Endocrine Physiology Exam Notes PDF

Principles of Endocrine Physiology 1. List the major endocrine glands, know their location within the body and recognize the primary actions of each. a. Hypothalamus i. Part of the brain; Controls pituitary endocrine secretions b. Pituitary i. Controls other endocrine glands + has direct effects on...

Principles of Endocrine Physiology 1. List the major endocrine glands, know their location within the body and recognize the primary actions of each. a. Hypothalamus i. Part of the brain; Controls pituitary endocrine secretions b. Pituitary i. Controls other endocrine glands + has direct effects on peripheral tissues ii. Hypothalamus + pituitary work together c. Pineal i. Circadian rhythm; Secretes melatonin d. Thyroid i. Controls metabolic rate, growth, and development e. Parathyroid i. Physically associated with thyroid, regulates calcium and phosphorus homeostasis f. Adrenal (cortex + medulla) i. Regulate metabolism, mineral balance, and stress responses g. Pancreatic islets of Langerhans i. Imbedded in exocrine pancreas; regulate metabolism and energy balance h. Ovaries & Testes i. Control maturation and development, sexual function, and pregnancy Examples of tissues w/secondary endocrine functions: 1. Adipose tissue: regulation of food intake (leptin) 2. Intestinal tract: control digestion and exocrine secretions (gastrin, secretin, CCK) 2. Recognize that individual hormones can have distinct effects in different tissues, and can coordinate multiple responses to a single stimulus. a. Coordinated multiple responses to a single stimulus i. Ex. central control of catecholamine output -> general sympathetic activation and epinephrine/norepinephrine both contribute to 1. Mobilization of glucose reserves 2. Changes in circulation 3. Increases in heart & respiratory rates 4. Increased energy use by all cells 3. Know the principle mechanisms of catecholamine signaling. a. Car accident example i. Saw/experienced car accident 1. Stimulate activation of adrenal medulla a. Secretes epinephrine + norepinephrine ii. This leads to changes in: 1. Changes in metabolism 2. Changes in circulation 3. Changes in cardiac activity 4. Changes in activation of energy utilization b. Mechanism i. Epi/NorEpi (Adrenaline/Noradrenaline) have overlapping affinities for the same receptors ii. Receptors 1. alpha-1 adrenergic receptors coupled to Gq 2. alpha -2 adrenergic receptors coupled to Gi 3. Beta adrenergic receptors coupled to Gs iii. Signaling pathways 1. Alpha-1 receptor/Gq protein a. IP3-Ca2+ signaling system → associated with metabolic responses (specifically in liver) and regulation of vasculature b. Important in vascular contraction (vasoconstriction) + metabolic activation in a variety of tissues 2. Alpha-2 receptor/Gi protein a. Gi→ decreased cAMP→ inhibits neurotransmitter release (adenylyl cyclase) b. Vascular contraction 3. Beta receptor/Gs protein a. Coupled to Gs→ increases cAMP→ b. Activation of heart muscle contraction c. Vascular relaxation (coronary relaxation) d. Axon metabolism activation IMPORTANT: Different cells have different repertoires of receptors, and those receptors couple to different downstream signaling pathways that allows epinephrine and norepinephrine to do different things in different tissues. This has coordinated responses across the body. 4. Understand the mechanisms of peptide hormone synthesis and secretion a. Gene encodes them → transcribed (processed through splicing to create mRNA)→ translated (yields protein) → secretory pathway i. Stored and released when needed Secretion of hormones from secretory granules (peptide hormones, catecholamines, neurotransmitters, etc) 1. Hormone is stored in the granules 2. Trigger for release a. Another hormone b. Metabolite c. Some other chemical or physical signal 3. Once stimulus is received, it activates signaling pathway inside cell a. Most stimuli that lead to secretion of hormones are related to calcium or cAMP 4. Process involves recruitment of secretory granules to the plasma membrane involving association with cytoskeleton and translocation 5. Association with plasma membrane 6. Fusion and release of the hormones **most of the stimuli that elicit hormone secretion will often return on the further synthesis of what is stored in the granules** 5. Contrast the mechanisms and properties of hormones working through membrane receptors and intracellular receptors. a. Hormones that work through membrane receptors b. Hormones that bind to Intracellular receptors i. Lipophilic ii. Don’t dissolve well in aqueous phase, but they dissolve and pass through membrane relatively easily (not very water soluble) iii. Need another mechanism to be distributed in the blood 6. Understand the effects of serum hormone binding proteins on access of hormones to their sites of action, and on their storage and degradation. a. Plasma Binding proteins affect available free hormone concentration + degradation i. The endocrine cell secretes the hormone, the hormone is free in the blood (not very soluble) ii. The carriers (ex: albumin or specific binding globulins) bind that free hormone in the dynamic equilibrium iii. Depending on the affinity of the binding protein, there will be some relationship between free and bound hormone iv. The bound hormones are carried in the blood and can distribute to various parts of the blood stream/ interstitial fluids v. Simultaneously, the free hormone can interact with the hormone receptor vi. Free hormone determines how much activation of the receptor at the level of the cell, and that determines the biological effects vii. Note: the free hormone also determines the rate of degradation 1. Typically the hormones are excreted/metabolized viii. If we want to measure the amount of active hormone, we need to measure the total hormone + the relationship between the free and the bound hormone (ideally measure free hormone (not always possible) and then the bound + free to calculate free) b. Specific Binding globulins i. TBG ii. Helps thyroid hormones distribute throughout the blood c. Non-specific proteins i. albumin 7. Recognize how the active hormone concentration in blood is affected by both rates of release and elimination (half-life). a. Half life i. If we stop producing that hormone, how long will it take for it to decay to 50% of the level that it was at before b. c. Graph analysis i. Left red 1. In one minute, half of the hormone has disappeared IMPORTANT CONCEPT!! d. Half life is directly associated to the time it takes for the hormone to increase again e. Determines how quickly a hormone can turn on and off f. Left red (1 minute half life) i. The hormone was rapidly being turned over (being produced and broken down quickly), and when it stopped being produced, it rapidly disappeared ii. If the hormone begins to synthesize again at the same rate, the hormone will increase back to its steady state 8. Understand the dose-response curve for a hormone binding to its receptor, and recognize how this can be modified by down-regulation and desensitization. a. Dose response i. Maximum response 1. Largest response 2. If you add more hormone, nothing will happen ii. Sensitivity 1. EC50 (defines affinity of the receptor) a. Half-maximal response iii. Threshold 1. How much hormone to see significant effect b. Receptor Down-regulation i. If we decrease the maximum responsiveness, we decrease the amount of maximum response to the hormone c. Receptor Desensitization i. If we decrease the apparent affinity of the receptor for its hormone, the dose response curve is shifted to the right ii. You can still get to the maximum response with more hormone, but the cells are less responsive to the hormone d. These effects are often induced by prolonged exposure to hormone 9. Explain the principle of negative feedback control of hormone secretion. a. Negative feedback in the endocrine system i. Something initiates a process that leads to some product, and that product feeds back and inhibits the initiating process ii. Very important in homeostasis Example: glucagon increases plasma glucose, which in turn inhibits glucagon secretion by negative feedback. When glucose falls, negative feedback is released and glucagon secretion rises. Hypothalamus & Pituitary Gland Growth hormone/somatostatin questions problems: https://quizlet.com/_cla8q8?x=1jqt&i=ivb0k 1. Understand how the anatomy of the hypothalamus/pituitary gives rise to the functional regulation of pituitary hormone secretion by the hypothalamus a. Hypothalamus i. Part of the CNS ii. Acts as interface between the brain + endocrine system b. Pituitary gland i. Composed of distinct neural + endocrine tissues ii. Receives signals from the hypothalamus + secretes hormones that circulate to the rest of the body c. Modes of hypothalamic control over endocrine-system i. Anterior Pituitary (2 step process) 1. Secretory products are made in neurons in the hypothalamus and are released locally into the pituitary gland 2. These secretory products control endocrine cells in the anterior pituitary which are then secreted into general circulation ii. Posterior pituitary (direct process) 1. Neuroendocrine 2. Cell bodies in the hypothalamus synthesize and release endocrine product that are released directly into the blood iii. Direct innervation of other parts of the body 1. Ex: adrenal medulla is innervated directly by sympathetic output of hypothalamus, and this allows control of secretion of epinephrine and norepinephrine 2. Contrast the anterior and posterior pituitary lobes with respect to cell types, vascular supply, developmental, and innervation, and explain the distinct mechanisms of control of hormone secretion in the two lobes. a. Posterior Pituitary (neurohypophysis) i. Function 1. Neural in origin and contains axons that project directly from the hypothalamus to nerve terminals that release hormones into the blood b. Anterior Pituitary (adenohypophysis) i. Function 1. Contains endocrine cells regulated indirectly by neuroendocrine signals from the hypothalamus that are released in the median eminence 3. Describe the mechanism of action of hypothalamic releasing and inhibitory hormones on hormone secretion from the anterior pituitary. a. Anterior Pituitary i. Releasing hormones ii. 1. Act on plasma membrane receptors of specific pituitary endocrine cells to stimulate exocytosis of a hormone. They also stimulate synthesis of these pituitary hormones Inhibiting hormones 1. Reduce secretion and synthesis of pituitary hormones at their target cells iii. iv. Releasing hormones act on receptors on pituitary endocrine cells 4. Identify appropriate hypothalamic factors that control the secretion of each of the anterior pituitary hormones. a. Secrete regulatory hormones that control release of 2nd hormones from ant. pituitary i. TRH, GnRH, CRH, GHRH, Somatostatin, PIF/Dopamine 5. Know the principal hormones secreted by the anterior and posterior pituitary. a. Posterior Pituitary (adenohypophysis) i. Hormones 1. Vasopressin (ADH) a. plays key role in the regulation of body fluid volume by enhancing the retention of free water by the kidney b. Main function: Increases water intake c. Increased intake of water + increased retention of water dilute the ECF back to where we want it d. (negative feedback) → reduce osmolality → reduce vasopressin secretion 2. Oxytocin a. The primary role is to stimulate the ejection of milk from the lactating mammary gland. Also can stimulate contraction of the uterus b. Suckling stimulates oxytocin release through afferent sensory neuronal signals to hypothalamus c. In pregnancy, stimulated by afferent nerves that detect stretch of uterus/cervix→ increase uterine contraction ii. b. Anterior Pituitary (neurohypophysis) i. Hormones 1. Thyrotropin-Releasing Hormone (TRH) 2. Gonadotropin-Releasing Hormone (GnRH) 3. 4. 5. 6. Corticotropin-Releasing Hormone (CRH) Growth Hormone-Releasing Hormone (GHRH) Growth Hormone-Inhibiting Hormone (Somatostatin) Prolactin-Inhibiting Factor (PIF, Dopamine) 6. Diagram the negative feedback control of anterior pituitary hormone secretion. a. Negative Feedback i. This is an important mechanism of regulation of pituitary hormone release 7. Describe the regulation of secretion and the principle actions of growth hormone, oxytocin, and prolactin. a. Growth hormone i. Functions 1. Polypeptide hormone secreted by somatotroph cells of anterior pituitary 2. Plays a key role in the stimulation of growth and development in children 3. Plays a key role in regulating metabolism 4. Regulated by both positive (GH-RH) and inhibitory (somatostatin, GH-IH) factors from hypothalamus ii. iii. Many effects of growth hormones are mediated by a second hormone = somatomedin (IGF) [secreted by liver] Somatomedin (IGF) exerts negative feedback on GH (regulates amount of GH secretion) b. Prolactin (secreted by gonadotrophs) i. Polypeptide hormone, structurally related to GH ii. Stimulates breast development and milk production iii. Prolactin levels increase during pregnancy iv. Regulation 1. Predominantly through dopamine (PIF) which is an inhibiting hormone 8. Understand how excess secretion of growth hormone causes acromegaly and vasopressin (ADH) deficiency causes diabetes insipidus. a. Vasopressin deficiency → diabetes insipidus i. Disease/trauma can cause damage of neurons responsible for secretion vasopressin (ADH) ii. Failure to secrete vasopressin can cause excessive loss of water in urine iii. This leads to frequent urination + individual must drink large volumes of water iv. Treatment = long half life vasopressin analog (desmopressin) b. Acromegaly caused by growth hormone i. Caused by sustained hypersecretion of GH (usually from pituitary somatotroph tumor) ii. Changes 1. Widening of bones 2. Accumulation of excess soft tissue 3. Thickening of skin + hair growth 4. Enlarged hands/feet 5. Overdevelopment of muscles 6. Diabetes may also occur iii. Treatment 1. Surgery or somatostatin analogs List of pituitary hormones Thyroid Thyroid Practice questions: https://quizlet.com/_cla7jc?x=1qqt&i=ivb0k 1. Identify the steps in the biosynthesis, storage and secretion of triiodothyronine (T3) and thyroxine (T4) Steps summary: 1. Active transport of iodide in follicular cell 2. Thyroglobulin → colloid 3. Iodination → synthesis of T3/T4 a. (DIT +DIT = T4) b. (MIT + DIT = T3) 4. Coupling 5. Uptake of iodinated thyroglobulin 6. Proteolytic release of iodinated thyroglobulin 7. Release of T3/T4 a. Accumulation of iodide i. Active transport ii. Na+/iodide active transport = results of large amount of iodide in follicular cell iii. Facilitated diffusion = colloid/follicular b. Formation of precursor protein (thyroglobulin) i. Thyroglobulin is secreted into the colloid with thyroid peroxidase (TPO) c. Formation of T3/T4 on protein (iodination of tyrosine residues) i. TPO 1. Causes oxidation of iodide 2. Reactive iodine + allows reaction with tyrosine aromatic ring ii. Transfers 1 tyrosine head group to another 1. T4+ backbone of protein iii. Can generate either T3 or T4, but mostly T4 d. Reuptake of iodinated thyroglobulin/release of T3/T4 i. Iodinated thyroglobulin protein is endocytosed back into the follicular cell ii. Follicular cell endocytotic vesicles with colloid fuse with lysosomes iii. Proteolytic enzymes in lysosomes break down thyroglobulin and release the free amino acid 2. Understand iodine distribution and metabolism in the body, including the use of radioactive iodine. a. The body has a steady state of 20-50 mg (largely in the thyroid, ~25%) b. Most iodine is in the form if iodide (I-) c. Daily need ~ 150ug; typical US diet ~500 ug/day d. Normal thyroid uses ~120 ug/day, mostly used to synthesize T3 and T4 e. Unused iodine appears in urine f. Iodine insufficiency = hypothyroidism g. Radioactive Iodine i. Can be used to monitor thyroid function ii. Can be used to destroy the thyroid in cases of thyroid cancer and Grave’s disease 3. Explain the importance of thyroid hormone binding in blood on free and total thyroid levels. a. Plasma protein: thyroxine binding globulin (TBG) i. Most important ii. Very high affinity for T4, slightly lower for T3 b. Other binding hormones i. Transerythin ii. Albumin 4. Understand the significance of the conversion of T4 to T3 and reverse T3 (rT3) in non-thyroid tissues. a. Deiodinase acts on 5’ of T4 and generates T3 b. T3 is more potent than T4 (activation step + occurs in peripheral tissues) c. 5-deiodinase generates reverse T3 (inactivation step) i. Further inactivation by further deiodinases removes more iodines = inactive forms of thyroid hormones 5. Describe the factors that regulate the synthesis, storage, and release of thyroid hormones. a. Regulation i. Thyrotropin-releasing hormone (TRH) stimulates synthesis and secretion of TSH ii. Thyroid-stimulating hormone (TSH) is primary regulator of the thyroid gland 1. Increases synthesis and secretion of T3 & T4 iii. Negative feedback 1. T3/T4 inhibit the release of TRH and TSH 2. This maintains thyroid hormone levels 3. FREE T3 & T4 controls TRH & TSH iv. T3/T4 decreased → inhibition relieved and TRH/TSH secreted → more T3 &T4→ normalizes level v. TSH effects on thyroid 1. Increased release of preformed T3 & T4 2. Increased iodide uptake 3. Increased tyrosine iodination + coupling 4. Increased endocytosis of colloid 5. Increased thyroglobulin proteolysis 6. Increased follicular cell height vi. Temperature 1. Decreased temperature = stimulates TRH release = elevated TSH = more T3/T4 6. Describe the key actions of thyroid hormone on metabolism and development. a. Stimulation of basal metabolic rate i. Basic level of maintenance that allows our body to function ii. Boosts capacity for metabolism iii. Increases heat production by activating mitochondrial metabolism Thyroid hormones essential for growth and development 1. Enhance bone and epiphyseal closure 2. Stimulate growth hormone secretion 3. Brain development 4. Proper formation of the cochlea 7. Understand the causes and consequences of (a) oversecretion and (b) under-secretion of thyroid hormones, and their relationship to hyper- and hypothyroid diseases. a. Hypothyroidism in children (low thyroid hormone) i. Symptoms 1. Cretinism a. Severe physical and mental defects ii. Causes 1. Maternal iodine deficiency 2. Fetal congenital abnormalities of thyroid or pituitary/hypothalamus 3. Maternal antithyroid antibodies that cross the placenta and damage fetal thyroid gland b. Hypothyroidism in adults i. Symptoms 1. Low metabolic rate 2. Poor cold tolerance 3. drying/yellowing of skin 4. Thinning hair 5. Mental symptoms ii. Causes 1. Caused by direct disease or dysfunction of the thyroid gland 2. Iodine deficiency = enlargement of thyroid (goiter) iii. a. Iodine deficiency goiter Conditions 1. Iodine deficiency goiter 2. Hashimoto’s thyroiditis a. Autoimmune disorder that gradually destroy thyroid gand follicles and reduces production of T3/T4 b. Lymphocyte inflammation/infiltration c. Hyperthyroidism i. Symptoms 1. Increased BMR 2. Increased food intake 3. Weight loss 4. Heat-intolerance 5. Sweating 6. Nervousness ii. Causes/Conditions 1. Grave’s disease a. Caused by autoimmune antibodies that stimulate the TSH receptor leading to unregulated T3/T4 release b. Large inhibition of TRH/TSH 2. TSH-secreting pituitary tumor a. Results in excess T3/T4 + goiter Pancreas 1. Identify the major hormones secreted from the endocrine pancreas, relate them to their cells of origin, and describe their chemical nature. a. Pancreas i. Islets of langerhans 1. Beta cells a. Insulin 2. Alpha cells a. Glucagon 3. Delta cells a. Somatostatin b. Hormones i. Insulin 1. Reduces blood glucose 2. Regulated by plasma glucose a. As glucose increases, insulin secretion is stimulated (graph) 3. Synthesis/structure a. Exogenous insulin i. Only A & B chain, not C ii. If you measure C, it indicates beta cell function 4. Insulin Synthesis Steps a. Insulin is synthesized and stored in beta cells b. Preproinsulin is converted to proinsulin by the removal of the signal sequence c. Proinsulin folds and forms 2 disulfide bonds d. Proinsulin is cleaved to yield A+B chains of active insulin e. C-peptide released by proteolytic cleavage f. Insulin packaged in secretory vesicles in complex with zinc ii. Glucagon 1. Increases blood glucose 2. Stimulates glycogen breakdown in the liver 2. Explain the relationship between blood glucose concentrations and insulin secretion, and describe the mechanism by which glucose regulates the secretion of insulin. a. Insulin secretion is activated by glucose metabolism b. Beta cells i. Specific glucose transporter = GLUT2 ii. GLUT 2 has low affinity for glucose c. When ATP increase w/glucose, K+ channels close, voltage gated C2+ open, calcium drives secretion of insulin d. Mechanism of insulin activation i. GLUT 4 transporters e. Glucose transporters i. GLUT 2 1. B cell glucose sensor 2. Transport out of intestinal and renal epithelial cells ii. GLUT 4 1. insulin-stimulated glucose uptake 3. List the other principal factors that modulate insulin secretion. 4. Recognize the major target organs for insulin action, describe the key effects of insulin on each, and classify the consequent changes in metabolism. a. Liver i. Increases conversion of glucose to glycogen and stimulates glycolysis (a pathway of glucose to triglycerides) b. Adipose c. Muscle i. Increases AA acid uptake 5. Describe the control of glucagon secretion and list the principal factors that modulate it. a. Glucagon secretion is stimulated when blood glucose is low b. Regulation i. Glucose is main inhibitor 6. Identify the targets for glucagon and describe its principal actions. a. Glucagon is degraded by major target organ: LIVER i. Breaks down glycogen and increases gluconeogenesis 7. Explain how the interactions between insulin and glucagon control carbohydrate and fat metabolism. a. 8. Identify the other major hormones that participate in metabolic regulation. a. Somatostatin i. Produced in islets of langerhans ii. Suppresses secretion of hormones in pituitary gland, and suppresses insulin + glucose secretion b. Epinephrine/norepinephrine i. Increases glucose output from the liver ii. Activates lipolysis (TAG→ free fatty acids) iii. In muscle, it inhibits the action of insulin to stimulate glucose uptake c. Cortisol i. Stress hormone/ starvation ii. Stimulates the mobilization of amino acids (primarily from muscle) and their conversion to glucose (liver) iii. Inhibits the stimulation of glucose uptake by insulin iv. Hyperglycemic (increases blood glucose like glucagon) 1. Long term effect d. Leptin i. Released from adipose tissue (amount released is proportional to amount of adipose tissue) ii. Satiety (appetite) 9. Recognize disease states caused by (a) over-secretion, (b) under-secretion of insulin, or (c ) decreased sensitivity to insulin, and explain the principal symptoms of each a. Hypoglycemia (over secretion of insulin) i. Cause 1. Excess insulin due to improper self-administration b. Diabetes i. Diabetes Mellitus (DM) -Failure of effect of insulin 1. Type 1 (insulin dependent) a. Primary failure of insulin secretion by endocrine pancreas b. Loss of beta cells c. Early onset diabetes (<30) d. Treatment - external administration e. Ketoacidosis is common 2. Type 2 (non-insulin dependent) a. Loss of insulin sensitivity of receptors b. Later onset (>40) c. Patients are generally obese d. Treatments: sulfonylureas, metformin (acts on liver to increase glucose output) , and diet 3. Both a. Polyuria (excessive urine output) b. Polydipsia (excessive thirst) c. Polyphagia (excessive eating) d. Hyperglycemia e. Glucosuria (glucose in urine) ii. Diagnosis of diabetes mellitus 1. Glucose tolerance test 2. Measurement of average blood glucose levels using Hb1c Calcium and Parathyroid Calcium/Parathyroid practice questions: https://quizlet.com/_claocw?x=1jqt&i=ivb0k Good calcium/phosphate/vitamin D regulation explanation: https://www.youtube.com/watch?v=EEM0iRJNhU8 Overview: 1. 1,25-(OH)2D3 a. Steroid hormone derivative of vitamin D3 b. Enhances intestinal Ca2+ absorption 2. Parathyroid hormone (PTH) a. Elevates plasma Ca2+ by mobilizing Ca2+ from bone 3. Calcitonin a. Peptide hormone secreted by follicular cells of thyroid b. Antagonist of PTH, decreases plasma Ca2+ levels c. Inhibits bone resorption by osteoclasts 1. Explain the distribution of calcium and phosphate in the body, and understand the relationship between free and non-exchangeable calcium. a. Physiological roles of calcium i. Intracellular Ca2+ 1. Muscle contraction 2. Neuronal excitability 3. secretion ii. Calcium in plasma 1. Blood coagulation (clotting) 2. Cell-cell interactions (glue) a. Ca2+ in extracellular fluid iii. Calcium salts in bone and teeth 1. Structural integrity/strength 2. growth iv. Calcium in extracellular fluid 1. Free: 1.18 mM 2. Ca2+ bound to albumin and other serum proteins: 1.16 mM 3. Ca2+ complexed to HCO3-, citrate, etc. 4. Total: 2.50 mM v. Effect of pH on calcium binding 1. As pH increases, the carboxyl group binding sites become more fully deprotonated, and Ca2+ binding affinity increases (less free Ca2+) 2. Hyperventilation can lead to alkalosis = Ca2+ levels decrease vi. Calcium Regulation 1. Most of the calcium in the body is in the bone (~1 kg) 2. Turns over at around 500 mg/day 3. The body is not as good at taking up calcium in body (~300 mg/day) 4. Key: a. Uptake (from intestines) b. Recycling of bone calcium c. Calcium recovery (reabsorption) from kidney i. This means you lose very little Ca2+ from the body vii. Phosphorus Turnover 1. We don’t have phosphorus in our body, we have phosphate 2. We are more efficient at absorbing phosphate than calcium 3. Biggest reservoir for phosphate: bone (~½ kg of phosphorus) + also in peripheral tissues 4. Places where phosphate is being taken up a. Gut b. Recycling in bone c. Resorption in the kidneys 2. Describe the role of osteoblasts and osteoclasts in bone remodeling. a. Osteoblasts i. Bone-forming cells that secrete the bone protein matrix (osteoid, primary collagen) on which Ca2+ and PO4 precipitate to form the rigid hydroxyapatite structure b. Osteoclasts i. Responsible for bone resorption ii. Breaks down osteoid (collagen matrix) iii. Also associate with bone remodeling 1. Breaks down old bone, and then osteoblasts refill the area c. Osteocytes i. Mature bone cells enclosed with bone matrix d. Osteolysis i. Transfer of Ca2+ from bone canaliculi to the external surface of the bone 1. Liberation of Ca2+ into plasma ii. 3. Identify the sources and biosynthesis of vitamin D and the active derivative 1,25-Dihydroxycholecalciferol (1,25(OH2)D3) (calcitriol) a. Features i. Steroid hormone ii. Main hormone to increase calcium uptake from the gut b. Synthesis i. Location ii. Spontaneous conversion of 7-dehydrocholesterol → vitamin D iii. Vitamin D then goes through 2 hydroxylase reactions 1. Reaction 1: 25 hydroxylase a. Takes place in the liver 2. Reaction 2: 1-alpha hydroxylase a. Takes place in the kidneys b. Generates 1,25-(OH)2D3 3. Alternate pathway a. Generates 24,25 (OH)2D c. Vitamin D + hydroxy cholecalciferol i. Vitamin D sources 1. Ingested in the diet 2. Formed in the skin with action of UV light ii. Activation of vitamin D 1. Vitamin D is initially inactive, so it needs 1,25-(OH)2D3 2. Involves 2 step process with P450 hydroxylase enzymes in liver + kidney a. 1st hydrolysis reaction i. In liver ii. Yields 25-(OH)D3 b. 2nd hydrolysis reaction i. In kidney catalyzed by 1-alpha-hydroxylase ii. Yields 1,25-(OH)2D3 (active form) d. Regulation i. Primary regulation site: kidney 1. Through activity of 1-alpha-hydroxylase 2. 1,25-(OH)2D3 synthesis is stimulated by PTH 3. Low levels of plasma calcium + phosphate also activate 1,25-(OH)2D3 synthesis 4. Feedback inhibition by elevated levels of 1,25-(OH)2D3, which then favors formation of inactive 24,25 (OH)2D 4. List the target organs of 1,25(OH2)D3 and describe its effects on these. a. Intestinal transporters that allow us uptake calcium i. Calcium diffuses down gradient (passive) ii. Once in the enterocyte, calcium diffusions from apical membrane to basal lateral membrane (diffusion is enhanced by binding proteins) 1. At basal lateral membrane, there is ATP dependent Ca2+ pump 2. Na/Ca2+ exchanger b. Bone i. It enhances the effect of PTH on bone resorption c. Parathyroid gland i. 1,25-(OH)2D3 acts on parathyroid gland to reduce PTH synthesis 5. Name the origin and describe the regulation of parathyroid hormone (PTH) secretion a. Features i. Acute regulator of calcium 1. Main effect of PTH: to mobilize calcium ii. Synthesized and secreted by chief cells of the parathyroid gland iii. PTH release is under the control of plasma Ca2+ b. Ca2+ sensing receptor (CaR) i. High plasma Ca2+ activates CaR, which stimulates phospholipase C (PLC) to generate IP3 and DAG ii. When Calcium is high → PTH secretion inhibited iii. When cAMP is low→ suppresses PTH secretion c. Regulation i. 1,25-(OH)2D3 1. Inhibits PTH synthesis ii. epinephrine, histamine, dopamine 1. Stimulated PTH secretion 2. 6. List the target organs for PTH and describe the effects on these. a. RANKL differentiation + activation of osteoclasts i. PTH acts on osteoblasts to generate second signal (paracrine) = RANKL ii. This acts on RANK receptor iii. OPG binds to RANKL and suppresses effects of RANKL iv. Important: estrogen opposes effects of PTH 1. Inhibits RANKL and increases OPG 2. Lack of estrogen - osteoporosis b. Effects of PTH i. ii. Bone 1. PTH stimulates osteolysis Kidney 1. PTH stimulates calcium reabsorption 2. Inhibits phosphate reabsorption a. You are mobilizing a lot of phosphate (don’t have phosphate deficiency) b. Hyperphosphatemia 3. Increases synthesis of 1,25-(OH)2D3 4. 7. Name the origin, tissue targets, and action of calcitonin. a. Primary effect: reduce plasma Ca2+ b. Less critical than PTH and 1,25-(OH)2D3 c. Stimulated by elevated plasma Ca2+ d. Major mechanism i. Antagonize the effects of PTH on bone by inhibiting osteoclast-mediated bone resorption e. In kidney i. Calcitonin decreases reabsorption of BOTH calcium + phosphate → increased urinary excretion of these ions f. Opposes effects of PTH 8. Explain the coordinated regulation of calcium, and phosphate by PTH, vitamin D and calcitonin. a. Calcium i. Decreased Ca2+ b. ii. 1. Increased Ca2+ c. 9. Recognize the consequences of abnormalities of PTH secretion and of vitamin D deficiency. a. Hypocalcemic tetany i. Low extracellular Ca2+ b. Osteoporosis i. Due primarily to estrogen deficiency ii. Not enough exercise c. Vitamin D deficiency i. Rickets 1. Failure to properly remineralize bones d. Primary hyperparathyroidism i. Excess PTH secretion → hypercalcemia e. Secondary hyperparathyroidism i. Results from chronic hypocalcemia 1. renal failure a. Excrete more Ca2+ than you should 2. High PTH ii. Bone resorption becomes significant issue f. Primary hypoparathyroidism (gland issue) i. Results from inadvertent removal of parathyroid glands during thyroid surgery ii. Low levels of PTH, hypocalcemia, and hyperphosphatemia 10. Histology bone review from videos a. Bone tissue i. Cortical bone (hard) 1. Osteon a. Composed of concentric lamellae i. Osteocytes are distributed throughout b. At center of osteon, there is canal ii. Trabecular bone (spongy) 1. Resists compression 2. Osteocytes are contained here a. Sense local changes in strength b. Osteoblasts +Osteoclasts i. Osteoblasts ii. iii. 1. Derived from cells associated with blood vessels a. Produces osteoid (made primarily of collagen) Osteoclasts 1. Monocyte derived (from bone marrow) Bone mineral density can assess strength of bone NOTE: For Dr. Beuve, I recommend that you look at her outlines that she provided!! Adrenal Cortex Overview: Major hormones of adrenal cortex (steroid hormones) 1. Cortisol a. Glucocorticoid b. Main function: increase the plasma glucose level i. Cortisol is able to do this by blocking GLUT4 2. Aldosterone a. Mineralocorticoid b. Main function: salt regulation (retention) + potassium release 1. Describe the synthesis and transport of corticoid hormones in general, and of cortisol and aldosterone, in particular a. Biosynthetic Pathways i. Cortisol synthesis 1. glucocorticoid ii. Aldosterone synthesis 1. Mineralocorticoid b. c. Zona glomerulosa i. Produces aldosterone 1. Only produces aldosterone since it doesn’t express a high level of the 17𝜶-hydroxylase (enzyme) d. Zona fasciculata i. Cortisol + androgens 1. The zona fasciculata doesn’t produce aldosterone synthase e. Zona reticularis i. Synthesis of androgens 1. Zona reticularis doesn’t express the 11β-hydroxylase f. Release + transport i. Cortisol 1. 90% transported by B 2. Less than 5% free; half life of 60-90 min (long) ii. Aldosterone 1. 50% bound wi3th low affinity to albumin (and CBG) 2. Half life: 20 mins (shorter) 2. Understand the molecular mechanism of action of cortisol (a glucocorticoid) and aldosterone (a mineralocorticoid). Describe their functions and be familiar with their sites of actions a. Cortisol/glucocorticoid mechanism (GR =receptor) i. The steroids are bound to the CBG (helper) ii. Once they reach their target (cells of liver–hepatocytes), the steroids are released from the complex and will diffuse and enter the target cells 1. They enter the cells because the steroids are lipophilic iii. The steroids bind to the glucocorticoid receptor and activate iv. With the binding of cortisol, hsp (heat shock protein) is released which activates them and allows for dimerization of glucocorticoid receptors that will enter the nucleus of the cell v. Then, the glucocorticoid receptors bind to a specific DNA sequence (glucocorticoid response element - GRE) vi. This leads to the stimulation of the transcription of RNA vii. Specific RNA will be translated into specific proteins that will be enzymes in production of glucose by the liver (specific to cortisol) b. Aldosterone/mineralocorticoid mechanism (MR = receptor) i. Aldosterone can diffuse through the plasma membrane through the target cells ii. Cells target: kidney (renal tubule cells) iii. Once aldosterone enters the renal tubule cells, it binds to mineralocorticoid receptors which releases the hsp iv. This allows the activated receptor to enter the nucleus where it will have a specific action v. This leads to the synthesis of proteins (sodium channels and sodium/potassium pumps) vi. Know: aldosterone function is to try and retain as much sodium as possible and decrease the level of potassium (regulator of salt balance of the body) 1. Recover the sodium from the lumen which enters the cells, and the sodium will be excreted back into the circulation 2. The potassium will re enter the cells and get excreted c. Problem i. MR (aldosterone receptor) has similar affinity for aldosterone and cortisol ii. When steroids are in the area of the renal tubule cells, they can diffuse and enter the kidney cells iii. With all of the MR, both aldosterone and cortisol have ability to activate the MR receptor iv. Problem: There is 1000x more cortisol than aldosterone v. If nothing else takes place, there will be an overstimulation of the mineralocorticoid receptor, and both aldosterone and cortisol participate in regulating salt vi. Cortisol cannot be doing the job of aldosterone = would retain too much salt vii. This increases blood pressure = increase blood volume (hypertension) d. Solution i. The kidney tubule cells have the enzyme 11β-OHSD which has the ability to convert cortisol into cortisone 1. Cortisone has NO affinity for aldosterone receptor 2. As soon as cortisol enters the kidney cells, it will be converted into cortisone, and there will be NO overactivation of aldosterone receptor 3. Note: licorice inhibits the enzyme 11β-OHSD which inhibits the conversion of cortisol to cortisone, which would cause activation of the MR receptor by cortisol 3. Explain their regulation by CRH-ACTH and the renin-angiotensin system a. ACTH stimulates production of glucocorticoid synthesis (nothing to do with aldosterone) b. Cortisol reaches a threshold i. Negative feedback 1. Elevated concentration of cortisol will interact in the hypothalamus and anterior pituitary to block the production of CRH and production of ACTH c. Control of cortisol synthesis by ACTH in zona fasiculata: i. ACTH binds to the melanocortin 2 receptor (GCPR) ii. This activates an adenylyl cyclase iii. cAMP activates protein kinase (A) iv. Protein kinase A stimulates different parts of the biosynthesis pathway 1. First: stimulates free release of cholesterol from cholesterol ester (phosphorylation) → cholesterol a. ACTH stimulates the transfer of cholesterol to the outer membrane of the mitochondria b. ACTH stimulates transfer of cholesterol from the outer membrane to the inner mitochondrial membrane c. ACTH stimulates P450scc that converts cholesterol into pregnenolone Renin-angiotensin control of aldosterone synthesis/secretion 1. 1. After reduced pressure in the kidney, renin is released 2. Renin cleaves angiotensinogen converting it to → angiotensin I which is then converted into → angiotensin II a. Angiotensin II stimulates aldosterone secretion by the adrenal cortex 3. Increased concentration of circulating K+ stimulates aldosterone secretion 4. Aldosterone secretion inhibited by atrial natriuretic peptide (ANP)-cGMP pathway 4. Illustrate their importance with pathologies related to adrenal steroid hormones a. Cushing’s syndrome i. Due to excess glucocorticoids ii. Common: 1. Exogenous therapeutic glucocorticoids iii. Uncommon: 1. anterior pituitary adenoma (ACTH-dependent) 2. Adrenal adenoma iv. Symptoms 1. Weight gain, central obesity 2. Hypertension 3. Impaired glucose tolerance/diabetes mellitus 4. Purple striae 5. Osteopenia/Osteoporosis 6. Proximal myopathy b. Addison’s disease i. Common: 1. Abrupt cessation of exogenous sources of glucocorticoids ii. Rare: 1. Primary adrenal insufficiency iii. Symptoms 1. Weakness 2. Weight loss 3. Pigmentation 4. Postural hypotension 5. Anorexia 6. Nausea Adrenal Medulla Overview: 1. Origin: neuronal origin 2. Consists of chromaffin cells 3. Hormones secreted: epinephrine + norepinephrine (catecholamines) a. Fight or flight hormones b. From tyrosine 1. Describe the synthesis and storage of catecholamines a. Synthesis i. Tyrosine → DOPA (by TH) ii. DOPA → Dopamine (by AAD) iii. Dopamine → Norepi (by DβH) iv. Norepi → Epi (PNMT) b. Molecular Mechanism of catecholamines i. Epinephrine will mostly bind to beta 1 + 2 adrenergic receptors ii. The signal of binding of epinephrine to the adrenergic receptor is mediated by g-proteins (Gs) 1. Gs is stimulating protein, which stimulates the adenylyl cyclase responsible for conversion of ATP into cAMP iii. Remember: Epi (mostly beta receptors): increases cAMP levels iv. Remember: NE (mostly alpha receptors): increases FREE calcium, decreases cAMP c. 2. Understand the role of epi/ norepinephrine in response to stress. a. Increase in glucose production (E + NE) b. Stimulation of lipolysis in fat (E) c. Dilation of bronchioles (E) i. Pulmonary vasodilation (epi/ β-receptors) d. Increase rate and force of contraction of the heart (E + NE) e. Constriction of blood vessels (NE in particular and E) f. Increased renin release (E + NE) These need to be working for fight or flight Regulation of secretion of catecholamines a. Stimuli = fear/hypoglycemia b. Stimulates preganglionic sympathetic neurons c. Leads to Ach release i. Adrenal medulla 1. Stimulates biosynthetic pathway of catecholamines 2. Helps exocytosis of granules a. Ca2+ dependent 3. The norepinephrine from medulla is only 30% of it in the body a. The remaining is produced upon stimulation of ACh of the sympathetic ganglion 4. Remember: half lives of NE and E: very short (1-3 minutes) g. 3. Recognize the pathology related to catecholamines a. Pheochromocytoma i. Tumors of adrenal medulla (arises from chromaffin cells) ii. Epi/NorEpi synthesized in excess iii. Clinical features 1. Headaches, chest pain, extreme anxiety, cold perspiration, high BP, tachycardia b. β-blockers and amphetamines i. Epinephrine used as vasoconstrictor + local anesthetic for oral surgery ii. β-blockers = antagonists iii. Amphetamines = agonists (general stimulants, nasal decongestants, appetite suppressants) 4. Illustrate the importance of their receptors with the use of agonists and antagonists for various therapies. a. Alpha receptors i. NE has more affinity for alpha receptors b. Βeta receptors i. Epinephrine has more affinity for beta receptors ii. Prolonged exposure of cells to catecholamines can be a problem in some clinical treatment with beta agonists Male Reproduction 1. Describe the role of Leydig and Sertoli cells in synthesis and regulation of testosterone. a. Leydig cells i. Production of testosterone 1. Important for spermatogenesis ii. Lie between the tubules b. Sertoli cells i. Synthesis of P-450 aromatase that converts testosterone → estradiol ii. Main component of the seminiferous tubules c. d. Mechanism of testosterone action (only 2% is free, the rest is bound to albumin) i. Testosterone is a steroid hormone, so it diffuses through membrane ii. When testosterone gets into target cell, there is expression of the androgen receptor iii. Testosterone binds to AR, and dimerization occurs iv. Enters the nucleus, mediates function of testosterone 1. Stimulates transcription of specific mRNA → specific protein (mediate specific functions of testosterone) v. Note: in some cells, testosterone is converted to DHT 1. DHT has high affinity = you only need very little to stimulate/activate the androgen receptor a. 30-50 fold higher biological activity than testosterone 2. 2. Recapitulate androgens regulation by FSH and LH a. The anterior pituitary gland secretes LH + FSH b. LH i. Acts on Leydig cells to increase 1. Intracellular concentration of free cholesterol ii. Transport to the mitochondria iii. Conversion of cholesterol of pregnenolone by P450scc c. FSH i. Acts on Sertoli cells to 1. Stimulate protein synthesis 2. Mobilization of energy resources 3. Production of testicular fluid 4. Output of sertoli cell proteins a. Inhibin, ABP, P450 aromatase, AMH, and 5ɑ-reductase ii. Negative feedback 1. Inhibin a. Inhibits synthesis of FSH at level of the pituitary gland 2. Testosterone a. Inhibition of the production of GnRH b. If GnRH is not produced, stimulation of LH and FSH will not occur iii. 3. Describe the role of androgens in: a. Sexual differentiation and their anabolic effects i. Y chromosome has Sry gene that encodes for Testis determining factor (TDF) 1. Only in male fetus ii. Somatic cells form sex cords (future sertoli cells) that incorporate into the primitive germ cells iii. Sertoli cells secrete anti-Mullerian hormone (AMH) iv. DHT effects 1. Urogenital sinus 2. External genitalia development (remember than testosterone can be converted into DHT) b. Gametogenesis i. Processes that occur in tubules 1. Mitosis a. Increases # of cells 2. Meiosis a. Reduction in number of chromosomes 3. Spermatogenesis a. Production of mature sperm 4. Erection/Ejaculation and role of NO-cGMP pathway a. Sensory stimulation induced vasodilation of arterioles b. Corpus spongiosum and cavernosum engorged with blood which results in erection c. At ejaculation, the semen is expelled from the posterior urethra Viagra: blocks the enzyme phosphodiesterase, which allows accumulation of cGMP that won’t be degraded into GMP (cGMP restores vasodilation +erection) 5. Identify pathology related to androgen levels a. 5-𝛼-reductase deficiency (hermaphrodism) i. Ambiguous genitalia at birth due to impaired external genital development b. AR deficiency i. Due to mutation in the androgen receptor ii. Various degrees of androgen insensitivity syndrome (AIS) iii. 46 XY 1. If there is no AR, testosterone will have lost its ability to stimulate the development of the duct into the epididymis, vas deferens, and seminal vesicles a. DHT has no effect b. Improper development of external and internal genitalia Female Reproduction Overview 1. Ovaries functions a. Synthesis of estrogens b. Gametogenesis 1. Summarize the biosynthetic pathway for androgens + estrogens a. Estrogen and progesterone are synthesized from cholesterol 2. Describe the sexual differentiation of the gonads a. Begins at 9 weeks b. Germ cells undergo mitosis and oocytes (oogonia) reach 7 million c. Oogonia undergo meiosis but STOP at prophase (primary oocytes) d. Note: Turner syndrome (X monosomy) i. No full ovarian development ii. Orthodontic abnormalities 3. Compare regulation of gonadal steroids by FSH and LH a. Except at ovulation, estradiol inhibits secretion of FSH and LH 4. Classify the development of ovarian follicles a. 1st stage i. Meiosis is suspended in prophase until sexual maturation b. 2nd stage i. At puberty, with increased GnRH, second stage of follicular development starts in response to increasing FSH levels ii. At puberty, entire supply of oocytes ~400,000 (no renewal) c. 2nd stage steps i. Step 1 1. FSH induced proliferation 2. Granulosa cells increases 3. Estradiol produced ii. Step 2 1. Estradiol increases FSH receptors + estradiol receptors 2. Sensitization of granulosa cells increases iii. Step 3 1. Estradiol induces LH receptors on theca cells iv. Step 4 1. LH stimulates progesterone production in granulosa cells 2. Progesterone to androgen conversion (in theca cells) v. Step 5 1. Dominant follicle secretes high levels of estradiol (and progesterone) 2. POSTIVE FEEDBACK a. Increase GnRH b. LH surge 5. Evalulate the different phases of menstrual cycle a. Follicular phase b. Luteal Phase i. Highest levels of progesterone, lower levels of estrogens ii. Corpus luteum formed iii. Granulosa cells synthesize progesterone iv. FSH receptors decrease, estradiol levels decrease 6. Predic the changes that occur during pregnancy a. The mother needs a cholesterol rich diet for synthesis of progesterone (from cholesterol) 1. 2. 3. 4. LH is replaced with HCG HCG stimulates secretion of progesterone Progesterone stimulates endometrial glands Placenta starts synthesis of progesterone and replaces corpus luteum Progesterone and estradiol bind to receptor (cytoplasmic) Somatic effect of estradiol 1. Increasing production of vasodilators NO and prostaglandin E2 2. Decrease vasoconstrictor endothelin-1 Increase in FSH is more than LH/ No inhibin Dr. Beuve Review 1. Pathologies associated with genetic deficiency in the steroid synthetic pathway Deficiency in 21-hydroxylase 1. Decreased synthesis of aldosterone and cortisol 2. Low plasma sodium, hypotension, elevated plasma K+ aldosterone functions to retain Na and increase water, and excrete K+ 3. Decrease in cortisol = decrease in energy 4. Virilization (excess androgens with Congenital Adrenal Hyperplasia, CAH) Deficiency in 11β-hydroxylase 1. Decreased aldosterone and cortisol 2. AME: apparent mineralocorticoid excess (high mineralocorticoid activity: high sodium level, hypertension) 3. Virilization (excess androgens with CAH) Congenital Adrenal Hyperplasia (CAH) 1. Loss of cortisol negative feedback loop leads to increased ACTH production, which in turn over-stimulates adrenal cortex, hence androgens production 2. Excess androgens in utero result in ambiguous genitalia at birth for girl 3. 11-β hydroxysteroid dehydrogenase type II (licorice) 1. Both aldosterone and cortisol get into renal tubule cells 2. 11-beta hydroxysteroid dehydrogenase converts cortisol into cortisone a. Cortisone has no affinity for MR 3. Deficiency of 11-β hydroxysteroid dehydrogenase = elevated Na+ levels, low K+ levels, hypertension 2. Female reproductive system follicular development Regulation of ovarian steroids by hypothalamo-pituitary axis 1. Corpus luteum dies, E and P levels fal 2. Pituitary responds to falling E and P by increasing FSH secretion 3. FSH recruits a cohort of large follicles to enter a rapid growth phase. Follicles secrete low amounts of E and inhibin. 4. E and inhibit negatively feedback on FSH 5. Dominant follicle with maximal growth produces high levels of E 6. High E has positive feedback on gonadotropes, LH and some FSH surges 7. LH surge induces meiotic maturation, ovulation and luteinization. The corpus luteum produces high P along with E and inhibin 8. High P, E, and inhibin negatively feedback on LH and FSH, returning them to basal levels Follicular Phase Luteal Phase Book Practice Problems!!! Book Practice Problems Answers