Evaluation and Management of Selected Pituitary Issues · PDF fileEvaluation and Management of...

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Evaluation and Management Evaluation and Management of Selected Pituitary Issuesof Selected Pituitary Issues

Dana Erickson, MDDana Erickson, MDNeena Natt, MDNeena Natt, MD

Mayo Clinic College of MedicineMayo Clinic College of MedicineRochester, MNRochester, MN

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Coronal section through cavernous sinusCoronal section through cavernous sinus

Cavernous sinusCavernous sinus

Oculomotor nerve (III)Oculomotor nerve (III)

Trochlear nerve (IV)Trochlear nerve (IV)

Abducens nerve (VI)Abducens nerve (VI)

Ophthalmic nerve (VOphthalmic nerve (V11))

Maxillary nerve (VMaxillary nerve (V22))

Optic chiasmOptic chiasm

PosteriorPosteriorcommunicating arterycommunicating artery

Internal carotid arteryInternal carotid artery

Hypophysis Hypophysis (pituitary gland)(pituitary gland)

Sphenoidal sinusSphenoidal sinus

NasopharynxNasopharynx

Mass Effects or Potential Mass EffectsMass Effects or Potential Mass EffectsAnatomyAnatomy

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Normal Pituitary on MRI ScanNormal Pituitary on MRI Scan

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Causes of Sellar MassesCauses of Sellar Masses

• Pituitary adenoma (10% intracranial Pituitary adenoma (10% intracranial neoplasms; microadenomas <1 cm, neoplasms; microadenomas <1 cm, macroadenomas >1 cm)macroadenomas >1 cm)• Cysts (Rathke’s cleft, arachnoid cysts)Cysts (Rathke’s cleft, arachnoid cysts)• CraniopharyngiomaCraniopharyngioma• MeningiomaMeningioma• Lymphocytic hypophysitisLymphocytic hypophysitis

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Causes of Sellar MassesCauses of Sellar Masses

• MalignanciesMalignanciesPrimary (germ cell tumors, chordoma, Primary (germ cell tumors, chordoma,

lymphoma, pituitary carcinoma)lymphoma, pituitary carcinoma)

Metastases (breast, lung, others)Metastases (breast, lung, others)

• Infiltrative disordersInfiltrative disorders

• Pituitary hyperplasia Pituitary hyperplasia

• Infections, AV fistulaInfections, AV fistula

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Pituitary TumorsPituitary Tumors

DiscoveredDiscovered

• IncidentallyIncidentally

•Clinical evidence of mass symptoms,Clinical evidence of mass symptoms,or hormonal excess or deficiency or hormonal excess or deficiency symptomssymptoms

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Genetics of Pituitary TumorsGenetics of Pituitary Tumors

Possible genes involved in certain Possible genes involved in certain tumorigenesistumorigenesis

• MEN1MEN1

• Gs-alphaGs-alpha

• PTTGPTTG

• FGF receptor 4FGF receptor 4

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Hormonal deficiencies Hormonal deficiencies • Anterior failure: ACTH, LH, FSH,Anterior failure: ACTH, LH, FSH,

TSH, GHTSH, GH• Posterior failure: ADHPosterior failure: ADH

Hormonal excessHormonal excess• Separately (prolactin, TSH, ACTH, GH)Separately (prolactin, TSH, ACTH, GH)• Combination of hormonal Combination of hormonal

overproductionoverproduction

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Sellar MassesSellar Masses

Mass effectMass effect

• HeadachesHeadaches

• Chiasmal compromiseChiasmal compromise

• Cranial nerve palsiesCranial nerve palsies

• CSF leakCSF leak

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MacroadenomaMacroadenoma

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Pituitary Microadenoma on MRI ScanPituitary Microadenoma on MRI Scan

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After careful hormonal evaluation treatment After careful hormonal evaluation treatment strategies depend onstrategies depend on

• Presence of mass effectPresence of mass effect

• Hormonal hypersecretion Hormonal hypersecretion

• Hormonal deficienciesHormonal deficiencies

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Primary therapy could include Primary therapy could include

• NeurosurgeryNeurosurgery

• ObservationObservation

• Medical therapy (prolactinoma, some Medical therapy (prolactinoma, some cases of acromegaly)cases of acromegaly)

• Radiation therapy (rarely)Radiation therapy (rarely)

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Surgical Goals for Pituitary TumorsSurgical Goals for Pituitary Tumors

1.1.Reverse or prevent mass effect Reverse or prevent mass effect

2.2.Reverse hormone deficiency Reverse hormone deficiency

3.3.Normalize hormone overproductionNormalize hormone overproduction

4.4.Minimize morbidityMinimize morbidity

5.5.Prevention of tumor recurrencePrevention of tumor recurrence

6.6.Tissue for pathologic diagnosisTissue for pathologic diagnosis

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Transsphenoidal Pituitary SurgeryTranssphenoidal Pituitary Surgery

• Sublabial transseptal approachSublabial transseptal approach

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Transsphenoidal Pituitary SurgeryTranssphenoidal Pituitary Surgery

• Transnasal endoscopic approachTransnasal endoscopic approach

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Pituitary tumorPituitary tumorSphenoid sinusSphenoid sinus

Sphenoid sinus ostiumSphenoid sinus ostium

Middle Middle turbinateturbinate

Septum

ChoanaChoana

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TransseptalTransseptal TransnasalTransnasal

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TransseptalTransseptal TransnasalTransnasal

10°10°

PitPit PitPitSphenoid Sphenoid sinussinus

Maxillary Maxillary sinussinus

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Endoscopic vs SublabialEndoscopic vs Sublabial

• No external incisionNo external incision

• Nasal septum intactNasal septum intact

• No postop nasal packingNo postop nasal packing

• Operating microscopeOperating microscope

• Smaller operating fieldSmaller operating field

• 10 degrees off center10 degrees off center

• Endoscopic visualization Endoscopic visualization

• Sublabial incisionSublabial incision

• Septum removed/replacedSeptum removed/replaced

• Postop packing 3-5 daysPostop packing 3-5 days

• Operating microscopeOperating microscope

• Larger operating fieldLarger operating field

• Field at 90 degreesField at 90 degrees

• N/AN/A

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** P<0.001P<0.001**** P<0.0001P<0.0001

0

2

4

6

OR time (hr) Anes time (hr) Hosp stay (days)

Dur

atio

n (h

r or d

ays)

Dur

atio

n (h

r or d

ays)

StandardStandardEndoscopicEndoscopic

3.43.4

2.72.7

4.44.4

3.63.6

4.54.5

2.62.6**

**

****

Procedure Duration and Postoperative Procedure Duration and Postoperative Hospitalization: Endoscopic vs StandardHospitalization: Endoscopic vs Standard

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Sheehan et al: Mayo Clin Proc 74:661, 1999Sheehan et al: Mayo Clin Proc 74:661, 1999

• Shorter operative timeShorter operative time• Shorter hospital stayShorter hospital stay• Similar extent of tumor resectionSimilar extent of tumor resection• Similar preservation of pituitary functionSimilar preservation of pituitary function• Similar preservation of visual fieldsSimilar preservation of visual fields• Off center sellar approachOff center sellar approach• 50% reduction in working channel diameter50% reduction in working channel diameter

Endoscopic Transnasal Pituitary SurgeryEndoscopic Transnasal Pituitary Surgery

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Non-Cushing’s patientsNon-Cushing’s patientsCortisolCortisol<5 ug/dL: replacement Rx<5 ug/dL: replacement Rx(reassess in 1-3 months)(reassess in 1-3 months)

5-10 ug/dL: gray area5-10 ug/dL: gray area

>10 ug/dL: no replacement necessary>10 ug/dL: no replacement necessary

Pituitary SurgeryPituitary SurgeryPostoperative Assessment of Adrenal AxisPostoperative Assessment of Adrenal Axis

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Pituitary Surgery – Posterior PituitaryPituitary Surgery – Posterior PituitaryMonitorMonitor• I and OI and O• Urine specific gravityUrine specific gravity• If needed, electrolytes, serum osmIf needed, electrolytes, serum osm

Let patient drink to thirstLet patient drink to thirst• Problems if hypothalamic thirst center damagedProblems if hypothalamic thirst center damaged• Most patients have dry mouth if nasal packingMost patients have dry mouth if nasal packing

DDAVP if neededDDAVP if needed• SQ route necessary with nasal packs or excess SQ route necessary with nasal packs or excess

nasal drainagenasal drainage• Usual dose: 1-2 mcg q day to bid prn (4 mcg/mL)Usual dose: 1-2 mcg q day to bid prn (4 mcg/mL)

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Pituitary IncidentalomaPituitary Incidentaloma

What tests should be done?What tests should be done?

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Pituitary IncidentalomaPituitary Incidentaloma

Pituitary incidentaloma (unsuspected Pituitary incidentaloma (unsuspected anatomic abnormality in pituitary gland)anatomic abnormality in pituitary gland)

• Autopsy: 10%, majority microadenomasAutopsy: 10%, majority microadenomas

• MRI studies: 1-30%MRI studies: 1-30%

• Etiology: majority cysts, adenomas Etiology: majority cysts, adenomas (prolactin producing 12-28%), others(prolactin producing 12-28%), others

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Case 2: Pituitary IncidentalomaCase 2: Pituitary Incidentaloma

Natural historyNatural history• Very small risk of enlargement in Very small risk of enlargement in

microadenomas (0.4-7%)microadenomas (0.4-7%)• Higher in macroadenomas Higher in macroadenomas • EvaluationEvaluation

Clinical symptomsClinical symptomsMacroadenoma: full hormonal evaluationMacroadenoma: full hormonal evaluationMicroadenoma: prolactin, ± IGF-1Microadenoma: prolactin, ± IGF-1

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Potential for hypopituitarismPotential for hypopituitarism

• Microadenomas: very low riskMicroadenomas: very low risk

• Macroadenomas: depends on how hard Macroadenomas: depends on how hard one looks (15-57%)one looks (15-57%)

Nishzawa, 1998; Nammour, 1997; Feldkamp, 1999; Donovan, 1995Nishzawa, 1998; Nammour, 1997; Feldkamp, 1999; Donovan, 1995

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Nonfunctioning Pituitary AdenomasNonfunctioning Pituitary Adenomas

• Tumors of pituitary gland that do not Tumors of pituitary gland that do not secrete pituitary hormones that lead tosecrete pituitary hormones that lead toa clinical syndromea clinical syndrome

• 30% of all pituitary tumors30% of all pituitary tumors

• Electron microscopy: small secretory Electron microscopy: small secretory granulesgranules

• Immunostaining: frequently positiveImmunostaining: frequently positivefor FSH, LHfor FSH, LH

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Non-Functioning Pituitary TumorsNon-Functioning Pituitary Tumors

• Do not secrete pituitary hormones that Do not secrete pituitary hormones that lead to a clinical syndromelead to a clinical syndrome

• Mass effectMass effect

• Hormonal deficienciesHormonal deficiencies

• Not all require surgical therapyNot all require surgical therapy

• Follow-up necessaryFollow-up necessary

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Follow-UpFollow-Up

• 3 and 9 months postoperatively: imaging, 3 and 9 months postoperatively: imaging, hormonal testinghormonal testing

• Further follow-up depending on clinical Further follow-up depending on clinical course: yearly imaging and hormonal course: yearly imaging and hormonal testing for 5 years, then less frequentlytesting for 5 years, then less frequently

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Potential for growthPotential for growth

• Microadenomas: low risk 0-7%Microadenomas: low risk 0-7%

• Macroadenomas: 12-26% overMacroadenomas: 12-26% over1-6 years1-6 years

Potential for apoplexy?Potential for apoplexy?

Reincke, 1990; Donovan, 1995; Feldkamp, 1999Reincke, 1990; Donovan, 1995; Feldkamp, 1999

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ProlactinomasProlactinomas

• 5% of pituitary autopsy studies5% of pituitary autopsy studies

• 30-40% clinically recognized30-40% clinically recognizedpituitary tumorspituitary tumors

• 90% microadenomas90% microadenomas

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ProlactinomaProlactinoma

DiagnosisDiagnosis

• Pathological hyperprolactinemiaPathological hyperprolactinemia

• Radiographic evidence of pituitary Radiographic evidence of pituitary adenomaadenoma

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HyperprolactinemiaHyperprolactinemia

PituitaryPituitary• ProlactinomaProlactinoma• Nonfunctioning Nonfunctioning

adenomaadenoma• HypophysitisHypophysitis• Stalk sectionStalk section• Infiltrative diseaseInfiltrative disease

HypothalmicHypothalmic• TumorsTumors• Infiltrative diseaseInfiltrative disease

SecondarySecondary• Renal failureRenal failure• Primary Primary

hypothyroidismhypothyroidism• Adrenal Adrenal

insufficiencyinsufficiency• Polycystic ovary Polycystic ovary

syndromesyndrome

PhysiologicalPhysiological• PregnancyPregnancy• Breast stimulationBreast stimulation• StressStress

MedicationMedication• AntipsychoticsAntipsychotics• AntiemeticsAntiemetics• AntihypertensivesAntihypertensives• EstrogenEstrogen

AnalyticalAnalytical• MacroprolactinMacroprolactin• Heterophilic Heterophilic

antibodiesantibodies

↑↑ prolactinprolactin

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• Monomeric (23 kDa) 85-95%Monomeric (23 kDa) 85-95%

• ““Big” prolactin (50 kDa) 5-10%Big” prolactin (50 kDa) 5-10%

• ““Big-big” prolactin/macroprolactin (170 Big-big” prolactin/macroprolactin (170 kDa) small % – biologically inactivekDa) small % – biologically inactive

• Post-translationally modified forms:Post-translationally modified forms:small %small %

Circulating ProlactinCirculating Prolactin

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MacroprolactinMacroprolactin

Separate out PRL molecules to quantify Separate out PRL molecules to quantify monomeric PRL concentrationmonomeric PRL concentration

• Gel-filtration chromatographyGel-filtration chromatography

• PEG precipitation with an electro-PEG precipitation with an electro-chemiluminescent assaychemiluminescent assay

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Treatment Options for ProlactinomasTreatment Options for Prolactinomas

• Medications: dopamine agonistsMedications: dopamine agonists

• SurgerySurgery

• RadiationRadiation

• ObservationObservation

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Prolactinomas – Medical TherapyProlactinomas – Medical Therapy

• Bromocriptine (2.5 mg 2-3 x per day)Bromocriptine (2.5 mg 2-3 x per day)• Cabergoline (0.25-1 mg once or Cabergoline (0.25-1 mg once or

twice/week at bedtime)twice/week at bedtime)• Quinagolide Quinagolide • Side effects: GI upset, postural Side effects: GI upset, postural

hypotension, nasal stuffiness, depressionhypotension, nasal stuffiness, depression• Incremental dosage schedule, tbl during Incremental dosage schedule, tbl during

the meal!the meal!

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Prospective Comparative Studies of Bromocriptine,Prospective Comparative Studies of Bromocriptine,Cabergoline, and QuinagolideCabergoline, and Quinagolide

aa Bromocriptine: total 276, PRL n: 157 (57%), G: 79%, AD: 67%, WD: 35 (13%); Cabergoline: total 294, PRL n: 256 Bromocriptine: total 276, PRL n: 157 (57%), G: 79%, AD: 67%, WD: 35 (13%); Cabergoline: total 294, PRL n: 256 (85%), G: 91%, AD: 37%, WD: 8 (2.5%); Quinagolide: total 112, PRL n:88 (78%), G: 84%, AD: 65%, WD: 4 (3.5%)(85%), G: 91%, AD: 37%, WD: 8 (2.5%); Quinagolide: total 112, PRL n:88 (78%), G: 84%, AD: 65%, WD: 4 (3.5%)

bb All other studies had a few macroadenomas (only 6 out of 643 patients).All other studies had a few macroadenomas (only 6 out of 643 patients).BCR, bromocriptine; CBG, cabergoline; QUI, quinagolide; R, Randomized; MC, multicenter; DB, double blind; NB, BCR, bromocriptine; CBG, cabergoline; QUI, quinagolide; R, Randomized; MC, multicenter; DB, double blind; NB,

nonblinded; CO, crossover; PRL n, PRL normalization; G, gonadal function; AD, adverse effects; WD, drug withdrawal; mic, nonblinded; CO, crossover; PRL n, PRL normalization; G, gonadal function; AD, adverse effects; WD, drug withdrawal; mic, microadenoma; mac, macroadenomamicroadenoma; mac, macroadenoma

ReturnReturnof mensesof mensesor normalor normal MildMild

StudyStudy ProlactinProlactin gonadalgonadal adverseadverse DrugDrugStudy authorStudy author TotalTotal design anddesign and normalizationnormalization functionfunction effectseffects withdrawalwithdrawal(year) (ref)(year) (ref) DrugsDrugsaa patientspatients durationduration (PRL n)(PRL n) (G) (%)(G) (%) (AD) (%)(AD) (%) (WD)(WD)

WebsterWebster BCRBCR 236236 MC, RMC, R 138 (58%)138 (58%) 8484 7878 27 (12%)27 (12%)(1994) (14)(1994) (14) CBGCBG 223223 DB (8 wk)DB (8 wk) 186 (83%)186 (83%) 9393 6868 7 (3%)7 (3%)

Van der HeijdenVan der Heijden BCRBCR 24 24 R, DB, R, DB, 14 (70%)14 (70%) 7979 6666 4 (16%)4 (16%)(1991) (15)(1991) (15) QUIQUI 23 23 24 wk24 wk 17 (81%)17 (81%) 8080 7878 1 (14%)1 (14%)

VerhelstVerhelst BCRBCR 5 5 R, DB, R, DB, 2 (40%)2 (40%) 7070 6060 00(1991) (16)(1991) (16) QUIQUI 7 7 24 wk24 wk 3 (43%)3 (43%) 8282 5757 1 (14%)1 (14%)

HomburghHomburgh BCFBCF 11 11 R, DB, R, DB, 3 (27%)3 (27%) 8282 6464 4 (36%)4 (36%)(1990) (17)(1990) (17) QUIQUI 11 11 24 wk24 wk 10 (91%)10 (91%) 9191 8282 00

GiustiGiusti CBGCBG 12 12 R, NBR, NB 10 (83%)10 (83%) 8282 5050 1 (8%)1 (8%)(1994) (18)(1994) (18) QUIQUI CO, 12 wkCO, 12 wk 6 (50%)6 (50%) 8080 9090 2 (16%)2 (16%)

Di SarnoDi Sarno CBGCBG 3939bb (23 (23 NB, CONB, CO 22 (95%) mic22 (95%) mic 100% (mic)100% (mic) 0 0 00(2000) (19)(2000) (19) mic andmic and 52 wk52 wk 14 (87%) mac14 (87%) mac

16 mac)16 mac)QUIQUI 23 (100%) mic23 (100%) mic 100% mic100% mic 3030 00

14 (87%) mac14 (87%) mac 62% mac62% mac

De Luis DADe Luis DA CBGCBG 20 20 R, NB, R, NB, 18 (90%)18 (90%) 9595 3030 00(2000) (20)(2000) (20) QUIQUI CO, 12 wkCO, 12 wk 15 (75%)15 (75%) 9090 5555 00

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• Effect on tumor sizeEffect on tumor sizeShrinkage >25%: 89%Shrinkage >25%: 89%Time course: 2 weeks-yearsTime course: 2 weeks-years

• VF improvement: 90%VF improvement: 90%

• Therapy resistant: 10% (cystic, Therapy resistant: 10% (cystic, deficiency of membrane-bound D2 deficiency of membrane-bound D2 receptors)receptors)

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Length of therapy?Length of therapy?

Microadenomas 2-5 years?Microadenomas 2-5 years?

Macroadenomas – lifelong?Macroadenomas – lifelong?

Withdrawal of dopamine agonistsWithdrawal of dopamine agonists

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Withdrawal of Dopamine AgonistsWithdrawal of Dopamine Agonists

• 200 patients: (70 macroprolactinomas,200 patients: (70 macroprolactinomas,105 microprolactinomas, 25 nontumoral 105 microprolactinomas, 25 nontumoral hyperprolactinemia)hyperprolactinemia)• Normal prolactin levels, MRI no tumor or Normal prolactin levels, MRI no tumor or

reduction of >50%, available for follow-upreduction of >50%, available for follow-upx 24 monthsx 24 months• Tumor not visible, or decreased byTumor not visible, or decreased by

50% by MRI50% by MRI• More than 5 mm from optic chiasmMore than 5 mm from optic chiasm

Colao et al: NEJM, 2003Colao et al: NEJM, 2003

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Withdrawal of Dopamine AgonistsWithdrawal of Dopamine Agonists

Recurrence of prolactin elevationRecurrence of prolactin elevation

• 24% idiopathic hyperprolactinemia24% idiopathic hyperprolactinemia

• 31% microprolactinomas31% microprolactinomas

• 36% macroprolactinomas36% macroprolactinomas

• No tumoral enlargementNo tumoral enlargement

Colao et al: NEJM, 2003Colao et al: NEJM, 2003

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Cabergoline WithdrawalCabergoline Withdrawal

• Extended study on 221 patients follow-up Extended study on 221 patients follow-up 24-96 months (29 exited after 36 months)24-96 months (29 exited after 36 months)

• Multiple regression analysisMultiple regression analysisNadir PRL levelsNadir PRL levelsNadir maximal tumor diameter prior to Nadir maximal tumor diameter prior to

withdrawalwithdrawalMaximal tumor diameter at DxMaximal tumor diameter at Dx

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Cabergoline WithdrawalCabergoline Withdrawal

0

25

50

75

100

0 10 20 30 40 50 60

Lack

of r

ecur

renc

eLa

ck o

f rec

urre

nce

afte

r with

draw

al (%

)af

ter w

ithdr

awal

(%)

Follow-up after withdrawal (mo)Follow-up after withdrawal (mo)

P<0.001P<0.001

Negative MRINegative MRI

Positive MRIPositive MRI

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0

20

40

60

80

100

0 12 24 36 48 60 72 84 96

Cabergoline WithdrawalCabergoline WithdrawalD

isea

se-fr

ee p

reva

lenc

e (%

)D

isea

se-fr

ee p

reva

lenc

e (%

)

Follow-up (months)Follow-up (months)

Chi-square 113.4Chi-square 113.4P<0.0001P<0.0001

NoneNone

Only nadir maximalOnly nadir maximaltumor diametertumor diameter

Only PRL nadirOnly PRL nadir

BothBoth

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Cabergoline Withdrawal Cabergoline Withdrawal

• 46 patients (majority microprolactinomas):46 patients (majority microprolactinomas):

Recurrence rate: 54%Recurrence rate: 54%

Estimated recurrence at 18 months: 63%Estimated recurrence at 18 months: 63%

Kharlip et al: JCEM, 2009Kharlip et al: JCEM, 2009

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DA + Cardiac ValvulopathiesDA + Cardiac Valvulopathies

Seen in patients treated for Parkinson Seen in patients treated for Parkinson diseasedisease• Daily doses of pergoglide greaterDaily doses of pergoglide greater

than 3 mgthan 3 mg• Daily doses of cabergoline greaterDaily doses of cabergoline greater

than 3 mgthan 3 mg• Duration of use of 6 months or moreDuration of use of 6 months or more

Zanetti et al: NEJM, 2007Zanetti et al: NEJM, 2007Schade et al: NEJM, 2007Schade et al: NEJM, 2007

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WHY?WHY?

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DA + Cardiac ValvulopathiesDA + Cardiac ValvulopathiesCross-Sectional Case Controlled Studies in Patients Cross-Sectional Case Controlled Studies in Patients

Treated with Cabergoline for ProlactinomaTreated with Cabergoline for Prolactinomaand Cardiac Valvulopathiesand Cardiac Valvulopathies

Moderate/severeModerate/severevalvulopathyvalvulopathy RegurgitationRegurgitation DoseDose DurationDuration

AuthorAuthor No.No. patients vs controlspatients vs controls patients vs controlspatients vs controls (mg)(mg) (months)(months)

Lancelloti, 2008Lancelloti, 2008 102102 2% vs 0%2% vs 0% 41% vs 50%41% vs 50% 204204 7979

Colao, 2008Colao, 2008 5050 54% vs 18%54% vs 18% 30% vs 32%30% vs 32% 280280 >12 in 68%>12 in 68%of ptof pt

Bogazzi, 2008Bogazzi, 2008 100100 7% vs 6%7% vs 6% 9% vs 8%9% vs 8% 279279 6767

Kars, 2008Kars, 2008 4747 17% vs 3%17% vs 3% 41% vs 26% (0.05)41% vs 26% (0.05) 363363 6464

Wakil, 2008Wakil, 2008 4444 0% vs 0%0% vs 0% 3.1 odds ratio (0.04)3.1 odds ratio (0.04) 311311 4545

Herring, 2009Herring, 2009 5050 0% vs 0%0% vs 0% 2 pt vs 4 controls2 pt vs 4 controls 443443 7979

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ProlactinomaProlactinoma

• Medical therapy even when mass effectMedical therapy even when mass effect

• Surgery second line treatmentSurgery second line treatment

• R/O pregnancyR/O pregnancy

• Delay therapy of hypogonadismDelay therapy of hypogonadism

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AcromegalyAcromegaly

• Diagnosis: clinical suspicion + biochemical Diagnosis: clinical suspicion + biochemical evaluationevaluation

Biochemical evaluation Biochemical evaluation

• IGF-1, ALS, IGBP-3IGF-1, ALS, IGBP-3

• GH level randomGH level random

• Oral glucose suppression test for GH (75 gm)Oral glucose suppression test for GH (75 gm)

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Fielder: Acta Paediatr ScandFielder: Acta Paediatr ScandSuppl 337:104, 1991Suppl 337:104, 1991

Target organTarget organ

IGFBPIGFBPIGFIGF

IGF synthesisIGF synthesis

GH-BPGH-BP

GH receptorGH receptor

HypothalamusHypothalamus

PituitaryPituitary

GHGH

Signal transductionSignal transduction

IGF receptorIGF receptor

Signal transductionSignal transduction

GrowthGrowth

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0

10

20

30

40

50

60

GH

(G

H ( µµ

g/L)

g/L)

ClocktimeClocktime

Normal subjectNormal subject

0

10

20

30

40

50

60

GH

(G

H ( µµ

g/L)

g/L)

ClocktimeClocktime


0900 2300 09000900 2300 0900

NormalNormal SleepSleep

Patient BPatient B

Patient APatient A

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Clinical signsClinical signs

• Somatic effectsSomatic effects

•Metabolic effectsMetabolic effects

• Local symptoms (headaches, VF Local symptoms (headaches, VF defects, cranial nerve palsies)defects, cranial nerve palsies)

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• Acral overgrowthAcral overgrowth

• Hypertrophic arthropathyHypertrophic arthropathy

• Cardiovascular abnormalities (HTN, left Cardiovascular abnormalities (HTN, left ventricular hypertrophy, CMP, ventricular hypertrophy, CMP, arrhythmias, valvular heart disease)arrhythmias, valvular heart disease)

• Visceral enlargement (cardiac, colon, Visceral enlargement (cardiac, colon, thyroid), soft tissue thickeningthyroid), soft tissue thickening

• Respiratory disease: sleep apneaRespiratory disease: sleep apnea

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• Psychosexual effects (decreased libido, Psychosexual effects (decreased libido, menstrual irregularities, impotence, menstrual irregularities, impotence, depression)depression)

• Increased risk of premalignant colonic Increased risk of premalignant colonic polypspolyps

• HypopituitarismHypopituitarism

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Metabolic EffectsMetabolic Effects

• Carbohydrates = diabetogenic Carbohydrates = diabetogenic

• Proteins = anabolic effectProteins = anabolic effect

• Lipids = hyperlipidemias Lipids = hyperlipidemias

• HypercalcemiaHypercalcemia

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MortalityMortality• 2-3 elevated to matched population 2-3 elevated to matched population

• Cause: cardiovascular, cerebrovascular Cause: cardiovascular, cerebrovascular and cancerand cancer

• Correlated with high GHCorrelated with high GH

•When GH returns to normal, IGF-1 When GH returns to normal, IGF-1 normal – mortality rate returns to normalnormal – mortality rate returns to normal

Swearingen, 1998: Holdaway, 2004Swearingen, 1998: Holdaway, 2004

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• Annual incidence 3-4 million peopleAnnual incidence 3-4 million people• EtiologyEtiologyPituitary tumorsPituitary tumorsGHRH producing tumorsGHRH producing tumors

(hypothalamic tumors, carcinoids, small-(hypothalamic tumors, carcinoids, small-cell lung cancers)cell lung cancers)

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Therapy of AcromegalyTherapy of Acromegaly

• NeurosurgeryNeurosurgery• Primary medical therapy or medical Primary medical therapy or medical

therapy for persistent postoperative or therapy for persistent postoperative or recurrent diseaserecurrent disease• Radiation – persistent or recurrent diseaseRadiation – persistent or recurrent disease• Observation – NOObservation – NO• Goals: normalization of IGF-1, GH levels Goals: normalization of IGF-1, GH levels

on glucose suppression test <1 ng/mLon glucose suppression test <1 ng/mL

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Surgical Therapy of AcromegalySurgical Therapy of Acromegaly

Goals of surgeryGoals of surgery• Normalization of GH secretion and IGF-INormalization of GH secretion and IGF-I• Elimination of mass effectElimination of mass effect• Alleviation of comorbiditiesAlleviation of comorbidities• Preservation of pituitary functionPreservation of pituitary function• Prevention of recurrence of tumorPrevention of recurrence of tumor• Tissue for pathologic DxTissue for pathologic Dx

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Surgical Therapy of AcromegalySurgical Therapy of Acromegaly

Surgical cure dependsSurgical cure depends

• Neurosurgeon Neurosurgeon

• Criteria used for cure Criteria used for cure

• Size, location of tumor (50-80%)Size, location of tumor (50-80%)

• Postoperative follow-up: IGF-1, oGTTPostoperative follow-up: IGF-1, oGTT2-3 months later2-3 months later

Gittoes, 1999; Clayton, 1999Gittoes, 1999; Clayton, 1999

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Medical Therapy of AcromegalyMedical Therapy of Acromegaly

• Dopamine agonists – normal IGF-1 <20% Dopamine agonists – normal IGF-1 <20% patients patients

• Somatostatin analogs – normal IGF-1 inSomatostatin analogs – normal IGF-1 in50-60% of patients50-60% of patients

Octreotide; short or long acting (sandostatin Octreotide; short or long acting (sandostatin LAR); lanreotideLAR); lanreotide(somatuline depot)(somatuline depot)

Tumors size – mild decrease 25-50%Tumors size – mild decrease 25-50%in 30-50% casesin 30-50% cases

Side effects! Side effects! Colao, 2001Colao, 2001

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Systematic review of primary medical Systematic review of primary medical therapy with somatostatin analogs therapy with somatostatin analogs decrease in tumor size in 37% patients decrease in tumor size in 37% patients (mean change 19%)(mean change 19%)

Melmed, 2005Melmed, 2005

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• GH receptor antagonist – pegvisomantGH receptor antagonist – pegvisomant• Substitution in GH moleculeSubstitution in GH molecule• Prevents dimerization of GH receptor, Prevents dimerization of GH receptor,

decrease in IGF-1, cannot monitor GH decrease in IGF-1, cannot monitor GH levelslevels• Normalization of IGF-1 in 97% of patientsNormalization of IGF-1 in 97% of patients• Side effects: LFT, ? enlargement of Side effects: LFT, ? enlargement of

residual tumorresidual tumorvan der Lely, 2001; Trainer, 2000van der Lely, 2001; Trainer, 2000

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Pradhanga S J Mol Endocrinol 29(1):13, 2002Pradhanga S J Mol Endocrinol 29(1):13, 2002

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• Combination therapy monthly Combination therapy monthly somatostatin analog + weekly somatostatin analog + weekly pegvisomant (60 mg) – 38% response pegvisomant (60 mg) – 38% response

• Costly!!!Costly!!!

Feenstra, 2005Feenstra, 2005

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Radiation Therapy for AcromegalyRadiation Therapy for Acromegaly

Conventional, fractionated radiationConventional, fractionated radiation• 45 GY over 4-5 weeks45 GY over 4-5 weeks• Long latency period (up to 10 years for Long latency period (up to 10 years for

effectiveness)effectiveness)• 75-80% normal GH in 10 years, 90% 20 75-80% normal GH in 10 years, 90% 20

yearsyears• Side effects: 90% hypopituitarism,? Side effects: 90% hypopituitarism,?

secondary brain tumors,? decline in secondary brain tumors,? decline in intellectual function intellectual function

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Stereotactic, focused radiation therapy Stereotactic, focused radiation therapy (gamma knife, LINEAC, proton beam)(gamma knife, LINEAC, proton beam)• Normal IGF-1 in 30-40%; 6 monthsNormal IGF-1 in 30-40%; 6 months

to 7 years to 7 years • Tumor shrinkage by 25% in 58% Tumor shrinkage by 25% in 58%

patients patients • Side effectsSide effects

Hypopituitarism 50-70%Hypopituitarism 50-70%

Attanasio 2003; Pollock, 2002Attanasio 2003; Pollock, 2002

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• 46 patients (1991-2004), 93% previous 46 patients (1991-2004), 93% previous pituitary surgery pituitary surgery • 50% biochemical remission at median 50% biochemical remission at median

36 months, continued up to 5 years36 months, continued up to 5 years• 80% biochemical remission in patients 80% biochemical remission in patients

with IGF-1 <2.25 ULN and no with IGF-1 <2.25 ULN and no suppressive pituitary medicationssuppressive pituitary medications• New pituitary deficits 33% at 5 yearsNew pituitary deficits 33% at 5 years

Pollock, 2007Pollock, 2007

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• Reserved for patients with residual Reserved for patients with residual diseasedisease

• Bridging with medical therapy until effects Bridging with medical therapy until effects take parttake part

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SummarySummary

Appropriate etiology guided treatmentAppropriate etiology guided treatment

• NeurosurgeryNeurosurgery

• Medical therapy for certain tumorsMedical therapy for certain tumors

• Radiation for residual and progressive Radiation for residual and progressive diseasedisease

• Observation, serial imaging studies and Observation, serial imaging studies and hormonal evaluation in selected caseshormonal evaluation in selected cases

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Diabetes Insipidus in HospitalDiabetes Insipidus in Hospital

Dg suspect when polyuria in patients at riskDg suspect when polyuria in patients at risk

• After pituitary surgeryAfter pituitary surgery

• Head traumaHead trauma

• Lithium or demeclocycline Lithium or demeclocycline (nephrogenic DI)(nephrogenic DI)

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• Measure simultaneously plasma and urine Measure simultaneously plasma and urine osmolality, serum sodium, glucose, BUNosmolality, serum sodium, glucose, BUN

• R/O hypercalcemia, hypokalemiaR/O hypercalcemia, hypokalemia• Dg: plasma osmolality >295 mOs/kg, Dg: plasma osmolality >295 mOs/kg,

serum NA >145 meq/L and urine serum NA >145 meq/L and urine osmolality <600 mOs/kg concomitantly osmolality <600 mOs/kg concomitantly with urine volume >150 mL/hrwith urine volume >150 mL/hr

• If data unclear repeat in 2-4 hoursIf data unclear repeat in 2-4 hours

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If DI confirmedIf DI confirmed• DDAVP 1 mcg sc or iv orDDAVP 1 mcg sc or iv or• 10 mcg intranasally or 0.1 mg orally 10 mcg intranasally or 0.1 mg orally • Verify tubular response: increase urine Verify tubular response: increase urine

osmolality >600 mOs/kg and decrease osmolality >600 mOs/kg and decrease urine volume by >50% over 4-6 hoursurine volume by >50% over 4-6 hours• Plasma ADH measurement when serum Plasma ADH measurement when serum

hyperosmolar, if nephrogenic DI hyperosmolar, if nephrogenic DI suspectedsuspected

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• Replace existing fluid deficit 50% overReplace existing fluid deficit 50% over24 hours with D5W if neurologically stable 24 hours with D5W if neurologically stable and serum Na <160 meq/L; do not reduce and serum Na <160 meq/L; do not reduce Na by >12 meq/L over 24 hoursNa by >12 meq/L over 24 hours• If serum Na >180 meq/L, patient obtunded If serum Na >180 meq/L, patient obtunded

and hypotensive give first NSand hypotensive give first NS• Recalculate fluid deficit every 24 hoursRecalculate fluid deficit every 24 hours• Replace ongoing other H2O lossesReplace ongoing other H2O losses

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• Distinguish polyuric phase of acute renal Distinguish polyuric phase of acute renal failure from Difailure from Di

• For chronic DDAP therapy dose equivalenciesFor chronic DDAP therapy dose equivalencies

• 1 1 µµg iv or sq = 10 g iv or sq = 10 µµg intranasalg intranasal

• 0.1 mg oral in evening0.1 mg oral in eveningSecond dose of DDAV given when daytime DI Second dose of DDAV given when daytime DI

recurrence verified biochemicallyrecurrence verified biochemically6 hours before scheduled evening dose6 hours before scheduled evening dose

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Diabetes Insipidus as OutpatientDiabetes Insipidus as Outpatient

• Polyuria >3 L (R/O DM, R/O primary Polyuria >3 L (R/O DM, R/O primary polydipsia), rate and severity of onsetpolydipsia), rate and severity of onset

• Water deprivation test to diagnose DI Water deprivation test to diagnose DI (partial, complete) and central vs (partial, complete) and central vs nephrogenic formnephrogenic form

• Evaluation of etiologyEvaluation of etiology

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EtiologyEtiology• Recent neurosurgery, head traumaRecent neurosurgery, head trauma• Autoimmune (hypophysitis)Autoimmune (hypophysitis)• Infiltrative stalk processes: sarcoidosis, Infiltrative stalk processes: sarcoidosis,

Wegener’s granulomatosis, Wegener’s granulomatosis, histiocytosis-Xhistiocytosis-X• Malignancy (germinoma, lymphoma)Malignancy (germinoma, lymphoma)• Hypothalamic tumorsHypothalamic tumors• Familiar forms Familiar forms • IdiopathicIdiopathic

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• Treatment with chronic DDAVPTreatment with chronic DDAVP• Start at bedtime (intranasal 10 mcgStart at bedtime (intranasal 10 mcg

DDAVP or oral 0.1 mg DDAVP) DDAVP or oral 0.1 mg DDAVP) • Repeat dose only for recurrence of Repeat dose only for recurrence of

polyuria 6 hours prior to scheduled polyuria 6 hours prior to scheduled evening doseevening dose

• Some patients with mild forms withSome patients with mild forms withintact thirst mechanism only drink to intact thirst mechanism only drink to satisfy thirstsatisfy thirst

• Do not over treat (hyponatremia)Do not over treat (hyponatremia)

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