Pituitary Disorders

Hormone-excess states (monoclonal adenoma)

• Sporadic somatic mutation: the great majority of prolactinomas, somatotroph, and corticotroph adenomas are sporadic monoclonal tumors; gsp (activating GNAS) mutations drive a subset of GH-secreting adenomas, and the same mutation underlies GH excess in McCune–Albright syndrome.
• Inherited syndromes (non-modifiable): MEN1 (pituitary + parathyroid + pancreatic islet — the "3 P's"), MEN4 (CDKN1B), Carney complex (PRKAR1A), and familial isolated pituitary adenoma from AIP mutations, which classically produces young-onset invasive somatotroph macroadenomas/gigantism.

Secondary (non-tumoral) hyperprolactinemia — the modifiable group examiners plant

• Dopamine antagonists: antipsychotics (risperidone, haloperidol), metoclopramide; also methyldopa, verapamil, opioids, and estrogens.
• Physiologic and systemic causes: pregnancy and lactation, nipple/chest-wall stimulation, primary hypothyroidism (TRH is a prolactin secretagogue), chronic kidney disease, cirrhosis.
• Stalk effect: any sellar mass interrupting the tuberoinfundibular tract removes dopaminergic inhibition, producing mild hyperprolactinemia with a large tumor.

Hypopituitarism

• Vascular/infarction: Sheehan syndrome after postpartum hemorrhage (modifiable — obstetric hemorrhage prevention); pituitary apoplexy, whose triggers include anticoagulation, major surgery, and dynamic pituitary testing.
• Iatrogenic: transsphenoidal surgery, cranial irradiation (deficits accrue for years), and immune checkpoint inhibitor hypophysitis — classically anti-CTLA-4 (ipilimumab).
• Infiltrative/inflammatory: lymphocytic hypophysitis (peripartum women), sarcoidosis, Langerhans cell histiocytosis, IgG4 disease, hemochromatosis; also traumatic brain injury, craniopharyngioma, and Rathke cleft cyst.

Posterior pituitary

• Central DI: neurosurgery/trauma, germinoma or craniopharyngioma, infundibuloneurohypophysitis, hereditary Wolfram (DIDMOAD).
• SIADH: small cell lung carcinoma (ectopic ADH), CNS insult, pneumonia/TB, pain, nausea, and drugs — SSRIs, carbamazepine, cyclophosphamide, MDMA. Lithium and hypercalcemia cause nephrogenic DI, not central.

Anterior Pituitary Disorders

• Pituitary adenomas — benign proliferation of hormone-secreting cells; prolactinomas (40% of adenomas) suppress dopamine-mediated inhibition; growth hormone-secreting adenomas cause acromegaly/gigantism; ACTH-secreting adenomas (corticotroph adenomas) cause Cushing's disease; TSH-secreting adenomas are rare; non-functioning adenomas compress surrounding tissue
• Mass effect mechanisms — compression of normal pituitary tissue → loss of trophic hormone secretion; compression of optic chiasm → bitemporal hemianopsia; compression of cranial nerves III, IV, VI → ophthalmoplegia; erosion into cavernous sinus or sphenoid sinus
• Hypopituitarism — loss of anterior pituitary cells from adenomas, surgery, radiation, infarction (Sheehan syndrome postpartum, pituitary apoplexy), infiltrative diseases (sarcoidosis, lymphocytic hypophysitis, hemochromatosis)
• Secondary hormone deficiencies — GH deficiency (growth retardation in children, metabolic abnormalities in adults); LH/FSH deficiency (hypogonadism); TSH deficiency (secondary hypothyroidism); ACTH deficiency (secondary adrenal insufficiency)

Posterior Pituitary Disorders

• Central diabetes insipidus (CDI) — loss of ADH-producing neurons in the supraoptic and paraventricular nuclei; results in inability to concentrate urine and polyuria
• Syndrome of Inappropriate ADH (SIADH) — ectopic ADH secretion (small cell lung cancer, CNS disorders, medications) or excessive pituitary ADH release; causes water retention and hyponatremia
• ADH resistance — nephrogenic DI results from renal unresponsiveness to ADH (not technically a pituitary disorder but important differential)

Pituitary Adenomas — General Mass Effects

• Vision loss — bitemporal hemianopsia (classic, from chiasm compression) progressing to complete blindness if untreated; visual field cuts from lateral compression
• Headaches — often frontal or retro-orbital; may indicate apoplexy if sudden onset with severe pain, neck stiffness, altered mental status
• Cranial nerve palsies — CN III (ptosis, mydriasis, "down and out" eye), CN IV, CN VI (lateral rectus palsy/diplopia); occur with cavernous sinus extension

Prolactinoma

• Reproductive dysfunction — amenorrhea/oligomenorrhea in women, erectile dysfunction and decreased libido in men; galactorrhea in both sexes
• Decreased libido and sexual dysfunction — from hypogonadism (elevated prolactin suppresses GnRH)
• Infertility — women may have anovulation; men have low sperm count
• Gynecomastia and breast tenderness — from elevated prolactin

Growth Hormone–Secreting Adenoma (Acromegaly/Gigantism)

• Gigantism — if GH excess occurs before epiphyseal plate closure in children (very tall stature)
• Acromegaly — if GH excess occurs in adults: coarse facial features, prognathism, macroglossia, carpal tunnel syndrome, deepening voice, arthropathy (especially hips and knees)
• Metabolic complications — hypertension, diabetes mellitus (40%), hyperlipidemia, sleep apnea
• Headaches and visual symptoms — from mass effect
• Increased mortality — if untreated, cardiovascular disease is leading cause of death

ACTH-Secreting Adenoma (Cushing's Disease)

• Cushinoid features — central obesity, purple striae, easy bruising, proximal muscle weakness, moon facies, buffalo hump
• Hypertension — from mineralocorticoid and glucocorticoid excess
• Hyperglycemia — insulin resistance from cortisol excess
• Psychiatric manifestations — depression, anxiety, cognitive dysfunction
• Osteoporosis — from long-standing cortisol excess

Hypopituitarism

• GH deficiency in children — growth retardation, short stature, delayed puberty
• GH deficiency in adults — decreased muscle mass, increased body fat, decreased quality of life; hypoglycemia with stress
• Gonadotropin deficiency — secondary hypogonadism with decreased libido, erectile dysfunction, infertility, gynecomastia (if estrogen present)
• TSH deficiency — secondary hypothyroidism with fatigue, cold intolerance, weight gain (but less severe than primary hypothyroidism)
• ACTH deficiency — secondary adrenal insufficiency with fatigue, weakness, hypotension; no hyperpigmentation (unlike primary adrenal insufficiency, which has elevated ACTH)
• Panhypopituitarism — combination of all deficiencies; life-threatening if acute

Central Diabetes Insipidus

• Polyuria — massive urine output (5-20 L/day) with dilute urine (osmolality <300 mOsm/kg)
• Polydipsia — intense thirst; patients drink constantly and may sleep with water at bedside
• Nocturia — frequent nighttime voiding
• Risk of dehydration and hypernatremia — if fluid intake restricted or unable to drink

SIADH

• Hyponatremia — often asymptomatic if chronic and mild; severe hyponatremia (<120 mEq/L) causes confusion, seizures, coma
• Euvolemia — edema absent; urine osmolality elevated (>200 mOsm/kg) despite low serum osmolality
• Neuropsychiatric symptoms — lethargy, confusion, restlessness, seizures, altered consciousness

Pituitary Adenoma Diagnosis

• MRI with contrast — imaging of choice; shows sellar mass, assesses relationship to optic chiasm and cavernous sinus; T2-weighted images show adenoma as hypointense relative to normal pituitary
• Visual field testing — formal perimetry to assess chiasm compression and document baseline before intervention
• Hormone levels — measure prolactin, morning cortisol/24-hour UFC, IGF-1, testosterone/estradiol, TSH, free T4; suppression and stimulation tests to differentiate adenoma hormone secretion from appropriate physiologic response
• Pituitary hormone reserve assessment — insulin tolerance test (ITT) or ACTH/cortisol stimulation; check all anterior pituitary axes

Prolactinoma Diagnosis

• Elevated prolactin — >20 ng/mL highly suggestive; measure carefully (obtain sitting after 20 min rest, no breast stimulation)
• TRH stimulation test — less commonly used; prolactin should rise with TRH; blunted response in prolactinoma
• Dopamine agonist test — rarely used; prolactin should suppress with dopamine agonist

Acromegaly Diagnosis

• Elevated IGF-1 — most sensitive screening test; measured once and elevated level is diagnostic
• Random GH level >1 ng/mL — concerning; normal fasting GH <0.4 ng/mL
• **Oral glucose tolerance test (OGTT

Immediate stabilization (emergencies first)

• Pituitary apoplexy: give stress-dose IV glucocorticoid (hydrocortisone) before imaging results return — ACTH deficiency with adrenal crisis kills faster than the mass; urgent transsphenoidal decompression is indicated for visual loss, ophthalmoplegia, or depressed consciousness (Pituitary Society/Endocrine Society guidance).
• Severe symptomatic hyponatremia (seizure, coma): 3% hypertonic saline in small boluses per the 2013 US expert panel consensus; limit correction to roughly 6–8 mEq/L in 24 hours to avoid osmotic demyelination.
• Adrenal crisis in panhypopituitarism: IV hydrocortisone plus isotonic saline. Always replace glucocorticoid before levothyroxine — thyroid hormone accelerates cortisol clearance and can precipitate crisis (Endocrine Society hypopituitarism guideline).

Prolactinoma — medical therapy is first-line, even for macroadenomas

• Dopamine agonists: cabergoline preferred over bromocriptine for efficacy and tolerability (Endocrine Society 2011); bromocriptine is favored when pregnancy is planned. Surgery is reserved for agonist resistance/intolerance or apoplexy.

Acromegaly (Endocrine Society 2014)

• Transsphenoidal surgery is first-line and potentially curative.
• Somatostatin receptor ligands (octreotide LAR, lanreotide) for persistent disease; GH receptor antagonist pegvisomant normalizes IGF-1 but does not shrink tumor; cabergoline adjunctively; radiotherapy third-line.

Cushing's disease (Endocrine Society 2015)

• Selective transsphenoidal adenomectomy first-line; repeat surgery or radiotherapy next.
• Medical: steroidogenesis inhibitors (osilodrostat, metyrapone, ketoconazole), pituitary-directed pasireotide, glucocorticoid receptor blocker mifepristone; bilateral adrenalectomy is the last resort.

Posterior pituitary

• Central DI: desmopressin plus free water access.
• SIADH: fluid restriction first, then salt/urea loading or a vasopressin receptor antagonist (tolvaptan) with close sodium monitoring.

Emergencies

• Pituitary apoplexy: hemorrhage/infarction into an adenoma → thunderclap headache, sudden ophthalmoplegia, visual loss, meningismus; ACTH loss causes hypotension refractory to fluids. Treat as an emergency.
• Adrenal crisis: unrecognized secondary adrenal insufficiency during illness or after starting levothyroxine → hypotension, hypoglycemia, hyponatremia; note no hyperpigmentation and no hyperkalemia (aldosterone is renin-driven and preserved).
• Osmotic demyelination syndrome: overly rapid correction of chronic hyponatremia → delayed (days later) dysarthria, spastic quadriparesis, locked-in syndrome; MRI shows central pontine signal change.
• Hypernatremic dehydration in DI: occurs when the patient cannot access water (postoperative, intubated, elderly) → altered mentation, shock.

Disease-related

• Chiasmal compression: progressive bitemporal hemianopsia → permanent optic atrophy if decompression is delayed.
• Acromegaly: biventricular hypertrophy and cardiomyopathy (leading cause of death), obstructive sleep apnea, diabetes, and an increased risk of colonic polyps prompting colonoscopy at diagnosis per Endocrine Society guidance.
• Cushing's disease: vertebral compression fracture from osteoporosis, venous thromboembolism, opportunistic infection, steroid psychosis.
• Prolactinoma: hypogonadism-driven bone loss and infertility.

Treatment-related

• Post-transsphenoidal: transient central DI, the triphasic response (DI → SIADH → permanent DI), delayed hyponatremia around postoperative day 7, CSF rhinorrhea (confirm with beta-2 transferrin) and meningitis, and new hypopituitarism.
• Dopamine agonists: nausea, orthostasis, impulse control disorders, and cardiac valvulopathy with high cumulative ergot doses.
• Somatostatin ligands: gallstones, bradycardia, hyperglycemia; pegvisomant: transaminitis with IGF-1 normalization but no tumor shrinkage.
• Bilateral adrenalectomy: Nelson syndrome — corticotroph tumor enlargement with intense ACTH-driven hyperpigmentation.
• Radiotherapy: progressive hypopituitarism over years, optic neuropathy, second neoplasms.

• Prolactin magnitude discriminates cause: markedly elevated prolactin with a sellar mass favors a true prolactinoma, whereas a large mass with only mildly elevated prolactin is stalk effect from a non-functioning adenoma — and that tumor needs surgery, not cabergoline.
• **The *hook effect*: a giant prolactinoma can saturate the immunoassay and report a deceptively normal prolactin. If the tumor is huge and prolactin looks low, the next step is to repeat the assay on a diluted sample**.
• Rule out the cheap causes first: before imaging hyperprolactinemia, check a pregnancy test, TSH, creatinine, and the medication list (antipsychotics, metoclopramide). Antipsychotic-induced hyperprolactinemia is the classic distractor for a prolactinoma stem.
• Acromegaly sequence: screen with IGF-1, confirm with failure of GH to suppress after oral glucose, then MRI. Ordering the MRI before biochemical confirmation is the trap — incidentalomas are common.
• Cushing's stepwise logic: prove hypercortisolism (late-night salivary cortisol, 24-h UFC, or low-dose dexamethasone), then measure ACTH; if ACTH-dependent, inferior petrosal sinus sampling distinguishes pituitary from ectopic source (Endocrine Society).
• Glucocorticoid before levothyroxine in newly diagnosed panhypopituitarism — reversing the order can precipitate adrenal crisis.
• Sheehan syndrome: postpartum hemorrhage followed by failure to lactate and failure to resume menses is the single most tested association.
• DI differentiation: after water deprivation, urine concentrates with desmopressin in central DI but not nephrogenic DI; lithium and hypercalcemia point to nephrogenic. In SIADH, the patient is euvolemic — hypovolemia or hypervolemia argues against it.