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Selective loss of somatostatin receptor 2 in octreotide-resistant growth hormone-secreting adenomas
Ursula Plöckinger1, Susann Albrecht, Christian Mawrin
1Interdisziplinäres Stoffwechsel-Centrum, Endokrinologie, Diabetes, und Stoffwechsel, Med. Klinik m. S. Hepatologie und Gastroenterologie, Campus Virchow-Klinikum, Charité-Universitätsmedizin Berlin, D-13353 Berlin, Germany.
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) mug/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.
Insights
Octreotide resistance in acromegaly is linked to the loss of somatostatin receptor subtype 2A (sst2A). Persistent sst1 and sst5 expression indicates potential for pan-somatostatin analog therapy in resistant cases.
Area of Science:
- Endocrinology
- Oncology
- Molecular Biology
Background:
- Octreotide, a somatostatin analog, targets somatostatin receptor subtype 2A (sst2A) and sst5.
- While sst2A and sst5 mRNAs are present in GH-secreting adenomas, octreotide efficacy varies, controlling GH secretion in only 65% of acromegaly patients.
- This suggests a disconnect between receptor mRNA expression and treatment response.
Purpose of the Study:
- To investigate the immunocytochemical expression of somatostatin receptors (sst) in somatotroph tumors from acromegalic patients.
- To identify potential mechanisms of octreotide resistance in GH-secreting adenomas.
- To explore alternative therapeutic targets in treatment-resistant cases.
Main Methods:
- Compared immunocytochemical sst expression in somatotroph adenomas from patients operated on without octreotide pretreatment (Group A, n=14) and those pretreated with octreotide (Group B, n=20).
- Group B patients were classified as GH responders (>50% GH reduction) or non-responders (<50% GH reduction) based on octreotide treatment.
- Utilized a panel of characterized antibodies to determine sst1, sst2A, sst3, and sst5 expression.
Main Results:
- All tumors in Group A and GH responders in Group B showed sst2A and sst5 expression.
- GH non-responders in Group B lacked detectable sst2A expression (P < 0.0001) but retained sst5 expression in 70% of cases.
- sst1 and sst3 were detected in a significant percentage of tumors regardless of octreotide treatment.
Conclusions:
- Octreotide resistance in GH-secreting adenomas is associated with the selective loss of sst2A.
- The continued presence of sst5 and sst1 receptors suggests these tumors remain susceptible to other somatostatin analogs.
- Targeting sst1 and sst5 may offer therapeutic options for patients resistant to standard octreotide therapy.
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