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Pituitary Tumors: Complete Clinical Reference

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1. Classification of Pituitary Adenomas

Functioning Adenoma Types and Their Syndromes

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2. Hormonal Tests for Each Adenoma Type

A. Prolactinoma (Lactotroph Adenoma)

• Serum PRL - fasting morning level (normal <20 µg/L)
  • PRL >200 µg/L: almost certainly a prolactinoma
  • PRL 100-200 µg/L: likely microadenoma or stalk compression
  • PRL <100 µg/L: may be microadenoma, non-lactotrope sellar mass, or non-neoplastic cause
• Macroprolactin screen - rule out biologically inactive aggregated PRL (falsely elevated)
• TSH + free T4 - exclude hypothyroidism (TRH stimulates PRL)
• Medications review - dopamine blockers cause hyperprolactinemia (see below)

• Drugs: antipsychotics (haloperidol, risperidone, chlorpromazine), metoclopramide, methyldopa, reserpine, opiates, verapamil, SSRIs, cimetidine, amitriptyline, estrogens
• Physiologic: pregnancy, breastfeeding, stress
• Pathologic: hypothyroidism, renal failure, hypothalamic/stalk disease

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B. Acromegaly / Gigantism (Somatotroph Adenoma)

• Serum IGF-1 (age- and sex-matched) - best initial test; correlates with 24-hour integrated GH secretion; elevated in acromegaly

• Oral Glucose Tolerance Test (OGTT) with GH measurement
  • Give 75 g oral glucose
  • Measure GH at 0, 30, 60, 90, 120 minutes
  • Normal: GH suppresses to <1 ng/mL (polyclonal assay) or <0.4 µg/L (chemiluminescent IRMA)
  • Acromegaly: GH fails to suppress below these thresholds
  • ~20% of patients show a paradoxical GH rise after glucose

• Serum PRL - co-secreted in ~25% of GH-secreting tumors (implications for dopamine agonist therapy)
• Thyroid function, gonadotropins, sex steroids - often attenuated by tumor mass effects
• ACTH reserve - usually deferred until after surgery
• Goldman-Cecil Medicine, p. 2406; Harrison's Principles 22E, p. 3052

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C. Cushing Disease (Corticotroph Adenoma)

Step 1: Screening for Hypercortisolism (any TWO of these)

• Pregnancy: use UFC; values >3x ULN needed (UFC normally rises in 2nd/3rd trimester)
• Renal failure (GFR <30): UFC unreliable; use 1-mg DST
• Cyclic Cushing: serial UFC or MSC
• Incidentaloma: 1-mg DST is superior

• Midnight plasma cortisol >7.5 µg/dL (207 nmol/L) - requires 48h hospital admission; 100% specificity
• Low-dose DST (LDDST, 2-day 2 mg): 0.5 mg dexamethasone q6h x 2 days; UFC collected; failure to suppress confirms Cushing syndrome
• Dexamethasone-CRH combined test: 1 µg/kg or 100 µg oCRH given 2 hours after LDDST; plasma cortisol >38 nmol/L at 15 min = Cushing syndrome (100% sensitivity and specificity vs. pseudo-Cushing)

Step 2: Localization - ACTH-Dependent vs. Independent

• Gold standard for localizing ACTH to pituitary vs. ectopic source
• Invasive; only at experienced centers
• Central:peripheral ACTH ratio >2:1 at baseline (>3:1 after CRH) = pituitary source (100% sensitivity and specificity)
• Ratio <1.4:1 = ectopic source
• Lateralization: side with higher petrosal sinus ACTH predicts tumor side in sella
• Henry's Clinical Diagnosis and Management by Laboratory Methods, pp. 477-479

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D. TSH-Secreting Adenoma (Thyrotropinoma)

• Serum TSH - paradoxically normal or elevated despite hyperthyroidism (central hyperthyroidism)
• Free T3, free T4 - elevated
• Alpha subunit - often disproportionately elevated; alpha subunit:TSH molar ratio >1 favors thyrotropinoma over thyroid hormone resistance
• TRH stimulation test - TSH fails to rise (lack of normal feedback regulation)
• T3 suppression test - TSH is not suppressed by exogenous T3 in thyrotropinoma (contrast to Graves' where TSH is already suppressed)
• MRI sella - usually macroadenoma

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E. Non-Functioning / Gonadotroph Adenoma

• Basal FSH, LH, alpha subunit - often mildly elevated or in normal range
• Often present due to mass effects rather than hormone excess
• Pituitary hormone reserve testing (below) - to detect hypopituitarism from compression
• MRI sella - usually macroadenoma at presentation

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3. Dynamic Tests - Summary Table

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4. Interpretation of Investigations

Radiological

• MRI sella with gadolinium is the modality of choice for all pituitary tumors
• Microadenomas (<1 cm): hypointense on T1, may not enhance; detected in only 50-60% of Cushing disease cases
• Macroadenomas: better visualized; assess suprasellar extension, cavernous sinus invasion, optic chiasm compression
• Visual field testing (Goldmann or automated perimetry): bitemporal hemianopia from optic chiasm compression
• CT head/chest/abdomen: for ectopic ACTH source (bronchial carcinoid, lung small cell)
• Adrenal CT: for ACTH-independent Cushing syndrome

Biochemical Interpretation Pearls

• Elevated PRL with any sellar mass: distinguish true prolactinoma (PRL usually correlates with tumor size) from "stalk effect" (PRL typically <100-150 µg/L regardless of tumor size)
• Cushing syndrome: imaging only after biochemical diagnosis is confirmed - incidentalomas of pituitary and adrenal occur in up to 10% of the population
• Hypopituitarism screen in any macroadenoma: measure 8 AM cortisol (or ITT), free T4, TSH, FSH, LH, testosterone (men) / estradiol (women), IGF-1, sodium (for DI)

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5. Management Principles

A. Prolactinoma

• Cabergoline (preferred): 0.5-1.0 mg twice weekly
  • Normalizes PRL and restores gonadal function in ~80% of microadenomas
  • Shrinks ~70% of macroprolactinomas
  • Mass effects (headache, visual defects) often improve within days
  • Repeat MRI at 16 weeks after starting in macroadenomas (striking shrinkage possible)
  • Superior to bromocriptine for efficacy and tolerability
• Bromocriptine: 0.625 mg at bedtime increasing to 2.5 mg TID; preferred when fertility desired (shorter half-life, more safety data in pregnancy)
• Side effects of DAs: nausea, postural hypotension, nasal stuffiness, nightmares, impulse control disorders (~5%); cardiac valvulopathy risk only at high Parkinson's doses (not at standard prolactinoma doses - echocardiogram recommended before starting)

• Dopamine resistance or intolerance
• Invasive macroadenoma with visual compromise not improving on DAs
• Initial PRL normalization: ~70% of microadenomas, ~40% of macroadenomas
• Recurrence: up to 20% in first year post-surgery; >50% long-term for macroadenomas

• Bromocriptine preferred over cabergoline when fertility desired
• Stop DAs when pregnancy confirmed; monitor PRL and symptoms
• Macroadenoma: regular visual field testing; restart DA or consider surgery if tumor growth occurs
• ~5% of microadenomas and 15-30% of macroadenomas grow during pregnancy - Harrison's 22E, p. 3051

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B. Acromegaly

• First-line for most patients
• Cure rate: 80-90% for microadenomas; <30% for macroadenomas
• Macroadenomas: GH substantially reduced even without cure
• Multidisciplinary approach (neurosurgeon + endocrinologist)

• Somatostatin receptor ligands (SRLs):
  • Octreotide LAR, Lanreotide (monthly IM injections): normalize IGF-1 in ~50-60%; reduce GH; may shrink tumor
  • Pasireotide LAR (40 or 60 mg IM q28 days): superior to first-gen SRLs for GH suppression; higher risk of hyperglycemia
• Dopamine agonists (cabergoline): useful in mixed GH+PRL tumors; less effective as monotherapy for GH
• GH receptor antagonist - Pegvisomant: blocks GH receptor peripherally; normalizes IGF-1 in >90%; does not reduce tumor size; used when SRLs fail; given as daily SC injection

• Not effective as primary therapy (GH normalization takes 5-15 years)
• Adjunct when surgery + medical therapy fails
• Stereotactic radiosurgery (Gamma Knife): faster than conventional; high risk of hypopituitarism long-term
• Goldman-Cecil Medicine, p. 2406; Harrison's 22E, p. 3052

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C. Cushing Disease

• Remission (post-op cortisol <2 µg/dL) achieved in 70-80% of microadenomas; lower for macroadenomas
• Post-op adrenal insufficiency expected - requires glucocorticoid replacement until HPA axis recovers (may take 6-18 months)

• Repeat TSS (if residual/recurrent pituitary tumor)
• Bilateral adrenalectomy: immediate cure of hypercortisolism; lifelong mineralocorticoid + glucocorticoid replacement required; risk of Nelson syndrome (rapid ACTH-secreting adenoma growth, hyperpigmentation) - up to 25% risk; requires pituitary radiotherapy after adrenalectomy
• Radiotherapy (pituitary): conventional or stereotactic; takes months-years for effect; adjunct to surgery
• Medical therapy (bridging or adjunct):
  • Steroidogenesis inhibitors: Ketoconazole (hepatotoxic), Metyrapone (blocks 11β-hydroxylase), Osilodrostat (newer, potent 11β-hydroxylase inhibitor), Mitotane (for adrenocortical carcinoma)
  • Glucocorticoid receptor antagonist: Mifepristone (blocks receptor; use in diabetes/glucose intolerance with Cushing)
  • Pituitary-directed: Pasireotide (somatostatin analog, reduces ACTH from corticotrophs; hyperglycemia major side effect), Cabergoline (modest efficacy on ACTH)

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D. Non-Functioning Adenoma (NFA) / Gonadotropinoma

• Surgery (TSS) when: visual field defects, apoplexy, significant mass effect, headache, hypopituitarism
• Observation for small incidental microadenomas without symptoms
• Hormone replacement for hypopituitarism (hydrocortisone, levothyroxine, sex hormone replacement, GH if indicated)
• No established medical therapy to shrink NFAs

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E. TSH-Secreting Adenoma (Thyrotropinoma)

• TSS is first-line
• Somatostatin analogs (octreotide, lanreotide): very effective - normalize TSH and T4 in >90%, can shrink tumor preoperatively
• Antithyroid drugs can be used as adjunct to control hyperthyroidism preoperatively

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6. Follow-Up Principles

Prolactinoma

• PRL levels every 3-6 months during DA titration; then every 6-12 months when stable
• MRI sella at 3-6 months after starting DA for macroadenomas; then annually if stable; every 1-2 years for microadenomas
• Monitor for DA side effects (nausea, cardiac valvulopathy at high doses)
• After DA withdrawal: PRL monitoring every 3 months for 1 year, then annually; MRI if PRL rises

Acromegaly

• IGF-1 and random GH (or post-OGTT GH) every 3-6 months after surgery
• Biochemical cure criteria: IGF-1 within normal range for age AND GH nadir <0.4 µg/L (chemiluminescent assay) on OGTT
• MRI sella at 3 months post-op, then at 6-12 months, then annually if residual tumor
• Screen for and manage comorbidities: colonoscopy (colon polyps), echocardiogram (cardiomyopathy), OGTT (diabetes), sleep study (sleep apnea), bone density (arthropathy)
• Patients on SRLs: liver ultrasound (gallstones - SRL side effect)

Cushing Disease

• Post-operative: 8 AM serum cortisol within 24-48 hours of surgery; target <2 µg/dL confirms remission
• Glucocorticoid replacement (hydrocortisone 10-20 mg/day) until HPA axis recovers; test with ITT or short Synacthen test at 6-12 months post-op
• Recurrence monitoring: 24h UFC, midnight salivary cortisol, or 1-mg DST every 6-12 months for at least 5 years (15-25% recur)
• MRI at 3 months post-op; annually for 2-3 years, then as clinically indicated
• After bilateral adrenalectomy: annual MRI to screen for Nelson syndrome; ACTH levels regularly

Non-Functioning Adenoma (post-surgery)

• Full pituitary hormone panel at 6 weeks post-op (TSH/free T4, 8 AM cortisol or ITT, IGF-1, FSH/LH, testosterone/estradiol)
• MRI sella at 3 months, 1 year, then every 1-2 years; residual tumors followed more closely (annual MRI)
• Hormone replacement as needed
• Visual field testing post-op; periodically if residual tumor

General Pituitary Follow-Up

• Screen for hypopituitarism in any macroadenoma (before and after treatment): cortisol, thyroid, gonadal, and GH axes
• Bone mineral density (DEXA scan): in hypogonadism, Cushing, or GH deficiency
• Annual clinical review including blood pressure, glucose, lipids (metabolic comorbidities)
• Ophthalmology review if suprasellar extension was present

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Key Images from Textbooks

• Acromegaly serial clinical photos showing progressive facial coarsening over 9 years, with corresponding pituitary MRI
• Features of gigantism vs. normal identical twin
• Prolactinoma: flowchart for diagnosis and treatment; MRI showing striking tumor shrinkage with cabergoline

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• Robbins & Kumar Basic Pathology (Robbins Pathology), p. 764
• Goldman-Cecil Medicine International Edition, pp. 2405-2406
• Harrison's Principles of Internal Medicine 22E (2025), pp. 3049-3052
• Henry's Clinical Diagnosis and Management by Laboratory Methods, pp. 477-479Here is the complete structured reference on pituitary tumors, compiled directly from Harrison's Principles 22E, Goldman-Cecil Medicine, Henry's Clinical Diagnosis and Management by Laboratory Methods, and Robbins Pathology.

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Pituitary Tumors: Complete Clinical Reference

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1. Classification

Adenoma Types and Clinical Syndromes

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2. Hormonal Tests for Each Adenoma Type

A. Prolactinoma

• Serum PRL (fasting morning level; normal <20 µg/L)
  • PRL >200 µg/L = almost certainly a prolactinoma
  • PRL 100-200 µg/L = likely microadenoma or stalk compression
  • PRL <100 µg/L = microadenoma, non-lactotrope sellar mass, or non-neoplastic cause
• Macroprolactin screen - exclude biologically inactive aggregated PRL forms (falsely elevated result)
• TSH + free T4 - exclude primary hypothyroidism (TRH stimulates PRL)
• Drug review - major cause of hyperprolactinemia

• Drugs: antipsychotics (haloperidol, risperidone, chlorpromazine), metoclopramide, methyldopa, reserpine, opiates, H2 blockers (cimetidine), SSRIs (fluoxetine), verapamil, estrogens, tricyclics
• Physiologic: pregnancy, breastfeeding, stress, chest wall stimulation
• Pathologic: hypothyroidism, renal failure, liver failure, stalk compression by any sellar mass
• Note: PRL >200 µg/L after excluding the above almost invariably indicates a prolactin-secreting adenoma - Harrison's 22E, p. 3049

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B. Acromegaly / Gigantism

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C. Cushing Disease (Corticotroph Adenoma)

Step 1 - Confirm Hypercortisolism (at least two abnormal tests required)

• Midnight plasma cortisol >7.5 µg/dL (207 nmol/L): 100% specificity (requires 48h hospitalization, IV line, patient asleep at midnight)
• 2-day LDDST: 0.5 mg dexa q6h × 2 days; failure of UFC suppression confirms Cushing syndrome
• Dexamethasone-CRH combined test: LDDST followed by 100 µg oCRH 2h later; plasma cortisol >38 nmol/L at 15 min = Cushing syndrome with 100% sensitivity and specificity vs. pseudo-Cushing

Step 2 - Locate the Source (ACTH-dependent vs. independent)

• Henry's Clinical Diagnosis, pp. 477-479; Harrison's 22E

• Central:peripheral ACTH ratio >2:1 basal or >3:1 after CRH = pituitary source (100% sensitivity and specificity)
• Ratio <1.4:1 = ectopic
• Lateralization: higher-ratio side predicts tumor side in the sella
• Invasive, technically demanding - only at experienced centers

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D. TSH-Secreting Adenoma (Thyrotropinoma)

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E. Non-Functioning Adenoma / Gonadotropinoma

• Basal FSH, LH, alpha subunit - often mildly elevated or normal
• Presents via mass effects: visual field defects, headache, hypopituitarism
• Full pituitary hormone reserve testing (see below) to detect deficiencies
• MRI sella: usually macroadenoma at presentation

• 8 AM cortisol (or ITT for definitive ACTH reserve)
• TSH + free T4
• FSH, LH, testosterone (men) / estradiol + menstrual history (women)
• IGF-1 (± GHRH-arginine or glucagon test for GH reserve)
• Serum sodium + urine/plasma osmolality (screen for diabetes insipidus)

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3. Dynamic Tests - Master Reference Table

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4. Interpretation of Investigations

Biochemical Interpretation Pearls

• PRL and tumor size correlation: In true prolactinoma, PRL level correlates with tumor size. PRL >250 µg/L usually accompanies a macroadenoma. A macroadenoma with PRL <100-150 µg/L suggests stalk compression by a non-lactotrope tumor - dopamine agonists may lower PRL but will not shrink the underlying lesion.
• Post-OGTT GH: After ultrasensitive GH assays, the normal nadir is even lower (<0.05 µg/L); about 20% of acromegalic patients show a paradoxical GH rise (not suppression) after glucose.
• Cushing syndrome vs. pseudo-Cushing: Pseudo-Cushing (depression, alcoholism, obesity, poorly controlled diabetes) causes mild UFC elevation and may fail LDDST; the midnight cortisol >7.5 µg/dL discriminates with 100% specificity; the Dexa-CRH test is definitive.
• Imaging only after biochemical diagnosis: Pituitary and adrenal incidentalomas occur in up to 10% of the population - do NOT start with imaging.
• MRI in Cushing disease: Shows adenoma in only 50-60% of cases; a negative MRI does not exclude pituitary Cushing - IPSS is needed.

Radiological Interpretation

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5. Management

A. Prolactinoma

• Cabergoline (preferred): 0.5-1.0 mg twice weekly
  • Normalizes PRL in ~80% of microadenomas; ~70% of macroadenomas shrink
  • Restores gonadal function in most; galactorrhea improves in 90%
  • MRI at 16 weeks after starting in macroadenomas (striking shrinkage possible)
  • Mass effect symptoms often improve within days of starting
  • Reduce to lowest effective maintenance dose once controlled
• Bromocriptine: 0.625-1.25 mg at bedtime, titrating to 2.5 mg TID; preferred when fertility desired (short half-life; most pregnancy safety data)
• Side effects of DAs: nausea (25%), postural hypotension, constipation, dry mouth, insomnia, nightmares; impulse control disorders in ~5%; cardiac valvulopathy only at high Parkinson doses - echocardiogram recommended before starting cabergoline
• ~20% of patients are dopamine-resistant (decreased D2 receptor numbers or post-receptor defect)

• Microadenoma cure: ~70%; macroadenoma: ~40%
• Recurrence: up to 20% in year 1; >50% long-term for macroadenomas

• Stop DAs when pregnancy confirmed
• Macroadenoma: regular visual field testing; restart DA or consider surgery if tumor grows
• ~5% of microadenomas and 15-30% of macroadenomas grow during pregnancy

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B. Acromegaly

• Microadenoma cure: 80-90%; macroadenoma: <30% (but GH substantially reduced)
• GH normalization post-op = cure

• NOT effective as primary therapy (GH normalization takes 5-15 years)
• Adjunct for residual/recurrent tumor after surgery + medical therapy
• Stereotactic radiosurgery (Gamma Knife): faster than conventional
• Major risk: late hypopituitarism

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C. Cushing Disease

• Remission in ~70-80% of microadenomas (post-op morning cortisol <2 µg/dL)
• Post-operative adrenal insufficiency is expected and desired - confirms remission
• Hydrocortisone replacement until HPA recovery (6-18 months)

• Repeat TSS (if identifiable residual/recurrent tumor)
• Pituitary radiotherapy (stereotactic or conventional): adjunct; months-years for full effect; high hypopituitarism risk long-term
• Bilateral adrenalectomy: immediate cure of hypercortisolism; requires lifelong mineralocorticoid + glucocorticoid replacement; Nelson syndrome risk (rapid ACTH tumor growth + severe hyperpigmentation in up to 25%) - pituitary radiotherapy recommended before or after adrenalectomy
• Medical therapy (bridging to surgery, or adjunct):

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D. Non-Functioning Adenoma

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E. Thyrotropinoma

• TSS first-line
• SRLs (octreotide, lanreotide) highly effective pre-operatively and as adjunct; normalize TSH and thyroid hormones in >90%
• Antithyroid drugs as adjunct for pre-op euthyroid control

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6. Follow-Up Principles

Prolactinoma

• PRL every 3-6 months during DA titration; then every 6-12 months when stable
• MRI sella: macroadenoma - at 3-6 months after starting DA; then annually; microadenoma - every 1-2 years
• After DA withdrawal: PRL every 3 months × 1 year, then annually; MRI if PRL rises
• Monitor for DA side effects

Acromegaly

• IGF-1 + GH (post-OGTT nadir or random) every 3-6 months post-operatively
• Biochemical cure: IGF-1 in age-matched normal range AND GH nadir <0.4 µg/L
• MRI sella: 3 months post-op, then 6-12 months, then annually if residual tumor
• Comorbidity surveillance:
  • Colonoscopy at diagnosis and every 3-5 years (colon polyps / cancer risk)
  • Echocardiogram at diagnosis (cardiomyopathy, LVH)
  • Glucose/HbA1c annually (25% develop diabetes)
  • Sleep study (>60% have obstructive sleep apnea)
  • Liver ultrasound if on SRLs (gallstones)
  • Bone density (arthropathy, fracture risk)
  • Blood pressure monitoring

Cushing Disease

• Post-op cortisol (8 AM, within 24-48 hours): target <2 µg/dL = remission
• Glucocorticoid replacement until HPA recovery; test recovery with ITT or short Synacthen at 6-12 months
• Recurrence monitoring: 24h UFC, midnight salivary cortisol, or 1-mg DST every 6-12 months for at least 5 years (recurrence in 15-25%)
• MRI sella: 3 months post-op; then annually for 2-3 years; more often if recurrent
• After bilateral adrenalectomy: annual MRI and ACTH levels for Nelson syndrome surveillance
• Screen and manage long-term consequences: hypertension, diabetes, osteoporosis, cardiovascular disease, neuropsychiatric effects

Non-Functioning Adenoma (post-surgery)

• Full pituitary panel at 6 weeks: TSH/free T4, 8 AM cortisol, IGF-1, FSH/LH, testosterone/estradiol
• MRI sella: 3 months, 1 year, then every 1-2 years; residual tumor followed annually
• Visual fields post-op; repeat if residual suprasellar mass
• Hormone replacement as needed; reassess pituitary function periodically

General Follow-Up Principles for All Macroadenomas

• Screen for hypopituitarism before and after any treatment
• DEXA scan (bone mineral density) if hypogonadal, Cushing, or GH-deficient
• Annual metabolic review: blood pressure, glucose, lipids
• Ophthalmology if suprasellar extension was present
• Register with an endocrinologist for long-term care - follow-up is lifelong for macroadenomas

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• Robbins & Kumar Basic Pathology, p. 764 - classification and pathology
• Goldman-Cecil Medicine International Edition, pp. 2404-2406 - acromegaly, GH deficiency
• Harrison's Principles of Internal Medicine 22E (2025), pp. 3049-3052 - prolactinoma, acromegaly (full clinical management)
• Henry's Clinical Diagnosis and Management by Laboratory Methods, pp. 477-479 - Cushing syndrome diagnostic testing in detail