BASICS
DESCRIPTION
Typically benign, slow-growing tumors that arise from cells in the pituitary gland é á
- Pituitary adenomas have been identified as the third most frequent intracranial tumor; accounts for 10 " ô25%.
- Subtypes (hormonal): prolactinoma (PRL) 50%, nonfunctioning pituitary adenomas 30%, somatotroph adenoma (growth hormone [GH]) 15 " ô20%, corticotroph adenoma (adrenocorticotrophic hormone [ACTH]) 5 " ô10%, thyrotroph adenoma (thyroid-stimulating hormone [TSH]) <1%, gonadotropinoma (luteinizing hormone/follicle-stimulating hormone [LH/FSH]), mixed
- Defined as microadenoma <10 mm and macroadenoma ≥10 mm
- May secrete hormones and/or cause mass effects
EPIDEMIOLOGY
- Predominant age: Age increases incidence.
- Predominant sex: female > male (3:2) for microadenomas (often delayed diagnosis in men)
Incidence
- Autopsy studies have found microadenomas in 3 " ô27% and macroadenomas in <0.5% of people without any pituitary disorders.
- MRI scans illustrate abnormalities consistent with pituitary adenoma in 1/10 persons.
- Clinically apparent pituitary tumors are seen in 18/100,000 persons.
ETIOLOGY AND PATHOPHYSIOLOGY
- Monoclonal adenohypophysial cell growth
- Hormonal effects of functional microadenomas often prompt diagnosis before mass effect.
- Prolactin increased by functional prolactinomas or inhibited dopaminergic suppression by stalk effect
Genetics
- Carney complex
- Familial isolated pituitary adenomas: ~15% have mutations in the aryl hydrocarbon receptor " ôinteracting protein gene (AIP); present at a younger age and are larger in size (1)
- McCune-Albright syndrome
- Multiple endocrine neoplasia type 1 (MEN1) " ôlike phenotype (MEN4): germline mutation in the cyclin-dependent kinase inhibitor 1B (CDKN1B) (1)
RISK FACTORS
Multiple endocrine neoplasias é á
DIAGNOSIS
HISTORY
- Common
- Hyperprolactinemia: infertility, amenorrhea, galactorrhea, gynecomastia, impotence
- Headache (sellar expansion)
- Visual disturbances: bitemporal hemianopsia
- Less common
- Hypersomatotropinemia: acromegaly (coarse facial features, hand/foot swelling, carpal tunnel syndrome, hyperhidrosis, left ventricular hypertrophy)
- Hyposomatotropinemia: failure to thrive (FTT) (children), asymptomatic (adults)
- Intracranial pressure (ICP) elevation: headache, nausea, seizures
- Hypercorticotropinemia: Cushing disease (supraclavicular/dorsocervical fat pad thickening, moon face, hirsutism, acne, plethora, abdominal striae, centripetal obesity with thin limbs, easy bruising and bleeding, hyperglycemia)
- Rare
- Apoplexy: headache, sudden collapse
- Secondary hyperthyroidism: palpitations, diaphoresis, heat intolerance, diarrhea
- Secondary adrenal insufficiency: weakness, irritability, anorexia, nausea/vomiting
- Hypothalamic compression: temperature, thirst/appetite disorders
PHYSICAL EXAM
- Common
- Visual disturbances: bitemporal hemianopsia
- Hyperprolactinemia: hypogonadism, galactorrhea, gynecomastia
- Hypersomatotropinemia: acromegaly (coarse features, hand/foot swelling, diaphoresis)
- Hyposomatotropinemia: FTT (children)
- Less common
- ICP elevation: papilledema, dementia
- Cushing disease: centripetal obesity, supraclavicular fat pad thickening, moon face, hirsutism, acne
- Rare
- Apoplexy: hypotension, hypoglycemia, tachycardia, oliguria
- Secondary hyperthyroidism: tachycardia, tachypnea, diaphoresis, warm/moist skin, tremor
- Adrenal crisis: orthostatic hypotension
- Hypothalamic compression: temperature dysregulation, obesity, increased urination
DIFFERENTIAL DIAGNOSIS
Pituitary hyperplasia (e.g., pregnancy, primary hypothyroidism, menopause), Rathke cleft cyst, granulomatous disease (e.g., tuberculosis), lymphocytic hypophysitis, metastatic tumor, germinoma, craniopharyngioma é á
DIAGNOSTIC TESTS & INTERPRETATION
Select based on dysfunction(s) suspected é á
- Somatotrophic (GH secreting: 40 to 130/million)
- Acromegaly/hypersomatotropinemia: serum IGF-1 elevated; oral glucose tolerance test with GH given at 0, 30, and 60 minutes (normally suppresses GH to <1 g/L)
- Hyposomatotropinemia: low growth hormone " ôreleasing hormone response
- Corticotropic
- Cushing disease/hypercorticotropinemia
- 24-hour urinary-free cortisol >50 Ä ╝g
- Overnight low-dose dexamethasone suppression test (DMST): normal free plasma cortisol (FPC) >1.8 Ä ╝g/dL at 8 am (after 1 mg given at 11 pm on night prior)
- ACTH level assay (if DMST results abnormal): <20 pg/mL = adrenal tumor; ≥20 pg/mL = ectopic/pituitary source
- Hypocorticotropinemia/secondary glucocorticoid deficiency: high-dose corticotropin stimulation test: FPC <10 g/dL at baseline, with an increase of <25% 1 hour after 250 Ä ╝g; metyrapone test: 11-deoxycortisol <150 ng/L after 2 g given (prepare to give steroids because test may worsen insufficiency)
- Gonadotrophic/hypogonadotropinism: gonadotropin-releasing hormone stimulation of LH/FSH blunted in pituitary hypergonadism but increased in primary hypogonadism
- Lactotrophic (prolactin secreting): hyperprolactinemia: serum PRL >20 ng/mL
- Thyrotrophic (TSH secreting): hyper-/hypothyroidism: TSH and free T4 both increased for pituitary hyperthyroidism and both decreased for pituitary hypothyroidism
Initial Tests (lab, imaging)
- A typical panel for asymptomatic tumors: prolactin, GH, IGF-1, ACTH, 24-hour urinary-free cortisol or overnight DMST, Ä ▓-HCG, FSH, LH, TSH, free T4
- Maintain the same GH and IGF-1 through patient management (2)[C].
- Screening for AIP mutations may be offered to families of patients with pituitary adenoma, where available.
- MRI preferred (>90% sensitivity and specificity) after biochemically confirmed
- Octreotide scintigraphy is useful in identifying tumors with somatostatin receptors (2)[B].
Diagnostic Procedures/Other
Inferior petrosal sinus sampling: ACTH sampled from inferior petrosal sinuses to distinguish Cushing disease (pituitary source) from ectopic ACTH é á
Test Interpretation
- Cell types identified by immunohistochemistry
- Light microscope: eosinophilic (GH, PRL), basophilic (FSH/LH, TSH, ACTH), chromophobic
TREATMENT
Medical therapy is primary therapy for prolactinomas and adjunct for other tumors. é á
MEDICATION
First Line
- Hyperprolactinemia: Dopamine agonists increase dopaminergic suppression of PRL.
- Cabergoline (Dostinex): D2 receptor " ôspecific
- Initial dose: 0.25 mg PO once or twice weekly
- Maintenance dose: Increase q4wk by 0.25 mg 2 times/week per PRL (max 2 mg/week).
- Contraindications: hypersensitivity (ergots), uncontrolled hypertension (HTN), pregnancy
- Precautions: caution with liver impairment
- Interactions: may be inhibited by tricyclic antidepressants, phenothiazines, opiates
- Adverse reactions: orthostatic hypotension, vertigo, dyspepsia, hot flashes
- Bromocriptine (Parlodel): D2 receptor " ôspecific
- Initial dose: 1.25 to 2.5 mg PO daily (give with food)
- Maintenance dose: increase by 2.5 mg/day q2 " ô7d (max 15 mg/day)
- Contraindications: hypersensitivity (ergots), uncontrolled HTN, pregnancy; preferred over cabergoline if required
- Precautions: caution with liver impairment.
- Interactions: may be inhibited by tricyclic antidepressants, phenothiazines, opiates
- Adverse reactions: orthostatic hypotension, seizures, hallucinations, stroke, myocardial infarction
- Somatotropinoma
- Long-acting analogues of somatostatin (Sandostatin LAR and lanreotide Autogel)
- Sandostatin LAR: 20 mg q28d (2)[A]; lanreotide Autogel 90 mg q28d; titrate per package insert.
- Contraindication: hypersensitivity
- Precautions: caution with biliary, thyroid, cardiac, liver, or kidney disease
- Interactions: pimozide increases risk of QT prolongation; variable effects with Ä ▓-blockers, diuretics, oral glycemic agents
- Adverse reactions: ascending cholangitis, arrhythmias, congestive heart failure, glycemic instability
- More effective as adjuvant than as primary treatment for somatotropinomas
- Consider use of somatostatin analogue or pegvisomant in patients with severe residual disease (2)[A].
- Consider use of cabergoline in patients with mild residual disease (3)[B].
- Pegvisomant (Somavert): GH receptor antagonist
- Initial dose: 40 mg SC â Ś 1, then 10 mg daily and titrate by 5 mg every 4 to 6 weeks based on IGF-1 levels (max 30 mg/day maintenance dose)
- Contraindication: hypersensitivity
- Precautions: caution if GH-secreting tumors, diabetes mellitus, impaired liver function
- Interactions: NSAIDs, opiates, insulins, oral glycemic agents
- Adverse reactions: hepatitis, tumor growth, GH secretion
- Corticotropinemia: peripheral inhibitors
- Mitotane (Lysodren)
- Initial dose: 2 to 6 g/day divided PO TID (max 19 g/day)
- Maintenance dose: 2 to 16 g TID
- Contraindication: hypersensitivity
- Precautions: caution with liver dysfunction and brain damage
- Interactions: contraindicated with rotavirus vaccine; caution with other vaccines
- Adverse reactions: HTN, orthostatic hypotension, hemorrhagic cystitis, rash
- Ketoconazole
- Dosing: 200 mg PO TID (max 1,200 mg/day)
- Contraindications: hypersensitivity, achlorhydria, fungal meningitis, impaired liver function
- Precautions: caution with liver dysfunction
- Interactions: contraindicated with dronedarone, methadone, statins, pimozide, sirolimus; caution with other antifungals
- Adverse reactions: adrenal insufficiency, thrombocytopenia, hepatic failure, hepatotoxicity, anaphylaxis, leukopenia, hemolytic anemia
- Signifor (pasireotide)
- Dosing: initially, 0.6 to 0.9 mg twice daily, then 0.3 to 0.9 mg twice daily
- Contraindication: none
- Precautions: hypocortisolism, hyperglycemia, bradycardia or QT prolongation, liver test elevations, cholelithiasis, and other pituitary hormone deficiencies
- Korlym (mifepristone):
- Dosing: Administer PO once daily with a meal. The recommended starting dose is 300 mg once daily. Not to exceed 600 mg daily in renal impairment
- Contraindication: pregnancy, use of simvastatin or lovastatin and CYP3A substrates with narrow therapeutic range, concurrent long-term corticosteroid use, women with history of unexplained vaginal bleeding, women with endometrial hyperplasia with atypia or endometrial carcinoma
- Precautions: adrenal insufficiency, hypokalemia, vaginal bleeding and endometrial changes, QT interval prolongation, use of strong CYP3A inhibitors
- Interactions: potential interactions with drugs metabolized by CYP3A, CYP2C8/9, CYP2B6, and hormonal contraceptives. Nursing mothers should discontinue drug or discontinue nursing.
- Adverse reactions: most common adverse reactions in Cushing syndrome ( ≥20%): nausea, fatigue, headache, decreased blood potassium, arthralgia, vomiting, peripheral edema, HTN, dizziness, decreased appetite, endometrial hypertrophy
- Gonadotropinemia
- Bromocriptine: See earlier discussion.
- Thyrotropinemia
- Somatostatin analogues: See earlier discussion.
Second Line
- Corticotropinemia: peripheral inhibitors
- Metyrapone
- Dose: 250 mg PO QID
- Contraindication: porphyria
- Precautions: caution in liver/thyroid disease
- Interactions: Dilantin increases metabolism.
- Adverse reactions: nausea, hypotension
- Gonadotropinemia
- Octreotide: See earlier discussion.
ISSUES FOR REFERRAL
- Neurosurgery consultation for symptomatic tumors (except for prolactinoma)
- Ophthalmologist evaluation prior to surgery
ADDITIONAL THERAPIES
- Fractionated radiotherapy: often effective as adjunctive when surgery is inadequate (3)[B]
- Stereotactic radiosurgery: alternative to surgery in high-risk patients or as adjunct (3)[B]
SURGERY/OTHER PROCEDURES
- Most are now done endoscopically via translabial/transsphenoidal approach (4)[A].
- Indications: symptoms or treatment-resistant
- Follow-up: serial neurologic/hormonal evaluations to evaluate complications (e.g., diabetes insipidus, CNS damage) and need for more treatment
- Remission rates: 72 " ô87% for microadenoma but only 50 " ô56% for macroadenomas
INPATIENT CONSIDERATIONS
Admission Criteria/Initial Stabilization
Outpatient management unless apoplexy or adrenal crisis é á
- Treat pituitary apoplexy immediately to prevent death (see "Complications " Ł) (4)[A].
- Consider stress-dose steroids in frail or hemodynamically unstable patients.
- Maintain BP with fluids and/or pressor agents.
- Check serum sodium, serum osmolality, and urine specific gravity if polyuric or electrolytes are imbalanced.
- Contact neurosurgery.
IV Fluids
- Diabetes insipidus: hyposmolar IV fluids
- Adrenal crisis: normal saline
Nursing
- Pituitary apoplexy: Monitor inputs/outputs (I/Os), central venous pressure, and ICP, and do frequent neurologic checks.
- Adrenal crisis: Monitor BP and I/Os.
Discharge Criteria
Keep as inpatient postoperatively until diabetes insipidus and/or adrenal insufficiency is managed. é á
ONGOING CARE
FOLLOW-UP RECOMMENDATIONS
Patient Monitoring
- Follow-up MRIs at 6 and 12 months after discharge
- Involved hormone(s) are followed postoperatively, especially after radiation because hypopituitarism may develop 10 to 15 years after treatment.
PROGNOSIS
Depends on type, size, symptoms, therapy é á
COMPLICATIONS
- Postoperative diabetes insipidus and/or hypogonadism (usually transient/common)
- Pituitary apoplexy (acute/uncommon): acute hemorrhagic pituitary infarction; adrenal crisis with severe headache; surgical decompression required to prevent shock, coma, and death
- Nelson syndrome (subacute/uncommon): rapid adenoma growth postadrenalectomy
- Pituitary hormone insufficiency (chronic/uncommon): often years after treatment
- Optic nerve neuropathy and brain necrosis after >60 Gy radiotherapy (chronic/rare)
REFERENCES
11 Georgitsi é áM, Raitila é áA, Karhu é áA, et al. Molecular diagnosis of pituitary adenoma predisposition caused by aryl hydrocarbon receptor-interacting protein gene mutations. Proc Natl Acad Sci U S A. 2007;104(10):4101 " ô4105.22 Tichomirowa é áMA, Daly é áAF, Beckers é áA. Treatment of pituitary tumors: somatostatin. Endocrine. 2005;28(1):93 " ô100.33 Mondok é áA, Szeifert é áGT, Mayer é áA, et al. Treatment of pituitary tumors: radiation. Endocrine. 2005;28(1):77 " ô85.44 Buchfelder é áM. Treatment of pituitary tumors: surgery. Endocrine. 2005;28(1):67 " ô75.
SEE ALSO
Cushing Disease and Cushing Syndrome; Galactorrhea é á
CODES
ICD10
D35.2 Benign neoplasm of pituitary gland é á
ICD9
227.3 Benign neoplasm of pituitary gland and craniopharyngeal duct é á
SNOMED
- 254956000 Pituitary adenoma (disorder)
- 134209002 Prolactinoma (disorder)
- 254957009 Somatotroph adenoma (disorder)
- 254958004 Corticotroph adenoma
- 254960002 Gonadotroph adenoma
CLINICAL PEARLS
- An incidentaloma is an asymptomatic microadenoma found on imaging. General labs include PRL, GH, IGF-1, ACTH, 24-hour urinary-free cortisol/overnight DMST, Ä ▓-subunit FSH, LH, TSH, and free T4. Obtain follow-up MRIs at 6 and 12 months if normal, but consult endocrinology if not.
- Initial treatment selected for symptomatic pituitary adenoma includes a dopamine agonist for prolactinomas and surgical resection for all others.
- Pituitary apoplexy is a rapid hemorrhagic pituitary infarction due to compression of the blood supply. It is fatal within hours unless surgically decompressed.