Adrenal Physiology - Trachte

Question 1

What are the three zones of the Adrenal Gland?

Answer 1

1. The outermost zone, the Zona glomerulosa, synthesizes the mineralocorticoid aldosterone
2. The middle zone, the Zona fasciculata, and the innermost zone
3. The Zona reticularis, synthesize the glucocorticoid cortisol and the androgens dehydroepiandrosterone (DHEA) and androstenedione

Question 2

What embryological tissue is the Adrenal Gland derived from?

Answer 2

neural crest

Question 3

What are the components of the Glucocorticoid Endocrine Axis?

Answer 3

Hypothalamus => CRH: corticotropin releasing hormone (via circadian rhythm/stress stimulation)

Anterior Pituitary => ACTH: adrenocorticotrophic hormone

Adrenal Gland => Cortisol: the principal actor of glucocorticoids

Question 4

What are the four general actions of the Glucocorticoids?

Answer 4

1. Immune System Fxn => suppressed
2. Liver Fxn => Gluconeogenesis
3. Muscle => Protein catabolism
4. Adipose tissue => Lipolysis

Question 5

Corticotropin Releasing Hormone (CRH) half life? Place of synthesis? Receptor? Effect?

Answer 5

Short t1/2 ~ 9 min
Synthesized in hypothalamus
Anterior pituitary corticotrophs have CRH R1 receptor
Gs-protein coupled receptor
Stimulates adenylyl cyclase to increase cAMP concentrations
Proinflammatory cytokines and chronic stress promote release of CRH

Question 6

Corticotroph CRH R1 receptor bound hormone induces what reaction in the target cell?

Answer 6

Gs - Adenylyl cyclase activity

Increased synthesis of the preprophormone, pro-opiomelanocortin.

Cleavage of POMC and release of hormones:

• Melanocyte stimulating hormone (MSH)
• ACTH adrenocorticotropic hormone
• lipotropin

Question 7

What does ACTH bind to? What is the effect?

Answer 7

binds to Melanocortin-2-receptor in adrenal cortical cells
a Gαs-coupled receptor, therefore it elevates cAMP concentrations to initiate a signal transduction cascade involving PKA

Rapidly promotes side-chain cleavage enzyme (CYP11A=P450scc) synthesis in adrenal cortex.

This reaction enzyme is required for cholesterol conversion to pregnenolone.

THIS IS A RATE-LIMITING STEP in adrenal steroid synthesis.

Question 8

What Glucocorticoid has the highest affinity and potency for Glucocorticoid Receptors?

Answer 8

Cortisol

Question 9

Where are Mineralocorticoid Receptors found?

Answer 9

kidney, colon, sweat glands, heart, hippocampus, brown adipose

Question 10

What Glucocorticoid has the highest affinity and potency for Mineralocorticoid Receptors?

Answer 10

Has ~ equal affinity for aldosterone and cortisol

(Although affinity might be the same, in mineralocorticoid-responsive tissues such as the kidney, cortisol is enzymatically converted to cortisone (can be prevented by liquorice), a metabolically inactive steroid so has no affect => selectivity for aldosterone)

Question 11

What are the actions of the Glucocorticoids?

Answer 11

Cause a rise in circulating glucose levels

• Cortisol mobilizes amino acids from proteins which are utilized by the liver to make glucose (via gluconeogenesis)
• Deficiency can cause hypoglycemia

Cortisol is the primary active glucocorticoid

Bind to glucocorticoid receptors (GR)

Question 12

What are the actions of the Mineralcorticoids?

Answer 12

Promote salt and water retention by the kidney

Aldosterone => Has little glucocorticoid activity

Bind to mineralocorticoid receptors (MR)

Question 13

How does cortisol circulate through the body?

Answer 13

10% circulates free

90% circulates bound => 60% to CBG (corticotropin binding globulin=transcortin) + 30% to albumin

Question 14

Where are Glucocorticoids metabolized?

Answer 14

Liver (CYP450)

Question 15

What are the clinical findings in Cushing Syndrome?

Answer 15

Moon face

Fat pads (buffalo hump)

Thin skin

High BP

Red striae (abdomen)

Pendulous abdomen

Thin arms and legs (fat redistribution)

Question 16

What is excess ACTH secretion usually due to?

Answer 16

usually due to pituitary adenomas = Cushing Disease

Question 17

What are the blood profiles in Cushing Disease?

ACTH, Cortisol, Aldosterone

Answer 17

Increased ACTH (hyperpigmentation

Increased Cortisol

+/- Aldosterone

Question 18

What is Cushing Syndrome? Blood profiles?

Answer 18

iatrogenic or due to primary glandular excess production or cortisol due to adrenal tumors

or tertiary causes: (morbid obesity, DM2, some psychiatric drugs, alcoholism)

Blood profiles: ↑ Cortisol, ↓ ACTH

Question 19

What are the effects of the mineralcorticoid Aldosterone?

Answer 19

Stimulates kidney reabsorption of Na+ and water

Stimulates Na+ and water reabsorption in the colon, salivary glands and sweat glands

Enhances kidney K+ excretion

Hypersecretion of aldosterone can cause hypertension

Question 20

What is the effect on CRH, ACTH and cortisol levels if there is damage resulting in no CRH secretion?

Answer 20

Everything is suppressed

Question 21

What is the effect on CRH, ACTH and cortisol levels in Pituitary damage resulting in no ACTH secretion?

Answer 21

High CRH
No ACTH
No Cortisol

Question 22

What is the effect on CRH, ACTH and cortisol levels in adrenal damage resulting in no corticol secretion?

Answer 22

High CRH
High ACTH
Low Cortisol

Question 23

What is the effect on CRH, ACTH and cortisol levels in receptor damage resulting in no efficacy of cortisol?

Answer 23

Everything would be elevated

Question 24

What is the effect on CRH, ACTH and cortisol levels in a tumor secreting excess CRH?

Answer 24

Everything would be elevated?

Question 25

What is the effect on CRH, ACTH and cortisol levels in a tumor secreting excess ACTH?

Answer 25

Low CRH High ACTH High Cortisol

Question 26

What is the effect on CRH, ACTH and cortisol levels in a tumor secreting excess cortisol?

Answer 26

Low CRH Low ACTH High Cortisol

Question 27

Where is the only place you can make Aldosterone in the body?

Answer 27

``` Adrenal glands (18 Lyase (aldosterone synthase) is unique to adrenal glomerulosa) ```

Question 28

What are the six important steps in Adrenocorticoid Synthesis?

Answer 28

1. All steroids are synthesized from cholesterol 2. CYP11A1 = Side Chain Cleavage-RATE LIMITING! 3. CYP17 = 17-alpha-hydroxylase 4. *CYP21A = 21-hydroxylase (defect accounts for 95% of genetic abnormalities; is a CAH congenital adrenal hyperplasia) 5. *CYP11B1 = 11-beta-hydroxylase (next most common defect; is also a CAH) 6. CYP11B2 = Aldosterone Synthase

Question 29

What is Addison's Disease? Cause? Effect?

Answer 29

congenital adrenal dysgenesis/hormone insufficiency Cause = usually due to immune mediated destruction of adrenal cortex ``` Effect = ↓Cortisol (knockout) ↓Aldosterone Compensatory ↑ CRH, POMC hence ↑ ACTH, ↑ MSH ```

Question 30

What are the symptoms of Addison's Disease?

Answer 30

Mucous membrane pigmentation Skin pigmentation, Vitiligo Pigment accentuation of nipples and friction areas Hypotension Fatigue and weakness Weight loss, emaciation, anorexia, vomiting, diarrhea

Question 31

What is secondary Adrenal insufficiency (aka hypocortisolism/hypoadrenalism)?

Answer 31

Iatrogenic following sudden withdrawal of exogenous glucocorticoid With exogenous cortisol, ↓endogenous ACTH

Question 32

What are adrenal steroids synthesized from?

Answer 32

Adrenal steroids, like all steroid hormones, are synthesized by enzymatic modification of cholesterol Most of the cholesterol used for steroidogenesis is acquired from dietary sources or synthesized in the liver. De novo synthesis is also possible.

Question 33

What controls the rate limiting step of glucocorticoid production?

Answer 33

Side chain cleavage enzyme (CYP11A1) is under ACTH regulation making the production of pregnenolone a rate limiting step

Question 34

What does Aldosterone regulate?

Answer 34

Aldosterone regulates sodium & K balance. | Aldosterone has no effect on ACTH secretion.