteinizing and follicle stimulating hormones (LH and FSH). 37 • HPT axis is the pathway that goes from the hypothalamus to the pituitary gland, to the thyroid. • HPA axis is the pathway that goes from the hypothalamus to the pituitary gland, to the adrenal gland. • HPG axis is the pathway that that goes from the hypothalamus to the pituitary gland, to the gonads. • The other hormones go straight to their target 38 cells with no intermediate target. HPT Axis • • • • • • Neuronal cell body is in hypothalamus, and the axons go to posterior pituitary. Some synapse onto a blood vessel. Some of the capillaries continue to another capillary bed (two capillary beds connected by a vessel is called a portal system). The hypothalamus can release hormones into the bloodstream directly (humeral mechanism) or release hormones just to the pituitary (neuronal mechanism). If the signal goes to the second capillary bed, and if the cells there have a receptor for the hormone, the pituitary will release its hormone, which will be carried to all cells in body. Example: Hypothalamus anterior pituitary thyroid gland target cells. TSH-RH TSH TH NOTE: You have to have enough TH for GH to work; helps prevent gigantism. 39 • How many controls are there over the thyroid? Three: TH, TSH, TRH. • Thyroid hormone goes to all cells of the body, including the thyroid gland itself, as well as the pituitary and the hypothalamus. As it does so, the receptors are bound, inhibiting the release of more hormones. The last hormone released is the one with the most significant role in feedback. In this case, the last hormone released is thyroid hormone. Therefore, the presence of thyroid hormone is what will stop the hypothalamus from wanting more. This is negative feedback, which is what most hormones have. 40 • The one hormone that uses positive feedback is luteinizing hormone (LH). When LH is released, it stimulates the release of more LH, and more LH, until it reaches a maximum level, then negative feedback kicks in. 41 What if a gland disobeys the negative feedback? • • • • Example: Thyroid gland is impaired by a tumor. A thyroid tumor might cause it to over-secrete or under-secrete TH. Under-secreting thyroid tumor: what happens to the other hormone levels? Start with the problem area (in this case, the thyroid is the place with the tumor), and then evaluate the other glands. – TH will be low (hypothyroidism) – TSH-RH will be high, since only a few hypothalamus receptors are bound – TSH levels will be high. Over-secreting thyroid tumor: – TH will be high (hyperthyroidism) – TSH-RH will be low – TSH levels will be low. This combination tells you the source of the problem is the thyroid. 42 Example: Pituitary tumor • Under-secreting pituitary tumor (Start with the problem area, the pituitary) – TSH is low – TH is low (hypothyroidism) – TSH-RH is high • Over-secreting pituitary tumor – TSH is high – TH is high (hyperthyroidism) – TSH-RH is low • • NOTE: If the problem is the TSH, we don’t bother injecting TSH, we just give the hormone that is lacking: Thyroid hormone. 43 Example: Hypothalamic Tumor • Under-secreting hypothalmic tumor (Start with the problem area, the pituitary) – TSH-RH is low – TSH is low – TH is low (hypothyroidism) • Over-secreting hypothalamic tumor – TSH-RH is high – TSH is high – TH is high (hyperthyroidism) 44 • The adrenal cortex has the same cycle as thyroid hormone; it needs ACTH-RH (adrenalcorticotropic releasing hormone), ACTH, CH. • You always palpate the thyroid during a physical exam. If it is too large, it is called a goiter. But you cannot just look at it and say its hyperthyroidism; it might be hypothyroidism. You have to measure the 45 hormone levels. Maintaining homeostasis: Hypothalamohypophyseal-Thyroid Axis (HPT) Now let’s use negative feed back to understand the Controls over the thyroid and how these controls can be disrupted: Hypothalamus does not “know” when to stop secreting! Continued release of TRH unless it is signaled to slow down. KEY to ARROWS: Green= stimulates Red = inhibits Hypothalamus Thyrotropin releasing hormone, TRH Adenohypophysis (AnteriorPituitary) Thyroid stimulating hormone, TSH Thyroid Thyroid hormone, TH Target Cells = all body cells 46 Controls over the thyroid: Hypothalamus Thyrotropin releasing hormone, TRH Adenohypophysis Thyroid stimulating hormone, TSH Thyroid Thyroid hormone, TH KEY to ARROWS: Green= stimulates Red = inhibits Target Cells = all body cells 47 Controls over the thyroid: Hypothalamus Thyrotropin releasing hormone, TRH Adenohypophysis Thyroid stimulating hormone, TSH Thyroid Thyroid hormone, TH KEY to ARROWS: Green= stimulates Red = inhibits Target Cells = all body cells 48 Controls over the thyroid: Hypothalamus Thyrotropin releasing hormone, TRH Adenohypophysis Thyroid stimulating hormone, TSH Thyroid Thyroid hormone, TH KEY to ARROWS: Green= stimulates Red = inhibits Target Cells = all body cells 49 What happens to hormone levels when….. …when thyroid function is impaired by either too much or too little activity? Hypothalamus TRH Adenohypophysis TSH Thyroid TH Target Cells = all body cells 50 What happens to hormone levels when….. …when ant. Pituitary function is impaired by either too much or too little activity? Hypothalamus TRH Adenohypophysis TSH Thyroid TH Target Cells = all body cells 51 What happens to hormone levels when….. …when hypothalamic function is impaired by either too much or too little activity? Hypothalamus TRH Adenohypophysis TSH Thyroid TH Target Cells = all body cells 52 • The functional unit of the thyroid gland is the thyroid follicle. The cells making up the perimeter of the follicle are called follicular cells. They make and secrete the light purple liquid within the follicle, called colloid. Colloid is water, filled with a lot of protein called thyroglobulin, which is made by the follicular cells. Since thyroglobulin is a protein, there is a gene that codes for it. TSH is what stimulates the follicular cells to make thyroglobulin. TSH also increases the size of the follicular cells 53 to accommodate all this protein. • When thyroglobulin is made, it is exocytosed from the follicular cell and stored outside of the cell, in the follicle. As it moves across the cell membrane, a peroxidase enzyme attaches iodine to the tyrosine (amino acid) portion of the thyroglobulin. This process is iodination. After TSH stimulation, the follicular cells drink it back into the cell, and another enzyme comes along and chops up the long thyroglobulin protein into smaller pieces, each with some iodine on them. 54 • If a segment has two iodines, it is called T2. If there are 3 iodines attached, it is called T3 (Triiodothyronine). If it has 4 iodines it is T4 (thyroxine). The T3 and T4 are then released into the bloodstream. Those thyroglobulin segments that have only 1-2 iodines are recycled for parts and are not released. 55 • T4 is the most abundant form, but it is inert (inactive). T3 has robust activity in the cell. So, T3 gets used first by the body cells. T4 takes longer to be ready; one iodine has to drop off. As T3 is used up, T4 is being converted to more T3. Read page 938 in the book about what TSH does to the thyroid. • • To make thyroid hormone, you need iodine in your body. Iodized salt has enough to meet this need. Iodine is brought into the follicular cells, gene expression occurs, thyroglobulin is made. Without enough iodine in the diet, thyroid hormone cannot be made, no matter how much TSH is present. 56 Thyroid Gland, Chap 76 • Thyroid follicles- hollow structures surrounded by follicular and parafollicular cells • Follicular cells produce Thyroglobulin (TG)- large glycoprotein made by follicular cells (~3300 aa of which ~70 are tyrosine.) • Building block of TH, chemically attaching I- to tyrosine. • In plasma, TH needs a “carrier molecule” or it will be cleared from body Tyrosine: a bulky amino acid containing a large benzyl ring. 57 Thyroid Hormone Synthesis & Secretion • Link two tyrosine aa’s together and add iodine • Thyroid hormone (TH)- controls metabolic rate and protein synthesis – Thyroxine – T4 : (93%) – T3: triiodothyronine (7%); 4x as potent • Active form Figure 76-3 Chemistry of thyroxine and triiodothyronine formation. 58 •TG is booted out of the cell (exocytosis) and stored inside the hollow chamber of the follicle. “Colloid” •When follicular cells receive signal to secrete (TSH), they take up TG (endocytosis), cleave off the TH from TG, and secrete it into blood (exocytosis.) •Page 938- know what TSH does to the thyroid! Figure 76-2; Guyton & Hall PTU blocks the peroxidase and organification process. Pg 939 59 What are the “actions” of TH? Incr GI motility Incr mental and endocrine activity Promotes growth and brain dvlpmt in fetal life, and early postnatal life. Stim fat metab, lipid mobilization from fat stores Excites CNS (B-adrenergic stimulant), muscle activity Sleep difficulty Na/K+ ATPase activitythermogenic affect 60 • Know what would happen to the three hormone levels (TSH, TSH-RH, TH) in the following conditions: • Antibodies attacking thyroid gland, destroying the gland • Antibodies binding to the TSH receptor, stimulating it • Graves Disease • Hashimoto’s Thyroiditis 61 • The TS ratio is the amount of iodine in thyroid /iodine in serum. There are 30x more iodine ions in the thyroid gland than in the plasma. ATP is used to bring iodine into cells against its electrical gradient. 62 • A protease is an enzyme that chops up proteins. In the case of thyroglobulin, the protease cleaves it into T1 (called MIT), T2 (called DIT), T3, T4, or sometimes it creates a segment called R-T3, a mirror image of T3, which is inert, not used. MIT and DIT are also recycled, not used. 63 • If someone has excess TSH, thyroid will get larger, called a goiter. • You can have a goiter with decreased TH also. The cause of this is PTU (propyltriouracil), which inhibits TH production by blocking the peroxidase enzyme that joins the iodine to the tyrosine. It results in low thyroid hormone levels, and a goiter develops. 64 • What happens when TSH is released? Every step in the process of making TH is increased: Follicular cells become larger, more columnar. Metabolism increases: increase in O2 use (especially in mitochondria), a large sodium gradient is outside, and a large K gradient is inside, requires ATP to keep them from diffusing across their concentration gradients; this process generates heat. The NA-K ATP gene is expressed. There are sympathetic (beta) receptors in the heart that become stimulated. The heart increases in force of contraction and rate. 65 • TH also stimulates neurons; the person feels more alert, observing their environment with more interest. With not enough TH, they lose interest, become sluggish. When there is too much TH, they get muscles tremors, liver cleaves stored glycogen to increase blood glucose levels, gluconeogenesis increases in the liver, body cells grow. Remember, you need TH present for GH to work. TH is also important for brain development in fetal life. • We can measure hormones in the blood by radioimmunoassay (RIA) or ELISA (enzyme-linked immunosorbent assay). 66 Diagnosing the etiology of hypo/hyperthyroidism • Methods of measuring plasma concentration of hormones: – RIA (radioimmunoassay) – ELISA (enzyme-linked immunosorbent assay) • Sample a small amount of patient’s blood; to lab • Concentration: picomolar concentration 67 RIA • In a dish are antibodies against a hormone we want to measure. Before adding blood, add the hormone with a radioactive tag that can be recognized by those antibodies. It forms a complex; wash away the unreacted hormone. Then measure the radioactivity that is given off, this is the saturation point (the starting point). Now add the patient’s blood sample. If it has a lot of the hormone that is already attached, it will compete to push off the radioactive hormone, and the radioactive signal will drop proportionally. If the patient does not have much hormone, there is not much decrease in radioactivity. This is an inverse relationship. The RIA test is expensive and dangerous, so ELISA is preferred. 68 ELISA • • • Pregnancy test is an example of an ELISA test. On the strip are antibodies. If pregnant, a hormone binds to the receptor. When the strip gets wet, a second set of antibodies move over the pregnancy hormone. The substrate, when cleaved, precipitates out of solution; it gives you a color, and a new line appears, turning the negative into a plus sign. If no hormone is present, there is no second set of antibodies, the enzyme is not cleaved, no color change. Is she a little or a lot pregnant? Well, there is no in-between, so is this test not considered quantitative? Actually, it can be quantitative: Suppose she had sex only a few hours ago. The test would be negative, since it takes 7 days for zygote to implant into uterus, which is when hormone levels are high enough for detection. If she is 6 months pregnant, the response time is faster. Since the response time is faster in the presence of higher hormone levels, we can quantify the pregnancy also. The parasite chomping into uterine artery can cause bleeding, seems like a period. She may be shocked to find out she’s pregnant. 69 Hyperthyroidism (Most commonly caused by Graves Disease) • Signs include thinness, eyes that stick out like a bug (exophthalmoses). • Graves Disease is a person who has antibodies against TSI. These antibodies bind to thyroid gland, tricks it into making excess TH, while TSH-RH and TSH levels are decreased. You can also get hyperthyroidism from over-secreting tumors. 70 Disorders of the thyroid-- hyperthyroidism •Graves disease/ TSI •Tumor (hypothalamic/hypophyseal/thyroid) Hypothalamus _ TRH + Thyrotrope _ Figure 76-8 Patient with exophthalmic hyperthyroidism. Note protrusion of the eyes and retraction of the superior eyelids. The basal metabolic rate was +40. (Courtesy Dr. Leonard Posey.) TSI Draw the disrupted pathways! TSH + + Thyroid T3, T4 71 There are two ways to treat this disease • You can have the thyroid oblated (killed off) by drinking radioactive iodine; it kills just thyroid tissue. As metabolic rate slows, gains weight again. They set off Geiger counters for months afterwards. Then start on artificial thyroxin, need to figure out what their set point is for normal. • • The other way (not so good) is to have the thyroid gland surgically removed. However, the parathyroid glands are often damaged or removed during this surgery. They often intentionally leave some thyroid tissue behind, in hopes of leaving enough parathyroid glands there. If too many of the parathyroid glands are removed, calcium levels go down, can go into cardiac arrest. Now the patient has to have two hormones replaced. 72 Hypothyroidism This can be caused by • Hashimoto’s thyroiditis • Iodide deficiency • Tumor • Defective enzyme in thyroid. Know the difference between cretinism and congenital hypothyroidism. 73 Disorders of Thyroid • Hypothyroidism – Hashimoto’s thyroiditis – Iodide deficiency – Tumor (undersecreting) – Defective thyroid (enzyme problem) • Draw the disrupted pathway! • Goiter? • Thyromegaly-TSH stimulation leads to increased number and size of thyroid cells • Cretinism- mental defects due to maternal deficiency • Myxedema • Hashimoto’s and idiopathic hypothyroidism are similar in symptoms 74 Figure 76-9 Patient with myxedema. (Courtesy Dr. Herbert Langford.) Cretinism Goiter Cretinism (diminished mental ability) • This term describes babies whose MOTHER had the lack of iodine. Baby now cannot get iodine, and the baby will have reduced growth and intellectual ability. Once it is born and gets a healthy diet, it still won’t go back to normal because TH is necessary for proper myelination and synaptic formation. 75 Congenital hypothyroidism • Congenital hypothyroidism is the term for a baby whose thyroid gland is not working correctly, the problem is only with baby, not with the mom. Congenital hypothyroidism and cretin babies have similar symptoms. Child will stay tiny because GH does not work without TH. 76 Hashimoto’s thyroiditis • Hashimoto’s thyroiditis is an autoimmune disorder, where antibodies attack and destroy the thyroid gland, and TH goes down while TSH-RH and TSH are elevated. The healthy remaining thyroid tissue will enlarge. • Myxedema is non-pitting edema. Touch it, feels solid, and does not leave a fingerprint when you push on it. People with Hashimoto’s thyroiditis have depressed mental and emotional activity, may have psychosis, not in touch with reality, detached. They gain weight easily, are tired and sleep a lot. 77 Iodide deficiency • Iodide deficiency has decreased TH, other hormones increased. • Other things that cause hypothyroidism are defects in any parts of the gene expression of thyroglobulin in follicular cells; TH not released in proper amounts. 78 symptoms Symptom of Hyperthyroidism Affected molecule or system Symptom of hypothyroidism Decreased weight Increased BMR Mitochondrial enzymes Increased weight Decreased BMR Heat intolerance Na/K ATPase Cold intolerance Increased heart rate B1-adrenergic receptor Decreased heart rate Irritable Sympathetic B-adrenergic Sluggish (increased receptors somnolence) Exophthalamos TSI (thyroid stimulating immunoglobulin) __________ Goiter TSI or TSH goiter Myelin Decreased mental development Growth Hormone Decreased growth 79 A summary of disrupted Hormonal pathways Hyperthyroid (excess T4) TRH from over-secreting tumor in hypothalamus-leads to (increased downstream hormones) TSH from over-secreting tumor in pituitary- leads to decreased TRH but elevated TSH and TH TSI –Graves disease, autoimmune activator of the TSH receptor- leads to increased TH, but decreased TRH and TSH Hypothyroid (decreased T4) Nutritional iodine deficiency (leads to increased TRH and TSH) Defective thyroid •Iodide uptake •Peroxidase •Deiodinase • leads to elevated TRH and TSH Hashimoto’s Thyroiditis (autoimmune destruction) •Leads to Elevated TRH and TSH 80 Adrenal glands • They are neuronal and hormonal, like the pituitary. • Both adrenal medulla glands together weigh only one gram! The adrenal medulla is an extension of the nervous system. If the chromatin cells there are detached, they will differentiate into a neuron! The adrenal cortex suppresses the full development of the nervous system development of the adrenal medulla. The adrenal glands release catecholamines, such as norepinephrine, and especially epinephrine. These catecholamines are released when the sympathetic nervous system is activated (“fight or flight”). 81 Epinephrine is antagonistic to insulin • When you run from a predator, is that when you want insulin to take glucose from blood? No, you want to keep it there so the brain can get the glucose. The brain needs to think of a way to escape, and thinking burns glucose. Fatty acids are broken down as another source of ATP. Heart rate and force increases. Digestion slows, respiratory passages open, bronchiole dilation occurs. BP goes up from vasoconstriction in less needed organs. 82 • The bulk of the adrenal gland is the adrenal cortex. It has layers, from superficial to deep: “GFR” • G = Zona glomerulosa: makes aldosterone • F = Zona fasciculate: makes androgens and glucocorticoids (cortisol and corticosteroids) • R = Zona reticularis: makes androgens and glucocorticoids (cortisol and corticosteroids) • (Don’t confuse this pneumonic with GFR in the kidney, which stands for glomerular filtration rate) 83 The Adrenal Glands- chapter 77 • • Located on the superior surface of the kidneys Two endocrine glands in one (different embryological origin) – Adrenal medulla – a knot of sympathetic nervous tissue • Chromaffin cells – modified postganglionic sympathetic neurons • Secrete epinephrine (mostly). • Active in “fight, flight, and fright” response • Glycogen broken down to glucose for ATP production • Fats broken down to fatty acids for ATP production • Heart rate and force increases – Adrenal cortex – bulk of the adrenal gland 84 The Adrenal Cortex • Secretes a variety of hormones- all are steroids made from cholesterol and are grouped into two main classes: – Glucocorticoids • Cortisol – secreted in response to ACTH and stimulates fat and protein catabolism and gluconeogenesis. – Mineralocorticoids • Aldosterone Sodium/water reabsorbed and loss of potassium 85 Androgens- small amount but still important • In the Z. glomerulosa, aldosterone (a mineral corticoid) is released. It targets the cells of kidney, increases the amount of salt and water that is reabsorbed. The other two zonas make glucocorticoids and androgens. Glucocorticoids are cortisol and corticosteroids. 86 • Androgens (DHEA; Dehydroepiandrosterone), is a testosterone-like steroid hormone, but is not the primary hormone responsible for the male characteristics; testosterone from the testes does that. However, since females do not have testes, they are sensitive to androgens present in their body, and the androgens in females cause them to have pubic and axillary hair. If that part of the adrenal cortex hypersecretes androgens, it won’t impact a male, because the testes makes more than that already. However, in females, hypersecretion causes masculinization. 87 • Aldosterone • The Z. Glomerulosa makes aldosteone, but it does not follow a typical HPA axis; it is a humeral release mechanism. A few things trigger it, especially high potassium plasma levels. That signals the kidneys to reabsorb sodium, and water comes with it. But potassium is secreted and then excreted. Potassium is secreted by the cells of nephron, sodium and water are regained, and that increases blood volume. A2 is angiotensin 2 (studied more in unit 4); there is a blood plasma protein called angiotensinogen. Any word that ends in – ogen means they are zymogens, the proteins are released in an inactive form. When activated, cascade events occur. When the kidney detects BP is too low, it releases rennin, which cuts angiotensinogen into its active form. Here is the process: 88 • Angiotensinogen angiotensin 1, travels through blood and ends in pulmonary capillary bed, cells have angiotensin converting enzyme, cuts A1 into A2, stimulates adrenal cortex to make more aldosterone, and hypothalamus to release ADH. If BP drops, this cascades into events that lead to water and salt retention, blood volume and BP goes up. 89 Cholesterol ACTH CH3 C O K+, A II Hormone Pregnenolone Biosynthesis HO CH3 C O in the Zona Progesterone Glomerulosa O CH2OH O C 11-Deoxycorticosterone O CH2OH C O HO Corticosterone O + Aldosterone K , A II Synthase HO O CH3 HC C O Aldosterone Copyright © 2006 by Elsevier, Inc. O Aldosterone does not follow a typical HPA axis-it’s a humoral release mechanism 90 Hypothalamohypophyseal-Adrenal Axis (HPA) Hypothalamus _ CRH + _ Corticotrope ACTH + Adrenal Cortex Glucocorticoid s 91 • Potassium and A2 are humeral mech. • ACTH is released by pituitary, is part of APH pathway. ACTH is required for adrenal to release CTH, corticotropic hormone. Need ACTH to get the cholesterol to be processed into aldosterone. Need it to start the biochemical pathway, but if you raise ACTH, you do not get a matching increase in aldosterone; it goes up, but not proportionally. Aldosterone is a humeral mechanism. • The HPA axis is a classic pathway; the same rules apply as the TH pathway. CRH is released by the hypothalamus, pituitary releases ACTH, adrenal cortex 92 releases corticoids, effects almost all cells in body. Increase in glucocorticoids causes things: • • • • • • • Cortisol is called a stress hormone; it does several things: Cortisol stimulates protein and triglyceride catabolism Stimulates gluconeogenesis in the liver Inhibits glucose uptake by the body but not the brain It elevates blood glucose (diabetogenic effect) It inhibits non essential functions like reproduction and growth It suppresses the immune response, Inhibition of inflammation also • It is prescribed to suppress inflammation and the immune system. 93 Metabolic Effects of Cortisol Glycogen Glucose Protein Amino acids Glucose-P Glucose precursors Stimulate Muscle • • • • • • Inhibit Liver Glucose Free fatty acids + Glycerol Adipose tissue Plasma Glucose Free fatty acids Amino acids Stimulates protein and triglyceride catabolism Stimulates “gluconeogenesis” in liver Inhibition of glucose uptake by body (insulin antagonism) but not by brain. Elevates blood glucose levels, “diabetogenic effect.” Nervous system becomes primary user of glucose during stress. Inhibition of non-essential functions (reproduction; growth) Cortisol tames immune response Inhibition of inflammation and immune responses (pharmacologic doses used to suppress immune system.) 94 • The gene code you got from parents is different from theirs, but not a lot. But the expression of your genes can be very different because of how they lived their life. How much activity, smoking, and weight gain has gone on before puberty will damage stem cells, and can silence or activate a gene. The children of these people can have genetic differences because of this. 95 • Children exposed to severe physical abuse are more likely to commit suicide later; their DNA is methylated, causing a reduced number of glucocorticoid receptors. They cannot bind cortisol, cannot deal with stress like other people. If you don’t eat a lot, your children and grandchildren will live 30 years longer, and live healthier lives. 96 • Cortisol (also known as corticosterol and also known as hydrocortisone) • The hypothalamus portion of the HPA axis releases ACTH-RH, pituitary releases ACTH, adrenal gland releases cortisol. The adrenal gland also can release androgens, which also follow this classic HPA pathway. When the HPA axis is over-stimulated because of an intense need to make cortisol in response to stress, and if the body cannot keep up with the demand for cortisol, excess ACTH might be shunted into the androgen production pathway. 97 • What is “stress” that causes cortisol production? Stress can be emotional or physical. Examples of physical stress can range from fighting an infection to just a little paper cut that needs to remodel tissue. Cortisol tells tissues to stop using glucose (except brain), but will mobilize fatty acids to release energy for the other tissues. It tells the skeletal muscle to start breaking down actin, myosin, and other proteins to release the free amino acids into bloodstream. The liver takes in these free amino acids and fatty acids and converts them into new glucose molecules that you did not acquire from your food. Since these are new glucose molecules being formed, this process is called gluconeogenisis (“generation of new glucose”). The new glucose molecules are released back into the blood (blood glucose levels rise) so the other tissues can have some 98 energy. • If a person has a lot of cortisol or prednisone in their body, blood sugar levels rise too much, and sugar spills out in the urine. They have symptoms of diabetes, although that is not their disease. You have some cortisol in you now to help maintain blood glucose levels between meals, and glucocorticoids stimulate smooth muscle in the vasculature to maintain BP. • In high doses only, prednisone may be given for asthma because it suppresses smooth muscle from constricting, and bronchioles cannot close up. What would you predict their hormone levels to be? 99 • Makes you hungry to be on this med (prednisone), hard time sleeping because brain is stimulated. Stop to fast, like Addison’s disease. Cant maintain bp, blood glucose drops, can go to hospital. A person on high dose for 1 or more weeks must be tapered off. There are two ways to use them: high dose, short duration, and they don’t wean off, can stop cold turkey. Use them for longer, need to wean off. 100 • Hypothalamus will lower ACTH-RH, pituitary will lower ACTH, and endogenous levels of CTH (cortisol) from their own adrenal gland will be low. The person’s own HPA axis will be suppressed. You cannot suddenly stop the medicine because it will cause a crash; the body’s own ACTH and CTH levels are not high enough to maintain the blood pressure and blood glucose levels (like having Addison’s disease). Being on prednisone makes you hungry, and it stimulates the brain, so you have a hard time sleeping. A person on high dose for 1 or more weeks must be tapered off. There are two ways to use pharmaceutical glucocorticoids: high dose, short duration (don’t need to taper off the meds, can stop cold turkey), or use them for longer duration, and they will need to taper off. 101 Pathophysiology of the Adrenal Gland Deficiencies • Primary Adrenal Insufficiency: Addison’s Disease – primary hypoadrenalism; entire adrenal gland is destroyed due to atrophy or autoimmune disorder – Tuberculosis –disease attacks adrenal gland – ACTH is increased (map the pathway!) • Secondary adrenal insufficiency – deficiency of ACTH – Rapid withdrawal of pharmacologic doses of cortisol • Signs/symptoms: Water/salt imbalance, plasma volume depletion, low blood glucose, pigmentation, Addisonian crisis http://www-clinpharm.medschl.cam.ac.uk/pages/teaching/images/addisons.jpg DRAW THE PATHWAYS! 102 ADDISON’S DISEASE • Also called Primary Adrenal Insufficiency and hypoadrenalism; mainly see effects in the hands, fingers, and gums. Addison’s disease may be caused by anything that disturbs the production of adrenal hormones (for some reason, Tuberculosis attacks the adrenal glands as well as the lungs, and can cause hypoadrenalism). In Addison’s disease, the adrenal cortex does not respond to HPA orders. Cortisol (CTH) levels are low, but pituitary ACTH and hypothalamus ACTH-RH hormones are high. 103 • ACTH is a peptide (protein) hormone, synthesized from a larger protein called POM-C (Pro-opiomelanocortin). From the large POM-C protein, you cut out one segment, called ACTH, and another segment called MSH (melanocyte simulating hormone). When the ACTH levels increase but you still need more, PROM-C cleavage continues to occur, and more MSH is generated at the same time. When MSH is in excess, you get darker skin (hyperpigmentation). 104 • Symptoms of Addison’s disease are decreased glucose levels, a drop in blood pressure from water and salt imbalance, and darkening of the skin. Aldosterone is also not being made, so kidneys cannot absorb salt and water as well, blood volume and pressure decreases even more. 105 • In Secondary Adrenal Insufficiency, the problem is in pituitary; it is not secreting enough ACTH, maybe because of a tumor. Cortisol levels drop, but hypothamus ACTH-RH increases. A person can also get secondary hypoadrenalism from rapid withdrawal of cortisol meds. Symptoms are the same as for primary adrenal insufficiency, except blood tests show that pituitary ACTH levels are low, adrenal hormones are low, and hypothalamus ACTHRH is high. 106 CUSHING’S DISEASE • Excess ACTH caused only by a pituitary tumor. Patient has excess cortisone, high blood pressure, high blood glucose, and too much aldosterone is produced. More salt and water is reabsorbed by the kidney, so the blood volume increases. In this disorder, the hypothalamus (ACTH-RH) levels are low, the other hormone levels (ACTH, cortisol, androgens, and aldosterone) are high. 107 CUSHING’S SYNDROME (Andrenogenital Syndrome) • Excess cortisol secretion, but not caused by the pituitary gland. It could be caused by primary hyperadrenalism, an adrenal tumor, or even by a tumor in the lungs that releases ACTH (ectopic ACTH producing tumor). In this disease, all adrenal cortical hormones (cortisol, androgens, and aldosterone) are elevated, but ACTH-RH and ACTH levels are low. 108 Symptoms of Cushing’s Disease and Cushing’s Syndrome • Fat deposition around waist, scapula (buffalo hump), and “moon” shaped face. There is muscle loss and weakness (cortisol tells muscles to break down), thin skin with striae, (High levels of cortisol leads to destruction of collagen, get thin and striae on skin), hyperglycemia, immune suppression. Excessive amounts of adrenal stimulation causes release of male steroids, causing male secondary characteristics, but only in females. Adult onset disease in females causes masculinization, including facial hair, thicker jaw and skull. 109 https://courses.stu.qmul.ac.uk/smd/kb/resources/endocrinologyresource/syndromes/cushingssynd.htm Excessive Adrenal Hormones Cushing’s Disease- pituitary tumor (excess ACTCH) Cushing’s Syndrome •Ectopic ACTH producing tumor (lungs) Glucocorticoid therapy •Iatrogenic •Primary hyperadrenalism -Functioning adrenal tumor-, all adrenocortical hormones elevated; adrenogenital syndrome Signs/symptoms: buffalo hump, moon face, muscle loss/weakness, thin skin with striae, hyperglycemia, immune suppression 110 • Congenital adrenal hyperplasia (CAH) in a female fetus causes the clitoris to enlarge and the labia major fuse into a scrotal sac. These babies have a mutation in a gene, some enzyme is not expressed which is required to convert cholesterol into corticosteroids, so cholesterol is shunted to the pathway that is not compromised: androgen production. Boys are not affected; girls need a surgery and cortisol for life, will be fine. The most common gene mutation is 21 beta or 11 beta hydroxylase to covert progesterone to corticosterone. If the presence of ACTH is driving the pathway, and it is blocked at this enzyme, the ACTH can only be used to make androgens. 111 CAH- Excessive and Deficient? • Congenital Adrenal Hyperplasia (CAH) – Autosomal recessive trait (congenital) – Deficiency of any of the five enzymes necessary for cortisol production. – Increased ACTH (leads to adrenal hyperplasia) MAP IT! – Leads to overstimulation of adrenal androgen pathways. – Mineralcorticoids may be excessive or deficient (depends on enzyme affected). – Males seldom diagnosed at birth, females have virilization (enlarged clitoris, fused labia, etc). – With treatment, surgery, sex characteristics and fertility is normal http://www.dshs.state.tx.us/newborn/cah2.shtm 21 - Hydroxylase deficiency 11 - Hydroxylase deficiency 112 Hormone Biosynthesis in the Zona Fasiculata & Reticularis CH3 Cholesterol ACTH HO 3-Hydroxysteroid dehydrogenase C O CH3 17a-Hydroxylase (P450 c17) Pregnenolone C O OH 17-Hydroxypregnenolone HO CH3 CH3 C O C O OH O 17, 20 Lyase (P450 c17) HO Dehydroepiandrosterone O O O 21-Hydroxylase (P450 c21) Progesterone 17-Hydroxyprogesterone O CH2OH CH2OH C C O 11-Deoxycorticosterone O 11-Hydroxylase (P450 c11) CH2OH CH2OH C O HO HO O Corticosterone O OH 11-Deoxycortisol O C Androstenedione O O OH Cortisol 113 STUDY TIP • What hormones are antagonistic to insulin? – GH – Cortisol – Epinephrine 114 GROWTH HORMONE (SOMATOTROPIN) • GH needs TH to be present. GH stimulates all cells to increase protein synthesis, fat utilization, and gluconeogenisis, but there is a decline in body usage of glucose as energy. The person is diabetogenic, gigantism is the result of excess GH during pre-puberty and acromegaly is the result of excess GH after growth plates closed. The genetic determination of a person’s height has multiple genes involved, so parents might be tall and have smaller children. There are no rules to predict it. A child may also be small due to a defect in the placenta, blocking nutrients during development. 115 Growth Hormone- somatotropin Chapter 75 • Increased protein synthesis • Increased fat utilization • Increased gluconeogenesis but decline in body usage of glucose as energy • Diabetogenic • Excess leads to gigantism during prepuberty and acromegaly after growth plates are closed 116 PARATHYROID GLANDS • There are several of these glands, embedded in the thyroid gland on the posterior surface. The parathyroid glands are the ones that are the most responsible for maintaining blood calcium levels. They accomplish this by releasing parathyroid hormone, which stimulates osteoclasts to chew away bone, releasing the bone’s calcium into the bloodstream. The antagonist of parathyroid hormone is calcitonin, which is produced in the thyroid gland, and stimulates osteoblasts to take calcium from the blood and deposit it in bone. Parathyroid levels are released by a humeral mechanism. If blood calcium levels are low, parathyroid hormone is released. If blood calcium levels are high, parathyroid levels are low. 117 • There are three ways that the parathyroid gland raises blood calcium levels • Stimulates osteoclasts to move bone calcium into the bloodstream • Stimulates the intestines to absorb more calcium from diet • Stimulates the kidneys to stop excreting calcium 118 Hormonal Control of Calcium Metabolismchapter 79 PTH and Vit D Actions • Bone – resorption ( osteoclasts) • Kidney – Ca2+ reabsorption • Intestine – Ca2+ absorption Figure 79-9; Guyton & Hall Figure 51-10; Boron & Boulpaep Osteoclast Lysosome Osteoblasts Acid secretion Calcitonin? Osteocytes 119