Endocrinology: Pancreas and Adrenal glands Flashcards Preview

MRCS A: Systems > Endocrinology: Pancreas and Adrenal glands > Flashcards

Flashcards in Endocrinology: Pancreas and Adrenal glands Deck (57)
Loading flashcards...

Adrenal cortex

Three layers:
1) Zona glomerulosa (15%)
2) Zona fasciculata (75%)
3) Zona reticularis (10%)

The zona glomerulosa, an indistinct layer lies just beneath the capsule of the adrenal gland and produces the mineralocorticoid, aldosterone.

The zona fasciculata and the zona reticularis (that surrounds the adrenal medulla) produce glucocorticoids (cortisol) and androgens (dehydroepiandrosterone – DHEA and
its sulphate) respectively.

DHEAS and androstenedione are relatively inactive hormones. Both fasciculata and reticularis layers are ACTH-responsive. Hormones are produced ‘on demand’ – they are not stored.



Corticotrophin releasing hormone (CRH) is
released from hypothalamic neurones in response to neural stimuli (e.g. circadian rhythm, stress) into the hypothalamic-hypophyseal portal venous system and stimulates adrenocorticotrophic hormone (ACTH) secretion from the anterior pituitary.



ACTH causes secretion of cortisol and other steroids from the adrenal cortex. Rising levels of glucocorticoid inhibit the synthesis and release of CRH and ACTH within minutes. The main effect of ACTH is at the cholesterol-pregnenolone conversion which occurs within minutes.

A more chronic effect of ACTH stimulation involves growth and DNA and RNA synthesis within adrenocortical cells. ACTH deficiency causes atrophy of the adrenal glands.

Functional ‘atrophy’ of the HPA axis may persist for
weeks or months after chronic administration of therapeutic glucocorticoids.

Circadian rhythm is generated by a ‘pacemaker’ in the hypothalamus. ACTH is secreted in pulsatile bursts at different times of the day which leads to the normal diurnal variation of plasma ACTH and cortisol. Levels are highest in the morning about the time of waking and lowest around midnight. Disease, surgical trauma, and psychological stress can all cause modification or loss of normal diurnal variation.


Mechanism of action of cortisol

In the plasma over 90% of cortisol is carried bound
to proteins, mainly cortisol binding globulin or, to albumin.

Protein binding allows uniform distribution
of hormone to cells of the target tissues. Free, unbound cortisol is biologically active; it enters the cells and binds with a glucocorticoid receptor.

The hormone receptor complex translocates to the nucleus, binds to DNA and regulates gene expression. In the liver, this causes an increase in protein synthesis: in most other tissues cortisol has a catabolic effect.


Effects on intermediary metabolism

In the liver, glycogen formation and gluconeogenesis is increased by activation of glucose-6-phosphatase and release of gluconeogenic amino acids from skeletal muscle.

Cortisol enhances the gluconeogenic actions of glucagon and catecholamines. Glucose uptake and utilisation is reduced in peripheral tissues. In fatty tissue there is increased lipolysis that results in the production of glycerol and free fatty acids. The fatty acids are then incorporated into the gluconeogenic process within the liver.

In glucocorticoid excess there is hyperinsulinaemia
almost certainly due to the effect of cortisol on glucose metabolism.

In disorders of glucocorticoid excess there is redistribution of body fat manifest as progressive, central obesity, the limbs are spared, often being wasted due to muscle breakdown.


Effects on central nervous system

Glucocorticoids influence sleep patterns and mood.
In excess, appetite is increased and there can be sleep disturbance. In early stages, cortisol excess is associated with a feeling of wellbeing which can progress to severe psychosis or depression.


Effects on musculoskeletal and connective

In excess, glucocorticoids cause osteopaenia as a result of inhibition of fibroblastic activity and decreased bone formation. Bone changes include vertebral body collapse, fractures and avascular necrosis – especially of the femoral head.
Children with cortisol excess show growth retardation, often severe. Many of the ‘classic signs’ of hypercortisolism are due its catabolic effects on muscle (wasting, myopathy), skin and connective tissue (thin, friable skin, poor wound healing, striae and an increased tendency to bruise).


Immunological effects of glucocorticoids:
• Effect on cells

— lymphocyte, monocyte, eosinophil reduction in blood
— increase in circulatory polymorphs
— inhibition of accumulation of inflammatory cells
— inhibition of lymphocyte production


Immunological effects of glucocorticoids:
• at sites of inflammation

• effects on cell function
— inhibition of prostaglandin synthesis
— inhibition of interleukins
— inhibition of T cell proliferation


Other effects

In excess, glucorticoids have a mineralocorticoid action, hypertension is common, hyponatraemia and hypokalaemia are common in patients on intravenous fluid therapy.

The association of chronic cortisol excess with peptic ulcer disease is not understood.



This is confirmed firstly by loss of the normal diurnal
variation – as indicated by elevated midnight and
morning plasma cortisol levels and/or an increase in
24-hour urinary free cortisol excretion.

Secondly, by loss of ACTH regulation of cortisol levels as indicated by the failure of cortisol to suppress after an oral dose of dexamethasone (a potent corticosteroid).

In this way Cushing’s syndrome (excess circulating cortisol) is confirmed. The next step is to determine whether the cortisol excess is ACTH dependent or ACTH independent.


ACTH levels and diagnosis

If ACTH levels are low (ACTH independent), this suggests primary adrenal disease and an abdominal CT or MRI will usually confirm abnormal adrenal morphology (adenoma or carcinoma).

If ACTH levels are normal or elevated (ACTH dependent) pituitary disease (Cushing’s disease) must be distinguished from ectopic ACTH production (e.g. small cell lung cancer) by further biochemical studies and cross-sectional imaging.



This may be due to adrenal disease, i.e. primary
adrenal insufficiency. Adrenocortical reserve is
tested by the administration of synthetic ACTH
(Synacthen); the cortisol response is then measured.

Secondary adrenal insufficiency (hypopituitarism)
is distinguished from tertiary adrenal insufficiency
(CRH deficiency) by giving CRH and measuring the
ACTH response.

Tests of the stress response assess the hypothalamic component of the axis and, therefore, potentially, the complete HPA axis. A satisfactory rise in plasma cortisol and ACTH in response to insulin-induced hypoglycaemia indicates a normally functioning axis.



Aldosterone is a mineralocorticoid and the other main product of the adrenal cortex. It is produced in the zona glomerulosa and is predominantly under the control of the renin-angiotensin mechanism. ACTH, hyponatraemia,
hyperkalaemia play a minor role in aldosterone

Decreased renal blood flow (haemorrhage, renal artery narrowing, dehydration) increases plasma renin levels.



Renin is produced in the juxtaglomerular apparatus
of the renal cortex and is released by three main

• Reduction in renal perfusion pressures via
baroreceptors in the afferent arterioles;
• Renal sympathetic nerve activity; and
• Sodium concentration in tubular fluid sensed by
the macula densa.



Renin cleaves angiotensinogen, which is secreted
by the liver, to form angiotensin I.

Angiotensin I is converted to angiotensin II by angiotensin-converting enzyme (ACE) mainly in the lungs.

Angiotensin II cleavage produces Angiotensin III. All have inotropic and vasoconstrictive actions.

Angiotensin III has greater activity than angiotensin II for stimulating aldosterone synthesis but only 20% of the pressor activity.

Angiotensin II and III increase aldosterone production. Aldosterone binds to a receptor in its target tissues and promotes active sodium transport and excretion of potassium. Its secretion results in sodium retention and increased plasma volume.


Treatment of hypertension

The treatment of hypertension may include the use
of two drugs that modify mineralocorticoid physiology.

1) The first, spironolactone, is an aldosterone antagonist– it competes for the aldosterone receptor sites – and is, therefore, used as a K+ sparing diuretic and in hyperaldosteronism.

2) The second, a group of drugs inhibiting
the angiotensin converting enzyme – ACE inhibitors.

3) One of their most potent effects is vasodilatation within the kidney – especially in the efferent arterioles of the glomerulus. They are effective in patients with renal hypertension and in diabetic patients with hypertension,
promoting a more favourable outlook for diabetic

However, a reduction in efferent
arteriolar tone and a fall in intraglomerular pressure
may be associated with adverse outcome, i.e. acute renal failure in patients with renal artery stenosis.


Investigating mineralocorticoid status

Primary hyperaldosteronism is associated with hypokalaemia.

High plasma aldosterone levels and a suppressed plasma renin activity in association with an increased urinary potassium excretion confirm the biochemical diagnosis.

Cross-sectional imaging and selective venous catheterisation of adrenal veins to identify aldosterone gradients can confirm the morphological abnormality.

In secondary hyperaldosteronism (congestive heart failure, cirrhosis, nephrotic syndrome,
and renal artery stenosis) the high aldosterone is associated with a high plasma renin activity.

Isolated adrenal hypoaldosteronism is rare.


Sex hormone secretion

DHEA, DHEAS and androstenedione are converted to biologically active metabolites – dihydrotestosterone testosterone – in peripheral tissues.

In men testosterone is mainly produced in the testis; in women by peripheral conversion. ACTH plays a role; plasma androgens parallel the circadian rhythm of cortisol.

Very small amounts of oestrone and oestradiol are secreted. In premenopausal women most oestrogens are produced by the ovary.

The peripheral conversion of androgens to oestrogens in adipose tissue by aromatase enzymes accounts for circulating oestrogen levels in men and post-menopausal women.


Addisons disease: Primary causes

Addison’s disease, a cause of primary adrenocortical insufficiency was described in the mid-19th century when the commonest cause of the condition was tuberculosis which is now rare.

Other causes include metastatic cancer (lung, breast), haemorrhage into the adrenals (anticoagulants, meningococcal septicaemia), and an autoimmune disorder – polyglandular autoimmune syndrome.


Addisons disease: Secondary causes

Secondary insufficiency is due to hypopituitarism resulting from destructive lesions of the pituitary (tumour, TB, histoplasmosis, hypophysitis, infarction) or cerebral trauma.


Addisons disease: Tertiary causes

The most common cause of tertiary insufficiency is exogenous pharmacological glucocorticoid therapy which results in suppression of ACTH production.

Other causes include tumour and cranial irradiation. After cure of Cushing’s syndrome (ACTH dependent or ACTH independent) adrenocortical tissue will be suppressed as occurs following exogenous steroid treatment.


Symptoms and signs of adrenal insufficiency

Signs and symptoms do not appear until 90% of cortical tissue is destroyed. In the acute scenario there will be hypotension, shock, nausea and vomiting.

Abdominal pain, confusion, fever, electrolyte imbalance and hypoglycaemia can occur. Immediate treatment with intravenous fluids and parenteral hydrocortisone is necessary.

In addition to those symptoms and signs described
above, patients may have facial plethora, acne,
hirsutism, thirst, urinary tract calculi, a loss of bone
density and glucose intolerance or frank diabetes.


Chronic primary adrenal insufficency

In patients with chronic primary adrenal insufficiency, symptoms and signs of glucocorticoid, mineralocorticoid, and in women, androgen deficiency may be present. These include malaise, weakness, weight
loss and anorexia. Abdominal pain and gastrointestinal symptoms are common. The striking feature of primary adrenal insufficiency will be skin pigmentation (and pigmentation of mucosa). This arises because
ACTH shares a shared subunit sequence with melanocyte stimulating hormone and binds to its receptors.


Adrenal insufficiency treatment

Replacement therapy with hydrocortisone and
fludrocortisone is required. Patients with secondary
and tertiary insufficiency usually maintain adequate
mineralocorticoid function. Any patient on (or with a
recent history of) long-term glucocorticoid treatment
(including some topical steroid-containing preparations) will almost certainly have suppressed ACTH levels or limited functional reserve. They will be at risk of an acute adrenal crisis when subjected to stress – such as an emergency or elective surgical procedure.

These patients will need additional perioperative
glucocorticoid cover and careful evaluation of hydration, serum electrolytes and blood pressure.



When Cushing’s syndrome is confirmed and the
cause identified, definitive treatment is indicated.
Adrenocortical adenoma or carcinoma is treated
by adrenalectomy.

Malignant disease of the adrenal
cortex has a poor prognosis; the tumours are often
large, locally invasive and have metastasised before
the diagnosis is made.

Nodular adrenal hyperplasia
may require bilateral adrenalectomy. Patients with
Cushing’s disease are treated with pituitary surgery
and/or radiotherapy.


Hypercortisolism: Treatment

Medical treatment with:

1) Metyrapone (blocks the final step in cortisol synthesis)

2) ketoconazole (acts mainly on the initial step of cortisol synthesis) is used prior to surgery in some
patients and when pituitary surgery fails.

3) Bilateral adrenalectomy is sometimes required in patients with ACTH dependent Cushing’s if surgical treatment is unsuccessful or, a source of ectopic ACTH cannot be identified. Hyperpigmentation (Nelson’s syndrome) may develop in patients with Cushing’s disease with continued ACTH production after bilateral adrenalectomy.

4) Patients must be maintained on cortisol (and
fludrocortisone after bilateral adrenalectomy) after
successful treatment of hypercortisolism until biochemical tests confirm full recovery of the HPA axis.

Bilateral adrenalectomy is without effect in terms of
adrenomedullary hypofunction. Autonomic failure or
neuropathy is especially important in diabetes mellitus. There may be severe problems with postural hypotension; the symptoms of hypoglycaemia may be masked.


Primary hyperaldosteronism

This is usually (80%) caused by a unilateral adrenal
adenoma, i.e. Conn’s syndrome, most of the remaining cases by bilateral hyperplasia of the zona glomerulosa.

Primary hyperaldosteronism accounts for at least
1% of cases of hypertension. The syndrome is associated, with hypertension (due to Na+ and water retention), hypokalaemia and metabolic alkalosis (caused by the intracellular shift of H!, and a loss of H+ in the kidney).

Symptoms include headache, muscle weakness,
tiredness and polyuria. Medical treatment with
spironolactone is indicated.


Primary hyperaldosteronism: Treatment

Adrenalectomy is indicated for patients with an adenoma when hypertension proves difficult to control or, when side effects of medical treatment are severe.

Bilateral adrenalectomy is not used in the treatment of bilateral hyperplasia.

Virilising and feminising tumours are rare and usually malignant. Congenital adrenal hyperplasia (CAH) is an inherited disorder of cortisol synthesis.

Signs of androgen excess in adrenal disease are due to androgenic cortisol precursors or DHEAS.


adrenal medulla

The adrenal medulla (10% of adrenal mass) mainly
comprises of chromaffin cells. Pre-ganglionic sympathetic nerve fibres contribute to the splanchnic nerves that innervate the adrenal medulla.

The chromaffin cells synthesise catecholamines–adrenaline and noradrenaline from tyrosine via dopa and dopamine to noradrenaline and thence adrenaline. Once produced, the hormones are stored as granules – causing the typical appearance of the chromaffin cells. The
medulla produces adrenaline (‘epinephrine’) predominantly and, to a much lesser extent, noradrenaline (‘nor-epinephrine’).