Hypopituitarism

Meet the patient

A 42-year-old woman is admitted three months after a postpartum haemorrhage so severe she nearly bled to death. She never managed to breastfeed, her periods never returned, and now she faints on standing, feels cold to the bone, and her axillary and pubic hair have fallen out. Her sodium is low, her potassium is normal, and her morning cortisol is undetectable.^[8]

The single question on the ward round is the one that decides whether she walks out: which hormone do you replace first? Get that order wrong — give the thyroid tablet before the hydrocortisone — and you can precipitate an adrenal crisis in the side room. Hold that one rule and the whole of hypopituitarism falls into place.^[3]

Meet the gland — and the rule that saves lives

Hypopituitarism is the partial or complete deficiency of one or more anterior pituitary hormones — growth hormone (GH), prolactin (PRL), adrenocorticotrophic hormone (ACTH), thyroid-stimulating hormone (TSH), luteinising hormone (LH) and follicle-stimulating hormone (FSH). The complete loss of all anterior hormones is termed panhypopituitarism. The posterior pituitary — which releases antidiuretic hormone (ADH/vasopressin) and oxytocin — is usually spared in primary pituitary destruction (because these hormones are synthesised in hypothalamic nuclei and only stored posteriorly), but is lost with stalk or hypothalamic lesions, producing diabetes insipidus.^[1]

The anterior pituitary (adenohypophysis) and posterior pituitary (neurohypophysis) differ in embryology and physiology, and this distinction matters clinically. The anterior lobe arises from Rathke's pouch (oral ectoderm) and is driven by hypothalamic releasing hormones (GHRH, TRH, CRH, GnRH, dopamine) that reach it via the hypophyseal portal venous system. The posterior lobe is a neural downgrowth that stores hormones synthesised in the supraoptic and paraventricular nuclei of the hypothalamus. A mass or infiltrative lesion that destroys the anterior gland therefore tends to spare ADH, while a lesion of the stalk or hypothalamus (e.g. craniopharyngioma, metastasis) interrupts both portal input and the neural tract, producing panhypopituitarism plus diabetes insipidus.^[1][2]

The clinical face of hypopituitarism ranges from an insidious, years-long decline (vague fatigue, weight loss, amenorrhoea, loss of body hair) to a rapid, life-threatening presentation in pituitary apoplexy or adrenal crisis. The two clinical rules that save lives are absolute: always replace hydrocortisone before levothyroxine (levothyroxine alone increases metabolic clearance of cortisol and precipitates crisis in uncorrected ACTH deficiency), and recognise pituitary apoplexy as a neurosurgical emergency.^[1][3]

^[1]

Four ways to slice the causes

Hypopituitarism is classified along four axes that examiners test deliberately.^[1][2]

By number of axes involved: isolated (single-hormone deficiency, e.g. isolated GH deficiency, isolated ACTH deficiency), multiple (two or more axes), or panhypopituitarism (all anterior hormones). Isolated deficiencies are usually genetic (e.g. PROP1 lineage) or autoimmune; multiple and panhypopituitarism are typically mass or vascular. ^[1]

By anatomical site: primary (pituitary destruction — adenoma, Sheehan, apoplexy, infiltrate, surgery) versus secondary (hypothalamic or stalk disease — craniopharyngioma, metastasis, sarcoidosis — where the releasing-hormone drive is lost). Secondary causes are more likely to involve diabetes insipidus and a mild prolactin rise from loss of dopamine (the prolactin-inhibiting hormone) via the stalk effect. ^[1]

By onset: congenital (genetic: PROP1, POU1F1, HESX1 mutations; septo-optic dysplasia) versus acquired; and acute (pituitary apoplexy) versus chronic (slowly growing macroadenoma, radiotherapy). ^[1]

By aetiology — the classification examiners reward most: ^[1]

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How common, and who loses their gland

Hypopituitarism has a reported prevalence of roughly 300 to 455 per million (30 to 45 per 100,000) and an incidence of 12 to 42 new cases per million per year — figures that are probably underestimated once post-traumatic cases are counted. In an analysis of more than 1300 patients, men slightly outnumbered women (52.7 vs 47.3 percent), so there is no true female predominance. Pituitary neuroendocrine tumours (adenomas) account for approximately half of adult cases — the commonest single causes in one large series were non-functioning tumour (20.9 percent), Sheehan syndrome (13.8 percent) and lactotroph tumour (11.1 percent) — while in children the causes are predominantly congenital, with craniopharyngioma the leading tumour. Mortality is increased compared with the general population — cerebrovascular mortality was raised more than three-fold (SMR 3.39) and overall cardiovascular mortality nearly two-fold (SMR 1.75) in a large Swedish cohort — driven by cardiovascular and cerebrovascular disease (possibly GH deficiency or inadequate substitution of other axes) and preventable adrenal crises.^[13][2][15]

Risk factors cluster by mechanism and should be sought actively in the history: ^[1]

^[1]

Sheehan syndrome is now rare where obstetric care is available, but remains common in regions with home or difficult delivery, where severe postpartum haemorrhage and shock produce low-flow ischaemic necrosis of the enlarged pregnant pituitary — gland height rises by about 0.08 mm per week through pregnancy, no normal gland exceeds 10 mm, and the largest glands are seen in the immediate postpartum period, while the low-pressure portal vascular supply is vulnerable to hypoperfusion. Pituitary apoplexy affects roughly 0.6 to 10 percent of pituitary tumours (average 2 percent of surgically removed tumours), often as the first presentation of an undiagnosed tumour; precipitating factors are identified in 30 to 40 percent and include hypertension, diabetes, major surgery, antiplatelet/anticoagulant or fibrinolytic therapy, coagulation disorders, pregnancy and complicated delivery, shock, head trauma — and dopamine-agonist initiation (bromocriptine > cabergoline), which shrinks a prolactinoma and can precipitate apoplexy.^[23][8][12]

The order hormones fall — and why cortisol loss kills

The anterior pituitary is driven by hypothalamic releasing hormones (GHRH, TRH, CRH, GnRH) that reach it via the hypophyseal portal venous system, a low-pressure capillary network that is uniquely vulnerable to ischaemia. The trophic hormones — ACTH, TSH, LH/FSH, GH and prolactin — then act on downstream target glands (adrenal cortex, thyroid, gonads, liver/bone/tissues, breast). Anything that destroys the gland, compresses it, interrupts the stalk, or replaces normal tissue removes that drive, and the target glands then atrophy through lack of trophic stimulation.^[1]

Mass lesions cause hormone loss in a predictable order, reflecting the spatial distribution of cell types and the vulnerability of the portal supply: GH first, then LH/FSH, then TSH, then ACTH, then prolactin — "the usual sequential pattern for hormonal deficiencies starts from the loss of GH, followed by the gonadotropins, then TSH and ACTH". Prolactin is often preserved or even elevated in stalk compression, because loss of hypothalamic dopamine (the prolactin-inhibiting hormone) removes tonic inhibition — the stalk effect. This explains why a patient with a non-functioning macroadenoma may present with galactorrhoea and amenorrhoea despite a normal lactotroph population: the prolactin rise is mechanistic, not neoplastic. Hypophysitis is the classic exception to the order — in pituitary inflammation (including immune-checkpoint-inhibitor hypophysitis), ACTH and TSH deficiencies are frequently the presenting deficits, not GH.^[14][2]

Why ACTH deficiency is the lethal axis: cortisol loss impairs vascular tone (permissive effect on catecholamines), gluconeogenesis, and the stress response, producing adrenal crisis — hypotension, hypoglycaemia, hyponatraemia, abdominal pain, and shock. Crucially, aldosterone is spared because it is driven by the renin–angiotensin–aldosterone system (RAAS), not ACTH — so there is no hyperkalaemia and no salt-wasting (unlike primary Addison disease, where zona glomerulosa destruction removes aldosterone). This single physiological fact — aldosterone spared — is the discriminator that decides whether the patient needs fludrocortisone (no) and predicts the absence of hyperkalaemia.^[2]

The levothyroxine trap: giving levothyroxine before glucocorticoid in a hypopituitary patient increases the rate of cortisol metabolism — thyroid hormones increase the activity of the liver enzymes that metabolise cortisol, so the already-deficient cortisol falls further and adrenal crisis is precipitated. The rule is absolute: hydrocortisone first, always — adrenal insufficiency must be evaluated and treated before levothyroxine is started. The reverse (giving hydrocortisone before levothyroxine) is safe and correct.^[3][2]

Sheehan = the enlarged pregnant pituitary has a limited, low-pressure vascular supply; severe postpartum haemorrhage and shock produce low-flow ischaemic necrosis, with the infarcted gland eventually replaced by scar (a partially empty sella on later imaging). Pituitary apoplexy = sudden haemorrhage or infarction into a pre-existing adenoma, causing acute gland swelling that compresses the optic chiasm (visual loss) and cavernous sinus (cranial nerves III, IV, V1, V2, VI) and abruptly abolishes ACTH secretion (adrenal crisis).^[4]

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The face of each failing axis

Presentation reflects which axes are deficient plus any mass effect from the underlying lesion. The tempo is usually slow and insidious (months to years), except in pituitary apoplexy, which is abrupt and dramatic.^[1][2]

Hormone-specific features

ACTH deficiency (secondary adrenal insufficiency) is the most dangerous axis to lose. It produces fatigue, weakness, postural hypotension, hypoglycaemia (especially in children), hyponatraemia, weight loss, anorexia, nausea, vomiting, and abdominal pain. The two features that are absent — and that distinguish it from primary Addison disease — are hyperpigmentation (because ACTH/pro-opiomelanocortin is low, not high) and hyperkalaemia (because aldosterone, driven by RAAS, is intact). There is no salt-craving and no salt-wasting. ^[1]

TSH deficiency (secondary hypothyroidism) produces fatigue, cold intolerance, dry skin, bradycardia, constipation, weight gain, delayed reflex relaxation, and cognitive slowing. It is often milder than primary hypothyroidism because some residual thyroid function persists; importantly, TSH is unreliable for diagnosis and monitoring (it is low or inappropriately normal despite low free T4). ^[1]

LH/FSH deficiency (hypogonadotropic hypogonadism) produces loss of libido, amenorrhoea or oligomenorrhoea, erectile dysfunction, infertility, loss of axillary and pubic hair (loss of adrenal and gonadal androgens), gynaecomastia in men, and osteopenia/osteoporosis from chronic sex-steroid deficiency. In women, breast atrophy and vaginal dryness develop over time. ^[1]

GH deficiency in adults produces reduced muscle bulk and exercise capacity, central adiposity, reduced bone mineral density, social isolation, fatigue, impaired quality of life, and an adverse lipid profile (increased total and LDL cholesterol). In children, growth failure (decreased height velocity, delayed bone age) is the dominant feature — and may be the first sign of a pituitary mass. ^[1]

Prolactin deficiency is clinically silent except in the postpartum period, where it causes failure of lactation (agalactia) — the hallmark of Sheehan syndrome. ^[1]

ADH deficiency (diabetes insipidus) — only with stalk or hypothalamic disease — produces polyuria (dilute, low-osmolality urine), polydipsia, nocturia, and hypernatraemia if water intake is inadequate. ^[1]

Mass effect (macroadenoma over 1 cm)

A macroadenoma causes bitemporal hemianopia (compression of the optic chiasm — the decussating nasal retinal fibres), headache (stretching of the diaphragma sellae dura), cranial nerve palsies (cavernous sinus — III, IV, V1, V2, VI), and a stalk-effect rise in prolactin with galactorrhoea and amenorrhoea. Very large or invasive tumours can cause CSF rhinorrhoea (erosion through the sphenoid sinus floor) and hypothalamic dysfunction (disturbed temperature, appetite, sleep). ^[1]

Acute presentation — pituitary apoplexy

Pituitary apoplexy presents with sudden thunderclap headache (often mistaken for subarachnoid haemorrhage), nausea and vomiting, altered consciousness, rapid visual loss (chiasmal compression), ophthalmoplegia (most commonly a cranial nerve III palsy — ptosis, divergent strabismus, fixed dilated pupil), meningism (blood in the subarachnoid space), and features of acute adrenal crisis (hypotension, hypoglycaemia) from abrupt ACTH loss. This is an endocrine and neurosurgical emergency.^[4]

Atypical presentations

The elderly may present only with confusion, falls, cognitive decline or hyponatraemia mistaken for SIADH or dementia; the postoperative patient turns up hypotensive and hyponatraemic days to weeks after pituitary surgery; the postpartum woman simply cannot lactate, and her amenorrhoea is dismissed as lactational; the patient on immune-checkpoint inhibitors presents weeks to months into therapy with headache, fatigue and visual symptoms (immune-checkpoint-inhibitor hypophysitis).^[7]

The mimics — pale, not pigmented

A patient with fatigue, hypotension and hyponatraemia is not always hypopituitary. The key is to distinguish primary from secondary adrenal insufficiency, primary from secondary hypothyroidism, and true hypopituitarism from functional mimics.^[2]

Primary versus secondary hypothyroidism — primary disease has a high TSH with low free T4; secondary (pituitary) has a low or inappropriately normal TSH with low free T4. The TSH level is the discriminator: in hypopituitarism it is never appropriately elevated. ^[1]

Anorexia nervosa, severe illness, and euthyroid-sick syndrome — all can produce low gonadotrophins, low T3, and apparent hypopituitarism. The history (weight loss, psychiatric features, recent severe illness) and a normal IGF-1 and normal dynamic testing distinguish them. Haemochromatosis deserves special mention: iron deposition in the pituitary causes hypogonadotropic hypogonadism as the dominant feature, with a high ferritin and abnormal iron studies pointing to the diagnosis. ^[1]

Stalk-effect hyperprolactinaemia — a non-functioning macroadenoma raises prolactin only mildly via stalk compression: in a recent pathology-confirmed surgical series, no non-functioning adenoma exceeded 200 ng/mL (about 4000 mU/L), whereas a macroprolactinoma typically drives prolactin markedly higher, roughly proportional to tumour size. But beware the grey zone: in that same series 42 percent of pathology-confirmed macroprolactinomas and 49 percent of non-functioning macroadenomas fell between the upper limit of normal and 200 ng/mL, so rigid thresholds misclassify and dopamine-agonist trial responses can mislead. The mildly raised prolactin of a large non-functioning tumour is a stalk effect, not a prolactinoma, and should not be treated with dopamine agonists as first-line (the tumour is not lactotroph). ^[21]

Hyponatraemia mimics — SIADH, primary adrenal insufficiency, hypothyroidism, diuretics, vomiting and diarrhoea. Hypopituitary hyponatraemia is hypotonic with normal potassium (vs the hyperkalaemia of Addison), is associated with other hormone deficits, and responds to glucocorticoid alone.^[2]

Cranial diabetes insipidus versus primary polydipsia — both cause polyuria and polydipsia, but primary polydipsia (psychogenic) has low serum sodium and a normal response to desmopressin (water excretion preserved); cranial DI has high-normal sodium and responds dramatically to desmopressin. A water deprivation test or hypertonic saline infusion distinguishes them. ^[1]

The bedside round — visual fields first

Vital signs reveal postural hypotension (ACTH deficiency — a drop of greater than 20 mmHg systolic on standing), bradycardia and hypothermia (TSH deficiency), and signs of dehydration (DI). General inspection: a pale (not pigmented) complexion (anaemia of chronic disease plus loss of ACTH/MSH), thin dry skin, loss of axillary and pubic hair (loss of gonadal and adrenal androgens), reduced muscle bulk with central adiposity (GH and gonadal deficiency), fine perioral wrinkles (GH deficiency), and delayed relaxation of reflexes (TSH deficiency).^[1]

Bedside manoeuvres: ^[1]

• Visual field testing by confrontation — sit opposite the patient, ask them to cover one eye, and bring a moving target (or your wiggling fingers) in from the four quadrants. A bitemporal hemianopia (loss of the temporal field in each eye) indicates optic chiasm compression by a macroadenoma. This is the single most important bedside sign in pituitary disease.
• Cranial nerve examination (III, IV, V1, V2, VI) for cavernous-sinus involvement — ptosis, divergent strabismus and a fixed pupil suggest a CN III palsy in apoplexy or a laterally invasive tumour.
• Secondary sexual characteristics and breast/gonadal examination — breast atrophy, testicular atrophy, gynaecomastia, loss of body hair, and (in women) vaginal dryness. Galactorrhoea suggests a stalk-effect or prolactinoma.
• Skin and pigmentation — the absence of pigmentation in a hypotensive, hyponatraemic patient is itself diagnostic: it tells you the ACTH is low (secondary), not high (primary Addison). ^[1]

Clinical triad of Sheehan: failure of lactation (agalactia) plus failure to resume menses plus symptoms of hypopituitarism (fatigue, hypotension, weight loss) following severe postpartum haemorrhage. Ask every hypotensive, hyponatraemic postpartum woman about lactation — the question takes five seconds and the diagnosis is often missed.^[1]

Clinical triad of pituitary apoplexy: sudden thunderclap headache plus rapid visual loss or ophthalmoplegia (CN III palsy) plus features of acute adrenal crisis (hypotension, hypoglycaemia, altered consciousness). Treat immediately — do not wait for imaging.^[4]

Low target hormone, low trophic hormone

The defining biochemical pattern is a LOW target hormone with a LOW or INAPPROPRIATELY NORMAL trophic hormone. This pattern — the inverse of primary target-gland failure — is the cornerstone of diagnosis.^[1][2]

Baseline panel (9 am where relevant)

• Cortisol low with low/normal ACTH; free T4 low with low/normal TSH; testosterone (men) or oestradiol (women) low with low/normal LH/FSH; IGF-1 low (with low GH on stimulation); prolactin (low in Sheehan; mildly raised in stalk effect; markedly raised in prolactinoma).
• U&Es — hyponatraemia with normal potassium (aldosterone spared). FBC — normocytic anaemia of chronic disease. Lipids — dyslipidaemia from GH/gonadal deficiency. Bone density (DEXA) — osteopenia/osteoporosis from gonadal and GH deficiency.
• Glucose — hypoglycaemia in ACTH deficiency (especially children). ^[1]

Dynamic tests

The short Synacthen (ACTH stimulation) test — give 250 micrograms of synthetic ACTH (Synacthen) IV and measure cortisol at 0, 30 and 60 minutes — is the standard first-line test for adrenal insufficiency. A normal response is a cortisol of 500 nmol/L (18 µg/dL) or more at 30 to 60 minutes. In primary Addison it is abnormal (the destroyed adrenal cannot respond). In secondary adrenal insufficiency it is reliable only when performed approximately 2 to 4 weeks after the presumed onset of ACTH deficiency — performed earlier it can be falsely normal, because ACTH is a trophic hormone that maintains adrenal integrity and the cortex has not yet atrophied; this is the classic pitfall.^[2][10]

The insulin tolerance test (ITT) is considered the gold standard for assessing both the hypothalamic–pituitary–adrenal axis and the GH axis: insulin-induced hypoglycaemia stresses the axis end-to-end, and cortisol and GH are measured through the test. Its use is limited by contraindications and safety issues — it requires supervised, adequate hypoglycaemia — so it is best reserved for confirming the HPA axis after pituitary surgery where ACTH 1-24 (Synacthen) testing is equivocal, and for diagnosing GH deficiency in a patient being considered for GH replacement.^[11][19]

The glucagon stimulation test is the practical alternative when the ITT is contraindicated or inconclusive: glucagon and arginine tests produce a pronounced GH response with few false positives, and the glucagon and overnight metyrapone tests are the usual substitutes — though none has yet displaced the ITT as the diagnostic standard, and the metyrapone and cosyntropin alternatives have suboptimal sensitivity.^[19][11]

Imaging and visual assessment

Pituitary MRI is the gold standard — it shows the adenoma (micro under 1 cm, macro over 1 cm), apoplexy (blood within the tumour — T1 hyperintense), empty sella, stalk lesion, infiltrate, or craniopharyngioma (cystic with calcification). CT is used if MRI is contraindicated. Formal visual-field perimetry (Humphrey) quantifies any chiasmal compression and is repeated after treatment to document recovery.^[1]

^[1]

Hydrocortisone first — the crisis bundle

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^{[14] [13] [9]}

ABCDE first. If adrenal crisis is suspected, treat immediately — do not wait for cortisol results. A delay of hours can be fatal.^[2][3]

^{[9] [13]}

Order rule (non-negotiable): always replace glucocorticoid before thyroid hormone. Levothyroxine alone increases cortisol clearance and precipitates adrenal crisis. In crisis, give hydrocortisone first and withhold levothyroxine until the cortisol axis is covered. Fludrocortisone is NOT required in acute or chronic secondary adrenal insufficiency — aldosterone, driven by RAAS, is intact.^[3]

Pituitary apoplexy resuscitation: classical apoplexy is a medical emergency in which rapid replacement with hydrocortisone may be life-saving — corticotroph axis involvement may itself produce severe hypotension and contribute to impaired consciousness. Management combines intravenous glucocorticoids with fluid and electrolyte monitoring and referral to a multidisciplinary team comprising, amongst others, a neurosurgeon and an endocrinologist. Although the majority ultimately require surgery — in a pooled analysis of 708 patients, 69.4 percent received surgery and 30.6 percent were treated exclusively conservatively — conservative management is the sole treatment in about one-third; apart from patients with worsening neurological symptoms (who need surgery), it remains unclear for most whether conservative or surgical management carries the best outcome.^[4][12]

The replacement ladder

Long-term management mimics normal physiology with hormone replacement, plus treatment of the underlying cause. The replacement ladder is hydrocortisone first, then levothyroxine, then sex steroids, then growth hormone, then desmopressin for diabetes insipidus.^[1][3][6]

^{[10] [13] [14] [16]}

Glucocorticoid replacement (ALWAYS FIRST)

ACTH deficiency is replaced with oral hydrocortisone 15 to 25 mg/day in two to three divided doses (alternatively cortisone acetate 20 to 35 mg/day), the standard immediate-release regimen; novel once-daily modified-release hydrocortisone aims for a more physiological glucocorticoid exposure. Titrate clinically — the dose regimens employed in clinical practice do not fully mimic the normal day-night (nycthemeral) rhythm of cortisol secretion and are still disputed.^[10][14][13]

Thyroid replacement (ONLY AFTER CORTISOL COVERED)

Levothyroxine 1.6 micrograms/kg/day (typical adult maintenance 75 to 150 micrograms once daily; 1.2 to 1.6 micrograms/kg is the usual adequate range), started only after hydrocortisone is established to avoid precipitating adrenal crisis. Monitor by free T4, not TSH — TSH is unreliable in pituitary disease (it may remain low even with adequate replacement). Target free T4 in the upper half of the reference range.^[3][14][2]

Sex-steroid replacement

Men: testosterone therapy for symptomatic deficiency — transdermal gels are commonly used (flexible dosing, ease of application, good skin tolerability, possibly less erythrocytosis than injectables); injectable testosterone undecanoate is an alternative, with the target at the end of the dosing interval in the low-normal range. Aim for concentrations in the mid-normal range overall, and follow a standardised monitoring plan: symptoms, adverse effects and compliance; serum testosterone and haematocrit concentrations; and prostate cancer risk evaluation during the first year of therapy.^[14][17]

Premenopausal women: oestrogen-progestogen HRT or a combined oral contraceptive, to maintain bone density, cardiovascular health, and quality of life. No progestogen is needed if the uterus was removed. ^[1]

Fertility: both sexes need gonadotrophin induction (hCG plus FSH) or pulsatile GnRH for hypogonadotropic hypogonadism; this is highly specialised and requires a reproductive endocrinologist. ^[1]

Growth hormone replacement

Somatropin (recombinant GH), given as a daily subcutaneous injection, for adults with GH deficiency confirmed by stimulation testing. GH therapy offers benefits in body composition, exercise capacity, skeletal integrity and quality-of-life measures, and is most likely to benefit patients with more severe deficiency; the risks of treatment are low. Dosing must be individualised — responsiveness differs substantially between patients (sex and sex-steroid replacement have the greatest impact, and women on oral oestrogen need the highest doses) — and serum IGF-1 is the most used biochemical biomarker for GH dose titration, though the best target is still debated. In children, GH is essential for linear growth.^[14][16][6]

Desmopressin for diabetes insipidus

Desmopressin (1-deamino-8-D-arginine vasopressin) — a therapeutic trial of 10 to 20 micrograms intranasally can control polyuria for up to 16 hours; oral, sublingual and parenteral preparations are used with individualised regimens (a single bedtime intranasal dose often suffices in mild diabetes insipidus). Titrate to control polyuria; avoid hyponatraemia. After pituitary surgery, higher grades of stalk damage can produce a triphasic pattern — early polyuria, then a transient SIADH-like phase as stored ADH leaks from degenerating neurons, then permanent DI — so sodium needs close monitoring, and DDAVP should periodically be withdrawn to test whether posterior pituitary function has recovered.^[14][22]

Sick-day rules and emergency preparedness

Teach every patient on glucocorticoid replacement these rules — they are life-saving. Patients on chronic replacement still suffer 5 to 10 adrenal crises per 100 patient-years, with a mortality of about 0.5 per 100 patient-years, and infections are the major precipitating cause:^[9]

• Adjust the hydrocortisone dose for stress — prevention requires appropriate dose adjustments during stressful medical procedures and intercurrent illness; patient education is the key to getting these adjustments right.^[9][10]
• Carry an emergency card and an emergency kit for parenteral hydrocortisone self-administration at all times; teach the patient and family to use it when a crisis is impending.^[9]
• Never stop steroids abruptly — and if vomiting makes oral absorption unreliable, use the emergency kit rather than missing doses.^[9]

Perioperative protocol: patients taking physiological replacement doses of corticosteroids for secondary adrenal insufficiency are at significant risk of adrenal crisis and must be given stress doses of hydrocortisone during the peri-operative period. Replacement dosing for surgical stress or illness is in addition to the usual steroid treatment, and undiagnosed adrenal insufficiency can present for the first time after surgical stress — where inadequate supplementation can prove fatal, so anaesthetists must recognise the symptoms and signs of acute adrenal insufficiency.^[18]

Treat the underlying cause

• Transsphenoidal surgery for a symptomatic macroadenoma (visual compromise), craniopharyngioma, or apoplexy with visual deterioration.
• Dopamine agonist (cabergoline, bromocriptine) if the underlying lesion is a prolactinoma — these often shrink dramatically and surgery is avoided.
• Radiotherapy (stereotactic or conventional) rarely, for residual or recurrent tumour after surgery; effects on hormone function develop over years (progressive loss).
• Immune-checkpoint-inhibitor hypophysitis: high-dose glucocorticoid initiation with careful tapering, and tailored long-term hormone replacement, are the mainstays of management; pituitary deficits are frequently persistent, with the potential for long-term or permanent multi-hormonal deficiencies. ^[24]

The subtypes that bite

Sheehan syndrome (postpartum pituitary necrosis)

Sheehan syndrome is ischaemic necrosis of the anterior pituitary following severe postpartum haemorrhage and shock. The enlarged pregnant pituitary — dependent on a low-pressure portal supply — is uniquely vulnerable to hypoperfusion. The classic presentation is the Sheehan triad: agalactia (failure to lactate), failure to resume menses (persistent amenorrhoea), and symptoms of hypopituitarism (fatigue, weight loss, hypotension, loss of body hair) following a complicated delivery. It may present acutely (postpartum collapse with hypotension and hypoglycaemia) or insidiously years later (chronic fatigue, amenorrhoea, secondary adrenal insufficiency). The posterior pituitary is usually spared (its blood supply is systemic, not portal), so DI is uncommon. Empty sella is seen on later imaging as the infarcted gland is replaced by CSF. Replace all deficient axes; the condition is preventable with good obstetric care and remains common only in regions with limited access to safe delivery.^[1][5]

Pituitary apoplexy

Pituitary apoplexy is acute haemorrhage or infarction into a pre-existing pituitary adenoma, producing sudden swelling that compresses the optic chiasm and cavernous sinus and abruptly abolishes ACTH secretion. Presentation is dramatic: thunderclap headache, rapid visual loss, ophthalmoplegia (CN III palsy), meningism, vomiting, altered consciousness, and acute adrenal crisis (hypotension, hypoglycaemia). It is often the first presentation of an undiagnosed adenoma. Risk factors: anticoagulation, pregnancy, dopamine agonist initiation, hypertension, diabetes, head trauma. ^[1]

Management (UK Pituitary Apoplexy Guidelines 2011):

• Rapid replacement with hydrocortisone — it may be life-saving, and corticotroph axis involvement may itself cause severe hypotension and impaired consciousness.
• Fluid and electrolyte monitoring with intravenous glucocorticoids — about one-third of patients can be treated conservatively on this regimen.
• Refer to a multidisciplinary team comprising, amongst others, a neurosurgeon and an endocrinologist.
• Surgery is indicated in patients with worsening neurological symptoms; for the majority it remains unclear whether conservative or surgical management carries the best outcome.
• Monitor long-term for recurrence of tumour growth after the apoplexy, and reassess all pituitary axes.^[4][12]

Empty sella syndrome

Cerebrospinal-fluid herniation into the sella turcica flattens the pituitary against the floor. In most cases an empty sella is an incidental neuroradiological finding without clinical implications; "empty sella syndrome" means hormone dysfunction and/or neurological symptoms, which may coexist with idiopathic intracranial hypertension — and among patients labelled with primary empty sella syndrome, hormone deficiency is reported in 31 to 65 percent. Secondary empty sella (after surgery, apoplexy, Sheehan, or radiotherapy) is commonly associated with partial or complete hypopituitarism. The diagnosis is radiological; hormone testing decides who needs treatment.^[2][14]

Traumatic brain injury and subarachnoid haemorrhage

Post-traumatic hypopituitarism is increasingly recognised and frequently missed. Mechanism: direct gland contusion, shearing of the stalk (the stalk is especially vulnerable), or vascular injury. Deficiency risk tracks the severity of the TBI — reported rates are GH 9 to 36 percent, TSH 2 to 33 percent, ACTH 10 percent (rising to 50 percent after severe TBI), and AVP deficiency 15 to 51 percent. Screen survivors of moderate-to-severe TBI with baseline axes and re-test over time: some deficits recover, some are permanent. Subarachnoid haemorrhage carries similar risk.^[2]

Genetic and congenital forms

Mutations of transcription factors — PROP1, POU1F1 (PIT1), HESX1, SOX2/3, LHX3/4 — cause combined pituitary hormone deficiency. The prototypic congenital syndrome is septo-optic dysplasia (de Morsier syndrome): the classic triad of optic nerve hypoplasia, hypoplasia of the hypothalamic–pituitary axis with hypopituitarism (62 to 80 percent, GH deficiency predominating), and midline brain defects such as agenesis of the septum pellucidum. Investigate the child with failure to thrive, growth failure, delayed puberty, or midline defects; check bone age, IGF-1, and a full pituitary panel, and arrange genetic workup and surveillance.^[2]

Immune-checkpoint-inhibitor hypophysitis

Immune-checkpoint inhibitors (ICIs) cause autoimmune hypophysitis far more often with the anti-CTLA4 agent ipilimumab (13.6 percent of patients) than with the anti-PD1 agents nivolumab or pembrolizumab (0.5 percent). Ipilimumab-associated hypophysitis is mass-like: headache occurred in 75 percent and pituitary enlargement on MRI in the great majority, whereas nivolumab/pembrolizumab hypophysitis produced headache in only 23 percent with little pituitary enlargement — a distinct, milder phenotype. Onset is also earlier with ipilimumab (median 9.3 weeks) than with nivolumab/pembrolizumab (median 25.8 weeks). Hypophysitis in the context of cancer immunotherapy is now a well-recognised cause of hypopituitarism; assess the axes and replace deficient hormones, starting with hydrocortisone.^[7][20]

Iatrogenic

After transsphenoidal surgery: transient or permanent anterior deficits and diabetes insipidus are common; assess all axes pre- and post-operatively; cortisol is the priority. After radiotherapy: hormone loss is a well-documented late complication, usually appearing several years after irradiation and progressive thereafter — somatotrophs are the most vulnerable cells, followed by gonadotrophs, thyrotrophs and corticotrophs — so monitoring should begin within a year of radiotherapy and continue long term. In children, doses above 18 Gy already raise GH-deficiency risk, and doses above 30 to 40 Gy threaten the other axes. ^[14][2]

How hypopituitary patients come to harm

Adrenal crisis — hypotension, shock, hypoglycaemia, hyponatraemia, abdominal pain, and collapse; fatal if untreated. Precipitants: infection, surgery, trauma, a missed dose, vomiting (inability to absorb oral steroids), or giving levothyroxine without steroid cover. Every patient on hydrocortisone must carry an emergency injection kit and a steroid card.^[2][3]

Permanent visual loss can follow a compressive macroadenoma or apoplexy that is not decompressed — although after treatment campimetric defects and visual acuity usually improve and ophthalmoplegia usually resolves in most cases. Whether earlier surgery buys better recovery remains debated, so a deteriorating patient should never wait. ^[12]

Hypopituitary coma — severe deficiency (usually combined ACTH and TSH) compounded by stress (cold, infection, sedatives) produces hypothermia, bradycardia, hypoventilation, and coma. Treat with IV hydrocortisone first, then levothyroxine, rewarming, and supportive care. ^[1]

Long-term complications:

• Reduced bone mineral density and osteoporotic fracture (untreated hypogonadism and GH deficiency).
• Dyslipidaemia and atherosclerotic cardiovascular disease (untreated GH and gonadal deficiency) — drives the excess mortality.
• Impaired fertility (hypogonadotropic hypogonadism) — correctable with gonadotrophin induction.
• Impaired quality of life (GH deficiency, fatigue, altered body composition). ^[1]

Over-replacement itself harms: Cushingoid features, osteoporosis, and glucose intolerance from excess hydrocortisone; atrial fibrillation and osteoporosis from over-replaced levothyroxine; prostatic/haematocrit effects from excess testosterone. Titrate to clinical and biochemical targets.^[3]

^[1]

Prognosis & Disposition

Hormone replacement therapy is the mainstay of treatment and significantly improves quality of life, but increased mortality might persist despite treatment — the Swedish cohort found an early age at onset of pituitary insufficiency and female sex predicted high cerebrovascular mortality. The excess is predominantly vascular: in that cohort of hypopituitary patients on conventional replacement, cerebrovascular mortality was raised more than three-fold (standardized mortality ratio 3.39) and overall cardiovascular mortality nearly two-fold (SMR 1.75), possibly due to GH deficiency or long-term lack or inadequacy of substitution for other pituitary hormones. Modern therapy including GH replacement has brought mortality and morbidity closer to normal. Fertility can be restored with gonadotrophin induction; lifelong follow-up catches under- and over-replacement.^[15][16][3]

Disposition: discharge on lifelong hormone replacement with comprehensive sick-day education, an emergency hydrocortisone injection kit, and MedicAlert identification. Endocrinology follow-up — annual review with monitoring of all axes (free T4, IGF-1, sex steroids, morning cortisol off hydrocortisone if reassessing, bone density every 2 to 5 years), dose adjustment, and reproductive counselling for fertility. Post-surgical patients need early re-testing of all axes and visual fields at 3 months. Patients with craniopharyngioma need lifelong surveillance for recurrence and progressive hormone loss. ^[1]

Special Populations

Pregnancy

Fertility in hypogonadotropic hypogonadism can be induced with gonadotrophin administration (indicated in gonadotrophin deficiency or GnRH resistance, and an alternative in defective GnRH secretion) or pulsatile GnRH (for GnRH deficiency with preserved gonadotrophin secretion). Pituitary disorders are rare in pregnancy because they usually cause gonadal dysfunction and infertility; the two pregnancy-specific pituitary disorders are Sheehan's syndrome and lymphocytic hypophysitis, and pregnant patients with hypopituitarism should ideally be managed at a pituitary tumour centre of excellence.^[13][5][20]

Paediatrics

Growth failure and delayed puberty dominate the paediatric presentation. Weight-based GH replacement (essential for linear growth), levothyroxine, hydrocortisone, and (at the appropriate age) sex steroids for puberty induction. Congenital forms need genetic workup (PROP1, POU1F1, HESX1) and lifelong surveillance. Assess bone age and growth velocity every 6 to 12 months. Children on chronic steroids need bone-density monitoring and adequate calcium/vitamin D. ^[1]

Elderly

Older patients risk delayed diagnosis: the clinical manifestations of hypopituitarism are often non-specific — fatigue, hypotension, cold intolerance — and are easily attributed to ageing, while acquired causes such as head trauma, medications and neoplasms accumulate with age. Keep a low threshold for screening pituitary axes in unexplained hypotension or hyponatraemia, and follow patients with comprehensive evaluation and continuous review.^[13][2]

Post-pituitary surgery

Transient or permanent anterior deficits and diabetes insipidus are common; assess all axes pre- and post-operatively, with cortisol as the priority (the most dangerous acute loss). Watch for the triphasic DI pattern (early DI → transient SIADH-like phase → permanent DI) after stalk injury, and periodically withdraw DDAVP to test for recovery. Re-test at 3 months and annually thereafter, as deficits may recover or develop late (especially after radiotherapy). ^[1][22][14]

Patients on immune-checkpoint inhibitors

Screen for hypophysitis with baseline pituitary axes before starting therapy, and a low threshold to re-check if headache, fatigue, visual symptoms, or hypotension develop. Onset clusters weeks to months into therapy — median 9.3 weeks with ipilimumab, 25.8 weeks with nivolumab/pembrolizumab. Assess and replace every deficient axis (central hypothyroidism and hypogonadism are the most frequent, secondary adrenal insufficiency in about half).^[7][2]

Evidence, Guidelines & Regional Differences

The Endocrine Society 2016 guideline ("Hormonal Replacement in Hypopituitarism in Adults," Fleseriu et al.) is the reference standard for adult replacement: it addresses appropriate biochemical assessments, therapeutic decisions to decrease the risk of co-morbidities from hormonal over-replacement or under-replacement, and the management of hypopituitarism during pregnancy, pituitary surgery and other types of surgery. Its sibling, the Endocrine Society adult GH deficiency guideline (Molitch et al.), recommends confirming GH deficiency by stimulation testing (usually required unless there is a proven genetic or structural lesion) and individualising GH dosing, weighing benefits against risks for the individual patient.^[3][6]

The UK Pituitary Apoplexy Guidelines (Rajasekaran et al. 2011) define classical apoplexy as a medical emergency in which rapid replacement with hydrocortisone may be life-saving, require referral to a multidisciplinary team including a neurosurgeon and an endocrinologist, and reserve surgery for patients with worsening neurological symptoms — noting that for the majority of patients it remains unclear whether conservative or surgical management carries the best outcome, and that careful monitoring for recurrence of tumour growth is needed after apoplexy. For adrenal crisis, expert guidance is that every patient should carry an emergency card and be provided with an emergency kit for parenteral hydrocortisone self-administration.^[4][9]

^[1]

Controversies and evolving areas:

• Hydrocortisone regimen — once-daily modified-release (Chronocort, Plenadren) versus twice-daily versus thrice-daily; aim for physiologic exposure without over-replacement.
• Who benefits from adult GH replacement — cost, IGF-1 titration, and long-term cardiovascular outcomes remain debated; the Endocrine Society supports it for proven deficiency with symptoms.
• Pituitary apoplexy — conservative versus surgical — surgery for visual deterioration; conservative (high-dose steroids) is acceptable for stable vision; the UK guidelines provide the framework.
• Immune-checkpoint-inhibitor hypophysitis — whether to give high-dose steroids or physiologic replacement only; whether to rechallenge the ICI; long-term outcomes still emerging.
• Post-TBI screening — the optimal timing and cost-effectiveness of screening all severe TBI survivors.^[2][7]

Exam Pearls

• No hyperpigmentation and no hyperkalaemia in secondary adrenal insufficiency (ACTH is low) — the single best discriminator from primary Addison, which has both.
• Always give hydrocortisone before levothyroxine — levothyroxine alone precipitates a fatal adrenal crisis by increasing cortisol clearance.
• Aldosterone is spared (RAAS intact) — so no fludrocortisone and no hyperkalaemia in secondary adrenal insufficiency.
• Order of hormone loss with a mass lesion: GH, then LH/FSH, then TSH, then ACTH, then prolactin (PRL often rises via the stalk effect from loss of dopamine inhibition).
• Sheehan triad: failure to lactate (agalactia), amenorrhoea, and hypopituitarism after severe postpartum haemorrhage.
• Pituitary apoplexy: thunderclap headache plus cranial nerve III palsy plus visual loss — emergency IV hydrocortisone plus neurosurgical decompression if vision compromised.
• Diagnosis: low target hormone with low or inappropriately normal trophic hormone; confirm with MRI; monitor levothyroxine by free T4, not TSH.
• The short Synacthen test can be falsely normal early in secondary adrenal insufficiency (the adrenal has not yet atrophied) — use an insulin tolerance test (gold standard) or glucagon stimulation test.
• Bitemporal hemianopia = optic chiasm compression by a macroadenoma; test visual fields by confrontation.
• Empty sella is usually an incidental radiological finding; when it forms part of "empty sella syndrome", hormone deficiency is reported in 31 to 65 percent, and the secondary form (after surgery, apoplexy, Sheehan) commonly has deficiency.
• TBI, SAH, and immune-checkpoint inhibitors are increasingly recognised causes — screen survivors.
• A mildly raised prolactin (below 200 ng/mL / about 4000 mU/L) with a macroadenoma is usually a stalk effect, not a prolactinoma — do not treat with dopamine agonists as first-line; the tumour is non-lactotroph (remember the grey zone below 200 ng/mL where even macroprolactinomas sit).
• Adult GH deficiency is defined as a peak GH under 3 ng/mL on the ITT; treat with somatropin titrated to IGF-1.
• Hyponatraemia in hypopituitarism is hypotonic with normal potassium and responds to hydrocortisone alone — distinguish from SIADH (fluid restriction) and Addison (hyperkalaemic). ^[1]

Ward-round test — three stems, thirty seconds each

Stem 1 — the woman from the top of the topic (answer)ShowHide

The postpartum woman who cannot lactate, faints on standing, has lost her body hair, sodium 128 mmol/L, potassium normal, cortisol undetectable. Which hormone do you replace first, and why? Model: This is Sheehan syndrome — ischaemic pituitary necrosis after severe postpartum haemorrhage; failure of postpartum lactation and failure to resume menses are its most common presenting symptoms, and it may range from abrupt postpartum collapse to mild disease that goes undiagnosed for years. Replace hydrocortisone FIRST: before starting L-thyroxine, concomitant corticotropin deficiency must be excluded to avoid acute adrenal insufficiency. If she has collapsed, treat as adrenal crisis — intravenous hydrocortisone as a 100 mg bolus followed by 200 mg over 24 hours with 0.9 percent saline, 1000 mL within the first hour; for stable chronic replacement, hydrocortisone 15 to 25 mg/day in two to three divided doses. Confirm the anatomy with pituitary MRI — the great majority of Sheehan patients show an empty sella on CT or MRI.^{[8][13][9][10]}

Stem 2 — the thunderclap headache with a droopy eyelid (answer)ShowHide

A 55-year-old man has sudden severe headache, vomiting, a fixed dilated pupil and ptosis on the right, and a falling blood pressure. The CT read is no aneurysm. What happened, and what is the first drug? Model: This is pituitary apoplexy — haemorrhage or infarction of the pituitary gland, clinically characterised by sudden onset headache with, by severity, nausea, vomiting, visual disturbance, cranial-nerve involvement and decreased consciousness. Corticotroph axis involvement may cause severe hypotension and contribute to the impaired consciousness — so the first drug is parenteral hydrocortisone (rapid replacement may be life-saving and must not wait for imaging or a cortisol result). Then urgent referral to a multidisciplinary team with pituitary expertise including a neurosurgeon: about 70 percent of patients require surgery, while roughly one-third can be treated conservatively with intravenous glucocorticoids and fluid and electrolyte monitoring.^[12][4]

Stem 3 — the hyponatraemia that is not SIADH (answer)ShowHide

A 68-year-old is admitted confused with sodium 122 mmol/L. Free T4 is low, TSH is low, cortisol is low with low ACTH. The registrar plans fluid restriction for SIADH and wants to start levothyroxine. Correct both errors. Model: This is the hyponatraemia of central (secondary) hypothyroidism with cortisol deficiency, not SIADH. Secondary hypothyroidism is diagnosed by low serum free T4 with an inappropriately normal or low TSH — exactly this pattern — and before starting L-thyroxine, concomitant corticotropin deficiency must be excluded to avoid acute adrenal insufficiency. So the registrar's levothyroxine-first plan is dangerous: cover the cortisol axis first. Fluid restriction for SIADH is the wrong frame here — the sodium will follow pituitary-axis replacement, not water restriction. Image the sella with pituitary MRI.^[13]

References24ShowHide

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