Exam #4: Adrenal Physiology

Question 1

Outline the HPA axis & the control mechanisms of the HPA axis.

Answer 1

The HPA axis regulates GLUCOCORTICOID production, which in humans is 95% cortisol

Question 2

What are the zones of the adrenal cortex?

Answer 2

From outer to inner:

1) Zona glomerulosa
2) Zona fasciculata=
3) Zona reticularis

Question 3

What are the main steroid hormones that are secreted by each of the zones of the adrenal cortex?

Answer 3

1) Zona glomerulosa= aldosterone (minercorticoid)

2) Zona fasciculata= primarily glucocorticoids
- Cortisol
- Corticosterone

3) Zona reticularis= primarily androgens
- Dehydroepiandosterone (DHEA)
- Andorostenedione

Question 4

Outline the pathways of cortisol, aldosterone, and the adrenal androgen synthesis.

Answer 4

N/A

Question 5

What is the function of 17a-hydroxylase? What is the clinical outcome of a deficiency in 17a-hydroxylase?

Answer 5

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Question 6

What is the function of 3B-hydroxysteroid dehydrogenase? What is the clinical outcome of a deficiency in 3B-hydroxysteroid dehydrogenase?

Answer 6

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Question 7

What is the function of 21-hydroxylase? What is the clinical outcome of a deficiency in 21-hydroxlase?

Answer 7

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Question 8

What is the function of 11B-hydroxylase? What is the clinical outcome of a deficiency in 11B-hydroxylase?

Answer 8

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Question 9

How does ACTH increase adrenal steroid synthesis?

Answer 9

Generally, ACTH stimulates the rate-limiting steps in cortisol synthesis. Specifically,

1) MC2R–>Gas–>cAMP–>PKA–>phosphorylation of cholesterol ester hydrolase, increasing availability of free cholesterol
2) Increased synthesis of StAR (Steroid Acute Regulatory Protein)
3) Increases activity of cholesterol desmolase

Question 10

What are the physiological effects of cortisol?

Answer 10

1) Metabolic= increased blood glucose
- Increased gluconeogensis
- Degradation of muscle & prevention of protein synthesis
- Lipolysis in fat cells
- Stimulation of hepatic glycogen synthesis

2) Anti-inflammatory= decreased synthesis of the precursor to prostaglandins & leukotrienes
3) Immunosuppressive= decreased lymphocyte production
4) Vascular reactivity= maintains the responsiveness of vascular smooth muscle to catecholamines

*****Note that in fetal development, glucocorticoids promote lung development

Question 11

What are the physiological effects of aldosterone?

Answer 11

Generally, aldosterone functions to increase Na+ & H20 REABSORPTION & K+ SECRETION in the distal convoluted tubule & collecting ducts of the kidney

Question 12

How does cortisol increase plasma glucose levels?

Answer 12

Cortisol increases plasma glucose by a variety of mechanisms including:

1) Increased gluconeogenesis
2) Muscle degradation and decreased amino acid uptake (shunted into gluconeogenesis)
3) Lipolysis of fat (shunted into gluconeogenesis)

Question 13

How does aldosterone increase water and Na+ reabsorption?

Answer 13

1) Expression of the amiloride sensitive epithelial sodium channel (ENaC)
2) Expression of the basolateral Na+/ K+ ATPase pump

Question 14

List the catcholamines released by the adrenal medulla.

Answer 14

NE
Epi
DA

Question 15

How does cortisol regulate synthesis of epinephrine?

Answer 15

The catecholamines are synthesized from tyrosine. Eventually, DA is packaged into secretory vesicles, and in the vesicles, DA can be converted to NE. NE leaks into the cytoplasm.

• **The cytoplasmic enzyme, PNMT converts NE into Epi.
• Cortisol increases the expression of PNMT, and thus increases concentrations of Epi.

Question 16

How does cortisol facilitate the effects of NE & epinephrine?

Answer 16

Cortisol maintains the responsiveness of the vascular smooth muscle to NE & Epi

Question 17

What causes Cushing’s Syndrome?

Answer 17

Chronic glucocorticoid excess i.e. excess cortisol, leads to Cushing’s Syndrome

Question 18

What are the symptoms of Cushing’s Syndrome?

Answer 18

HTN 
Hypokalemia 
Buffalo hump 
Moon face 
Muscle wasting 
Emotional problems 
Increased susceptibility to infection 
Hyperglycemia

Virilization & hirsutism from excess androgens

Question 19

Outline the pathophysiology of Cushing’s Syndrome.

Answer 19

1) Pituitary tumor hypersecreting ACTH
2) Chronic glucocorticoid therapy
3) Ectopic hypersecretion of ACTH
4) Hypersecretion of CRH
5) Adrenal tumor hypersecreting cortisol
6) Iatrogenic from exogenous glucocorticoid administration

Question 20

What is the general difference between primary and secondary adrenal insufficiency?

Answer 20

Adrenal insufficiency refers to a dysfunction of the adrenal cortex & deficient secretion of cortisol & aldosterone

• Primary= damage to the adrenal cortex
• Secondary= suppression of ACTH induced cortisol production

Question 21

What causes primary adrenal insufficiency?

Answer 21

Primary adrenal insufficiency is caused by autoimmune destruction of the adrenal cortex, infection, and cancer

Question 22

What causes secondary adrenal insufficiency?

Answer 22

Secondary adrenal insufficiency is caused by suppression of ACTH- induced cortisol production

• Hypothalmic or pituitary disorder
• Chronic exogenous glucocorticoid administration

Question 23

What are the symptoms of primary adrenal insufficiency?

Answer 23

• Postural hypotension
• Hyponatremia
• Hyperkalemia
• Hypoglycemia

Question 24

What are the symptoms of secondary adrenal insufficiency?

Answer 24

• Postural hypotension
• Hyponatremia
• Hyperkalemia
• Hypoglycemia

**Note that these can be life-threatening in the abrupt cessation of exogenous glucocorticoid administration

Question 25

What are the symptoms of 21-hydroxylase deficiency?

Answer 25

This is a steroid hormone biosynthesis disorder that called “congenital adrenal hyperplasia.” Symptoms include:

1) Increased growth of the adrenal cortex
2) Females born with male sex characteristics/ males with early development of adult characteristics
3) “Salt Wasting” leading to:
- Hypotension
- Hyponatremia
- Hypokalemia

Question 26

Outline the pathophysiology of 21-hydroxylase deficiency..

Answer 26

Without 21-hydroxylase, aldosterone and cortisol cannot be produced; rather, the androgens are synthesized.

• Decreased cortisol leads to increased ACTH
• Elevated ACTH leads to growth of the adrenal cortex & increased production of the androgens (again b/c aldosterone & cortisol cannot be produced)

Question 27

Where is the receptor for CRH?

Answer 27

Corticotroph cells of the anterior pituitary

Question 28

What is pro-opiomelanocortin?

Answer 28

The large precursor protein of ACTH, which is also called POMC for short

Question 29

List the POMC cleavage products.

Answer 29

1) ACTH
2) Melanocyte-stimulating hormones
3) Endogenous opioid peptide

Question 30

What is the receptor for ACTH? Where is this receptor located?

Answer 30

Melanocortin 2 Receptor (MC2R), which is located on the surface of the adrenal cortex

Question 31

Describe the fluctuations of cortisol throughout the day. What is the clinical significance?

Answer 31

• ACTH release follows a circadian rhythm and is higher just before and after waking
• Consequently, cortisol levels are highest in the morning

*****If glucocorticoid deficiency is suspected, cortisol levels should be measured early in the morning,

Question 32

How does cortisol exert negative feedback on the anterior pituitary and hypothalamus.

Answer 32

Binding to the glucocorticoid receptor (GR)

Question 33

What is the function of StAR?

Answer 33

This the Steroid Acute Regulatory Protein, it transports cholesterol into the inner mitochondrial membrane

Question 34

MR’s have a similar affinity for cortisol and aldosterone & cortisol concentrations are much higher in the plasma, what prevents cortisol action at these receptors?

Answer 34

Expression of an enzyme by aldosterone target tissues that cleaves cortisol into inactive cortisone

*****Note that in states of cortisol excess, these enzymes are saturated and cortisol will bind & activate MR’s