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Pituitary disease

Applied Sciences Lecture Course. Pituitary disease. Prof Julian Davis Endocrinology Group, School of Biomedicine, University of Manchester Department of Endocrinology, Manchester Royal Infirmary. Prolactinoma and hyperprolactinaemia. Non- tumour hyperprolactinaemia Microadenoma

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Pituitary disease

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  1. Applied Sciences Lecture Course Pituitary disease Prof Julian Davis Endocrinology Group, School of Biomedicine, University of Manchester Department of Endocrinology, Manchester Royal Infirmary

  2. Prolactinoma and hyperprolactinaemia Non-tumourhyperprolactinaemia Microadenoma Macroadenoma • PRL suppresses gonadal function: • Women • amenorrhoea • galactorrhoea • loss of libido • Men • Hypogonadism, loss of libido, erectile dysfunction • mass effects

  3. Prolactinoma and hyperprolactinaemia Hyperprolactinaemia Prolactinoma lactotroph

  4. Drug therapy: regulation of prolactin • Hypothalamic regulation • Dopamine INHIBITION • Peripheral hormones • oestrogen • Overall: • stress • circadian time • breast-feeding

  5. Causes of hyperprolactinaemia Drugs Dopamine antagonists – phenothiazines, metoclopramide, domperidone, sulpiride SSRIs: fluoxetine etc. Monoamine oxidase inhibitors Tricyclic antidepressants Fenfluramine Methyldopa Verapamil MiscellaneousHypothyroidism Polycystic ovary syndrome Acromegaly Chronic renal failure Cirrhosis Chest wall lesions Hypothal-pituitary diseaseProlactinoma Pit. stalk disconnection: trauma; pituitary adenoma; empty sella craniopharyngioma, meningioma, glioma, dysgerminoma Idiopathic

  6. Dopamine agonists suppress prolactin

  7. Dopamine agonists • Bromocriptine • introduced 1971 • D2 receptor agonist: ergot alkaloid structure • reduces prolactin in 85-90% • restores gonadal function in 80-90% (women) • significant tumour shrinkage in 80% • mostly in first 3 months, but effect continues • useful shrinkage in 24-48h • side-effects… 12% cannot tolerate • nausea • postural hypotension • abdo pain • mood change

  8. Newer dopamine D2R agonists • Cabergoline • given 1-2 weekly: 0.5-4mg/week • normalises prolactin in up to 85% • Quinagolide • given daily 75-150ug • similar efficacy to Cab and BCR • Side-effects…less common than BCR • nausea • postural hypotension • abdo pain • mood change

  9. Cessation of dopamine agonists: prospective study - Colao et al, (2003) NEJM, 349:2023 • 200 patients 25 non-tumoral • 105 microprolactinoma • 70 macroprolactinoma • -stable on cabergoline, PRL suppressed to normal (25µg/L; 550mU/L) • -small tumour residue, or no residue • Cabergoline withdrawn after 2-5y: recurrence rates… • Non-tumoral hyperprolactinaemia 24% • Microprolactinoma 30% • Macroprolactinoma 36% • 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

  10. Prolactin: milestones 1971 - human prolactin assay developed - prolactinomas identified - CB154 (bromocriptine) suppresses prolactin 1984 - prolactin gene cloned - similar to GH 1988 - prolactin receptor cloned 1990s - protein structure deduced evolution from a lymphocyte cytokine

  11. A role for PRL antagonists? Potential problems: DA treatment contraindicated, eg antipsychotic DA side-effects Other local roles for paracrine PRL breast & prostate cancer? cancer cells express PRL-R, and local PRL cell proliferation dependent on PRL in vitro Epidemiological evidence for higher PRL levels and increased breast cancer risk (1.8-fold )

  12. PRL antagonists? Ligand-receptor mapping to determine key residues: Gly129 position in binding site 2 Functional antagonist: 1-9 - G129R-hPRL – Arg substitutes for Gly at 129, blocks cleft in site 2; N-terminal truncation reduces agonist activity Goffin et al NCPEM 2006

  13. Acromegaly therapy Surgery Selective, transsphenoidal, adenomectomy Radiotherapy External beam radiation Drug therapy Receptor agonists somatostatin SSTR agonists Pit hormone antagonists GH antagonists

  14. Potential targets for medical therapy of GH tumours

  15. Somatostatin receptors: SSTRs 5 SSTRs cloned 1990s – wide tissue distribution SSTR-2 and SSTR-5 most highly expressed in pituitary

  16. GH suppression with somatostatin analogue Somatostatin (SRIF) – short-lived Octreotide, lanreotide agonists: - stable analogues of SS, - suppress GH secretion over long periods Monitor GH profiles IGF-1

  17. GHR antagonist design: pegvisomant

  18. Do somatotroph tumours shrink with drug therapy? Modest shrinkage with long-term somatostatin agonists Acromegaly: 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

  19. Pituitary tumour shrinkage – response varies Prolactinomas - 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, ERC, 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?

  20. Pituitary tumour therapy – at present Drug therapy receptor agonists – D2R, SSTR-2/-5 hormone antagonists – GH (PRL) 80-90% response rates side effects Surgery 50-80% cure rates Radiotherapy slow onset, hypopituitarism Other options?

  21. Pituitary tumour pathogenesis • Little definite conclusive evidence • Hormonal environment can predispose to tumours: • oestrogens can induce prolactinoma in rats • D2R knockouts get prolactinoma • NGF overexpression causes prolactinoma • reversible ‘trophic changes’ in pituitary populations may lead to overgrowth of clonal populations? • Intrinsic genetic alterations lead to clonal expansion • gsp mutation can ‘explain’ 40% of Ghomas • no other characteristic mutations identified

  22. Genetic advances – familial pituitary adenomas • MEN-1 • Menin gene 11q13 • Carney Complex • PRKAR1A, 17q22-24; 2nd locus… • McCune-Albright • Gsp oncogene • Familial predisposition syndrome • AIP

  23. Familial adenoma predisposition:discovery of AIP Two 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 genotyping done on 16 individuals Linkage to 11q13, but no MEN1 mutations AIP gene identified, mutations in cases Vierimaa et al, Science 2006

  24. AIP: Aryl hydrocarbon Interacting Protein • AIP 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 protein A. Normal pit; B. AIP-proficient adenoma C-D: acromegaly, AIP Q14X mutation, -ve ICC Georgitsi et al, PNAS 2007

  25. Combined model of pathogenesis Occasional mutations arise … Gs activating (gsp) Hormonal environment favours cell proliferation: ?oestrogens ?dopamine ?corticosteroids ?growth factors Selective growth of clones carrying gene mutations that favour cell growth/survival – eg AIP?

  26. Boikos & Stratakis, Hum Mol Genet, 2007

  27. Multiple endocrine neoplasia-1 Autosomal dominant Familial tumours of pituitary parathyroid pancreas Assoc 11q13 deletion MEN-1 gene identified Menin protein: nuclear protein… +/- transgenic mice get typical tumours Menin is a pituitary/pancreas/parathyroid TSG, but not commonly mutated in sporadic tumours

  28. MEN-1 11q13

  29. Tumour suppressor genes: 2-hit hypothesis Normal 2 normal alleles normal protein expression

  30. Tumour suppressor genes: 2-hit hypothesis * Normal 1st hit 2 normal alleles 1st allele has a mutation normal protein expression reduced protein expression

  31. Tumour suppressor genes: 2-hit hypothesis * * Normal 1st hit 2nd hit 2 normal alleles 1st allele has a mutation 2nd allele has a hit normal protein expression reduced protein expression no protein expressed

  32. Knudson 2-hit hypothesis: tumour suppressor gene

  33. MEN-1: autosomal dominant disease, recessive gene mutation • Autosomal dominant inheritance • High penetrance • First mutation in germ line, affects all cells: • ‘recessive’ as no effect • Second mutation in isolated somatic cells: • loss of / mutation in single remaining allele • rare event, only needs to occur once in a susceptible tissue • causes a tumour to arise, which will be detected

  34. MEN-1 -/- mouse Crabtree et al, PNAS, 2001

  35. MEN-1 +/- mouse: pancreatic, parathyroid, pituitary and adrenal tumours Heterozygous mouse: Hyperplastic islets and islet-cell tumour Parathyroid adenoma + hyperplasia Pituitary adenoma Crabtree et al, PNAS, 2001

  36. Menin • Predicted tumour suppressor role (‘Knudson 2-hit model’) • Mutations lead to loss-of-function, at least 68 mutations identified, then loss of other wild-type allele • 9 coding exons, 610 amino acids, nuclear, ubiquitous, function unclear, no homology • Mouse +/- model consistent with human disease

  37. Consensus statement: MEN-1 (Brandi, JCEM 2001) Important morbidity Mostly controlled by medication PT: >90% develop hyperparathyroidism Subtotal parathyroidectomy most common operation Pancreas: functioning or functionless adenomas Surgery or medical treatment – surgery for enlarging tumours, insulinoma Pituitary: tumours managed normally Genetics: 10-20% MEN1 kindreds lack MEN1 mutation Carrier identification informative rather than decision-making Genotype should not influence management Annual biochemical screening advised, with imaging

  38. Clinical case: MEN-1 Female, 29y Pituitary 1996: small non-functioning pituitary adenoma Pancreas 2007: tail of pancreas, well-differentiated adenoma Pancreas 2009 : insulinoma Parathyroid: calcium & PTH normal Screening: annual pancreatic hormones annual pituitary hormones annual calcium & PTH regular scans: pituitary & pancreas MR

  39. Animal models for understanding pituitary biology • Gene therapy evaluation • Transgenic studies of pituitary structure and function

  40. Gene therapy: recombinant adenovirus vectors Broad range of host cells Infects non-dividing cells High efficiency Cloning capacity 7.5kb Remain episomal - no risk of insertional damage to host genome E1 E3 0 100 promoter transcription unit

  41. Pituitary tumour ablation? Adenoviral cytotoxin expression Lee et al, JCEM, 1999

  42. Inflammatory changes in sheep pituitary gland after adenovirus injection Venulitis, inflammatory infiltrate Normal Lymphocytic infiltrate Davis et al, J Endocrinol, 2002

  43. Transgenic studies of pituitary structure & function Luciferase or d2EGFP hPRL locus, 6p22: BAC RP11-237G3 -115kb -5kb +10kb +35kb Fischer-344 rats (oestrogen sensitive)

  44. Pituitary PRL promoter activity in vivo: luminescence imaging Luciferin ip, 30-minute in vivo imaging under anaesthesia Semprini, White, Davis, Mullins, Mol Endo, 2009; Endo 2012

  45. Comparison of signal patterns: intact pituitary slices v. dispersed primary cell cultures

  46. Fluctuations in PRL promoter activity in pituitary cells • Luminescence imaging: • 5-15 mins image acquisition • repeat images over 12-72h • Pulsatile promoter activity: • non-circadian, not synchronised • related to cell environment? • intrinsic to transcription complex? Takasuka et al, Endocrinol,1998 McFerran et al, Endocrinol, 2001 Norris et al, Mol Endocrinol, 2003

  47. Model for cyclical transcription

  48. Questions • Does tissue architecture co-ordinate networks of cells with similar dynamic behaviour? Bonnefont et al, PNAS, 2005

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