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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