CASE 2 - Hyperpituitarism Flashcards
The anterior pituitary is of _______ origin and makes up __% of the gland.
The posterior pituitary is of ______ origin.
The anterior pituitary is of GLANDULAR origin and makes up 80% of the gland.
The posterior pituitary is of NEURAL origin.
Name the 2 parts of the adrenal gland and their respective functions
CORTEX: outer, larger region that is divided into 3 separate zones, each secreting a different hormone.
MEDULLA: located in the centre of the adrenal gland and secretes stress hormones (e.g. adrenaline, noradrenaline)
Name the 3 zones of the adrenal cortex and the hormones they produce (GFR)
- Zona glomerulosa: aldosterone
- Zona fasciculata: glucocorticoids (e.g. cortisol)
- Zona reticularis: androgens & glucocorticoids
What is the benefit of the zona glomerulosa being located superficially?
The zona glomerulosa secretes aldosterone, which acts on the kidneys.
Its proximity to the kidney optimises its function.
The CORTEX of the adrenal gland is under _________ control whereas the MEDULLA is under _________ control.
The CORTEX of the adrenal gland is under PARASYMPATHETIC control whereas the MEDULLA is under SYMPATHETIC control.
The anterior pituitary is in close proximity to which visual structure?
Optic chiasm
Name the hormones secreted by the anterior pituitary
Prolactin
ACTH
TSH
LH
FSH
Growth hormones
Name the 2 hormones secreted by the posterior pituitary
Oxytocin
Anti-diuretic hormone (ADH)
What is the difference between Cushing’s disease and Cushing’s syndrome?
Cushing’s syndrome = ANY cause of hypercortisolism
Cushing’s disease = secondary hypercortisolism due to excessive ACTH production by pituitary adenomas
What are the 2 causes of Cushing’s syndrome? Give examples.
EXOGENOUS (iatrogenic) Cushing’s = external source of cortisol (e.g. glucocorticoid or steroid therapy)
ENDOGENOUS Cushing’s = excess cortisol production by the body (e.g. adrenal adenoma, pituitary adenoma, paraneoplastic syndrome)
Which is more common: exogenous or endogenous Cushing’s?
EXOGENOUS
Outline the physiology behind cortisol secretion, starting in the hypothalamus.
- Stress and the diurnal rhythm (cortisol increases in the morning) controls CRH (corticotropin releasing hormone) release
- CRH stimulates the anterior pituitary to release ACTH (adrenocorticotropic hormone)
- ACTH stimulates the zona fasciculata to release cortisol
- Negative feedback mechanism maintained by cortisol’s inhibitory effect on CRH and ACTH release.
Name the 3 actions of cortisol
- Gluconeogenesis & inhibition of glucose uptake –> increased BGL
- Proteolysis –> increased protein breakdown
- Lipolysis –> increased serum fatty acids
Name 7 SYMPTOMS of Cushing’s syndrome
- Lethargy
- Muscle weakness
- Decreased libido
- Amenorrhoea
- Increased susceptibility to infections
- Easy bruising
- Weight gain: moon facies + buffalo hump + central obesity
- Sleep disturbances
Name 5 SIGNS of Cushing’s syndrome
- Hirsutism
- Stretch marks (classically purple abdominal striae)
- Acne
- Hypertension
- Thin skin
- Facial flushing
- Hyperpigmentation (in secondary hypercortisolism)
- Muscle weakness
What would you discover in the following investigations if a patient had Cushing’s syndrome?
- BGL
- Lipid panel
- DEXA scan
- Upper/lower limb neurological exam
- BGL: hyperglycaemia
- Lipid panel: dyslipidaemia
- DEXA scan: osteopenia, osteoporosis
- Upper/lower limb neurological exam: muscle weakness
Use the acronym ‘CUSHINGOID’ to list the side effects of corticosteroid use (which align very well with Cushing’s syndrome)
C - cataracts U - ulcers S - striae H - hirsutism/hyperglycaemia/hypertension/hyperpigmentation I - infections N - necrosis (of the femoral head) G - glucose elevation O - osteoporosis/obesity I - immunosuppression D - depression/diabetes
Describe the pathophysiology behind the cushingoid appearance of central obesity, buffalo hump, moon facies, and thin extremities.
Excess cortisol leads to high insulin levels (with this insulin preferentially targeting fat cells in the centre of the body). Activation of lipoprotein lipase causes fat accumulation in those areas.
Cortisol also leads to proteolysis and muscle breakdown.
How does Cushing’s lead to hypertension?
Cortisol has the following effects:
- Amplifies effect of catecholamines (e.g. adrenaline, noradrenaline) on blood vessels
- Cortisol is structurally similar to mineralocorticoid, so it binds to mineralocorticoid receptors and exerts fluid-retaining effects
How does Cushing’s lead to reproductive abnormalities (e.g. irregular menstruation and virilization)?
Excess cortisol inhibits GnRH production
How does Cushing’s lead to osteoporosis/osteopenia/pathological fractures?
- Inhibition of calcitriol synthesis by cortisol - calcitriol is an active form of vitamin D that increases calcium absorption in the duodenum
- Blocks calcium absorption
- Hypercalciuria
How can exogenous steroid medication cause Cushing’s syndrome?
Exogenous steroids are very similar to cortisol, so they mimic its actions on various tissues
Name the 3 types of ENDOGENOUS Cushing’s syndrome.
- PRIMARY hypercortisolism / ACTH-INDEPENDENT Cushing’s syndrome: autonomous cortisol production by the adrenal glands (e.g. due to adrenal adenoma or carcinoma)
- SECONDARY hypercortisolism / ACTH-DEPENDENT Cushing’s syndrome: pituitary ACTH production (e.g. pituitary adenoma), ectopic ACTH production (e.g. paraneoplastic syndrome, carcinomas - especially small cell lung carcinoma)
Which type of ENDOGENOUS Cushing’s is most common?
Pituitary ACTH production due to pituitary adenoma (Cushing’s disease)
Name 3 screening tests used for Cushing’s
- 1mg overnight dexamethasone suppression test
2. Free cortisol measurements: 24-hour urinary cortisol & late-night salivary cortisol
How does the low-dose (1mg) dexamethasone suppression test work? What does it show if cortisol results are normal?
Dexamethasone is a powerful glucocorticoid that acts similarly to cortisol.
It acts on the hypothalamus to suppress CRH, which then suppresses ACTH and hence DECREASES cortisol production.
If you have Cushing’s syndrome, cortisol is already so high that the 1mg of dexamethasone is not sufficient to cause suppression.
Therefore, individuals with Cushing’s will have NORMAL or HIGH levels of cortisol.
https://www.youtube.com/watch?v=ZINZOob04IY
In NORMAL individuals, a low-dose (1mg) dexamethasone suppression test will show what result?
Decreased cortisol levels
Why is a HIGH-DOSE (8mg) dexamethasone suppression test used?
How does this differ from the low-dose (1mg) test?
It is useful for DIAGNOSIS.
This higher dose of dexamethasone is enough to suppress CRH/ACTH in Cushing’s DISEASE (pituitary adenoma causing ACTH secretion), therefore DECREASING cortisol levels.
If, however, the cause of Cushing’s is due to ectopic foci (i.e. adrenal or pituitary adenomas and carcinomas), cortisol levels will remain NORMAL because these ectopic foci are resistant to negative feedback.
DECREASED cortisol levels after a HIGH-DOSE dexamethasone suppression test is indicative of which pathology?
Cushing’s disease (pituitary adenomas causing excess ACTH secretion)
Which causes of ENDOGENOUS Cushing’s are suspected based on the following serum ACTH results?
LOW SERUM ACTH
NORMAL/HIGH SERUM ACTH
LOW SERUM ACTH: primary hypercortisolism/ACTH-INDEPENDENT (e.g. adrenal adenoma, carcinoma)
NORMAL/HIGH SERUM ACTH: secondary hypercortisolism (e.g. ectopic foci, pituitary adenoma)
Why is serum ACTH LOW in primary hypercortisolism (e.g. due to an adrenal adenoma)?
Excess cortisol production –> negative feedback –> decreased CRH and ACTH
Why is serum ACTH HIGH in secondary hypercortisolism (e.g. due to a pituitary adenoma or small cell lung carcinoma)?
Excess ACTH production due to pituitary adenoma or paraneoplastic syndrome
What is the CRH stimulation test?
What does it show if ACTH and cortisol are elevated vs. unchanged?
A test used to differentiate between pituitary and ectopic sources of excess ACTH (i.e. the secondary causes of hypercortisolism).
If both ACTH and cortisol increase, the diagnosis is Cushing’s DISEASE (pituitary adenoma)
If ACTH and cortisol levels show no change, the diagnosis is ECTOPIC FOCI (since these are not under control from the hypothalamus/normal physiological mechanisms).
What is the most common cause of hyperpituitarism?
Pituitary adenoma
In which age group are pituitary adenomas most common?
Adults 30 - 50 years old
What is the mechanism of action of beclamethasone, and what is it used for?
MOA: reduce airway inflammation and bronchial hyper-reactivity. It is an inhaled corticosteroid
USE: asthma
What activities are impacted by a proximal weakness?
- Getting out of a chair
- Walking up stairs
- Hanging up washing
What is hyperpituitarism, and what are the 3 most commonly-affected hormones?
HYPERPITUITARISM = excess of one or more pituitary hormones, most commonly caused by a pituitary adenoma.
3 most commonly-affected hormones: ACTH, prolactin, growth hormone
What are the clinical features of ACTH excess?
Clinical features of Cushing's syndrome: - Central obesity - Purple abdominal striae - Moon facies - Buffalo hump - Hypertension - Hyperglycaemia etc.
What is the pathophysiology of hyperprolactinaemia causing HYPOgonadotrophic hypogonadism?
Increased prolactin –> suppression of GnRH –> decreased LH and FSH production –> decreased oestrogen and testosterone –> hypogonadotrophic hypogonadism
What are the clinical features of of hyperprolactinaemia? (differentiate between men and women)
WOMEN: galactorrhea, irregular menses or amenorrhoea, loss of libido, vaginal atrophy, infertility, osteoporosis (after many years)
MEN: galactorrhea is rare, clinical features of decreased testosterone (loss of libido, gynecomastia, loss of facial hair, osteoporosis), erectile dysfunction
https://www.amboss.com/us/knowledge/Hyperprolactinemia/
Name 3 potential causes of hyperprolactinaemia
- Prolactin-secreting pituitary adenoma (prolactinoma) - MOST COMMON
- Damage to the hypothalamus or infundibular stalk
- Drugs (e.g. dopamine antagonists, TCAs, OCP, verapamil)
- Hypothyroidism
How do dopamine antagonists cause hyperprolactinaemia ?
Dopamine INHIBITS prolactin secretion.
Therefore, dopamine ANTAGONISTS will decrease dopamine levels and the loss of inhibition results in MORE prolactin secretion
Name 2 investigations that can be used to diagnose hyperprolactinaemia
- Basal prolactin levels
2. Cranial contrast MRI (to rule out pituitary adenoma)
Which cause of hyperprolactinaemia is indicated by the following basal prolactin results?
- Blood prolactin levels permanently >200ng/mL
- Mild blood prolactin elevation of <100ng/mL
- Blood prolactin levels permanently >200ng/mL = PROLACTINOMA
- Mild blood prolactin elevation of <100ng/mL = hypothyroidism or drug-induced hyperprolactinaemia
What are the clinical features of growth hormone excess/acromegaly?
- Enlargement of the face, hands, and feet
- Voice deepening
- Excessive sweating
Why do people with Cushing’s syndrome develop hyperglycaemia?
Cortisol stimulates gluconeogenesis and decreases peripheral utilisation of glucose
Why do people with Cushing’s syndrome develop hypernatremia, hypokalaemia, and metabolic alkalosis?
Excess cortisol –> saturation of enzymes that normally prevent cortisol from binding to mineralocorticoid receptors –> more cortisol binds to mineralocorticoid receptors
CONSEQUENCES:
- Water and sodium uptake
- Potassium and H+ excretion
What are mineralocorticoids?
Mineralocorticoids are a class of corticosteroids. They are produced in the adrenal cortex and influence salt and water balances.
The primary mineralocorticoid is aldosterone
Patients with hyperprolactinaemia due to a pituitary adenoma can present with which 2 characteristic manifestations?
- Bitemporal hemianopsia
2. Headache
What types of imaging can be done to establish the cause of Cushing’s syndrome?
CT/MRI of the abdomen or skull: for adrenal and pituitary tumours.
CXR, abdominal, or pelvic CT if there is ectopic ACTH production
In the diagnosis of hypercortisolism, which type of investigation is done first, and why?
Blood/hormone tests are done first.
This is because pituitary microadenomas do not always appear on imaging, and imaging can reveal inactive tumours in healthy individuals.
What is the most common type of pituitary adenoma?
Prolactinoma
Hyperprolactinemia refers to the increased production of prolactin by the anterior pituitary. When does this occur PHYSIOLOGICALLY?
During pregnancy
What are the functions of FSH and LH?
FSH and LH and gonadotropins: they stimulate the gonads (testes & ovaries).
FSH = maturation of sperm and ovarian follicles.
LH = ovulation, corpus luteum development, oestrogen and progesterone secretion in women.
Testosterone secretion in men.
Name the bony depression in which the pituitary gland sits
Sella turcica of the sphenoid bone
What is the primary target of prolactin?
Breast tissue
Which hormone does prolactin suppress?
GnRH
How are prolactin levels regulated?
Increased levels of prolactin in the blood signal the hypothalamus to produce dopamine, suppressing the release of prolactin
A decrease in FSH will cause which signs & symptoms in women?
Amenorrhoea
Lack of ovulation
A decrease in LH will cause which signs & symptoms in men?
Signs/symptoms of low testosterone:
- Low libido
- Loss of body hair
- ED
- Fatigue & hot flashes
- Increased body fat
- Sleep disturbances
What is Cabergoline? What is its mechanism of action?
Cabergoline is a dopamine agonist; it stimulates dopamine production, suppressing prolactin secretion.
What are the effects of Cabergoline?
- Decreases the size of prolactinomas
- Decreases growth hormone concentration in people with acromegaly
Outline the steps taken to diagnose the cause of Cushing’s syndrome.
- SCREENING TEST TO CONFIRM HYPERCORTISOLISM: 24-hour urine cortisol, low-dose dexamethasone suppression test, late-night salivary cortisol
- SERUM ACTH: differentiate between primary (ACTH-dependent) and secondary (ACTH-independent)
If ACTH-INDEPENDENT: abdominal CT/MRI to look for adrenal adenoma/carcinoma
If ACTH-DEPENDENT: high-dose dexamethasone suppression test or CRH stimulation test to ascertain whether it’s a pituitary adenoma or ectopic foci
How can pituitary adenomas be classified according to their size?
What is the clinical picture of each of these?
MICROADENOMA: <1cm in diameter. Tends to cause hormone hypersecretion.
MACROADENOMA: >1cm in diameter. Usually clinically silent until they cause mass effects.
How does excess prolactin / hyperprolactinaemia cause decreased levels of FSH and LH?
Prolactin inhibits GnRH, which normally stimulates the release of FSH and LH from the anterior pituitary.
Excess prolactin –> no GnRH release –> no FSH and LH
How does primary hypothyroidism cause hyperprolactinaemia?
Decreased T3 and T4 production leads to a compensatory rise in TRH, which stimulates PROLACTIN release. Therefore you get hyperprolactinaemia.
Name 5 things to ask about in a history to ascertain the CAUSE of hyperprolactinaemia
- Pregnancy (non pathological cause)
- Drugs (e.g. dopamine antagonist, neuroepileptic drugs, antidepressants)
- Headache & visual symptoms
- Sx hypothyroidism
- Hx of renal disease
Name 5 drugs that can cause hyperprolactinaemia
- Dopamine antagonists (e.g. halopiredol)
- Neuroepileptic drugs (e.g. risperidone)
- Antidepressants
- Verapamil
- Methyldopa
Outline the surgical and non-surgical management of a prolactinoma
NON-SURGICAL: dopamine agonist (e.g. Cabergoline, bromocriptine)
SURGICAL: transsphenoidal resection of the pituitary adenoma
RADIOTHERAPY: if the adenoma continues expanding despite medication and surgery
How are other causes of hyperprolactinaemia (not a prolactinoma) treated?
TREAT THE UNDERLYING CAUSE:
- Renal failure –> renal transplant
- Primary hypothyroidism –> thyroxine replacement therapy
- Drugs –> lower or cease drug
Name 2 investigations that can be used to diagnose hyperprolactinoma
- Basal prolactin levels
2. Pituitary MRI with contrast: to see if it’s a pituitary adenoma (the most common cause of hyperprolactinoma)
Name 3 complications of a transsphenoidal resection of a pituitary adenoma
- Hormone deficiencies
- Damage to parasellar structures (e.g. internal carotids, optic chiasm)
- CSF rhinorrhoea
On dopamine agonists (e.g. cabergoline) prolactin levels take _ to _ weeks to fall. The prolactinoma decreases in size after _ weeks to _ months.
Gonadal function returns within …
On dopamine agonists (e.g. cabergoline) prolactin levels take 2 to 3 weeks to fall. The prolactinoma decreases in size after 6 weeks to 6 months.
Gonadal function returns within a few months
Name 3 adverse effects of the dopamine AGNOIST cabergoline
Common: cardiac fibrosis, GIT (NV, abdo pain, constipation), orthostatic hypotension
Name 3 electrolyte abnormalities that can occur in Cushing’s syndrome
- Hypernatremia
- Hypokalemia
- Metabolic alkalosis
Which cause of SECONDARY/ACTH-INDEPENDENT Cushing’s syndrome remains (partially) susceptible to the high-dose dexamethasone and CRH stimulations tests?
Cushing’s DISEASE (pituitary adenoma/carcinoma)
Compare the causes of primary vs secondary hypogonadism
PRIMARY HYPOGONADISM: hypergonadotrophic hypogonadism. Caused by insufficient sex steroid production in the gonads (e.g. Turner syndrome, chemotherapy, damage to leydig cells or ovarian tissue)
SECONDARY HYPOGONASIM: hypogonadotrophic hypogonadism. Caused by insufficient GnRH (e.g. genetic disorders, hypothalamic/pituitary lesions, infection)
Compare the laboratory findings in primary vs secondary hypogonadism
PRIMARY HYPOGONADISM: low testosterone/oestrogen, HIGH GnRH, LH, & FSH
SECONDARY HYPOGONADISM: low testosterone/oestrogen, LOW GnRH, LH, &FSH
How does severe hypothyroidism lead to hyperprolactinaemia?
Hypothyroidism –> decreased T3/T4 –> upregulates TRH –> TRH is a prolactin-releasing hormone –> high prolactin
