Endocrinology Flashcards
What is Sheehan’s syndrome?
Post-partum hypopituitarism secondary to hypotension (due to post-partum haemorrhage). Partly due to the fact that the adenohypophysis enlarges during pregnancy due to lactotroph hyperplasia, so diminished blood supply due to PPH causes pituitary infarction.
Give symptoms of Sheehan’s syndrome.
Lethargy, anorexia, weight loss, failure of lactation and failure to resume menses. However, these are all relatively common symptoms post-partum meaning diagnosis is often delayed.
What is pituitary apoplexy?
Intra-pituitary haemorrhage or (less commonly) infarction. Sever sudden onset headache, with bitemporal hemianopia due to pressure on optic chiasm.
Why is a dynamic pituitary test necessary to assess plasma levels of adenohypophyseal hormones?
Because interpretations of a single plasma reading are limited due to natural fluctuations in levels of circulating hormones. E.g. cortisol is undetectable at certain points of the day, T4 has a half-life of 6 days, FSH/LH is cyclical and ACTH is pulsatile.
What is given in a dynamic pituitary function test?
TRH - causes TSH release.
GnRH to stimulate FSH & LH release.
Insulin to induce hypoglycaemia (<2.2mM) acting as a stressor to induce the release of GH and ACTH.
What can we use to replace each of the adenohypophyseal hormones? What should me monitor to check levels?
Hydrocortisone to replace ACTH. Monitor serum cortisol.
Thyroxine to replace TSH. Monitor serum free T4.
HRT (E2 + progestogen) to replace LH/FSH in women. Monitor symptom improvements.
Testosterone to replace LH/FSH in men. Monitor serum testosterone and symptom improvements.
GH to replace GH
Give signs of somatotrophin deficiency in adults.
Reduced lean mass, increased adiposity, increased waist: hip ratio, reduced muscle strength and bulk, reduced exercise performance, reduced HDL-cholesterol and raised LDL-cholesterol.
Why is hypersecretion of adenohypophyseal hormones often associated with bitemporal hemianopia?
Due to suprasella tumour compressing optic chiasm.
What does an excess in each of the anterior pituitary hormones cause?
ACTH: Cushing's DISEASE (pituitary tumour). TSH: thyrotoxicosis. LH/FSH: precocious puberty in children Prolactin: hyperprolactinaemia. GH: gigantism, acromegaly.
Give physiological and pathological causes of hyperprolactinaemia.
Physiological: pregnancy, breast-feeding.
Pathological: prolactinoma.
What drugs can be used to treat hyperprolactinaemia?
D2 receptor agonists which bind to D2 receptors on lactotrophs and inhibit prolactin secretion.
Examples = bromocriptine; cabergoline.
How does excess growth hormone lead to diabetes mellitus?
GH leads to increased endogenous glucose production, leading to reduced muscle glucose uptake. This increased insulin production increases insulin resistance, so glucose tolerance is impaired and diabetes mellitus ensues.
Give symptoms of acromegaly.
Obstructive sleep apnoea, hypertension, cardiomyopathy, hyperhidrosis, enlarged tongue.
Prolactin also often high (secondary hypogonadism and associated symptoms).
How is acromegaly treated?
Surgical resection of tumour. Somatostatin analogues may be given pre-surgery to reduce GH secretion and tumour size - making removal easier.
What sort of change in shape of osmoreceptors leads to INCREASED osmoreceptor firing?
SHRINKAGE (since the EC fluid must have a higher osmolarity than the cell)
Give causes of acquired cranial diabetes insipidus.
Traumatic brain injury, pituitary surgery, pituitary tumours, TB.
What can cause nephrogenic diabetes insipidus?
Certain drugs, such as lithium toxicity.
Give symptoms of diabetes insipidus.
Large volumes of urine (polyuria), dilute urine (hypo-osmolar), thirst (polydipsia), dehydration (if no access to water).
NO HYPERGLYCAEMIA.
What biochemistry of the blood would you expect to find in a patient suffering diabetes insipidus?
HYPERnatraemia
Raised urea
Raised plasma osmolality.
What biochemistry of the blood would you expect to find in a patient suffering psychogenic polydipsia?
Mild HYPOnatraemia
LOW plasma osmolality
What is desmopressin?
A selective vasopressin receptor peptidergic agonist (selective for V2). Mimics vasopressin and results in a decrease in urine volume and concentration.
How would you differentiate between cranial and nephrogenic diabetes insipidus diagnostically?
Using a fluid deprivation test.
Neither group can concentrate their urine when deprived of fluid, however upon the administration of DDAVP, central DI sufferers can concentrate their urine. Nephrogenic DI sufferers cannot.
MUST STOP IF LOSE >3% OF BODY WEIGHT
What is syndrome of inappropriate ADH (SIADH)?
The plasma vasopressin concentration is inappropriately high for the existing plasma osmolality.
Give 2 ways in which SIADH causes hyponatraemia.
Increased circulating vasopressin leads to increased water reabsorption from the collecting ducts. This causes an expansion of the ECF volume, leading to hyponatraemia.
Increased water reabsorption also increases the volume of the blood, stretching the atria and causing ANP release. ANP induces natriuresis, leading to hyponatraemia.
Give signs of SIADH
Significantly raised urine osmolality.
Decreased urine volume.
Decreased Na+ concentration in the blood.
Give symptoms of SIADH.
Can be symptomless.
If p(Na+) falls below 120mM: generalised weakness, poor mental function and nausea ensue.
If it falls below 110mM, confusion leading to a coma and ultimately death can occur.
What does demeclocycline do?
It is a V2receptor antagonist, which inhibits AQ2 synthesis. Thus prevents water reabsorption, causing AQUARESIS (not diuresis as electrolytes are still reabsorbed).
How would you treat SIADH?
Immediately fluid restrict and administer drugs such as demeclocycline which counter the effects of excess vasopressin. If a tumour, resect.
How would you decide the dose of levothyroxine to give to someone with primary hypothyroidism?
Use TSH as a guidance marker - aim to suppress TSH into the reference range with the dose of TSH.
How would you decide the dose of levothyroxine to give to someone with secondary hypothyroidism?
Can’t use TSH due to adenohypophyseal failure. Aim for fT4 (free T4) to be in the middle of the reference range.
What complications may arise from giving T3 (liothyronine) or a combination T3/T4 therapy?
Toxicity: palpitations, tremor, anxiety etc.
What %s of T3 and T4 are bound (mainly to TBG)?
99.97% of T4 is bound (0.03% is free), 99.70% of T3 is bound (0.3% is free).
Give the 3 symptoms caused by the antibodies in Graves’ disease.
Smooth goitre/ overactive thyroid gland due to antibody which binds to TSH receptor on follicular cells.
Exophthalmos due to antibody which binds to muscle behind eye.
Pretibial myxoedema due to stimulation of growth of soft tissues of shin.
What is Plummer’s disease?
A cause of hyperthyroidism (not of immune origin). Due to benign adenoma that is overactive at making thyroxine.
Toxic nodular goitre.
What effects does thyroxine have on the sympathetic nervous system?
It sensitises B-adrenoceptors to ambient levels of adrenaline and noradrenaline. Thus there’s apparent sympathetic activation.
Symptoms: tachycardia, palpitations, tremor in hands, lid lag, diarrhoea, sweating, heat intolerance, weight loss despite increased appetite.
What is thyroid storm?
Hyperthyroidism PLUS 2 or more of the following:
Hyperpyrexia (extremely high fever) >41 degrees.
Accelerated tachycardia/ cardial failure
Delirium/ frank psychosis.
Hepatocellular dysfunction; jaundice
Most common in patients with underlying Grave’s disease. Probably results from acute elevation of catecholamines (infection, surgery, cessation of meds, stress).
What is propylthiouracil (PTU)?
A thionamide which inhibits the thyroid peroxidase enzyme, hence inhibiting T3/T4 production. May also suppress antibody production in Grave’s and reduce the conversion of T4 to T3 in peripheral tissues.
Why is propranolol, a non-selective B-blocker, given alongside thionamides to treat hyperthyroidism?
Because thionamides take weeks to exert clinical effects (due to stores of T3/4 in the colloids (biochemical effects do take place after hours). Propranolol gives much faster relief of symptoms.
How does iodide (for example potassium iodide) work as a therapy for hyperthyroidism?
Due to the WOLFF-CHAIKOFF EFFECT. Iodide prevents iodination of thyroglobulin.
Why is iodide a useful treatment for surgery preparation?
Since within 10-14 days of first administering iodide, the vascularity and size of the gland is reduced.
How does radioiodine (I-131) work in treating hyperthyroidism?
The radioiodine accumulates in the colloid, emits B particles which destroy follicular cells.
Radioactive t1/2 is 8 days; radioactivity negligible after 2 months (avoid close contract with small children - contra-indicated by pregnancy and breast-feeding.
What are the causes of Cushing’s syndrome?
Pituitary adenoma (Cushing’s disease); excess steroid usage; ectopic ACTH (e.g. from lung cancer); adrenal adenoma secreting cortisol.
What would you expect to happen in a normal patient during a low dose dexamethasone suppression test?
You’d expect cortisol production to decrease.
How does treatment using metyrapone cause unwanted salt retention and hypertension?
Metyrapone arrests steroid synthesis at the 11-deoxycortisol stage (by inhibiting 11B-hydroxylase) in the zona fasciculata and reticularis. This causes 11-deoxycorticosterone to accumulate in the zona glomerulosa (which has aldosterone-like activity).
How can Cushing’s be treated surgically?
Dependent upon aetiology:
Pituitary resection.
Bilateral adrenalectomy.
Unilateral adrenalectomy (for an adrenal mass).
Why might eplerenone be favoured over spironolactone as an MR antagonist?
Spironolactone isn’t very specific: it binds to progesterone receptors to cause menstrual irregularities and inhibits androgen receptors to cause gynaecomastia in men. Eplerenone has a similar affinity for the MR, yet is more specific.
What are phaeochromocytomas?
Tumours of the adrenal medulla (secrete catecholamines; A, NA).
Give symptoms of Addison’s.
Postural hypotension, increased pigmentation and patches of vitiligo (loss of pigmentation - strong indicator of autoimmune cause), hypotension.
How would you investigate and diagnose Addison’s disease?
Perform a blood test: biochemical indicators are low sodium, high potassium, low cortisol at 9am; high ACTH.
Synacthen test: would expect a rise in cortisol after the administration of synthetic ACTH: otherwise is an indicator of Addison’s.
Adrenal autoantibody blood test.
Give symptoms of Cushing’s.
Abdominal weight gain (centripetal obesity), plethoric face, hypertension, proximal myopathy, abdominal striae, hirsutism, thin skin, bruising.
Patient appears cushingoid.
What investigations would you perform to reach a diagnosis of Cushing’s syndrome?
24-hour urine free cortisol collection.
Low dose dexamethasone suppression test.
Midnight/sleeping cortisol - expected to be low but would be high in cushingoid patients.
What is congenital adrenal hyperplasia?
Born with non-functioning cortex enzymes. Most commonly 21-hydroxylase. Can be deficiency (partial) or absence (complete).
How would a neonate present with congenital adrenal hyperplasia resulting in 21-hydroxylase absence (CAH)?
Present with salt-losing addisonian crisis. Before birth (in utero), foetus gets steroid across the placenta. Girls might have ambiguous genitalia (virilised by adrenal testosterone).
How do people with partial 21-hydroxylase deficiency present and why?
Deficient cortisol and aldosterone, but excess sex steroid and testosterone due to high ACTH (no negative feedback). Leads to hirsutism and virilisation in girls and precocious puberty in boys due to adrenal testosterone.
Why does 11-hydroxylase deficiency lead to hypertension and hypokalaemia?
Because 11-deoxycorticosterone builds-up in the zona glomerulosa. 11-deoxycorticosterone behaves like aldosterone, so despite there being an aldosterone deficiency, there is an excess of mineralcorticosteroids.
Describe 17-hydroxylase deficiency.
Deficiency of both cortisol and sex steroids. Excess 11-deoxycorticosterone and aldosterone (mineralocorticois). Leads to hypertension, hypokalaemia and symptoms associated with glucuocorticoid and sex steroid deficiencies.
Give 4 aldosterone release triggers
Aldosterone release stimulated by angiotensin II. Triggered by hyperkalaemia, hyponatraemia, reduction in renal blood flow and B1-adrenoceptor stimulation.
Which regions of the adrenal cortex produce which corticosteroids?
Sex steroids (androgens, oestrogens) are produced in the zona reticularis. Glucocorticoids (cortisol) are produced in the zona fasciculata. Mineralocorticoids (aldosterone) are produced in the zona glomerulosa.
Compare, briefly, the glucocorticoid and mineralocorticoid receptor (GR and MR).
GR: wide distribution, selective for glucocorticoids however low affinity for cortisol.
MR: discrete distribution (kidney), do not distinguish between aldosterone and cortisol, high affinity for cortisol.
In Cushing’s syndrome, why may you get excessive stimulation of mineralocorticoid receptors, leading to hypokalaemia and hypernatraemia?
Normally, cortisol is converted to an inactive form, cortisone, by 11b-hydroxysteroid dehydrogenase 2 (11bhsd2) in the kidneys. In Cushing’s, this enzyme is overwhelmed due to excessive amounts of cortisol, leading to stimulation of the MR receptor.
What is fludrocortisone?
An aldosterone analogue, used as an aldosterone substitute in Addison’s disease. It binds to the mineralocorticoid receptor. Given orally.
What is hydrocortisone?
A glucocorticoid with mineralocorticoid activity at high doses (hence it binds to both receptors). It has a duration of 8 hours. Given orally: may be given parenterally (intravenous or intramuscularly).
What is dexamethasone?
A synthetic glucocorticoid with NO mineralocorticoid activity. Hence, it binds exclusively to the glucocorticoid receptor. It has a duration of 40 hours. Can be administered orally or parenterally.
What is prednisolone?
A glucocorticoid with weak mineralocorticoid activity (binds to glucocorticoid receptor / mineralocorticoid receptor weakly).
What would you give to treat primary adrenocortical failure (Addison’s)?
Hydrocortisone and fludrocortisone to replace lack of cortisol and aldosterone.
What would you give to treat secondary adrenocortical failure (ACTH deficiency)?
Lack of cortisol but aldosterone is normal (aldosterone secretions determined by angiotensin II) hence give HYDROCORTISONE ONLY.
How would you treat someone in Addisonian crisis (acute adrenocortical failure)?
Give i.v. 0.9% NaCl to rehydrate patient.
High dose hydrocortisone - i.v. infusion or i.m. every 6 hours. At high doses, hydrocortisone has mineralocorticoid effect (overwhelms 11B-hsd 2) so replaces aldosterone too.
Give 5% dextrose if hypoglycaemic.
What are the objectives of treating congenital adrenal hyperplasia (CAH) and how are these realised?
Replace cortisol and suppress ACTH production (in turn suppressing the excessive androgen production). This is realised by giving dexamethasone 1/day, pm or hydrocortisone 2/3 a day.
Replace aldosterone - realised by giving fludrocortisone.
Why should glucocorticoid doses be increased in times of stress, such as minor illnesses?
Cortisol is the stress hormone. People with adrenal failure can’t regulate their cortisol production, so their dose needs to be adjusted to help them deal with stresses.
Normal cortisol production in around 20mg a day. In stress, this can rise by up to 10 times.
Getting doses right is tricky. How can you tell in a woman suffering adrenocortical failure if the prescribed glucocorticoid dose is too high or low.
If the GC dose is too high, the patient appears CUSHINGOID.
If it’s too low, ACTH will rise causing excess androgen production, leading to hirsutism,
Give symptoms of phaeochromocytomas.
Hypertension in young people; episodic severe hypertension (can cause MI or stroke); high adrenaline can cause VF and possibly death.
What is the precursor of aldosterone which behaves like aldosterone causing hypertension and hypokalaemia in 11-hydroxylase deficiency?
11-deoxycorticosterone.
Contrast expected blood levels of LH, FSH and testosterone/oestradiol for primary gonadal failure and hypothalamic/pituitary disease.
Primary gonadal failure: high LH & FSH, low testosterone/oestradiol.
Hypothalamic/pituitary disorder: low LH/FSH, low testosterone and oestradiol.
Give symptoms of hypogonadism in males.
Loss of libido, impotence (inability to achieve erection/orgasm), decreased muscle bulk, osteoporosis, small testes.
What is the cause of hypogonadism in Kallmann syndrome?
Hypothalamic failure (fails to produce GnRH).
Upon finding a male’s LH, FSH and testosterone were all low, how would you proceed?
MRI the pituitary.
Define azoospermia and oligospermia.
Azoospermia is the absence of sperm in the ejaculate.
Oligospermia is a reduced number of sperm in the ejaculate.
