> Table of Contents > Pituitary Adenoma
Pituitary Adenoma
Anup K. Sabharwal, MD, MBA, FACE, CCD
Lewis S. Blevins Jr., MD
image BASICS
DESCRIPTION
Typically benign, slow-growing tumors that arise from cells in the pituitary gland
  • Pituitary adenomas have been identified as the third most frequent intracranial tumor; accounts for 10-25%.
  • Subtypes (hormonal): prolactinoma (PRL) 50%, nonfunctioning pituitary adenomas 30%, somatotroph adenoma (growth hormone [GH]) 15-20%, corticotroph adenoma (adrenocorticotrophic hormone [ACTH]) 5-10%, 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 3-27% 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-interacting protein gene (AIP); present at a younger age and are larger in size (1)
  • McCune-Albright syndrome
  • Multiple endocrine neoplasia type 1 (MEN1)-like phenotype (MEN4): germline mutation in the cyclindependent kinase inhibitor 1B (CDKN1B) (1)
RISK FACTORS
Multiple endocrine neoplasias
image DIAGNOSIS
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
DIAGNOSTIC TESTS & INTERPRETATION
Select based on dysfunction(s) suspected
  • 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-releasing hormone response
  • Corticotropic
    • Cushing disease/hypercorticotropinemia
    • 24-hour urinary-free cortisol >50 &mgr;g
    • Overnight low-dose dexamethasone suppression test (DMST): normal free plasma cortisol (FPC) >1.8 &mgr;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 &mgr;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, &bgr;-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
Test Interpretation
  • Cell types identified by immunohistochemistry
  • Light microscope: eosinophilic (GH, PRL), basophilic (FSH/LH, TSH, ACTH), chromophobic
image TREATMENT
Medical therapy is primary therapy for prolactinomas and adjunct for other tumors.
MEDICATION
First Line
  • Hyperprolactinemia: Dopamine agonists increase dopaminergic suppression of PRL.
    • Cabergoline (Dostinex): D2 receptor-specific
      • 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-specific
      • Initial dose: 1.25 to 2.5 mg PO daily (give with food)
      • Maintenance dose: increase by 2.5 mg/day q2-7d (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
      • P.805

      • Precautions: caution with biliary, thyroid, cardiac, liver, or kidney disease
      • Interactions: pimozide increases risk of QT prolongation; variable effects with &bgr;-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 × 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: 72-87% for microadenoma but only 50-56% for macroadenomas
INPATIENT CONSIDERATIONS
Admission Criteria/Initial Stabilization
Outpatient management unless apoplexy or adrenal crisis
  • Treat pituitary apoplexy immediately to prevent death (see “Complications”) (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.
image 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
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
1. Georgitsi M, Raitila A, Karhu A, 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):4101-4105.
2. Tichomirowa MA, Daly AF, Beckers A. Treatment of pituitary tumors: somatostatin. Endocrine. 2005;28(1):93-100.
3. Mondok A, Szeifert GT, Mayer A, et al. Treatment of pituitary tumors: radiation. Endocrine. 2005;28(1): 77-85.
4. Buchfelder M. Treatment of pituitary tumors: surgery. Endocrine. 2005;28(1):67-75.
See Also
&NA;
Cushing Disease and Cushing Syndrome; Galactorrhea
Codes
&NA;
ICD10
D35.2 Benign neoplasm of pituitary gland
Clinical Pearls
&NA;
  • An incidentaloma is an asymptomatic microadenoma found on imaging. General labs include PRL, GH, IGF-1, ACTH, 24-hour urinary-free cortisol/overnight DMST, &bgr;-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.