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147 Cards in this Set
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Over time, skeletal muscle cells and adipose cells become desensitized to insulin in the presence of high glucose. What physically happens as these cells lose their sensitivity? (sp. GLUT4 and TG synthesis)
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1. Decrease in GLUT4 transporters (note- GLUT4 is the insulin-regulated glucose transporter that is responsible for insulin-regulated glucose translocation into the cell)
2. Decreased TG sysnthesis (b/c adipocytes have decreased insulin sensitivity and hence fewer GLUT4, less glucose moves into the cell) |
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What biochemical sequelae are associated with the decreased TG synthesis found in diabetic patients?
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With a decrease in TG synthesis in the adipocyte, there is decreased VLDL removal from the blood stream --> more VLDL in blood stream results in conversion to LDL --> the more LDL, the greater the risk of coronary heart disease
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What is meant by 'lipotoxicity' in diabetic patients?
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Because the adipocyte response to insulin is low, hormone sensitive lipase activity is increased, releasing more FFA into the blood stream. In reponse to the lipotoxicity, cytokines are released and cause inflammaotry damage, especially to the vasculature.
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Because of the chronic elevations in blood glucose, the body starts glycosylating things that should not be glycosylated. What is the most detrimental glycosylated entity?
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There is so much glucose, the body starts to non enzymatically glycosylate proteins. Glycosylated proteins are more prone to crosslink into advanced glycosylation end products (AGE). AGE love to deposit in collagen, resulting in nephropathy, retinopathy and vascular disease.
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Normally, glucose is converted to fructose without complications. This is not the case in diabetics. What happens instead?
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Normally:
Glucose --> sorbitol is converted by aldose reductase Sorbitol --> fructose by sorbitol dehydrogenase Although aldose reductase is much faster at converting glucose to sorbitol than sorbitol reductase is at converting sorbitol to fructose. This is not usually a problem because not much glucose is needs to be converted to fructose anyways, but in chronic glucose elevation, too much sorbitol builds up. Sorbitol is osmotically active and can cause buildup and edema in the lens (cataracts), retina, liver and kidney. |
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Describe the mechanism of Insulin action on its receptor. What class of hormone is Insulin?
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Upon insulin binding to its tyrosine kinase receptor, trans-autophosphorylation occurs followed yby phosphorylation of insulin receptor substrates. This stimulates the downstream events.
Insulin is a polypeptide hormone. |
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Describe the mechanism of Growth Hormone and Prolactin action on its receptor. What type of hormones are GH and Prolactin?
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Upon binding of GH or prolactin, receptors bind cytokines, dimerize and bind JAK. JAKs phosphorylate eachother --> bind STATS --> STAT dissociates from receptor and translocates to the nucleus.
GH and prolactin are polypeptide hormones. |
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This first step in steroid hormone synthesis is common to all steroid hormones.
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Cholesterol --> pregnenolone via CPY11A
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How does ACTH upregulate steroid hormone synthesis?
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1. upregulates STAR protein to bring free cholesterol into mitochondria
2. upregulates HSL action on lipid droplet to make free cholesterol |
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If trauma to the pituitary stalk compromised blood flow to the pituitary gland, which hormones would increase and which would decrease? Why?
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Increase in:
1. Prolactin- loss of blood connection would result in the loss of tonic dopamine inhibition 2. ADH- if you can't release ACTH, you will have a decrease in cortisol (leading to a decrease in blood pressure) so ADH will increase Decrease: All other pituitary hormones |
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What is hyperthyroidism? What is the most common cause?
What is hypothyroidism? What is the most common cause? |
Hyperthryoidism: hypermatabolic state secondary to increased free T3 and T4 levels
Most common cause is Graves disease (antibodies to TSH receptors --> tonic activation) Hypothryoidism is a hypometabolic state secondary to decrease free T3 and T4. Most common cause world wide is iodine deficiency. Most common cause in the US is Hashimoto's (antibodies to TPO and Tg). |
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Adrenal hyperplasia can manifest in any of the four layers of the adrenal gland. What are the clinical symptoms seen with hyperplasia in the various layers?
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Zona glomerulosa --> hypersecretion of mineralocorticoids (aldosterone) --> hypernatremia, hypokalemia, weakness, parethesias, tetany (d/t hypolakemia), increased ECF, hypertension
Zona fasiculata --> hypersecretion of glucocorticoids (cortisol) --> cushings syndrome --> central obesity, buffalo hump, striae, hirsutism, glucose intolerance, nasty Zona reticularis --> hypersecretion of androgens --> it sucks |
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Somatropin and Somatrem are what type of agents? What are they used for? What are their adverse effects?
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Somatropin and Somatrem are GH analogs.
They are used to treat secondary GH deficiency, Turners Syndrome, end stage renal disease and AIDs wasting. In adults, they can cause peripheral edema, carpal tunnel syndrome and arthralgias. In kids, they can cause scolisis, hypothyroidism (GH increases somatostatin levels which goes back and inhibits thyroid releasing hormone) and intracranial hypertension (lots of IGF receptors on choroid plexus that increases the formation of CSF) |
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What type of agent is Mecasermin? What is it used for? Adverse effects? When should patients take it?
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Mecasermin is recombinant IGF. Used in severe primary IGF deficiency. Can cause hypoglycemia (it is binding up all of your insulin) so take it with food.
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What type of agents are octreotide and lanreotide? What are they used for? What are their side effects?
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Octreotide and lanreotide are somatostatin analogues.
Used to treat acromegaly and gigantism. Also treats carcinoid syndrome and VIPoma (90% of these tumors have somatostatin receptors on them, when octreotide/lanreotide bind, they inhibit release of hormones). Adverse effects include- gallbladder contraction inhibition --> gallstones and 'biliary sludge', inhibition of insulin and glucagon secretion --> hypo/hyperglycemia and steatorrhea |
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What type of agent is pegvisomant? What is it used for?
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Pegvisomant is a GH receptor blocker, so it can nomalize IGF levels in the blood.
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Bromocriptine and Cabergoline are what type of agents? What are they used for? What are some side effects?
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Bromocriptine and Cabergoline are D2 agonists.
They are used to treat prolactinomas by decreasing serum prolactin, restoring ovulation and decreasing tumor size. They commonly have CNS effects inclugind psychosis, hallucinations, nightmares and insomnia. |
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What are the possible treatment regiments for Hashimoto's thyroiditis?
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Hashimoto's is hypothyroid. Treatment with synthetic T3 and T4 is needed.
Use Levothyroixine (T4) preferentially, could use liothyronine (T3). |
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What treatment would you use in myxedema coma? What is myxedema coma?
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Liothyronine (T3) because it is already active and has a faster onset.
Myxedema coma is severe hypothyroidism |
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Compare and contrast Methimazole and Propylthiouracil. What are they used for? What are their side effects?
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Both Methimazole and Propylthiouracil are thioamides.
Methimazole blocks TPO only and is contraindicated in pregnancy. Methimazole also has a slower response. Propylthiouracil blocks TPO and the peripheral conversion of T4 --> T3. It can be used in pregnancy. It has a faster onset. They can both be used to treat Graves disease (hyperthyroid). Side effects include ALLERGIC REACTION |
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Patient presents with syptoms of severe hyperthroidism. What would you use to treat them rapidly?
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Thyroid storm --> use iodide salts
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What would you most likely use to treat a patient with Addison's Disease? What is Addison's Disease?
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Addison's disease is primary adrenal cortex destruction --> decrease in glucocorticoids, mineralocorticoids, androgens
You would want to use both: a mineralocorticoid --> fludrocortisone a glucocorticoid --> hydrocortisone (short duration) > prednisone (medium duration) > dexamethasone (long duration) |
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What would you most likely use to treat a patient with secondary adrenal insufficiency (pituitary tumor)? Why?
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You would only need to use a glucocortoid: hydrocortisone, prednisone or dexamethasone
You would not need to use a mineralocorticoid because RAAS is still intact. |
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What is the diagnostic test for Cushing's syndrome? How is it interpreted?
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Dexamethasone suppression test
1. in normal subjects, dexamethasone results in suppression of ACTH and cortisol secretion (via negative feedback). In Cushings, it takes a higher dose to get the same response. 2. If levels do not even respond to a high dose of dexamethasone, you have ectopic secretion or cortisol. |
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What is the main treatment for Cushing's Syndrome? What if that doesn't work?
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Surgery
Pharmacology--> mitotane (kills off gland), aminoglutethiamide, ketoconazole (inhibits corticosteroid synthesis) |
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What is the mechanism of calcitonin? What is it used to treat?
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Calcitonin decreases osteoclast activity on bone and increases calcium excretion in the kidney.
It can be used to treat acute hypercalcemia, Paget's Disease and Osteoporosis. |
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Alendronate, etidronate and tiludronate are what types of drugs? What are they used to treat? What are their side effects?
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They are bisphosphonates. They work by binding to hydroxyapatite in bone to inhibit osteoclasts. Because they bind to site of remodeling, they will give a much more sustained lowering of serum calcium.
Used in Paget's and osteoporosis. Side effects include esophagitis (so take with water and remain upright) and osteonecrosis of the jaw. |
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What is cinacalet?
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Cinacalet enhances the sensitivity of the calcium sensing receptors in the parathyroid, so lower levels of calcium are needed to suppress PTH --> decreased PTH secretion --> decreased serum calcium
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What is the advantage of giving Calcitriol over Cholecalciferol to a patient with hypocalcemia secondary to chronic renal failure?
How does Vitamin D increase calcium levels? |
Calcitriol is active vitamin D. Cholecalciferol needs to be activated. If the patient is in chronic renal failure, they will not be able to activate vitamin D.
Vitamin D increases serum calcium levels by increasing calcium absorption in the small intestine. |
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Patient on Calcitrol has very high serum calcium levels. What can you administer to bring them back down?
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Paricalcitol!
Paricalcitol is a D3 analog only decreases PTH secretion, not Calcium levels. |
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What drugs can you use to treat osteoporosis or Pagets?
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Calcitonin or bisphosphonates?
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What is teriparatide? What is it used for? What is the most concerning side effect?
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Teriparatide is recombinant PTH. It is used to treat osteoporosis. Because it is a recombinant, it only does half of what normal PTH does --> it only stimulates osteoblast activity.
There is a long term concern about increasing risk of osteosarcoma (because so much bone is being made). |
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What antibodies are present in:
Hashimoto's Grave's |
Hashimoto's: anti-TPO, anti-TG
Grave's: anti- TSH receptor |
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What is the difference between a toxic and non toxic goiter? How can you tell the difference?
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Toxic goiters are indicative of an active thyroid gland making lots of hormone.
Non toxic goiters are inactive glands that the body is trying to stimulate to make more hormone. Do an I-131. |
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Best imaging study for:
Thyroid Adrenals PItuitary Pancreas Parathyroid |
Thyroid- US
Adrenals- CT Pituitary- MRI Pancreas- CT Parathyroid- Nuc Med |
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'Cyclic' elevations in blood pressure commonly leads to what adrenal diagnosis? How would you treat this?
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Pheochromocytoma - tumor in medulla releasing too many catecholamines.
Surgery- but treat with an alpha blocker first. |
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OD of fludrocortisone would show what labs regarding sodium and potassium?
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Fludrocortisone--> synthetic aldosterone --> hypernatremia and hypokalemia
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What is the pathogenesis of Type I DM? What do we think it is due to?
How does it present? |
Type I DM is a lack of insulin d/t autoimmune destruction of beta cells --> absolutely dependent on insulin to prevent diabetic ketoacidosis and coma
Thought to be caused by an autoimmune reaction triggered by an infection (coxsackie B) in a genetically susceptible individual Ssx: polypidsia, polyuria, polyphagia, metabolic ketoacidosis |
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What is the pathogenesis of Type II DM?
How does it present? |
Relative reduced insulin secretion coupled with peripheral insulin resistance.
Ssx: frequently asymptomatic, bu twhen it is symptomatic, presents with polydipsia, polyphagia, polyuria and hyperosmolar nonketotic diabetic coma |
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Compare the risk factors of Type I and Type II DM.
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Type I DM: European ancestry, HLA DQ**, DR3, DR4
Type II DM: obesity, old age, genetic predisposition |
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Diabetes is a major risk factors for various vascular pathologies. What do these include?
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Atherosclerosis
MI (most common cause of death) CVA PVD (claudication, ulcers, gangrene) |
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Diabetic patient presents with massive proteinuria and thickened renal basement membranes. Is this nephrotic or nephritic syndrome? What would you expect to see under the microscope?
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Diabetic nephropathy
Nodular glomerulosclerosis--> nephrotic syndrome, Kimmelsteil Wilson nodules |
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A 40 year old, obese patient presents to the ER in acute respiratory distress with stabbing epigastric abdominal pain radiating to the back. Labs show elevated serum amylase and lipase. What is your diagnosis and mechanism of injury? What is the most common cause of this in this particular patient's presentation?
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Acute pancreatitis
Fat, fertile, forty, female --> probably d/t a gallstone Pancreatic acinar cell inury resulting in activation of pancreatic enzymes and destruction of pancreatic parenchyma |
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Pancreatic carcinoma is the fifth most common cause of cancer death in the US. Discuss the typical presentation, what labs you would run to test for it, where you would probably find it and the usually prognosis.
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Pancreatic carcinoma is most common in patients between the ages of 60 and 80 and presents with vague signs until later in it's course. Once you start having symptoms, you can see migratory thrombophlebitis (Trosseaus) and jaundice.
Most commonly in the pancreatic head. Tumor markers: CEA and CA 19-9 Prognosis: very poor, less than one year |
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How is diabetes diagnosed?
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Presence of classic symptoms (polyuria, polydipsia, polyphagia, weight loss) plus:
Casual plasma glucose >200 mg/dL HbA1c > 6.5 Morning FBG >126 mg/dL |
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How is glucose intolerance diagnosed? Why is this a big deal?
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100 < morning < 126mg/dL
140 < 2 hour PG < 200mg/dL Glucose intolerance is not a clinical entitiy on its own but is a RF for progression to clinical diabetes --> start calorie restriciton and increase physical activity |
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If a patient discloses to you that he enjoys 'ass and titties', what else could you assume he enjoys?
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big booty bitches.
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What is gestational diabetes?
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Progressive insulin resistance that begins near midpregnancy and progresses through the third trimester.
Due to increased maternal adiposity and insulin desensitizing effects of hormones produced by the placenta (increase insulin resistance). RF for developing diabetes later in life. |
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What is Maturity onset diabetes of the young?
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A hereditary form of diabetes caused by mutations in an autosomal dominant gene disrupting insulin production --> hyperglycemia
Onset is usually before 25 |
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Drugs can cause secondary diabetes. Which drug is usually responsible?
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corticosteroids, especially glycocorticoids
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A mutation of the insulin receptor can often manifest as what two symptoms?
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Acanthosis nigricans- thickening and discoloration of the skin esp in skin folds
Polycystic ovarian syndrome |
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Congenital rubella is the most common virus implicated in the development of...
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diabetes
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In type I DM, immune dysregulation leads to the development of autoantibodies, including:
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glutamic acid decarbosylase (GAD65) this is the biggie
islet cell antibodies (IA) insulin antibodies (IAA) These antibodies can thus serve as markers for DM-1 --> the best predictor for future development of DM-1 is the expression of multiple autoantibodies. |
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In type I DM, there is a complete lack of insulin production, whereas in type II DM:
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there are varying degrees of insulin resistance --> beta islet cells increase amount of insulin secreted --> destruction of beta cells --> insulin deficiency
It is the health of the beta cell that determines the development of hyperglycemia |
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A man comes in complaining of erectile dysfunction. What are some of the initial tests you should run?
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Check testosterone levels and glucose levels.
Microvascular complications can lead to autonomic neuropathy --> sexual dysfunction |
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What are the microvascular and macrovascular complications of diabetes?
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Microvascular complications: retinopathy, nephropathy, peripheral neruopathy, autonomic neuropathy (leads to silent MI)
Macrovascular complications: main cause of mortality, coronary heart disease, peripheral vascular disease, CVA |
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What is the alphabet strategy for approaching a patient with diabetes?
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A- advice (lifestyle changes: stop smoking, diet and exercise)
B- blood pressure (should be less than 130/80, every patient should be on an ACEi or ARB) C- cholesterol (statin should be added to therapy) D- diabetes control (metformin is the first line treatment) E- eye examinations (diabetic retinopathy is the most common cause of blindness in the western world) F- foot checks G- guardian drugs: aspirin (81mg/day) because diabetics are at an increased CV risk H- heart disease (2x more common in people with diabetes) |
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What are cardiac risk factors?
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CAD HDL
Cigarettes Age/Sex Diabetes Hypertension Death from MI in family Lipids are high |
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In patients with CHF, what diabetes medications are contraindicated? **
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Metformin
Thiazolidinedione (TZD) |
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Diabetic Ketoacidosis occurs more commonly in what population?
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Those with Type I DM
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What values are needed to diagnose DKA?
What will you note clinically in a patient with DKA? |
Blood glucose level >250
Ketones in the serum > 5 Blood pH < 7.3 Clinically will have fruity breath odor (blowing off acetone) and Kussmaul respirations |
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What is the most common trigger of DKA? What are some other triggers?
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Most common trigger is noncompliance!
Also caused by infection (pneumonia and UTI most frequently) Drugs: corticosteroids or thiazide diuretics |
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What is the pathogenesis of DKA?
* everything from start to finish * |
1. Insulin deficiency (pt not taking their meds properly) causes an elevation in GH, catecholamines and cortisol
2. unopposed catecholamine action activates protein kinase which stimulates TG breakdown to FFA and glycerol 3. Increase in FFA --> increased beta oxidation --> increased ketones 4. Increased ketones --> acidosis |
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Patients in DKA do not present with tachycardia or decreased blood pressure. Why?
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There is a bunch of glucose in the blood stream --> osmols pulling fluid from intracellular space to extracellular space (sp the intravascular space) --> circulating volume is ok, but the cells themselves are dehydrated
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Treatment of DKA follows very specific progression. What is this progression and describe the physiology of each step.
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1. Administration of isotonic saline: keeps the fluid restricted to the extracellular space, we don't want it shiftin in yet because then all the electrolytes will move in too
2. Subsequent fluid replacement with hypotonic saline and dextrose: we want to start moving fluid into the cells to normalize osmotic gradient; we want to keep the sugar high with a dextrose infusion to train the cells to kick over from FA metabolism --> continue with hyperglycemia til the anion gap closes because when it closes, this means taht they are not kicking off ketones anymore and their metabolism has normalized 3. start insulin drip to help correct the acidosis |
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Which electrolyte must we monitor in DKA? Why is it so important?
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Potassium is the main intracellular ion, but in an acidosis, it shifts to the extracellular space. When it is in the extracellular space, it can be excreted by the kidney. You have to replace it.
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Overhydration must be avoided when treating DKA. Why?
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If they are on massive fluids and they suddenly normalize, Na will shift into the cell --> water will follow --> severe edema
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Insulin and glucose must continue to be administered in DKA until...
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the anion gap closes
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When treating DKA, you must do the following because..
1. never give insulin first 2. monitor fluids closely 3. monitor potassium closely 4. never give bicarbonate |
1. never give insulin first because they are dehydrated. You may get a huge fluid shift, but the acidosis will not correct.
2. Monitor fluids closely because over correction results in cerebral edema 3. Monitor potassium closely because hypolakemia can kill you quickly (arrhythmia) 4. Never give bicarbonate because fluids shift too quickly |
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What is Metformin? How does it work? What type of patient takes it? What is good about it?
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Metformin acts on liver to decrease hepatic glucose output and acts on skeletal muscle and adipose tissue to enhance insulin stimulated glucose uptake.
It is used in patients with Type II DM. It does not induce hypoglycemia (does not make more insulin, just makes the insulin you have more effective), promotes weight loss, decreases TG and decreases LDL |
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You recently diagnosed your patient with type II DM. You started him on medication. He now comes back to you complaining of a metallic taste in his mouth. What drug is he on and how often does he take it?
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Metformin = metallic
Taken with meals |
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What are some contraindications to Metformin use?
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Renal disease --> increased risk of lactic acidosis
Must be discontinued prior to surgery (circulatory compromise) or administration of IV contrast media (precipitation ARF) --> lactic acidosis |
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What is the mechanism of action of thiaxolidinediones (TZDs)? What type of patient are they used in? What are some of the side effects?
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Pioglitazone and rosiglitazone are TZDs. TZDs stimulate PPAR gamma (decrease insulin resisitance)
PPAR gamma is an intracellular receptor found in adipose tissue, skeletal muscle and pancreatic B cells that increases the transcription of GLUT 4 --> increases uptake and utilization of glucose Used in type II DM patients Side effects include edema, differentiation of pre adipocytes into mature fat cells --> weight gain |
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Why is there an increased risk of bone fracture with TZDs?
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TZDs activate PPAR gamma --> causes differentiation of preadipocytes to mature fat cells --> bone cells replaced by fat --> fracture
WOMEN ONLY |
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Diabetic patient presents with class II CHF, what drug is contraindicated?
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TZDs (pioglitazone, rosiglitazone)
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What are some examples of sulfonylurea drugs? What is their mechanism of action? What side effects are we most concerned about?
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Glimepiride, Glipizide and Glyburide are sulfonylureas. They act by binding to K channels on beta cells, closign them and preventing K efflux, depolarizing the cell and opening the voltage gated Ca channel --> increase intracellular Ca stimulates the release of insulin
Sulfonylureas increase the amount of insulin secreted with each pulse, not the number of pulses SULFONylura = allergic reactions |
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What is the difference between sulfonylureas and meglitinides?
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Both sulfonylureas and meglitinides inhibits the ATP sensitive K channels, but they bind to different sites to do so.
Meglitinides have a very fast onset and so are taken before a mean to control postprandial glycemia |
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What is GLP1? How is it metabolized?
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GLP1 is produced by L cell in ileum and slows gastric emptying, promotes satiety, increase insulin secretion and decreases glucagon secretion.
It is metabolized by DPP4 |
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How can you increase GLP1 in the body? What drugs accomplish this?
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Give GLP1 agonists --> exenatide, liraglutide
Inhibit DPP4 --> sitagliptin, saxagliptin (keeps GLP1 around longer) |
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What are the side effects of the GLP1 agonists? What are the agonists again?
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Exenatide, liraglutide: hypoglycemia, pruitis, urticaria, rash, increased risk of thyroid CA with liraglutide
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What are the side effects of DDP4 inhibitors? What are the drugs again?
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Sitagliptin, saxagliptin: hypoglycemia, allergic reactions (SJS)
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What is pramilintide? Why is it important? Adverse effects?
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Pramilintide is an amylin mimetic. Amylin is secreted with insulin and works with insulin to regulate glucose levesl by inhibiting glucagon secretion, delaying gastric emptying and increasing satiety. Diabetics who inject insulin at mealtimes use this to help the inulin work.
Adverse effects- hypoglycemia, headache |
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Acarbose and miglitol are what types of drugs? How do they work? What are the side effects?
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They are reversible inhibitors of alpha glucosidase, an enzyme attache to the intestinal brush border that cleaves complex carbs to yield glucose --> if it is inhibited, the carbs just pass through
carbs pass through to colon --> bacteria metabolize them --> flatulence |
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Why might your patients stop taking their acarbose or miglitol?
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FARTY FART FART
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What is the mechanism of insulin secretion?
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Glucose enters the cell via the GLUT2 transporter --> increase glucose influx and glucose metabolism stimulates an increase in ATP --> increase ATP inhibits the ATP sensitive K channels --> cell becomes depolarized -->depolarization activates a voltage gated Ca channel in the plasma membrane --> elevated Ca leads to exocytosis and release of insulin into the bloodstream
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What is the mechanism of action of insulin on a cell?
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Insulin binds to its receptor --> subunits dimerize and phosphorylate --> GLUT4 moves to membrane
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What is amylin?
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Amylin is co secreted with insulin in response to nutrient load.
It inhibits gastric emptying, promotes feeling of satiety, inhibits glucagon secretion |
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What effect does somatostatin have on insulin?
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Somatostatin inhibits insulin via the G protein coupled receptor SSTR5
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When does normal puberty begin in girls?
Boys? When is puberty considered delayed? |
Girls: 8-12
Boys: 9-14 ** Puberty is considered delayed if they is no sexual maturation by age 14 in boys and 13 in girls or if menarch has not occured by age 16 or 5 years after pubertal onset. |
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What are the typical first exam findings of puberty?
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In boys --> testicular enlargement
In girls --> breast bud development |
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Around what Tanner stage does the menstrual cycle typically start?
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Tanner Stage IV
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In Tanner Stage II, for females, what typically develops first, breasts or pubic hair?
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Stage II breast development usually occurs before stage II pubic hair development.
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In what Tanner Stage is the first sign of puberty in boys? What is this sign?
In what Tanner Stage is there typically a growth spurt in boys? |
Tanner Stage II- testicles enlarge and become pendulous
Typically see a growth spurt in Tanner Stage IV |
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What is hypergonadotriphic hypogonadism? What are some examples?
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Elevated gonadotrophins d/t gonadal failure (elevated LH/FSH, decreased testosterone)
Turner Syndrome Klinefelter Syndrome |
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What are the typical findings in Klinefelter Syndrome (labs and characteristics)?
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High serum FSH/LH
Low testosterone Small testicles, tall, breast tissue, central obesity, tall with long limbs |
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What is hypogonadotrophic hypogonadism? What are some examples?
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Inadequate function of the gonads due to failure to secrete normal levels of gonadotrophins.
Deficiency of GnRH Kallman Syndrome |
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What is precocious puberty in females? Males?
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Girls: breast or pubic hair development < 7 years old or menarche < 9 years old
Boys: testicular changes, penile enlargement or pubic/axillary hair < 9 years old |
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What is the diagnostic test for central precocious puberty? How is it interpreted?
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GnRH Stimulation Test:
GnRH is injected into the patient and LH is measured. If the pituitary has already been exposed to GnRH (ie they are in puberty), the pituitary will know to start secreting LH --> so you will see an increase in LH above 5IU/L A pituitary gland with no previous exposure would only produce a small amount of LH |
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A mother brings her 6 month old daughter in for an exam because she is concerned about the growth of what she thinks are boobies/titties/jumblies/heehaws. What should you tell her?
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Premature thelarche is a very common condiiton that usually presents in the first two years of life. Usually will go to Stage II, regress and will not come back til the normal onset of puberty.
JUST WATCH IT, no treatment or workup is necessary unless she has pubic hair development |
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A mother brings her 2 year old daughter in for an exam because she is concerned about her apparent growth of pubic hair. What should you tell her?
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Premature adrenarche is common in girls before the age of 5. Growth is normal. Usually no evaluation or treatment is necessary.
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What is the interplay between theca cells and granulosa cells?
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Theca cells are stimulated by LH to produce testosterone
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Why would disgenesis of gonads be associated with anosmia?
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GnRH neurons originate outside the CNS from the nasal placode and migrate into the CNS during development
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What is the dominant hormone in the follicular phase? Ovulation? Luteal phase?
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At the onset of menses, the growth of the FOLLICLE causes an increase in ESTROGEN --> keeps the secretion of LH/FSH in check
Once estrogen reaches a high enough concentration for a long enough period of time, it has a stimulatory effect on GnRH and increases LH/FSH --> LH SPIKE causes OVULATION After ovulation, the corpus luteum produces PROGESTERONE during the LUTEAL phase to support the egg for a successful fertilization |
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The primordial follicle is surrounded by granulosa cells. At what stage do we start to see Theca cells emerge?
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In the follicular phase, specifically at the antral follicle (early tertiary follicle)
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Why is it necessary to have a cumulus expansion during ovulation?
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Granulosa/cumulus cells must disperse for two reasons:
1. so sperm is able to get through 2. it facilitates pickup/transfer via fimbrae for appropriate movement into the oviduct (reduce change of ECTOPIC PREGNANCY) |
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Please describe the interplay between theca and granulosa cells in the developing oocyte (ie in follicular steroidogenesis)?
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Theca cells have an LH receptor on them --> LH binds and causes the conversions as follows:
cholesterol --> pregnenolone --> progesterone (via 3BHSD) OR androstenedione (via 17aOH) Androstenedione diffuses across the basement membrane to the granulosa cells Granulosa cells have FSH receptors to make their own progesterone. They also have aromatase to convert androstenedione to estradiol. During follicular steriodogenesis, this estradiol production makes up the majority of the endocrine environment. |
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Describe the interplay between the theca and granulosa cells during luteal steroidogenesis?
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Normally, the thecal cells posess the majority of LH receptors and the granulosal cells posess the majority of FSH receptors. During the luteal phase, LH receptors are upregulated on both the theca and granulosa cells. Both cell types have P450 and 3BHSD to produce progesterone.
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What is AMH? What does hyper or hyposecretion tell us about pathology?
What levels would you see in menopause? Why? |
AMH is Anti Mullerian hormone. It is produced by granulosa cells from the secondary stage to the small antral stage of development to halt growth of any more primordial follicles.
AMH is used to assess follicular reserve: hypersecretion is indicative of a problem with follicular development --> polycystic ovary disease hyposecretion is assoicated with premature ovarian failure --> follicles can't grow and produce enough you see HIGH levels of AMH with menopause. you don't want to ovulate anymore. |
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Mary's enitre menstrual cycle lasts 28 days.
Wanda's entire menstrual cycle lasts 32 days. Why don't they last for the same amount of time? |
Variability in menstrual cycles arise from the timeline in follicular development (primordial --> Graafian).
There is no variability in the luteal phase, it is always 14 days because unless the corpus luteum receieves a signal within those 14 days, it will regress into a corpus albicans. |
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Every month, 5-7 small antral follicles are stimulated to grow, so why do we only have one follicle that will eventually be ovulated?
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Small antral follicles are stimulated by the increase in FSH that occurs at the end of the cycle and are recruited to grow.
As these follicles grow, they produce estrogen and inhibin and feedback inhibit the secretion of FSH, effectively lowering its concentration. Follicular development is asychronous, so one follicle is further along in development and is able to continue growing despite the decrease in FSH because this follicle is at the developmental stage where there are LH receptors on both the thecal and granulosal cells --> this cell continues to produce estrogen and inhibin, keeping FSH low and preventing the growth of other antral follicles. |
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The LH surge seen around day 15 predisposes 4 main events. What are they?
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ovulation
luteinization oocyte maturation (resumption of meiosis and cytoplasmic mautration) cumulus expansion |
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The abrupt cessation of progesterone and estrogen causes what to happen?
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Menstruation --> the stratum functional is the layer that is shed
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Follicular Phase vs. Luteal Phase
Response from: oviduct cervix vagina breast |
In the follicular phase, the oviduce increase ciliogenesis, the cervix increases watery mucous production, the vagina increases glycogen deposition and the breast increases fat deposition and ductal development.
In the luteal phase, the oviduct increases secretions, the cervix decreases viscous mucous production, the vagina increases desquamation (decrease pH) and breasts increase alveolar development and ductal branching. It is easiest to get pregnant during the follicular phase, which is why the body changes its environment making it easer for sperm to get all up in there. |
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How does age affect female fertility?
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Pool of primordial follicles decrease --> old follicles don't produce as much inhibin and estradiol --> less negative feedback --> increased FSH/LH
The longer an egg is in there, the more ROS it is exposed to --> meiotic nondisfunction --> Down's |
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What is one of the major maternal consequences of IVF?
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Ovarian hyperstimulation syndrome: unsure of the cause, but most likely d/t increased permeability of capillaries in ovary leading to loss of protein rich fluid
mild: abdominal discomfort moderate: abdominal distention, diarrhea, vomiting severe: electrolyte imbalance, ascites, shock ARDS |
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What are some of the fetal consequences of ART (assisted reproductive technology)?
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Children born out of ART are at an increased risk for:
Angelman syndrome- methylation problem on maternal genes --> severe mental retardation, ataxic, jerky movements, frequent smiling and laughter Beckwith-Wiedemann syndrome: large body size, large organs and other problems altered fat composition higher BP and fasting glucose |
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What is menopause?
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A decrease in teh number of ovarian follicles below the threshold necessary to maintain ovulatory cycles
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What is the number one cause of infertility in premenopausal women? Please describe it.
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Polycystic Ovarian Syndrome is the number one cause of infertility in premenopausal women.
PCOS occurs when ovaries are stimulated to produce excess androgens d/t excess LH --> oligoovulation OR d/t insulin resistence increasing androgen production |
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Woman presents to your office with hypertension, dyslipidemia and highly pigmented creases in her armpits and hands. What is going on?
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Polycystic Ovary Syndrome d/t Diabetes
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Women with polycystic ovary syndrome are at an increased risk for what?
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hyperovarian stimulation syndrome
gestational diabetes preeclampsia |
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Offspring obesity can partly be attributed to under-nutrition or over-nutrition of the mother during pregnancy. What hormone is though to be the cause of this?
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Under-nutrition: lack of leptin
Over-nutrition: leptin resistance |
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During pregnancy, women can become hyperthyroid. Why?
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hCG produced by the developing embryo after conception and later by the syncytiotrophoblast
It has an alpha chain that is similar to TSH, LH and FSH (beta chain confers uniqueness) --> can stimulate thyroid (increase in total T4 and T3, but no change in free T4 and T3) |
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What happens to the pituitary gland during pregnancy?
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It enlarges d/t hyperplasia of lactotrophs
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What glands get larger during pregnancy?
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Pituitary gland (hyperplasia of lactotrophs)
Parathyroid gland Pancreas (prolactin and human placental lactogen bind to TK receptor on B cell --> activate JAK --> STAT5 activation --> upregulates GLUT2 --> increased insulin secretion) Adrenal cortex |
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What role does human placental lactogen play in fetal nutrition?
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Human placental lactogen decreases maternal insulin sensitivity, raises maternal blood glucose and decrease maternal glucose utilization to ensure adequate fetal nutrition
Release of HPL during fasting causes FFA to become available for maternal fuel so more glucose can be used by the fetus |
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The maternal-fetal-placental unit is necessary for steroid production because..
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The placenta lacks 17alphaOH --> no androgen production on its own
The fetal andrenal gland lacks 3betaHSD --> no progesterone produced |
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What roles does progesterone have during pregnancy?
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inhibits myometrial contractions by blocking oxytocin receptors and inhibiting COX2 (decrease PG synthesis)
it also suppresses maternal immune system |
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What roles does estrogen have during pregnancy?
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increases myometrial oxytocin receptor number, increases PG production, increase gap junctions in myometrial cells
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We are unsure of the exact trigger for parturition, but we know it involves a decrease of what hormone?
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removal of progesterone block
*remember, progesterone inhibits myometrial contraction by blocking oxytocin receptors and inhibiting COX2 when progesterone is removed, estrogen can take over *remember, estrogen increases myometrial oxytocin receptor numbers, increases PG production and increases gap junctions between myometrial cells |
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How does fetal production of cortisol help lead to myometrial contraction and parturition?
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fetal system produces cortisol as a result of CRH stimulation from the placenta --> leads to lung maturation in fetus --> surfactant and phospholipid production --> increases inflammation in the placenta --> produces PGF2 and PGE--> PGF2 increases myometrial contraction and PGE increases cervical ripening
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What is the Ferguson reflex?
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Pressure on the vaginal wall or cervix --> Gaq --> increase PG production --> increase Ca stimulates myosin light chain kinase --> contraction
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Is spermatogenesis synchronous or asynchronous? What about oogenesis?
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Spermatogenesis is synchronous
Oogenesis is asynchronous |
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Where does testosterone come from in the male and what is it responsible for?
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LH receptors on Leydig cells secrete testosterone.
Testosterone maintains Sertoli cell function, matures epididymus, prostate and seminal vesicles circulates bound to albumin or sex hormone binding globulin |
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What is the function of Sertoli cells?
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SUPPORTIVE: structure and organization, responsible for blood testis barrier (gap junctions between the sertoli cells)
phagocytic secretory: makes inhibin, androgen binding protein and growth factors |
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Where does sperm mature?
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Epididymus: secrets glycoproteins, sialic acid; gain motility here
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What is capacitation and where does it occur?
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Capiacitation is a change in membrane fluidity, metabolism, ions and pH, rendering the spermatazoan fertilization competent
This happens in the female reproductive tract --> female produces capacitation factors in which the sperm must be resident in for a while (so the first sperm to the egg does not necessarily fertilize if it has not been in the capacitation factor long enough) |
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Explain the physiology of an erection (I'm not even sure what that is...)
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parasympathetic nerves stimulate release of NO --> activates guanylyl cyclase --> increase cGMP --> activate kinase --> decrease Ca concentration and open K channels --> hyperpolarization --> smooth muscle relaxation
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Darth Vader wants to maintain his SITH longer. What is one way he can do that?
**note: SITH = erection |
cyclic GMP is converted to GMP by phosphodiesterase 5
inhibiting phosphodiesterase 5 will keep a higher concentration of cGMP --> activatation of kinase --> smooth muscle relaxation |
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Sympathetic activation is the cornerstone of orgasm/ejaculation. What happens?
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sympathetics cause closure of bladder sphinceter and cause you to JIZZ IN YOUR PANTS
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What effect does metabolic syndrome have on male fertility?
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DM II effect on pituitary causes hypogonadism
Fat deposits in scrotal sac, increasing temperature Dyslipidemia and increased C reactive protein and inflammation yields reactive oxygen species --> DNA damage --> spermatozoa damage |
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Lutropin is what type of drug? What does it treat? What are it's side effects?
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Recombinant human LH --> stimulates ovulation and leutinization of ovarian follicles in females and stimulates leydig cells to serete testosterone in males
side effects: increased fertility in men and women, multiple pregnancies, ovarian hyperstimulation syndrome (presence of multiple leutenizedcysts in ovaries) |
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Follitropin is what type of drug? What does it treat? What are it's side effects?
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Follitropin is recombinant human FSH --> used to promote follicular development
Side effects: ovarian hyperstimulation syndrome, multiple pregnancies |
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What type of drug is choriogonadotropin alfa? What does it treat?
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choriogonatdotropin alfa is recombinant human hCG --> used to induce ovulation, promote descent of testes in cryptorchidism, and to restart testosterone synthesis after use of anabolic steroids
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A male patient comes in with cryptorchidism. How can you treat this?
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Cryptorchidism- balls don't drop
administer choriogonadotropin alfa (recombinant hCG) |
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A woman comes into your practice because she has been trying with her husband to get pregnant for months with no success. H&P reveals recurring pelvic pain, dysmenorrhea, dyspareunia and dysuria. Biopsy of her ovary reveals endometrial cells. What is going on and how would you treat her?
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Endometriosis is the presence of endometrial cells outside of the uterus and is a major cause of infertility. Most common presentation is recurring pelvic pain.
Start her on leuprolide (GnRH analog) |
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Histrelin, gosrelin, leuprolide, triptorelin and nafarelin are what type of drugs? What can they treat? How long should you use them?
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GnRH analogs --> used to treat PMS, endometriosis (esp leuprolide), prostate CA and central precocious puberty (GnRH agonists stimulate the pituitary to release FSH and LH, however, when used regularly, GnRH agonists cause a decreased release of FSH and LH)
These drugs cause menopause like symptoms, so don't use for more than 6 months |
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A woman has decided to undergo IVF. She must harvest some of her eggs to be fertilized and then reimplanted. How would you pretreat her for the procedure?
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GnRH antagonists (ganirelix, cetrorelix) can be used to inhibit the LH surge prior to harvesting eggs for IVF
Side effects: life threatening anaphylaxis |
