• The pituitary gland (hypophysis) sits in the sella turcica ("Turkish saddle") of the sphenoid bone
• Weight: ~0.5 g; Size: ~13 × 9 × 6 mm ^[1]
• Relations — these are critical for understanding the clinical features of pituitary lesions:
  • Superiorly: optic chiasm (separated by the diaphragma sellae) — why suprasellar extension causes bitemporal hemianopia
  • Laterally: cavernous sinuses containing cranial nerves III, IV, V₁, V₂, and VI, plus the internal carotid artery — why lateral extension causes ophthalmoplegia and diplopia
  • Inferiorly: sphenoid sinus — the surgical route for transsphenoidal surgery
  • Superiorly/posteriorly: hypothalamus — connected via the pituitary stalk (infundibulum)

The anterior pituitary develops from Rathke's pouch (an ectodermal outgrowth from the oral cavity — hence "adeno" = glandular). It produces six major hormones, each from distinct cell types:

The posterior pituitary develops from a downward extension of the hypothalamus (neural ectoderm — hence "neuro"). It does not synthesize hormones; rather, it stores and releases hormones made by hypothalamic nuclei:

Central diabetes insipidus results from deficiency of AVP. It is more common with hypothalamic/stalk lesions (craniopharyngioma, surgery, histiocytosis) than with pituitary adenomas alone, because AVP is synthesized in the hypothalamus and travels down the stalk — a pituitary adenoma growing from below typically does not destroy the stalk until very late ^[1][2].

This is the most elegant vascular arrangement in the body and understanding it is key:

1. Superior hypophyseal arteries (from the internal carotid) form a primary capillary plexus in the median eminence of the hypothalamus
2. Hypothalamic releasing/inhibiting hormones are secreted into this plexus
3. Blood then flows downward through long portal veins along the pituitary stalk
4. This reaches a secondary capillary plexus in the anterior pituitary, delivering hypothalamic hormones at high concentration directly to anterior pituitary cells
5. The posterior pituitary has its own direct arterial supply from inferior hypophyseal arteries

Clinical relevance: The anterior pituitary relies on portal blood via the stalk. Any lesion compressing or transecting the stalk (tumour, surgery, trauma) disrupts this system → loss of hypothalamic releasing hormones → hypopituitarism. Additionally, the anterior pituitary has a tenuous blood supply, making it vulnerable to ischaemia during hypotension (e.g., post-partum haemorrhage → Sheehan's syndrome).

During pregnancy, the pituitary gland enlarges by up to 120–136% of normal size due to lactotroph hyperplasia driven by oestrogen ^[1]. This makes it more susceptible to ischaemia if there is haemodynamic compromise → basis of Sheehan's syndrome.

The pituitary is remarkably resilient — > 75% of pituitary tissue must be destroyed before clinical hypopituitarism becomes manifest ^[1]. This is why:

• Microadenomas (< 1 cm) rarely cause hypopituitarism
• Macroadenomas (≥ 1 cm), especially with significant suprasellar extension, do

When the pituitary is gradually compressed or destroyed (e.g., by a growing adenoma or radiation), hormones are lost in a characteristic sequence:

GH → LH/FSH → ACTH → TSH (mnemonic: "Go Look For ACTH and TSH" or simply "G > F > A > T") ^[1][2]

In practice, patients with hypopituitarism rarely present with isolated axis loss. They present with combinations:

• The middle-aged woman with fatigue, weight gain, amenorrhoea, cold intolerance, constipation, and dry skin — she has lost TSH, LH/FSH, and probably GH
• The middle-aged man with decreased libido, impotence, loss of body hair, fatigue, and a "smooth" youthful-looking face with fine wrinkles — he has lost LH/FSH and GH
• The young mother who cannot breastfeed, never resumed her periods after delivery, is profoundly tired, and looks pale — Sheehan's syndrome
• The NPC survivor presenting 10 years later with short stature (if treated as child), fatigue, and amenorrhoea — post-radiation hypopituitarism

Cortisol normally inhibits ADH secretion. In ACTH/cortisol deficiency:

• ADH is "disinhibited" → excessive water retention → dilutional hyponatraemia
• This can mask central DI — when you start cortisol replacement, the DI may become apparent (unmasked DI)

• GH inhibits 11β-HSD1 (the enzyme that converts inactive cortisone → active cortisol in tissues)
• Starting GH replacement in a patient with subclinical ACTH deficiency can unmask cortisol deficiency → adrenal crisis
• Always assess the ACTH axis before starting GH replacement

Several conditions can produce clinical features that look like hypopituitarism but have a different mechanism:

When a woman presents with amenorrhoea, the differential is wide and hypopituitarism is only one cause:

This distinction is one of the most commonly tested differentials in endocrinology ^[12][14]:

When a patient with a sellar lesion presents with polyuria and polydipsia, differentiate:

Copeptin is a surrogate marker for AVP — AVP has a very short half-life, so copeptin (co-secreted from the same precursor in equimolar amounts, but with a much longer half-life) is used instead. It can differentiate central DI (low copeptin) from nephrogenic DI (high copeptin) without the need for water deprivation testing ^[16].

The SST is also not reliable ≤ 2 weeks of pituitary surgery ^[12].

Key point for post-menopausal women: In a post-menopausal woman, LH/FSH should be HIGH (because ovaries have failed → loss of negative feedback → gonadotropin rise). If LH/FSH are low or "normal" in a post-menopausal woman, this is inappropriately low and suggests pituitary failure ^[18].

The "stressed prolactin" between 3–10× the upper limit of normal is a grey zone — could be a small prolactinoma OR stalk compression. True prolactinomas are usually > 10× ULN ^[9].

• CBC: anaemia (cortisol deficiency → normocytic anaemia; hypothyroidism → macrocytic anaemia)
• LRFT: hyponatraemia (cortisol deficiency → ↑ADH → dilutional hyponatraemia; hypothyroidism → impaired free water excretion); hypoglycaemia (cortisol and GH deficiency)
• Calcium, phosphate: assess parathyroid function if post-surgical
• Lipid profile: GH deficiency → ↑TC, ↑LDL-C, ↓HDL-C ^[2]
• HbA1c: secondary DM (acromegaly, Cushing's); hypoglycaemia tendency in hypopituitarism

The key principle: in endocrine disorders, biochemistry comes before imaging ^[17].

The "pituitary bright spot": On T1-weighted MRI, the posterior pituitary normally appears as a hyperintense (bright) signal due to the high concentration of stored vasopressin-neurophysin granules. Absence of the bright spot suggests posterior pituitary dysfunction or central DI ^[18].

This patient has panhypopituitarism (all axes affected) with stalk effect hyperprolactinaemia — classic picture of a large non-functioning macroadenoma.

Pattern: GH lost first, then gonadotropins, then ACTH beginning to fail, TSH still intact — consistent with the G > F > A > T order and typical of radiation-induced progressive hypopituitarism ^[4].

"Synacthen" = tetracosactrin = synthetic ACTH (first 24 amino acids of ACTH) ^[12]

Caveats ^[12]:

• Does not test the whole HPA axis (only tests the adrenal's ability to respond; does not assess hypothalamus or pituitary directly)
• Not reliable ≤ 2 weeks of pituitary surgery
• Cut-off values may vary slightly with assay used
• Cut-off values NOT applicable to women on OC or pregnant (oestrogen increases cortisol-binding globulin → total cortisol may appear falsely elevated)
• Highly dependent on accurate dosage preparation and proper administration
• Reports of allergic reaction (rare), especially in children with history of allergic disorders ^[12]

Clinical implication: A patient who has had pituitary RT needs lifelong monitoring for progressive hormone loss, even if all axes were intact at the time of treatment. GH deficiency may emerge years later, followed by gonadotropin, then ACTH, then TSH deficiency ^[4].

Side effects of dopamine agonists ^[13][19]:

• Nausea, vomiting
• Orthostatic hypotension (DA vasodilatory effect)
• Constipation
• Nasal congestion
• Psychosis (rare)
• Retroperitoneal fibrosis, cardiac valve fibrosis (tricuspid regurgitation) — particularly with higher doses of cabergoline; requires echocardiographic monitoring

Important: Domperidone (a peripheral D₂ antagonist antiemetic) causes hyperprolactinaemia because the pituitary has no blood-brain barrier. However, domperidone does NOT cause extrapyramidal side effects because it does NOT cross the BBB (unlike metoclopramide) ^[13].

Pituitary apoplexy is a neurosurgical emergency ^[5]:

Why must ACTH axis be assessed before starting GH? GH inhibits 11β-HSD1, the enzyme that converts inactive cortisone to active cortisol in peripheral tissues. Starting GH in a patient with subclinical ACTH deficiency reduces tissue cortisol further → can precipitate adrenal crisis ^[2].

• Hydrocortisone: dose may need to increase (especially in 3rd trimester); stress dosing for labour/delivery
• Levothyroxine: dose typically increases by 25–50% during pregnancy; monitor FT4
• DDAVP: safe in pregnancy (does not cross placenta); DI may worsen or improve (placental vasopressinase can degrade native AVP but not DDAVP)
• GH: usually discontinued (placental GH takes over from mid-pregnancy)
• Sex hormones: discontinued once pregnancy is established

• High-dose IV glucocorticoids (methylprednisolone or dexamethasone) for acute presentation
• ACTH deficiency is usually permanent (does not recover even with steroid treatment)
• TSH and gonadotropin axes may partially recover
• Checkpoint inhibitor may be continued under endocrine cover if oncologically necessary — this is a joint decision between oncology and endocrinology

Why is adrenal crisis more dangerous than any other axis deficiency? Because cortisol deficiency can kill within hours. Thyroid hormone deficiency takes weeks to months to become life-threatening (myxoedema coma). Gonadotropin and GH deficiency are not immediately life-threatening. ADH deficiency is dangerous only if water access is restricted. Cortisol is the only pituitary-dependent hormone whose acute loss is rapidly fatal.

Already covered in detail in the Management section. Key points:

• Sudden haemorrhagic infarction of a pituitary adenoma ^[5]
• Excruciating headache, diplopia (CN III), visual loss, hypopituitarism (especially adrenal crisis), altered consciousness ^[5]
• Neurosurgical emergency — IV hydrocortisone immediately, then surgical decompression if neurologically compromised ^[5]

• Non-functioning pituitary adenomas: recurrence rate after transsphenoidal surgery can be 12–46% over 10 years, especially for macroadenomas with incomplete resection ^[9]
• Craniopharyngiomas: high recurrence rate even after apparently complete resection — hence the role of adjuvant radiotherapy
• Requires long-term MRI surveillance

Complications of transsphenoidal surgery ^{[5][9][13][19]}:

If not diagnosed early (which is common in resource-limited settings), Sheehan's syndrome can cause:

• Chronic fatigue and disability (unrecognised cortisol/thyroid deficiency)
• Premature ageing (GH deficiency)
• Persistent amenorrhoea and infertility (LH/FSH deficiency)
• Osteoporosis (oestrogen + GH deficiency)
• Recurrent hypoglycaemia (ACTH + GH deficiency)
• Empty sella on delayed imaging (post-infarction pituitary atrophy)

Iron overload from chronic transfusions (e.g., thalassaemia major) causes endocrine organ damage ^[21]:

Each unit of blood contains approximately 200 mg of iron, while only 1 mg/day is excreted ^[21]. Iron accumulates inexorably with chronic transfusions. Iron chelation therapy (desferrioxamine, deferasirox) is essential to prevent end-organ damage.

• ACTH deficiency is usually permanent — does not recover even after stopping the checkpoint inhibitor and treating with steroids
• TSH and gonadotropin axes may partially or fully recover — so periodic re-testing is warranted
• The checkpoint inhibitor may need to be continued for oncological reasons — hypopituitarism is managed with replacement therapy concurrently
• Long-term cardiovascular and metabolic monitoring is needed (as with any cause of hypopituitarism)