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DOI: 10.1530/eje.1.02350
European Journal of Endocrinology, Vol 156, suppl_1, S45-S51
Copyright © 2007 by European Society of Endocrinology
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ARTICLE

Preclinical and clinical experiences with the role of somatostatin receptors in the treatment of pituitary adenomas

Joost van der Hoek, Steven W J Lamberts and Leo J Hofland

Department of Internal Medicine, Section Endocrinology, Room Ee30b, Erasmus MC, Dr Molewaterplein 50, 3015 GE, Rotterdam, The Netherlands

(Correspondence should be addressed to L J Hofland; Email: l.hofland{at}erasmusmc.nl)

This paper was presented at a symposium held at the Erasmus Medical Center, Rotterdam, The Netherlands, 2005. The symposium was jointly organized by LJ Hofland, Erasmus Medical Center, and A Colao, Federico II University of Naples, Italy. Ipsen partially supported the publication of these proceedings.

Abstract

The patho-physiological role of somatostatin receptor subtypes (sst) in neuro endocrine diseases has gained enhanced scientific interest in the past few years. The development of novel somatotropin-release inhibiting factor analogs, both sst-specific and universal ligands, seem promising as a tool to further increase fundamental insights in sst function. Eventually, this research should result in novel medical therapeutic opportunities in patients suffering from neuro-endocrine diseases. In the present review, the functional role of sst in all types of pituitary adenomas, based on recent preclinical and clinical studies, is being discussed.

Introduction

Somatostatin, also known as somatotropin-release inhibiting factor (SRIF), is a cyclopeptide that has broad inhibitory effects on the secretion of hormones such as growth hormone, insulin and glucagon. These effects have formed the basis for the clinical use of SRIF-analogs in the treatment of acromegaly and endocrine tumors. The discovery of the five SRIF receptor subtypes (sst) in the 1990s further enhanced the understanding of the biological roles of SRIF and SRIF analogs, and paved the way for new therapeutic opportunities. In this review, recent preclinical and clinical advances in sst-targeted treatment of human pituitary adenomas are discussed.

GH-secreting pituitary adenomas

Acromegaly is predominantly caused by a growth hormone (GH) secreting pituitary adenoma, resulting in high circulating GH and insulin-like growth factor I (IGF-I) hormone concentrations. Over the years, a triad of therapeutical options has been formed: surgery, irradiation and medical treatment (1). These treatment modules had the aim of inducing tumor shrinkage and normalizing GH and IGF-I levels, thereby reducing the risk of long-term complications including the development of malignant neoplasms, cardio- and cerebrovascular disease, respiratory and metabolic dysfunction (2). The clinical introduction of the long-acting SRIF analogs in the early 1980s added a new dimension to the treatment of acromegaly (3–5). The short half-life of SRIF and the subsequent need for i.v. administration however, as well as the post-infusion hypersecretion of GH, insulin and glucagon, has rendered the native peptide impractical for therapeutic use (6). The short stable synthetic octapeptide SRIF analogs, octreotide (OCT) and lanreotide, appeared not to have these disadvantages and were administered in acromegalic patients to assess their role as a novel treatment option in acromegaly. Indeed, after the first reports that demonstrated the long-acting inhibitory effect of OCT on plasma GH levels, as well as a rapid amelioration of the clinical signs and symptoms, 20 years of endocrine practice and science has turned OCT and lanreotide into the widely accepted first medical treatment option for acromegaly (7).

The current clinically available octapeptide SRIF analogs have been consistently shown to be able to reduce hormonal hypersecretion and to normalize IGF-I levels in a significant proportion of treated patients. Recently, Freda, summarizing the literature data on this topic (8), showed the achievement of safe GH levels in 56% of patients treated with sandostatin-LAR (OCT incorporated into microspheres of a biodegradable polymer that results in therapeutical blood concentrations of the peptide for 24–42 days) and in 49% of those treated with lanreotide 30 mg. The respective figures for IGF-I normalization were 66 and 48%. However, a large majority of the patients enrolled in these studies were preselected for SRIF analog responsiveness (8). Therefore, several studies were initiated in which newly diagnosed patients were treated with somatostatin analogs. To date, efficacy numbers have been reported for normalizing GH (43–79%) and IGF-I (53–68%), which are comparable with efficacy numbers for adjuvant SRIF analog therapy (9–15).

Human GH-secreting pituitary adenomas express multiple sst subtypes. sst2 and sst5 receptors are the predominantly expressed sst, both at the mRNA (Table 1Go; (16–19)) and the protein level (20). Several studies reported a variable sst2 mRNA expression and a relatively high expression of sst5 (16, 18, 21). The sst2 seems a predominant receptor in determining the inhibitory effect of OCT or lanreotide on circulating GH release in acromegalic patients. sst2 mRNA expression in GH-secreting pituitary adenomas shows a positive correlation with the in vivo GH suppression induced by an acute test using a single injection of 200 µg OCT (21), as well as with the in vitro and in vivo responsiveness to OCT in another series of patients (18). Moreover, it has recently become clear that apart from sst2, sst5 receptors play an important role in regulating GH secretion by human GH-secreting pituitary adenoma cells as well. In this respect, the regulation of fetal human GH secretion (22) is similar to that in human GH-secreting pituitary adenomas. In primary cultures of human GH-secreting pituitary adenomas, new SRIF-analogs with enhanced sst2-binding affinities inhibit GH secretion more potently compared with the clinically used octapeptide SRIF analogs, OCT and lanreotide. In addition, some adenomas show a better response to sst2-specific analogs, whereas in others sst5-specific analogs are more potent in suppressing GH release (23). Moreover, the combined activation of sst2 and sst5 results in additive inhibitory effects on GH secretion. Interestingly, the sst5 preferential analog BIM-23 268 inhibited GH release in only 7 of 15 cases, whereas, in agreement with the results of Shimon and coworkers (23), partial additive effects in suppressing GH release were found in OCT-partially responding cultures when the sst2- and sst5- specific compounds were used in combination. Taking these data together, it can be concluded that sst2 is the predominant receptor in regulating GH release by GH-secreting pituitary adenoma cells, whereas sst5 receptors may mediate an inhibitory effect on GH secretion as well. The additive inhibitory effects on GH release following activation of both sst2 and sst5 are probably mediated via a functional association of both sst subtypes. Ren and coworkers (24) demonstrated in human fetal pituitary cell cultures that an sst2 selective antagonist was capable of reversing the GH suppressive effects of sst2/sst5 biselective agonists or that of sst2 and sst5 agonists in combination, suggesting a functional interaction between both sst subtypes. In adenomas co-secreting GH and prolactin (PRL), PRL secretion is preferentially inhibited by sst5-specific SRIF analogs (16, 18, 23). The observed additive GH-suppressive effect of activating both sst2 and sst5 also initiated the development of analogs with selectivity to multiple sst subtypes. One of these compounds, the sst2-and sst5-bispecific compound BIM-23 244, indeed inhibits GH release in a subgroup of partially OCT-sensitive adenomas more potently when compared with OCT. In this subgroup of adenomas sst2 mRNA expression was ninefold lower, and sst5 mRNA expression approximately sevenfold higher than in the OCT-sensitive adenomas (21). These studies suggest that in tumors expressing a low sst2 level and a high sst5/sst2 ratio, sst5 is of increasing importance in regulating GH release (21). Another recently developed compound has a more universal sst-binding profile. This compound, named SOM230, has a 25-, 5- and 40 times higher binding affinity to sst1, sst3, and sst5 receptors respectively, and 2.5 times lower affinity to sst2, when compared with OCT (25). The SOM-230 inhibits GH release in a higher number of GH-secreting pituitary adenomas, both in vitro (18) and in vivo (see below). SOM230 suppressed GH secretion in primary cultures from human fetal pituitary cells (26). The preclinical reports of enhanced GH suppression via the combined activation of sst2 and sst5 receptors in cultures of GH-secreting pituitary adenomas initiated a proof-of-concept clinical trial with SOM230 in 12 patients with active acromegaly (27). A single s.c. injection of 250 µg SOM230 compared with 100 µg OCT showed comparable efficacy in suppressing circulating GH concentrations in eight patients, and showed a significantly enhanced suppression in 3 of 12 acromegalic patients (27; Fig. 1Go). The observation that SOM230 demonstrates potent inhibitory effects upon GH release in patients with GH-secreting pituitary adenomas expressing a low amount of sst2 and a high amount of sst5 suggests that the sst5 subtype may indeed play an essential role in mediating in vivo GH suppressive actions in OCT-partial responders. Therefore, the enhanced efficacy of SOM230 can be explained by high sst5 expression in this type of adenomas and its 40-fold higher binding affinity for sst5 as compared with OCT. Since SOM230 is able to lower GH levels in both OCT responders and partial responders, this novel SRIF analog has a clear advantage over OCT and might increase the number of patients that can be biochemically controlled during long-term medical treatment.


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  		Table 1 Percentage of human pituitary tumors expressing SRIF receptors.
 

Figure 1
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  		Figure 1 In vivo effects of SOM230 in acromegaly. The bars represent mean ± S.E.M. percentage GH suppression induced by octreotide 100 µg (black bars) and SOM230 250 µg (white bars) 2–8 h after s.c. injection compared with the control day. A: Group showing equal response to octreotide and SOM230 (n=8). B: Group showing higher sensitivity to SOM230 (n=3; *P<0.05). Adapted from (27).

 
Finally, a role for sst1 in the control of GH-secreting pituitary adenoma cell function has been proposed. Activation of sst1 receptors by the sst1-selective agonist BIM-23 296 results in a dose-dependent inhibitory effect in the nanomolar range on GH and PRL secretion by GH-secreting pituitary adenomas. In addition to lowering GH and PRL secretion this SRIF analog induced a decrease in cell viability as well (28). Moreover, BIM-23 745, another sst1-selective agonist, was further demonstrated to significantly suppress GH secretion in vitro in a series of GH-secreting pituitary adenomas from patients resistant or partially responsive to OCT or lanreotide in vivo (29).

ACTH-secreting pituitary adenomas

The endogenous Cushing’s syndrome is predominantly caused byexcess adrenocorticotropin (ACTH) release from an ACTH-secreting pituitary adenoma, also known as Cushing’s disease (CD; (30)). Since significant mortality and morbidity accompany this condition, proper medical intervention is necessary. Transsphenoidal surgery is the treatment of choice for pituitary-dependent CD. Although transsphenoidal surgery allows cure of CD, the reported success rates vary between 50 and 90% (31–35). If surgery fails, radiotherapy, either alone or in combination with adrenolytic agents, may be used. Unfortunately, none of the current treatment modalities ensure a full and permanent cure, as the rate of recurrence of the disease, depending on the criteria of initial cure, varies between 5 and 24% in the literature (36, 37). Therefore, physicians have explored new medical strategies, preferably based on fundamental and (patho-) physiological pathways, with the hope to increase the chances of cure in this group of patients. Neuromodulatory agents, such as dopamine (DA) and SRIF, have been proposed to be of therapeutic interest in the medical treatment of CD. The conclusion of various case reports, however, is that the sst2-preferring analog OCT is ineffective in treating CD (38–40). Recently, it was demonstrated that glucocorticoid treatment induces remarkable differences with respect to the role of sst2 and sst5 in regulating ACTH release in mouse corticotrope AtT-20 cells, predominantly expressing sst2 and sst5 (41). In the absence of dexamethasone (DEX), OCT and SOM230 potently inhibited corticotropin-releasing hormone (CRH)-induced ACTH release, while the sst5-specific analog BIM-23 268 appeared to be the least potent. In the presence of DEX, a physiological nanomolar concentration of SOM230 and BIM-23 268 still inhibited CRH-induced ACTH release, whereas the suppressive effects of OCT were almost completely blocked. In addition, the IC50 values for OCT and BIM-23 268 after DEX treatment shift toward their sst5-binding affinity. The high potency for SOM230 was not affected by DEX. These data suggest down-regulation of sst2 by DEX, while sst5 receptors seem more resistant to DEX. This was indeed confirmed by the mRNA as well as by the sst membrane-binding studies. These data suggest that in untreated patients with CD the expression level of sst2 is too low for OCT to lower ACTH and cortisol levels. Indeed, relatively low levels of sst2 mRNA in a series of primary human corticotrope adenomas of patients with CD were found. On the other hand, a predominant expression of sst5 mRNA in corticotrope adenomas was observed (42). This sst mRNA profile in human corticotrope adenomas, i.e. a low sst2 and a significant sst5 mRNA expression, supports the concept that glucocorticoids down-regulate sst2 expression in human corticotrope adenomas, while sst5 receptors are more resistant to glucocorticoid pressure. These observations also support the lack of efficacy of OCT in lowering circulating ACTH and cortisol levels in these patients, because sst2 expression is too low and sst5-membrane binding affinity of OCT is not high enough to make OCT therapeutically active in patients with CD. Support is formed by SOM230-induced inhibition of basal and CRH-stimulated ACTH release by the corticotrophe adenomas, which appeared comparable with the observations in AtT20-cells, i.e. significant inhibition by SOM230 when compared with OCT, even in the presence of DEX. SOM230 did not inhibit AtT20 cell-proliferation or pro-opiomelanocortin synthesis during 72 h incubation in vitro. Therefore, increased ACTH breakdown may form an additional explanation for the inhibitory effect of SOM230 (and SRIF) on basal ACTH secretion. It is suggested, therefore, that sst2 +sst5 preferring SRIF analogs, such as SOM230, might become of therapeutic interest in CD. The suppression of ACTH levels by activation of sst5 in patients with CD might lower cortisol levels. Since cortisol lowers sst2 expression, these suppressive effects might subsequently be (partially) abrogated, and enhanced ACTH inhibition via restored sst2 expression becomes suggestive. Therefore, prolonged treatment with SOM230 may be able to lower ACTH levels in CD even more, because it could now function via both sst5 and sst2 receptor subtypes (Fig. 2Go). An open label phase II trial in nine patients with untreated or recurrent CD has demonstrated promising results with SOM230 (43). After 2 weeks of SOM230 treatment, 600 µg s.c. twice daily, free urinary cortisol levels normalized in three patients, while in the remaining six patients urinary cortisol levels were suppressed by 17–60%. A prolonged treatment shall reveal whether this multiligand can indeed be of clinical potential for this serious neuro-endocrine condition. On the other hand, glucose intolerance in all patients studied was documented during this short treatment period, and one patient even withdrew from the trial due to overt diabetes mellitus. In addition, a transient increase in glucose levels after SOM230 was already observed in acromegalic patients (44), whereby SOM230 was well tolerated and, in contrast to OCT, did not suppress insulin concentrations. Even though patients with CD and acromegaly are already known to suffer from glucose intolerance, it seems crucial for the future clinical development of SOM230 to retrieve answers with respect to this serious side effect.


Figure 2
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  		Figure 2 SOM230 in untreated pituitary-dependent Cushing’s disease. A de novo human corticotrophe adenoma has predominant expression of sst5 and low expression of sst2. The elevated ACTH and cortisol levels down-regulate sst2 expression on the tumor, making it almost impossible for the current clinically available sst2-preferring SRIF-analogs to inhibit ACTH and cortisol secretion (left). SOM230, however, through activation of sst5, should be able to lower ACTH and cortisol levels. In this relative hypocortisolemic state, the down-regulation of sst2 by cortisol might be abrogated. Subsequently, because SOM230 also binds with good affinity to sst2, enhanced suppression of ACTH and cortisol via restored sst2 expression becomes suggestive (right).

 
Prolactinomas

Dopamine agonists have been shown to be highly effective in the medical treatment of PRL secreting pituitary adenomas (45, 46). Still, several patients seem intolerant for these drugs and some of them are resistant or partially responsive to DA agonist treatment. Therefore, can SRIF analogs become of interest to treat this small group of prolactinoma patients? In three DA agonist sensitive prolactinomas, SOM230 was significantly more potent than OCT in lowering PRL secretion in vitro (18). In two of the prolactinomas, there was a clear relationship between the expression of sst5 mRNA in the adenoma cells and the percentage inhibition of PRL secretion by SOM230. In one prolactinoma culture, which expressed high levels of sst5 mRNA and no other sst mRNAs, PRL secretion was reduced to the same extent as that induced by bromocriptine (Fig. 3Go). One other prolactinoma, which showed a significantly lower responsiveness to SOM230, had very low sst5 mRNA levels. The lower potency of OCT in reducing PRL secretion by prolactinomas seems related to the very low sst2 levels as demonstrated in a series of 10 prolactinomas by Jaquet et al. (47). These data further underline the role of sst5 in mediating its suppressive effect on PRL secretion. However, as already mentioned, the potential clinical importance of these findings should be considered in view of the very high proportion of patients with prolactinomas responding to DA agonist treatment with a normalization of PRL levels and tumor shrinkage (45, 46). In addition, Jaquet et al. (47) showed previously that the effects of sst5 selective compounds on prolactinoma cells are superimposable, at higher concentrations to those of the DA agonists, but not additive, particularly in adenomas resistant to dopaminergic suppression of PRL release.


Figure 3
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  		Figure 3 Upper: effects of SOM230 (10 nM), OCT (10 nM) and bromocriptine (10 nM) on PRL release in a primary culture of a prolactinoma. *P<0.01 vs untreated control cells. Incubation time: 72 h. Lower: sst subtype mRNA expression in the prolactinoma cells. Adapted from (18).

 
TSH-secreting pituitary adenomas

TSH-secreting pituitary adenomas are rare and transsphenoidal surgery is considered the first treatment approach for these tumors, leading to normalization of thyroid hormone levels and the disappearance of pituitary tumors in approximately 44% of patients (48, 49). The current clinically available SRIF analogs OCT and lanreotide induce normalization of thyroid hormone levels in the large majority of patients with TSH-secreting adenomas, although limited data are available. In approximately 80% of patients normalization of TSH levels has been reported, while significant tumor shrinkage is observed in 50% of cases (49–51). These data suggest that sst2 receptors seem to be involved in the beneficial effects of the current clinically available sst2-preferring SRIF analogs.

Clinically non-functioning pituitary adenomas

Clinically non-functioning pituitary adenomas (NFAs) represent a very heterogeneous group of tumors because a consistent proportion of them (up to 90%) are shown to secrete low amounts of intact follicle-stimulating hormone and luteinizing hormone and/or their {alpha}- and ß-subunits either in vitro or in vivo. NFAs express sst subtypes, allowing researchers to attempt treatment with SRIF analogs. Despite favorable anti-proliferative effects of OCT treatment on NFA cells in vitro, few clinical trials have been reported in NFAs, but tumor reduction was observed only in 11–13% of cases, indicating a weak correlation between sst expression and treatment efficacy with OCT in these patients (52). More recently, the suggested predominant expression of sst3 mRNA in this group of pituitary adenomas (Hofland et al., unpublished data) and the in vitro support that sst3 can induce apoptosis via the induction of p53 and BAX (53), might reveal a new medical treatment option for patients with NFAs.

Conclusion

In the last two decades, SRIF analogs were used for the treatment of hormone-secreting pituitary adenomas. However, a significant proportion of these patients were found to be (partially) resistant to the suppressive effects of current clinically available sst2-preferring SRIF analogs. With the improved understanding of SRIF and sst physiology and interactions, and with the increasing involvement of the industry in novel SRIF formulation production, well-characterized sst selective and universal SRIF analogs were developed. Using these novel SRIF analogs in in vitro pituitary cell cultures resulted in new concepts and potential mechanisms for the treatment of pituitary hormone hypersecretion. These concepts include ligand binding to both sst2 and sst5 or to sst1 alone, resulting in greater efficacy to suppress GH in acromegaly; binding to sst5 to suppress PRL in prolactinomas; binding to predominantly sst5 and concomitantly to sst2 resulting in suppression of ACTH release in CD; and finally, binding to sst3 might induce pituitary adenoma cell shrinkage in NFAs. In addition, interactions among sst subtypes and receptors of other G-protein coupled receptors, such as the dopamine D2 receptor, may form another therapeutic tool in the medical treatment of pituitary adenomas (54–59). This interactive multireceptor system of ligand activation and cross-talk at the membrane and intracellular levels may improve manipulation of pituitary hormone regulation, and enhance efficacy of medical therapy for pituitary hormone hypersecretion.

References

    1. Melmed S, Jackson I, Kleinberg D & Klibanski A. Current treatment guidelines for acromegaly. Journal of Clinical Endocrinology and Metabolism 1998 83 2646–2652.[Abstract/Free Full Text]

    2. Rajasoorya C, Holdaway IM, Wrightson P, Scott DJ & Ibbertson HK. Determinants of clinical outcome and survival in acromegaly. Clinical Endocrinology 1994 41 95–102.[Medline]

    3. Bauer W, Briner U, Doepfner W, Haller R, Huguenin R, Marbach P & Petcher TJ. Pless. SMS 201-995: a very potent and selective octapeptide analogue of somatostatin with prolonged action. Life Sciences 1982 31 1133–1140.[CrossRef][ISI][Medline]

    4. Lamberts SW, Oosterom R, Neufeld M & del Pozo E. The somatostatin analog SMS 201-995 induces long-acting inhibition of growth hormone secretion without rebound hypersecretion in acromegalic patients. Journal of Clinical Endocrinology and Metabolism 1985 60 1161–1165.[Abstract]

    5. Lamberts SW, Uitterlinden P, Verschoor L, van Dongen KJ & del Pozo E. Long-term treatment of acromegaly with the somatostatin analogue SMS 201-995. New England Journal of Medicine 1985 313 1576–1580.[Abstract]

    6. Reichlin S. Somatostatin. New England Journal of Medicine 1983 309 1495–1501.[ISI][Medline]

    7. Lamberts SW, van der Lely AJ, de Herder WW & Hofland LJ. Octreotide. New England Journal of Medicine 1996 334 246–254.[Free Full Text]

    8. Freda PU. Somatostatin analogs in acromegaly. Journal of Clinical Endocrinology and Metabolism 2002 87 3013–3018.[Free Full Text]

    9. Bevan JS, Atkin SL, Atkinson AB, Bouloux PM, Hanna F, Harris PE, James RA, McConnell M, Roberts GA, Scanlon MF, Stewart PM, Teasdale E, Turner HE, Wass JA & Wardlaw JM. Primary medical therapy for acromegaly: an open, prospective, multicenter study of the effects of subcutaneous and intramuscular slow- release octreotide on growth hormone, insulin-like growth factor-I, and tumor size. Journal of Clinical Endocrinology and Metabolism 2002 87 4554–4563.[Abstract/Free Full Text]

    10. Attanasio R, Baldelli R, Pivonello R, Grottoli S, Bocca L, Gasco V, Giusti M, Tamburrano G, Colao A & Cozzi R. Lanreotide 60 mg, a new long-acting formulation: effectiveness in the chronic treatment of acromegaly. Journal of Clinical Endocrinology and Metabolism 2003 88 5258–5265.[Abstract/Free Full Text]

    11. Colao A, Ferone D, Marzullo P, Cappabianca P, Cirillo S, Boerlin V, Lancranjan I & Lombardi G. Long-term effects of depot long-acting somatostatin analog octreotide on hormone levels and tumor mass in acromegaly. Journal of Clinical Endocrinology and Metabolism 2001 86 2779–2786.[Abstract/Free Full Text]

    12. Ayuk J, Stewart SE, Stewart PM & Sheppard MC. Long-term safety and efficacy of depot long-acting somatostatin analogs for the treatment of acromegaly. Journal of Clinical Endocrinology and Metabolism 2002 87 4142–4146.[Abstract/Free Full Text]

    13. Danoff A & Kleinberg D. Somatostatin analogs as primary medical therapy for acromegaly. Endocrine 2003 20 291–298.[ISI][Medline]

    14. Sheppard MC. Primary medical therapy for acromegaly. Clinical Endocrinology 2003 58 387–399.[CrossRef][Medline]

    15. Newman CB, Melmed S, George A, Torigian D, Duhaney M, Snyder P, Young W, Klibanski A, Molitch ME, Gagel R, Sheeler L, Cook D, Malarkey W, Jackson I, Vance ML, Barkan A, Frohman L & Kleinberg DL. Octreotide as primary therapy for acromegaly. Journal of Clinical Endocrinology and Metabolism 1998 83 3034–3040.[Abstract/Free Full Text]

    16. Jaquet P, Saveanu A, Gunz G, Fina F, Zamora AJ, Grino M, Culler MD, Moreau JP, Enjalbert A & Ouafik LH. Human somatostatin receptor subtypes in acromegaly: distinct patterns of messenger ribonucleic acid expression and hormone suppression identify different tumoral phenotypes. Journal of Clinical Endocrinology and Metabolism 2000 85 781–792.[Abstract/Free Full Text]

    17. Murabe H, Shimatsu A, Ihara C, Mizuta H, Nakamura Y, Nagata I, Kikuchi H & Nakao K. Expression of somatostatin receptor (SSTR) subtypes in pituitary adenomas: quantitative analysis of SSTR2 mRNA by reverse transcription-polymerase chain reaction. Journal of Neuroendocrinology 1996 8 605–610.[CrossRef][ISI][Medline]

    18. Hofland LJ, van der Hoek J, van Koetsveld PM, de Herder WW, Waaijers M, Sprij-Mooij D, Bruns C, Weckbecker G, Feelders R, van der Lely AJ, Beckers A & Lamberts SW. The novel somatostatin analog SOM230 is a potent inhibitor of hormone release by growth hormone- and prolactin-secreting pituitary adenomas in vitro. Journal of Clinical Endocrinology and Metabolism 2004 89 1577–1585.[Abstract/Free Full Text]

    19. Hofland LJ & Lamberts SW. The pathophysiological consequences of somatostatin receptor internalization and resistance. Endocrine Reviews 2003 24 28–47.[Abstract/Free Full Text]

    20. Reubi JC, Waser B, Schaer JC & Laissue JA. Somatostatin receptor sst1-sst5 expression in normal and neoplastic human tissues using receptor autoradiography with subtype-selective ligands. European Journal of Nuclear Medicine 2001 28 836–846.[CrossRef][ISI][Medline]

    21. Saveanu A, Gunz G, Dufour H, Caron P, Fina F, Ouafik L, Culler MD, Moreau JP, Enjalbert A & Jaquet P. Bim-23244, a somatostatin receptor subtype 2- and 5-selective analog with enhanced efficacy in suppressing growth hormone (GH) from octreotide-resistant human GH-secreting adenomas. Journal of Clinical Endocrinology and Metabolism 2001 86 140–145.[Abstract/Free Full Text]

    22. Shimon I, Taylor JE, Dong JZ, Bitonte RA, Kim S, Morgan B, Coy DH, Culler MD & Melmed S. Somatostatin receptor subtype specificity in human fetal pituitary cultures. Differential role of SSTR2 and SSTR5 for growth hormone, thyroid-stimulating hormone, and prolactin regulation. Journal of Clinical Investigation 1997 99 789–798.[ISI][Medline]

    23. Shimon I, Yan X, Taylor JE, Weiss MH, Culler MD & Melmed S. Somatostatin receptor (SSTR) subtype-selective analogues differentially suppress in vitro growth hormone and prolactin in human pituitary adenomas. Novel potential therapy for functional pituitary tumors. Journal of Clinical Investigation 1997 100 2386–2392.[ISI][Medline]

    24. Ren SG, Taylor J, Dong J, Yu R, Culler MD & Melmed S. Functional association of somatostatin receptor subtypes 2 and 5 in inhibiting human growth hormone secretion. Journal of Clinical Endocrinology and Metabolism 2003 88 4239–4245.[Abstract/Free Full Text]

    25. Bruns C, Lewis I, Briner U, Meno-Tetang G & Weckbecker G. SOM230: a novel somatostatin peptidomimetic with broad somatotropin release inhibiting factor (SRIF) receptor binding and a unique antisecretory profile. European Journal of Endocrinology 2002 146 707–716.[Abstract]

    26. Murray RD, Kim K, Ren SG, Lewis I, Weckbecker G, Bruns C & Melmed S. The novel somatostatin ligand (SOM230) regulates human and rat anterior pituitary hormone secretion. Journal of Clinical Endocrinology and Metabolism 2004 89 3027–3032.[Abstract/Free Full Text]

    27. van der Hoek J, de Herder WW, Feelders RA, van der Lely AJ, Uitterlinden P, Boerlin V, Bruns C, Poon KW, Lewis I, Weckbecker G, Krahnke T, Hofland LJ & Lamberts SW. A single-dose comparison of the acute effects between the new somatostatin analog SOM230 and octreotide in acromegalic patients. Journal of Clinical Endocrinology and Metabolism 2004 89 638–645.[Abstract/Free Full Text]

    28. Zatelli MC, Piccin D, Tagliati F, Ambrosio MR, Margutti A, Padovani R, Scanarini M, Culler MD & degli Uberti EC. Somatostatin receptor subtype 1 selective activation in human growth hormone (GH)- and prolactin (PRL)-secreting pituitary adenomas: effects on cell viability, GH, and PRL secretion. Journal of Clinical Endocrinology and Metabolism 2003 88 2797–2802.[Abstract/Free Full Text]

    29. Matrone C, Pivonello R, Colao A, Cappabianca P, Cavallo LM, Del Basso De Caro ML, Taylor JE, Culler MD, Lombardi G, Di Renzo GF & Annunziato L. Expression and function of somatostatin receptor subtype 1 in human growth hormone secreting pituitary tumors deriving from patients partially responsive or resistant to long-term treatment with somatostatin analogs. Neuroendocrinology 2004 79 142–148.[ISI][Medline]

    30. Newell-Price J, Trainer P, Besser M & Grossman A. The diagnosis and differential diagnosis of Cushing’s syndrome and pseudo-Cushing’s states. Endocrine Reviews 1998 19 647–672.[Abstract/Free Full Text]

    31. Mampalam TJ, Tyrrell JB & Wilson CB. Transsphenoidal microsurgery for Cushing disease. A report of 216 cases. Annals of Internal Medicine 1988 109 487–493.[ISI][Medline]

    32. Swearingen B, Biller BM, Barker FG, II, Katznelson L, Grinspoon S, Klibanski A & Zervas NT. Long-term mortality after transsphenoidal surgery for Cushing disease. Annals of Internal Medicine 1999 130 821–824.[Abstract/Free Full Text]

    33. Trainer PJ, Lawrie HS, Verhelst J, Howlett TA, Lowe DG, Grossman AB, Savage MO, Afshar F & Besser GM. Transsphenoidal resection in Cushing’s disease: undetectable serum cortisol as the definition of successful treatment. Clinical Endocrinology 1993 38 73–78.[Medline]

    34. Knappe UJ & Ludecke DK. Persistent and recurrent hyper-cortisolism after transsphenoidal surgery for Cushing’s disease. Acta Neurochirurgica. Supplementf 1996 65 31–34.[Medline]

    35. Boggan JE, Tyrrell JB & Wilson CB. Transsphenoidal microsurgical management of Cushing’s disease. Report of 100 cases. Journal of Neurosurgery 1983 59 195–200.[ISI][Medline]

    36. Sonino N, Zielezny M, Fava GA, Fallo F & Boscaro M. Risk factors and long-term outcome in pituitary-dependent Cushing’s disease. Journal of Clinical Endocrinology and Metabolism 1996 81 2647–2652.[Abstract]

    37. Miller JW & Crapo L. The medical treatment of Cushing’s syndrome. Endocrine Reviews 1993 14 443–458.[CrossRef][ISI][Medline]

    38. Lamberts SW, Uitterlinden P & Klijn JM. The effect of the long-acting somatostatin analogue SMS 201-995 on ACTH secretion in Nelson’s syndrome and Cushing’s disease. Acta Endocrinologica 1989 120 760–766.[Abstract/Free Full Text]

    39. Stalla GK, Brockmeier SJ, Renner U, Newton C, Buchfelder M, Stalla J & Muller OA. Octreotide exerts different effects in vivo and in vitro in Cushing’s disease. European Journal of Endocrinology 1994 130 125–131.[Abstract/Free Full Text]

    40. Ambrosi B, Bochicchio D, Fadin C, Colombo P & Faglia G. Failure of somatostatin and octreotide to acutely affect the hypothalamic-pituitary-adrenal function in patients with corticotropin hypersecretion. Journal of Endocrinological Investigation 1990 13 257–261.[ISI][Medline]

    41. van der Hock J, Waaijers A, van Koetsveld P, Sprij-Mooij D, Feelders RA, Schmid HA, PS, Hoyer D, Cervia D, JET, MDC, Lamberts SWJ & Hofland LJ. Distinct functional properties of native somatostatin receptor subtype 5 compared with subtype 2 in the regulation of ACTH release by corticotroph tumor cells. American Journal of Physiology, Endocrinology and Metabolism 2005 289 E278–E287.[Abstract/Free Full Text]

    42. Hofland LJ, van der Hoek J, Feelders R, van Aken MO, van Koetsveld PM, Waaijers M, Sprij-Mooij D, Bruns C, Weckbecker G, de Herder WW, Beckers A & Lamberts SWJ. The multiligand somatostatin analog SOM230 inhibits ACTH secretion by cultured human corticotroph adenomas via somatostatin receptor subtype 5. European Journal of Endocrinology 2005 152 645–654.[Abstract/Free Full Text]

    43. Boscaro M, Brew Atkinson A, Bertherat J, Petersenn S, Glusman JE, Gao B & Tran LL. Early data on the efficacy and safety of the novel multi-ligand somatostatin analog, SOM230, in patients with Cushing’s disease. The Endocrine Society Meeting, 2005 P2–531.

    44. van der Hoek J, van der Lely AJ, Feelders RA, de Herder WW, Uitterlinden P, Poon KW, Boerlin V, Lewis I, Krahnke T, Hofland LJ & Lamberts SW. The somatostatin analog SOM230, compared with octreotide, induces differential effects in several metabolic pathways in acromegalic patients. Clinical Endocrinology 2005 63 176–184.[CrossRef][Medline]

    45. Colao A, di Sarno A, Pivonello R, di Somma C & Lombardi G. Dopamine receptor agonists for treating prolactinomas. Expert Opinion on Investigational Drugs 2002 11 787–800.[CrossRef][ISI][Medline]

    46. Webster J. Clinical management of prolactinomas. Baillieres Best Practice and Research. Clinical Endocrinology and Metabolism 1999 13 395–408.

    47. Jaquet P, Ouafik L, Saveanu A, Gunz G, Fina F, Dufour H, Culler MD, Moreau JP & Enjalbert A. Quantitative and functional expression of somatostatin receptor subtypes in human prolactinomas. Journal of Clinical Endocrinology and Metabolism 1999 84 3268–3276.[Abstract/Free Full Text]

    48. Beck-Peccoz P, Brucker-Davis F, Persani L, Smallridge RC & Weintraub BD. Thyrotropin-secreting pituitary tumors. Endocrine Reviews 1996 17 610–638.[CrossRef][ISI][Medline]

    49. Beck-Peccoz P, Persani L, Mantovani S, Cortelazzi D & Asteria C. Thyrotropin-secreting pituitary adenomas. Metabolism 1996 45 75–79.[CrossRef][ISI][Medline]

    50. Comi RJ, Gesundheit N, Murray L, Gorden P & Weintraub BD. Response of thyrotropin-secreting pituitary adenomas to a long-acting somatostatin analogue. New England Journal of Medicine 1987 317 12–17.[Abstract]

    51. Chanson P, Weintraub BD & Harris AG. Octreotide therapy for thyroid-stimulating hormone-secreting pituitary adenomas. A follow-up of 52 patients. Annals of Internal Medicine 1993 119 236–240.[Abstract/Free Full Text]

    52. Colao A, Filippella M, Somma C, Manzi S, Rota F, Pivonello R, Gaccione M, Rosa M & Lombardi G. Somatostatin analogs in treatment of non-growth hormone-secreting pituitary adenomas. Endocrine 2003 20 279–284.[ISI][Medline]

    53. Sharma K, Patel YC & Srikant CB. Subtype-selective induction of wild-type p53 and apoptosis, but not cell cycle arrest, by human somatostatin receptor 3. Molecular Endocrinology 1996 10 1688–1696.[Abstract]

    54. Baragli A, Kumar U, Patel R C, Patel Y C. Hetero-oligomerisation of dopamine (D2R) and somatostatin receptors (sstr2) in CHO-K1 cells and cortical cultures neurons. 2003 In Proceedings of the 85th Annual Meeting of the Endocrine Society. Philadelphia, 2003, p 2469.

    55. George SR, O’Dowd BF & Lee SP. G-protein-coupled receptor oligomerization and its potential for drug discovery. Nature Reviews. Drug Discovery 2002 1 808–820.[CrossRef][ISI][Medline]

    56. Jaquet P, Gunz G, Saveanu A, Dufour H, Taylor J, Dong J, Kim S, Moreau JP, Enjalbert A & Culler MD. Efficacy of chimeric molecules directed towards multiple somatostatin and dopamine receptors on inhibition of GH and prolactin secretion from GH-secreting pituitary adenomas classified as partially responsive to somatostatin analog therapy. European Journal of Endocrinology 2005 153 135–141.[Abstract/Free Full Text]

    57. Jaquet P, Gunz G, Saveanu A, Barlier A, Dufour H, Taylor J, Dong J, Kim S, Moreau JP & Culler MD. BIM-23A760, a chimeric molecule directed towards somatostatin and dopamine receptors, vs universal somatostatin receptors ligands in GH-secreting pituitary adenomas partial responders to octreotide. Journal of Endocrinological Investigation 2005 28 21–27.[Medline]

    58. Ren SG, Kim S, Taylor J, Dong J, Moreau JP, Culler MD & Melmed S. Suppression of rat and human growth hormone and prolactin secretion by a novel somatostatin/dopaminergic chimeric ligand. Journal of Clinical Endocrinology and Metabolism 2003 88 5414–5421.[Abstract/Free Full Text]

    59. Saveanu A, Lavaque E, Gunz G, Barlier A, Kim S, Taylor JE, Culler MD, Enjalbert A & Jaquet P. Demonstration of enhanced potency of a chimeric somatostatin-dopamine molecule, BIM-23A387, in suppressing growth hormone and prolactin secretion from human pituitary somatotroph adenoma cells. Journal of Clinical Endocrinology and Metabolism 2002 87 5545–5552.[Abstract/Free Full Text]

Received 12 January 2007
Accepted 18 January 2007





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