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Pituitary Adenoma

BASICS

DESCRIPTION

- Rare - Apoplexy: headache, sudden collapse - Secondary hyperthyroidism: palpitations, diaphoresis, heat intolerance, diarrhea - Secondary adrenal insufficiency: weakness, irritability, anorexia, nausea/vomiting

- Rare - Apoplexy: hypotension, hypoglycemia, tachycardia, oliguria - Secondary hyperthyroidism: tachycardia, tachypnea, diaphoresis, warm/moist skin, tremor - Adrenal crisis: orthostatic hypotension

- 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)

- 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

- 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

- Gonadotropinemia - Bromocriptine: See earlier discussion.

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

  • CommonHyperprolactinemia: infertility, amenorrhea, galactorrhea, gynecomastia, impotenceHeadache (sellar expansion)Visual disturbances: bitemporal hemianopsia
  • Less commonHypersomatotropinemia: 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, seizuresHypercorticotropinemia: Cushing disease (supraclavicular/dorsocervical fat pad thickening, moon face, hirsutism, acne, plethora, abdominal striae, centripetal obesity with thin limbs, easy bruising and bleeding, hyperglycemia)
  • RareApoplexy: headache, sudden collapseSecondary hyperthyroidism: palpitations, diaphoresis, heat intolerance, diarrheaSecondary adrenal insufficiency: weakness, irritability, anorexia, nausea/vomiting
  • Hypothalamic compression: temperature, thirst/appetite disorders

PHYSICAL EXAM

  • CommonVisual disturbances: bitemporal hemianopsiaHyperprolactinemia: hypogonadism, galactorrhea, gynecomastiaHypersomatotropinemia: acromegaly (coarse features, hand/foot swelling, diaphoresis)Hyposomatotropinemia: FTT (children)
  • Less commonICP elevation: papilledema, dementiaCushing disease: centripetal obesity, supraclavicular fat pad thickening, moon face, hirsutism, acne
  • RareApoplexy: hypotension, hypoglycemia, tachycardia, oliguriaSecondary hyperthyroidism: tachycardia, tachypnea, diaphoresis, warm/moist skin, tremorAdrenal 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
  • CorticotropicCushing disease/hypercorticotropinemia24-hour urinary-free cortisol >50 Ä ╝gOvernight 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 sourceHypocorticotropinemia/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 " ôspecificInitial dose: 0.25 mg PO once or twice weeklyMaintenance dose: Increase q4wk by 0.25 mg 2 times/week per PRL (max 2 mg/week).Contraindications: hypersensitivity (ergots), uncontrolled hypertension (HTN), pregnancyPrecautions: caution with liver impairmentInteractions: may be inhibited by tricyclic antidepressants, phenothiazines, opiatesAdverse reactions: orthostatic hypotension, vertigo, dyspepsia, hot flashesBromocriptine (Parlodel): D2 receptor " ôspecificInitial 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 requiredPrecautions: caution with liver impairment.Interactions: may be inhibited by tricyclic antidepressants, phenothiazines, opiatesAdverse reactions: orthostatic hypotension, seizures, hallucinations, stroke, myocardial infarction
  • SomatotropinomaLong-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: hypersensitivityPrecautions: caution with biliary, thyroid, cardiac, liver, or kidney diseaseInteractions: pimozide increases risk of QT prolongation; variable effects with Ä ▓-blockers, diuretics, oral glycemic agentsAdverse reactions: ascending cholangitis, arrhythmias, congestive heart failure, glycemic instabilityMore effective as adjuvant than as primary treatment for somatotropinomasConsider 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 antagonistInitial 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: hypersensitivityPrecautions: caution if GH-secreting tumors, diabetes mellitus, impaired liver functionInteractions: NSAIDs, opiates, insulins, oral glycemic agentsAdverse reactions: hepatitis, tumor growth, GH secretion
  • Corticotropinemia: peripheral inhibitorsMitotane (Lysodren)Initial dose: 2 to 6 g/day divided PO TID (max 19 g/day)Maintenance dose: 2 to 16 g TIDContraindication: hypersensitivityPrecautions: caution with liver dysfunction and brain damageInteractions: contraindicated with rotavirus vaccine; caution with other vaccinesAdverse reactions: HTN, orthostatic hypotension, hemorrhagic cystitis, rashKetoconazoleDosing: 200 mg PO TID (max 1,200 mg/day)Contraindications: hypersensitivity, achlorhydria, fungal meningitis, impaired liver functionPrecautions: caution with liver dysfunctionInteractions: contraindicated with dronedarone, methadone, statins, pimozide, sirolimus; caution with other antifungalsAdverse reactions: adrenal insufficiency, thrombocytopenia, hepatic failure, hepatotoxicity, anaphylaxis, leukopenia, hemolytic anemiaSignifor (pasireotide)Dosing: initially, 0.6 to 0.9 mg twice daily, then 0.3 to 0.9 mg twice dailyContraindication: nonePrecautions: hypocortisolism, hyperglycemia, bradycardia or QT prolongation, liver test elevations, cholelithiasis, and other pituitary hormone deficienciesKorlym (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 impairmentContraindication: 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 carcinomaPrecautions: adrenal insufficiency, hypokalemia, vaginal bleeding and endometrial changes, QT interval prolongation, use of strong CYP3A inhibitorsInteractions: 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
  • GonadotropinemiaBromocriptine: See earlier discussion.
  • ThyrotropinemiaSomatostatin analogues: See earlier discussion.

Second Line

  • Corticotropinemia: peripheral inhibitorsMetyraponeDose: 250 mg PO QIDContraindication: porphyriaPrecautions: caution in liver/thyroid diseaseInteractions: Dilantin increases metabolism.Adverse reactions: nausea, hypotension
  • GonadotropinemiaOctreotide: 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.