Session 9

Question 1

What are the adrenal glands?

Answer 1

The adrenal glands are a pair of multifunctional endocrine glands that cap the upper poles of the kidneys and lie against the diaphragm in the retroperitoneal space. They are small in size and have a combined weight of 6-8 g (slightly less in the female).

Question 2

Describe the structure of the adrenal glands and what hormones they produce

Answer 2

The gland consists of two regions, an outer cortex and an inner medulla and produces the following hormones:

Cortex
• Mineralocorticoids – e.g. aldosterone (C21 steroid)
• Glucocorticoids – e.g. cortisol and corticosterone (C21 steroids) – the major steroids produced by the cortex.
• Androgens – e.g. dehydroepiandrosterone (C19 steroid) - only produced in small amounts.

Medulla
• Adrenaline (epinephrine)
• Noradrenaline (norepinephrine)

Question 3

Describe the embryonic development of the adrenal glands

Answer 3

During embryonic development, the cortex is derived from mesoderm, whereas the medulla is derived from neural crest cells which subsequently migrate into the developing cortex.

Question 4

Describe the structure and function of the adrenal cortex

Answer 4

The adrenal cortex lies under a connective tissue capsule which contains plexus of blood vessels (capsular plexus). Three zones can be recognised within the cortex which have different arrangements of secretory cells and associated network of capillaries and sinusoids:
1. Zona Glomerulosa. The cells in this outermost zone secrete the mineralocorticoids (e.g. aldosterone) that regulate body Na+ and K+ levels.

2. Zona Fasciculata. The cells in this zone produce the glucocorticoids (e.g. cortisol) that have a number of important functions including the regulation of carbohydrate metabolism.
3. Zona Reticularis. This is the deepest cortical zone and the cells secrete glucocorticoids and small amounts of androgens (dehydroepiandrosterone).

Question 5

What is aldosterone and what is its function?

Answer 5

Aldosterone is the major steroid hormone produced by Zona glomerulosa cells in the adrenal cortex. This mineralocorticoid plays a central role in determining extracellular fluid volume by controlling the rate at which Na+ ions are reabsorbed or excreted by the kidneys. Since Na+ is the primary osmotically active ion in extracellular fluid, the amount of Na+ present also controls the amount of water and therefore extracellular volume. Since extracellular volume is a prime determinant of arterial blood pressure, aldosterone is also a prime regulator of arterial blood pressure. Aldosterone acts on the distal tubules and collecting ducts of nephrons in the kidney, causing an increased reabsorption of Na+ and water and the secretion of K+ into the tubular lumen. This will be covered in more detail in the Urinary unit but essentially aldosterone acting at nuclear mineralocorticoid receptors within principal cells of the distal tubule and collecting duct upregulates expression of the basolateral Na+/K+ pump. This pumps 3 Na+ ions out of the cell into interstitial fluid and 2 K+ ions into the cell thereby promoting a concentration gradient which allows the retention of Na+ and water (water will follow the Na+ ions) in blood and excretion of K+ into urine. Aldosterone also upregulates expression of epithelial sodium channels (termed ENaCs) in the collecting duct and also the colon promoting Na+ absorption. Aldosterone is an integral part of the renin–angiotensin-aldosterone system.

Question 6

What is the structure of cortisol?

Answer 6

Cortisol is the primary glucocorticoid hormone in humans and is a member of the C21 steroid family. All the steroid hormones are lipophilic and are synthesised from cholesterol via a series of enzyme catalysed reactions.

Question 7

How is cortisol secretion controlled?

Answer 7

Adrenocorticotropic Hormone (ACTH or corticotropin) secreted from the corticotropes of the anterior pituitary is the main factor controlling the release of cortisol. ACTH is secreted with a circadian rhythm with a pulsatile secretion superimposed. The secretion of ACTH is under the control of corticotropin releasing factor (CRF), a 41 amino acid polypeptide produced in the hypothalamus. CRF is secreted in response to physical (temperature, pain), chemical (hypoglycaemia) and emotional stressors. There is also negative feedback by glucocorticoids on both the hypothalamus and pituitary. Blood cortisol varies during the day from a peak at about 7.00 am to a trough at about 7 pm. For this reason the time should always be noted when taking a sample of blood for cortisol measurement and repeated measurements should be taken at the same time of day

Question 8

What is ACTH, what does it do and how does it do this?

Answer 8

ACTH is a 39 amino acid, single chain polypeptide hormone. The initial biosynthetic precursor is a large protein (~250 amino acids) called proopiomelanocortin (POMC). Post-translational processing of POMC at different sites produces a range of biologically active peptides including ACTH, α-MSH (melanocyte stimulating hormone) and
endorphins. The α-MSH sequence of 13 amino acids is contained within the ACTH sequence in POMC giving ACTH some MSH-like activity when present in excess. ACTH has a short half-life in the circulation (~8min) and is released in pulses that follow a circadian rhythm. Peak plasma levels occur in the early hours of the morning and the lowest levels are seen in the late evening. ACTH is hydrophilic and interacts with high affinity receptors on the surface of cells in the zona fasciculata and reticularis. The binding of ACTH to these receptors leads to activation of cholesterol esterase increasing the conversion of cholesterol esters to free cholesterol. It also stimulates other steps in the synthesis of cortisol from cholesterol. The clinical consequences of over-secretion of ACTH relate to the direct effects of ACTH on tissues (increased pigmentation due to partial MSH activity) and the effects of ACTH on the adrenal cortex that produces adrenal hyperplasia and over-production of cortisol. Under secretion of ACTH produces symptoms related to the lack of glucocorticoids but not those related to lack of mineralocorticoids as aldosterone secretion is normal (not controlled by ACTH). ACTH is a peptide hormone and acts on G-protein coupled receptors on the plasma membrane of target cells. The specific GPCR for ACTH is a type of melanocortin receptor (type 2), known as MC2, It is also sometimes called the corticotropin receptor. This receptor uses cAMP as a second messenger. The mechanism of action of the peptide hormone ACTH should not be confused with the mechanism of action of a steroid hormone, such as cortisol (see below); they are quite different.

Question 9

How is cortisol transported in the plasma?

Answer 9

Cortisol, like all steroids, is lipophilic and must be transported bound to plasma proteins. The major transport protein is transcortin, also known as corticosteroid-binding globulin (CBG), and this carries ~90% of the plasma cortisol with the remaining ~10% being bound by serum albumin.

Question 10

What is the mechanism of action of cortisol upon target cells?

Answer 10

Cortisol can cross the plasma membranes of target cells and bind to cytoplasmic receptors. The hormone/receptor complex then enters the nucleus and interacts with specific regions of DNA. This interaction changes the rate of transcription of specific genes and may take time to occur

Question 11

What are the actions of cortisol on target cells?

Answer 11

Cortisol is an important component of the stress response and has a number of important effects on metabolism. Most cell types contain receptors for the glucocorticoids. These are located in the cytoplasm, and binding of cortisol causes cortisol-receptor complex to translocate to the nucleus where it associates with glucocorticoid response elements in genomic DNA to modulate gene transcription. The major metabolic effects of cortisol are in the starved and stressed states where it affects the availability of all major metabolic substrates by increasing proteolysis, lipolysis and gluconeogenesis. The metabolic actions of cortisol include:
↓ Amino acid uptake
↓ Protein synthesis & ↑ proteolysis in most tissues (not liver).
↑ Hepatic gluconeogenesis and glycogenolysis.
↑ Lipolysis in adipose tissue N.B. high levels of cortisol
↑ lipogenesis in adipose tissue.
↓ Peripheral uptake of glucose (anti-insulin).

In addition to its general metabolic actions cortisol also has direct effects on cardiac muscle, bone and the immune system.

Question 12

What does the adrenal medulla do?

Answer 12

The adrenal medulla is, in essence, a modified sympathetic ganglion that synthesises various catecholamines including the hormone adrenaline (epinephrine) and the neurotransmitters noradrenaline (norepinephrine) and dopamine. The adrenal medulla therefore serves as an important link between the endocrine and sympathetic nervous systems.

Question 13

Explain catecholamine synthesis

Answer 13

The catecholamines are synthesised in chromaffin cells of the medulla by a series of enzyme-catalysed steps that convert the amino acid tyrosine into dopamine. Dopamine is then converted to noradrenaline and noradrenaline to adrenaline. The catecholamines are stored in the chromaffin cells in membrane-limited vesicles before release into the bloodstream.

Question 14

What are the actions of adrenaline?

Answer 14

Adrenaline is released as part of the fright, flight or fight response in man and it is secreted in response to stressful situations. It has effects on:
• Cardiovascular system (↑ cardiac output, ↑ blood supply to muscle).
• Central nervous system (↑ mental alertness).
• Carbohydrate metabolism (↑ glycogenolysis in liver and muscle).
• Lipid metabolism (↑ lipolysis in adipose tissue).

Question 15

What are adrenergic receptors and what do they do?

Answer 15

Adrenaline (and smaller amounts of noradrenaline) released in response to sympathetic stimulation of chromaffin cells in the adrenal medulla travels through the bloodstream to stimulate adrenergic receptors in target tissues. These cell surface receptors are G protein coupled and the type of response produced the target cell depends on the type of adrenergic receptor expressed. There are two main types of adrenoceptor termed α and β. The α type has two subtypes; α1 receptors facilitate an increase in intracellular Ca2+ via coupling to Gαq and α2 receptors facilitate a decrease in the intracellular second messenger cAMP via coupling to the inhibitory G protein Gαi. There are three subtypes of β adrenoceptor termed β1, β2 and β3 and all these promote an increase in cAMP by coupling to the stimulatory G protein Gαs.

Question 16

What are the clinical consequences of over-secretion of adrenaline?

Answer 16

Overproduction of adrenaline by the adrenal medulla, usually due to a tumour (Phaeochromocytoma), may be associated with hypertension, anxiety, palpitations, pallor, sweating and glucose intolerance.

Question 17

What is the renin-angiotensin-aldosterone system

Answer 17

The renin–angiotensin–aldosterone system is a system of hormones involved in the regulation of plasma sodium concentration and arterial blood pressure. You will cover this system in more detail in the cardiovascular system and Urinary units and the intention here is to introduce you to the components and overall function of this system

Question 18

What controls the activation and function of the renin-angiotensin-aldosterone system? (Could add a picture to answer from page 182 of MEH workbook)

Answer 18

If the concentration of plasma Na+ or the flow of blood through the kidney falls, the juxtaglomerular cells of the kidney nephrons release the enzyme renin into the general circulation. A fall in blood pressure or a loss of blood volume e.g. due to haemorrhage or dehydration can also simulate the release of renin since baroreceptors in the carotid sinus detect these changes and initiate an increase in sympathetic tone to the kidney. Once released into the plasma, renin can act on its target protein angiotensinogen. Angiotensinogen is a globular protein that is constitutively released into blood by the liver and the function of renin is to cleave a short biologically inactive peptide (10 amino acids long) known as angiotensin I from angiotensinogen. Angiotensin I is further cleaved (2 amino acids are removed) by the enzyme angiotensin-converting enzyme (ACE), primarily within the capillaries of the lungs. Angiotensin II is the biologically active product of this cleavage system and is a potent vasoconstrictor causing arterioles to constrict resulting in an increase in arterial blood pressure. A second action of angiotensin II is to stimulate the adrenal cortex to secrete aldosterone. As we saw earlier, aldosterone acts on the distal tubules and collecting ducts of nephrons in the kidney to cause an increased reabsorption of Na+ and water back into blood and an increased secretion of K+ into urine resulting in increased blood volume and pressure. A third action of angiotensin II is to increase the release of antidiuretic hormone from the posterior pituitary. ADH complements the actions of aldosterone in the kidney by inducing translocation of aquaporin water channels in the plasma membrane of the collecting duct cells allowing more reabsorption of water back into the blood.

Question 19

How can drugs act on the RAAS?

Answer 19

High blood pressure can result from an overactive RAAS and several types of drug have been developed that dampen the effects of this system. The most widely used are the Inhibitors of angiotensin converting enzyme (so called ACE inhibitors) that reduce the formation of angiotensin II. However, angiotensin receptor blockers can be used to block the actions of angiotensin II and inhibitors of the enzyme renin have also been developed.

Question 20

Hyperactivity of the adrenal cortex leading to increased secretion of cortisol gives rise to what condition?

Answer 20

Cushing’s syndrome

Question 21

What may cause hyperactivity of the adrenal cortex?

Answer 21

• Increased activity of the adrenal cortex due to a primary cortisol producing adrenal adenoma. • Disorders in the secretion of ACTH caused by a pituitary adenoma (specifically called Cushing’s disease) or in rare cases ectopic secretion of ACTH from a tumour at a site remote from the pituitary (e.g. Small cell tumour of the lung).

Question 22

What are the signs and symptoms of excess cortisol?

Answer 22

The signs and symptoms of excess cortisol may include:
• Increased muscle proteolysis and hepatic gluconeogenesis that may lead to hyperglycaemia with associated polyuria and polydipsia (“steroid diabetes”).
• Increased muscle proteolysis leads to wasting of proximal muscles and producing thin arms and legs and muscle weakness.
• Increased lipogenesis in adipose tissue leading to deposition of fat in abdomen, neck and face and producing characteristic body shape, moon-shaped face and weight gain.
• Purple striae on lower abdomen, upper arms and thighs reflecting the catabolic effects on protein structures in the skin and leading to easy bruising because of thinning of skin and subcutaneous tissue.
• Immunosuppressive, anti-inflammatory and anti-allergic reactions of cortisol leading to increased susceptibility to bacterial infections and producing acne.
• May be back pain and collapse of ribs due to osteoporosis caused by disturbances in calcium metabolism and loss of bone matrix protein.
• Mineralocorticoid effects of excess cortisol may produce hypertension due to sodium and fluid retention.

Many of these signs and symptoms occur in patients receiving long term treatment with glucocorticoids for various chronic inflammatory conditions. Examples include hydrocortisone & prednisone.

Question 23

What’s the difference between Cushing’s disease and Cushing’s syndrome?

Answer 23

Cushing’s disease is not the same as Cushing’s syndrome. Cushing’s syndrome refers to the general constellation of symptoms resulting from chronic excessive exposure to cortisol whereas Cushing’s disease refers to the specific case of a benign ACTH secreting pituitary adenoma. Cushing’s syndrome is much more common than Cushing’s disease

Question 24

What causes Cushing’s syndrome?

Answer 24

External causes: (Most common cause)
Prescribed glucocorticoids
Endogenous causes (Rare):
Benign pituitary adenoma secreting ACTH (Cushing’s disease)
Excess cortisol produced by adrenal tumour (Adrenal Cushing’s)
Non pituitary-adrenal tumours secreting ACTH e.g small cell lung cancer (Very rare)

Question 25

What is Addison’s disease?

Answer 25

Decreased activity of the adrenal cortex

Question 26

What can cause Addison’s disease?

Answer 26

• Diseases of the adrenal cortex (auto-immune destruction) – reduces glucocorticoids and mineralocorticoids.
• Disorders in pituitary or hypothalamus that lead to decreased secretion of ACTH or CRF – affects glucocorticoids.

Question 27

How does Addison’s disease and an Addisonian crisis present and what can cause it?

Answer 27

Auto-immune destruction of the adrenal gland would involve the loss of both cortisol and mineralocorticoids and produces a complex situation that may present as an acute emergency (Addisonian Crisis) or as a chronic debilitating disorder (Addison’s disease):
• Insidious onset with initial non-specific symptoms of tiredness, extreme muscular weakness, anorexia, vague abdominal pain, weight loss and occasional dizziness.
• Extreme muscular weakness and dehydration.
• A more specific sign is increased skin pigmentation, particularly on exposed areas of the body, points of friction, buccal mucosa, scars and palmar creases. This is due to an increase in ACTH as well as other products of POMC (α-MSH and γ-MSH) all of which stimulate melanocytes to produce more melanin.
• Decreased blood pressure due to sodium and fluid depletion.
• Postural hypotension due to fluid depletion.
• Hypoglycaemic episodes especially on fasting due to lack of glucocorticoid.

These effects may be exacerbated by stress such as trauma or severe infection and lead to nausea, vomiting, extreme dehydration, hypotension, confusion, fever and even coma (Addisonian crisis). This constitutes a clinical emergency that must be treated with intravenous cortisol and fluid replacement (dextrose in normal saline) to avoid death.

Question 28

What are the clinical tests of adrenocortical function?

Answer 28

Measurement of plasma cortisol and ACTH levels and the 24hr urinary excretion of cortisol and its breakdown products (17-hydroxysteroids) are important in investigating suspected adrenocortical disease. In addition, dynamic function tests (e.g. dexamethasone suppression tests and ACTH stimulation tests) may be used in the differential diagnosis of adrenocortical disease.
Dexamethasone is a potent synthetic steroid that, when given orally would normally suppress (by feedback inhibition) the secretion of ACTH and thus cortisol. Dexamethasone suppression of plasma cortisol by >50% is characteristic of Cushing’s disease because for the diseased pituitary, even though it is relatively insensitive to cortisol, it does retain some sensitivity to potent synthetic steroids. Suppression does not normally occur in adrenal tumours or ectopic ACTH production. The administration of Synacthen (a synthetic analogue of ACTH) intramuscularly, would normally increase plasma cortisol by >200 nmol/L. A normal response usually excludes Addison’s disease

Question 29

What is congenital adrenal hyperplasia?

Answer 29

A number of clinical conditions arise as a consequence of a genetic defect in one or more of the enzymes required for the synthesis of the corticosteroid hormones from cholesterol. Due to a lack of cortisol the pituitary is not subjected to negative feedback control and therefore secretes large amounts of ACTH which in turn causes enlargement of the adrenal cortex (hyperplasia). The severity and consequences of these conditions depend on which enzyme(s) is affected. The most common form is deficiency of the enzyme 21-hydroxylase. The position of this enzyme in the biosynthetic pathway of corticosteroid hormones means that enzyme deficiency results in less glucocorticoid and mineralocorticoid production. The precursor of these hormones,
17α-hydroxypregnenolone, is therefore diverted to more androgen synthesis (androstenedione & testosterone). This can result in genital ambiguity in females infants and “Salt-wasting crises” due to a high rate of sodium loss in urine (due to loss of aldosterone).

Question 30

What happens when there’s a mineralocorticoid excess?

Answer 30

Primary hyperaldosteronism (Conn’s Syndrome) can be caused by hyperactivity of one (unilateral disease) or both (bilateral disease) adrenal glands. The unilateral form of the disease is usually caused by an adenoma whereas rare genetic syndromes like familial hyperaldosteronism type I and II may cause both glands to be hyperactive. Signs and symptoms of the disease include High blood pressure, occasional muscular weakness & spasms, tingling sensations, and excessive urination. Excess aldosterone has effects on most cells but clinically the most important are actions in the kidney where it increases sodium reabsorption and potassium secretion resulting in an increased blood volume and pressure. Increased blood pressure and renal perfusion cause a decrease in renin release from the kidney. In a normal individual decreased renin would lead to decreased aldosterone. However, in Conn’s syndrome the decreased renin (and angiotensin II) does not lead to a decrease in aldosterone and this can be used as a diagnostic criteria for the disease.

Question 31

Explain steroid hormone receptor homology

Answer 31

The steroid receptors form part of a family of nuclear DNA-binding proteins that include the thyroid and vitamin D receptors. They all have three main regions, a hydrophobic hormone-binding region, a DNAbinding region rich in cysteine and basic amino acids and a variable region. There is sequence homology in the hormone binding regions of the receptors. The percentage homology of the hormone binding region of the glucocorticoid receptor with the mineralocorticoid, androgen, oestrogen and thyroid receptors is ~64%, ~62%, ~31% and ~24% respectively. Thus, cortisol will bind to the mineralocorticoid and androgen receptors with low affinity. This binding may become significant when high levels of the hormone are present

Question 32

What are the actions of androgens and oestrogens?

Answer 32

Androgens stimulate the growth and development of male genital tract and male secondary sexual characteristics including height, body shape, facial and body hair, lower voice pitch. They also have anabolic actions especially on muscle protein. Over secretion of adrenal androgens produces effects in the female that include: excessive body hair growth (hirsutism), acne, menstrual problems, virilisation, increased muscle bulk and a deepening voice.

Oestrogens stimulate growth and development of female genital tract, breasts and female secondary characteristics including broad hips, accumulation of fat in breasts and buttocks, body hair distribution. They are weakly anabolic and decrease circulating cholesterol levels.