RESISTANCE TO SOMATOSTATIN (SRIH) ANALOG THERAPY IN ACROMEGALY - REEVALUATION OF THE CORRELATION BETWEEN THE SRIH RECEPTOR STATUS OF THE PITUITARY-TUMOR AND THE INVIVO INHIBITION OF GH SECRETION IN RESPONSE TO SRIH ANALOG

The development of a long-acting somatostatin (SRIH) analog (octreotide. Sandoz) has been a major breakthrough in the treatment of acromegaly. However, in 20-30% of the patients, growth hormone (GH) plasma levels remain elevated (> 10 mug/1) despite treatment with octreotide. This raised the concept of resistance to SRIH analog therapy in acromegaly. Indeed, in vivo response to SRIH analogs varies greatly among acromegalic patients. According to the reviews in the literature and our own autoradiographic data, no direct correlation can be established between the GH response to octreotide and the number or affinity of the SRIH receptors located on the tumor. In our series a greater density of SRIH receptors is present on tumors from patients very sensitive to the SRIH agonist. A subset of patients resistant to octreotide could result from a very low density of SRIH receptor although this type of GH-secreting tumor constitutes certainly a rare case. A subset of GH-secreting pituitary tumors can be characterized by a mutation on the a subunit of the guanine nucleotide-dependent protein coupled to the stimulation of adenylate cyclase (Gas). This mutation results in a high basal adenylate cyclase activity and a low GHRH-stimulated activity. However, when the adenomas are separated according to their basal adenylate cyclase activity, SRIH is able to decrease cAMP levels in both types of tumor. In addition, in our series no direct correlation is observed between the SRIH inhibition of adenylate cyclase and the amount of SRIH-binding sites. Taken together, these findings suggest that in addition to a lack of SRIH-binding sites on some rare octreotide-resistant GH-secreting tumors, other mechanisms could be involved in the differential sensitivity to SRIH analogs.