Expression pattern of the Hedgehog signaling pathway in pituitary adenomas.

Several studies have demonstrated the role of Wnt and Notch signaling in the pathogenesis of pituitary adenomas, but data are scarce regarding the role of Hedgehog signaling. In this study we investigated the differential expression of gene targets of the Hedgehog signaling pathway. Formalin-fixed, paraffin-embedded specimens from adult patients who underwent transphenoidal resection and normal human pituitary tissues that were obtained from autopsies were used. Clinical information and data from pre-operative MRI scan (extracellular tumor extension, tumor size, displacement of the optic chiasm) were retrieved from the Hospital's database. We used a customized RT(2) Profiler PCR Array, to investigate the expression of genes related to Notch and Hedgehog signaling pathways (PTCH1, PTCH2, GLI1, GLI3, NOTCH3, JAG1, HES1, and HIP). A total of 52 pituitary adenomas (32 non-functioning adenomas, 15 somatotropinomas and 5 prolactinomas) were used in the final analysis. In non-functioning pituitary adenomas there was a significant decrease (approximately 75%) in expression of all Hedgehog related genes that were tested, while Notch3 and Jagged-1 expression was found significantly increased, compared with normal pituitary tissue controls. In contrast, somatotropinomas demonstrated a significant increase in expression of all Hedgehog related genes and a decrease in the expression of Notch3 and Jagged-1. There was no significant difference in the expression of Hedgehog and Notch related genes between prolactinomas and healthy pituitary tissues. Hedgehog signalling appears to be activated in somatotropinomas but not in non-functioning pituitary adenomas in contrast to the expression pattern of Notch signalling pathway.

The role of Notch and Hedgehog signaling pathways in pituitary development and pathogenesis of pituitary adenomas.

Pituitary adenomas are usually benign tumors that cause symptoms by compression of surrounding structures or impaired hormone secretion. Treatment, whether surgical or medical depends, on the tumor subtype and degree of compression; however, a significant proportion of patients do not achieve optimal control of mass effects or hormonal hypersecretion. Unraveling the pathogenesis of pituitary adenomas is a critical step in the quest for new subcellular treatment targets that will decrease morbidity and mortality related to these tumors. A large diversity of pathogenetic mechanisms has been described so far including deregulation of cell cycle, molecular pathways and angiogenesis. Major signaling pathways such as Notch, Wnt and Hedgehog, which are mainly active in the early phase of pituitary organogenesis and are essential for the development of somatotrophs, lactotrophs thyrotrophs and corticotrophs, have been implicated in the pathogenesis of pituitary adenomas. In this review we present novel data regarding the role of Notch and Hedgehog regulatory networks in pituitary development and pathogenesis of pituitary adenomas.

Non tumoral hyperserotoninaemia responsive to octreotide due to dual polymorphism in UGT1A1 and UGT1A6.

Gilbert's syndrome is a common inherited metabolic disorder, caused by genetic aberration in the enzyme UDP-glucuronosyl-transferase 1A1 that leads to reduced glucuronidation of bilirubin. Recent advances in molecular genetics have frequently reported the concurrence of dual genetic polymorphisms in UDP glucuronosyl-transferases 1A6 and 1A1 in patients with Gilbert's syndrome, leading to defective glucuronidation of bilirubin, as well as several other endogenous and exogenous substrates, such as serotonin. We present a case of Gilbert's syndrome with severe persistent hyperserotoninaemia, mimicking carcinoid syndrome, due to dual polymorphisms in UDP-glucuronosyl-transferases 1A1 and 1A6. The patient was treated with a long-acting somatostatin analogue (octreotide) for 8 months, resulting in a significant reduction in serum serotonin levels and immediate relief of the symptomatology, followed by a long-term remission. The frequent occurrence of hyperserotoninaemia in Gilbert's syndrome may contribute, at least partly, to the nonspecific symptomatology commonly seen in these patients and should be promptly evaluated.