week 10- hormones Flashcards
• Where are hormones made in adrenal cortex?
o mineralocorticoids: zona glomerulosa (outer cortex)
o glucocorticoids: zona fasciculate (middle)
o androgens: zona reticularis (inner)
o catecholamines: medulla
• what is adrenal steroidogenesis?
o cholesterol → pregnenolone, in mitochondria
o → (SER) mineralcorticoids, glucocorticoids, androgens ( 3 diff pathways)
• What is pregnenolone? What hormones does it make?
o The “mother” hormone o from cholesterol o Pregnenolone → progesterone OR DHEA o Progesterone → mineralocorticoids, glucocorticoids, OR T/E o DHEA → T/E
• What is DHEA?
o Produced in Adrenal Glands, Gonads, Brain
o DHEA → Androsterone →Testosterone & Estrone
o Peaks ~30
o Most abundant steroid hormone
• What can suppress DHEA? Low levels assoc w?
o Suppress: stress, excess corticol
o Assoc: Immune dysfunction, AI, DM II, CA, HTN, CVD, Depression, Cognitive dysfunction, Low libido, Osteoporosis
• What is the DHEA pathway?
o Pregnenolone → 17-OH-pregnenolone → DHEA
o → androsterone, etiocholanolone, androstenedione
o Androstenedione → T/E
• What is aldosterone?
o mineral and water balance
o ↑ Na re-absorption in distal tubules of kidney, + passive absorption of water by osmosis
o excretion of potassium (active and passive)
o ↑ Na re-absorption in sweat glands.
o ↓ BP, Na →JGCs → renin → angiotensinogen (liver) → angiotensin I → angiotensin II → adrenal → aldosterone → kidney tubules → ↑BP, Na
• What is cortisol?
o steroid hormone
o essential for life (long term); net effects are catabolic
o prevents hypoglycemia
o promotes gluconeogenesis, breakdown of skeletal muscle protein
o enhances fat breakdown (lipolysis)
o suppresses immune system
o breakdown of bone matrix (high doses)
• how is cortisol anti-inflammatory?
o ↓ capillary permeability (↓ entrance of cells to inflamed areas)
o Stabilize lysosomal membranes (↓ release lysozomes)
o ↓phagocytosis by WBCs, ↓ fever
o ↓T lymphocytes (↓ immunity), eosinophils (↓allergic rxns)
o ↓ synthesis interleukins
o inhibits synthesis collagenase
o → slow, but less painful healing
o Useful in transplant operations to reduce organ rejection
• What happens to cortisol in chronic stress?
o Prolonged ↑ cortisol → break down of muscle, excessive Epi release, hyperglycemia, weakening of bone, destruction of immune system, inhibition of reproductive function, other complications.
• How is cortisol release regulated?
o primarily neuroendocrine control
o ACTH stimulates adrenal gland to release cortisol
o (-) feedback on hypothalamus (CRH), pituitary (ACTH)
• What is the daily pattern of cortisol release?
o Changes ~30 mins after changes in ACTH
o ↑ few hours after sleep, then ↓ (diurnal rhythm)
o Lowest shortly before and shortly after sleep begins
o ↑ on waking in morning (peak), and sporadically throughout day
• How is cortisol transported?
o 95% bound to cortisol binding globulin (aka transcortin), 5% circulating is free
o not biologically available when bound to CBG
o CBG is made in liver (↑ by estradiol)
• How is cortisol metabolized?
o 90 min half-life
o in liver →conjugated to glucuronic acid
o = ↑solubility in water, excreted via kidneys
• What are the pahses of the general adaptation syndrome?
o Fight or flight
o Resistance
o exhaustion
• What is the “fight or flight” phase of the general adaptation syndrome?
o immediate short term response to crisis
o Sympathetic stim → adrenal medulla → Epi, NE
o Mobilize glucose reserves
o Changes in circulation
o ↑ HR and RR
o ↑ cell metabolism (energy)
• What is the resistance phase of the general adaptation syndrome?
o Long-term metabolic adjustmens
o GC/GH- mobilize remaining energy reserves: lipids, amino acids; conserve glucose
o GC/Glucagon: ↑ blood glucose, liver synthesis
o MC (RAAS): conserve salts, water; lose K, H
• What is the exhaustion phase of the general adaptation syndrome?
o Collapse of vital systems
o Dt exhaust lipid reserves, can’t make GCs, electrolyte imbalance, vital organ damage
• What are normal blood cortisol levels (mg/dL)? Interfering factors?
o Adult: 6-28 (8am); 2-12 (4pm) o Child: 3-21 (8am); 3-10 (4pm) o ↑ w Pregnancy o ↑ w Physical & emotional stress o Drugs
• What is Cushing’s syndrome? Dz?
o Syndrome= Supraphysiologic availability of glucocorticoid hormones (cause ↑ cortisol)
o Etio: Exogenous, Endogenous, Pseudo-Cushing’s (alcoholism)
o Dz: ACTH producing pituitary adenoma
• What are physiologic effects of Cushing’s?
o Hyperglycemia: stimulation of gluconeogenesis & glycogenolysis
o Negative nitrogen balance: osteoporosis, muscle wasting, reduced fibrogenesis, thin skin, easy bruising
o Salt and water retention: tendency to CHF with hypokalemia, HTN
o Reduced immune response: increased susceptibility to infection
• What are ssx of Cushing’s?
o Central obesity, Facial plethora, Striae o Glucose intolerance o Myopathy o Hypertension o Bruising o Hirsuitism, Acne o Oligo/amenorrhea, Impotence o Ankle edema o Fracture
• What are basic lab findings for Cushing’s?
o CBC: leukocytosis, lymphocytopenia, ↓eosinophils
o CMP: hyperglycemia, hypokalemia, hypernatremia
o Thyroid Function: ↓T3, TSH
• What are recommended test for Cushing’s?
o 1st line: UFC (urinary free cortisol), Low dose or overnight dexamethasone test, Night-time salivary cortisol
o test pts w multiple sxs
o if abn result: see endocrinologist for 2nd test (above) or serum midnight cortisol or dexamethasone-CRH test
• what is 24-hr UFC?
o Integration of plasma cortisol throughout day
o Assays (HPLC or MS) normal range 10-34 ug, M > F
o Pseudo-Cushings patients: mb have N values in newer assays, but ↑ in older assays
o Many Cushing’s patients N in new assay
o Most Cushing’s are periodic (need multiple days of collections)
o mb normal if high at night, low during day
• what is the diurnal plasma cortisol test?
o Normal or pseudo have pronounced diurnal rhythm (↑morning, ↓ night)
o Cushing: no diurnal variation
o Cushing likely if midnight plasma cortisol > 7.5 ug/dL
o OCPs: have ↑ CBG, false high serum cortisol
o Pretty good test, but hard to arrange (difficult to get midnight plasma if outpatient)
• What is the diurnal salivary cortisol test?
o Salivary reflect plasma levels
o “Salivette”, chew cotton tube for 2-3 mins. samples stable for 1 week at room temp
o salivary cortisol is independent of rate of saliva production
o Cushings: usu > 3.6 nmol/L (0.13 ug/dL)
o Normal: < 3.6
• What is the overnight dexamethasone test?
o Give 1 mg dexamethasone at midnight- collect 8 am plasma cortisol
o = synthetic steroid, low dose suppresses ACTH secretion in normal people (↓ Cortisol by 50%)
o Cushing’s: resistant to glucocorticoid feedback; need high dose to get effect
o Must stop prednisone 24 hrs before test
• What is addison’s dz?
o Destruction of adrenal glands: AI, TB, Tumor/infiltration, Infective (meningococcus)
o Hormone deficiency: Cortisol, Aldosterone
o Despite very high ACTH and MSH (melanocyte stimulating hormone)
o Ssx: bronzed pigmentation (JFK), hypovolemia, hypotension, hyperkalemia
• What are sxs of primary adrenal insufficiency? PE?
o Fatigue, Weakness o Orthostatic hypotension o Wt loss, Poor appetite o Neuropsychiatric: Apathy, Confusion o N/V, Abd pain, Salt craving o PE: Hyperpigmentation, Hypotension, Orthostatic changes, Weak pulses, Shock, Loss of axillary/pubic hair (women)
• What is the significance of melanocyte stimulating hormone with PAI?
o destruction of adrenal cortex → disrupt feedback inhibition of hypothalamus and anterior pituitary gland → corticotropin secreted continuously
o corticotropin cleaved from prohormone, MSH also released
o ↑ MSH → characteristic bronze hyperpigmentation of PAI
• What is ACTH?
o =adrenocorticotropic hormone
o Pre-cursor = pre-POMC (pro-opiomelanocortin); made in anterior pit
o Stress induces synthesis and release (via CRH, vasopressin, from hypothalamus)
o Controlled by feedback mechanisms of HPA
• What are lab findings w PAI?
o CMP: Hyponatremia, hyperkalemia, metabolic acidosis (dt ↓ aldosterone); ↑ BUN and creatinine dt hypovolemia
o Hypoglycemia: dt ↑ peripheral use of glucose, ↑ insulin sensitivity. more in kids and w 2nd adrenocortical insufficiency
o ↑ Urinary and sweat sodium
o CBC: normo, normo anemia
o Thyroid function (PAI, Addison, 2nd AI): ↑ TSH, mb ↓T4, mb thyroid auto-Abs, mb hypothyroid sxs; dt ACTH def; mb slowly reversible with cortisol replacement
• What is the rapid ACTH stimulation test?
o Blood in 2 tubes for baseline cortisol and aldosterone
o Synthetic ACTH (1-24 aa’s), 250 mcg (0.25 mg), IM or IV
o 30-60 mins after ACTH injection, 2 more blood samples drawn (1 for cortisol, aldosterone)
o 2 PAI dx criteria: ↑ from baseline 7+ mcg/dL; must rise to 20+ mcg/dL (= normal adrenal glucocorticoid function)
o Further testing is don’t meet 2 dx criteria
o Addison: both cortisol and aldosterone show minimal or no change
• What is the synacthen test?
o synthetic ACTH analogue Causes adrenal gland to make cortisol
o Normal response: rise in cortisol
o Baseline cortisol mb normal in Addison’s
• ↑Cortisol, ↓ACTH:
o Cushing’s syndrome
• ↑Cortisol, ↑ACTH
o Cushing’s dz
• ↓Cortisol, ↑ACTH:
o Addison’s dz
• ↓Cortisol, ↓ACTH:
o Hypopituitarism
• What is the salivary adrenal function test?
o Preferred Test for Adrenal Fatigue
o Use 1 day collection (4 vials) as baseline
o Pt records ssx, date and time of sample
o If possible, take blood sugar at same time as cortisol level.
o Test other steroid hormones
• What is growth hormone?
o Hypothalamus releases GHRH
o Anterior Pituitary releases GH
o GH induces release of Insulin-like Growth Factor
o Triggers = Tissue growth/ repair
o ↑ protein synthesis, growth, etc.
o ↑ GH and release of somatostatin → ↓ GHRH and GH release (during absorptive phase)
o Antagonizes insulin effects (during carb intake)
• What are normal levels of hGH?
o Newborns: 5-40 ng/ml o Children: 0-20 o Women: < 10 o Men: 5 o But there are many variables o Better to do HGH stimulation test or measure Insulin-like growth factor.
• What is insulin-like growth factor?
o Peaks around 17 yrs
• What are ssx of def GH?
o Short Stature (in children) o Exercise intolerance o Decreased Strength o Increased Body fat o Glucose intolerance o Dyslipidemia o Fragility of skin and blood vessels o Decreased Immune function
• What are ssx of acromegaly (↑GH)?
o Gigantism (pre-puberty) o Pituitary deficit o Visceral enlargement o Enlarged jaw, hands, feet (shoe/ring size) o Spreading of teeth o Coarse facies o Hypertrophic joint disease o Hypertension o Left Ventricular Hypertrophy
• What is normal GH release? In acromegaly?
o N: peaks throughout day (7am, 12pm, 8pm, 1am)
o A: constant high level, with slight peaks
• What are tests for GH?
o Quantitative GH: Fasting level
o Provocative test for suspected def: Hypoglycemia causes ↑ GH; Give insulin, L-dopa or arginine; samples at 0, 15, 39, 45, 60, 90, and 120 minutes; Small rise = partial def; No rise = def
o Suppression test: Hyperglycemia ↓ GH but not in autonomous or ↑GH; Give glucose; GH does not drop in Acromegaly
• Why would you test insulin-like growth factor?
o IGF-1 levels reflect average daily GH; but don’t fluctuate
o ↓ = GH def, malnutrition and anorexia (monitor)
o ↑ High = acromegaly and gigantism
o Can asses CVD risk ( ↓ IFG-1, esp w DM)
o Cancer risk??
• What are normal PTH levels? Interfering factors?
o Normal for Intact PTH: 10-65 ng/L
o Diurnal variation: highest at 2 AM
o PO4 raise PTH up to 125%, so need to fast
o Interfere: ↑blood lipids, Hemolysis, Drugs
• How is PTH regulated?
o From Chief cells parathyroid gland, posterior to thyroid gland
o Stimulated by ↓ plasma Ca (NOT PO4)
o max release if Ca < 3.5 mg/dL → ↑cAMP →PTH secretion
o Lowest when Ca2+ > 5.5 mg/dL:
o Responds to Ca levels in seconds (unique Ca receptor)
o 1,25-(OH)2-D inhibits PTH gene expression
• What does PTH do?
o ↑ plasma Ca, ↓ PO4
o Bones: stim Ca resorption
o Kidney: Ca reabsorption in distal tubule of kidney; inhibit PO4 resorption (stim excretion)
o acts indirectly on intestine: stim 1,25-(OH)2-D synthesis.
• What is primary hyperparathyroidism?
o Ca homeostatic loss dt ↑ PTH secretion from adenomatous or hyperplastic parathyroid tissue
o → Hypercalcemia dt PTH-induced bone resorption, intestinal calcium absorption, renal tubular reabsorption
o dt both ↑PTH and ↑1,25-(OH)2-D
• what is hypoparathyroidism? 2 types?
o inadequate response of Vitamin D-PTH axis to hypocalcemic stimuli
o Hypocalcemia is often multifactorial
o Bihormonal: also ↓1,25-(OH)2-D
o PTH-deficient hypoparathyroidism: Reduced or absent synthesis of PTH; dt inadvertent removal of excessive parathyroid tissue during thyroid or parathyroid surgery
o PTH-ineffective hypoparathyroidism: Synthesis of biologically inactive PTH
• What is pseudohypoparathyroidism?
o PTH-resistant hypoparathyroidism
o defect in PTH receptor-adenylate cyclase complex
o Mutation in Gas subunit
o also resistant to TSH, glucagon and gonadotropins
• when would you test for PTH levels?
o To evaluate hyperparathyroidism
o Primary: Parathyroid neoplasia; ↑ PTH and Ca
o Secondary: chronic renal failure; ↑ PTH, normal/slightly ↓Ca
o Tertiary: CRF causes severe imbalance in Ca-PO4 ratio; ↑PTH, Ca
• What is calcitonin?
o acts to ↓ plasma Ca (only hormone that does so)
o from parafollicular cells of thyroid; distinct from follicular cells by their large size, pale cytoplasm, small secretory granules
o major stimulus is ↑ plasma Ca
o = physiological antagonist to PTH with regard to Ca homeostasis
o Used to tx hypercalcelmia, bone diseases
o Chronic ↑ does not produce hypocalcemia; removal of parafollicular cells does not cause hypercalcemia
o mb more important in regulating bone remodeling than in Ca homeostasis.
• What is Vit D?
o fat soluble; a prehormone
o in some food and made in body after exposure to UV rays
o Major biological function = maintain normal blood levels of Ca and Po4
o Other tissues like M0s, prostate also have Vit D receptor
o Def= rickets, eradicated in US
• How is vit D made?
o 7-dehydrocholesterol (sun UVB) → previtamin D (heat) → vitamin D3 → liver → 25(OH)D → kidney → 1,25-OH-D
• What are functions of Vit D?
o Endocrine (kidney): Ca homeostasis, muscle/bone/CV health, reg BP, neuro, immune o Paracrine (M0, mono): immunomdulation: prevent AI dz, control pathogens o Intracrine (prostate, breast, colon, lung, keratinocytes): regulate cell growth and differentiation
• What are tests for Vit D?
o for both 25(OH)D and 1,25-D
o 25(OH)D closely reflects total amount of vit D produced in skin and from diet
o D2 and D3: have similar biological activity, both can be measured
o DO NOT USE 1,25-D. often normal w vit D def (Volatile and does not give stable serum levels)
• Who is at risk for Vit D def?
o Low dietary intake o Malabsorption syndrome o Severe liver dis o Kidney disease o Drugs o Higher latitudes o People who spend little time outside o Older adults o Decreased sun exposure due to cultural reasons o Races with high skin melanin levels
what is recommended screening for Vit D def?
o only if at risk for deficiency o use serum 25(OH)D o def= 25(OH)D < 20 ng/ml o insufficiency = 25(OH) D 21–29 o only use 1,25(OH)2D in monitoring certain conditions
• who are candidate for 25(OH)D screening?
o Rickets, Osteomalacia, Osteoporosis
o Chronic kidney disease, Hepatic failure
o Malabsorption syndromes, Cystic fibrosis, Inflammatory bowel disease, Crohn’s disease, Bariatric surgery, Radiation enteritis
o Hyperparathyroidism
o Antiseizure medications, Glucocorticoids, AIDS medications, Antifungals, e.g. ketoconazole, Cholestyramine
o African-American and Hispanic children and adults
o Pregnant and lactating women
o Older adults with history of falls, nontraumatic fractures
o Obese children and adults (BMI 30 kg/m2)
o Granuloma-forming disorders: Sarcoidosis, Tuberculosis, Histoplasmosis, Coccidiomycosis, Berylliosis, Some lymphomas
• What are normal 25(OH)D levels?
o To prevent deficiency disease: > 25 nmol / L
o To prevent complications of insufficiency:
o 36-40 nmol/L (or >50)
o Toxic: >150
