ACROMEGALY Prof. Gaetano Lombardi Prof. Gaetano Lombardi Dept. of Clinical and Molecular Endocrinology and Oncology University “Federico II”, Naples, Italy

Sporadic pituitary tumor

Syndromic/Familial Pituitary Tumors

MEN1 Pituitary Tumor Primary Hyperparathyroidism Endocrine Pancreatic Tumor Autosomal dominant Gene Men1 11q13

McCune-Albright Syndrome Polyostotic fibrous dysplasia Skin pigmentation Hormonal dysfunction - Precocious puberty - Thyrotoxicosis - Gigantism - Cushing’s Syndrome Macroadenoma (50% of cases) Mutation di Gs-alpha

Carney Syndrome Autosomal dominant 2p16 Mutation of PRKAR1A Chiazze di iperpigmantazione cutanea Mixoma cardiaco Iperfunzione endocrina sindrome di Cushing acromegalia Hyperplasia or multiple microadenomas

RARE DISEASE

Balance of GH influences on cell growth regulation Pathogenesis of cell proliferation/apoptosis in acromegaly

COLON CANCER IN ACROMEGALY

TREATMENT GOALS Mortality rate reduction Tumor shrinkage Treatment of comorbidities Relief of symptoms directly caused by GH excess    

Medical Therapy SSA, DA, GH-A Radiotherapyconventional stereotactic stereotactic Surgery trans-cranium trans-sphenoidal

SURGERY SUCCESS RATE: 72% microadenomas, 50% macroadenomas, 17% giant adenomas Improvement in pituitary function in 60-97% Improvement of visual field defect in 70% Low morbidity and mortality (0-1%) Reduction in tumor size in 90% Tumor residual in 15-50% Complications in 5-18%

MEDICAL THERAPY Dopamine-AgonistsBromocriptineCabergoline Lisuride – Pergolide - Quinagolide Somatostatin Analogues OctreotideLanreotide GH-receptor antagonist GH-receptor antagonist

Headache Hypotension Nausea Gastro-intestinal SIDE EFFECTS

SOMATOSTATIN ANALOGUES EFFECTIVENESS Clinical Improvement in 70-90% Normalisation of GH levels in 65-70% Normalisation of IGF-I levels in 65-70% Tumor shrinkage >50%   

Baseline 5 month-OCT LAR 10 month-OCT LAR

SIDE EFFECTS Gastro-intestinal Biliary sludge Gallstones Diarrhea

PEGVISOMANT  GH analog (191 amino acids)  9 different amino acids  PEG  molecular weight D  half-life >70 hours  subcutaneous administration GH is not a marker of disease Goal of therapy – to reduce IGF-I levels to normal range for age and sex

STOP

IC50 nM ◊ sst1 9.3  0.1 ◊ sst21.0  0.1 ◊ sst31.5  0.3 ◊ sst4> 100 ◊ sst50.2  0.1

SOMATOSTATIN AND DOPAMINE RECEPTOR AGONIST

R.S. Auriemma, A. Cozzolino, M. De Leo, M.C. De Martino, C. Di Somma, A. Faggiano, M. Galdiero, L.F.S. Grasso, E. Guerra, F. Milone, R. Pivonello, M.C. Savanelli, P. Vitale, L. Vuolo & A. Colao Dept. of Clinical and Molecular Endocrinology and Oncology

QUESTION 1 Induce clinical improvement in 30% Normalize GH levels in 30% Normalize IGF-I levels in 65-70% Induce tumor shrinkage in <20%    SOMATOSTATIN ANALOGUES:

QUESTION 2 Normalize IGF-I levels in 30% Normalize IGF-I levels in 50% Normalize IGF-I levels in 70% Normalize IGF-I levels in up to 95%    THE GH-RECEPTOR ANTAGONIST PEGVISOMANT:

QUESTION 3 COLONIC NEOPLASM DEVELOPMENT IN ACROMEGALY: Is correlated to GH levels Is correlated to IGF-BP1 levels Is correlated to insulin levels Is correlated to tumor size   