L19 -Physiology of adrenal cortex and medulla

Question 1

Define the 3 layers of adrenal cortex and the hormone produced?

Answer 1

Zona glomerulosa - Mineralcorticoids: Aldosterone

Zona Fasciculata: Glucocorticoids: Cortisol

Zona Reticularis: Androgens

Question 2

Organelle for production of andrenocortical steroids?

Answer 2

ER and mitochondria

Question 3

Describe the first rate-limiting step in steroidogenesis?

Answer 3

transfer of cholesterol from the cytoplasm to the inner mitochondrial membrane:

regulated by steroidogenic acute regulatory protein (StAR protein)

Question 4

Describe the formation for the immediate precursor of all steroid hormones?

Answer 4

Cholesterol –[CYP11A1]–> Pregnenolone**

Question 5

How is the synthesis of different steroids controlled in the adrenal cortex?

Answer 5

Depends on type of enzyme expressed in each cortical zone

Question 6

Explain why hypersecretion of cortisol can lead to hyperaldosteronism?

Answer 6

CYP11B1 = form Cortisol in Zona Fasciculata

CYP11B2 = form Aldosterone in Zona glomerulosa

Loci for the 2 enzymes are closely related, hyperactivation could occur concurrently

Question 7

Describe the cellular effect of Aldosterone?

Answer 7

1) Aldosterone bind to mineralcorticoid receptor (MR) in DCT
2) Aldosterone- MR complex translocate into nucleus&raquo_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

Question 8

Describe the regulation of Aldosterone secretion (renin-angiotensin system)?

Answer 8

Low Na, Low BP or High K:

1) JG cells secrete renin&raquo_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

Question 9

List the physiological effects of aldosterone?

Answer 9

Increase sodium and water retention&raquo_space; increase extracellular fluid volume&raquo_space; increase BP

Increase K secretion

Question 10

List 3 causes of hyperaldosteronism?

Answer 10

1) Functional adenoma (Conn syndrome)
2) Inherited CYP11B2 hyperactivity
3) Renovascular diseases» abnormal renin-angiotensin system activation

Question 11

Symptoms of hyperaldosteronism?

Answer 11

Alkalosis

Shallow respiration
Irritability
Constipation

Weakness, Lethargy
Arrhythmia, Weak pulse

Question 12

Explain how hyperaldosteronism cause alkalosis?

Answer 12

• Increased excretion of K in kidney
• Low K stimulates H+/K+- ATPase in collecting duct
• Excrete H+ to retain K
• Less [H+] = alkalosis

Question 13

Explain how hyperaldosteronism causes muscle weakness?

Answer 13

Decrease extracellular K increases the -ve membrane potential across membrane

> > more difficult to fire AP

Question 14

List 4 causes of hypoaldosteronism?

Answer 14

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

Question 15

Symptoms of hypoaldosteronism?

Answer 15

All due to hyperkalemia:

• Hypotension, circulatory shock
• Arrhythmia, cardiac toxicity
• Muscle cramps, Abdominal cramping
• Metabolic acidosis

Question 16

Which brain regions stimulate the hypothalamic corticotropin-releasing hormone (CRH) neurons in the hypothalamic-pituitary-adrenal (HPA) axis ?

Answer 16

1) Brainstem: Nucleus tractus solitarius&raquo_space; stimulate under major distress: blood loss, respiratory distress, pain
2) Amygdala&raquo_space; stimulate under negative emotions, fear, emotion
3) Hippocampus&raquo_space; suppress** HPA to regulate stress

Question 17

Describe the different action of cortisol to alter gene transcription?

Answer 17

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

Question 18

Summarize the effects of cortisol on energy metabolism? (4)

Answer 18

• 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)

Question 19

Summarize the effects of cortisol on bones and connective tissue?

Answer 19

• 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

Question 20

Summarize the effects of cortisol on inflammation and immunity?

Answer 20

• 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

Question 21

Summarize the effects of cortisol on reproductive function?

Answer 21

• Decrease GnRH release from hypothalamus (like prolactin)

- Inhibit synthesis and release of LH and FSH from pituitary

Question 22

List some synptoms of Cushing’s syndrome?

Answer 22

Hyperglycemia 
Increase risk of infection 
High BP 
Fat redistribution, central obesity 
Osteoporosis

Question 23

Compare the contribution of adrenal androgens in male and female?

Answer 23

Male = negligible

Female = 50% circulating active androgens, needed for growth of axillary and pubic hair + libido

Question 24

Explain why Cushing disease can lead to polycystic ovarian syndrome?

Answer 24

Cushing disease: Large increase in ACTH:

Stimulate MC2R on Zona fasciulata&raquo_space; Produce cortisol&raquo_space; negative feedback on hypothalamus and pituitary

Stimulat MC2R on Zona reticularis&raquo_space; increase androgen production but NO NEGATIVE FEEDBACK

Excessive androgen = hirsutism and ovarian dysovulation

Question 25

Cause of polycystic ovarian syndrome? Symptoms?

Answer 25

Elevated testosterone in female >> affect development and release of eggs during ovulation >> abnormal eggs in ovary cause thickening - Lack of ovulation - Lack/ irregular menstruation - Facial hair, acne, pelvic pain - infertile

Question 26

Site of catecholamine production? Which type predominante?

Answer 26

Adrenal medulla: Chromaffin cells Epinephrine/ Adrenaline = 80% NE = 20%

Question 27

Describe the regulation of Epinephrine/ NE release?

Answer 27

1) Sympathetic preganglionic neuron synapse at chromaffin cells >> increase Tyrosine Hydroxylase activity (rate-limiting) >> Convert Tyrosine to Dopa >> to NE/E 2) Cortisol from adrenal cortex induce PNMT expression >> increase NE to Epinephrine conversion

Question 28

Describe how Amygdala controls NE and Epinephrine release? Mechanism of NE/E release?

Answer 28

Stress >> amygdala >> Ach from sympathetic preganglionic fiber >> chromaffin cell nicotinic receptor Membrane depol. + Ca entry >> activate tyrosine hydroxylase >> secrete catecholamines

Question 29

Compare the trigger and functions of α and β adrenergic receptors?

Answer 29

α1= bind NE and Epinephrine >> GPCR coupled to Gaq >> activate PLC >> IP3 and DAG >> Ca signalling α2 = bind NE/E >> GPCR coupled to Gai >> decrease cAMP production β1 and β2 = bind epinephrine only >> GPCR coupled to Gas >> cAMP production

Question 30

List some physiological effects caused by both NE and Epinephrine

Answer 30

Increase glycogenolysis Increase gluconeogenesis Increase cardiac contractility, BP, respiration rate

Question 31

List some physiological effects caused by ephinephrine more than NE?

Answer 31

Primarily stimulate β** adrenergic receptor: ``` Lipolysis **** Calorigenesis Glucagon secretion Muscle K uptake Increase HR **** ```

Question 32

List some physiological effects caused by NE more than epinephrine?

Answer 32

Primarily stimulate α** adrenergic receptor: - Increase arteriole vasoconstriction - Increase sphicter contraction - Increase platelet aggregation - Dilation of pupils

Question 33

List some long term stress response due to chronic NE/E release?

Answer 33

- 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*

Question 34

Clinical manifestation of adrenal catecholamine deficiency?

Answer 34

None | No clinical consequences

Question 35

Symptoms of adrenal fatigue?

Answer 35

- Chronic fatigue - Hunger and weight change - Emotional instability - Frequent urination

Question 36

Give one cause of adrenal catecholamine hypersecretion?

Answer 36

Pheochromocytoma