Adrenal Flashcards
the adrenals are a pair of glands weighing a total of about ____g, which are located one near each _____.
10g
kidney
each adrenal is actually ___ glands in one, the outer _____ that produces _____ and inner _____ that produces _____.
2 outer adrenal cortex steroid hormones (cortisol, androgens) inner adrenal medulla catecholamines (NE & E)
the adrenal cortex is around ____% of adrenal mass
90%
the adrenal medulla is around ____% of adrenal mass
10%
blood flowing through adrenal cortex drains into medullary ______, hence part of the blood supply supplying adrenal medulla is rich in _______.
what is the clinical significance of this? (what is the function)
medullary capillary sinusoids
corticosteroids (cortical steroids)
the corticosteroid-rich blood modulates or fine-tunes the ratio of E:NE released from the medulla such that elevated cortisol will increase the proportion of E
T/F: cortisol increases ratio of epinephrine secreted from adrenal medulla
TRUE
What are the 3 layers of the adrenal cortex and what does each produce? (superficial to deep)
- zona glomerulosa - aldosterone
- zona fasciculata - cortisol
- zona reticularis - cortisol & androgens (dehydroepiandosterone & androsternedione)
what are the 2 androgens that are produced in the zona reticularis of the adrenal cortex?
dehydroepiandosterone
androstenedione
T/F: you can live without the adrenal cortex (loss by disease or surgery)
FALSE - you will die within 1-2 weeks
What is the most likely cause of death from loss of the adrenal cortex by disease or surgery?
what happens when calorie intake is limited?
sodium depletion –> circulatory collapse
hypoglycemia
what are the 2 types of adrenocortical hormones? what does each produce? what is the function of each hormone produced?
- mineralocorticoids - aldosterone (Na/K+ balance)
2. glucocorticoids - cortisol (maintaining carbohydrate reserves)
T/F: the adrenal androgens have stronger effects than those of male testicular hormones (T, DHT) in puberty
FALSE - similar but weaker than male hormones
T/F: adrenal androgrens appear to be of importance in both sexes in mediating changes occurring in puberty
TRUE
How does the fetal adrenal compare with adult? what does it have?
fetal adrenal is bigger, for body size, than that of the adult
large steroidogenic “fetal zone”
The adrenal medulla embryologically arises from ____ and is innervated by neurons whose cell bodies reside in the _________. axons from these cells pass through the __________ to form ______ nerves.
neuroectoderm
spinal cord
paravertebral sympathetic ganglia
splanchnic nerves
The adrenal medulla stores _____g of catecholamines in _____ granules within ______ cells that stain with ______.
5-6g
secretory
chromaffin
chromium
the cells of the adrenal medulla are modified ____neurons
post-ganglionic
what do adrenal cortical hormones derive from?
cholesterol
what is the rate-limiting step in cortisol synthesis?
the first step: cholesterol –> pregnenolone
what is the role of StAR? (steroid acute regulatory protein)
stimulates transport of cholesterol from cytosol into the mitochondria where it can be acted on by enzyme –> pregnenolone
T/F: mineralocorticoid activity is predominantly associated with aldosterone and glucocorticoid activity with cortisol
TRUE
T/F: cortisol has both glucocorticoid and mineralocorticoid effect
TRUE
why doesn’t cortisol bind and influence mineralocorticoid receptors?
mineralocorticoid sensitive tissues contain Type II 11 beta-hydroxysteroid dehydrogenase (Type2 11beta-HSDH) that converts cortisol into cortisone, reducing mineralocorticoid effect
what is the role of Type II 11 beta-hydroxysteroid dehydrogenase
cortisol –> cortisone (reduce mineralocorticoid effect of cortisol)
steroid secretion represents _____ synthesis, since steroid hormones can’t be stored.
de novo (synthesis from scratch)
T/F: catecholamines of adrenal medulla cannot be adequately stored
FALSE - stored in chromaffin cells
T/F: steroid hormones cross the membrane by going down their concentration gradient to enter circulation
TRUE - lipid soluble, so passively diffuse through membrane down their conc gradient
in circulation, what are steroid hormones bound to? (3)
transcortin (plasma binding protein)
CBG (corticosteroid binding globulin)
plasma albumin
most adrenal androgens travel in circulation bound to ______ and in the _____ form
albumin
sulfated
how does glucocorticoid binding of albumin differ from that of mineralocorticoids like aldosterone? % bound?
how does this binding affect the hormone effect (half life)?
glucocorticoids binding is favored over aldosterone
95% of glucocorticoids bound
60% of aldosterone bound
glucocorticoids have longer half life in plasma (90 minute vs 30 minutes for aldosterone) and has longer hormonal effect
how does half life and stability of DHEAS differ from that of glucocorticoids/mineralocorticoids?
DHEAS more stable
half life 10-20 hours (longest)
total plasma conc exceeds of other adrenal steroids in young adults
T/F: clearance of hormones is largely by renal/hepatic mechanisms
TRUE
compare b/w steroid hormones and peptide/amine hormones:
entry into cells
binding to what?
target
steroid entry: passive diffusion
peptide entry: don’t enter (work via secondary messengers at membrane)
steroid binding: cytoplasmic receptor proteins
peptide binding: plasma membrane receptors
steroid target: nucleus
peptide target: plasma membrane
what receptors do mineralocorticoids and glucocorticoids bind in cytosol? is there overlap?
mineralocorticoids bind type 1 receptors
glucocorticoids bind preferentially to type 2 receptors but can also bind to type 1 but usually intercepted in mineralocorticoid-sensitive tissues by type2beta11HSDH and inactivated
where are the greatest amounts of type 1 receptor for mineralocorticoids found?
kidney
colon
sweat/salivary glands
give the full mechanism in which steroid hormones affect gene trx
free steroid hormones diffuse through plasma membrane of cell
displace heat shock proteins (HSP90) which give up receptors that can now bind to ligand/hormone
HR complex enters nuclear membrane and binds to HRE (palindromic on DNA)
affected DNA sequence creates appropriate proteins for hormonal response
ACTH is derived from what pituitary prohormone?
it is required for the normal function of the zona ____ and zona ______. ACTH is the controlling factor for the synthesis/secretion of _____. in the absence of ACTH, the 2 zonas _____.
POMC
zone fasciculata and reticularis (where is secretes cortisol)
cortisol and androgens
atrophy
T/F: ACTH binds to only receptors in the zona fasciculata and zona reticularis of the adrenal cortex
FALSE - ACTH binds to receptors in all three layers of the adrenal cortex
in the zona glomerulosa, ACTH has a (major/minor) role in aldosterone production, although the prime regulator in this layer is _____.
minor
AngII
what layer of the adrenal cortex has necessary enzymes for DHEA production?
zona reticularis
how does ACTH stimulate the production of androgrens (steroid hormones)?
give the mechanism with all substrates and related enzymes
ACTH binds to receptor –> rise in intracellular cAMP
production of StAR protein that stimulates entry of cholesterol from cytosol to mitochondria –> cholesterol into pregnenolone
T/F: ACTH stimulation of steroid hormone secretion takes hours
1-2 minutes (peaking 15 minutes)
what controls the production of ACTH?
CRH (hypothalamic neuron)
T/F: ACTH has a circadian rhythm
TRUE
T/F: cortisol has a circadian rhythm
TRUE
How does ACTH secretion rates differ in the morning and evening?
peak rate in the morning before you wake up
steady decline in the evening hours
How does cortisol secretion rates differ in the morning and evening?
same as ACTH
peak rate in the morning (cortisol wakes you up)
steady decline in the evening hours
T/F: CRH and ACTH secretion is subject to negative feedback inhibition by cortisol
TRUE - long loop negative feedback
T/F: circadian rhythm of ACTH appears to be the result of changes in the sensitivity of CRH secreting cells to cortisol
TRUE
how does sensitivity of CRH to cortisol differ in the morning and evening?
morning: low sensitivity to cortisol, less negative feedback, high secretion rates of CRH, more basal ACTH and cortisol secretion
evening: higher sensitivity to cortisol, more negative feedback, decline in CRH, ACTH, cortisol levels
T/F: Stress and ACTH override each other (antagonists)
FALSE - they both stimulate cortisol secretion, dont override if they have the same effect
stressful stimuli lead to increases in CRH secretion, by neural pathways, overriding the ______
diurnal (circadian) rhythm
so like if its night time and ACTH and cortisol secretion rates are low, but you got mad stress, it don’t matter that its night time and your cortisol/ACTH levels gon go up
T/F: acute stress will lead to establishment of new steady state of ACTH and cortisol production
FALSE - chronic stress
what hormone is the “stress” hormone?
what are its main physiological purpose?
cortisol
maintain vital functions during periods of prolonged stress (physiological stress and sometimes psychological) and contain inflammatory response
what does it mean that functions of cortisol are permissive?
cortisol doesn’t itself initiate changes but is required for the changes to be expressed fully
ex. cortisol is required for effect catecholamine response and it is the increased responsiveness of cells to catecholamines that allow the effects of cortisol to take place
what happens in a cortisol deficit?
decrease cardiovascular responsiveness to catecholamines
reduced mobilization of fuel stores
increased vulnerability to stress
what is the effect of cortisol on blood glucose?
what disease can this lead to?
increases blood glucose
oppose insulin
(body wants more sugar/energy for fight or flight)
diabetes
what is the effect of cortisol on proteins?
promotes protein catabolism (breakdown) from muscles and CT to free the amino acids –> use in gluconeogenesis for sugar
stimulates production of gluconeogenic enzymes in liver
(don’t need to be making more muscle, need amino acids and sugar for energy)
what is the effect of cortisol on use of glucose?
inhibits glucose transport into cells (EXCEPT THE BRAIN)
increases plasma glucose allowing body to use sugar/energy for survival
T/F: cortisol administration will cause loss of action potentials and neuronal function
FALSE - cortisol inhibits glucose uptake by cells everywhere but the brain (glucose enters via GLUT1 channels)
what is the effect of cortisol on protein synthesis?
decreases protein synthesis (promotes protein breakdown/catabolism) everywhere BUT THE LIVER
reduce uptake of amino acids into muscle cells
plasma amino acid levels increase
what is the effect of cortisol on fat metabolism?
increases fat breakdown to liberate amino acids and glycerol for gluconeogenesis
HOWEVER, increases fat deposition on trunk and face
why does fat metabolism response to cortisol vary?
different receptor responsivities to cortisol in different adipose tissues
what is the effect of cortisol on CNS?
what happens in cortisol deficiency and excess?
feedback inhibition of CRH and ACTH in hypothalamus and adenohypophysis
affects perception
cortisol deficiency - accentuate (increase sensitivity) of taste, hearing, smell
cortisol excess - initial euphoria followed depression
what is the effect of cortisol on cardiovascular?
what happens in cortisol deficiency?
required to maintain sensitivity of vasculature to catecholamines (NE/E)
deficiency - widespread vasodilation and hypotension
what is the effect of cortisol on developmental effects?
cortisol has important role in maturation in fetal development
production of intestinal enzymes and pulmonary surfactant (giving corticosteroids to mother during late pregnancy with a potential premature baby can prevent RDS)
what is the effect of cortisol on renal?
what happens with no cortisol?
CRH (produces ACTH –> cortisol) also produces ADH
no cortisol - increases secretion of CRH and ADH (no negative feedback), renal water absorption increases, can’t produce hypotonic urine (free water) even if the person has low osm
what 2 factors count for water intoxication in cortisol deficient patients?
- increases secretion of CRH and ADH (no negative feedback), renal water absorption increases, can’t produce hypotonic urine (free water) even if the person has low osm
- hypotension in the absence of cortisol contributes to high plasma ADH levels
what is the effect of cortisol on bones?
what happens with cortisol excess?
promotes bone breakdown
excess - enhance osteoclastic activity (breakdown) –> osteoporosis
what is the effect of cortisol on immunity?
what are the mechanisms in which it affects immunity?
contains inflammatory response (decrease immunity)
- stabilize lysosomal membranes (prevent release of degradative enzymes)
- decrease capillary permeability
- depress phagocyte activity
- suppress synthesis of IL-1
- inhibit production of eicosanoids (prostaglandins, leukotrienes)
- depress release of histamine from mast cells in lung
- reduce allergic responses
how can cortisol be beneficial and detrimental on immune system?
benefits - can reduce swelling/tissue damage in auto-immune diseases like rheumatoid arthritis
cons - can allow resurgence of latent infections
what is the effect of pharmacological administration of glucocorticoids (cortisol)?
prolonged administration of cortisol leads to feedback inhibition of ACTh production, atrophy of dependent adrenal cells (zona fasciculata and reticularis), reduce ability for body to endogenously create cortisol
withdrawal from meds needs to be GRADUAL DECLINE of meds
how is cortisol eliminated in body?
free plasma cortisol filtered in kidney –> reduced to tetrahydrocortisol and conjugated with glucuronic acid –> excreted in urine as glucuronide metabolites
what is the difference in which cortisol and androgens are excreted in urine?
androgens - sulfated form in urine
cortisol - reduced to tetrahydrocortisol and conjugated with glucuronic acid –> excreted in urine as glucuronide metabolites
adrenal androgens are produced in ___ quantities in fetus and are very important during _______.
large
fetal development
how does adrenal androgen production levels differ during fetal development?
large in fetus
postnatal production is low
rises during pre-pubertal period (adrenarche)
contributes to events after puberty (onset of axillary and pubic hair growth, secretion from axillary sebaceous glands)
define adrenarche
pre-puberty
development of zona reticularis, early stage of sexual maturation
in adult females, the adrenals are a major source of ____ and after conversion into _____ in the periphery, contribute to stimulation of axillary and pubic hair growth. some _____ is also converted in the periphery to estrogen. this is a major source of _____ in post-menopausal women whose ____ are no longer active. there is some evidence that ___ levels have an influence on libido in women.
estrogen testosterone androstenedione estrogen ovaries DHEA
in adult males, DHEA is insignificant in comparison to _____, produced in the testes AND _____ produced from testosterone.
testosterone
dihydrotestosterone
what is the aim of dietary DHEA supplementation?
reverse the effects of aging
what controls adrenal androgen production?
ACTH
how is free DHEA excreted in urine?
free DHEA-S in plasma is filtered in kidney and excreted in urine in the sulfated form
where in the adrenal cortex is aldosterone formed?
zona glomerulosa
what is the primary function of aldosterone?
its production is under the control of what? (3)
what happens in its absence? can cortisol save the body?
Na+ reabsorption in distal nephron and secretion of K+
AngII, plasma K+, ACTH (less extent)
disrupt fluid and ion balance, but if sufficient cortisol is present, cortisol’s mineralocorticoid effects can prevent progressive fluid loss
how is AngII produced?
rising levels of renin
renin is a _____ produced by _____ of the ______. it is stimulated by _____ at the AA or by ____ stimulation via renal nerve
protease granular cells JGA fall in perfusion pressure SNS
how does AngII stimulate aldosterone production at zona glomerulosa?
via receptor mediated increase in IP3 –> increases StAR (cholesterol into mito)
T/F: aldosterone levels are increased by elevated estrogen
TRUE - during pregnancy
estrogen-stimulated increase in angiotensinogen production in liver
aldosterone increases the activity of ____ in the basolateral membrane of target cells and also increasing rate of ___ entry on the luminal surface through added ____ channels.
Na+-K+-ATPase
sodium
sodium
in addition to the distal nephron, where else are mineralocorticoid receptors found? (aldosterone receptors)
where sodium is excreted
ex. sweat/salivary glands and colon
what are the ratios of storage of…
E:NE
ATP:catecholamines
ATP:E:NE
E:NE –> 5:1
ATP:catecholamines –> 1:4
ATP:E:NE –> 1:20:4
5:1 is the ratio of what?
E:NE
1:4 is the ratio of what?
ATP:catecholamines
give the mechanism of catecholamine biosynthesis
tyrosine --> DOPA --> dopamine dopamine enters chromaffin cell dopamine --> NE NE leaves chromaffin cell NE --> E via PNMT E enters chromaffin cell
NE and E both in chromaffin cell until used
how is chromaffin exocytosis stimulated?
binding of Ach (sympathetic cholinergic stimulation) to chromaffin cells –> rise in intracellular calcium levels –> exocytosis
T/F: chromaffin cell exocytosis of catecholamines is associated with an increase in intracellular cAMP levels
FALSE - intracellular calcium levels
what % of catecholamines are free in circulation and what % of catecholamines are loosely associated with albumin?
50% bound, 50% free in circulation
T/F: catecholamines are slowly cleared from circulation
FALSE - rapidly cleared, half life of 10-15 seconds, very unstable
90% of catecholamines go through vasculature in one go
compare response time of medullary catecholamines to cortical corticosteroids
catecholamines - rapid response time, fast turn-over
corticosteroids - slower, longer lasting effects of hormone
what are the two ways catecholamines are uptaken by cells?
- neuronal - repackaged for reuse or degraded by neuronal cytosolic enzyme MAO (coupled with sulfate or glucuronic acid –> urine)
- non-neuronal - inactivated enzymatically by MAO and catecholamine-O-methyl transferase (COMT)
what is a non-invasive way of monitoring circulating hormone levels? for corticosteroids
measure urinary concentrations of its degradation products
- neuronal - repackaged for reuse or degraded by neuronal cytosolic enzyme MAO (coupled with sulfate or glucuronic acid –> urine)
compare the effects of catecholamines (NE and E) on the different types of plasma membrane receptors (alpha, beta1, beta2)
NE and E have similar effects on B1 receptors
NE - potent A agonist, little effect on B2
E - stronger A agonist, potent B2 agonist
the fetal zone of the adrenal gland produces what androgen?
DHEA
T/F: the zona glomerulosa is one of the few places of adrenal gland that produces aldosterone
FALSE - its the ONLY place in adrenal gland that produces aldosterone
T/F: the zona reticularis primarily secretes weak androgens
FALSE - strong androgens
what serves as a primary source of cholesterol to adrenals?
LDL
T/F: DHEA and Androstenedione are downstream metabolites of pregnenolone
TRUE
What are 2 examples of androgens?
DHEA
androstenedione
out of cortisol, aldosterone, DHEA, DHEA-S, and androstenedione –> which has the highest secretion rate?
cortisol or DHEA
out of cortisol, aldosterone, DHEA, DHEA-S, and androstenedione –> which has the highest plasma conc?
DHEA-S
T/F: StAR is rate limiting
TRUE
T/F: high excess cortisol doses can reduce mass of lymphoid tissue like spleen, thymus, lymph nodes
TRUE
what is cushing’s syndrome?
hyperadrenocorticism
too much cortisol –> fat builds in face and trunk
what is addison’s disease?
hypocortisolism
too little cortisol
how does congenital adrenal hyperplasia (CAH) differ b/w females and males?
males - leads to adrenogenital syndrome
no change in external genitalia, early development of secondary sex characteristics, accelerated masculinisation
females - may cause pseudohermaphroditism
external genitalia masculinisation, child may be mistaken for male
T/F: AngII is rapidly metabolized
TRUE
T/F: adrenal medulla is more nerve than gland
FALSE - ductless gland, more gland
what are the two types of chromaffin cells and what do they store?
A - 80%, small granules, EPINEPHRINE
N - 20%, large granules, NOREPINEPHRINE
epinephrine especially effects B2 receptors
what organ has a rich distribution of B2?
liver
