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Flashcards in Week 128 - Gen Endocrine Deck (100):

Which two hormones are secreted by the hypothalamus to stimulate the release of ACTH from the anterior pituitary gland?



Hypothalamic-pituitary-adrenal axis: What is CRH?

• Corticotropin-releasing hormone.
• It is secreted by the hypothalamus and causes stimulation to release ACTH from the anterior pituitary gland.


Hypothalamic-pituitary-adrenal axis: What is ADH?

• Anti-diuretic hormone.
• It is secreted by the hypothalamus and causes stimulation of the anterior pituitary gland to release ACTH.


Hypothalamic-pituitary-adrenal axis: What is ACTH?

• Adrenocorticotropic hormone.
• Secreted by the anterior pituitary gland in response to CRH and ADH.


What occurs when Adrenocorticotropic hormone binds to a adrenocortical cell? (Briefly).

• It causes adenylate cyclase to convert ATP into cAMP, which in turn starts a protein cascade that results in the production of pregnenolone from cholesterol.
• Pregnenolone is a prehormone for mineralcorticoids, glucocorticoids, androgens, estrogens and neuroactive steroids.


What is Cushing's Syndrome?

A clinical state of increased free circulating cortisol.


Cushing's syndrome is normally classified into two groups, what are they?

1) ACTH-dependant Cushing's.
2) ACTH-independant Cushing's.


What is the most common cause of Cushing's syndrome?

Iatrogenic causes, injections of synthetic ACTH.


Give some examples of ACTH-dependant Cushing's.

1) Cushing's Disease (The most common cause of spontaneous Cushing's disease) increased ACTH from the pituitary.
2) Ectopic ACTH-producing tumour.


Give some examples of ACTH-independant Cushing's.

1) Adrenal tumour.
2) Nodular hyperplasia.


What are the major clinical features of Cushing's Syndrome?

• Plethora, Proximal neuropathy, Purple Striae, Skin thinning, bruising.
• Central weight gain, moon face, backache, malaise, hirsutism, nocturia/polyuria, oligomenorrhoea/amenorrhoea, hypertension, glycosuria.


What are the three main investigations to confirm the diagnosis of Cushing's syndrome?

1) 48hr low-dose dexamethasone test.
2) 24hr urinary free cortisol measurements.
3) Circadian rhythm.


Cushing's Syndrome: What is the 48hr low-dose dexamethasone test?

• In normal individuals administration of dexamethasone would result in suppression of cortisol levels to s will show a decrease in cortisol levels after a period and a higher dose.


Cushing's Syndrome: What is the circadian rhythm test?

• After 48 hours in hospital, cortisol samples are taken at 9am and midnight.
• Normal patients show a pronounced variation whilst those with Cushing's Syndrome may have a normal 9am value but a high midnight value.


Once diagnosis of Cushing's Syndrome has been confirmed what investigations can be undertaken to determine the cause?

• Plasma ACTH - Low levels are a strong indicator of non-ACTH-dependant disease.
• CT,MRI, X-ray - In order to find a tumour.
• Plasma potassium levels - Hypokalaemia is common with ectopic ACTH secretions.
• High-dose dexamethasone test - Failure to suppress cortisol levels suggests ectopic sources of ACTH or adrenal tumour.
• CRH test - Exogenous CRH is given, an exaggerated ACTH and cortisol response suggests pituitary-dependant Cushing's Disease.


What is the drug of choice for treating Cushing's Disease and what is its mode of action?

Metyrapone, blocks the conversion of 11-deoxycortisol into cortisol thus reducing circulating levels of cortisol.


What is Congenital adrenal hyperplasia?

• This is an autosomal recessive disorder where there is a deficiency of one of the enzymes in the cortisol synthetic pathways.
• This results in reduced cortisol secretion, feedback causes increased ACTH secretion which leads to adrenal hyperplasia.


What is the most common type of congenital adrenal hyperplasia? What is the incidence?

21-hydroxylase deficiency, 1 in 15000 births.


21-hydroxylase deficiency is the leading cause of congenital adrenal hyperplasia, it causes disruption of the cortisol synthesis pathway. Down which pathway do the precursors get diverted?

• The androgenic steroid pathway.
• Resulting in increased levels of 17-hydroxyprogesterone, androstenedione and testosterone which leads to virilization.


What is salt-wasting and how is it caused in congenital adrenal hyperplasia?

• Loss of excessive amounts of sodium in urine, which can lead to potentially fatal electrolyte and water imbalance.
• This is due to a deficiency in aldosterone production.


What are the three primary manifestations of 21-hydroxylase deficiency?

1) Simple Virilizing Form
2) Salt-wasting Form
3) Non-classical Form


What are the clinical presentations of the simple virilizing form of 21-hyroxylase deficiency? (congenital adrenal hyperplasia)

• In females, sexual ambiguity.
• Both sexes, normal rate of growth as a child but epiphyseal plates fuse early resulting in short stature.


What are the clinical presentations of the non-classical form of 21-hydrocylase deficiency? (Congenital adrenal hyperplasia)

• Usually mild, with presentations of androgen excess. (Hirsutism, amenorrhoea, precocious puberty).


What investigations should be performed during the diagnosis of Congenital adrenal hyperplasia?

A profile of adrenocorticoid hormones should be measured before and one hour after synacthen administration.
- Increased levels of 17-hydroxyprogesterone.
- Increased pregnanetriol excretion.
- Raised levels of Androstenedione
- Raised basal levels of ACTH


What is the treatment for Congenital adrenal hyperplasia?

• Glucocorticoid replacement therapy and mineralcorticoids (if there is a aldosterone deficiency).
• Dexamethasone at night - To suppress ACTH secretion.
• Corrective surgery


What is synacthen?

Tetracosactide, it is the first 24 amino acids of ACTH, and is used in diagnosis.


What is Addison's Disease?

• Primary hypoadrenalism, destruction of the entire adrenal cortex. Glucocorticoid, mineralcorticoid and sex hormone are therefore all reduced.


What is the incidence of Addison's disease?

3-4 per million per year.


What are the main causes of Addison's Disease?

• Autoimmune disease
• T.B.
• Adrenalectomy
• Adrenal infarction
• Metastatic tumour
• AIDs


What are the main signs of Addison's Disease?

• Pigmentation, especially around new scars, palmar creases.
• Postural hypotension - Due to hypovolaemia.
• Loss of weight, General wasting, Dehydration, Fatigue, Malaise, Weakness, Fever.


What investigations are performed for suspected Addison's Disease?

• Single cortisol measurement - 80ng/L) with a low cortisol confirms primary hypoadrenalism.
• Adrenal antibodies - present in many cases of autoimmune hypoadrenalism.
• Electrolytes, Urea, glucose
• Chest X-ray


What is the treatment for Addison's Disease?

• Dexamethasone whilst waiting for results.

• Replacement of Glucocorticoids (Hydrocortisone) and mineralcorticoids (Fludrocortisone).
• 'Steroid Card'
• 'Medic-alert' bracelet.


What is Dexamethasone?

It is a glucocorticoid that is 25 times more potent than cortisol, it is used in the treatment of some endocrine pathologies in order to suppress ACTH production.


What is Conn's Syndrome?

Endocrine Hypertension caused by excess production of Aldosterone from the zona glomerulosa. This is due to 65% bilateral hyperplasia or adrenal adenoma.


What are the signs/symptoms of Conn's Disease?

Hypertension, (Hypokalaemia, metabolic alkalosis).


What are the three investigations for Conn's Disease?

• 9am Aldosterone:Renin ratio (Low renin, high aldosterone)
• Adrenal venous sampling.
• CT scan Adrenals.


What are the treatment options for Conn's Disease?

• Adrenalectomy
• Low sodium diet
• Spironolactone (Competitive antagonist of Aldosterone)


What is Phaeochromacytoma?

• Excess production of catecholamines.
• Caused by adrenal or extra adrenal tumour.


What are the signs and symptoms of Phaeochromacytoma?

• Intermittent or sustained hypertension.
• Hypertension
• Sweating
• Tachycardia
• Headaches


What are the two main investigations for Phaeochromacytoma?

• 24hr catecholamine levels.
• CT/MRI to localise tumour.


What are the treatment options for Phaeochromacytoma?

• Alpha and Beta blockers (Phenoxybenzamine and Propanolol)
• High salt diet
• Surgery


What effect does PTH have on the regulation of calcium homeostasis? And what stimulates it's secretion?

• Increased calcium
• Decreased phosphate

• It is stimulated by a decrease in serum Ca2+ levels.


What effect does Calcitonin have on the regulation of calcium homeostasis? And what stimulates it's secretion?

• Decreased calcium
• Decreased phosphate

• Secreted in response to increased serum Ca2+ levels and gastrin.


What effect do Vitamin D metabolites have on the regulation of calcium homeostasis? And what stimulates it's secretion?

• Increased Calcium
• Increased phosphate

• Secreted in response to increased PTH and decreased phosphate.


What cell is PTH secreted from?

Chief cells of the parathyroid gland.


How does PTH increase Calcium concentrations in the blood?

• Renal tubular calcium reabsorption.
• Osteoclast mediated bone calcium resorption.


What is primary hyperparathyroidism?

• Adenoma or hyperplasia of the parathyroid gland causing an excess of PTH and elevated calcium.


What is secondary hyperparathyroidism?

• This is parathyroid hyperplasia resulting from hypocalcaemia leading to an increased PTH.


What is tertiary hyperparathyroidism?

• This is an autonomous secretion of ATH resulting from long-term hypocalcaemia.


What is malignant hypercalcaemia?

• This is where malignancy results in increased osteoclast bone resorption. The most common malignancies with hypercalcaemia are lung followed by breast.


Hyperparathyroidism causes hypercalcaemia, what are the symptoms and signs of hypercalcaemia?

• Generally asymptomatic.
• But it can cause; tiredness, muscle weakness, dehydration, anorexia, nausea, polyuria, mental confusion, peptic ulcers, bone pain, cardiac arrhythmia's, kidney stones.


What is the prevalence of primary hyperparathyroidism? Which demographic is it most associated with?

• Women, Over 50 years, post menopausal.


When investigating hyperparathyroidism?

• Serum PTH
• Serum phosphate
• Serum calcium
• Hyperchloraemic acidosis - often mild
• Renal function
• 24hr urinary calcium
• Elevated serum alkaline phosphatase


What would you expect to find in investigation of primary hyperparathyroidism?

• High PTH
• High Ca
• Low PO4
• High urinary calcium


What would you expect to find in investigation of secondary hyperparathyroidism?

• High PTH
• Normal Ca (as they already have hypocalcaemia)
• High PO4


What would you expect to find in investigation of tertiary hyperparathyroidism?

• High PTH
• High Ca
• Low PO4


What would you expect to find in investigation of malignant hypercalcaemia?

• Normal PTH
• High Ca
• Low PO4


What are the three broad aspects of treatment for primary hyperparathyroidism?

• Conservative
• Medical
• Surgical


What is the conservative treatment of primary hyperparathyroidism?

• Adequate hydration
• Ambulation
• Avoid diuretics
• Diet


What is the medical treatment of primary hyperparathyroidism?

There are some medicines, that require further clinical trials, that inhibit the effect of PTH on bones.


What are the indications for surgical treatment of primary hyperparathyroidism?

• If there are specific symptoms
• Where observation is not desirable.
• Age 0.25 above normal range
• Bone mineral density <2.5 at any site


What are the symptoms of severe hypercalcaemia?

• Serum calcium >3.5mmol/L
• Impaired tubular reabsorption
• Extracellular volume depletion
• dehydration, nocturia, polyuria, drowsiness, altered consciousness.


What is the immediate treatment required for severe hypercalcaemia?

• Rehydrate
• Intravenous Biphosphonates
• Prednisolone
• Calcitonin
• Oral phosphates


What are the main causes of hypocalcaemia?

• Hypoparathyroidism
• Reduced PTH secretion
• PTH resistance in target organs
• Vitamin D-related disorders


What are the signs/symptoms of hypocalcaemia?

• Chvosteks sign
• Trousseaus sign
• Increased neuromuscular sensitivity
• Tingling of extremities
• Tetany
• epileptic convulsions
• ECG abnormalities
• Cataracts


What is the treatment for hypocalcaemia?

• I.V. Calcium
• I.V. Magnesium (If cause is hypomagnesaemia)

• Oral calcium
• Oral Magnesium
• Oral or parenteral phosphate


What is Chvosteks sign?

The facial nerve is tapped on the angle of the jaw causing contraction of the face on that side. This is due to nerve hyper excitability (tetany).


What is Trousseaus sign?

A blood pressure cuff is placed around the arm and inflated to a pressure above systolic pressure and held for three minutes.
In the presence of hypocalcaemia the muscles of the hand and forearm go into spasm.


What are some of the causes of hypoparathyroidism?

• Surgical, transient or permanent.
• Postradioactive iodine
• Polyendocrine deficiency syndromes
• Idiopathic


What would you expect to find in investigation of hypoparathyroidism?

• Low PTH
• Low Ca
• Low PO4


What is pseudohypoparathyroidism?

This is resistance to PTH rather than a lack of it, it is associated to deficient G unit activity.


What is the presentation of pseudohypoparathyroidism?

Type 1a presents with a phenotypic appearance (Albright's Hereditary Dystrophy).


What is Albrights Hereditary Dystrophy?

• Short
• Round face
• Short Metacarpals


What is Aldosterone? What stimulates it's secretion? What are it's effects?

• Mineralcorticoid, secreted by the Zona Glomerulosa of the adrenal cortex.
• Secreted in response to Angiotensin and ACTH.
• Increases Na+ retention and increases K+ excretion.


What is Conn's Syndrome?

• Primary Hyperaldosteronism
• Due to Adrenal hyperplasia or adrenal tumour.


What are the symptoms of Conn's Syndrome?

• Usually asymptomatic other than hypertension.
• Hypertension, Retinopathy, Hypokalaemia, Hypernatraemia.


What investigations should be performed for Conn's Syndrome and what would you expect to find?

• Bloods - Decreased Renin and Decreased K+.
• CT


What is Cushing's Syndrome?

This is a clinical state of increased serum cortisol.


What is cortisol? What is it secreted in response to? What are it's effects?

• A glucocorticoid produced by Zona fasiculata of the adrenal cortex.
• It is Stimulated by ACTH and normally has a circadian rhythm.
• It increases blood glucose and inhibits the immune system.


What are the main causes of Cushing's Syndrome?

• Iatrogenic
• 1˚ causes - Excess production, i.e. adrenal tumour.
2˚ causes - Cushing's Disease - A pituitary tumour that causes an excess of ACTH and therefore an excess of cortisol.


What are the symptoms of Cushing's Syndrome?

• Central obesity and thin peripheries.
• Purple Striae
• Hirsutism
• Increased Blood glucose
• Appearance - Moon face and buffalo hump.


How do you confirm a diagnosis of Cushing's Syndrome?

24hr Urinary - Cortisol will be high.


What tests can you perform to distinguish between 1˚ and 2˚ causes of Cushing's Syndrome?

• Dexamethasone test- mimics cortisol but doesn't show up on assays.
- Normal response suppression of cortisol
- High dose response in pituitary based Cushing's.
- No response in adrenal origin of Cushing's.


What would you expect the ACTH levels to be in 1˚ and 2˚ Cushing's syndrome?

1˚ - Low levels
2˚ - High levels


What is Addison's disease?

It is the most common source of adrenal cortex insufficiency.


What are the symptoms of adrenal insufficiency?

• Postural hypotension
• Malaise, N&V
• Addisonian crisis - Hypotension, Hypoglycaemia, collapse, sudden onset of leg/back/abdo pain.


What are the additional symptoms of Addison's disease (in addition to those associated with adrenal insufficiency).

• Hyperpigmentation, Associated autoimmune disease.


What is phaochromocytoma?

• Tumour of the adrenal medulla that results in an increased production of catecholamines.


What are the symptoms of phaochromoctoma?

• Sweating, Hypertension, Tachycardia
• Weight loss, increased blood glucose.


Week 128 - Gen Endocrine: What effect does PTH have on levels of Calcium and Phosphate? What stimulates it's release?

• Increases calcium.
• Decreases phosphate.

• Released in response to low serum Ca2+.


Week 128 - Gen Endocrine: What effect does calcitonin have on levels of Calcium and Phosphate? What stimulates it's release?

• Decreases calcium.
• Decreases phosphate.

• Released in response to high serum Ca2+.


Week 128 - Gen Endocrine: What effect do Vitamin D metabolites have on levels of Calcium and Phosphate? What stimulates the release?

• Increases calcium.
• Increases phosphate.

• Released in response to low levels of phosphate and high levels of PTH.


Week 128 - Gen Endocrine: What are the three physiological functions of PTH?

• Enhances renal tubular reabsorption.
• Enhances osteoclast mediated bone resorption.
• Conversion of 25(OH) Vit D into 1,25(OH) Vit D3.


Week 128 - Gen Endocrine: PTH converts which form of Vit D into which other form?

• 25(OH) Vit D into 1,25(OH) Vit D3.


Week 128 - Gen Endocrine: PTH is produced from where?

• Chief cells of the parathyroid.


Week 128 - Gen Endocrine: What are the main causes of hypercalcaemia?

• Hyperparathyoidism
• Malignancy


Week 128 - Gen Endocrine: What are the causes of primary hyperparathyroidism?

• Adenoma
• Carcinoma
• Hyperplasia


Week 128 - Gen Endocrine: What are the causes of secondary hyperparathyroidism?

• Compensatory
• Elevated PTH secondary to hypocalcaemia with parathyroid gland hyperplasia.


Week 128 - Gen Endocrine: What are the causes of tertiary hyperparathyroidism?

• Autonomous secretion of PTH following long term hypocalcaemia.


Week 128 - Gen Endocrine: Hyperparathyoidism is generally asymptomatic, but what are some of the possible symptoms?

• Renal - Stones, polyuria.
• Musculoskeletal - Bone pain, osteopenia, fractures.
• Gastrointestinal - Nausea, Vomitting, Constipation
• Neurological - Tiredness, Lethargy, Depression, Confusion
• Cardiac - Bradycardia, Heartblock