Lecture 13: Adrenal Gland Flashcards
CUSHING’S presentations
- C- central obesity, collagen fiber weakness
- U - urinary free cortisol and glucose increase
- S - striae, suppressed immunity
- H - hypercortisolism, hypertension, hyperglycemia, hypercholesterolemia
- I - iatrogenic
- N - neoplasms
- G - glucose intolerance, growth retardation
endogenous vs exogenous causes of cushings syndrome
ENDOGENOUS overproduction of cortisol
EXOGENOUS taking medicines containing glucocorticoids like hydrocortisone
the zona glomerulosa produces ….
mineralocorticocoides which target the kidney
the zona fasciulata produces..
glucocorticoids which target the liver
the zona reticularis produces..
androgens which target M+F sex organs
the medulla of the adrenals produces..
catecholamines which target liver, muscle, heart
why do all cells within the adrenal gland cortex have lipid droplets, mitochondria, and smooth ER
b/c the hormones are released as they are produced - there is no storage mechanism for steroid hormones anywhere in the body
what is the major catecholamine produced by the central portion of the adrenal medulla
epinephrine
norenipenphrine
conversion of cholesterol into pregnenolone is regulated by what
HPA axis: ACTH
conversion of pregnenolone into mineralocorticoids like aldosterone is regulated by what
the renin-angiotensin system and ACTH
conversion of pregnenolone into glucocorticoids and or androgens is regulated by what
HPA axis: ACTH
what is the medulla of the adrenal cortex regulated by
autonomic control of the sympathetic NS
_______hydroxylase activity differentiates adrenal corticoids from progesterone
C-21
_____ Hydroxylase differentiates cortisol from aldosterone
C-17
The zona glomerulosa lacks _____ hydroxylase, the enzyme necessary for cortisol and androgen synthesis
17-α hydroxylase
so pregnenolone can only be converted to progesterone by 3β-HSD
the zona glomerulosa does NOT synthesize ______ or ______
glucocorticoids or androgens
what stimuli activate the RAAS cascade
- decreases in bp
- decrease in ECF volume
K+ increases _______ which increases _____ excretion in the kidney
aldosterone, K
when Aldosterone binds mineralocorticoid receptor, it activates what target genes
- Apical ENaC (recovery of Na)
- basolateral Na/K ATPase
what is the main regulator of the aldosterone pathway
Angiotensin II
effects of aldosterone on solute transport
- Na+ reabsorption
- K+ secretion
- increase in extracellular fluid
- BP increases
- H+ excretion sitmulated
what is Conn’s Syndrome
pretty rare
primary hyperaldosteronism
usually caused by aldosterone secreting tumor
what are the physiological effects of Conn’s syndrome
- Increased Na resorption: hypernatremia, fluid retention, hypertension
- increased K+ secretion: hypokalemia
- increased H+ secretion: metabolic alkalosis
- RAAS inhibited: low renin
symptoms of Conn’s Syndrome
- polydipsia
- hypertension
- fatigue
- frequent urination
- heachae
- visual disturbances
- neuropathy
zona _____ has all the enzymes needed for cortisol synthesis, including 17-α hydroxylase
fasciculata
steroid transport requires ______
b
binding proteins
* corticosteroid binidng globulin or transcortin bind 75% of cortisol
* 15% bound to albumin
* 10% free
albumin carries ____% of aldosterone and ___% is found w/ transcortin, leaving 40% free
50%
10%
steroid transport requires binding proteins however it is the ______ hormone that is available to signal
Free
there is no _____ of steroids in the endocrine glands, they are released as they are synthesized
storage
the rate at which a hormone is _______ is the primary driver of its levels in blood
secreted
but can also be influenced by the rate at which hormones are broken down or the rate at which they are excreted in the kidneys
Glucocorticoid and mineralocorticoid receptors are ______
cytoplasmic
Mineralocorticoid receptors (MRs) and Glucocorticoid receptors (GR) have a shared homology in their lignand and DNA binding domians… what problem does this cause
- plasma CORT concentration is 100-1000x higher than that of aldosterone
- CORT binds MR w/ high affinity
How can selectivity of aldosterone for MRs be achieved??
How can selectivity between MRs and GRs be achieved?
in tissues targeted by aldosterone, the activity of 11β-hydroxysteroid dehydrogenase II (11β-HSD2)** converts cortisol into cortisone, **a form that does NOT activate the MRs b/c it is inactive
what would a decrease in 11β-HSD2 lead to
decreased conversion of CORT to cortisone and increased aldosterone like effects
CORT binds to MR w high affinity and produces aldosterone like effects including Na+ retention
in males, androgens come from the _____ and in females, the major source of androgens is _____
males - testes
females - cortex
zona reticularis has ___,___ lyslase which is necessary for DHEA and androstenedione
17,20 lyslase
17,20 lysase promotes conversion of pregnenolone to _____ and ______
DHEA and Androstenedione
Zona reticularis lacks ____ which limits aldoesterone synthesis
21β-hydroxylase
steroid synthesis requires the presence of catalytic enzymes, thus adrenal steroid synthesis, like gonadal steroid synthesis, is _______
regional
plasma binding protein for DHEA
Albumin
plasma binding protein for cortisol
transcortin
plasma binding protein for aldosterone
albumin
what is the receptor for aldosterone
Mineralocorticoid Receptor (MR)
what is the receptor for cortisol
Glucocorticoid receptor (GR)
what is the receptor for DHEA
Androgen receptor (AR)
component of the autonomic NS, innervated by sympathetic fibers
Adrena medulla
primary hormones of the adrenal medulla
Norepinephrine (NE) and epinephrine (E)
the sympathetic NS innervates the adrena medulla w/ a ______ fiber that releases _______
preganglionic fiber that releases acetylcholine
______ cells in the adrenal medulla are modified neuronal tissue
Chromaffin
what do Chromaffin cells do
release NE and E into the blood
where does catecholamine synthesis occur
in chromaffin cells from tyrosine
enzyme dependent
what are the norepinephrine producing enzymes in catecholamine synthesis
- Tyrosine Hydroxylase (TH)
- L-aromatic amino acid decarboxylase (AADD)
- Dopamine β hydroxylase (DBH)
what is the epinephrine producing enzyme in catecholamine synthesis
Phenylethanolamine-N-methyltransferase (PNMT)
chromaffin cells are specialized to store catecholamines for release when sitmulated by…
the sympathetic NS
what hormone activates the last step of catecholamine synthesis
cortisol
Chromaffin cells that express ______ can convert NE to E
Phenylethanolamine-N-methyltransferase (PNMT)
80% E to 20% NE ratio
dopamine causes a negative feedback on ____ activity
tyrosine
what are the physiological effects of catecholamine
- effects are RAPID and short lived (half life 2 min)
- increases cardiac contractility, HR, BP, arteriolar vasoconstriction
- bronchiolar dilation
- pupillary dilation
- decreases GI function
- increases alertness and brain activity
- mobilizes fuel in times of shock
what is the goal of catecholamine in mobilizing fuel when stimulated for fight or flight
promote glucose production for use by the brain
what things cause an increased secretion of catecholamine
- fight or flight response
- hypotension
- shock
- heart failure
- hypoglycemia
NE effects on α1 and α2 receptors
α1: arteriolar smooth muscle contraction
α2: sympathetic nerve endings and sm contraction
NE effects on β1 and β2 receptors
β1: affects heart activity
β2: sm relaxation and metabolism
what are the 2 main enzymes for E and NE degradation
- monoamine oxidase (MAO)
- catechol-O-methyltransferase (COMT)
primary degradation enzyme for NE
MAO in neuronal cytoplasm
primary degradation enzyme for E
COMT in interstitial fluid of synapse, heart, liver, kidney
what is the metabolic byproduct of catecholamine degradation
Vanillylmandelic acid (VMA)
excreted in urine and can serve as a measure of SNS activity
what is the metabolic byproduct of catecholamine degradation that can be used to measure SNS activity
Vanillylmandelic acid (VMA)
term for adrenomedullary hyperfunction
Pheochromocytoma
- catecholamine secreting tumor
- >20x more secretion than normal
symptoms of adrenomedullary hyperfunction(Pheochromocytoma)
- hypertension, rapid pulse, chest pain
- excessive sweating
- headache, fatigue
- hyperglycemia
endogenous causes of cushing’s syndrome…
- pituitary tumor = cushing’s disease (70% of cases)
- adrenal tumor (15% of cases)
- other or unknown causes
breeds in which Cushing’s disease is common
- poodles (esp. miniature)
- dachshunds
- boxers
- boston terriors
- yorkies
- saffordshire terriers
canine specific serum abnormalities that co-occur w/ Cushing’s
- elevated alkaline phosphatase (SAP)
- elevated alanine transaminase (ATL)
- hypercholesterolemia
- hyperglycermia
- decreased BUN
explain the (-) feedback loop b/w CORT and ACTH
- low blood CORT stimulates pituitary gland to produce ACTH
- ACTH stimulates adrenals to produce CORT
- once blood CORT levels return to normal, ACTH production slows to prevent an excess in CORT
what would an elevated urine cortisol: creatnine ratio indicate
hyperadrenocorticism
low dose dexamethasone suppression test
give low dose dexmethasone suppression test, then measure CORT levels 4-8 hours after
a reduction in CORT below a certain level or no change, would suggest HPA axis working normally
if cort levels increase, >50% from baseline, cushings
what is dexmethasone
Dex is a synthetic corticosteroid w/ high affinity for Glucose receptors
high dose dexamthasone test
tests for negative feedback
a high dose of dex followed by reduced ACTHsupports diagnosis of pituitary origin
if ACTH is unchanged suggests an adrenal or ectopic tumor
can also measure CORT
High dose dex followed by low CORT = pituitary origin
