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Flashcards in Adrenal Physiology Deck (25):
1

Adrenal Gland Architecture

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)

2

Cortiocotropin Releasing Hormone/Factor

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

3

CRFR1 receptor

Gs adenylyl cyclase activity
- increased synthesis of pro-opiomelanocortin
- cleavage of POMC --> MSH, ACTH, lipotropin

4

ACTH

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

5

Melanocortin receptor

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)

6

Glucocorticoids

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

7

Mineralocorticoids

promotes salt and water retention by kidney = aldosterone
- binds mineralocorticoid receptors

8

Sex steroids

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

9

Glucocorticoid Receptors

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

10

Mineralocorticoid Receptor

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

11

Glucocorticoid metabolism

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

12

Glucocorticoids affects of glucose

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

13

Effects of Mineralocorticoids (Aldosterone)

- 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

14

Glucocorticoid Axis

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

15

Adrenocorticoid Synthesis

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

16

Pregnenolone synthesis

synthesized from 27-carbon cholesterol into 21 carbon
- catalyzed by CYP11A1 --> rate limiting step

17

Aldosterone Synthesis

zona glomerulosa lacks 17alpha-hydroxylase but expresses aldosterone synthase

18

Cortisol Synthesis

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

19

Androgen Synthesis

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

20

Mineralocorticoid axis

Normal ACTH is tonic and at high levels ACTH is stimulatory
- angiotensin II is stimulatory
--> ang II and ACTH increase BP

21

Secondary hypersecretion due to hypothalamic problem?

increase CRH --> increase ACTH --> increase cortisol

22

Secondary hypersecretion due to pituitary problem

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

23

Primary hypersecretion due to problem with adrenal cortex

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

24

Cushing Syndrome/Disease

increased ACTH, increased cortisol, +/- of aldosterone

25

Adrenal Insufficiency

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