• Pituitary adenomas account for 10–15% of all primary intracranial neoplasms ^[1][3][4]
• Found in 12–22% of autopsy series — meaning many are clinically silent "incidentalomas" ^[2][3]
• 20–25% at autopsy per neurosurgical lecture data ^[4]
• Up to 10% of normal middle-aged individuals have pituitary abnormalities on MRI — hence MRI pituitary should NOT be performed without clinical indication ^[2]
• Most common cause of sellar mass from the 3rd decade onwards ^[5]
• Clinically significant pituitary adenomas have an estimated prevalence of ~80–100 per 100,000 population

• In children, pituitary adenomas are rare — craniopharyngiomas are the more common sellar mass ^[3]
• In adults, pituitary adenoma is the dominant sellar pathology ^[3][5]

Descending order of frequency ^[2][5]:

1. Prolactinoma (most common overall, ~40–45% of all functioning adenomas)
2. Non-functioning adenoma (25–35%)
3. Somatotroph (GH-secreting) adenoma (~12%)
4. Corticotroph (ACTH-secreting) adenoma (~5–10%)
5. Thyrotroph (TSH-secreting) adenoma (~1%, very rare)
6. Gonadotroph adenoma — technically the most common non-functioning macroadenoma (70–90% of "non-functioning" adenomas are gonadotroph in origin), but classified as non-functioning because they don't produce a clinical hormonal syndrome ^[5]

The pituitary gland sits in the sella turcica (Latin: "Turkish saddle" — because the bony depression in the sphenoid bone looks like a saddle). It is normally < 0.8 cm deep ^[2].

Key anatomical relations — these explain every symptom of pituitary adenomas:

^[2][3][5]

Connects the hypothalamus to the pituitary. Contains:

• Portal vessels carrying hypothalamic releasing/inhibiting hormones to the anterior lobe
• Nerve fibres from hypothalamus to the posterior lobe

Compression or transection of the stalk (by tumour, surgery, or trauma) leads to:

• Hypopituitarism (loss of stimulatory signals to anterior pituitary)
• Hyperprolactinaemia (loss of inhibitory dopamine → "stalk effect")
• Diabetes insipidus (loss of ADH transport to posterior pituitary)

A paired venous sinus lateral to the sella. Contains:

• Cranial nerve III (oculomotor) — most medial, hence most vulnerable to lateral tumour extension
• Cranial nerve IV (trochlear)
• Cranial nerve V1 (ophthalmic division of trigeminal)
• Cranial nerve V2 (maxillary division of trigeminal)
• Cranial nerve VI (abducens) — runs within the sinus itself, close to the ICA
• Internal carotid artery (ICA)

Invasion of the cavernous sinus by an aggressive/invasive adenoma can produce CN palsies and is a critical consideration for surgical planning (cavernous sinus invasion = incomplete surgical resection likely) ^[2][5].

• No clearly established modifiable risk factors for sporadic pituitary adenomas
• High-dose ionising radiation is the only proven environmental risk factor for brain tumours including meningiomas and gliomas; its role in pituitary adenomas is less clear but prior cranial irradiation may increase risk ^[7]
• Familial syndromes as above (MEN1, Carney complex, FIPA, McCune-Albright)
• Longstanding end-organ failure can cause pituitary hyperplasia (which may be mistaken for adenoma):
  • Longstanding primary hypothyroidism → thyrotroph hyperplasia (due to loss of T4 negative feedback → chronic TSH stimulation → hyperplasia)
  • Longstanding primary hypogonadism → gonadotroph hyperplasia
  • Pregnancy → lactotroph hyperplasia (physiological)
  • Ectopic GHRH secretion → somatotroph hyperplasia ^[5]

These hyperplastic conditions are not true adenomas but can mimic them on imaging and must be distinguished clinically.

• The distribution of pituitary adenoma types in Hong Kong follows international patterns
• Prolactinoma remains the most common functioning adenoma
• Non-functioning adenomas are frequently encountered in neurosurgical and endocrine clinics
• MEN1 screening is performed in families with identified mutations; genetic counselling services are available at major centres (Queen Mary Hospital, Prince of Wales Hospital)
• Incidental pituitary lesions are increasingly detected due to widespread MRI use in Hong Kong's public and private healthcare systems
• Traditional Chinese medicine and herbal remedies should be considered as potential causes of iatrogenic Cushing's syndrome (steroids hidden in herbal preparations) — this is particularly relevant in the Hong Kong context when evaluating ACTH-dependent vs independent causes ^[2]

^[4][5]

^[2][3][5]

The 2017/2022 WHO classification shifted from purely functional to transcription factor–based classification, recognising that each pituitary cell lineage is driven by specific transcription factors:

• Enclosed adenomas: confined within the sella
• Invasive adenomas: extend into cavernous sinus (Knosp grade), sphenoid sinus, or suprasellar region
• Knosp classification (grades 0–4): based on relationship to the intracavernous ICA on coronal MRI
  • Grade 0–2: medial to ICA tangent lines → potentially resectable
  • Grade 3–4: lateral to or encasing ICA → cavernous sinus invasion → unlikely complete surgical resection

Certain subtypes are recognised as "aggressive" or "high-risk" and are more likely to recur or resist treatment:

• Sparsely granulated somatotroph adenoma (responds poorly to somatostatin analogues)
• Silent corticotroph adenoma (often invasive)
• Crooke's cell adenoma (aggressive corticotroph variant)
• Male prolactinoma (often larger and more invasive than in women)
• Plurihormonal PIT-1 positive adenoma (previously "silent subtype 3")

When a growing adenoma compresses the surrounding normal pituitary tissue, hormone deficiencies develop in a predictable sequential order:

Classical order of hormone loss ^[2][3]:

GH → FSH/LH → ACTH → TSH (→ Prolactin last, if ever)

Mnemonic: "Go Look For ACTH and TSH" — or simply remember that GH is the most sensitive and TSH the most resistant.

Why this order?

• GH-secreting cells (somatotrophs) are the most numerous (~50% of anterior pituitary cells) and are located laterally — vulnerable to compression
• Gonadotrophs are scattered throughout — vulnerable to even moderate compression
• Corticotrophs and thyrotrophs are more centrally located and fewer in number, but their pathways are more robust
• Prolactin is under tonic inhibition, so compression of the stalk actually increases PRL (stalk effect) rather than decreasing it — PRL deficiency is exceedingly rare and essentially only occurs after complete destruction of the gland

Pituitary apoplexy is a neurosurgical emergency ^[2][3][4]:

Definition: Sudden haemorrhagic infarction of a pituitary adenoma (or rarely, of the normal gland).

Pathophysiology:

• Pituitary adenomas can outgrow their blood supply → ischaemic necrosis ± secondary haemorrhage
• The sudden swelling within the confined bony sella turcica → rapid compression of adjacent structures

Presentation (sudden or subacute over 1–2 days) ^[3]:

• Excruciating headache (stretching/rupture of sella)
• Diplopia (pressure on CN III — the most medial nerve in the cavernous sinus)
• Hypopituitarism, especially adrenal crisis (acute cortisol deficiency = life-threatening)
• ± Visual field defects (acute chiasmal compression)
• ± Altered consciousness, vertigo ^[3]
• May mimic subarachnoid haemorrhage (blood can leak into CSF)

Imaging: hyperdensity (acute blood) in pituitary on CT; MRI shows haemorrhage ^[3][4]

Management: steroid cover (hydrocortisone) + urgent surgical decompression if ^[2][3]:

• Signs of raised ICP
• Change in conscious state
• Evidence of compression on neighbouring structures

^[5][2][3]

^[2][3][4][5]

^[2][3][4][5]

This is the most important functional DDx because mild hyperprolactinaemia has a vast differential, and mistaking a non-functioning macroadenoma with stalk effect for a prolactinoma (and treating with dopamine agonist alone) would be a critical error.

The key differentiator: if the pituitary is diffusely enlarged (hyperplasia) rather than showing a focal adenoma, suspect ectopic GHRH secretion. Measure serum GHRH levels ^[2].

This is a well-structured DDx covered in detail in Cushing's syndrome notes, but here is the pituitary-relevant summary:

^[2][9]

When you find elevated fT4 with non-suppressed TSH (i.e., TSH is normal or elevated when it should be suppressed):

The critical distinction here is between a TSH-secreting adenoma and thyroid hormone resistance — both show ↑fT4 with non-suppressed TSH. α-subunit : TSH molar ratio > 1 favours TSHoma; a TRH stimulation test (blunted TSH response in TSHoma, normal in resistance) can help.

If a patient has a large sellar mass with hypopituitarism but no hormonal hypersecretion, the DDx includes:

Bitemporal hemianopia points to the optic chiasm, but not all chiasmal lesions are pituitary adenomas:

^[3][4][8]

When a patient presents with diplopia from CN III involvement near the sella:

^[2][3][4][8]

Pituitary apoplexy presents with sudden headache ± meningism ± visual loss. The DDx of sudden severe headache includes ^[3][10]:

Note: pituitary apoplexy can mimic SAH because blood from the haemorrhagic adenoma can leak into the subarachnoid space → meningism. Always check the sella on imaging in "SAH-negative" thunderclap headache presentations.

The approach to hormonal assessment depends on the mode of secretion ^[2]:

^[2]

MRI pituitary is the single best imaging procedure for most sellar masses ^[5][2][3].

Protocol: Dedicated pituitary MRI with thin coronal and sagittal cuts (3 mm or less) through the sella, pre- and post-gadolinium contrast.

Key MRI findings in pituitary adenoma:

If a sellar lesion can be seen as separate from the normal pituitary gland, this indicates the mass is NOT a pituitary adenoma ^[5] — consider craniopharyngioma, meningioma, Rathke's cleft cyst, etc.

CT is better than MRI for detecting calcification ^[2][3][5]:

Seldom done nowadays due to low sensitivity and specificity ^[10], but classic findings include:

• Double-floor sign of the sella turcica — asymmetrical enlargement of the sella by a pituitary adenoma causes the floor to appear duplicated on lateral skull XR ^[2][3]
• Erosion of posterior clinoid processes — sign of raised ICP ^[10]
• Calcification above the sella → craniopharyngioma ^[10]

Classical order of hormone loss in hypopituitarism: GH → FSH/LH → ACTH → TSH ^[2][3]

Observation is indicated for non-functional pituitary adenomas < 1 cm without mass effect or hormonal abnormality ^[5][2][3]

Why can we observe?

• Many microadenomas are discovered incidentally and remain stable for years or even decades
• The natural history of non-functioning microadenomas is generally benign — only ~10% enlarge over 5 years
• Unnecessary surgery carries risks (hypopituitarism, DI, CSF leak) that outweigh the benefit for a stable, asymptomatic lesion

Follow-up every 3–6 months ^[5] initially, then less frequently if stable:

Why does medical therapy work for prolactinoma but not for other adenomas?

This is elegant pharmacology rooted in physiology. Recall that prolactin is the only anterior pituitary hormone under tonic inhibition by dopamine from the hypothalamus. Lactotroph cells express abundant dopamine D2 receptors. When you give a dopamine agonist, it:

1. Binds D2 receptors on tumour cells → directly inhibits prolactin synthesis and secretion → PRL falls within days
2. Induces tumour cell shrinkage → cytoplasmic involution + perivascular fibrosis → tumour volume decreases over weeks to months (often dramatically — a 3 cm prolactinoma can shrink to nothing)

No other pituitary adenoma subtype has such a clean pharmacological target, which is why dopamine agonists are only first-line for prolactinoma.

^[2][4][5]

Dopamine agonists are 1st line treatment for patients with hyperprolactinaemia of any cause, including lactotroph adenoma of any size ^[5]

Management milestones for prolactinoma on DA therapy ^[2]:

Medical therapy for acromegaly is used when surgery is not curative (residual tumour), when surgery is contraindicated, or while awaiting the effect of radiotherapy ^[2]:

^[2][3]

Why is surgery first-line for acromegaly, not SSAs? Because SSAs only normalise IGF-1 in ~60% and rarely cure the disease. Transsphenoidal surgery has an 80–90% cure rate for microadenomas and can debulk large macroadenomas to improve subsequent medical efficacy ^[3]. The surgical "first strike" maximises the chance of biochemical remission.

Medical therapy here is not curative — it is used to:

• Control hypercortisolism pre-operatively (to reduce surgical risk) ^[2]
• Manage patients contraindicated for surgery or with persistent disease after surgery
• Bridge until radiotherapy takes effect (6–12 months delay)

Two strategies for medical cortisol control ^[2]:

• Block-and-replace: Total suppression of cortisol with inhibitors + add back physiological hydrocortisone replacement. Used when cortisol production is highly variable
• Normalisation: Titrate inhibitor dose to normalise UFC without replacement. Used when cortisol production is relatively stable

• Somatostatin analogues (octreotide, lanreotide): used as adjunctive therapy post-surgery or pre-operatively; can normalise TSH and fT4 in ~80% and shrink tumour in ~40%

^{[2][3][4][5][10]}

^[2][5][10]

Why is endoscopic transsphenoidal surgery now preferred over microscopic?

• The endoscope provides a wide-angle, panoramic view of the surgical field
• Allows better visualisation of the lateral recesses (cavernous sinus margins), suprasellar extension, and diaphragma sellae descent
• Enables more complete tumour removal with lower rates of residual disease in experienced hands
• Both approaches have similar complication rates; the choice often depends on surgeon preference and expertise

Advantages of surgery ^[2]:

• Rapid reduction in hormone secretion and tumour size → biochemical remission achievable in days to weeks
• Remission > 85% for microadenomas; 40–50% for macroadenomas

Disadvantages of surgery ^[2]:

• Residual disease or recurrence, especially with macroadenomas (2–8% recurrence rate)
• Hypopituitarism — risk of new hormone deficiencies
• Diabetes insipidus — from surgical injury to the stalk or posterior pituitary (may be transient or permanent)

This is explicitly listed as essential knowledge in the lecture slides ^[4]:

^[5][10]

or radiosurgery ^[4] — the lecture slides specifically mention radiosurgery as an alternative for residual/recurrent disease.

• Adjunct to surgery for residual tumour (most common use)
• Primary therapy for patients who are not surgical candidates (elderly, comorbid)
• Macroprolactinoma refractory to dopamine agonist and surgery
• Recurrent adenoma after prior surgery
• Cushing's disease: pituitary irradiation + medical therapy if residual non-resectable disease ^[2]

Stereotactic radiosurgery is NOT used if the tumour is < 5 mm from the optic chiasm ^[2] — the optic apparatus has limited radiation tolerance (~8–10 Gy single dose), and a single high-dose radiosurgery fraction would risk optic neuropathy and blindness.

• Delayed effect on secretion — not useful for acute symptom control; maximum effect 6–12 months for hormone normalisation
• Higher incidence of hypopituitarism — progressive loss of pituitary function over years (GH first, then other axes); patients need lifelong endocrine follow-up
• Risk of damage to surrounding structures — optic nerve, temporal lobes (cognitive decline), cranial nerves
• Secondary malignancy — very rare but reported (meningioma, glioma in the irradiated field, years later)
• Cerebrovascular disease — increased stroke risk years after cranial RT

^[2][4][5]

Transsphenoidal surgery is 1st line: 80–90% curative for micro-, < 50% for macroadenoma. Can repeat surgery if MRI detects residual tumour ^[3]

Risk of Nelson syndrome (8–25% in adults, > 50% in children) following bilateral adrenalectomy ^[2]: the removal of cortisol negative feedback causes the residual corticotroph adenoma to grow aggressively and secrete very high ACTH → skin hyperpigmentation + expanding sellar mass. This is why bilateral adrenalectomy is a last resort and patients need long-term MRI surveillance.

^[2][11]

Pituitary apoplexy is a neurosurgical emergency ^[2][4][10].

• Definition: Acute haemorrhagic infarction of a pituitary adenoma — a catastrophic event where the adenoma suddenly outgrows its blood supply, undergoes ischaemic necrosis, and haemorrhages. The confined bony sella cannot accommodate the sudden volume expansion → acute compression of surrounding structures.
• Why it happens: Pituitary adenomas are more vascular than normal pituitary tissue yet have fragile, disorganised neovasculature. Precipitants include anticoagulation, post-surgical hypotension, dynamic endocrine testing, pregnancy, and sometimes no identifiable trigger.

Clinical presentation ^[2][4][10]:

• Acute haemorrhagic infarction ± SAH ^[4]
• Headache, visual loss, coma ^[4]
• Acute cortisol insufficiency requiring replacement ^[4]
• Diplopia (CN III compression in cavernous sinus)
• Meningism if blood leaks into subarachnoid space

Key management principles from the lecture slides ^[4]:

• Give cortisol before T4 — this is emphasised on the lecture slide because levothyroxine increases cortisol metabolism; giving T4 without cortisol cover in an acutely hypopituitary patient precipitates adrenal crisis ^[4]
• "Which can predispose DI" ^[4] — acute cortisol insufficiency in apoplexy can unmask or predispose to diabetes insipidus because cortisol normally suppresses ADH release; when you give cortisol replacement, the ADH suppression is restored and polyuria may become apparent
• Urgent surgery for decompression — if visual deterioration, altered consciousness, or signs of raised ICP ^[4][10]

Bitemporal hemianopia is the classic visual complication ^[4]:

• Pathophysiology: Suprasellar extension of a macroadenoma compresses the optic chiasm from below. The crossing nasal retinal fibres (subserving temporal visual fields) are most vulnerable because they sit in the inferior-central part of the chiasm, directly above the pituitary.
• Progression: Upper temporal quadrantanopia (early, inferior chiasmal fibres affected first) → complete bitemporal hemianopia → decreased visual acuity → optic atrophy (chronic compression → irreversible axonal degeneration)
• Why it matters: Visual field defects may be reversible if decompressed early (within weeks to months), but chronic compression leads to optic atrophy and permanent visual loss. This is why close visual monitoring post-op is essential ^[4].

As the adenoma grows, it compresses and destroys the surrounding normal pituitary tissue. The consequences depend on which hormonal axes are lost:

Classical order of hormone loss: GH → FSH/LH → ACTH → TSH ^[2][3]

Hypopituitarism can cause shock (cortisol) ^[4] — this is explicitly highlighted on the lecture slide. Acute cortisol deficiency (from tumour compression, apoplexy, or post-surgery) is the most dangerous endocrine complication because cortisol is essential for vascular tone, gluconeogenesis, and the stress response. Without cortisol replacement, patients can develop refractory hypotension and die.

Hydrocephalus (at III ventricle) ^[4]:

• Pathophysiology: Very large or giant adenomas ( > 4 cm) can extend superiorly to obstruct the foramen of Monro or compress the third ventricle → obstructive hydrocephalus → raised ICP
• Symptoms: Headache (worse in the morning, with coughing/straining), nausea/vomiting, drowsiness, papilloedema, eventual coning if untreated
• Management: Urgent neurosurgical decompression; CSF diversion (external ventricular drain or shunt) if rapid deterioration ^[11]

Cranial nerve palsy ^[4]:

• Mechanism: Lateral extension of the adenoma into the cavernous sinus compresses CN III (most commonly), CN IV, CN VI, CN V1, or CN V2
• CN III palsy is most common because it runs most medially along the cavernous sinus wall, closest to the expanding pituitary adenoma ^[8]
• Clinical features: Diplopia, ptosis, "down and out" eye (CN III); lateral gaze palsy (CN VI); facial numbness (CN V1/V2)
• Cavernous sinus invasion is a marker of an aggressive/invasive adenoma and often precludes complete surgical resection

This is explicitly listed as essential knowledge in the lecture slides: "Treatment principles for pituitary adenoma & complications of transsphenoidal surgery" ^[4]

The lecture slide lists these complications directly ^[4]:

^[4][5][10]

Radiotherapy (conventional EBRT or stereotactic radiosurgery) carries its own set of long-term complications:

Overall mortality 1.72× compared to the general population, mainly due to cardiovascular risk ^[2][3]

^[2][3]

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

Cushingoid features generally resolve 2–12 months after definitive treatment ^[2], but some complications (osteoporosis, cardiovascular remodelling, neurocognitive effects) may be irreversible.

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

• Pathophysiology: Bilateral adrenalectomy removes all cortisol production, completely eliminating negative feedback on the pituitary corticotroph adenoma. Without the cortisol "brake," the residual ACTH-secreting tumour grows aggressively and hypersecretes ACTH.
• Clinical features:
  • Plasma ACTH > 200 pg/mL ^[2]
  • Intense skin hyperpigmentation — very high ACTH (and its co-secreted precursor POMC-derived α-MSH) stimulates melanocytes
  • Enlarging pituitary tumour — can cause visual loss, headache, cavernous sinus invasion
• Diagnosis: Rising ACTH + hyperpigmentation + growing sellar mass on MRI ^[2]
• Treatment: Transsphenoidal surgery before the tumour becomes a macroadenoma ^[2]
• Prevention: Pituitary irradiation should be performed before bilateral adrenalectomy in Cushing's disease to minimise the risk of Nelson syndrome ^[2]

• All pituitary adenoma subtypes carry a risk of recurrence after treatment
• Rates vary by subtype and completeness of resection:
  • Non-functioning macroadenoma: ~15–25% recurrence at 10 years after gross total resection; higher if subtotal
  • GH-secreting macroadenoma: ~30–40% if not biochemically cured
  • ACTH-secreting: ~15–20% recurrence after initially successful surgery
  • Prolactinoma: ~30–40% relapse after DA withdrawal; recurrence after surgery ~15–20%
• Long-term MRI surveillance is essential (at 1y, 2y, 5y, 10y post-surgery) ^[2]

• Exceedingly rare (< 0.2% of pituitary tumours)
• Defined by: craniospinal or systemic metastasis (not by histological features of the primary tumour)
• Cannot be predicted reliably by histology alone, though high Ki-67 index ( > 3%), p53 positivity, and certain aggressive subtypes (Crooke's cell, sparsely granulated somatotroph) carry higher risk
• Management: surgery + RT + temozolomide (alkylating chemotherapy agent with some evidence in aggressive pituitary tumours)