PBL 12 - Adrenal Glands

ILOs
1. Outline the anatomy and histology of the adrenal glands
2. Describe the synthesis, function and importance of cortisol and aldosterone, identifying their target
tissues and mechanisms of action within those tissues
3. Outline the functional relationships between the hypothalamus, the anterior pituitary and the adrenal
cortex (HPA-axis)
4. List the tests used to investigate adrenal insufficiency
5. Outline investigations used to investigate possible cortisol excess and how iatrogenic and endogenous
cortisol excess can be distinguished biochemically
6. Distinguish primary and secondary adrenocortical insufficiency
7. Explain how corticosteroid hormones can be replaced and the importance of patient education in
ensuring this is done safely
8. Understand the metabolic and biochemical consequences of long-term exposure to excess
corticosteroid

Question 1
Outline the anatomy and histology of the adrenal glands

• The adrenal glands are endocrine glands situated in the abdomen above the
kidneys, each about 4-6cm in length. It lies at the level of the 12th rib.
• They are yellow in colour due to high cholesterol.
• They have a rich blood and nerve supply (the medulla is a part of the sympathetic
nervous system). The blood supply reaches the outer surface of the gland before
entering and supplying each layer (centripetal flow)
• A dense fibrous capsule firmly attaches each adrenal gland to the kidney.
• The adrenal glands consist of the outer cortex and inner medulla. The cortex is split
into 3 zones, the zona glomerulosa, the zona fasciculata and the zona reticularis.

• Zona Glomerulosa - produces mineralocorticoids e.g. Aldosterone which is important in the balances
of electrolytes (K+ and Na+) and the maintenance of water. The cells of this region form small, dense
clusters
• Zona Fasciculata - produces glucocorticoids due to their effects on glucose metabolism e.g. Cortisol
which is regulated by ACTH. This region takes up most of the cortical region (75%). The cells contain
more lipids and appear foamy and pale. They are arranged to form individual cords composed of stacks
of cells. Adjacent cords are separated by fenestrated capillaries.
• Zona Reticularis - produces androgens, DHEA that is also regulated by ACTH. This is an important
source of androgens in women. The endocrine cells of this region form a folded, branching network and
fenestrated capillaries that wrap around cells.

• Adrenal Medulla - Catecholamine production, 80% adrenaline & 20% noradrenaline.

 Blood Flow

Question 2
Describe the synthesis, function and importance of cortisol and aldosterone, identifying their target
tissues and mechanisms of action within those tissues

Cortisol “Stress Hormone”

• In response to ACTH, the zona fasciculata release cortisol and corticosterone.
• Cortisol will suppress its own production via negative feedback of the hypothalamus and anterior
pituitary gland.
• The ACTH receptor is a G-protein coupled receptor. Upon its activation, it causes an increase in cAMP
and activation of PKA and Ca2+ influx. There is subsequent rapid cholesterol delivery to the mitochondria.
Genes for steroidogenic enzymes are turned on (enzymes that process cholesterols into their end
products) → ultimately results in increased cortisol/androgen production.
• Functions of Cortisol:

Metabolic
• Stimulates gluconeogenesis in the liver - glucose is synthesised
from non-hexose substrates such as amino acids and lipids.
• Stimulation of lipolysis in adipose tissue.
• Glycogenesis - cortisol aims to store away glucose produced via
glujconeogeneis as glycogen in periods of stress.
• Opposes insulin - increases blood glucose
Immunosuppression
• Decreases lymphoid tissue volume and activity (↓ antibodies &
lymphocytes)
• They show anti-inflammatory effects by inhibiting WBCs
Systemic
• Increased appetite
• Increased bone resorption.
• Increased breakdown of skeletal muscle protein.
• Decreased Vitamin D3 and therefore decreased calcium reabsorption
• Promotes the effects of adrenaline → increased vascular tone and BP.

Aldosterone
• Aldosterone is a mineralocorticoid that is regulated by the RAAS that
causes Na+ retention and K+ excretion.
• It acts on mineralocorticoid receptors (MR) in the principal cells of the distal
tubule and collecting duct. Since aldosterone is a steroid, the MR receptors
are found in the cytosol. It has 2 main actions:
• It causes the up regulation of basolateral Na+/K+ pumps.
• It also upregulates the number of ENaC transporters in the apical
membrane, thus increasing the permeability to Na+
Question 3
Outline the functional relationships between the hypothalamus, the anterior pituitary and the
adrenal cortex (HPA-axis)

• The hypothalamus release CRH in response to illness, stress and time of day (early morning). It acts on
the anterior pituitary which then produces ACTH. This hormone acts on the adrenal cortex to produce
cortisol.
• Cortisol is released in a Circadian rhythm (24 hour clock), being highest during the mornings.
• ACTH is a long peptide which is cleaved off from a precursor molecule, POMC
Adrenal Insufficiency
Primary Adrenal Insufficiency - Failure of the Adrenal Cortex.
• Addison’s Disease - chronic adrenal insufficiency (most common cause of primary insufficiency)
• Congenital Adrenal Hyperplasia (CAH)
• Insufficiency leads to decreased production of steroid hormones (glucocorticoids, mineralocorticoids,
androgens).

Secondary Adrenal Insufficiency - Failure of the Pituitary Gland.

• Lack of ACTH production and stimulation of the adrenal gland, which can be caused by
• Excess exogenous steroid (iatrogenic)
• Pituitary/hypothalamic disorders.
• Glucocorticoids are affected, however mineralocorticoid production (aldosterone) remains intact.

Addison’s Disease
• Addison’s Disease is the destruction of the entire adrenal cortex due
to atrophy.
• ↓ in ALL productions of the cortex
• Mineralocorticoids, Glucocorticoids & Androgens.
• ↓ in Cortisol levels, which results in ↑ CRH & ACTH production
• ACTH acts on melanocytes and causes hyper-pigmentation.
• Autoimmune Destruction, > 90% of the adrenal cortex is destroyed
before it becomes symptomatic. Autoantibodies are found in 70% of
patients.
• Tuberculosis (<10% in the UK)

Clinical Features
• Anorexia, Weight Loss
• Fatigue/Lethargy
• Dizziness - Postural Hypotension
• Abdominal Pain, Diarrhoea, Vomiting
• Skin Pigmentation - due to ↑ ACTH
• Dehydration - mineralocorticoid deficiency
• ↓ Na+ reabsorption → hyponatremia
• ↓ Water reabsorption → dehydration
• ↓ K+ excretion → hyperkalaemia

Investigations
• ‘Suspicious’ Biochemistry
• ↑ K+ , ↓Na+ , hypoglycaemia
• Short SynACTHen test
• Measures plasma cortisol before and 30 minutes after
IV ACTH injection. Patient should not respond to ACTH
i.e. cortisol levels should stay the same
• ACTH ↑
• Renin ↑, Aldosterone ↓
• Adrenal auto-antibodies (70% present in Addison’s)
• Chest X-Ray - Tuberculosis

Management
• Mineralocorticoid Replacement
• Fludrocortisone - aldosterone replacement
• Must be used carefully, as it can increase water reabsorption and thus ↑ BP
• Glucocorticoid Replacement
• Hydrocortisone - try to mimic the diurnal rhythm.
• Education of Steroid Use
• Sick day rules - double in febrile illness (fever).
• Steroids cannot be stopped suddenly, since the adrenal glands are not producing any cortisol. It
can result in adrenal crisis. Patients must carry steroid cards.
Hyperadrenalism - Cushing’s Syndrome
• Cushing’s syndrome is the term used to describe the clinical state
of increased free circulating glucocorticoid (cortisol)
• There are 2 types:
• ACTH dependent - ↑ ACTH and therefore ↑ Cortisol
• Pituitary adenoma, ectopic non-pituitary causes, ectopic CRH
• ACTH independent - ↓ Cortisol
• Long-term glucocorticoid administration
• Adrenal adenoma, adrenal carcinoma, nodular hyperplasia

Finding the source of cortisol excess

Diagnosis
• Establish cortisol excess
• Dexamethasone suppression test
• 24 hour unready free cortisol
• Late night salivary cortisol

Treatment & Management

• Surgical
• Transsphenoidal pituitary surgery
• Laparoscopic adrenalectomy
• Removal of ACTH source
• Medical
• Metyrapone/ketoconazole - inhibit cortisol production
• Short term measure
 Mineralocorticoids Receptors (MR) vs Glucocorticoid Receptors (GR)

Found in the distal nephron, salivary Widespread

glands, sweat glands, large intestine,
brain, vascular tissue and the heart.

Cortisol binds to its normal GR, but it can also bind to MR, thus competing with Aldosterone for its receptor.
Aldosterone however has a higher affinity for MR than Cortisol. Although, cortisol is at a much higher
concentration in the blood than Aldosterone. An enzyme 11β-HSDII catalyses the conversion cortisol
(active) to cortisone (inactive) in selective tissues e.g. kidney, allowing aldosterone to function normally.

Primary Aldosteronism
• Primary hyperaldosteronism is a disorder of the adrenal cortex characterised by excess aldosterone
production leading to Na+ retention, K+ loss and the combination of hypokalaemia and hypertension.
• This is due to either a single adrenal adenoma (Conn’s Syndrome) or bilateral adrenal nodules.
• It is the commonest secondary cause of hypertension.

Clinical Features
• Significant hypertension
• Hypokalaemia (in up to 50%)
• Alkalosis

Diagnosis
• Blood biochemistry
• Plasma aldosterone elevated (that are not surpassed with IV 0.9% saline load or fludrocortisone
administration
• Plasma renin concentration suppressed
• Hypokalaemia
• Urinary Potassium Loss > 30mmoL/day
• Adrenal CT scan

Management & Treatment

• Surgical
• Unilateral laparoscopic adrenalectomy, only if there is an adrenal adenoma
• It cures hypokalaemia and cures hypertension in 30-70% of cases
• Medical
• MR antagonists (spironolactone)
• Or Amiloride (blocks Na+ reabsorption by acting on ENaC)
Corticosteroid Production & Regulation Lecture
1. Understand the anatomical and functional zonation of the adrenal cortex
2. Outline the key steps in the biosynthesis of cortisol and how this is regulated
3. Describe the biosynthetic steps required to synthesise aldosterone and its regulation by the renin-
angiotensin system
4. Describe how both cortisol and aldosterone exert their effects via receptors located in the cell nucleus
5. Explain the multiple physiological effects of cortisol
6. Understand the main physiological role of aldosterone
7. Describe adrenal androgen production and how this is regulated

Adrenal Gland Lecture

1. Explain the pathophysiology and consequences of glucocorticoid over and underproduction
2. Outline principles of glucocorticoid replacement therapy and the role of patient education in this process
3. Understand the difference of primary and secondary adrenal insufficiency
4. Outline the causes and consequences of mineralocorticoid excess
5. Describe the anatomy of the adrenal medulla and its physiological role
6. Outline the clinical features of catecholamine excess