L19 -Physiology of adrenal cortex and medulla Flashcards
Define the 3 layers of adrenal cortex and the hormone produced?
Zona glomerulosa - Mineralcorticoids: Aldosterone
Zona Fasciculata: Glucocorticoids: Cortisol
Zona Reticularis: Androgens
Organelle for production of andrenocortical steroids?
ER and mitochondria
Describe the first rate-limiting step in steroidogenesis?
transfer of cholesterol from the cytoplasm to the inner mitochondrial membrane:
regulated by steroidogenic acute regulatory protein (StAR protein)
Describe the formation for the immediate precursor of all steroid hormones?
Cholesterol –[CYP11A1]–> Pregnenolone**
How is the synthesis of different steroids controlled in the adrenal cortex?
Depends on type of enzyme expressed in each cortical zone
Explain why hypersecretion of cortisol can lead to hyperaldosteronism?
CYP11B1 = form Cortisol in Zona Fasciculata
CYP11B2 = form Aldosterone in Zona glomerulosa
Loci for the 2 enzymes are closely related, hyperactivation could occur concurrently
Describe the cellular effect of Aldosterone?
1) Aldosterone bind to mineralcorticoid receptor (MR) in DCT
2) Aldosterone- MR complex translocate into nucleus»_space; bind HRE in regulatory region of target gene promoters
3)
i) Induction of Na+/K+-ATPase expression on the basolateral membrane
ii) Activate epithelial Na+ channel (ENaC) and renal outer medullary K+ channel (ROMK) on apical membrane
> > > > Na+ reabsorption and K+ excretion + water reabsorption
Describe the regulation of Aldosterone secretion (renin-angiotensin system)?
Low Na, Low BP or High K:
1) JG cells secrete renin»_space; convert angiotensin to angiotensin- I from liver
2) Angiotensin converting enzyme in pulmonary blood: convert angiotensin-I to II
3) Angiotensin-II bind to Angiotensin-II receptor on adrenal cortex
4) Increase aldosterone secretion
List the physiological effects of aldosterone?
Increase sodium and water retention»_space; increase extracellular fluid volume»_space; increase BP
Increase K secretion
List 3 causes of hyperaldosteronism?
1) Functional adenoma (Conn syndrome)
2) Inherited CYP11B2 hyperactivity
3) Renovascular diseases» abnormal renin-angiotensin system activation
Symptoms of hyperaldosteronism?
Alkalosis
Shallow respiration
Irritability
Constipation
Weakness, Lethargy
Arrhythmia, Weak pulse
Explain how hyperaldosteronism cause alkalosis?
- Increased excretion of K in kidney
- Low K stimulates H+/K+- ATPase in collecting duct
- Excrete H+ to retain K
- Less [H+] = alkalosis
Explain how hyperaldosteronism causes muscle weakness?
Decrease extracellular K increases the -ve membrane potential across membrane
> > more difficult to fire AP
List 4 causes of hypoaldosteronism?
1) Adrenal insufficiency (primary, secondary, tertiary)
2) Aldosterone synthase deficiency (CYP11B2 loss of function)
3) Renal insufficiency due to diabetic nephropathy
4) Anti-hypertensive drugs e.g. ACEi, ARB, Renin inhibitors
Symptoms of hypoaldosteronism?
All due to hyperkalemia:
- Hypotension, circulatory shock
- Arrhythmia, cardiac toxicity
- Muscle cramps, Abdominal cramping
- Metabolic acidosis
Which brain regions stimulate the hypothalamic corticotropin-releasing hormone (CRH) neurons in the hypothalamic-pituitary-adrenal (HPA) axis ?
1) Brainstem: Nucleus tractus solitarius»_space; stimulate under major distress: blood loss, respiratory distress, pain
2) Amygdala»_space; stimulate under negative emotions, fear, emotion
3) Hippocampus»_space; suppress** HPA to regulate stress
Describe the different action of cortisol to alter gene transcription?
Glucocorticoid/Cortisol activate glucocorticoid receptor (GR):
1) GR bind with glucocorticoid responsive elements (GRE) = enhance gene transcription
2) GR bind with CREB = repression of gene transcription
Summarize the effects of cortisol on energy metabolism? (4)
- Increases expression of liver enzymes for gluconeogenesis
- Increase muscle proteolysis
- Inhibit insulin secretion and trigger apoptosis of pancreatic β cells
- Impairs glucose uptake in peripheral tissues (stop GLUT-4 traffick)
Summarize the effects of cortisol on bones and connective tissue?
- Increase bone resorption by inducing Oct maturation (RANKL)
- Reduces bone formation by inhibiting Ob prolif.
- Inhibit chondrocyte function in cartilage
- Inhibit fibroblast proliferation and collagen formation
Summarize the effects of cortisol on inflammation and immunity?
- Inhibit mast cell degranulation
- Decrease T cell in circulation and migration
- Promote atrophy of thymus + lymphoid tissue
- Repress pro-inflammatory cytokines production
- Antipyretic: lower IL-1 release
Summarize the effects of cortisol on reproductive function?
- Decrease GnRH release from hypothalamus (like prolactin)
- Inhibit synthesis and release of LH and FSH from pituitary
List some synptoms of Cushing’s syndrome?
Hyperglycemia Increase risk of infection High BP Fat redistribution, central obesity Osteoporosis
Compare the contribution of adrenal androgens in male and female?
Male = negligible
Female = 50% circulating active androgens, needed for growth of axillary and pubic hair + libido
Explain why Cushing disease can lead to polycystic ovarian syndrome?
Cushing disease: Large increase in ACTH:
Stimulate MC2R on Zona fasciulata»_space; Produce cortisol»_space; negative feedback on hypothalamus and pituitary
Stimulat MC2R on Zona reticularis»_space; increase androgen production but NO NEGATIVE FEEDBACK
Excessive androgen = hirsutism and ovarian dysovulation
Cause of polycystic ovarian syndrome? Symptoms?
Elevated testosterone in female»_space; affect development and release of eggs during ovulation»_space; abnormal eggs in ovary cause thickening
- Lack of ovulation
- Lack/ irregular menstruation
- Facial hair, acne, pelvic pain
- infertile
Site of catecholamine production? Which type predominante?
Adrenal medulla: Chromaffin cells
Epinephrine/ Adrenaline = 80%
NE = 20%
Describe the regulation of Epinephrine/ NE release?
1) Sympathetic preganglionic neuron synapse at chromaffin cells
» increase Tyrosine Hydroxylase activity (rate-limiting)
» Convert Tyrosine to Dopa»_space; to NE/E
2) Cortisol from adrenal cortex induce PNMT expression»_space; increase NE to Epinephrine conversion
Describe how Amygdala controls NE and Epinephrine release? Mechanism of NE/E release?
Stress»_space; amygdala»_space; Ach from sympathetic preganglionic fiber»_space; chromaffin cell nicotinic receptor
Membrane depol. + Ca entry»_space; activate tyrosine hydroxylase»_space; secrete catecholamines
Compare the trigger and functions of α and β adrenergic receptors?
α1= bind NE and Epinephrine»_space; GPCR coupled to Gaq»_space; activate PLC»_space; IP3 and DAG»_space; Ca signalling
α2 = bind NE/E»_space; GPCR coupled to Gai»_space; decrease cAMP production
β1 and β2 = bind epinephrine only»_space; GPCR coupled to Gas»_space; cAMP production
List some physiological effects caused by both NE and Epinephrine
Increase glycogenolysis
Increase gluconeogenesis
Increase cardiac contractility, BP, respiration rate
List some physiological effects caused by ephinephrine more than NE?
Primarily stimulate β** adrenergic receptor:
Lipolysis **** Calorigenesis Glucagon secretion Muscle K uptake Increase HR ****
List some physiological effects caused by NE more than epinephrine?
Primarily stimulate α** adrenergic receptor:
- Increase arteriole vasoconstriction
- Increase sphicter contraction
- Increase platelet aggregation
- Dilation of pupils
List some long term stress response due to chronic NE/E release?
- Increased proteolysis and lipolysis
- Increased blood glucose
- Suppressed immune system
- Adrenal fatigue (weaken, unable to make cortisol)
Alteration of glycogen stores only in short-term response
Clinical manifestation of adrenal catecholamine deficiency?
None
No clinical consequences
Symptoms of adrenal fatigue?
- Chronic fatigue
- Hunger and weight change
- Emotional instability
- Frequent urination
Give one cause of adrenal catecholamine hypersecretion?
Pheochromocytoma
