Pituitary Flashcards
Where is the pituitary gland what structures is it close to?
Sits in pituitary fossa
Below: sphenoid air sinus
Above: optic chiasm
Lateral: cavernous sinus containing CN III, IV, V1, V2, VI, carotid artery
All these structures can be affected by expanding mass lesion
Blood supply for the pituitary gland
From the hypothalamus
= Hypothalamo-hypophyseal circulation
Also the source of hypothalamic hormones
Which hormones are produced by the anterior and posterior pituitary gland?
Anterior: FSH/LH, TSH, ACTH, GH, prolactin
Posterior: oxytocin, ADH
Anterior pituitary produces 6 hormones which are in turn controlled by the hypothalamus which are mostly stimulatory except …
Somatostatin –> inhibitory for GH
Which hypothalamic hormones controls the following
1) FSH/LH
2) TSH
3) Increased GH
4) Decreased GH
5) ACTH
6) Decreased prolactin
1) GnRH
2) TRH
3) GRF (stimulatory)
4) Somatostatin (inhiibotry)
5) CRF
6) Dopamine
Where do the following hormones act and what do they do?
1) ACTH (adrenocorticotropin hormone)
2) TSH
3) FSH
4) LH
5) GH
6) Prolactin
1) Adrenals = increase cortisol
2) Thyroid = increase thyroid hormones
3) Gonads = produce sperm and egg
4) Gonads = increase sex hormones
5) Liver and other tissues = increase IGF-1
6) Breasts = lactation
What does ADH do?
Goes to kidneys to promote water reabsorption
Lack of ADH = central diabetes insipidus = 10-20L UO/day
What happens when a pituitary adenoma compresses the optic chiasm?
Bitemporal hemianopia (can initially be upper quadrantanopia)
How do non-functioning pituitary adenomas present?
1) Incidental on imaging
2) Compress optic chiasm, cavernous sinus (CN structures)
3) Compress anterior pituitary –> reduction in hormone production
4) Mass effect - headache, visual changes, raised ICP
How do you treat pituitary adenomas?
Surgery usually transphenoidal (through upper lip or behind nose –> through sphenoid sinus –> base of sella turcica)
Radiotherapy usually post-op when you can’t remove the whole tumour. Alone is rare.
- Beware can cause pituitary failure
Temozolamide (alkylating agent) for aggressive tumours. Not widely use.
Causes of hypopituitarism
1) Pituitary tumour (commonest) - usually benign but can be metastatic malignancy
2) Other CNS tumours - craniopharyngioma, lymphomas
3) Previous pituitary surgery/radiation
4) Autoimmune - thyroiditis
5) Postpartum lymphocytic hypophysitis - pituitary gland gets infiltrated by lymphocytes, becomes enlarged with impaired function
6) Post concussion
7) SAH
8) Infiltration - haemochromatosis, sarcoidosis, histocytosis
9) Sheehan’s syndrome - massive hypotension post antiparum bleed, get pituitary necrosis
10) Rare genetic causes
11) Drugs - ipilimumab causing hypophysitis
What happens when you are deficient in the following anterior pituitary hormones?
1) ACTH/cortisol
2) TSH
3) FSH/LH
4) Prolactin
5) GH
1) Hypotension, weak, diarrhoea, vomiting, weight loss
2) Cold intolerance, fatigue
3) Loss of menses, libido, stop shaving due to loss of testosterone (men)
4) None except possible loss of lactation
5) Subtle effects on ET, fatigue, body composition (lose lean muscle, increase in fat), metabolism. Growth failure in children.
What uses causes a deficiency or posterior pituitary hormones (ADH, oxytocin)?
Hypothalamic lesion
Tumour or trauma
How to test for ACTH/cortisol deficiency?
1) Morning cortisol 7-9am + ACTH at the same time
- If low cortisol, high ACTH then you have your diagnosis of Addison’s
- If levels are indeterminate, do short synacthen test
2) Short synacthen test
- Inject ACTH then test cortisol level 1 hour later to see if there is a normal response to ACTH
3) Insulin tolerance test (gold standard)
- Give insulin –> induce stress with extreme hypoglycaemia BSL <2.2 –> ACTH and GH are released as part of stress response –> produce cortisol
- Potentially dangerous
How to test for GH deficiency?
GH is secreted in pulsations. We therefore cannot measure random GH level.
Hence must measure IGF-1 (t1/2 25-30 hours)
+/- with GH stimulation test i.e. insulin tolerance test or can do other similar provocative tests with arginine, glucagon - should increase IGF-1
+/- with glucose suppression test - giving glucose should suppress IGF-1
How to test for ADH deficiency?
1) Water deprivation test (old gold standard)
- Fluid restrict –> inability to concentrate urine with large amounts of dilute urine in diabetes insipidus (DI); concentrated urine in primary polydipsia –> inject ADH –> improves with central DI, but not with peripheral DI (kidney problem)
2) Hypertonic saline (new gold standard)
- Lots of side effects
- 250ml hypertonic saline –>
- In primary polydipsia, get high Copeptin to retain water
- In central DI, get low Copeptin
- Measure Copeptin
Which 2 anterior pituitary hormones are essential for life?
ACTH/cortisol
TSH
Rx ACTH deficiency
Replace cortisol with hydrocortisone or cortisol (usually 2/3 dose mane, 1/3 dose nocte)
Don’t need to replace mineralcorticoid
No single blood test to monitor replacement. Monitor for symptoms like fatigue, weight, bone density, postural BP
Rx TSH deficiency
Thyroxine (converted to T3 in periphery)
Monitor free T4
Rx FSH/LH deficiency
Females: OCP
Males: testosterone
Will not restore fertility
Rx GH deficiency
Subcut GH injections
PBS criteria:
1) Hypothalamic or pituitary lesion +
2) Suppressed GH on insulin tolerance test/arginine/glucagon +
3) Reduced QOL
AE: worsen diabetes, OSA, HTN, carpal tunnel syndrome
Rx prolactin deficiency
No treatment needed
Rx posterior pituitary hypofunction i.e. ADH deficiency
Long-term treatment with intranasal desmopressin (Brand name minirin)
Need to drink and void constantly
Started at night to reduce nocturnal diuresis
Titrate dose according to symptoms and serum Na+
What does a functioning pituitary adenoma mean?
Produces hormones - almost always one hormone only
What happens when you have excess GH?
Acromegaly/gigantism Hypertension Cardiomegaly/cardiomyopathy Bone disease OSA Mass effect of organs Increased malignancy particularly colorectal through colonic polyps OA Diabetes
Reduced life expectancy due to cardio respiratory problems
What happens when you have excess prolactin?
Pre-menopausal women: amenorrhoea, galactorrhoea, infertility (early diagnosis), galactorrhoea, estrogen deficiency (reduced vaginal lubrication, osteoporosis)
Post-menopausal women: mass effect only
Men: hypogonadism, impotence, reduced libido, gynaecomastia (often late diagnosis until there’s mass effect)
High prolactin inhibits pulsatile gonadotropin release –> hypogonadism
What happens when you have excess TSH?
Hyperthyroidism
What is the most common functioning pituitary adenoma?
Prolactinoma - prolactin secreting adenoma
Causes of high prolactin
Tumour (prolactinoma) Drugs - antipsychotics, TCAs Estrogen, pregnancy Stress Hypothalamic or pituitary stalk damage Hypothyroidism
> 2-4 times ULN, usually due to tumour
Pathophysiology of prolactin-secreting adenomas
Hypothalamus inhibits prolactin secretion from pituitary through dopamine which comes down pituitary stalk. Any lesion that compresses pituitary stalk –> reduces dopamine –> increases prolactin.
Note that while prolactin increases, other pituitary hormones decrease.
Rx prolactinoma
Who should be treated?
Macroadenoma or symptomatic
1st line: Medical therapy
Dopamine agonist - bromocriptine (pregnancy preferred) or carbergoline (preferred due to once/twice weekly and less side effects)
2nd line: surgery +/- radiotherapy
3rd line: chemotherapy (not surgical candidate and do not respond to medical therapy or radiotherapy)
Rx acromegaly/GH excess
Pituitary resection +/- medical therapy, radiotherapy
Medical therapy options
1) Somatostatin - reduces GH production from pituitary
2) Pegvisomant (GH receptor antagonist)
3) Dopamine agonist if cosecreting prolactin
Clinical features of Cushing’s syndrome (excess cortisol)
Central adioposity Buffalo hump Facial plethora Striae Moon facies Hypertension Glucose intolerance Mood Reduced attention/concentration Androgen excess Bruising Osteoporosis with fractures Proximal muscle weakness Infection
Causes of hypercortisolism
ACTH dependent
1) Pituitary adenoma - overproduction of ACTH
2) Ectopic ACTH production - bronchial adenoma, thyroid
ACTH independent
3) Adrenal adenoma
4) Adrenal carcinoma
5) Iatrogenic (most common)
How to approach suspected Cushing’s?
1) Is there excess cortisol?
- 24h urine cortisol collection (x2 test) OR late night salivary cortisol OR 1mg dexamethasone suppression test (failure to suppress)
- Late night salivary cortisol has very good sensitivity and specificity but easily contaminated
- 1mg dex suppression test has very good sensitivity but not specific. So if you have a a negative result, then you’re unlikely to have Cushing’s
2) Is it ACTH dependent?
- Serum ACTH
3) If low ACTH –> image adrenals
If high ACTH –> coming from the pituitary or ectopic
- Image pituitary
- High dose dexamethasone test - usually suppress pituitary but not ectopic
- CRH stimulation test - should increase pituitary production but not ectopic production of ACTH
- Inferior petrosal sinus sampling - whether its central or peripherally producing ACTH
Rx: pituitary Cushing’s
Resection of pituitary adenoma - high recurrence rate (preferred)
Radiotherapy - slow effect
Medical therapy (similar to acromegaly)
- Pesireotide (GH receptor antagonist)
- Carbergoline (DA agonist)
- Block cortisol production with ketoconazole, metyrapone
Bilateral adrenalectomy
What is Nelson’s syndrome post bilateral adrenalectomy?
Bilateral adrenalectomy is done in pituitary Cushing’s
Remove both adrenals –> remove cortisol (negative feedback) –> increase ACTH –> increase tumour growth (Nelson’s syndrome)
To prevent this, need post-operative radiotherapy of pituitary
Investigations to confirm TSH-secreting tumour
TRH stimulation test
- TRH would normally stimulate TSH to rise but it doesn’t happen in TSH-secreting tumour
- T3 suppression test - normally suppresses T4 production but doesn’t in TSH secreting tumour
Rx TSH-secreting tumour
Surgery
Radiotherapy
Octreotide
What type of secreting pituitary tumours are the most common?
Prolactinomas
Are prolactinomas usually microadenomas or macroadenomas?
Microadenomas <1cm
Pituitary prolactinomas can cosecrete which hormone?
GH –> acromegaly
How does pregnancy cause hypercortisolaemia?
Placenta –> CRH –> acts on pituitary –> release ACTH –> stimulates adrenal gland to release cortisol
Causes of growth hormone deficiency
Pituitary tumour or consequence of tumour surgery/radiation
Other intracranial tumours e.g. craniopharyngioma
Sheehan syndrome
Sarcoidosis
How likely are you going to get GH deficiency with other pituitary hormone deficits?
GH deficiency occurs in 45% who have not other pituitary hormone deficits, and 99% in patients with multiple deficits
Presentation and risk of GH deficiency
Decrease in lean body mass Increase in fat mass Decrease in BMD Increased CVD risk Increase mortality
Management of GH deficiency
Exogenous GH replacement
Conflicting guidelines as to whether adult onset GH deficiency should be treated or not given high cost, daily injections required and AE with limited benfits
Increases muscle mass, decreases body fat
May improve cardiac function
Limited evidence that it improves BMD, muscle strength or energy levels
Risk of taking estrogen or testosterone HRT or pregnancyin macroprolactinomas?
Risk of progressive growth
Central diabetes insipidus treatment
Desmopressin
Injection, drops, spray, tablets, melts
Requires close fluid monitoring
Patients will still have some polyuria, if not they can iatrogenically cause hyponatraemia
Out of all the hormone producing cells in the anterior pituitary gland, which type of cell is the most prevalent?
Somatotrophs (produce GH)
Insulin tolerance test
What is it?
Lower BSL to 2.5 –> physiological stress –> trigger hypothalamic pituitary adrenal axis and GH
To look for GH deficiency
Which is the most common pituitary adenoma?
Prolactinoma or non-functioning > GH > Corticotropin
Non-secreting pituitary adenomas
What is the most common lineage?
Gonadotroph lineage
Remember they are the most common cells in the anterior pituitary
Even though they’re not hormone producing, they can demonstrate aggressive behaviour.
When does GH go up during the day?
During sleep
How to measure GH excess?
IGF-1
Confirmatory testing - 75g OGTT to suppress GH
If true acromegaly, can’t suppress this then do MRI to confirm
30% of patients with acromegaly have …
Elevated prolactin level
Management of acromegaly
Transsphenoidal surgery (most patients)
Radiotherapy not used much anymore
Persistent disease:
Somatostatin receptor ligand (for most) e.g. octreotide
Dopamine agonist (mild disease)
Pegvisomant (GH receptor antagonist) - very effective as it blocks 4 out of 5 receptors; can cause hyperglycaemia and diabetes
Difference between Cushing’s disease and Cushing’s syndrome
Cushing’s disease: pituitary problem (too much ACTH)
Cushing’s syndrome: too much cortisol
Majority of Cushing’s syndrome is Cushing’s disease!
Prolactinomas in pregnancy
Treat until they fall pregnant, then can stop treatment
BUT macroadenoma - swap over to bromocriptine if continuing. Visual field testing in each trimester.
Treatment hypopituitarism
Replace glucocorticoid first –> then thyroxine (T4) –> then gonadal hormone (testosterone/E2) –> then GH (IGF-1)
If not in this order, can precipitate Addisonian crisis
Which immunotherapies cause hypophysitis?
Anti-CTLA4 Ipilimumab
Anti-PD1 Nivolumab
Combine both = much higher incidence
