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Describe the structure of the adrenal glands.

Size: 4-6cm
Weight: 6-8g

RIGHT - pyramidal
LEFT - semilunar


List the structures surrounding the adrenal glands.

1. Perinephric fat
2. Renal fascia


Describe the blood supply of the adrenal glands.

1. Inferior phrenic arteries
a. Superior suprarenal arteries

2. Abdominal aorta
a. Middle suprarenal arteries

3. Renal arteries
a. Inferior suprarenal arteries


Describe the venous drainage of the adrenal glands.

1. Medullary veins
a. Exit via the hilum
b. Form the suprarenal veins

2. Suprarenal veins
a. Right --> inferior vena cava
b. Left --> left renal vein


What is the lymphatic drainage of the adrenal glands?

Para-aortic glands


What is the innervation of the adrenal glands?

What is the function of this innervation?

Sympathetic innervation via:
1. Coeliac plexus
2. Thoracic splanchnic nerves

1. Innervation of chromaffin cells in medulla
2. Stimulation of chatecholamine productin in the medulla


List the layers in the adrenal glands.

1. Fibrous capsule

2. Cortex
a. Zona glomerulosa
b. Zona fasciculata
c. Zona reticularis

3. Medulla


Describe the features of the different levels of the medulla.

1. Zona glomerulosa
a. Cells in round/ovoid clusters
b. Fibrous trabeculae
c. Small cells
d. Fewer lipid droplets
e. Prominent capillaries

2. Zona fasciculata
a. Narrow cords of cells
b. Collagen strands between cords
c. More lipid droplets

3. Zona reticularis
a. Irregular arrangement of cords/clusters
b. Smaller cells
c. Fewer lipid droplets


What are the functions of each layer of the adrenal cortex?

Zona glomerulosa:
1. Mineralocorticoid production (ADH)

Zona fasciculata
1. Glucocorticoid production (cortisol)

Zona reticularis
1. Androgen production


What are the histological features of the adrenal medulla?

1. Large central vein
2. Chromaffin cells


Describe the general process of steroid hormone synthesis.

1. Cholesterol is transported to the inner mitochondrial membrane via cytochrome P450 (rate limiting step)

2. Cholesterol is converted to pregnenolone via StAR (steroidogenic acute regulatory protein)
a. This involves cleaving side chains

3. Pregnenolone undergoes further shortening of side chains
a. Various enzymes involved, e.g. CYP11A1

4. Intermediates are further modified by addition of substituents in a stereo-specific manner
a. This forms different hormones


List the steps in the formation of cortisol, and important enzymes involved.

1. Cholesterol
a. StAR

2. Pregnenolone

3. 17-OH-pregnenolone

4. 17-OH-progesterone
a. 21 hydroxylase

5. 11-deoxycortisol
a. 11 beta hydroxylase

6. Cortisol


Describe the mechanism of action of cortisol.

1. Cortisol is lipid soluble and easily diffuses into the cell

2. Intracellular glucocorticoid receptor is activated by binding to cortisol

3. Hormone-receptor complex enters the nucleus and binds to DNA
a. Happens at the glucocorticoid response element

5. This acts as a transcription factor and stimulates production of mRNA


List some of the effects of cortisol.

1. Stimulates gluconeogenesis (liver)

2. Permissive effect on glucagon/NA
a. Stimulates their effectt
b. Inhibits insulin release

3. Stimulates lipolysis (adipose)
a. Releases FAs and glycerol
b. Used for energy production

4. Stimulates break down of muscle proteins
a. Muscle wasting

5. Increases blood pressure

6. Growth and development of foetus

7. Stimulates initiation of post-partum lactation

8. CNS effects

9. Anti-inflammatory effects
a. Decreased circulating T cells and eosinophils
b. Increased circulating neutrophils


List the steps in the synthesis of aldosterone, and the important enzymes involved.

1. Cholesterol
a. StAR

2. Pregnenolone

3. Progesterone
a. 21 hydroxylase

4. 11-deoxycorticosterone
a. 11 beta hydroxylase

5. Corticosterone
a. 18 hydroxylase

6. 15-OH-corticosterone
a. Aldosterone synthase

7. Aldosterone


Where are mineralocorticoid receptors found?

1. DCT of kidney
2. Salivary/sweat glands
3. Large intestine
4. Brain
5. Vascular tissue


Describe the mechanism of action of aldosterone.

1. Aldosterone is lipid soluble and easily diffuses into the cell

2. Intracellular mineralocorticoid receptor is activated by binding to aldosterone


What is the function of aldosterone?

How does it do this?

1. Increases sodium and water excretion
2. Increases H+ and potassium excretion

Upregulates the following channels:
1. Na+/K+ ATPase
2. Na+ channels
3. K+ channels
4. Na+/H+ exchangers


How is cortisol production controlled?

1. Hypothalamus releases CRH
a. Stimulated by: stress, time of day, illness

2. Anterior pituitary secretes ACTH

3. ACTH stimulates adrenal cortex

4. Cortisol has a negative feedback action on CRH/ACTH


Describe the mechanism of action of ACTH.

1. ACTH binds to ACTH (M2) receptor (G protein coupled)

2. This causes a conformational change in the ACTH receptor, so the alpha subunit detaches and activates adenyl cyclase
a. Activates cAMP
b. Activates PKA

3. Causes Ca2+ influx into cell, causing:
a. Stimulation of cholesterol transport to mitochondria via cytochrome P450
b. Increased transcription of genes encoding steroidogenic enzymes (e.g. 11 beta hydroxylase)
c. Increased cortisol reaction


How is aldosterone secretion controlled?

Renin-angiotensin-aldosterone system


Describe the mechanism of action of angiotensin II.

1. Angiotensin II binds to the AngII type 1 receptor in the adrenal gland (G protein coupled)

2. Conformational change causes the alpha subunit to detach, which activates phospholipiase C
a. Converts PIP2 into PIP3 and DAG

3. PIP3 causes release of stored Ca2+, causing Ca2+ influx

4. Ca2+ influx activates calmodulin-dependent protein kinases (CaMKs), which cause:
a. Increased StAR transcription
b. Increased cytochrome P450 action
c. Increased aldosterone production


Define Cushing's syndrome and Cushing's disease.

Cushing's syndrome: "condition resulting from excess corticosteroid hormones in the body"

Cushing's disease: "Cushing's syndrome when caused by a pituitary gland tumour"


List the causes of Cushing's syndrome.

1. Endogenous cortisol excess
a. Cushing's disease
b. Ectopic ACTH syndrome
c. Adrenal adenoma
d. Adrenal carcinoma
e. Pseudo-Cushing's syndrome due to non-endocrine disease

2. Iatrogenic cortisol excess
a. Chronic glucocorticoid therapy
b. Glucocorticoid therapy overdose


List some of the clinical features of Cushing's disease.

1. Facial plethora (swelling with blood)
2. Hair thinning
3. Hirsutism
4. Psychosis
5. Moon face
6. Hypertension
7. Muscle wasting
8. Osteoporosis
9. Central obesity
10. Weakness
11. Bruising
12. Diminished immune response
13. Striae


List the investigations used for Cushing's syndrome.

1. 24 hour free urinary cortisol levels
2. Overnight dexamethasone suppression test
3. Low dose dexamethasone suppression test
4. High dose dexamethasone suppression test
5. Diurnal rhythm of plasma cortisol
6. Insulin tolerance test
7. CRH test
8. ACTH levels
9. Inferior petrosal sinus sampling


How is an overnight dexamethasone test done?

1. Dexomethasone is a corticosteroid, therefore taking it would normally suppress ACTH release and therefore decrease cortisol levels

2. Therefore, if dexamethasone does NOT decrease cortisol levels, this means there is Cushing's syndrome


What does a high dose dexamethasone test show?

Differentiates between pituitary-dependent disease and ectopic ACTH syndrome

PITUITARY DEPENDENT DISEASE: urine cortisol is LESS than 50% of the basal rate

ECTOPIC ACTH SYNDROME: urine cortisol is MORE than 50% of the basal rate


List the methods of treating Cushing's syndrome.

1. Trans-sphenoidal pituitary adenomectomy

2. Bilateral adrenalectomy

3. Medical treatment
a. Somatostatin analogues
b. Steroidogenesis inhibitors
c. GR antagonists

4. Pituitary radiotherapy

5. Surgical removal of other tumours


List the potential consequences of long term exposure to excess corticosteroids.

1. Cushing's syndrome
2. Diabetes
3. Depression/anxiety
4. Androgen disruption
5. Acne
6. Osteoporosis
7. Gynaecomastia