Physiology Block 3 Week 14 08 Adrenal Gland Flashcards Preview

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1

What steroid does each area of the adrenal gland produce?

Cortex:
-Zona glomerulosa
-Zona fasciculata
-Zona reticularis

Medulla

Zona glomerulosa
--aldosterone (mineralocorticoid)

Zona fasciculata and reticularis
--cortisol (glucocorticoid) and androgens (DHEA, androstenedione)

Medulla
--catecholamines

What steroid is produced by which zone is entirely determined by the zonal expression of specific steroidogenic enzymes

2

Loss of adrenocortical function =

Loss of adrenal medulla =

Bilateral Adrenalectomy =

Complete loss of adrenocortical function is fatal

Adrenal medulla is NOT necessary for life--does not have essential hormones (produces catecholamines)

Patients with bilateral adrenalectomy NEEDS treatment with glucocorticoid and mineralocorticoid, but not with catecholamine replacement

3

Major Steroid Hormones Produced by Adrenal Gland

Cortisol
Aldosterone
Corticosterone
Dehydroepiandrosterone (DHEA)
Androstenedione

4

Cortisol

MAJOR Glucocorticoid

5

Aldosterone

MAJOR Mineralocorticoid

Much more potent mineralocorticoid than cortisol
weaker glucocorticoid than cortisol

6

Corticosterone

Has both glucocorticoid and mineralocorticoid

weaker glucocorticoid than cortisol
more potent mineralocorticoid than cortisol

Rats and mice DO NOT make cortisol
--depend on corticosterone for glucocorticoid activity

7

Dehydroepiandrosterone (DHEA) and Androstenedione

Androgens (weaker than testosterone)
--effects in early puberty
--effects in menopause

8

What chemical differences between cortisol, corticosterone, and aldosterone could account for their different affinities for their cognate receptors?

Cortisol--2 hydroxyl groups

Corticosterone--1 hydroxyl group

Aldosterone--1 hydroxyl group + aldo carbonyl group

9

Steroidogenesis

1. ACTH binds to its G-coupled membrane receptor
2. Low density Lipoprotein (LDL) taken up and cholesterol esters stored in lipid droplets
3. ACTH inc cAMP production

10

ACTH increases cAMP production has two effects

1. Increases cholesterol ester hydrolase activity such that more cholesterol (released from lipid droplet) is available for transport to the mito

2. Increases steroidogenic acute regulatory (StAR) protein activity
--required for cholesterol transport across mito membrane
--StAR transportation is rate-limiting step

3. Once cholesterol inside mito, steroidogenesis by specific enzymes to cortisol
--first and last steps = mito enzymes
--intermediate steps = smooth ER enzymes

4. Cortisol diffuses out of the cell
--adrenal cortisol content is proportional to release
--Cortisol (lipid) is not stored in granules like a peptide or amine

11

Steroidogenic Pathways

P450 side chain cleavage

P450c17 (17-hydroxylase)

3-beta-hydroxysteroid dehydrogenase

P450c21 (21-hydroxylase)

P450c11 (11-beta-hydroxylase)

12

P450scc

Mitochondrial

**Catalyzes first step**

Cholesterol to Pregnenolone

13

P450c17 (17-hydroxylase)

Smooth ER

Pregnenolone --> 17-OH-pregnenolone --> DHEA

Progesterone --> 17-OH-Progesterone --> Androstenedione

14

3-beta-hydroxysteroid dehydrogenase

Smooth ER

Only non P450 enzyme

3 reactions

Pregnenolone --> Progesterone

17-OH-pregnenolone --> 17-OH-progesterone

DHEA --> Androstenedione

15

P450c21 (21-hydroxylase)

Smooth ER

Progesterone --> 11-Deoxycorticosterone

17-OH-progesterone --> 11-deoxycortisol

16

P450c11 (11-beta-hydroxylase)

Mitochondrial

11-Deoxycortisol --> cortisol

17

What enzyme is most common decrease of function mutation in congenital adrenal hyperplasia?

P450c21 (21-hydroxylase)

Results in huge adrenal glands (size of the kidney!)

18

What will happen to cortisol production, adrenal 17-hydroxyprogesterone content, plasma DHEA, hypothalamic CRH release, plasma ACTH concentration, and adrenal size with a 90% reduction in fetal adrenal P450c21 expression?

What would happen to the fetus if the P450c21 mutation led to a 100% loss of enzyme function?

Cortisol is not being produced adequately

Need cortisol in developing fetus for lungs to develop
--results in ACTH increase!!!

ACTH results in the adrenal gland to work harder and get bigger (HYPERPLASIA)

The buildup of 17-hydroxyprogesterone spills into Androgen pathway-->Androstenedione
--lots of adrenal androgens produced

In boys, apparent after birth when androgen levels should come down

In girls, should have only very little testosterone
Exposure of a fetus to androgen results in turning a female phenotype into a male or ambiguous

Tx: If knew fetus had enzyme deficiency, what would you give the mother?
--Dexamethasone--extremely potent glucocorticoid
--crosses placenta and suppresses fetal ACTH
--no hypertrophy = no androgen produced

19

Synthetic Glucocorticoids

Pharmaceutical

-minimal mineralocorticoid activity

Prednisone < Methylprednisone < Tiamcinolone <<< Dexamethasone

20

Synthetic Mineralocorticoid

Fluorocortisol

Potent glucocorticoid but MUCH MORE POTENT mineralocorticoid activity

21

Mineralocoriticoid activity

Mineralocoriticoid activity is related to retaining salt, NaCl. Mineralocorticoids maintain electroylte balance by retaining Na+ and promoting K+ excretion.

22

Glucocorticoid Activity

Important for the biosynthesis and metabolism of carbohydrates, proteins and lipids

They are also involved in immune responses

Possess anti-inflammatory activity

23

Mechanism of Glucocorticoid Action via Glucocorticoid Receptor (GR)

Steroid hormones circulate plasma bound to binding proteins--long half-life

Cortisol bound to cortisol binding protein (CBG)
-dissociates and diffuses into the cytoplasm

Cortisol binds to GR
-dissociation from heat shock protein (HSP) complex

Conformational change allows cortisol-GR complex to enter the nucleus
--dimerizes and binds to glucocorticoid response elements (GRE) upstream from specific genes

Induces transcription of new mRNA and translation of new protein in the cytoplasm
--causes cellular function

Results in increased blood glucose over several hours (not instantaneous)

24

What if there was GRE mutation?

Every cell that responds to cortisol will be affected

Increased ACTH, leads to androgen synthesis, leads to hypertrophy

25

Glucocorticoid effect on CNS

Decrease in hypothalamic CRH

Decreases ADH (posterior pituitary)
--induces water diuresis

Increase in appetite
--Cushing's Syndrome

26

Glucocorticoid effect on cardiovascular

Absence of cortisol (adrenal insufficiency) results in hypotensive shock

Excess cortisol causes hypertension

27

Glucocorticoid effect on Liver

Increases gluconeogenesis = increased glucose

28

Glucocorticoid effect on Lungs

Required for normal surfactant production

Premature babies usually deficient in surfactant leading to respiratory distress syndrome

29

Glucocorticoid effect on Pituitary

Decreases ACTH (negative feedback)

30

Glucocorticoid effect on Kidney

Increases GFR