Pituitary diseaseProf Julian Davis

Endocrinology Group, School of Biomedicine, University of Manchester

Department of Endocrinology, Manchester Royal Infirmary

Hypothalamic-pituitary hormone axesHypothalPituitary hormone - cellTarget hormone

CRHACTH - corticotrophcortisolTRHTSH- thyrotrophthyroxineGnRHLH - gonadotrophT, E2GnRHFSH - gonadotrophinhibinGHRHGH - somatotrophIGF-1

DAProlactin - lactotroph

Normal pituitary gland: cell types intermingledNormal pituitary - mixed cell typesACTH corticotrophsTSH - thyrotrophsLH, FSH - gonadotrophsGH - somatotrophsProlactin - lactotrophs

Pituitary tumours the spectrum

Pituitary adenomasBenign, slow-growingDifferentiatedLocal expansionIncidental small tumours common

Mass effects - headache, visual lossHormonal effects - hormone overproduction

Pituitary tumour typesDifferentiated tumours containing single pituitary cell types

Lactotroph:PRLprolactinomaSomatotroph: GHacromegalyCorticotroph:ACTHCushings disease

Gonadotroph:LH, FSH= non-functioningThyrotroph:TSH

Investigation: pituitary imagingLateral skull X-rayCT scan: axial coronal

Pituitary imaging: MR scans are best

Functioning clonal tumours give endocrine syndromes: PRL excess (prolactinoma) lactation, amenorrhoeaAmenorrhoeaHypogonadismInfertility

Galactorrhoea

GH excess: gigantism and acromegalyGH excessSoft tissue and bone growthTall statureEnlarged face, hands, feetMetabolic effects: BP, diabetes

ACTH excess, adrenal hyperplasia, Cushings syndrome

Non-functioning adenomasLH/FSH gonadotroph adenomas: LH or FSH excess rareusually just - or -subunits, no endocrine effect, hence non-functioning mass effect & hypopituitarism

TSH thyrotroph adenomas:TSHoma = very rare cause of thyrotoxicosis

CraniopharyngiomaRare benign tumours

Remnants of Rathkes pouch

Solid tissue, cysts, calcified nodules

Within or above the pituitary

Pituitary tumour pathogenesisLittle definite conclusive evidenceHormonal environment can predispose to tumours: oestrogens can induce prolactinoma in ratsD2R knockouts get prolactinomaNGF overexpression causes prolactinomareversible trophic changes in pituitary populations may lead to overgrowth of clonal populations?

Intrinsic genetic alterations lead to clonal expansiongsp mutation can explain 40% of Ghomasno other characteristic mutations identified

Genetic advances familial pituitary adenomasMEN-1Menin gene 11q13

Carney ComplexPRKAR1A, 17q22-24; 2nd locus

McCune-AlbrightGsp oncogene

Familial predisposition syndromeAIP

Familial adenoma predisposition: discovery of AIPTwo extended families, northern Finland

Two clusters linked as 1 family by genealogy(generation I from 1700s):3 cases of acromegaly/gigantism

Low penetrance familial adenoma predisposition to PRLoma and GHoma

Whole-genome SNP genotypingdone on 16 individuals

Linkage to 11q13, but no MEN1 mutations

AIP gene identified, mutations in casesVierimaa et al, Science 2006

AIP: Aryl hydrocarbon Interacting ProteinAIP 330 amino-acids

FKBP-homology domain 3 tetratricopeptide repeats (TPRs)

AIP complexes with aryl hydrocarbon receptor (AHR) and Hsp90(AHR = ligand-activated TF)

AIP also binds and impairs function of phosphosdiesterase PDE4A5 and PPAR

Mutations render AIP inactive;many AIP-assoc adenomas null for AIP proteinGeorgitsi et al, PNAS 2007A. Normal pit; B. AIP-proficient adenomaC-D: acromegaly, AIP Q14X mutation, -ve ICC

Natural historyAutopsy and scanning dataAutopsy (meta-analysis by Molitch, 1997)Variable rates: 1-27%, average 11%males=females3 / 1403 are macroadenomas46% stained for prolactinScanning:CT: >3mm adenomas in 4-20% (Molitch, 97)MR: 10 / 100 if 2 reviewers agreed, 25-48 / 100 if one only (Hall, 94)

Long-term follow-up

156 patients followed over 8y (Molitch, 1999)tumour expansion in 6%PRL levels stable or fell in 75%

i.e. prolactinomas may be very indolent, may remit, may not need treatmentWorth a trial of withdrawal of drug treatmentNatural history

Pituitary tumour therapySurgery

Radiotherapy

Drug therapy DAs Somatostatin analogues GH antagonists

Transsphenoidal pituitary surgery Potential for long-term cure and avoidance of DA side-effects

Outcomes poor for PRLomas even in specialist hands - 50-75% long-term endocrine remission for microadenomas

Endoscopic transphenoidal surgery Manchester experience2005-2007125 consecutive patientsendoscopic approachsingle surgeon

Comparison of two consecutive 15 month periods

05-0606-07totalNF adenomas224567Acromegaly15722Cushings4610PRLoma639Cranio224Apoplexy156

Macroadenoma4066106Surgical duration12091101

Hospital stay7 (3-36)4 (3-15)5 Leach et al, Neurosurgery, 2010

Endoscopic surgery - outcomes61 (49%) had VF deficits improved in 54 unchanged/worse in 7

Endocrine remission

Acro 12/156/718/22 (82%)Cush.2/45/67/10

Hypopit17%25%22%New DI4%6%5%

Complications9% (CSF leak/meningitis, sphenoid sinusitis)Reoperations15% (CSF leak, residual tumour)

Leach et al, Neurosurgery, 2010

Radiotherapy Prevents tumour regrowth

Slow effect

Gradual hypopituitarism,Over 10-15 years

Role of radiotherapyOften used post-op after non-curative surgery

Progression-free 15y survival:93% after RT33% for non-RT

Dopamine agonistsBromocriptineintroduced 1971reduces prolactin in 85-90%restores gonadal function in 80-90% (women)significant tumour shrinkage in 80%mostly in first 3 months, but effect continuesuseful shrinkage in 24-48h

Cabergoline, Quinagolideintroduced 1990ssimilar PRL response ratesimilar adenoma shrinkage rate

Bromocriptine: PRL suppression 55y female

PRL 656,000mU/L (NR 100-500)

BCR treatment only

Bromocriptine: prolactinoma shrinkage

Typical macroprolactinoma shrinkage with cabergoline

Cessation of dopamine agonists:prospective study - Colao et al, (2003) NEJM, 349:2023200 patients25 non-tumoral105 microprolactinoma70 macroprolactinoma-stable on cabergoline, PRL suppressed to normal (25g/L; 550mU/L)-small tumour residue, or no residue

Cabergoline withdrawn after 2-5y: recurrence rates

Non-tumoral hyperprolactinaemia24%Microprolactinoma30%Macroprolactinoma36%

possibility of permanent remission, even for macroadenomas chances better if scan showed no tumour residue caution for longer term follow-up, but worth trial withdrawal follow-up study (Clin Endo 2007): PRL and tumour size criteria

Is acromegaly different? SSTRs: receptor targets for medical therapy of GH tumours5 SSTRs cloned 1990s wide tissue distribution

SSTR-2 and SSTR-5 most highly expressed in pituitary

Somatotroph tumours: modest shrinkage with long-term somatostatin agonistsAcromegaly:MRI assessment of primary octreotide therapy

25 patients: 76% showed >25% of tumour shrinkage, after 6 months of treatment.

Tumour shrinkage: Mild in 40% - IGF1 normalised in 5/10 Moderate in 24% - IGF1 normalised in 4/6 Remarkable in 12% - IGF1 normalised in 3/3

Figure shows a patient who achieved 75% of tumour shrinkage, but no IGF-I/GH normalization.Jallad, Bronstein et al, Clin Endo 2005

Pituitary tumour shrinkage response variesProlactinomas - dramatic shrinkage in 80%+ with dopamine agonists- change in size with oestrogen (more marked in rodent models)

Somatotrophinomas - mild-moderate slow shrinkage in ~50% with somatostatin analogues

Gonadotroph adenomas little evidence: eg 7/13 showed 10% shrinkage with long-term dopamine agonist (Lohman, Pituitary, 2001) Review - 5/100 shrinkage with octreotide in 11 studies- 55/199 shrinkage with DAs in 24 studies (Colao, Endo Rel Cancer, 2008)

Corticotroph adenomas no evidence

Mechanism the plastic pituitary, or the plastic lactotroph?

Apoptosis in PRLomas? increased reticulin staining in surgical specimens after DAs

Alteration in lactotoph cell size vs cell number?

Clinical databases for measuring and understanding outcomesUK National Acromegaly RegisterEstablished 199722 centres1920 patients

Outcomes analysis:Radiotherapy study, 1840 patientsJenkins et al, JCEM 2006Transsphenoidal surgery outcomes, 785 patientsBates et al, Clin Endo 2007

safe GHnormal IGF-11319 patients underwent TS surgery;1185 as primary treatment;

Interpretable GH data in 785Interpretable IGF-1 data in 430

Variation in success rates:

20-68% among centres with >10 cases;Overall safe GH rate 39%Bates et al, Clin Endo, 2007Acromegaly surgical outcomes

Surgery for acromegaly:trend for improving results: pre-1985 to 2004Messages:

Increased scrutiny of outcomes by colleagues and patients

Improving practice, fewer more specialised pituitary surgeons

Stated desirable case-loads (>20 functioning tumours/year)

SummaryPituitary tumours: benign, indolent, locally destructive.

Cell type of origin determines clinical picture (prolactinoma, acromegaly, Cushings, non-functioning etc)

Pituitary adenoma pathogenesis becoming better understood, but still few candidate genes for sporadic adenomas

Natural history of disease more variable than thought remission occurs

Therapy and outcomes undergoing more scrutiny role of disease databases

Slide 001The Cardiovascular Examination OSCE StationThis slide show is aimed at showing you the basics skills required of a cardiovascular examination during an 8 minute OSCE station. It should be used in conjunction with the accompanying video and, most importantly, practice on as many patients as possible.