Octreotide Response Research Articles

MON-LB53 Prior Injectable Somatostatin Receptor Ligand Dose Does Not Predict Oral Octreotide Response In The Treatment Of Acromegaly: Results From The Phase 3 OPTIMAL Study

Background: Injectable somatostatin receptor ligands (SRLs) are the most widely used therapy to control acromegaly. Oral octreotide capsules have been formulated as a potential therapy for this disorder and the efficacy and safety was evaluated in the CHIASMA OPTIMAL prospective phase 3 study in patients with acromegaly who were controlled on injectable SRL treatment of varying doses (Samson et al. ENDO 2020). Methods: Patients with confirmed acromegaly, who had been receiving a stable dose of injectable SRL (≥3 months) up until study entry, were randomized to receive octreotide capsules (40 mg/day) or placebo for 36 weeks. Patients were dose titrated to 60 or 80 mg of oral octreotide or equivalent placebo through week 24 at the investigator’s discretion based on increase of IGF-I levels or worsening of acromegaly signs and symptoms. The primary efficacy endpoint was the proportion of patients who maintained their biochemical response at the end of 36 weeks, defined as average IGF-I ≤1 x ULN between Weeks 34 and 36. An analysis evaluated maintenance of response based on prior dose of injectable SRL. Prior doses of injectable SRL were categorized based on the following classifications: octreotide 10 mg every 4 weeks or lanreotide 60 mg every 4 weeks or 120 mg every 8 weeks were stratified as low; octreotide 20 mg every 4 weeks or lanreotide 90 mg every 4 weeks or 120 mg every 6 weeks were stratified as medium; octreotide 30 mg or 40 mg or lanreotide 120 mg every 4 weeks were stratified as high. Randomization was stratified based on low dose vs med/high dose and efficacy results compared for these strata. The response rates reported for the primary end point are slightly adjusted for stratification differences as prespecified in the statistical analysis plan. Results: Six patients (21.4%) in the octreotide capsule group had received prior treatment with low doses of injectable SRLs while 22 (78.6%) had received prior treatment with medium-high doses of injectable SRLs. Maintenance of response was observed in 16 patients receiving oral octreotide. This included 66.7% of patients (n=4) previously receiving low doses of injected SRLs and 54.5% of patients (n=12) on medium-high injected doses. The treatment effect was consistent irrespective of prior dose of injectable SRL (odds ratio: 5.4 in low dose and 5.9 in medium-high dose). Conclusion: The CHIASMA OPTIMAL study recruited a population receiving predominantly medium-high doses of injectable SRLs and demonstrated maintenance of response in 58% of patients. Oral octreotide treatment effect was consistent irrespective of prior dose of injectable SRL.

Abstract LB-061: Systematic, network-based, comparative analysis of differential mechanisms of action of lanreotide and octreotide in neuroendocrine tumor derived cell lines

Abstract Lanreotide and octreotide are somatostatin receptor (SSTR) agonists thought to exhibit overlapping Mechanism of Action (MoA), despite small differences in their SSTRs affinity and differential PK response in vivo [1]. To systematically and quantitatively assess both concentration- and time-dependent MoA differences at the molecular level —by characterizing the full protein repertoire that mediates the compound's pharmacological effects— we assessed the protein-specific activity of lanreotide and octreotide in two gastroenteropancreatic neuroendocrine tumor (GEP-NET) derived cell lines (H-STS and KRJ-1). We performed RNASeq profiling at 4 different time points (24h -96h), following cell perturbation at 4 non-toxic doses (2 nM - 1 μM). RNASeq profiles were used to assess compound activity on 6,276 regulatory proteins, using VIPER, an experimentally-validated algorithm to infer protein activity based on the expression of its targets [2]. The analysis was performed using a GEP-NET-specific regulatory model inferred from a collection of 212 primary and metastatic human samples. Concentrations above the EC50 of the drugs were selected to (a) assess potential off-target effects and (b) discount potential effects from differential compound degradation. Confirming the robust nature of our approach, short-term (24h and 48h) transcriptional and protein activity profiles, following compound perturbation, were virtually identical across both cell lines and drug concentration (FET p-value < 10-12). However, the sensitivity and reproducibility of VIPER analysis, which represents the foundation for two NYS CLIA approved tests, allowed identification of 367 proteins affected differentially by these drugs (FDR < 0.05), which were enriched in cancer-relevant functional categories, including apoptosis, immune response, cell differentiation, cell proliferation and DNA-repair (FDR < 10-5). Most critically, while lanreotide-modulated proteins were virtually unchanged over time (from 24h to 96h, p < 0.05), the effect of octreotide on the same proteins was transient and virtually lost at 72h. This discrepancy cannot be attributed to concentration-related effects, since it was manifested identically across all tested concentrations. This work constitutes the first systematic, genome-wide characterization of the MoA of two clinically relevant SSTR agonists, showing both common as well as differentially affected pathways. Two key elements which may account for differential clinical response in patients emerged from the analysis: (1) Differences in the repertoire of affected proteins (MoA) by each compound, and (2) different response kinetics, with sustained lanreotide response from 24h to 96h vs. transient octreotide response with subsequent adaptive cell response after 48h. [1] Enzler et.al (2017) Sem. Oncol. 44:141.[2] Alvarez et.al (2016) Nat. Genet. 48:838. Citation Format: Mariano J. Alvarez, Gideon Bosker, Roswitha Pfragner, Mark Kidd, Irvin Modlin, Andrea Califano. Systematic, network-based, comparative analysis of differential mechanisms of action of lanreotide and octreotide in neuroendocrine tumor derived cell lines [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-061.

Abnormal small bowel motility in patients with hereditary transthyretin amyloidosis

Gastrointestinal complications are common in hereditary transthyretin amyloid (ATTRm) amyloidosis. The underlying mechanisms have not been fully elucidated, and the patients' small bowel function remains largely unexplored. The aim of the present study was to compare the small bowel motility in ATTRm amyloidosis patients with that in non-amyloidosis patient controls. ATTRm amyloidosis patients undergoing evaluation for liver transplantation were consecutively investigated with 24-hour duodenojejunal manometry (n=19). The somatostatin analogue octreotide was used to induce fasting motility. Patients with age at onset of ≥50years were defined as late-onset cases. For each patient, three age- and sex-matched patient controls (n=57) were selected from the total pool of investigated patients. Manometry was judged as abnormal in 58% of the patients and in 26% of the patient controls (P=.01). Patients displayed significantly more daytime phase III migrating motor complexes than patient controls (median 4 vs 2, P<.01), and had a higher frequency of low-amplitude complexes (16% vs 4%; however, this difference did not reach statistical significance, P=.10). Furthermore, late-onset patients showed a delay in octreotide response (5.4 vs 3.8minutes, P<.01), but this was not observed for early-onset patients or within the control group. Patients with ATTRm amyloidosis displayed abnormalities in their small bowel motility more frequently than non-amyloidosis patient controls, and the manometric pattern was probably best consistent with a combined neuromyopathic disorder. The delayed octreotide response in late-onset patients warrants further investigation.

AIP and the somatostatin system in pituitary tumours.

Classic somatostatin analogues aimed at somatostatin receptor type 2, such as octreotide and lanreotide, represent the mainstay of medical treatment for acromegaly. These agents have the potential to decrease hormone secretion and reduce tumour size. Patients with a germline mutation in the aryl hydrocarbon receptor-interacting protein gene, AIP, develop young-onset acromegaly, poorly responsive to pharmacological therapy. In this review, we summarise the most recent studies on AIP-related pituitary adenomas, paying special attention to the causes of somatostatin resistance; the somatostatin receptor profile including type 2, type 5 and truncated variants; the role of G proteins in this pathology; the use of first and second generation somatostatin analogues; and the role of ZAC1, a zinc-finger protein with expression linked to AIP in somatotrophinoma models and acting as a key mediator of octreotide response.

Blood Glucose and Insulin Concentrations after Octreotide Administration in Horses With Insulin Dysregulation.

BackgroundOctreotide is a somatostatin analog that suppresses insulin secretion.HypothesisWe hypothesized that octreotide would suppress insulin concentrations in horses and that normal (N) horses and those with insulin dysregulation (ID) would differ significantly in their plasma glucose and insulin responses to administration of octreotide.AnimalsTwelve horses, N = 5, ID = 7.MethodsProspective study. An oral sugar test was performed to assign horses to N and ID groups. Octreotide (1.0 μg/kg IV) was then administered, and blood was collected at 0, 5, 10, 15, 20, 25, 30, 45, 60, 75, and 90 minute, and 2, 3, 4, 6, 8, 12, and 24 hour for measurement of glucose and insulin concentrations. Area under the curve (AUC) values were calculated.ResultsMean AUC values for glucose and insulin did not differ between normal (n = 5) and ID (n = 7) groups after octreotide injection. Significant time (P < .001) effects were detected for glucose and insulin concentrations. A group × time interaction (P = .091) was detected for insulin concentrations after administration of octreotide, but the group (P = .33) effect was not significant.Conclusions and Clinical ImportanceOctreotide suppresses insulin secretion, resulting in hyperglycemia, and then concentrations increase above baseline as glycemic control is restored. Our hypothesis that octreotide causes insulin concentrations to decrease in horses was supported, but differences between N and ID groups did not reach statistical significance when blood glucose and insulin responses were compared. The utility of an octreotide response test remains to be determined.

Octreotide therapy in meningiomas: in vitro study, clinical correlation, and literature review.

OBJECTIVE Meningiomas express somatostatin receptor subtype 2 (SST2), which is targeted by the somatostatin analog octreotide. However, to date, using somatostatin analog therapy for the treatment of these tumors in clinical practice has been debated. This study aims to clarify the in vitro effects of octreotide on meningiomas for precise clinical applications. METHODS The effects of octreotide were analyzed in a large series of 80 meningiomas, including 31 World Health Organization (WHO) Grade II and 4 WHO Grade III tumors, using fresh primary cell cultures to study the impact on cell viability, apoptosis, and signal transduction pathways. RESULTS SST2 mRNA was detected in 100% of the tested meningiomas at levels similar to those observed in other SST2-expressing tumors, neuroendocrine tumors, or pituitary adenomas. Octreotide significantly decreased cell proliferation in 88% of meningiomas but did not induce cell death. On average, cell proliferation was more inhibited in the meningioma group expressing a high level of SST2 than in the low-SST2 group. Moreover, octreotide response was positively correlated to the level of merlin protein and inversely correlated to the level of phosphorylated p70-S6 kinase, a downstream effector of the PI3K/Akt/mammalian target of rapamycin (mTOR) pathway. Octreotide inhibited Akt phosphorylation and activated tyrosine phosphatase without impacting the extracellular regulated kinase (ERK) pathway. CONCLUSIONS Octreotide acts exclusively as an antiproliferative agent and does not promote apoptosis in meningioma in vitro. Therefore, in vivo, octreotide is likely to limit tumor growth rather than induce tumor shrinkage. A meta-analysis of the literature reveals an interest in octreotide for the treatment of WHO Grade I tumors, particularly those in the skull base for which the 6-month progression-free survival level reached 92%. Moreover, somatostatin analogs, which are well-tolerated drugs, could be of interest for use as co-targeting therapies for aggressive meningiomas.

Utility of Octreotide in Advancing Enteral Feeds in Children with Chronic Intestinal Pseudo-Obstruction.

Chronic intestinal pseudo-obstruction (CIPO) is a challenging disorder with high morbidity and mortality due to limited effective therapies that improve enteral tolerance. We aimed to present our experience using octreotide in children with CIPO and evaluate factors predicting therapy response. The study population included total parenteral nutrition (TPN)-dependent children with CIPO receiving octreotide at a tertiary care center. Octreotide response was defined as an enteral feeding increase of ≥10cc/kg/day. A total of 16 children were included (median age 5 years, range 1-18; 88% female). We observed an overall feed increase in 11/16 (69%) subjects and 7/16 (44%) were considered responders: three tolerated >65cc/kg/day (discontinued TPN), one tolerated >30cc/kg/day (decreased TPN) and three patients tolerated 10-12cc/kg/day. We found an association between therapeutic octreotide response and both the presence of octreotide-induced intestinal phase III of the migrating motor complex (MMC) as well as a higher median increase in intestinal motility index after octreotide challenge during the antroduodenal manometry (p=0.03 and <0.01, respectively). We did not find an association between octreotide response and age, presence of ileostomy, and colonic manometry testing parameters. Side effects were observed in four patients: an allergic reaction and hyperglycemia requiring octreotide discontinuation, hypertension that responded to dose reduction, and cholecystitis (gallstones) with octreotide successfully restarted after cholecystectomy. Octreotide is safe and effective in improving enteral tolerance in TPN-dependent children with CIPO and the antroduodenal manometry may be helpful in predicting octreotide response. Prospective studies are needed to evaluate the safety and efficacy of octreotide in children with CIPO.

Delayed small bowel octreotide response in patients with hereditary transthyretin amyloidosis

Background Gastrointestinal (GI) complications such as constipation, diarrhea and gastroparesis are common in hereditary transthyretin (ATTR) amyloidosis. The mechanisms behind these disturbances have not been fully elucidated and the patients’ small bowel function remains largely unexplored. The aim of the present study was to compare the small bowel motility in patients with hereditary ATTR amyloidosis with that in non-amyloidosis controls.

Truncated somatostatin receptor variant sst5TMD4 confers aggressive features (proliferation, invasion and reduced octreotide response) to somatotropinomas

The GH/IGF1 response of somatotropinomas to somatostatin analogues (SSA) is associated with their pattern of somatostatin receptor (sst1-sst5) expression. Recently, we demonstrated that expression of a truncated sst5-variant (sst5TMD4) can influence the secretory response of somatotropinomas to SSA-therapy; however, its potential relationship with aggressive features (e.g. invasion/proliferation) is still unknown. Here, we show that sst5TMD4 is present in 50% of non-functioning pituitary-adenomas (NFPA) (n = 30) and 89% of somatotropinomas (n = 36), its expression levels being highest in somatotropinomas > > NFPAs > > > normal pituitaries (negligible expression; n = 8). In somatotropinomas, sst5TMD4 mRNA and protein levels correlated positively, and its expression was directly associated with tumor invasiveness (cavernous/sphenoid sinus), and inversely correlated with age and GH/IGF1 reduction after 3–6 months with octreotide-LAR therapy. GNAS+ somatotropinomas expressed lower sst5TMD4 levels. ROC analysis revealed sst5TMD4 expression as the only marker, within all sst-subtypes, capable to predict tumor invasiveness in somatotropinomas. sst5TMD4 overexpression increased cell viability in cultured somatotropinoma (n = 5). Hence, presence of sst5TMD4 associates with increased aggressive features and worse prognosis in somatotropinomas, thereby providing a potentially useful tool to refine somatotropinoma diagnosis, predict outcome of clinical response to SSA-therapy and develop new therapeutic targets.

Constitutive Somatostatin Receptor Subtype 2 Activity Attenuates GH Synthesis

Somatostatin signals predominantly through somatostatin receptor (SSTR) subtype 2 to attenuate GH release. However, the independent role of the receptor in regulating GH synthesis is unclear. Because we had previously demonstrated constitutive SSTR2 activity in mouse corticotrophs, we now analyzed GH regulation in rat pituitary somatotroph (GC) tumor cells, which express SSTR2 exclusively and are devoid of endogenous somatostatin ligand. We demonstrate that moderately stable SSTR2 overexpression (GpSSTR2(WT) cells) was associated with decreased GH promoter activity, GH mRNA, and hormone levels compared with those of control transfectants (GpCon cells). In contrast, levels of GH mRNA and peptide and GH promoter activity were unchanged in GpSSTR2(DRY) stable transfectants moderately expressing DRY motif mutated SSTR2 (R140A). GpSSTR(2DRY) did not exhibit an enhanced octreotide response as did GpSSTR2(WT) cells; however, both SSTR2(WT)-enhanced yellow fluorescent protein (eYFP) and SSTR2(DRY)-eYFP internalized on octreotide treatment. Suberoylanilide hydroxamic acid (SAHA), a histone deacetylase inhibitor, increased GH synthesis in wild-type GC cells and primary pituitary cultures. GpSSTR2(WT) cells induced GH synthesis more strongly on SAHA treatment, evident by both higher GH peptide and mRNA levels compared with the moderate but similar GH increase observed in GpCon and GpSSTR2(DRY) cells. In vivo SAHA also increased GH release from GpSSTR2(WT) but not from control xenografts. Endogenous rat GH promoter chromatin immunoprecipitation showed decreased baseline acetylation of the GH promoter with exacerbated acetylation after SAHA treatment in GpSSTR2(WT) compared with that of either GpSSTR(2DRY) or control cells, the latter 2 transfectants exhibiting similar GH promoter acetylation levels. In conclusion, modestly increased SSTR2 expression constitutively decreases GH synthesis, an effect partially mediated by GH promoter histone deacetylation.

The clinical response to somatostatin analogues in acromegaly correlates to the somatostatin receptor subtype 2a protein expression of the adenoma

Reduced expression of the somatostatin receptor subtype 2 (SSTR2) has been suggested as an explanation for the poor response to octreotide in acromegaly, but studies correlating levels of SSTR2 mRNA to octreotide efficacy have been contradictory. Some studies have found better responses to somatostatin analogues in G-protein alpha subunit (Gsalpha) mutation (gsp oncogene)-positive adenomas. The aim of this study was to determine adenoma SSTR2a protein expression and gsp status in a large group of patients with acromegaly, and relate this to the clinical effect of octreotide. Seventy-one patients were included. All underwent transsphenoidal surgery, 23 patients after preoperative octreotide treatment. The adenoma SSTR2a expression was examined by immunohistochemistry and Western blot analysis, and gsp status determined. An acute octreotide test was performed, and the change in IGF-1 level after 6 months preoperative octreotide treatment was recorded. The acute octreotide response in non-pretreated patients and the preoperative long-term octreotide response were significantly better in patients with adenomas containing a large proportion of cells that stained positively for SSTR2a by immunohistochemistry. However, the SSTR2a protein level assessed by Western blot did not correlate with the octreotide response. The preoperatively treated group had lower SSTR2a protein levels and fewer adenomas with a large percentage of positively stained cells. The gsp oncogene was detected in 43% of the adenomas but did not correlate to the octreotide response. The clinical effect of octreotide correlates with the proportion of cells positive for SSTR2a in immunohistochemical staining, rather than the adenoma SSTR2a protein level. There may be a down-regulation of SSTR2a during octreotide treatment.

Somatostatin (SRIF) receptor subtype 2 and 5 gene expression in growth hormone-secreting pituitary adenomas: the relationship with endogenous srif activity and response to octreotide.

To investigate the potential pathophysiologic role of human SRIF receptor gene expression in GH-secreting adenomas in acromegalic patients, we studied the relationship between the SRIF receptor gene expression, endogenous SRIF activity and exogenous response to octreotide in 16 acromagalic patients. Hypothalamic somatostatinergic activity (HSA) was assessed by glucose-induced suppression of TRH-stimulated TSH secretion. As an indicator of somatotrope sensitivity to HSA, glucose-induced suppression of TRH-stimulated GH secretion was determined. For the acute octreotide response, a 100 microg bolus of octreotide was injected intravenously and GH was measured hourly for 6 hr. Pituitary tumor SRIF receptor subtype 2 and 5 (sst2 and sst5) mRNA levels were measured by real-time RT-PCR. Gsp oncogene was also detected by direct PCR sequencing. Sst2 and sst5 mRNA levels were detected in all tumors. Sst2 mRNA levels positively correlated with that of sst5. Sst2 and sst5 mRNA levels did not show any correlation with basal GH values (nadir or peak). Expression of sst2, but not sst5, showed a positive correlation with the GH response to HSA, while the octreotide response positively correlated with the sum of sst2 and sst5 mRNA levels. Individuals with gsp-positive tumors were more responsive to octreotide than those with gsp-negative tumors but sst2 and sst5 mRNA levels did not differ between these two groups. These results suggest common transcriptional and/or post-transcriptonal regulatory mechanisms for these SRIF receptor subtypes within GH-secreting pituitary adenomas. The functional observations suggest that the degree (or level) of sst2 and sst5 expression is critical for the ultimate GH response of somatotropinomas to endogenous SRIF tone and exogenous SRIF analogue therapy. However, sst2 and sst5 mRNA levels are not the only factors mediating the response to SRIF.

Growth hormone response to the hypothalamic somatostatinergic activity in acromegalic patients.

Oral glucose administration suppresses the TRH-induced TSH response by enhancing the hypothalamic somatostatinergic activity (HSA). We assessed the HSA in 13 acromegalic patients by measuring glucose-induced suppression of TRH-stimulated TSH secretion. The HSA showed wide variation with up to 64% suppression. The mean HSA of the patients (25 +/- 6%) did not differ from that in normal young men (19 +/- 4%) in our previous study. Six patients had normal or low HSA, and the other 7 patients had high HSA. The mean TRH-stimulated TSH levels of the patients with normal or low HSA was significantly lower than that of the patients with high HSA (5.13 +/- 0.10 vs. 11.30 +/- 2.80 mU/L). The HSA did not relate to sex, age, tumor size, basal GH levels, the paradoxical responses to TRH and GnRH, octreotide response, or the gsp oncogene. In the combined glucose-TRH test, glucose pretreatment completely suppressed the paradoxical increase in GH level at 30 min in 4 patients. However, it could suppress the paradoxical GH response by only 6-51% in the other 5 patients who also showed the paradoxical response in TRH test. The tumor diameter of patients with good response to the HSA was significantly larger than that of the patients with poor response (31 +/- 5 vs. 14 +/- 2 mm) as was the tumor grade (3.3 +/- 0.3 vs. 1.7 +/- 0.2). This study supports the idea that a reduction of HSA is not a primary cause of acromegaly, and the HSA seems to increase to suppress the autonomous secretion of GH from the pituitary adenomas. HSA as well as the response of tumors to HSA do not determine tumor growth.

Characteristics of acromegalic patients with a good response to octreotide, a somatostatin analogue

In GH-secreting pituitary tumours somatostatin receptor density has been correlated with octreotide responsiveness. Little is known about the other endocrine characteristics of patients with good responses to octreotide. The purpose of this study was to determine the characteristics of these patients. We studied 30 patients with active acromegaly. Five had been treated with either transsphenoidal adenomectomy or conventional radiotherapy without cure of GH excess. Patients were divided into good or poor octreotide responders. Patients whose GH level decreased to less than 20% of basal and below 20 mU/I after a subcutaneous injection of 100 micrograms of octreotide were defined as good octreotide responders. We compared tumour size, basal GH secretory pattern, responses to TRH, GnRH and bromocriptine, and mutation of the alpha-subunit of stimulatory GTP-binding protein (G alpha s) between the two groups. Tumour size was determined by CT or MRI. Basal GH level was measured hourly between 0800 and 1600 h. GH responses to TRH and GnRH were measured every 30 minutes for 2 hours, and the GH response to oral bromocriptine was measured hourly for 6 hours. The mutation of G alpha s gene between codons 184 and 251 was examined by direct sequencing using PCR in 5 patients of each group whose tumour tissues were available for the genomic DNA extraction. Seventeen patients (57%) were good octreotide responders (group I) and 13 (43%) were poor responders (group II). The mean age, sex, tumour size, tumour grade and the basal GH secretory pattern were not significant different between the two groups. Group I responded more frequently than group II to TRH (65 vs 25%). Fifty-three per cent of group I patients and none of group II were good bromocriptine responders. Forty-one per cent of group I patients responded to both TRH and bromocriptine. Three of 5 group I tumours had point mutations at codon 201 of the G alpha s gene, none of 5 group II tumours had mutations. CGT(Arg) was replaced with TGT(Cys) in two tumours and with AGT(Ser) in one. No mutations were found at codon 227. All three tumours with mutations were from patients responsive to TRH. Two of the three were also good bromocriptine responders. These data suggest that good octreotide responders are more likely to respond to TRH or bromocriptine. Good octreotide responders may include subgroups with different levels of TRH and dopamine receptor expression. A possible relation between octreotide response and the mutation of G alpha s gene should be investigated.

Clinically nonfunctioning pituitary adenoma and octreotide response to long term high dose treatment, and studies in vitro.

We have studied seven patients with a clinically nonfunctioning or alpha-subunit-secreting pituitary macroadenoma, four of whom received long term, high dose octreotide treatment. We have attempted to correlate the presence of somatostatin receptors (SS-R) in the adenomas and the outcome of octreotide treatment, as measured by tumor size, improvements in visual field defects, and hormonal response. The presence of SS-R in the pituitary adenomas was demonstrated in vivo using [111indium]octreotide scintigraphy and in vitro by autoradiography of tissue fragments obtained after transsphenoidal surgery. Adenomas from six of the seven subjects were SS-R positive. High dose (1200 micrograms, sc, daily) octreotide treatment was given to four subjects, three of whom were SS-R positive. Improvement of the visual field defects was observed in three of four patients (including the SS-R-negative subject), although no computed tomographic scan-assessed tumor size reduction was found. Two of four patients showed small but significant reductions in serum FSH concentrations (to 83% and 93% of initial values) with treatment. These in vivo responses to high dose octreotide treatment could not be predicted by pretreatment responses to 200 micrograms TRH or 100 micrograms octreotide. Tissue fragments for cell culture were obtained from six patients, and in vitro release of gonadotropins and/or alpha-subunit could be demonstrated in five cultures. In vitro, octreotide (10 nmol/L) significantly decreased gonadotropiin or subunit release in three of five cultures, whereas bromocriptine (10 nmol/L) significantly reduced the release in four of five cultures and to a significantly greater extent than octreotide. In conclusion, in six of seven patients with a clinically nonfunctioning or alpha-subunit-secreting pituitary adenoma, SS-R were demonstrated in the tumor. In vitro incubation of adenoma cells with octreotide resulted in mild inhibition of gonadotropin or alpha-subunit release. Although in vivo long term treatment with high doses of octreotide did not result in substantial tumor size reduction, improvement of visual field defects was observed in three of four subjects.

Clinically nonfunctioning pituitary adenoma and octreotide response to long term high dose treatment, and studies in vitro

Clinically nonfunctioning pituitary adenoma and octreotide response to long term high dose treatment, and studies in vitro