Week 27 Adrenals Flashcards
xfxfWhat are glucocorticoids primarily used for?
Anti-inflammatory or immunosuppressive agents.
What types of diseases are glucocorticoids used for?
Asthma, RA, IBS, cerebral edema, SLE, organ transplant rejection.
What are the 4 layers of the adrenal gland
CORTEX:
Zona Glomerulosa - Mineralcorticoids; Aldosterone
Zona Fasiculata - Glucocorticoids > Androgens; Cortisol
Zona Reticularis - Androgens > Glucocorticoids; DHEA, Androstenedione
Medulla: Catecholamines; Nor Epi, Epi
What is the precursor for steroid hormones produced in the adrenal cortex?
Cholesterol
What is the precursor for catecholamines produced in the adrenal medulla?
Tyrosine
From what 2 sources does the cholesterol used in steroid hormones come from?
- Circulating cholesterol with LDL **MAJOR SOURCE
- De novo synthesis of cholesterol from acetate.
What is the protein needed to produce any of the products of the adrenal glands from cholesterol?
Steriodogenic acute regulatory protein StAR
What is needed to convert cortocosterone to aldosterone?
Aldosterone synthase, only in the glomerulosa cells.
What regulates the synthesis of cortisol?
Stress induces release of CRH in hypothalamus.
CRH induces release of ACTH in ant. pituitary.
ACTH induces production of cortisol in Adrenal cortex (Zona fasiculata > Zona reticularis).
What is the action of glucocorticoids on blood glucose?
Counter regulatory action, increases blood glucose.
What regulates the release/synthesis of Aldosterone?
RAAS: Low BP or decreased Na/Cl causes release of Renin from juxtaglomerular cells.
Renin causes conversion of Angiotensinogen to Ang. I
Ang I converted to Ang II via ACE in lungs.
Ang II stimulates release of aldosterone from adrenal gland.
K+: Increased K+ levels directly stimulate aldosterone release so that Na can be exchanged for K and K is excreted via kidneys.
ACTH: directly stimulates synthesis of aldosterone via Melanocort 2 receptors, also minorly modulates aldosterone secretion.
Why measure the HCO3 serum levels when investigating a potential adrenal dysfunction?
Aldosterone (in the kidney) increases H+ in the urine and CO3- into the blood, increasing blood pH via alpha intercalated cells.
Increased CO3- (increased blood pH) could mean that there is increased aldosterone.
Could help differentiate between primary and secondary hyperaldosteronism when compared to ACTH levels.
What receptors does steroid hormones act on?
Nuclear receptors.
Lipid, can pass through membranes.
List the ligands (classic hormones and vitamins) that act on nuclear receptors and their receptor type.
Cortisol - glucocorticoid receptor
Testosterone - androgen receptor
Estrogen - Estrogen receptor
Progesterone - progesterone receptor
Aldosterone - mineralocorticoid receptor
T3 - thyroid hormone receptor
Vitamin D - Vitamin D receptor
All-trans retinoic acid - retinoic acid receptor
What are the requirements of nuclear receptors?
- Ligand binding domain.
- Dimerization domain.
- Nuclear localization signal.
- DNA binding domain.
- Activation domains.
What do nuclear receptor dimers bind to?
A specific sequence in the promoter of their target gene:
HORMONE RESPONSE ELEMENT.
What is the clinical significance of nuclear receptors?
Important targets for therapeutics.
Small molecule drugs.
How are steroid hormones metabolized?
Converted to an inactive compound in the liver.
Hydrophilic, eliminated as urinary metabolites.
Consists of reductions, oxidations, hydroxylations then a conjugation.
Composition of aldosterone in the blood.
30-50% free circulating, remainder bound to albumin.
Short half life (15-20 min).
How does aldosterone mediate its physiological effects?
Binds to mineralocorticoid receptor (nuclear receptor).
This both regulates gene expression and induces rapid effects.
To what receptors of the adrenal cortex does ACTH bind?
Menocortin-2 receptors (G-protein coupled receptors)
What are the actions of ACTH
Promotes free cholesterol formation.
Increases de novo synthesis of cholesterol.
Increases LDL uptake.
Increases StAR activity.
Maintains adrenocortical cells.
Regulates adrenal androgen secretion.
When are ACTH an cortisol levels. highest?
Highest in early morning, low at midnight.
Circadian regulation (dark/light).
How do glucocorticoids circulate in the blood?
90% are bound to corticosteroid-binding globulin (CBG or transcortin).
7% are bound to albumin.
3% free circulating cortisol.
Where are glucocorticoid receptors found?
Almost all tissues.
Regulates the expression of many genes.
Discuss glucocorticoid binding affinity
Bind GR and MR with equal affinity.
Tissue specific regulation of cortisol metabolism prevents MR mediated cortisol effects.
Discuss the cortisone-cortisol shunt
11B-HSD1 in liver converts cortisone (inactive) to cortisol.
11B-HSD2 in kidney converts cortisol to cortisone (prevents cortisol binding to MR).
What is the clinical implication of the cortisone-cortisol shunt.
Skin expresses 11B-HSD1 so inactive cortisone applied topically becomes converted to active cortisol for localized treatment.
Physiological functions of glucocorticoids
METABOLISM
Fed state: minimal effects
Fasted state:
Increases gluconeogenesis, glycogen deposition in liver.
Decreases glucose uptake, increases catabolism of pr in muscle.
Stimulates lipolysis in adipose.
Reduces intestinal Ca absorption.
Increases fluid and salt retention.
IMMUNE
Immunosuppressive and anti-inflammatory
GROWTH AND DEVELOPMENT
Promote differentiation and maturation of organ systems in fetal development.
Suppress bone formation and inhibit fibroblast division and collagen synthesis.
CV
Increase CO, increase tone.
REPRODUCTIVE
Decrease LH/FSH release
OTHER
Cognition, behaviour, regulation of appetitie, libido, renal function
Sources of blood glucose
Exogenous: diet
Endogenous: Glycogenolysis, Gluconeogenesis
Fates of blood glucose
Energy: glycolysis
Storage: glycogenesis, lipid synthesis.
What is the effect of cortisol on blood glucose?
Raises blood glucose levels.
Pathological excess of glucocorticoids
Depression/psychosis
Decreased LH, FSH, TSH, GH
Glaucoma
Peptic ulcerations
HTN
Overall diabetogenic effect
Visceral obesity
Decrease bone formation and linear growth
Protein/collagen breakdown
Immunosuppression/Anti inflammatory
Blood supply for adrenals
Aorta -> inferior phrenic artery -> renal arteries -> adrenal artiers -> plexus -> cortex -> medulla.
Corticomedullary portal system.
R adrenal vein -> IVC
L adrenal vein -> inferior phrenic vein -> L renal vein -> IVC
What is the name of the cells of the adrenal medulla?
Chromaffiin cells or pheocromocytes.
Basic release of Epinephrine
Splanchnic nerve -> Ach -> Nicotinic receptor in medulla -> release epi
Basic release of Nor epi
Preganglionic nerve -> Ach -> nicotinic receptor on post ganglionic nerve -> Nor epi
Biosynthesis of catecholamines
Made from tyrosine from diet or phenylalanine in:
Chromaffin cells of medulla,
Postganglionic neurons of SNS,
Noradrenergic & dopaminergic neurons of CNS,
Paraganglia of periphery.
What is the rate limiting step of catecholamine synthesis
Conversion of tyrosine to Dopa via tryrosine hydroxylase
1/2 life of catecholamines
VERY short, 10-100 seconds.
50% bound loosely to albumin.
Leads to wide fluctuations of levels in the plasma.
Discuss the spatial organization of catecholamine biosynthesis
Tryrosine taken into chromaffin cells via active transport.
Conversion to dopamine occurs in cytoplasm.
Dopamine transported to chromaffin granules for conversion to Nor Epi. (Final step in postganglionic neurons and some chromaffin cells).
80% of chromaffin cells Nor Epi is transported out of the granule nad converted to Epi in the cytoplasm.
Epi transported to storage in chromaffin granule.
What enzyme converts Nor Epi to Epi?
PNMT.
Is regulated by glucocorticoids via portal system.
Key enzymes in catecholamine metabolism
MAO (monoamine oxidase)
COMT (catechol-O-methyltransferase)
Discuss the dynamic process of catecholamine metabolism
Granule leakage and sequestration
Leakage metabolized by MAO and then loss via deamination.
Release and reuptake to sequestration back into granule.
Discuss clinical applications of MAO inhibitors and ARIs
MAO inhibitors for severe depression
ARIs (adrenergic reuptake inhibitors) for ADHD, narcolepsy, MDD
How does cocaine and amphetamines affect catecholamine levels?
Cocaine selectively blocks transport of MAOs, resulting in high levels of neurotransmitters in the synaptic cleft.
Amphetamines competitively inhibit MAO transporters and vesicle transporters, resulting in increase [dopamine] and [Nor epi] in synaptic cleft.
increased [catecholamine] at synapse results in sensations of euphoria, increased energy, improved focus, anxiety, paranoia, jitteriness.
Discuss the 3 catecholamine receptors
All are G coupled protein receptors
Dopamine receptors; D1, D2
a Adrenergic receptors; a1, a2
B Adrenergic receptors; B1, B2, B3
alpha and beta interact with epi and nor epi.
D1 receptors
Found on cerebral, renal, mesenteric, and coronary vasculatures.
Stimulation causes vasodilation.
D2 receptors
Found pre and post synapse of sympathetics, brain, lactotrophs.
Stimulation causes inhibition of nor epi, ganglionic transmission, and prolactin.
a1 receptors
Found on heart, vessels, smooth mm.
Stimulatory:
vascular and sm mm ctx,
Vasoctx, increased systemic resistance, increased BP
a2 receptors
Found on heart, vessels, smooth mm.
Inhibitory:
Inhibits nor epi release.
Down regulates central sympathetic outflow.
Decreases BP
B1, B2, B3 receptors
B1 - heart/kidney. More responsive to isoproterenol than to epi or NE.
Stimulation = increased contractile force & HR, increased renin secretion, lipolysis
Therapeutics: beta blockers for angina, HTN, arrhythmias.
B2 - heart, lungs, vessels, kidneys, liver
Stimulation = bronchodilation, vasodilatation in skm, glycogenolysis, release of nor epi.
Therapeutics: inhaled formulations for asthma.
B3 - heart, adipose tissue
Regulates energy expenditure, lipolysis in white fat, thermogenesis in brown fat.
