Adrenal Physiology

Question 1

Adrenal Gland Architecture

Answer 1

Cortex composed of 3 zones
1. Outer - zona glomerulosa (mineralocorticoids)
2. Middle - zona fasciculata (glucocorticoids)
3. Inner - zona reticularis (androgens)
Medulla derived from neural crest cells (considered modified sympathetic ganglion -> directly release catecholamines)

Question 2

Cortiocotropin Releasing Hormone/Factor

Answer 2

mature polypeptide, short half-life ~9 min

• synthesized in hypothalamus
• anterior pituitary corticotrophs have CRFR 1 receptor (Gs protein coupled receptor)
• proinflammatory cytokines and chronic stress promotes release of CRF

Question 3

CRFR1 receptor

Answer 3

Gs adenylyl cyclase activity

• increased synthesis of pro-opiomelanocortin
• cleavage of POMC –> MSH, ACTH, lipotropin

Question 4

ACTH

Answer 4

39 AA polypeptide -> synthesized in corticotrophs as part of larger 241 AA precursor

• binds Melanocortin-2-recptor in adrenal cortical cells -> Gs alpha -> cAMP -> signal transduction
• rapidly promotes side-chain cleavage enzyme (CYP11A) synthesis in adrenal cortex (required for cholesterol conversion to pregnenolone) –> Rate Limiting Step in adrenal synthesis

Question 5

Melanocortin receptor

Answer 5

MC1-R => principal melanocortin receptor in skin -> pigmentation
- excess POMC levels cause increase of MSH and ACTH both which can stimulate hyperpigmentation
MCR-2 => primary ACTH receptor
- expressed predominantly in adrenal cortex (also present in skin, adipocytes)

Question 6

Glucocorticoids

Answer 6

recognized early to cause rise in circulating glucose levels
- cortisol mobilizes AA from proteins, deficiency can cause hypoglycemia
- cortisol is primary active glucocorticoid
10% circulate free
60% circulate with CBG (transcortin)
30% circulate with albumin

Question 7

Mineralocorticoids

Answer 7

promotes salt and water retention by kidney = aldosterone

- binds mineralocorticoid receptors

Question 8

Sex steroids

Answer 8

dehydroepiandosterone (DHEA), androstenedione, some testosterone
- binds androgen receptors

Question 9

Glucocorticoid Receptors

Answer 9

belongs to nuclear receptor super family

• cortisol has highest affinity and potency
• cytoplasmic location of receptors
• homodimers act as transcription factors -> bind genes with GRE, recruits transcriptional cofactors and initiates or inhibits transcription
• regulates development, metabolism, and immune response

Question 10

Mineralocorticoid Receptor

Answer 10

• aldosterone receptor*
• found in kidney, colon, sweat glands, heart, hippocampus
• equaly affinity for aldosterone and cortisol (cortisol has no effect tho)

Question 11

Glucocorticoid metabolism

Answer 11

1. intracellular conversion of active glucocorticoid to inactive steroid (11-beta hydroxylase type 2)
2. Inactive steroid cannot activate receptor
3. Inactive steroids can be converted back to active steroid (11-beta hydroxylase type 1)
4. Tissue location of 11b hydroxyalse defines net result in that tissue
   * most metabolism occurs in liver where cortisone and cortisol can be rapidly conjugated to form tetrahydrocortisone

Question 12

Glucocorticoids affects of glucose

Answer 12

1. increase gluconeogenesis, decrease glucose uptake, increase plasma glucose, increase hepatic glycogen synthesis
2. increase peripheral lipolysis, increase plasma FFA
3. increase proteolysis, increase urinary nitrogen excretion

Question 13

Effects of Mineralocorticoids (Aldosterone)

Answer 13

• stimulates kidney reabsorption of Na and water
• stimulates Na and water reabsorption in colon, salivary glands, and sweat glands
• enhances kidney K+ excretion
• hypersecretion of aldosterone can cause hypertension

Question 14

Glucocorticoid Axis

Answer 14

CRH –> ACTH –> Cortisol (negatively feedbacks to previous two to decrease secretion)
- cortisol –> supresses immunity, increases gluconeogenesis, increases protein catabolism, increases lipolysis

Question 15

Adrenocorticoid Synthesis

Answer 15

1. All steroids are synthesized from cholesterol
2. CYP11A1 –> side chain cleavage –> rate limiting step
3. CYP17 –> 17alpha-hydroxylase
4. CYP21A –> 21-hydroxylase
5. CYP11B1 –> 11beta-hydroxylase

Question 16

Pregnenolone synthesis

Answer 16

synthesized from 27-carbon cholesterol into 21 carbon

- catalyzed by CYP11A1 –> rate limiting step

Question 17

Aldosterone Synthesis

Answer 17

zona glomerulosa lacks 17alpha-hydroxylase but expresses aldosterone synthase

Question 18

Cortisol Synthesis

Answer 18

Pregnenolone into progesterone –(21 hydroxylase)-> 11-deoxycortisol -(CYP11B1)-> cortisol

Question 19

Androgen Synthesis

Answer 19

Pregnenolone and Progesterone turn into androstenediol and testosterone respectively via 17, 20 desmolase

Question 20

Mineralocorticoid axis

Answer 20

Normal ACTH is tonic and at high levels ACTH is stimulatory

• angiotensin II is stimulatory
• -> ang II and ACTH increase BP

Question 21

Secondary hypersecretion due to hypothalamic problem?

Answer 21

increase CRH –> increase ACTH –> increase cortisol

Question 22

Secondary hypersecretion due to pituitary problem

Answer 22

increased ACTH –> increased cortisol –> feedback (decreased CRH)

Question 23

Primary hypersecretion due to problem with adrenal cortex

Answer 23

increase cortisol –> feedback (decreases both ACTH and CRH)

Question 24

Cushing Syndrome/Disease

Answer 24

increased ACTH, increased cortisol, +/- of aldosterone

Question 25

Adrenal Insufficiency

Answer 25

Addison’s disease = decreased cortisol, decreased aldosterone, compensatory increase ACTH, MSH (hyperpigmentation)