Molecular biology of the somatotroph adenoma cell

Despite considerable progress during the last 15 years, the pathogenesis of acromegaly is still poorly understood. GH producing adenoma cells are monoclonal in origin and as many other neoplastic cell types, are most likely the result of a series of genetic alterations. This involves expression of oncogenes such as gsp, which was reported to be expressed in 30 to 40% of somatotroph adenmomas and which induces constitutive GH production. Loss of heterozygosity and subsequent loss or inactivation of different tumour suppressors has also been found in sporadic and hereditary somatotroph tumours. However, none of the oncogenes or tumour suppressors studied so far has been consistently overexpressed or lost in all somatotroph adenomas demonstrating the heterogeneity of this tumour type. Once a transformed somatotroph tumour cells has emerged, the developing tumour slowly, but continuously expands and starts to produce excessive amounts of GH. This indicates that the mechanisms that inhibit GH secretion (feedback-inhibition through IGF-1; GH suppression by hypothalamic somatostatin) are impaired. Desensitation, downregulation or mutation of the IGF-1 receptor or the somatostatin receptor subtypes as well as disturbances of signalling induced by these receptors have been discussed as the cause of missing inhibitory control of GH release. Moreover, impaired auto-/paracrine-acting intrapituitary growth factor and cytokine loops seem to be disturbed and may contribute to the pathophysiology and progression of somatotroph tumors. In the presentation intra- and intercellular molecular changes associated with somatotroph pituitary adenomas will be summarised and discussed.