Use LEFT and RIGHT arrow keys to navigate between flashcards;
Use UP and DOWN arrow keys to flip the card;
H to show hint;
A reads text to speech;
74 Cards in this Set
- Front
- Back
why is target gland secretion not normal when a patient with a poorly functioning pituitary gland has the target gland is stimulated with exogenous trophic hormone?
|
the target gland probably atrophies due to lack of trophic hormone
|
|
what factors alter the release of growth hormone?
|
GHRH (growth hormone releasing hormone) stimulate GH release
somatostatin (growth hormone inhibiting factor) block GH release insulin-like growth factor (IGF-1) feedback inhibits release of growth hormone dopamine agonists stimulate GH release |
|
where is somatostatin produced?
|
hypothalamus
delta cells of the pancreas |
|
what are the functions of somatostatin?
|
block release of growth hormone
block insulin secretion enhances use of fat as energy (along with other metabolic fcns) |
|
how are the actions of growth hormone mediated?
|
insulin-like growth factors (esp. IGF-1) aka somatomedins are released from the liver (mainly) upon stimulation from growth hormone, and they cause metabolic changes in secondary target tissues
|
|
why is replacement therapy for GH easy?
|
the target tissue product, IGF-1 has a long half-life
|
|
what is the primary use of GH replacement therapy?
|
treatment of male pituitary dwarfism
|
|
what was the first source of growth hormone?
|
cadavers (1960s to 70s)
in the late 70s, 4 ppl died of Creutzfeldt-Jakob disease which caused GH use to be ceased |
|
somatropin
|
recombinant growth hormone for GH replacement therapy
IGF-1 that is released in response has a long half-life, so only need 1-2 injections per week IMPORTANT: human growth hormone has a short half-life |
|
acromegaly
|
hypersecretion of growth hormone from a pituitary tumor
main symptom is excessive growth Tx: surgical removal/irradiation; dopaminergic analog (ropinirole); somatostatin analog (octreotide) |
|
ropinirole
|
dopaminergic agonist
exerts a paradoxical inhibitory effect upon GH release in persons with GH-secreting tumors used in treatment of acromegaly preferentially over levodopa b/c it has fewer side effects than levodopa used in treatment of hyperprolactinemia (mimics dopamine and therefore inhibits prolactin release) |
|
octreotide
|
somatostatin analog with a long half-life
inhibits GH release in acromegalic patient useful for Tx of alcoholic esophageal varices, b/c it lowers pressure in the portal circulation |
|
physiological actions of prolactin
|
stimulation of growth and development of the mammary glands in pregnancy and of lactation after delivery
inhibits the LH surge that is responsible for ovulation either causes mammary tumors or potentiates the effects of other drugs to do so |
|
stimuli for prolactin release
|
prolactin releasing hormone
opiates estrogens stress exercise |
|
what hormone inhibits the release of prolactin?
|
dopamine (prolactin releasing inhibitory hormone)
dopamine is the final control for prolactin release - it is very dominant, and overrides all other stimuli |
|
exogenous hyperprolactinemia
|
increased prolactin caused by drugs that decrease dopamine levels (antipsychotics)
Sx: galactorrhea, gynecomastia, infertility (negation of FSH and LH) |
|
what is the treatment for hyperprolactinemia?
|
if endogenous, surgically remove tumor
ropinirole inhibits prolactin release by mimicking dopamine |
|
what is produced in the medulla of the adrenal gland?
|
catecholamines
|
|
what is produced in the zona glomerulosa of the adrenal cortex?
|
aldosterone
stimulated by angiotensin II and elevated plasma potassium |
|
what is produced in the zona fasciculata of the adrenal cortex?
|
cortisol
stimulated by ACTH |
|
what is produced in the zona reticularis of the adrenal cortex?
|
androgens
stimulated by ACTH |
|
what are the layers of the adrenal cortex from inside out? what are the products of each layer?
|
zona reticularis - androgens
zona fasciculata - cortisol zona glomerulosa - aldosterone |
|
what is the major source of androgens in women?
|
testosterone
|
|
aminoglutethimide
|
anti-corticosteroid drug
blocks aromatase (converts of testosterone to estrogen) blocks CYPscc (converts cholesterol to pregnenolone) useful for Tx of Cushing's syndrome (blocks cortisol formation) and breast CA (blocks androgen/estrogen conversion) |
|
ketoconazole
|
blocks 17alpha-hydroxylase
blocks synthesis of cortisol, so effective as a Tx for Cushing's syndrome |
|
what is the main inhibitor of ACTH release?
|
cortisol (feedback inhibition)
|
|
what reactions are enhanced by ACTH?
|
CYPscc (converts cholesterol to pregnenolone)
17alpha-hydroxylase (converts pregnenolone to 17-hydroxy-pregnenolone, a precursor for cortisol and testosterone) 11beta-hydroxylase (converts 11-deoxycorticosterone to corticosterone, a precursor for aldosterone) |
|
metyrapone
|
blocks 11beta-hydroxylase
- inhibits corticosterone and subsequently aldosterone synthesis - inhibits cortisol synthesis Tx for Cushing's syndrome |
|
how are doses administered for cortisol replacement therapy?
|
2/3 of the dose are given in the morning
1/3 of the dose is given in the evening |
|
when are cortisol levels highest?
|
8am (levels rise overnight to a peak at 8 am, and then decrease throughout the day)
|
|
what are the functions of cortisol?
|
(1) stimulates gluconeogenesis
(2) stimulates protein mobilization (3) stimulates fat mobilization (4) stabilizes lysosomes -> dec. inflammation (5) helps alpha1 receptors work -> sensitizes arterioles to NE (6) feedback inhibits CRH release from hypothalamus and ACTH release from anterior pituitary |
|
why are urinary metabolites of cortisol (17-hydroxycorticoids) measured rather than plasma cortisol levels?
|
the plasma cortisol levels are highly variable due to the pulsatile release of the cortisol
|
|
cosyntropin
|
synthetic ACTH with identical activity to endogenous ACTH
on administration: with normal adrenal cortex -> cortisol secretion occurs with diseased adrenal cortex -> cortisol secretion is decreased or absent |
|
symptoms of Addison's Syndrome
|
Addison's Syndrome = deficient cortisol
Sx = muscle fatigue, listlessness, sensitivity to stress, hypotension |
|
primary adrenal insufficiency
|
aka Addison's Disease
results from deranged adrenal cortex ACTH is secreted by pituitary, but cortex is unable to synthesize cortisol in response to the trophic hormone, and therefore ACTH levels are high because there is no negative feedback by cortisol excess levels of trophic hormone cause hypertrophy of the adrenal cortex |
|
secondary adrenal insufficiency
|
aka Addison's syndrome
results from insufficient ACTH secretion by ant. pituitary ant. pituitary doesn't secrete ACTH, so the adrenal cortex doesn't have sufficient stimulation to produce cortisol lack of trophic hormone results in atrophy of the adrenal cortex |
|
what are the observations in a patient with adrenal insufficiency (Addison's Syndrome)?
|
primary adrenal insufficiency results in hyperpigmentation, but secondary adrenal insufficiency does not
ACTH originates from a family of peptides including MSH, and it has some MSH activity so increased levels of ACTH (as in primary insufficiency) causes hyperpigmentation |
|
what ACTH levels are found in adrenal insufficiency?
|
primary (adrenal cortex itself is defective) - elevated ACTH
secondary (inadequate ACTH is produced by ant. pit.) - reduced ACTH |
|
what happens to plasma cortisol levels in patients with adrenal insufficiency on administration of synthetic ACTH (cosyntropin)? how does this compare to normal?
|
normal: plasma cortisol levels inc. with increasing cosyntropin
primary insufficiency: plasma cortisol levels remain constant no matter how much cosyntropin is added secondary insufficiency: plasma cortisol levels inc. with increasing cosyntropin, but levels don't get as high as those of normal patients because the gland atrophy prevents the normal response |
|
what is the treatment for primary adrenal insufficiency (Addison's disease)?
|
cortisol replacement therapy (2/3 in the morning and 1/3 in the evening to mimic natural secretion)
mineralocorticoid must be replaced b/c entire adrenal cortex is damaged |
|
what is the treatment for secondary adrenal insufficiency (Addison's syndrome)?
|
cortisol replacement therapy (2/3 in the morning and 1/3 in the evening to mimic natural secretion)
|
|
what is the treatment for congenital adrenal hyperplasia?
|
cortisol replacement therapy
mineralocorticoids |
|
what causes congenital adrenal hyperplasia?
|
defect in one of the enzymes responsible for cortisol synthesis (usually 21beta-hydroxylase therefore everything is shifted to androgen synthesis)
|
|
Sx of Cushing's syndrome (excessive cortisol)
|
truncal obesity (wasting of peripheral muscles coupled with truncal deposition of fat)
moon facies (deposition of fat in face) diabetes (hyperglycemia from mobilization of fat stores) generalized peripheral edema (excessive secretion of mineralocorticoids and cortisol, which leads to HTN) hirsutism in females (excessive androgen production) |
|
what is Cushing's disease?
|
pituitary dependent adrenal hyperplasia, resulting from excessive secretion of ACTH by an adenoma of the anterior pituitary
sensitivity of ant. pit. is decreased so it takes higher levels of cortisol to inhibit ACTH secretion and ACTH is secreted in excess until the hyperplastic adrenal cortex produces enough cortisol to result in feedback inhibition 2/3 of cases of endogenous Cushing's disease |
|
what is Cushing's syndrome?
|
excessive cortisol resulting from:
- adrenal adenoma or carcinoma increases cortisol levels via tumor secretion of the hormone (ACTH is not necessary for stimulation of tumor secretion) - ACTH-secreting ectopic tumor results in stimulation of excess cortisol secretions by high levels of ACTH (pituitary ACTH levels decrease while circulating ACTH levels increase) - Exogenous disease from treatment with steroids |
|
where are ectopic ACTH-secreting tumors commonly found?
|
lungs
|
|
what is the effect, on plasma cortisol levels, of dexamethasone administration in normal patients vs. patients with excessive cortisol (cushing's syndrome)?
|
dexamethasone = glucocorticoid (imitates cortisol)
normal: increased dexamethasone causes decreased plasma cortisol levels pituitary-dependent (pituitary adenoma): increasing dexamethasone decreases plasma cortisol levels, but the level doesn't get as low as a normal patient b/c sensitivity of ant. pit. to negative feedback is decreased ectopic/adrenal tumor: administration of dexamethasone has no effect (cortisol secretion is uncoupled from ACTH) |
|
what is the effect, on plasma ACTH levels, of metyrapone administration in normal patients vs. patients with excessive cortisol (cushing's syndrome)?
|
normal: metyrapone administration increases plasma ACTH
pituitary ACTH-secreting adenoma: metyrapone administration increases plasma ACTH even more than in a normal patient (inhibition on tumor is released) ectopic ACTH-secreting tumor: plasma ACTH is high without metyrapone, but administration of metyrapone has no effect adrenal tumor: metyrapone administration increases plasma ACTH levels, but plasma ACTH levels are less than in normal patients at all times |
|
treatment for excessive cortisol (Cushing's syndrome)
|
1) adrenalectomy
2) aminoglutethimide (block conversion of cholesterol to pregnenolone) 3) mitotane (destroys adrenal gland chemically) 4) metyrapone (block 11beta-hydroxylase, last step in cortisol synthesis) 5) ketoconazole (blocks 17alpha-hydroxylase, converts pregnenolone to a cortisol precursor) |
|
what is the effect of corticosteroids on arachidonic acid, prostaglandins, and leukotrienes?
|
inhibited in part by glucocorticoid induction of a protein (lipocortin) that inhibits phospholipase A2
occurs in many tissues/cell types |
|
what is the effect of corticosteroids on cytokines (IL-1, IL-6, TNF-alpha)?
|
block production and release (keeps T cells from being stimulated)
|
|
what is the effect of corticosteroids on ELAM-1 and ICAM-1?
|
ELAM-1 = endothelial leukocyte adhesion molecule-1
ICAM-1 = intracellular adhesion molecule-1 - both are intracellular adhesion molecules in endothelial cells that are critical for leukocyte localization expression is blocked by corticosteroids |
|
what is the effect of corticosteroids on basophils?
|
IgE-dependent release of histamine, and LTC4 is inhibited
|
|
why are glucocorticoids used to treat lymphomas?
|
several cytokines required for lymphocyte proliferation are blocked by glucocorticoids
**not used alone** |
|
what are the indications for glucocorticoid use?
|
- inflammatory disorders (asthma)
- hematologic disorders - cerebral edema due to CA mets - collagen vascular disorders - inflammatory dermatologic diseases - inflammatory GI disorders - hypercalcemia - inflammatory hepatic disease - autoimmune neuromuscular disorders - inflammatory ocular disease - prevent permanent paralysis in spinal cord compression |
|
for what hematologic disorders are glucocorticoids indicated?
|
autoimmune hemolytic anemia
lymphomas hodgkin's disease lymphatic leukemia multiple myeloma |
|
what are the problems associated with glucocorticoid treatment of dermatologic diseases associated with inflammation?
|
candida overgrowth
skin thinning |
|
why do corticosteroids cause hypercalcemia?
|
they act as physiologic antagonists of vitamin D, thereby decreasing GI calcium absorption
|
|
what neuromuscular disorders can be treated with corticosteroids?
|
myasthenia gravis
multiple sclerosis **both have autoimmune component** |
|
why could corticosteroids be used to treat spinal cord compression?
|
helps to prevent permanent paralysis
|
|
what problem with older corticosteroids has been mostly overcome by the newer corticosteroids?
|
older corticosteroids had some mineralocorticoid ability which caused edema and hypokalemia, and sometimes hypertension
newer corticosteroids have little mineralocorticoid activity, so these problems have mostly been overcome |
|
why do corticosteroids cause osteoporosis?
|
(1) decrease GI calcium absorption
(2) inhibit osteoblast activity (depositing bone matrix) (1) and (2) cause increased parathyroid hormone secretion which stimulates osteoclast activity and causes osteoporosis |
|
what are the adverse reactions to corticosteroids?
|
- osteoporosis
- growth suppression in kids - aggravation of diabetes - altered mental status (irritable) - myopathy (wasting of muscle proteins for glucose production) - infections (suppressed immune fcn) - suppressed diagnostic Sx of inflammation - Addison's syndrome (HPA axis is suppressed -> dec. ACTH) GI ulceration (loss of protective PGs in stomach) |
|
why do corticosteroids cause GI ulceration?
|
block production of prostaglandins in the stomach, which are usually protective of the stomach wall
|
|
guidelines for non-endocrine corticosteroid therapy
|
a) accurate diagnosis must be made
b) alternative therapies must have failed c) minimum dose needed to produce desired effect d) risk of adverse effects = dosage X length of therapy - short term-high dose therapy (asthma) - long term-low dose therapy (RA) |
|
what is the cutoff for needing to taper a dose of corticosteroid therapy?
|
if therapy is longer than two weeks, then you must slowly taper the dose to zero
the hypothalamic-pituitary-adrenal axis is not suppressed if the therapy lasts less than two weeks |
|
prednisone
|
synthetic corticosteroid
more glucocorticoid activity than cortisol less mineralocorticoid activity than cortisol duration of action: 12-36 hrs |
|
prednisolone
|
synthetic corticosteroid
more glucocorticoid activity than cortisol less mineralocorticoid activity than cortisol duration of action: 12-36 hrs |
|
methylprednisolone
|
synthetic corticosteroid
more glucocorticoid activity than cortisol less mineralocorticoid activity than cortisol duration of action: 12-36 hrs |
|
dexamethasone
|
synthetic corticosteroid
pure glucocorticoid activity NO mineralocorticoid activity duration of action: 36-72 hours |
|
fludrocortisone
|
synthetic corticosteroid
NO glucocorticoid activity pure mineralocorticoid activity duration of action: 8-12 hours |
|
in what ways are synthetic corticosteroids improved over cortisol?
|
longer duration of action
more specificity for glucocorticoid activity |
|
what synthetic corticosteroids are potent and pure glucocorticoids?
|
"methasones" i.e. dexamethasone
|