Adrenal Steroids-Burkin Flashcards
What does CRH release? What does TRH release? What do somatostatin & dopamine release?
CRH–>ACTH increases
TRH–>TSH & prolactin increases
somatostatin–>GH decreases
dopamine–>prolactin decreases
When do you get the most GH release? What is its pattern of release?
diurnal 24 hour secretion
highest secretion at night
What is the source of GH?
somatotropes & somatomammotropes of ant pit.
What are the actions of GH?
decreases insulin sensitivity
increases lipolysis
increases IGF-1–>increases protein synthesis & epiphyseal bone growth
What stimulates the release of GH?
GHRH hypoglycemia exercise AA sleep
What inhibits the release of GH?
somatostatin
hyperglycemia
IGF-1 via neg. feedback
What is a major determinant of size in dogs?
IGF-1 allele
What is a possible cause of GH excess?
somatotrope tumor–>can cause gigantism or acromegaly
What is a good treatment for a somatotrope tumor?
surgical removal
somatostatin analogs–octreotide
What are some possible causes of GH deficiency?
hypothalamic or pituitary lesions
GH receptor defect in target tissues-Laron dwarfs
IGF-1 deficiency–African pygmies
What are some possible results of hypothalamic or pituitary lesions, leading to GH deficiency?
dwarfism
adult hypopituitarism–weakness, wrinkly & pale skin, loss of libido, genital atrophy, amenorrhea
What is the treatment for GH deficiency?
GH (somatrophin) & IGF-1 replacement
What are some times when you need to use exogenous GH?
Turner’s syndrome-can increase height
failure to thrive
AIDs wasting–can help treat
increase milk production in cows
WHat are examples of GHRH analogs?
can increase GH release
sermoelin
geref
what is the source of prolactin?
lactotropes & somatomammotropes of ant pit
What are the actions of prolactin?
milk production
maternal behavior
decreases gonadatropin action, decreased steroid production
What stimulates prolactin release? WHat inhibits prolactin release?
stimulated: oxytocin, TRH, VIP, estrogen
inhibited: dopamine
What are some things that can cause hyperprolactinemia?
lactotrope adenoma
dopamine receptor blocker (psychiatric med)
stress/vigorous exercise
What are the effects of hyperprolactinemia in females?
amenorrhea
infertility
galactorrhea
What are the effects of hyperprolactinemia in males?
impotence
infertility
decreased sperm count
What is a good treatment for hyperprolactinemia?
dopamine agonist (bromocryptine)–suppresses prolactin
What does oxytocin released from the post pit do?
stimulates milk production
stimulates uterine contractions
What does ADH release from the post pit do?
increases water absorption
released when BP drops or blood conc’n increases
What happens when you have a deficiency of vasopressin? Treatment?
diabetes insipidus
treated w/ desmopressin acetate
How is GH deficiency diagnosed?
A GH level obtained after 30 mins of exercise was low and a preliminary diagnosis of GHD was made.
10g of arginine 10% I.V. (0.5 g/kg) over 30 mins and later 2 units of regular human insulin IV (0.1 unit/kg) to stimulate GH secretion. GH levels drawn after administration of both agents rose to 3 mg/L (normal is >10). The study was repeated with similar results and a definitive diagnosis of GHD was made.
What is an appropriate treatment for GH deficiency? Good alternative?
use recombinant GH (human)
**alternative–IGF-1
Pt has short stature secondary to GH deficiency. Management?
GHRF (not enough GH coming from ant pit)
sometimes used for patients with height <5th percentile
patients with renal failure
What is Addison’s disease?
partial or complete loss of adrenocortical function
What is Cushing’s disease?
excessive secretion of adrenocorticoid steroids
metabolic disorder
What does pro-opiomelanocortin do?
makes like 8 peptides, including ACTH (39 AA).
What are 2 important domains of ACTH?
activation & binding domain.
Describe the 3 zones of the adrenal cortex & what each secretes.
Outer–Inner
Zona Glomerulosa: Aldosterone
Zona Fasciculata: Cortisol
Zona Reticularis: Androgens
____ mainly targets the fasciculata & reticularis.
____ mainly targets the glomerulosa.
ACTH–>fasciculata & reticularis
Ang II–>glomerulosa
Describe the receptor that binds ACTH in the adrenal cortex.
cell surface G protein receptor
linked to adenylyl cyclase.
More cAMP, which activates protein kinase.
This activation causes increased transport of cholesterol to the mitochondrial matrix & increased steroid synthesis in the long run.
Cholesterol is transported into the mitochondrial matrix & P450scc & becomes other types of steroids. What is the regulator of this ?
StAR
steroidogenic acute regulatory protein
What is the rate limiting step in steroid synthesis?
delivery of cholesterol to mitochondria
T/F The steroid synthetic capacity of the adrenal gland is markedly enhanced by the action of ACTH.
True.
After cholesterol is in the mitochondria w/ P450scc & triggered by ACTH or Ang II…what is produced?
pregnenolone
**that can make 17alpha hydroxypregnenolone (which can go on to be cortisol or androgens) OR make progesterone (which can feed into all 3 pathways)
Describe the mineral corticoid pathway.
Zona glomerulosa
cholesterol–>pregnenolone–>progesterone–>–>Aldosterone w/ the help of Ang II mainly
Describe the glucocorticoid pathway.
zona fasciculata
cholesterol–>pregnenolone–>17-alpha hydroxypregnenolone OR progesterone–>17-alpha hydroxyprogesterone–>11-deoxycortisol–>cortisol
Describe the androgenic pathway.
Zona reticularis.
cholesterol–>pregnenolone–>17-alpha hydroxypregnenolone–>DHEA–>androstenedione–>testosterone–>estrogen
Starting from the hypothalamus….how do you get cortisol etc from the adrenal gland?
Hypothalamus secretes CRH.
CRH acts on the ant pit & secretes ACTH.
ACTH acts on the adrenal cortex & gives you DHEA, aldosterone, and cortisol.
DHEA is a major source of androgens for which gender?
females
What does cortisol do?
increases metabolic fuels
increased blood glucose
increased amino acids & fatty acids
Describe the synthesis & secretion of ACTH.
diurnal synthesis controlled by light-dark cycle
cortisol levels are highest in the morning
aldosterone levels are pretty steady
How much cortisol is released each day?
approx 10 mg
higher conc’n in the morning
About how much aldosterone is released each day?
0.125 mg/day
steady throughout the day
How does cortisol travel in the body?
bound to transcortin (cortisol binding globulin) & albumin
How can synthetic ACTH be administered? What is its half life?
injection (parenteral)
As Acthar or cosyntropin
t1/2=15 min
When might you give a patient synthetic ACTH?
when you are diagnosing adrenal insufficiency
A bunch of ACTH–>should get increase in cortisol.
WHat is the action of ACTH?
homeostatic hormone
w/o adrenal cortex can only survive in perfect conditions
a small amount of cortisol can cause a lot of lipolysis (unlike catecholamines)
Cortisol has important actions for carb, protein, and lipid fcn. What are its actions?
- *stimulates protein breakdown to AA
- *facilitates lipid breakdown in adipose tissue (w/ high levels, get weird fat distribution)
- *promotes hepatic gluconeogenesis
- *makes glucose available to brain by inhibiting other things from using it all up!
What does it mean that cortisol is permissive?
small amount of it is required for metabolisms, esp those promoted by catecholamines, by lipolysis, bronchodilation
What does DHEA do for females?
pubertal growth spurt
secondary sex characteristics: pubic & axillary hair
libido
DHEA–>estrogen via aromatase in peripheral tissues
OF the following drugs, give the 2 with the lowest anti-inflammatory effects? Greatest Na+ retaining effects? Cortisol Cortisone Fludrocortisone Prednisone Prednisolone methylprednisolone triamcinolone betamethasone dexamethasone
Anti-inflammatory (low effects)
Cortisol-1
Cortisone-0.8
Na+ retaining effects (high)
Cortisol-1
Fludrocortisone–125
WHich of the following drugs have short half lives? Long half lives? Cortisol Cortisone Fludrocortisone Prednisone Prednisolone methylprednisolone triamcinolone betamethasone dexamethasone
Cortisol-S Cortisone-S Fludrocortisone-S betamethasone-L dexamethasone-L
Give some drugs that have similar actions to cortisol but longer half lives & lower Na+ retaining effects?
prednisone
prednisolone
dexamethasone
triamcinolone
What is betamethasone used for?
low degree of protein binding
given to pregnant women in premature labor to hasten lung maturation w/ surfactant production
What is fludrocortisone used for?
Remember-125 on a scale of Na+ retaining–so acts like aldosterone
but has longer half life.
good for treatment following adrenalectomy or something.
Describe the differences & similarities in the actions of mineral corticoids & glucocorticoids on target cells.
Same receptor pathway.
transporter protein–>receptor–shock proteins into nucleus–>bind target genes & alter transcription.
Mineralcorticoids act mainly on kidney. If they are targeted by cortisol–>they convert it to cortisone (inactive).
Glucocorticoids act on a bunch of different tissues, just prevented from acting on kidney by inactivation.
Which conditions exemplify aldosterone excess? What are their causes & symptoms?
Aldosterone Excess-Primary Hyperaldosteronism (Conn’s), Secondary hyperaldosteronism
**hypersecreting tumor of zona glomerulosa
**High RAAS
**Symptoms: hypernatremia
hypokalemia
HTN
Which conditions exemplify cortisol excess? What are their causes & symptoms?
Cortisol Excess-->Cushing's Syndrome Causes: Hypothalamic or Pituitary Tumor Adrenal Tumor Ectopic ACTH (from lung cancer or something) Symptoms: Hyperglycemia Excess proteolysis Abnormal fat distribution Insulin resistance low immune response low inflammatory response
Which conditions exemplify androgen excess? What are their causes & symptoms?
Androgen Excess–>Congenital Adrenal Hyperplasia
Genetic deficiency in cortisol enzymes (messed up hydroxylation by 21 & 11-OH enzymes)
Symptoms:
pseudohermaphroditism, pseudopuberty, virilization, inappropriate masculinization
Which conditions exemplify cortisol & aldosterone deficiency? What are their causes & symptoms?
primary adrenal insufficiency (Addison’s)
Causes-destruction of adrenal cortex
Symptoms: poor response to stress, hypoglycemia, low metabolic activities
Which conditions exemplify cortisol deficiency? What are their causes & symptoms?
Secondary adrenal insufficiency
insufficient ACTH
Symptoms:
hyperkalemia, hyponatremia, Hypotension
also cortisol deficiency symptoms??
What are the signs & symptoms of Cushing’s syndrome?
myopathy, central obesity, Moon face, Acne, hirsutism, bruising and capillary fragility, hypertension, glucose intolerance, hypokalemia, arteriosclerosis, infections, osteoporosis, hypogonadism
What % of Cushing’s syndrome cases are ACTH dependent (like too much ACTH being secreted) 7 what % are ACTH-independent?
80% ACTH-dependent
20% ACTH -independent
What are examples of ACTH-dependent causes of Cushing’s syndrome?
Pituitary tumors (most common) Lung cancers
What are some examples of ACTH-independent causes of Cushing’s syndrome?
Benign Adrenal Tumors (adenoma)–more common
Malignant Adrenal Tumors (adrenal cell carcinoma)
How do you confirm Cushing’s?
dexamethasone suppression test
w/ a bunch of dexamethasone on board the body should be like–let’s stop producing so much cortisol!!
If not–>cushing’s
Once again, what is the effect of corticosteroids on carb & protein metabolism?
glucose–increases
peripheral utilization of glucose–decreases (more for the brain!)
storage of glucose as glycogen–increases
Once again, what is the effect of corticosteroids on lipid metabolism?
redistribution of body fat buffalo hump moon face thinning in extremities Note: all these effects can be seen in patients on high dose long term corticosteroid therapy.
What are the CNS effects of corticosteroids? What are the CNS effects of its absence?
- *causes a feeling of well being
* *w/o it–>like w/ Adddison’s-apathy, depression, irritability, psychosis
What do glucocorticoids do to the blood?
increase hemoglobin & RBCs
increase in neutrophils & decrease in lymphocytes, eosinophils etc.
Cushing’s–see polycythemia
Addison’s–see normochromic normocytic anemia
How are glucocorticoids anti-inflammatory?
Decrease circulating lymphocytes and suppress release of cytokines
Suppress inflammation to all stimuli
Block both early and late events in the inflammatory process and effect both cellular and humoral pathways
Extremely useful as anti-inflammatory agents in numerous clinical settings e.g. transplantation
How exactly do glucocorticoids block the formation of cytokines?
go into the nucleus & block the transcription factor from binding to the receptor site on the gene. Less synthesis of protein cytokines.
T/F All types of inflammatory cells, including endothelial cells, fibroblasts etc are affected by the anti-inflammatory effects of glucocorticoids.
True.
What forms do glucocorticoid drugs come in?
all forms! injectable enema oral topical inhalation
What happens if you are on a high dose of corticosteroids & you withdraw suddenly?
corticosteroid toxicity
adrenal insufficiency
fever, myalgia, arthralgia, malaise
**should taper down on steroids.
Describe in more detail the characteristics/symptoms of corticosteroid toxicity.
Hypokalemic alkalosis and edema Increased susceptibility to infection Peptic ulceration (H. pylori) Myopathy Behavioral disturbance Cataracts Osteoporosis & vertebral compression fractures Growth arrest in children
Where do mineral corticoids act?
DCT of kidney–>increased reabsorption of Na+
K+ wasting. H+ leaves too.
If you have too much aldosterone–>what are the symptoms?
hypernatremia
hypokalemia
alkalosis
increased ECF–>edema
What does aminoglutethamide do?
at low dose–messes with estrogen synthesis (blocks aromatase)
at high doses–inhibits P450 side chain cleaving enzyme & production of pregnenolone.
Therefore–blocks cortisol & aldosterone
When might aminoglutethimide be used clinically?
treatment of Cushing’s disease
might need to administer cortisol or mineral corticoid supplements to counteract the deficiency that you create.
What is the deal with ketoconazole?
blocks ergosterol synthesis in fungi.
inhibits P450 17 alpha enzymes for cortisol synthesis.
at high doses–also blocks P450scc (blocking aldosterone too)
Which conditions is ketoconazole used to treat?
Cushing’s syndrome
adrenal carcinoma
hirsutism
breast & prostate cancer
What’s the deal with trilostane?
inhibits 3-beta-hydroxy steroid dehydrogenase
blocks formation of cortisol & aldosterone
While taking trilostane you get more excretion of which thing?
17-keto steroids
Which condition is trilostane used to treat? Is it legal in the US?
pulled from US market
used in treatment of Cushing’s
What’s the deal with metyrapone?
blocks 11-beta hydroxylation (last step before cortisol)
not used often but used in assessment for pituitary release of ACTH or Cushing’s
Describe how metyrapone can be used diagnostically.
you’re wondering if ACTH is being released from the pituitary appropriately.
give metyrapone.
more ACTH production.
more 17-OH steroid in the urine (if everything is working properly)
What should be the first treatment attempted for a rheumatoid arthritis patient?
NSAID
Corticosteroids
NSAID to prevent corticosteroid toxicity. At some point, it will hurt their stomach liver etc & won’t be powerful enough so you will have to switch.
What time of day do you want to give prednisone to a patient with rheumatoid arthritis?
in the morning, to mimic the diurnal secretion of cortisol.
Prednisone is given to patients usu in alternative-day therapy when it is in high doses. Why might that be?
want to do your best to preserve body’s natural production of cortisol.
What drugs can be used to treat Cushing’s?
aminoglutethamide
ketoconazole
maybe (less likely)–metyrapone
NOT trilostane (illegal)
