• The pituitary gland (hypophysis) weighs ~0.5–0.6 g (slightly larger in women, especially during pregnancy/lactation)
• It sits within the sella turcica ("Turkish saddle") of the sphenoid bone
• Connected to the hypothalamus superiorly by the pituitary stalk (infundibulum)
• Covered superiorly by a fold of dura mater called the diaphragma sellae, through which the stalk passes

This is the anatomical basis for virtually all "local symptoms" of pituitary tumours:

GC lecture point: The classical headache for pituitary tumours is non-specific, dull-aching — not related to acutely increased ICP since pituitary tumours are very slow growing ^[1][6]

This is a portal venous system (two capillary beds connected in series) that delivers hypothalamic releasing and inhibiting hormones directly to the anterior pituitary:

• Releasing hormones: GHRH, GnRH, TRH, CRH
• Inhibiting hormones: Dopamine (inhibits prolactin — this is crucial), Somatostatin (inhibits GH and TSH)

The key concept: Prolactin is the only anterior pituitary hormone under tonic INHIBITION (by dopamine). Therefore, anything that disrupts the stalk (and thus dopamine delivery) will cause HYPERPROLACTINAEMIA — the "stalk effect" ^[1][2]

Not every sellar mass is a pituitary adenoma. The differential includes ^[2][3][4]:

GC lecture point: Types of pituitary tumours — (1) Pituitary adenomas → adults, (2) Craniopharyngiomas → children, (3) Pituitary carcinoma → very rare, primary or secondary. Alternative name for pituitary adenomas is pituitary neuroendocrine tumours (PitNET). Generally pituitary adenomas are slow growing, but there are some that are more aggressive and grow fast → based on genetic profile ^[1][6]

Pituitary adenomas are monoclonal neoplasms arising from a single mutated cell in the anterior pituitary. The pathogenesis involves:

1. Initiating mutations — cell-autonomous genetic alterations that drive clonal expansion:

   • GNAS1 activating mutations (in ~40% of somatotroph adenomas) — constitutively activates Gsα → ↑cAMP → ↑GH secretion and cell proliferation
   • USP8 mutations in corticotroph adenomas (~40%) → ↑EGFR signalling → ↑ACTH
   • Most prolactinomas and non-functioning adenomas: specific driver mutations often not identified (epigenetic changes may be important)

2. Tumour suppressor loss — e.g. MEN1 gene (menin), CDKN1B (p27), AIP

3. Hypothalamic dysregulation — rarely the primary cause (unlike what was historically believed), but excessive GHRH or CRH stimulation can cause hyperplasia (not true adenoma)

This is the modern classification, based on the transcription factor that drives differentiation of the cell lineage, rather than just the hormone secreted:

GC lecture & senior notes: Prolactinoma (25%) > Non-functioning (~50%) > GH-producing (12%) > ACTH-producing (5–10%) > Glycoprotein-secreting (1%) ^[2][4]

Used to describe the extent of sellar and parasellar invasion, relevant for surgical planning:

With suprasellar extension graded A–E (A = suprasellar cistern; B = 3rd ventricle recess; C = 3rd ventricle; D = intracranial but extradural; E = cavernous sinus).

The Knosp classification is used specifically for cavernous sinus invasion (Grades 0–4, based on relationship to the intracavernous ICA segments on coronal MRI).

The pituitary gland sits in a confined bony space (sella turcica). As a tumour grows:

Each functional adenoma type produces a distinct clinical syndrome due to excess of its specific hormone. The pathophysiology of each syndrome is discussed briefly here (detailed clinical features below):

Prolactinoma (↑Prolactin):

• Prolactin normally inhibits GnRH pulsatility at the hypothalamic level → ↓LH/FSH → hypogonadotropic hypogonadism
• Prolactin also stimulates breast epithelium → galactorrhoea

Somatotroph adenoma (↑GH → ↑IGF-1):

• GH acts on the liver to produce IGF-1
• IGF-1 stimulates growth of bone, cartilage, soft tissues, and viscera
• In adults (closed epiphyses) → acromegaly (acral and soft tissue overgrowth)
• In children (open epiphyses) → gigantism (linear growth excess)
• GH is also diabetogenic (↑insulin resistance) → glucose intolerance/DM

Corticotroph adenoma (↑ACTH → ↑Cortisol):

• Excess ACTH drives bilateral adrenal hyperplasia → hypercortisolism = Cushing's disease
• (Cushing's disease specifically = ACTH-secreting pituitary adenoma; Cushing's syndrome = any cause of hypercortisolism)

Thyrotroph adenoma (↑TSH):

• Excess TSH → thyroid hyperstimulation → secondary hyperthyroidism
• Key distinguishing feature: TSH is inappropriately normal or elevated in the presence of high fT4/fT3 (unlike Graves' where TSH is suppressed)

Mechanism of hypopituitarism in pituitary tumours:

1. Direct compression of normal pituitary cells by expanding adenoma
2. Stalk compression/disruption → loss of hypothalamic releasing hormones reaching the anterior pituitary
3. Vascular compromise — compression of portal vessels in the stalk

The sequential loss of pituitary hormones follows a classic order (mnemonic: "GHS PTA = Good Hope School Parent-Teacher Association"): ^[7]

1. GH (most sensitive to compression — earliest to be lost)
2. Sex hormones (LH/FSH)
3. Prolactin (note: paradoxically, prolactin may be elevated early on due to stalk effect; it falls only with extensive anterior pituitary destruction)
4. TSH
5. ACTH (most resistant — last to be lost; its loss is the most dangerous → adrenal crisis)

Pituitary apoplexy = sudden haemorrhage and/or infarction within a pituitary adenoma ^[2][3][4]

• Pituitary adenomas outgrow their blood supply → relative ischaemia → necrosis → haemorrhage
• Precipitants: anticoagulation, major surgery (especially cardiac), dynamic pituitary testing, pregnancy
• The sudden expansion within the confined sella causes:
  • Excruciating headache (stretching of dura/diaphragma sellae)
  • Diplopia (pressure on CN III in the cavernous sinus — most commonly affected nerve)
  • Acute hypopituitarism — most dangerously ACTH deficiency → adrenal crisis (hypotension, hyponatraemia, hypoglycaemia, cardiovascular collapse)
  • Visual field defects (rapid chiasmal compression)
  • Altered consciousness (hypothalamic compression or raised ICP)

Any lesion compressing the optic chiasm from any direction can cause this:

Felix PY Lai notes: If originating superior to the optic chiasm such as in craniopharyngioma, the visual field defect will first appear as bitemporal inferior quadrantanopia. If originating inferior to the optic chiasm such as in pituitary adenoma, the visual field defect will first appear as bitemporal superior quadrantanopia ^[8]

This is an elegant anatomical point: the direction of compression determines which fibres are hit first. Fibres from the inferior nasal retina (carrying the superior temporal visual field) cross inferiorly in the chiasm — so compression from below (pituitary adenoma pushing up) hits these first → superior temporal field loss first. The converse applies for compression from above.

This is a critical exam topic because elevated prolactin does NOT always mean prolactinoma:

GC lecture case: F/40 with oligomenorrhoea, PRL 1923 mU/L (< 500), 2.1 cm pituitary tumour. Bromocriptine reduced PRL to 145 mU/L but no tumour shrinkage → Diagnosis: hyperprolactinaemia due to stalk compression by non-functioning pituitary macroadenoma ^[1]

The first question when approaching Cushing's syndrome is always: "Is it ACTH-dependent or ACTH-independent?" ^[9][10]

Organised by site of pathology ^[7][11]:

This combination should trigger consideration of:

GC lecture slide: MRI (magnetic resonance imaging): imaging modality of choice ^[1]

Senior notes: Anatomical diagnosis — Skull X-ray (double flooring), MRI pituitary (T1-weighted), visual field testing (perimetry) ^[10]

Diagnostic triad ^[2][4][6]:

1. Serum prolactin markedly elevated (> 10× ULN; for macroprolactinoma typically > 200 ng/mL; PRL level correlates with tumour size)
2. Pituitary adenoma on MRI
3. Tumour shrinkage > 50% with dopamine agonist therapy (confirmatory; seen in ~90%) ^[6]

Endocrine Society 2014 / AACE 2011 ^[2][6][10]:

1. Elevated serum IGF-1 for age and sex (screening)
2. GH not suppressed on OGTT: nadir GH > 1 ng/mL (AES 2014) or > 0.4 ng/mL (AACE 2011) (confirmatory)
3. Pituitary adenoma on MRI (in most cases)

Requires ≥ 2 positive first-line screening tests ^[2][4][5]:

1. Confirm endogenous hypercortisolism (≥ 2 of: elevated 24h UFC, elevated late-night salivary cortisol, failure of cortisol suppression on 1 mg ONDST)
2. ACTH-dependent (plasma ACTH elevated or inappropriately normal)
3. Pituitary source confirmed (HDDST suppression, CRH exaggerated response, IPSS central-to-peripheral ratio > 2–3, pituitary adenoma on MRI)

1. Sellar mass on MRI consistent with adenoma
2. No biochemical evidence of hormonal hypersecretion (all hormones in normal range or deficient)
3. ±Elevated α-subunit or gonadotropin subunits (but not to a clinically significant degree)
4. Exclude stalk effect (mild PRL elevation < 100 ng/mL does not make it a prolactinoma)

Clinical diagnosis supported by imaging ^[2]:

1. Sudden excruciating headache + diplopia ± visual field defects ± altered consciousness
2. Evidence of acute haemorrhage/infarction on CT (hyperdense) or MRI (T1 bright in acute stage)
3. Biochemical evidence of acute hypopituitarism (especially cortisol deficiency)

GC lecture: For prolactinomas, medical treatment may be preferred ^[1]

Why dopamine agonists work: Recall that prolactin is the only anterior pituitary hormone under tonic dopaminergic inhibition. Dopamine acts on D2 receptors on lactotroph cells to (1) inhibit prolactin synthesis and secretion, and (2) inhibit cell proliferation → tumour shrinkage. Dopamine agonists mimic this natural mechanism.

Side effects of dopamine agonists:

• Nausea, vomiting (dopamine stimulates the chemoreceptor trigger zone — area postrema has no BBB)
• Orthostatic (postural) hypotension (dopamine inhibits sympathetic outflow) ^[7]
• Nasal congestion ^[7]
• Constipation
• Psychosis (rare — dopamine excess in mesolimbic pathway)
• Retroperitoneal fibrosis, cardiac valve fibrosis (especially tricuspid regurgitation) — more associated with high-dose cabergoline used in Parkinson's disease; at prolactinoma doses the risk is low but warrants periodic echocardiography if high cumulative dose ^[10]

Special considerations:

• Advise contraception as fertility may return once PRL normalises ^[10] — important counselling point
• Pregnancy: bromocriptine has longer safety track record in pregnancy than cabergoline. Generally, dopamine agonists are stopped once pregnancy is confirmed for microprolactinomas but may need to continue for macroprolactinomas (risk of tumour expansion during pregnancy due to oestrogen-driven lactotroph hyperplasia)

Indications for surgery in prolactinoma (2nd line) ^[7][10][17]:

• Remain symptomatic or high PRL despite adequate medical treatment
• Dopamine agonist fails to shrink the macroadenoma significantly
• Intolerance to dopamine agonists (intractable nausea, psychiatric side effects)
• Pituitary apoplexy
• Women with giant lactotroph adenoma > 3 cm who wish to become pregnant — even if responding to DA agonist, because discontinuation during pregnancy may lead to clinically significant tumour enlargement before delivery ^[7]
• CSF rhinorrhoea from tumour erosion through sellar floor

Medical therapy in acromegaly is used when:

• Not a surgical candidate (medical comorbidities, large unresectable tumours)
• Bridging therapy while awaiting RT effect (may take 5–10 years!) ^[10]
• Persistent disease after surgery ± RT

Surgery is 1st line for Cushing's disease. Medical therapy is used pre-operatively to reduce hypercortisolism, or as 2nd line if surgery fails/recurs ^{[9][10][14][17]}

Perioperative management of Cushing's ^[9][10][18]:

• Before surgery: reduce hypercortisolism (metyrapone/ketoconazole)
• Control and correct: blood pressure, diabetes, hypokalaemia
• Prophylaxis: steroid cover (normal HPA axis is usually suppressed by chronic hypercortisolism), antibiotics, DVT prophylaxis (high risk of infections and VTE due to immunosuppression)
• Post-operative: glucocorticoid ± mineralocorticoid replacement until HPA axis recovers (~1 year) → Synacthen test before stopping ^[10]

GC lecture: Transsphenoidal: route of choice. Approach: transnasal endoscopic or sub-labial ^[1]

Specific surgical indications by tumour type:

GC lecture: Advantage of surgery — rapid ↓ in secretion and tumour size ^[1]

GC lecture: Disadvantages of surgery — residual/recurrence especially if macroadenomas; hypopituitarism, diabetes insipidus. Acute complications: post-operative bleeding; CSF rhinorrhoea ^[1]

GC lecture: Transfrontal — for very large suprasellar extension, severe chiasmal compression ^[1]

This is a high-yield topic for exams ^[1][2][3][7]:

Senior notes (acromegaly): Surgery (debulking) for macroadenoma abutting or adjacent to optic chiasm followed by medical therapy can improve subsequent response to medical therapy ^[17]

This is a neurosurgical emergency ^[2][3]

GC 108 lecture slide: Pituitary apoplexy — An emergency!! Acute haemorrhagic infarction ± SAH. Headache, visual loss, coma. Acute cortisol insufficiency requiring replacement (which can predispose DI). Give cortisol before T4. Urgent surgery for decompression ^[19]

The tumour compresses normal pituitary tissue → progressive loss of anterior pituitary hormones in the classical sequential order.

GC 067 lecture slide: Usually no hypopituitarism if microadenoma ( < 1 cm) ^[1]

• Rare from pituitary adenomas themselves (arise from anterior pituitary, which doesn't produce ADH)
• More common in craniopharyngiomas, metastases, hypophysitis, or stalk lesions — due to disruption of ADH transport from hypothalamus to posterior pituitary
• Presents with polyuria, polydipsia, nocturia, hypernatraemia if fluid intake inadequate

Overall mortality 1.72× the general population, mainly due to cardiovascular risk ^[2]

Untreated Cushing's syndrome is often fatal due to cardiovascular and thromboembolic complications ^[2][14]

This is one of the most examined topics — the GC lecture explicitly lists these:

GC 108 lecture slide: Complications of transsphenoidal surgery — Mortality (very rare); Hypopituitarism (can cause shock from cortisol deficiency); Diabetes insipidus (polyuria, haemoconcentration); CSF leakage and meningitis; Visual loss (close monitoring post-op); ENT symptoms (epistaxis, anosmia, sinusitis); Vascular injury; Intracranial haemorrhage. Beta-2-transferrin positive confirms CSF. Pneumocephaly may be seen. ^[19]

GC 067 lecture slide: Disadvantages — residual/recurrence especially if macroadenomas; hypopituitarism, diabetes insipidus. Acute complications: post-operative bleeding; CSF rhinorrhoea ^[1]

GC 067 lecture slide: Complication of radiotherapy for head and neck tumours such as nasopharyngeal carcinoma (NPC) — may be hypothalamic in origin → ↑prolactin and diabetes insipidus often present ^[1]

Nelson's syndrome: 8–25% of adults, > 50% of children following bilateral adrenalectomy for Cushing's disease ^[2][14]