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Selective Loss of Somatostatin Receptor 2 in Octreotide-Resistant Growth Hormone-Secreting Adenomas

Interdisziplinäres Stoffwechsel-Centrum (U.P., S.A.), Endokrinologie, Diabetes, und Stoffwechsel, Med. Klinik m. S. Hepatologie und Gastroenterologie, Campus Virchow-Klinikum, Charité-Universitätsmedizin Berlin, D-13353 Berlin, Germany; Department of Neuropathology (C.M.), Klinikum der Friedrich-Schiller-Universität Jena, 07740 Jena, Germany; Institute of Pathology (W.S.), Marien Krankenhaus, 22087 Hamburg, Germany; Department of Neurosurgery (M.B.), Friedrich-Alexander University, 91054 Erlangen-Nürnberg, Germany; Division of Endocrinology (S.P.), University of Duisburg-Essen, D-45122 Essen, Germany; and Department of Pharmacology and Toxicology (S.S.), Bayerische Julius-Maximilians-Universität, 97078 Würzburg, Germany

Address all correspondence and requests for reprints to: Dr. Stefan Schulz, Department of Pharmacology and Toxicology, Bayerische Julius-Maximilians-Universität, Versbacher Str. 9, 97078 Würzburg, Germany. E-mail: stefan.schulz{at}toxi.uni-wuerzburg.de.

Objective: The somatostatin analog octreotide preferentially binds to somatostatin receptor (sst) 2A and to a lesser extent to sst5. Although sst2A and sst5 mRNAs are consistently expressed in GH-secreting adenomas, octreotide controls GH secretion only in 65% of acromegalic patients. Hence, we investigated the immunocytochemical expression of sst in a large group of somatotroph tumors.

Methods: Acromegalic patients, cared for in a university referral center, were either operated on without pretreatment (group A, n = 14) or pretreated with octreotide [median (minimum-maximum): dose 1250 (300–1500) µg/d for 5.6 (3–9) months] before surgery (group B, n = 20). In group B octreotide reduced GH secretion by more than 50% in 14 patients (70%) (GH responders). Six patients with less than 50% GH suppression were considered GH nonresponders. We used a panel of extensively characterized antibodies to determine the immunocytochemical sst status in somatotroph adenomas and compared their expression between the groups.

Results: All group A tumors demonstrated immunoreactive sst2A, and all but one had sst5. A similar pattern was found in the GH responders of group B. In contrast, none of the GH nonresponders exhibited detectable sst2A (sst2A: GH responders vs. GH nonresponders, P < 0.0001), whereas sst5 was found in 70%. sst1 and sst3 were detected in 85 and 24% of all cases, independent of previous octreotide treatment.

Conclusions: Our findings suggest that octreotide resistance in GH-secreting adenomas occurs due to a selective loss of sst2A. The persistent expression of sst1 and sst5 receptors suggests that these tumors are potential targets for pan-somatostatin analogs.

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