Adrenal Glands Cortex and Medulla Part 1

What are features of Adrenal Cortex Hormones?

- Corticosteroids

-> Glucocorticoids, mineralocorticoids

- Androgens

- derived from cholesterol

-> Synthesised from acetate (acetyl coA)

-> Dietary - taken up fro circulation

- Synthesis of corticosteroids

- P450 cytochrome enzymes

What are the three zones (layers) in the adrenal cortex?

- Zona glomerulosa - outermost layer

- Zona fasciculata - middle and thickest layer

- Zona reticularis - innermost cortical layer (closest to medulla)

What is the main hormone produced in the Zona glomerulosa?

- Mineralocorticoids (mainly aldosterone)

What is the main hormone produced in the Zona fasciculata?

- Glucocorticoids (mainly cortisol)

What is the main hormone produced in the Zona reticularis?

- Androgens

Where does catecholamine synthesis occur in the adrenal?

- Medulla

What are steroids made from?

- Cholesterol

What is the rate-limiting step in steroid synthesis?

- Transport of cholesterol into the mitochondria - dependent on StAR enzyme

What is the structure of StAR protein?

- Contains a cholesterol transfer domain (StAR related transfer domain - START)

When is StAR produced?

- In response to stimulation usually through a cAMP second messenger system

What is StAR promoted?

- ACTH

- LH

What is StAR suppressed by?

- Alcohol

Where is cholesterol converted to Pregnenolone?

- Mitochondria

How is cholesterol converted to Pregnenolone?

- Cytochrome P450scc enzyme (aka side-chin-cleavage or 20,22 Desmolase) (CYP11A) is located on the inner membrane of the mitochondria and faces of the interior

- 2 hydroxylase reactions produce 20,22-dihydroxycholesterol

- Final stage cleavage of bond between carbon 20 and 22 (removes 6 carbons off the total chain) to produce Pregnenolone

What are glucocorticoids?

- C21 steroids

- Examples:

--> Cortisol (aka hydrocortisone)

--> Corticosterone

note: cortisone is inactive and is converted to cholesterol by the body

What happens in the biosynthesis of glucocorticoid?

- Produced mainly in the Zona fasciculata

- Involves lots of enzymes of different layers and different intracellular compartments

How is cortisol transported in the blood?

- 90+% bound to plasma protein

--> Transcortin (CBG) - 80+%

--> Albumin - 10%

How is ACTH generated?

- ACTH acts on the adrenal, but is also a prohormone - can be cleaved into α-MSH and CLIP

- α-MSH regulated melanocytes and CLIP as no known function

What is the mechanism of ACTH?

1) ACTH released from anterior pituitary and acts on adrenal cortex

2) ACTH binds to melanocortin 2 receptor on cell membrane - activates cAMP

3) cAMP then has cellular effects

- Immediate - increases cholesterol transport into mitochondria (starts steroid hormone synthesis

- Subsequent - increases expression of enzymes (hydroxylases) and LDL receptors needed for continued steroid production

- Long-term - increases size and number of cells (-> adrenal hyperplasia) to sustain hormone output over time

What is the mechanism of action of glucocorticoids?

- Responsive cells

- Intracellular receptors (GR)

- GRE

- Protein synthesis

--> e.g lipcortin

What is the System Actions of glucocorticoids?

- Metabolism

- Electrolyte balance

- Bones

- CNS

- Immune System

How do Glucocorticoids affect metabolism?

-> Carbohydrate:

- increased plasma glucose

- increased hepatic gluconeogenesis

- inhibits glucose entry into tissues

-> Protein:

- muscles

- increased breakdown of protein into AA

- Wasting/growth retardation

-> Liver

- Increased uptake of AA

- Protein synthesis

- Gluconeogenesis

-> Fat

- increased mobilisation of fatty acids from adipose tissue

- Gluconeogenesis

- Redistribution

- Extremities -> trunk area

How do Glucocorticoids affect electrolyte balance?

- LARGE amounts = mineralocorticoid activity

How do Glucocorticoids affect bones?

- Decreased absorption of Ca2+

- Increased excretion

- Inhibition of osteoblasts

- Osteoporosis

How do Glucocorticoids affect the CNS?

- Mood/cognition

How do Glucocorticoids affect the Immune System?

- Decreased lymphocytes, eosinophils

- Increased neutrophils, red blood cells (RBCs), platelets

What are the therapeutic actions of glucocorticoids?

-> Anti-inflammatory

- in large quantities

- decreased leukocyte action

- Rheumatoid arthritis

- decreased proteolysis at site of damage

-> Anti-allergic

- decreased histamine synthesis and release

-> Immunosuppression

What are the different causes of excess glucocorticoids?

-> Cushing's syndrome

- Pituitary tumour

- Ectopic ACTH producing tumour

- Autonomous adrenal adenoma

-> Iatrogenic - illness caused by medical treatment

- Long-term immunosuppression with synthetic cortisol analogues

-> Chronic stress

What are the treatments for excess glucocorticoids?

- Surgery/Radiotherapy

- Drugs - Metyrapone - 11 hydroxylase inhibitor

What is decreased adrenal function cause?

- Glucocorticoid deficiency

What does decreased adrenal function lead to?

1) Addison's disease

- 65+% autoimmune

2)

- disease of pituitary (decreased ACTH)

- Stopping long-term glucocorticoid therapy

What are the symptoms of Addison's disease?

- Fatigue - hypoglycaemia

- Weight loss

- Skin pigmentation

- Ion imbalance

How is Addison's disease treated?

- Cortisol replacement therapy

- Mineralocorticoid replacement

What does the adrenal cortex produce?

-> Corticosteroids

- Glucocorticoids

- Mineralocorticoids

- Androgens

What is the HPA axis regulated by?

- Cortisol via ACTH