PituitaryTumor Syndromes¶
Chapter 392 | Part 12: Endocrinology and Metabolism · Part 12 – Endocrinology & Metabolism · Chapter 392
Key Clinical Points¶
- Pituitary adenomas are the most common cause of pituitary hormone hypersecretion and hyposecretion syndromes in adults, accounting for ~15% of all intracranial neoplasms.
- Hyperprolactinemia is the most common pituitary hormone hypersecretion syndrome; PRL levels >200 μg/L suggest a prolactinoma, while levels <200 μg/L are often due to stalk compression or drugs.
- Visual field defects (bitemporal hemianopia) are the hallmark of suprasellar extension compressing the optic chiasm; nasal fibers are most vulnerable.
- MRI with gadolinium is the imaging modality of choice; adenomas typically show lower density than normal tissue on T1 and increased signal on T2.
- Transsphenoidal surgery is the preferred surgical approach for most pituitary tumors; radiation therapy is reserved for residual tumor or nonfunctioning tumors.
- MEN1 syndrome (MENIN mutation) is associated with pituitary adenomas in ~40% of patients, often prolactinomas.
- Familial acromegaly is associated with germline mutations in the AIP gene (aryl hydrocarbon receptor interacting protein).
- Craniopharyngiomas are benign, suprasellar cystic masses derived from Rathke's pouch; ~75% recur without radiotherapy.
- Drug-induced hyperprolactinemia is common with antipsychotics (e.g., risperidone), methyldopa, and verapamil.
- GnRH testing (100 μg IV) distinguishes hypothalamic from pituitary causes of hypogonadism; a normal response suggests intact pituitary function.
1. DEFINITION & OVERVIEW¶
• Pituitary Adenomas: Benign neoplasms arising from one of the five anterior pituitary cell types. They account for ~15% of all intracranial neoplasms and have a population prevalence of ~80/100,000. • Incidence: At autopsy, up to one-quarter of all pituitary glands harbor an unsuspected microadenoma (<10 mm diameter). Pituitary imaging detects small clinically inapparent lesions in at least 10% of individuals. • Sellar Mass Classification: • Microadenoma: ≤ 10 mm in diameter; often clinically inapparent. • Macroadenoma: >10 mm in diameter; approximately one-third become invasive or cause local pressure effects. • Pituitary Anatomy (MRI with Gadolinium): • Dimensions: Height ranges from 6 mm (children) to 8 mm (adults); during pregnancy and puberty, height may reach 10–12 mm. • Morphology: The upper aspect of the adult pituitary is flat or slightly concave; in adolescents/pregnant individuals, it may be convex. • Stalk: Should be midline and vertical; deviation suggests pathology.
1.1 Sellar Mass Classification¶
• Incidentalomas: Most sellar masses are pituitary adenomas found incidentally on MRI. • Management of Incidentalomas: • No hormone hypersecretion → Monitor safely with annual MRI (frequency decreases if no growth). • Large macroadenomas → Resection considered due to 1/3 risk of invasion or local pressure effects.
2. EPIDEMIOLOGY¶
• Prevalence: Pituitary adenomas are the most common cause of pituitary hormone hypersecretion and hyposecretion syndromes in adults. • Incidence: ~15% of all intracranial neoplasms; population prevalence ≈ 80/100,000.
3. ETIOLOGY & PATHOPHYSIOLOGY¶
• Cell-Type Specificity: • Lactotrope → PRL • Somatotrope → GH • Corticotrope → ACTH • Thyrotrope → TSH • Gonadotrope → LH, FSH • Plurihormonal tumors express combinations of GH, PRL, TSH, ACTH, or α/β subunits. • Pathogenesis: • Gα Mutations: Found in ~35% of GH-secreting tumors; leads to constitutive cAMP elevation and somatotrope proliferation. • Growth Factors: bFGF (mitogenesis) and EGFR (hormone synthesis/proliferation). • Other Factors: USP8 mutations (ACTH-secreting), loss of negative-feedback inhibition, and estrogen-mediated angiogenesis. • Genetic Syndromes: • MEN1 (MENIN mutation): Autosomal dominant; 40% present with pituitary adenomas (mostly prolactinomas). • Carney Complex (PRKAR1A): Pituitary hyperplasia/adenomas in 10%; also includes atrial myxomas and lentigines. • Familial Acromegaly: Linked to germline mutations in the AIP gene.
Table 392-4: Familial Pituitary Tumor Syndromes¶
• MEN1 (11q13): Hyperparathyroidism; Pancreatic neuroendocrine tumors; Foregut carcinoids; Adrenal adenomas; Skin lesions; Pituitary adenomas (40%). • MEN4 (12p13): Pituitary adenomas; Other tumors. • Carney Complex (17q23-24): Pituitary hyperplasia and adenomas (10%); Atrial myxomas; Schwannomas; Adrenal hyperplasia; Lentigines. • Familial Pituitary Adenomas (11q13.2): Acromegaly/gigantism (~15% of affected families).
4. CLINICAL FEATURES¶
• Local Mass Effects: • Headache: Common even in small tumors; severity correlates poorly with size. • Vision Loss: Most commonly bitemporal hemianopia (optic chiasm compression); rare direct optic nerve invasion or CSF flow obstruction. • Stalk Compression: Results in early hyperprolactinemia and later loss of other pituitary hormones due to lack of dopamine/hypothalamic input. • Cranial Nerve Palsies: Caused by cavernous sinus involvement (CN III, IV, VI) and trigeminal nerve branches (facial numbness). • Hypothalamic Impact: Temperature dysregulation, appetite/thirst disorders, obesity, sleep disturbances, and endocrine changes (e.g., precocious puberty). • Hormonal Hypersecretion: • Autonomy: Hormones secreted independently of feedback. • Size vs. Function: Small adenomas can cause significant symptoms; large ones may be clinically silent.
Table 392-1: Features of Sellar Mass Lesions¶
• Pituitary: Hypogonadism, Hypothyroidism, Growth failure/GH deficiency, Hypoadrenalism, Hyperprolactinemia (stalk compression). • Optic Chiasm: Bitemporal hemianopia, Superior or bitemporal field defect, Scotoma, Blindness. • Hypothalamus: Temperature dysregulation, Appetite/thirst disorders, Obesity, Sleep disorders, Behavioral dysfunction, Autonomic dysfunction. • Cavernous Sinus: Ophthalmoplegia (with/without ptosis/diplopia), Facial numbness. • Frontal Lobe: Personality disorder, Anosmia. • Brain: Headache, Hydrocephalus, Psychosis, Dementia, Laughing seizures.
Table 392-3: Classification of Pituitary Adenomas¶
• Lactotrope: PRL → Hypogonadism, galactorrhea. • Gonadotrope: FSH, LH, subunits → Silent/nonfunctioning, ovarian hyperstimulation, hypogonadism. • Somatotrope: GH → Acromegaly/gigantism. • Corticotrope: ACTH → Cushing's disease or silent. • Mixed (Lacto/Somato): GH, PRL → Acromegaly, hypogonadism, galactorrhea. • Acidophil stem cell: PRL, GH → Hypogonadism, galactorrhea, acromegaly. • Mammosomatotrope: PRL, GH → Hypogonadism, galactorrhea, acromegaly. • Thyrotrope: TSH → Thyrotoxicosis. • Oncocytoma: None → Hypopituitarism/none.
Hypothalamic Lesions¶
• Anterior/Preoptic Regions: Paradoxical vasoconstriction, tachycardia, hyperthermia. • Posterior Hypothalamus: Central disorders of thermoregulation (e.g., periodic hypothermia syndrome: <30°C, sweating, bradycardia). • Ventromedial Nuclei: Hyperphagia and obesity. • Preoptic Nuclei: Polydipsia/hypodipsia (damage to central osmoreceptors). • Central Hypothalamus: Sympathetic activation → elevated catecholamines/cortisol → risk of arrhythmias, hypertension, gastric erosions.
5. DIFFERENTIAL DIAGNOSIS¶
• Craniopharyngiomas: • Origin: Rathke's pouch. • Features: Benign, suprasellar cystic masses; often large, cystic, and locally invasive; frequently calcified (visible on CT/X-ray). • Demographics: >50% present before age 20. • Clinical: Headache, vomiting, papilledema, hydrocephalus, hypopituitarism (~90%), AVP-D (~10%). • Recurrence: ~75% recur without radiotherapy. • Rathke's Cysts: • Size: Small (<5 mm). • Features: Cyst wall visible on MRI; common in 20% of autopsies. • Other Sellar Masses: • Sellar Chordomas: Bone clival erosion, local invasiveness, calcification. • Meningiomas: May show calcification or bone erosion; hard to distinguish from nonfunctioning adenomas. • Histiocytosis X: AVP-D, exophthalmos, punched-out lytic bone lesions (Hand-Schüller-Christian). • Pituitary Metastases: ~3% of cancer patients; mostly in posterior pituitary → AVP-D. Common in breast cancer (~50%). • Hamartomas/Gangliocytomas: Can produce GnRH → precocious puberty, psychomotor delay, laughing seizures.
6. INVESTIGATIONS & DIAGNOSIS¶
- Initial Imaging: MRI of sellar region to identify mass and assess pituitary function.
- Baseline Laboratory Evaluation: • Prolactin (PRL) • IGF-1 • 24-h Urinary Free Cortisol (UFC) or Overnight Dexamethasone (1 mg) suppression. • α subunit, FSH, LH • Thyroid Function Tests
- Specialized Testing: • GnRH Test (100 μg IV): • Normal response (LH peaks in 30 min, FSH plateaus over 60 min) → Pituitary function intact → Hypothalamic cause. • Absent/Blunted response → Pituitary dysfunction.
- Histopathology: Immunohistochemical staining of tissue from transsphenoidal surgery to confirm cell type and hormone production.
Table 392-2: Screening Tests for Functional Pituitary Adenomas¶
• Acromegaly: Serum IGF-1 (interpret vs. age/sex); Oral glucose tolerance test with GH at 0, 30, 60 min (Normal → suppress to <1 μg/L). • Cushing's Disease: 24-h UFC; Dexamethasone (1 mg) at 11 P.m. and fasting plasma cortisol at 8 a.m. (Normal → <5 μg/dL); Late night salivary cortisol; ACTH assay; CRH stimulation test (distinguishes pituitary from ectopic). • TSH-producing Adenoma: Free T3, Free T4, TSH, free α subunit. Key: Inappropriately normal or high TSH with elevated free T3/T4.
7. MANAGEMENT & TREATMENT¶
- Surgical Intervention: • Transsphenoidal Surgery: Preferred approach for most tumors. • Radiation Therapy: Reserved for residual tumor or nonfunctioning tumors.
- Medical Management: • Dopamine Agonists (e.g., Cabergoline): Primary treatment for prolactinomas; can reduce size and normalize PRL levels. • Somatostatin Receptor Ligands (SRL): Used in acromegaly (e.g., octreotide, lanreotide). • Other Agents: Peglisomant, Pasireotide (for Cushing's or refractory cases).
- Hormone Replacement: • Required for patients with hypopituitarism before further testing/surgery.
Flowchart 2: Management of Prolactinoma¶
- Initial Step: Identify Prolactinoma (Exclude secondary causes/MRI evidence).
- Classification: Determine if Microadenoma or Macroadenoma.
- Microadenoma Pathway: • Titrate dopamine agonist → Measure Serum PRL. • If <20 μ ext{g/L} → Maintenance Rx. • If 20-50 μ ext{g/L} → Reassess diagnosis / Increase dose. • If >50 μ ext{g/L} → Change dopamine agonist → (Consider Surgery if criteria met).
- Macroadenoma Pathway: • Test visual fields & pituitary reserve → Titrate dopamine agonist → Repeat MRI in 4 months. • If 'Tumor shrinkage and prolactin normalized' → Monitor PRL; repeat MRI annually. • If 'Drug intolerance' → Change dopamine agonist. • If 'No tumor shrinkage or tumor growing or persistent hyperprolactinemia' → Consider Surgery.
Flowchart 3: Management of Acromegaly¶
- Initial Choice: Surgery OR Primary SRL (if surgery not feasible).
- Post-Surgery Assessment: • If Well controlled → Monitor IGF-1. • If Not controlled → Cabergoline.
- Cabergoline Evaluation: • If Well controlled → Monitor IGF-1. • If Not controlled → SRL.
- SRL Evaluation: • If Not controlled → [Peglisomant / Increase SRL dose / Reoperation].
- Advanced Management (if needed): • If Peglisomant not controlled → [SRL + peglisomant, Pasireotide, or Radiotherapy/Re-operation]. • If Pasireotide not controlled → [Pasireotide + peglisomant, or Re-operation].
Flowchart 4: Management of Cushing's Disease¶
- Initial Step: ACTH-dependent hypercortisolism → Imaging/Sampling → Identify Pituitary Adenoma.
- Exclusion: Ensure Ectopic ACTH is excluded before proceeding to pituitary surgery (Criteria: Dexamethasone suppression <5 μ ext{g/dL}, CRH test).
- Post-Surgery Assessment: • If 'Biochemical cure' → Follow up (Glucocorticoid replacement if needed). • If 'Persistent hypercortisolism' → Medical options: Pasireotide, Glucocorticoid receptor antagonists, or Steroidogenic inhibitors.
- Radiology/Surgery: • If medical fails → Pituitary irradiation. • If 'Risk of Nelson's syndrome' → Adrenalectomy.
Flowchart 5: Management of Nonfunctioning Pituitary Mass¶
- Initial Assessment: MRI/Clinical features → Dynamic testing.
- Classification: Identify as 'Nonfunctioning adenoma' or 'Other sellar mass'.
- Adenoma Path: • If Microadenoma → Low risk of visual loss → Observe → Follow-up MRI. • If Macroadenoma → Surgery → [Parallel: MRI AND Trophic hormone testing and replacement].
- Other Mass Path: • Exclude aneurysm → Surgery → Histologic diagnosis → [Parallel: MRI, potentially disease-specific therapy, and Trophic hormone testing and replacement].
9. SPECIAL CONSIDERATIONS¶
• Drug-Induced Hyperprolactinemia: • Dopamine receptor blockers: Antipsychotics (risperidone), Phenothiazines, Butyrophenones, Thioxanthenes. • Other Drugs: α-Methyldopa, Reserpine, Opiates, H antagonists, Cimetidine/ranitidine, Imprimamines, Amitriptyline, Fluoxetine, Verapamil, Estrogens.
Table 5: Etiology of Hyperprolactinemia¶
• Physiologic: Pregnancy, Lactation, Chest wall stimulation, Sleep, Stress. • Stalk Damage: Pituitary adenoma, Suprasellar mass, Craniopharyngioma, Meningioma, Dysgerminoma, Metastases, Empty sella, Lymphocytic hypophysitis, Granulomas, Rathke's cyst, Irradiation, Trauma, Stalk section, Surgery. • Adenoma: Prolactinoma, Acromegaly. • Systemic: Renal failure, Hypothyroidism, Cirrhosis, Pseudocyesis, Seizures. • Drug-induced: Dopamine blockers (risperidone, chlorpromazine), α-Methyldopa, Reserpine, Opiates, H antagonists, Cimetidine, Ranitidine, Imprimamines, Amitriptyline, Fluoxetine, Verapamil, Estrogens.
10. KEY PEARLS & CLINICAL TRAPS¶
• Diagnostic Clues: • Prolactin >200 μ ext{g/L} is highly suggestive of a prolactinoma. • Bitemporal hemianopia indicates optic chiasm involvement. • GnRH test: Normal response = Pituitary intact; Abnormal = Pituitary failure. • Craniopharyngiomas are often calcified and occur in children. • Clinical Traps: • Do not assume all hyperprolactinemia is a tumor (check drugs, pregnancy, and renal failure). • Ensure ectopic ACTH is ruled out before assuming Cushing's disease is from a pituitary adenoma.
Reference Tables¶
TABLE 392-1 Features of Sellar Mass Lesions a¶
Harrison's 22e, p.2999
| IMPACTED STRUCTURE | CLINICAL IMPACT |
|---|---|
| Pituitary | Hypogonadism Hypothyroidism Growth failure, adult growth hormone deficiency Hypoadrenalism Hyperprolactinema (stalk compression) |
| Hypothalamus | Temperature dysregulation Appetite and thirst disorders Obesity Arginine vasopression deficiency Sleep disorders Behavioral dysfunction Autonomic dysfunction |
| Frontal lobe | Personality disorder Anosmia |
TABLE 392-2 Screening Tests for Functional Pituitary Adenomas Acromegaly¶
Harrison's 22e, p.3001
| TEST | COMMENTS | |
|---|---|---|
| Acromegaly | Serum IGF-1 Oral glucose tolerance test with GH obtained at 0, 30, and 60 min |
Interpret IGF-1 relative to age- and sex-matched controls Normal subjects should suppress growth hormone to <1 μg/L |
| Serum PRL | ||
| Cushing’s disease | 24-h urinary free cortisol Dexamethasone (1 mg) at 11 P.m. and fasting plasma cortisol measured at 8 a.m. Late night salivary cortisol ACTH assay CRH stimulation test with measurements of cortisol and ACTH from peripheral and/or petrosal sinus blood |
Ensure urine collection is total and accurate Normal subjects suppress to <5 μg/dL Distinguishes adrenal adenoma (ACTH suppressed) from ectopic ACTH or Cushing’s disease (ACTH normal or elevated) The CRH test is used primarily to distinguish pituitary adenomas from ectopic ACTH sources |
| Baseline FSH, LH, free α subunit, ovarian hyperstimulation, estrogen (females), testosterone (males) TRH stimulation test with assays for LH, FSH, free α subunit, free LHβ, free FSHβ subunits |
||
| TSH-producing adenoma |
Free T, free T, TSH, free 4 3 α subunit |
Key feature is an inappropriately normal or high TSH in the setting of elevated free T and T 4 3 |
TABLE 392-3 Classification of Pituitary Adenomas a¶
Harrison's 22e, p.3003
| ADENOMA CELL ORIGIN | HORMONE PRODUCT |
CLINICAL SYNDROME |
|---|---|---|
| Lactotrope | PRL | Hypogonadism, galactorrhea |
| FSH, LH, subunits |
||
| Somatotrope | GH | Acromegaly/gigantism |
| ACTH/none | ||
| Mixed lactotrope and somatotrope |
GH, PRL | Acromegaly, hypogonadism, galactorrhea |
| Any | ||
| Acidophil stem cell | PRL, GH | Hypogonadism, galactorrhea, acromegaly |
| PRL, GH | ||
| Thyrotrope | TSH | Thyrotoxicosis |
| None | ||
| Oncocytoma | None | Hypopituitarism/none |
TABLE 392-4 Familial Pituitary Tumor Syndromes (See Chap. 400) Multiple endocrine neoplasia 1 (MEN 1)¶
Harrison's 22e, p.3004
| GENE MUTATED | CLINICAL FEATURES | |
|---|---|---|
| Multiple endocrine neoplasia 1 (MEN 1) |
MEN1 (11q13) |
Hyperparathyroidism Pancreatic neuroendocrine tumors Foregut carcinoids Adrenal adenomas Skin lesions Pituitary adenomas (40%) |
| CDKNIB (12p13) |
||
| Carney complex | PRKAR1A (17q23-24) |
Pituitary hyperplasia and adenomas (10%) Atrial myxomas Schwannomas Adrenal hyperplasia Lentigines |
| AIP (11q13.2) |
TABLE 392-5 Etiology of Hyperprolactinemia I. Physiologic hypersecretion¶
Harrison's 22e, p.3005
- I. Physiologic hypersecretion
Pregnancy
Lactation
Chest wall stimulation
Sleep
Stress - II. Hypothalamic-pituitary stalk damage
Pituitary adenoma with stalk compression
Suprasellar mass
Craniopharyngioma
Meningioma
Dysgerminoma
Metastases
Empty sella
Lymphocytic hypophysitis
Granulomas
Rathke’s cyst
Irradiation
Trauma
Pituitary stalk section
Suprasellar surgery
III. Pituitary adenoma hypersecretion
Prolactinoma
Acromegaly
IV. Systemic disorders
Chronic renal failure
Hypothyroidism
Cirrhosis
Pseudocyesis
Epileptic seizures
V. Drug-induced hypersecretion
Dopamine receptor blockers
Atypical antipsychotics: risperidone
Phenothiazines: chlorpromazine, perphenazine
Butyrophenones: haloperidol
Thioxanthenes
Metoclopramide
Dopamine synthesis inhibitors
α-Methyldopa
Catecholamine depletors
Reserpine
Opiates
H antagonists
2
Cimetidine, ranitidine
Imipramines
Amitriptyline, amoxapine
Serotonin reuptake inhibitors
Fluoxetine
Calcium channel blockers
Verapamil
Estrogens
Thyrotropin-releasing hormone
TABLE 392-6 Causes of Acromegaly Excess Growth Hormone Secretion Pituitary¶
Harrison's 22e, p.3008
| PREVALENCE, % | |
|---|---|
| Excess Growth Hormone Secretion | |
| Pituitary Densely or sparsely granulated GH cell adenoma Mixed GH cell and PRL cell adenoma Mammosomatotrope cell adenoma Plurihormonal adenoma GH cell carcinoma or metastases Multiple endocrine neoplasia 1 (GH cell adenoma) McCune-Albright syndrome Ectopic sphenoid or parapharyngeal sinus pituitary adenoma Extrapituitary tumor Pancreatic islet cell tumor Lymphoma |
98 60 25 10 <1 |
| Excess Growth Hormone–Releasing Hormone Secretion |
TABLE 392-7 Clinical Features of Cushing’s Syndrome (All Ages) SYMPTOMS/SIGNS Obesity or weight gain (>115% ideal body…¶
Harrison's 22e, p.3011
| SYMPTOMS/SIGNS | FREQUENCY, % |
|---|---|
| Obesity or weight gain (>115% ideal body weight) | 80 |
| Moon facies | 75 |
| Purple skin striae | 65 |
| Menstrual disorders (usually amenorrhea) | 60 |
| Abnormal glucose tolerance | 55 |
| Proximal muscle weakness | 50 |
| Acne | 45 |
| Mental changes | 45 |
| Edema of lower extremities | 30 |
| Hypokalemic alkalosis | 15 |
TABLE 392-8 Differential Diagnosis of ACTH-Dependent Cushing’s Syndrome a¶
Harrison's 22e, p.3011
| ACTH-SECRETING PITUITARY TUMOR |
ECTOPIC ACTH SECRETION |
|
|---|---|---|
| Etiology | Pituitary corticotrope adenoma Plurihormonal adenoma |
Bronchial, abdominal carcinoid Small-cell lung cancer Thymoma, other sources |
| F > M | ||
| Clinical features | Slow onset | Rapid onset Pigmentation Severe myopathy |
| <10% | ||
| 24-h UFC | High | High |
| Inappropriately high | ||
| Dexamethasone suppression 1 mg overnight Low-dose (0.5 mg q6h) |
Cortisol >5 μg/dL | Cortisol >5 μg/dL |
| High-dose (2 mg q6h) | Cortisol <5 μg/dL | Cortisol >5 μg/dL |
| Microadenomas: 90% Macroadenomas: 50% |
||
| Inferior petrosal sinus sampling |
||
| Basal central: peripheral |
>2 | <2 |
| CRH-induced central: peripheral |
>3 | <3 |