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19 Cards in this Set
- Front
- Back
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Know where cortisol comes from, stimulus for release, main function of glucocorticoids, and relate functions to clinical things when you have too much cortisol present
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Identify the functional zones & innervation of the adrenal glands and the principle hormones secreted
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✩Zona Glomerulosa - produces aldosterone which regulates K+ and Na+ levels
✩Zona Fasciculata - produces mostly glucocorticoids (cortisol) (also corticosterone) which regulate fuel metabolism and respond to injury or stress ✩Zona Reticularis - produces mostly androgens (dehydroepiandrosterone and androstenedione) ✩Adrenal medulla - catecholamines (noradrenaline and adrenaline) |
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Describe steroid hormone structure
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✩21 Carbon Steroids
-include progesterone, deoxycorticosterone, aldosterone, and cortisol -progesterone is the precursor for the others in the 21 carbon series ✩19 Carbon Steroids -have androgenc activity and are precursors to the estrogens ✩18 Carbon Steroids -have estrogenic activity |
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Describe the synthesis of steroid hormones
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Cholesterol → Pregnenolone by cholesterol side chain cleavage enzyme (cholesterol desmolase) is always the first step
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Describe glucocorticoid secretion
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-oscillates with a 24 hour periodicity or circadian rhythm
✩Hypothalamic control - corticotrophin releasing hormone -CRH containing neurons are located in the paraventricular nuclei of the hypothalamus -when these neurons are stimulated CRH is released into the hypothalamic-phyophysial portal blood and delivered to the anterior pituitary -CRH binds to receptors on corticotrophs of the anterior pituitary and directed them to synthesize POMC (the precursor to ACTH) and secrete ACTH -the second messenger for CRH is cAMP ✩Anterior lobe of the pituitary - ACTH -ACTH increases steroid hormone synthesis in all zones of the adrenal cortex by stimulating cholesterol desmolase and increasing the conversion of cholesterol to pregnenolone -ACTH also upregulates its own receptor so that the sensitivity of the adrenal cortex to ACTH is increased -Chronically increased levels of ACTH cause hypertrophy of the adrenal cortex -the second messenger for ACTH is cAMP ✩NEGATIVE FEEDBACK CONTROL - cortisol -cortisol inhibits the secretion of CRH from the hypothalamus and the secretion of ACTH from the anterior pituitary -when cortisol (glucocorticoid levels are chronically elevated, the secretion of CRH and ACTH is inhibited by negative feedback -the dexamethasone suppression test is based on the ability of dexamethasone (a synthetic glucocorticoid) to inhibit ACTH secretion -in normal animals, low-dose dexamethasone inhibits or "suppresses" ACTH secretion and, consequently, cortisol secretion -in animals with ACTH secreting tumors, low dose dexamethasone does not inhibit cortisol secretion, but high dose dexamethasone does -in persons with adrenal cortical tumors, neither low- nor high-dose dexamethasone inhibits cortisol secretion |
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Describe the transport & removal of adrenocortical hormones
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-adrenal steroid hormones transported in blood bound to corticosteroid-binding globulin (transcortin), and albumin
-90% of glucocorticoids in blood are bound to protein and have a relatively long half life in blood ~ (60-90 min) -steroid nucleus cannot be degraded -adrenocortical hormones are inactivated in the liver by reduction of double bonds and ketone groups, then conjugations with water sulphates and glucuronides → this decreases their binding to blood proteins and makes them more water soluble for excretion in the urine |
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Describe the steroid mechanism of action
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-cortisol and aldosterone bind to a glucocorticoid receptor (GR) or mineral corticoid receptors (MR) in the cytoplasm that translocate to the nucleus and modulates transcription in multiple tissues following hormone binding
-the cytoplasmic receptors in unbound form are complexed to a chaperone protein (heat shock protein hsp90) -binding of the hormone causes the chaperone to dissociate from the receptor and thus allows the hormone receptor complex to translocate to the nucleus -in the case of cortisol, the cortisol-receptor complex associates with glucocorticoid response elements (GREs) on the 5' untranslated region of multiple genes to either enhance or diminish gene expression -activity of the glucorticoid-receptor complex requires dimerization of two identical receptor complexes (ie. the GR function as a homodimer) on the site of the GRE on the chormatin resulting in modulation of gene transcription |
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What are the metabolic actions of glucocorticoids?
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-cortisol increases plasma glucose by mobilization of amino acids from proteins in many tissues and enhances the ability of the liver to convert these amino acids into glucose and glycogen by activating gluconeogenesis
-targets most body tissues including CNS, bone, skin, liver fat, and muscle METABOLIC ACTIONS: 1) Raises blood glucose by increasing liver output of glucose: ✩promotes gluconeogenesis by inducing the synthesis of additional gluconeogenic enzymes ✩promotes proteolysis and inhibit protein synthesis thus freeing up amino acids for gluconeogenesis ✩in liver, cortisol induces the synthesis of enzymes that are involved in the metabolism of amino acids, thus facilitating their conversion to carbohydrates through gluconeogenesis -in muscle, cortisol stimulates the breakdown of muscle protein, thus providing amino acid substrate to the circulation and subsequently to the liver -cortisol stimulates lipolysis in adipose tissue, which forms glycerol (used by liver as substrate for gluconeogenesis) and fatty acides (which are metabolized by the liver for energy) *OVERALL the most important metabolic effect of cortisol is the conversion of fat and muscle protein into glycogen. Cortisol is called a glucocorticoid because one of its long term effects is to increase blood glucose (hyperglycemia) 2. Prior action of cortisol → build up of glycogen stores → used as a substrate for glucagon and adrenaline 3. Enhances release of glucagon from pancreas α cells 4. Antagonizes the action of insulin on muscle and adipose tissue glucose uptake inhibits glut 4 transport 5. Cortisol is a permissive hormone ✩In adipose tissue it must be present for catecholamines to stimulate hormone sensitive lipase ✩In liver other gluconeogenic hormones are ineffective without the permissive effects of glucocorticoids -cortisol enhances glycogenolytic + gluconeogenic actions of glucagon and adrenaline ✩Cortisol is important for permitting catecholamine function on sympathetic nerves and blood vessels -cortisol blocks removal of noradrenaline from synapses by blocking uptake by transporter, thus increasing levels of neurotransmitter -cortisol increases amount of adrenergic receptors in smooth muscle of blood vessel walls |
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What are the anti-inflammatory effects of glucocorticoids?
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-inhibits prostaglandin and leukotriene production
-decreases release of pro-inflammatory cytokines IL-1, IL-6, and TNF-α -reduces IL-2 production inhibiting lymphocyte proliferation -reduced proliferation of fibroblast. Slows wound healing |
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What causes hyperadrenocorticism (Cushings disease)?
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Excess secretion of corticosteroids is due to:
1. A pituitary tumor (85% of cases) - Pituitary dependent hyperadrenocorticism -microscopic benign pituitary tumor (microadenoma) which oversecretes ACTH and ignores feedback mechanisms -normally have 2 large adrenal glands 2. Adrenal tumor - adrenal based hyperadrenocorticism - 50% benign adenomas and 50% malignant adenocarcinomas -feedback mechanisms not working and one adrenal normally large (tumor) and the other small (feedback working) 3. Excess administration of corticosteroid - iatrogenic a) cortisone (synthetic) = cortisol b) predinisone (synthetic) = 4 x cortisol c) dexamethasone (synthetic) = 30 x cortisol |
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What are the symptoms of hyperadrenocorticism? (Cushings disease)
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-bulging sagging (pot-bellied) belly
-muscle weakness, loss of muscle mass with increased breakdown of muscle protein -hair loss & thinning of skin -weak bones -thin skin -bruising -polyphagia -polydipsia -polyuria (urinary accidents in house trained dogs) -poor wound healing -weight gain or its appearance due to fat redistribution, weakening of abdominal muscles and enlargment of liver -susceptibility to infections, particularly bladder -diabetes -exercise intolerance -sparse hair coat →glucocorticoids decrease utilization of glucose by muscle and adipose tissue and lower the sensitivity of these tissues to insulin -about 10-20% of dogs with Cushing's disease are diabetic, virtually all of the remainder have some milder impairment of glucose metabolism |
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How do we diagnose Cushing's disease?
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Elevated blood glucose, cholesterol, elevated liver enzymes eg alkaline phosphatase, urinalysis for high protein and low specific gravity (dilute urine), ultrasound for enlarged liver or enlarged or atrophied adrenal glands.
Diagnostic test include urine cortisol/creatinine ratio test, ACTH levels, and low and high dose dexamethasone suppression tests. ❤Low Dose Dexamethasone Suppression Test: Baseline blood sample from fasting dog taken. A small amount of dexamethasone, (synthetic glucocorticoid), administered and follow-up blood samples are taken 4 and 8 hours later. Normally dexamethasone will suppress cortisol output throughout the test. Dog with Cushing’s disease will not suppress blood cortisol in response to the dexamethasone injection, because their feedback mechanisms are not working properly. ❤Urine Cortisol/Creatinine Ratio Screening Test: cortisol in urine versus creatinine (reference to control for the degree of dilution of the urine). High cortisol in urine is suggestive (not definitive) of high cortisol in the blood. ❤ACTH levels : Patient with a pituitary tumour will have high ACTH levelswhereas if there is low or no measurable ACTH levels it probably is an adrenal tumour ❤High Dose Dexamethasone Suppression Test: A dog with an adrenal tumor will not suppress at all. His adrenal tumour simply doesn't "care" about the level of blood cortisol; it keeps pumping out cortisol. A dog with a pituitary tumor still has some limited ability to respond to feedback and thus should respond to a high dose of dexamethasone with a suppressed cortisol level |
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How do we treat Cushings diease?
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1. Surgery
2. Drugs a. Lysodren : destroys adrenal cortex tissue b. Trilostane (Vetoryl). Stops corticosteroid biosynthesis by inhibiting 3 beta hydroxysteroid dehydrogenase. c. Ketoconazole: competitive inhibitor for several enzymes required for cortisol synthesis d. Anipryl: inhibits ACTH by increasing dopamine levels. |
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How is aldosterone secretion controlled?
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-is under tonic control by ACTH, but is seperately regulated by the renin-angiotensin system and by potassium
1) Renin-angiotensin-aldosterone system ❤decreases in blood volume causes a decrease in renal perfusion pressure, which in turn increases renin secretion. Renin, an enzyme, catalyzes the conversion of angiotensinogen to angiotensin I. Angiotensin I is converted to angiotensin II by angiotensin converting enzyme ❤Angiotensin II acts on the zona glomerulosa of the adrenal cortex to increase the conversion of corticosterone to aldosterone ❤Aldosterone increases renal Na+ reabsorption, thereby restoring extracellular fluid (ECF) volume and blood volume to normal 2) Hyperkalemia increases aldosterone secretion via a Gq protien (PIP mechanism). Aldosterone increases renal K+ secretion, restoring blood [K+] to normal |
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What are the actions of aldosterone?
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-↑ renal Na+ reabsorption (action on the principal cells of the late distal tubule and collecting duct)
-↑ renal K+ secretion (action on the principal cells of the late distal tubule and collecting duct) -↑ renal H+ (action on the α-intercalated cells of the late distal tubule and collecting duct) - regulation of acid/base balance -can also act on the central nervous system via the posterior pituitary gland to release vasopressin (ADH) - conserves water by direct actions on renal tubular resorption |
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What happens when aldosterone is reduced? What symptoms do we see in Addison's disease, what do we see in biochemistry, what causes it and how do we treat it?
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-increased concentrations of K+ result in the partial depolarisation of plasma membranes of all cells leading to cardiac arrhythmias and weakness of muscles
-hyponatraemia causes a drop in blood pressure from the combined effects of decreased vascular volume (hypovolemia), decreased cardiac contractility, and decreased response of vascular smooth muscle to vasoconstrictor agents ❤ADDISON'S DISEASE -is an insufficiency of adrenocortical hormones -signs are lethargy, weakness, dehydration and collapse -low plasma Na+, increased K+, increased BUN -causes: pathological destruction (e.g. autoimmune disease) -treatment: synthetic mineralcorticoids +/- glucocorticoids |
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What does the adrenal medulla produce? What is the stimuli for release?
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-the adrenal medular contains chromaffin cells, which are modified postganglionic sympathetic neurons
-preganglionic sympathetic axons (via splanchnic nerves) synapse on chromaffin cells, and upon stimulation cause chromaffin cells to secrete catecholamines: epinephrine (90%) and norepinephrine (10%) -epinephrine-containing cells comprise a majority of the chromaffin cells in the medulla and contain small, homogenous, light-staining granules -all of the circulating epinephrine in the blood is derived from the adrenal medulla -epinephrine binds to α and β-adrenergic receptors, which are G-protein linked receptors -epinephrine has a half-life of 1-3 mins as it is metabolized by the liver and excreted in the urine as free epinephrine or metanephine -norepinephrine-containing cells comprise a minority of the chromaffin cells in the medulla and contain large, electron-dense core granules -majority of norepinephrine is from post-ganglionic sympathetic neurons -norepinephrine binds to α and β-adrenergic receptors, which are G-protein linked receptors -also has a half life of 1-3 mins and is metabolized by the liver STIMULI FOR RELEASE -hypoglycemia, stress, and exercise are major stimuli -stimulation of nicotinic ACh receptors opens Ca2+ ion channels on chromaffin cells that produce a localized depolarization and entrance of Ca2+ resulting in exocytosis of adenaline and noradrenaline |
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Describe the biosynthesis of catecholamines
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These hormones are produced within chromaffin cells and are synthesised in a stepwise manner from
1. Tyrosine 2. Dopa 3. Dopamine 4. Noradrenaline 5. Adrenaline -Key enzymes tyrosine hydroxylase & dopamine βhydroxylase stimulated by sympathetic stimulation. These enzymes undertake hydroxylation and decarboxylation of tyrosine. -Methylation of noradrenaline by results in adrenaline (step aided by cortisol) -Noradrenaline exerts negative feedback on conversion of tyrosine to dopamine -Adrenalin and noradrenalin are stored secretory granuales within the chromaffin cells |
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What receptors do catcholamines act on?
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1. α1 - Increased free Ca2+ (Gaq, PIP2) (post-synaptic) [Noradrenaline > Adrenaline]
2 α2 - Decreased cyclic AMP(Gi) (pre- and post-synaptic) [NA > A] 3. β1 - Increased cyclic AMP (Gs) (Mainly in the heart) [NA > A] 4. β2 - Increased cAMP (Gs) (smooth mm and metabolic effects) [A > NA] 5. β3 - Increased cyclic AMP (Gs) (adipose tissue) [A = NA] |
