HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Abstract Full Text (PDF) All Versions of this Article: ERC-08-0181v1 15/4/905    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (10) Citing Articles via Google Scholar Google Scholar Articles by Colao, A. Articles by Savastano, S. Search for Related Content PubMed PubMed Citation Articles by Colao, A. Articles by Savastano, S.

Department of Molecular and Clinical Endocrinology and Oncology, ‘Federico II’ University, Via Sergio Pansini 5, 80131 Naples, Italy

(Correspondence should be addressed to A Colao; Email: colao{at}unina.it)

	Abstract

Top Abstract Introduction Experimental background of... Results of treatment with... Results of treatment with... Results of treatment with... Results of treatment with... Other medical approaches Conclusions Declaration of interest References

 
Surgery is the first-line treatment of patients with clinically non-functioning pituitary adenomas (NFAs). Because of lack of clinical syndrome these tumours are diagnosed with a variable delay, when patients suffer from compression symptoms (hypopituitarism, headache and visual field defects) due to the extension of the tumour outside the pituitary fossa. Surgery is followed by residual tumour tissue in most patients. In these cases, radiotherapy is generally used to prevent tumour regrowth. However, NFA cell membranes, in analogy with GH- and PRL-secreting adenomas, express somatostatin and dopamine receptors. Treatment with somatostatin analogues (SSA) and dopamine agonists (DA) induced some beneficial effects on visual field defects and was also followed by tumour shrinkage in a minority of cases. DA seem to be more effective on tumour shrinkage than SSA. More recently, a combination treatment with both SSA and DA have been tested in a few patients with interesting results. Lack of randomized, placebo-controlled trials prevents any conclusion on the efficacy of these drugs. By contrast, use of gonatotrophin-releasing hormone analogues has been abandoned.

	Introduction

Top Abstract Introduction Experimental background of... Results of treatment with... Results of treatment with... Results of treatment with... Results of treatment with... Other medical approaches Conclusions Declaration of interest References

 
Non-functioning pituitary adenomas (NFAs) represent a very heterogeneous group of tumours, accounting for 25% of all pituitary adenomas (Katznelson et al. 1993). They often present with macroadenomas that cause neurological symptoms due to mass effects, as hormonal inactivity led to delayed diagnosis when compared with functioning pituitary adenomas. In fact, as recently reported by the results of a large database (Ferrante et al. 2006), almost all tumours were macroadenomas (96.5%) and the main presenting symptoms are visual defects (67.8%) and headache (41.4%), and the most frequent pituitary deficit was hypogonadism (43.3%).

Neurosurgery is the treatment of choice of these tumours (Jaffe 2006). However, because of frequent supra- or parasellar extension, surgery is infrequently curative, leaving tumour remnants that regrow during long-term follow-up in a significant proportion of cases (Ebersold et al. 1986, Harris et al. 1989, Colao et al. 1998). The use of post-operative radiotherapy is still controversial. Despite the demonstrated efficacy of radiotherapy in preventing tumour regrowth (Colao et al. 1998, Turner et al. 1999, Boelaert & Gittoes 2001), the selection of patients who will benefit by this therapy is made difficult by the absence of specific markers of tumour aggressiveness along with the potential side effects of this procedure that include hypopituitarism, neurocognitive dysfunction and cerebrovascular disease (Gittoes 2003, Greenman et al. 2003, Erfurth & Hagmar 2005). In addition, development of secondary intracranial tumour might rarely follow radiotherapy (Gittoes 2003, Greenman et al. 2003).

However, by immunocytochemistry, the large majority of these tumours are glycoprotein producing, and less commonly are non-functioning somatotroph, lactotroph or corticotroph adenomas (Jaffe 2006). In analogy with actively secreting adenomas, a proportion of NFA (up to 90%) is shown to secrete low amounts of FSH and LH and/or their - and β-subunits either in vitro or in vivo (Katznelson et al. 1993, Jaffe 2006), and the vast majority of NFA also express on cell membranes different subtypes of somatostatin and dopamine receptors in a variable amount. Based on this feature, both dopamine agonists (DA) and somatostatin analogues (SSA) have a rationale in the treatment of NFA. However, the results of DA and SSA so far have been rather disappointing (Colao et al. 2000a), except for some case reports.

The existence of a functional interaction between dopamine and somatostatin receptors (Rocheville et al. 2000) has opened a new perspective of medical treatment for such tumours.

This review focuses on the experimental background of pharmacotherapy in NFA and summarizes literature data reporting on (SSA (octreotide or lanreotide)), (DA (bromocriptine, quinagolide or cabergoline)), or a combination of both in NFA-bearing patients. Though abandoned from several years, the data on gonadotrophins suppression using gonadotrophin-releasing hormone (GnRH) analogues is also briefly revised.

	Experimental background of medical therapy in NFA

Top Abstract Introduction Experimental background of... Results of treatment with... Results of treatment with... Results of treatment with... Results of treatment with... Other medical approaches Conclusions Declaration of interest References

 
Somatostatin and dopamine actions are mediated by five specific receptor subtypes respectively, sst₁-sst₅ and D₁-D₅ (Missale et al. 1998, Hofland & Lamberts 2004). Two different isoforms of sst₂ and D₂ have also been found and characterized (Missale et al. 1998, Hofland & Lamberts 2004). The different somatostatin and dopamine receptors have variable organ-, tissue- and cytospecific distribution and play different physiological roles.

Somatostatin receptors

Somatostatin receptors have been demonstrated to be highly expressed in all pituitary adenomas, with a predominance of sst₂ and sst₅ and infrequent expression of sst₄ (Greenman & Melmed 1994a,b, Hofland & Lamberts 2001). The expression of sst₂ predicts the response to octreotide and lanreotide, the two SSA most widely used in clinical practice, showing high affinity for sst₂ and sst₅ and low affinity for sst₃ (van der Hoek et al. 2007). In NFA, the receptor subtype expressed in a higher amount was found to be the sst₃ followed by the sst₂ (which is the most expressed receptor in GH-secreting adenomas) while sst₁, sst₄ and sst₅ transcripts were detected only in a few tumours (Taboada et al. 2007). Native somatostatin (binding all ssts) and selective analogues for sst₃ and sst₂ inhibited chromogranin-A (CgA) and -subunit levels (Pawlikowski et al. 2007). CgA inhibition also correlated with sst₅ expression (Pawlikowski et al. 2007). The expression of sst₂ and sst₅ in NFA was also associated with reduced cell viability by 20-80% (in 8 of 13 tumours sst₂ positive) and 15-80% (in 10 of 13 tumours, all but three sst₅ positive; Padova et al. 2008). Accordingly, pasireotide (SOM230), a somatostatin analogue binding sst_1-3 and sst₅, completely abrogated the promoting effects of vascular endothelial growth factor on NFA cell viability (Zatelli et al. 2007).

Dopamine receptors

In the normal pituitary, the D₂ mediates the tonic inhibitory control of prolactin (PRL) secretion (Lamberts & MacLeod 1990) by dopamine, and in prolactinomas drugs acting on D₂ level are able to reduce the size of the tumour and control PRL excess (Duet et al. 1994). Ligand-binding studies and scintigraphic evaluations have shown the presence of dopamine-binding sites (most likely D₂) in NFA (Bevan & Burke 1986, Hedner & Valdemarsson 1989, Kwekkboom & Lamberts 1992, Ferone et al. 1998, Colao et al. 2000b, Pivonello et al. 2004). A heterogeneous expression of D₂ isoforms was observed in 16 out of 18 NFA, while in the remaining two no D₂ expression was found (Renner et al. 1998). In gonadotrophin-immunopositive adenomas, the D₂ was mainly localized in the LH- and FSH-immunopositive cells (Renner et al. 1998). Similarly, the D₂ was found to be expressed in 67% of NFA with a prevalence of D_2long (50%) when compared with the D_2short (17%), and with both D₂ isoforms expressed in 33% of cases (Pivonello et al. 2004). The D₂ receptor is not the only dopamine receptor expressed in the pituitary gland. Indeed, the D₄ receptor, in particular its D_4.4variant, is also expressed, though its role in the physiology of the pituitary gland is not known (Van Tol et al. 1992). The D₄ was found to be expressed in 17% of NFA (Pivonello et al. 2004). Based on these data, the effects of different DA were investigated in these tumours both in vivo and in vitro (Bevan et al. 1992). Cabergoline administration in vitro inhibited -subunit concentration in 56% of cases and this result was associated with D₂ expression (Pivonello et al. 2004).

Interaction between somatostatin and dopamine receptors

As mentioned before, D₂ and sst₅ interact physically through hetero-oligomerization to create a novel receptor with enhanced functional activity (Rocheville et al. 2000). Based on this observation, several investigators investigated whether the combination treatment with selective ligands of these two individual receptors as well as new molecules binding both receptors simultaneously could be effective in NFA cell cultures. Florio et al. (2008) recently reported on 38 fibroblast-deprived NFA characterized for GH, POMC, sst_1-5 and D₂ and (in 15 of 38 cases) D₂ long and short isoforms mRNA expression, and for -subunit, LH and FSH release. They demonstrated that BIM-23A760, a molecule with high affinity for D₂ and sst₂, significantly inhibited ^3Hthymidine incorporation in 23 out of 38 (60%) NFA cultures (Florio et al. 2008). However, BIM-23A760 effects were similar to those induced by cabergoline (Florio et al. 2008).

Clinical trials will clarify whether the experimental results will be confirmed.

	Results of treatment with SSA

Top Abstract Introduction Experimental background of... Results of treatment with... Results of treatment with... Results of treatment with... Results of treatment with... Other medical approaches Conclusions Declaration of interest References

 
During the past 20 years, different SSAs have been used. The first available SSA is the short-acting form of octreotide (OCT), an octapeptide with preferential binding to sst₂ and sst₅, for s.c. administration, then another analogue, the slow-release lanreotide (LAN), showing that a similar receptor affinity for sst of OCT was made available for i.m. injections every 7-14 days. More recently, OCT and LAN have been made available for injections either i.m. or s.c. every 28-56 days respectively. The former represents OCT incorporated in microspheres of a biodegradable polymer, poly (DL-lactide-co-glycolide glucose) thus allowing the i.m. injection every 28 days (LAR), while the latter is LAN in water with no additional excipients (autogel (ATG)). The only available data so far have been produced using OCT. LAN was only tested in vitro in 12 NFA specimens which was shown to inhibit phorbol myristate acetate-induced cell proliferation (Florio et al. 1999), while no data are available for LAR and ATG.

A few clinical trials have been conducted to evaluate potential effects of OCT in patients with NFA (Warnet et al. 1989, 1997, Liuzzi et al. 1991, Turpin et al. 1991, De Bruin et al. 1992, Katznelson et al. 1992, Gasperi et al. 1993, Merola et al. 1993, Plockinger et al. 1994, Borson-Chazot et al. 1997, Colao et al. 1999), as summarized in Table 1. Tumour reduction was reported only in 12% of cases, while the vast majority of patients had stable remnant tumours (Table 1). Importantly, only in 5% of the patients the tumour was found to increase during treatment, but generally follow-up of patients was too short (6 months in average) to draw final conclusion on a potential effect of OCT in preventing tumour regrowth. There are controversial data on the potential use of scintigraphy depicting sst expression of ¹¹¹In-pentatreotide and treatment efficacy with OCT in NFA patients (Faglia et al. 1991, Duet et al. 1994, Plockinger et al. 1994, Warnet et al 1997, Colao et al. 1999). Duet et al. (1994) demonstrated that of the five patients with NFA who had pituitary uptake of ¹¹¹In-DTPAd-phe¹-octreotide, only the patient with very high uptake (index of 15.1) had significant tumour shrinkage after OCT treatment. Similarly, we reported (Colao et al. 1999) significant tumour shrinkage (30% of baseline size) in two of six NFA during long-term OCT therapy. We also found a significant correlation between percentage of -subunit suppression after 6-12 months of OCT therapy and tumour-to-background ratio in both early and late images. In fact, -subunit levels were significantly reduced in the six patients with moderate to intense uptake of ¹¹¹In-DTPAd-phe¹-octreotide calculated on the pituitary background ratios (Colao et al. 1999). It should be stated, however, that ¹¹¹In-DTPAd-phe¹-octreotide scintigraphy is not anymore used in patients with pituitary adenomas.

	Results of treatment with DA

Top Abstract Introduction Experimental background of... Results of treatment with... Results of treatment with... Results of treatment with... Results of treatment with... Other medical approaches Conclusions Declaration of interest References

 
DA are the main treatment in prolactinomas (Gillam et al. 2006). In NFA, as shown in Table 2, the cumulative evidence for tumour shrinkage after DA therapy is 27.6% (Johnston et al. 1981, Wass et al. 1982, Barrow et al. 1984, Grossman et al. 1985, Pullan et al. 1985, Verde et al. 1985, Zárate et al. 1985, D'Emden & Harrison 1986, Bevan et al. 1987, Klibanski et al. 1988, García-Luna et al. 1989, van Schaardenburg et al. 1989, Abs et al. 1991, Kwekkboom & Lamberts 1992, Van Tol et al. 1992, Ferone et al. 1998, Colao et al. 2000b, Giusti et al. 2000, Nobels et al. 2000, Hofland & Lamberts 2001, Lohmann et al. 2001, Pivonello et al. 2004, Greenman et al. 2005). When compared with that obtained with SSA (5%), the latter was significantly different (² test, P<0.0001). Additionally, as also observed in patients treated with SSA, there was an improvement in visual field defects (20.2%), which was similar to that obtained with SSA (32.1%). To note, prevalence of improvement in visual field defects is even higher than that calculated in Tables 1 and 2, as we reported the data related to the entire population and not to the population of patients presenting with visual field defects before starting treatment, as this information was not available in every study. Interestingly, the rate of tumour regrowth was as low as in the SSA-treated cohort (8.5 vs 12%, P=0.46). Short duration of follow-ups, both in patients treated with SSA and DA, is clearly a limitation in investigating the prevalence of tumour growth. As already mentioned for ¹¹¹In-DTPAd-phe¹-octreotide scintigraphy in predicting tumour shrinkage, scintigraphy with radiolabelled dopamine analogue ¹²³I-methoxybenzamide was used to predict hormone inhibition and tumour shrinkage in NFA-bearing patients. In two different patients’ series, intense uptake of ¹²³I-methoxybenzamide was associated with tumour shrinkage after CV or cabergoline (CAB) (Faglia et al. 1991, Florio et al. 2008). More recently, in 18 patients with NFA treated either with CAB or CV, in vivo imaging of D₂ using ¹²³I-epidepride was not associated with tumour shrinkage (de Herder et al. 2006). However, since medical treatment is applicable only after surgery at present, more interesting is the possibility to analyse D₂ expression on tumour specimens after surgical removal to correlate with subsequent response to DA treatment. Pivonello et al. (2004) demonstrated that 1 year of CAB treatment at the dose of 3 mg/week induced a more than 25% tumour shrinkage in 56% of patients with histologically proven NFA. Tumour shrinkage after CAB treatment was significantly correlated with D₂ expression (Fig. 1). Since this is only a single experience, more data have to be accumulated before a definitive conclusion can be drawn. However, the reported finding of tumour enlargement after stopping BRC treatment in NFA experiencing tumour shrinkage (Clark et al. 1985) support the use of DA in such patients. According with Greenman (2007), the routine use of DA can be suggested in patients with NFA for prevention of post-operative tumour remnant regrowth based on the available data and the associated sequelae to pituitary radiotherapy.

	Results of treatment with a combination treatment with SSA plus DA

Top Abstract Introduction Experimental background of... Results of treatment with... Results of treatment with... Results of treatment with... Results of treatment with... Other medical approaches Conclusions Declaration of interest References

	Results of treatment with GnRH analogues

Top Abstract Introduction Experimental background of... Results of treatment with... Results of treatment with... Results of treatment with... Results of treatment with... Other medical approaches Conclusions Declaration of interest References

	Other medical approaches

Top Abstract Introduction Experimental background of... Results of treatment with... Results of treatment with... Results of treatment with... Results of treatment with... Other medical approaches Conclusions Declaration of interest References

	Conclusions

Top Abstract Introduction Experimental background of... Results of treatment with... Results of treatment with... Results of treatment with... Results of treatment with... Other medical approaches Conclusions Declaration of interest References

 
First-line therapy of patients with NFA is surgery. However, since these tumours are generally large at diagnosis, most patients present remnant tumours after surgery. In fact, of the 295 patients included into a database (Ferrante et al. 2006), 290 (98%) underwent surgery and on the basis of radiological findings, only 105 patients (35.5%) were considered cured (i.e. they had total tumour debulking) after surgery. Therefore, there is a need for an additional treatment in the vast majority of NFA-bearing patients. Conventional radiotherapy is reported to delay tumour regrowth (Turner et al. 1999, Ferrante et al. 2006) but causes hypopituitarism in virtually all patients after 10 years (Colao et al. 1998), and is associated with early cerebrovascular mortality in patients with acromegaly (Ayuk et al. 2004, Kauppinen-Makelin et al. 2005) but also in patients with NFA (Erfurth & Hagmar 2005). There is, thus, need for efficacious medical treatments for patients bearing remnant tumours after surgery. Both SSA and DA were found to be of some efficacy in selected patients with NFA, with the latter drugs being significantly more effective in reducing tumour volumes. However, no placebo-controlled long-term studies are available to suggest the use of SSA or DA or a combination of them. Therefore, on a practical point of view, the use of these compounds in patients with NFA is not evidence based.

Interestingly, Dekkers et al. (2007) recently reported that in 28 non-operated patients with NFA, tumour growth occurred in 14 patients (50%) after 118±24 months, but spontaneous reduction of tumour volume also occurred in eight patients (29%). They thus suggested that even observation alone might be considered as a safe alternative to surgery in selected NFA patients, provided that no risk of irreversibly compromising visual function occurs. These latter findings indicate that a more conservative approach can also be attempted since NFAs are proven to grow very slowly so that surgery can be used only in patients with tumour compressive symptoms such as visual field defects, headache or hypopituitarism.

	Declaration of interest

Top Abstract Introduction Experimental background of... Results of treatment with... Results of treatment with... Results of treatment with... Results of treatment with... Other medical approaches Conclusions Declaration of interest References

 
There is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.

	Funding

 
This research did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.

	References

Top Abstract Introduction Experimental background of... Results of treatment with... Results of treatment with... Results of treatment with... Results of treatment with... Other medical approaches Conclusions Declaration of interest References

 
Abs R, Parizel PM & Beckers A 1991 Acute effects of Parlodel-LAR and response to long-term treatment with bromocriptine in a patient with a follicle stimulating hormone-secreting pituitary adenoma. Journal of Endocrinological Investigation 14 135-138.[Medline]

Andersen M, Bjerre P, Schrøder HD, Edal A, Høilund-Carlsen PF, Pedersen PH & Hagen C 2001 In vivo secretory potential and the effect of combination therapy with octreotide and cabergoline in patients with clinically non-functioning pituitary adenomas. Clinical Endocrinology 54 23-30.[CrossRef][Medline]

Ayuk J, Clayton RN, Holder G, Sheppard MC, Stewart PM & Bates AS 2004 Growth hormone and pituitary radiotherapy, but not serum insulin-like growth factor-I concentrations, predict excess mortality in patients with acromegaly. Journal of Clinical Endocrinology and Metabolism 89 1613-1617.[Abstract/Free Full Text]

Barrow DL, Tindall GT, Kovacs K, Thorner MO, Horvath E & Hoffman JC Jr 1984 Clinical and pathological effects of bromocriptine on prolactin-secreting and other pituitary tumours. Journal of Neurosurgery 60 1-7.[Medline]

Bevan JS & Burke CW 1986 Non-functioning pituitary adenomas do not regress during bromocriptine therapy but possess membrane-bound dopamine receptors which bind bromocriptine. Clinical Endocrinology 25 561-572.[Medline]

Bevan JS, Adams CB, Burke CW, Morton KE, Molyneux AJ, Moore RA & Esiri MM 1987 Factors in the outcome of transsphenoidal surgery for prolactinoma and non-functioning pituitary tumour, including pre-operative bromocriptine therapy. Clinical Endocrinology 26 541-556.[Medline]

Bevan JS, Webster J, Burke CW & Scanlon MF 1992 Dopamine agonists and pituitary shrinkage. Endocrine Reviews 13 220-240.[Abstract/Free Full Text]

Boelaert K & Gittoes NJ 2001 Radiotherapy for non-functioning pituitary adenomas. European Journal of Endocrinology 144 569-575.[Abstract]

Borson-Chazot F, Houzard C, Ajzenberg C, Nocaudie M, Duet M, Mundler O, Marchandise X, Epelbaum J, Gomez De Alzaga M, Schäfer J et al. 1997 Somatostatin receptor imaging in somatotroph and non-functioning pituitary adenomas: correlation with hormonal and visual responses to octreotide. Clinical Endocrinology 47 589-598.[CrossRef][Medline]

De Bruin TWA, Kwekkeboom DJ, van't Verlaat JW, Reubi JC, Krenning EP, Lamberts SW & Croughs RJ 1992 Clinically nonfunctioning pituitary adenoma and octreotide response to long term high dose treatment, and studies in vitro. Journal of Clinical Endocrinology and Metabolism 75 1310-1317.[Abstract]

Chapman AJ, MacFarlane IA, Shalet SM, Beardwell CG, Dutton J & Sutton ML 1984 Discordant serum alpha-subunit and FSH concentrations in a woman with a pituitary tumour. Clinical Endocrinology 21 123-129.[CrossRef][Medline]

Clark JD, Wheatley T & Edwards OM 1985 Rapid enlargement of non-functioning pituitary tumour following withdrawal of bromocriptine. Journal of Neurology, Neurosurgery, and Psychiatry 48 287[Free Full Text]

Colao A, Cerbone G, Cappabianca P, Ferone D, Alfieri A, Di Salle F, Faggiano A, Merola B, de Divitiis E & Lombardi G 1998 Effect of surgery and radiotherapy in visual and endocrine function in nonfunctioning pituitary adenomas. Journal of Endocrinological Investigation 21 284-290.[Web of Science][Medline]

Colao A, Lastoria S, Ferone D, Varrella P, Marzullo P, Pivonello R, Cerbone G, Acampa W, Salvatore M & Lombardi G 1999 Pituitary uptake of In-111-DTPA-D-Phe¹-octreotide in the normal pituitary and in pituitary adenomas. Journal of Endocrinological Investigation 22 176-183.[Web of Science][Medline]

Colao A, Di Sarno A, Marzullo P, Di Somma C, Cerbone G, Landi ML, Faggiano A, Merola B & Lombardi GNew medical approaches in pituitary adenomasHormone Research 53 Suppl_3 2000a 76-87.[CrossRef][Web of Science][Medline]

Colao A, Ferone D, Lastoria S, Cerbone G, Di Sarno A, Di Somma C, Lucci R & Lombardi G 2000b Hormone levels and tumour size response to quinagolide and cabergoline in patients with prolactin-secreting and clinically nonfunctioning pituitary adenomas: predictive value of pituitary scintigraphy with ¹²³I-methoxybenzamide. Clinical Endocrinology 52 437-445.[CrossRef][Medline]

Colao A, Filippella M, Di Somma C, Manzi S, Rota F, Pivonello R, Gaccione M, De Rosa M & Lombardi G 2003 Somatostatin analogs in treatment of non-growth hormone-secreting pituitary adenomas. Endocrine 20 279-283.[Web of Science][Medline]

Colao A, Filippella M, Pivonello R, Di Somma C, Faggiano A & Lombardi GCombined therapy of somatostatin analogues and dopamine agonists in the treatment of pituitary tumoursEuropean Journal of Endocrinology 156 Suppl 3 2007 S57-S63(Erratum in: European Journal of Endocrinology 2007 157 543)[Abstract/Free Full Text]

Colombo P, Ambrosi B, Saccomanno K, Bassetti M, Cortelazzi D & Faglia G 1994 Effects of long-term treatment with the gonadotropin-releasing hormone analog nafarelin in patients with non-functioning pituitary adenomas. European Journal of Endocrinology 130 339-345.[Abstract/Free Full Text]

Daneshdoost L, Pavlou SN, Molitch ME, Gennarelli TA, Savino PJ, Sergott RC, Bosley TM, River JE, Vale WW & Snyder PJ 1990 Inhibition of follicle-stimulating hormone secretion from gonadotroph adenomas by repetitive administration of a gonadotropin-releasing hormone antagonist. Journal of Clinical Endocrinology and Metabolism 71 92-97.[Abstract/Free Full Text]

Dekkers OM, Hammer S, de Keizer RJ, Roelfsema F, Schutte PJ, Smit JW, Romijn JA & Pereira AM 2007 The natural course of non-functioning pituitary macroadenomas. European Journal of Endocrinology 156 217-224.[Abstract/Free Full Text]

D'Emden MC & Harrison LC 1986 Rapid improvement in visual field defects following bromocriptine treatment of patients with non-functioning pituitary adenomas. Clinical Endocrinology 25 697-702.[CrossRef][Medline]

Duet M, Mundler O, Ajzenberg C, Berolatti B, Chedin P, Duranteau L & Warnet A 1994 Somatostatin receptor imaging in non-functioning pituitary adenomas: value of an uptake index. European Journal of Nuclear Medicine 21 647-650.[CrossRef][Medline]

Ebersold MJ, Quast LM, Laws ER, Scheitauer B & Randall RV 1986 Long-term results in transsphenoidal removal of nonfunctioning pituitary adenoma. Journal of Neurosurgery 64 713-719.[Web of Science][Medline]

Erfurth EM & Hagmar L 2005 Cerebrovascular disease in patients with pituitary tumours. Trends in Endocrinology and Metabolism 16 334-342.[CrossRef][Web of Science][Medline]

Faglia G, Bazzoni N, Spada A, Arosio M, Ambrosi B, Spinelli F, Sara R, Bonino C & Lunghi F 1991 In vivo detection of somatostatin receptors in patients with functionless pituitary adenomas by means of a radio-iodinated analog of somatostatin ([¹²³I]SDZ204-090). Journal of Clinical Endocrinology and Metabolism 73 850-856.[Abstract/Free Full Text]

Ferone D, Lastoria S, Colao A, Varrella P, Cerbone G, Acampa W, Merola B, Salvatore M & Lombardi G 1998 Correlation of scintigraphic results using ¹²³I-methoxybenzamide with hormone levels and tumour size response to quinagolide in patients with pituitary adenomas. Journal of Clinical Endocrinology and Metabolism 83 248-252.[Abstract/Free Full Text]

Ferrante E, Ferraroni M, Castrignanò T, Menicatti L, Anagni M, Reimondo G, Del Monte P, Bernasconi D, Loli P, Faustini-Fustini M et al. 2006 Non-functioning pituitary adenoma database: a useful resource to improve the clinical management of pituitary tumours. European Journal of Endocrinology 155 823-829.[Abstract/Free Full Text]

Florio T, Thellung S, Arena S, Corsaro A, Spaziante R, Gussoni G, Acuto G, Giusti M, Giordano G & Schettini G 1999 Somatostatin and its analog lanreotide inhibit the proliferation of dispersed human non-functioning pituitary adenomas cells in vitro. European Journal of Endocrinology 141 396-408.[Abstract]

Florio T, Barbieri F, Spaziante R, Zona G, Hofland LJ, van Koetsveld PM, Feelders RA, Stalla GK, Theodoropoulou M, Culler MD et al. 2008 Efficacy of a dopamine-somatostatin chimeric molecule, BIM-23A760, in the control of cell growth from primary cultures of human non-functioning pituitary adenomas: a multi-center study. Endocrine-Related Cancer 15 583-596.[Abstract/Free Full Text]

García-Luna PP, Leal-Cerro A, Pereira JL, Montero C, Acosta D, Trujillo F, Mazuelos C & Astorga R 1989 Rapid improvement of visual defects with parenteral depot-bromocriptine in a patient with a non-functioning pituitary adenoma. Hormone Research 32 183-187.[Medline]

Gasperi M, Petrini L, Pilosu R, Nardi M, Marcello AA, Mastio F, Bartalena L & Martino E 1993 Octreotide treatment does not affect the size of most non-functioning pituitary adenomas. Journal of Endocrinological Investigation 16 541-543.[Web of Science][Medline]

Gillam MP, Molitch ME, Lombardi G & Colao A 2006 Advances in the treatment of prolactinomas. Endocrine Reviews 27 485-534.[Abstract/Free Full Text]

Gittoes NJ 2003 Radiotherapy for non-functioning pituitary tumours - when and under what circumstances? Pituitary 6 103-108.[CrossRef][Medline]

Giusti M, Bocca L, Florio T, Foppiani L, Corsaro A, Auriati L, Spaziante R, Schettini G & Giordano G 2000 Cabergoline modulation of alpha-subunits and FSH secretion in a gonadotroph adenoma. Journal of Endocrinological Investigation 23 463-466.[Medline]

Greenman Y 2007 Dopaminergic treatment of nonfunctioning pituitary adenomas. Nature Clinical Practice. Endocrinology & Metabolism 3 554-555.[CrossRef][Web of Science][Medline]

Greenman Y & Melmed S 1994a Expression of three somatostatin receptor subtypes in pituitary adenomas: evidence for preferential SSTR 5 expression in the mammosomatotroph linage. Journal of Clinical Endocrinology and Metabolism 79 724-729.[Abstract]

Greenman Y & Melmed S 1994b Heterogeneous expression of two somatostatin receptor subtypes in pituitary tumours. Journal of Clinical Endocrinology and Metabolism 78 398-403.[Abstract]

Greenman Y, Ouaknine G, Veshchev I, Reider-Groswasser II, Segev Y & Stem N 2003 Postoperative surveillance of clinically nonfunctioning pituitary macroadenomas: markers of tumour quiescence and regrowth. Clinical Endocrinology 58 763-769.[CrossRef][Medline]

Greenman Y, Tordjman K, Osher E, Veshchev I, Shenkerman G, Reider-Groswasser II, Segev Y, Ouaknine G & Stern N 2005 Postoperative treatment of clinically nonfunctioning pituitary adenomas with dopamine agonists decreases tumour remnant growth. Clinical Endocrinology 63 39-44.[CrossRef][Medline]

Grossman A, Ross R, Charlesworth M, Adams CBT, Wass JAH, Doniach I & Besser GM 1985 The effect of dopamine agonist therapy on large functionless pituitary tumours. Clinical Endocrinology 22 679-686.[Medline]

Harris PE, Afshar F, Coates P, Doniach I, Wass JA, Besser GM & Grossman A 1989 The effects of transsphenoidal surgery on endocrine function and visual fields in patients with functionless pituitary adenomas. Quarterly Journal of Medicine 71 417-427.[Abstract/Free Full Text]

Hedner P & Valdemarsson S 1989 Reduced size of a hormonally silent pituitary adenoma during treatment with CV 205-502, a new dopamine agonist mainly stimulating D₂ receptors. Neurosurgery 25 948-950.[Web of Science][Medline]

de Herder WW, Reijs AE, Feelders RA, van Aken MO, Krenning EP, Tanghe HL, van der Lely AJ & Kwekkeboom DJ 2006 Dopamine agonist therapy of clinically non-functioning pituitary macroadenomas. Is there a role for ¹²³I-epidepride dopamine D₂ receptor imaging? European Journal of Endocrinology 155 717-723.[Abstract/Free Full Text]

van der Hoek J, Lamberts SW & Hofland LJPreclinical and clinical experiences with the role of somatostatin receptors in the treatment of pituitary adenomasEuropean Journal of Endocrinology 156 Suppl 1 2007 S45-S51(Review. Erratum in: European Journal of Endocrinology 2007 157 543)[Abstract/Free Full Text]

Hofland LJ & Lamberts SWSomatostatin receptor subtype expression in human tumoursAnnals of Oncology 12 Suppl 2 2001 S31-S36.[Abstract]

Hofland LJ & Lamberts SW 2004 Somatostatin receptors in pituitary function, diagnosis and therapy. Frontiers of Hormone Research 32 235-252.[Web of Science][Medline]

Hofland LJ, de Herder WW, Waaijers M, Zuijderwijk J, Uitterlinden P, van Koetsveld PM & Lamberts SWJ 1999 Interferon--2a is a potent inhibitor of hormone secretion by cultured human pituitary adenomas. Journal of Clinical Endocrinology and Metabolism 84 3336-3343.[Abstract/Free Full Text]

Jaffe CA 2006 Clinically non-functioning pituitary adenoma. Pituitary 9 317-321.[Medline]

Johnston DG, Hall K, McGregor A, Ross WM, Kendall-Taylor P & Hall R 1981 Bromocriptine therapy for ‘nonfunctioning’ pituitary tumours. American Journal of Medicine 71 1059-1061.[Medline]

Katznelson L, Oppenheim DS, Coughlin JF, Kliman B, Schoenfeld DA & Klibanski A 1992 Chronic somatostatin analog administration in patients with a-subunit-secreting pituitary tumours. Journal of Clinical Endocrinology and Metabolism 75 1318-1325.[Abstract]

Katznelson L, Alexander JM & Klibanski A 1993 Clinically nonfunctioning pituitary adenomas. Journal of Clinical Endocrinology and Metabolism 76 1089-1094.[CrossRef][Web of Science][Medline]

Kauppinen-Makelin R, Sane T, Reunanen A, Valimaki MJ, Niskanen L, Markkanen H, Löyttyniemi E, Ebeling T, Jaatinen P, Laine H et al. 2005 A nationwide survey of mortality in acromegaly. Journal of Clinical Endocrinology and Metabolism 90 4081-4086.[Abstract/Free Full Text]

Klibanski A, Deutsch PJ, Jameson JL, Ridgway EC, Crowley WF, Hsu DW, Habener JF & Black PM 1987 Luteinizing hormone-secreting pituitary tumour: biosynthetic characterization and clinical studies. Journal of Clinical Endocrinology and Metabolism 64 536-542.[Abstract/Free Full Text]

Klibanski A, Shupnik MA, Bikkal HA, Black PM, Kliman B & Zervas NT 1988 Dopaminergic regulation of alpha-subunit secretion and messenger ribonucleic acid levels in alpha-secreting pituitary tumours. Journal of Clinical Endocrinology and Metabolism 66 96-102.[Abstract/Free Full Text]

Klibanski A, Jameson JL, Biller BM, Crowley WF Jr, Zervas NT, Rivier J, Vale WW & Bikkal H 1989 Gonadotropin and alpha-subunit responses to chronic gonadotropin-releasing hormone analog administration in patients with glycoprotein hormone-secreting pituitary tumours. Journal of Clinical Endocrinology and Metabolism 68 81-86.[Abstract/Free Full Text]

Kwekkboom DJ & Lamberts SWJ 1992 Long-term treatment with dopamine agonist CV 205-502 of patients with clinically non-functioning, gonadotroph, or -subunit secreting pituitary adenoma. Clinical Endocrinology 36 171-176.[Medline]

Lamberts SWJ & MacLeod RM 1990 Regulation of prolactin secretion at the level of the lactotroph. Physiological Reviews 70 279-318.[Free Full Text]

Lamberts SWJ, de Herder WW, van der Lely AJ & Hofland LJ 1995 Imaging and medical management of clinically nonfunctioning pituitary tumours. Endocrinologist 5 448-451.[CrossRef]

Liuzzi A, Dallabonzana D & Oppizzi G 1991 Is there a real medical treatment for the ‘non-secreting’ pituitary adenomas? (abstract). Journal of Endocrinological Investigation 14 18

Lohmann T, Trantakis C, Biesold M, Prothmann S, Guenzel S, Schober R & Paschke R 2001 Minor tumour shrinkage in non-functioning pituitary adenomas by long-term treatment with the dopamine agonist cabergoline. Pituitary 4 173-178.[CrossRef][Medline]

Merola B, Colao A, Ferone D, Selleri A, Di Sarno A, Marzullo P, Biondi B, Spaziante R, Rossi E & Lombardi G 1993 Effects of a chronic treatment with octreotide in patients with functionless pituitary adenomas. Hormone Research 40 149-155.[Web of Science][Medline]

Missale C, Nash SR, Robinson SW, Jaber M & Caron MG 1998 Dopamine receptors: from structure to function. Physiological Reviews 78 189-225.[Abstract/Free Full Text]

Nobels FR, de Herder WW, van den Brink WM, Kwekkeboom DJ, Hofland LJ, Zuyderwijk J, de Jong FH & Lamberts SW 2000 Long-term treatment with the dopamine agonist quinagolide of patients with clinically non-functioning pituitary adenoma. European Journal of Endocrinology 143 615-621.[Abstract]

Padova H, Rubinfeld H, Hadani M, Cohen ZR, Nass D, Taylor JE, Culler MD & Shimon I 2008 Effects of selective somatostatin analogs and cortistatin on cell viability in cultured human non-functioning pituitary adenomas. Molecular and Cellular Endocrinology 286 214-218.

Pawlikowski M, Lawnicka H, Pisarek H, Kunert-Radek J, Radek M & Culler MD 2007 Effects of somatostatin-14 and the receptor-specific somatostatin analogs on chromogranin A and alpha-subunit (alpha-SU) release from ‘clinically nonfunctioning’ pituitary adenoma cells incubated in vitro. Journal of Physiology and Pharmacology 58 179-188.[Medline]

Pivonello R, Matrone C, Filippella M, Cavallo LM, Di Somma C, Cappabianca P, Colao A, Annunziato L & Lombardi G 2004 Dopamine receptor expression and function in clinically nonfunctioning pituitary tumours: comparison with the effectiveness of cabergoline treatment. Journal of Clinical Endocrinology and Metabolism 89 1674-1683.[Abstract/Free Full Text]

Plockinger U, Reichel M, Fett U, Saeger W & Quabbe HJ 1994 Preoperative octreotide treatment of growth hormone-secreting and clinically nonfunctioning pituitary macroadenomas: effect on tumour volume and lack of correlation with immunohistochemistry and somatostatin receptor scintigraphy. Journal of Clinical Endocrinology and Metabolism 79 1416-1423.[Abstract]

Pullan PT, Carroll WM, Chakera TM, Khangure MS & Vaughan RJ 1985 Management of extra-sellar pituitary tumours with bromocriptine: comparison of prolactin secreting and non-functioning tumours using half-field visual evoked potentials and computerised tomography. Australian and New Zealand Journal of Medicine 15 203-208.[Medline]

Renner U, Arzberger T, Pagotto U, Leimgruber S, Uhl E, Muller A, Lange M, Weindl A & Stalla GK 1998 Heterogeneous dopamine D₂ receptor subtype messenger ribonucleic acid expression in clinically nonfunctioning pituitary adenomas. Journal of Clinical Endocrinology and Metabolism 83 1368-1375.[Abstract/Free Full Text]

Rocheville M, Lange DC, Kumar U, Patel SC, Patel RC & Patel YC 2000 Receptors for dopamine and somatostatin: formation of hetero-oligomers with enhanced functional activity. Science 288 154-157.[Abstract/Free Full Text]

Roman SH, Goldstein M, Kourides IA, Comite F, Bardin CW & Krieger DT 1984 The luteinizing hormone-releasing hormone (LHRH) agonist [D-Trp6-Pro9-NEt]LHRH increased rather than lowered LH and alpha-subunit levels in a patient with an LH-secreting pituitary tumour. Journal of Clinical Endocrinology and Metabolism 58 313-319.[Abstract/Free Full Text]

Sassolas G, Lejeune H, Trouillas J, Forest MG, Claustrat B, Lahlou N & Loras B 1988 Gonadotropin-releasing hormone agonists are unsuccessful in reducing tumoural gonadotropin secretion in two patients with gonadotropin-secreting pituitary adenomas. Journal of Clinical Endocrinology and Metabolism 67 180-185.[Abstract/Free Full Text]

van Schaardenburg D, Roelfsema F, van Seters AP & Vielvoye GJ 1989 Bromocriptine therapy for non-functioning pituitary adenoma. Clinical Endocrinology 30 475-484.[Medline]

Taboada GF, Luque RM, Bastos W, Guimarães RF, Marcondes JB, Chimelli LM, Fontes R, Mata PJ, Filho PN, Carvalho DP et al. 2007 Quantitative analysis of somatostatin receptor subtype (SSTR1-5) gene expression levels in somatotropinomas and non-functioning pituitary adenomas. European Journal of Endocrinology 156 65-74.[Abstract/Free Full Text]

Van Tol HHM, Wu CM, Guan HC, Ohara K, Bunzow JR, Civelli O, Kennedy J, Seeman P, Niznik HB & Jovanovic V 1992 Multiple dopamine D4 receptor variants in the human population. Nature 358 149-152.[CrossRef][Medline]

Turner HE, Stratton IM, Byrne JV, Adams CB & Wass JA 1999 Audit of selected patients with nonfunctioning pituitary adenomas treated without irradiation - a follow-up study. Clinical Endocrinology 51 281-284.[CrossRef][Medline]

Turpin G, Foubert L, Noel-Wekstein S, Kujas M & De Gennes JL 1991 Analgesic effect on headaches of octreotide, a somatostatin analogue, in a case of non-functioning pituitary adenoma. Presse Médicale 20 2219-2220.

Vance ML, Ridgeway EC & Thorner MO 1985 Follicle-stimulating hormone and -subunit-secreting pituitary tumour treated with bromocriptine. Journal of Clinical Endocrinology and Metabolism 61 580-584.[Abstract/Free Full Text]

Verde G, Oppizzi G, Chiodini PG, Dallabonzana D, Luccarelli G & Liuzzi A 1985 Effect of chronic bromocriptine administration on tumour size in patients with ‘nonsecreting’ pituitary adenomas. Journal of Endocrinological Investigation 8 113-115.[Medline]

Vitale G, Caraglia M, van Koetsveld PM, Maroni P, Marra M, Colao A, Lamberts SW, Cavagnini F & Hofland LJ 2008 Potential role of type I interferons in the treatment of pituitary adenomas. Reviews in Endocrine and Metabolic Disorders[in press]

Warnet A, Timsit J, Chanson P, Guillausseau PJ, Zamfirescu F, Harris AG, Derome P, Cophignon J & Lubetzki J 1989 The effect of somatostatin analogue on chiasmal dysfunction from pituitary macroadenomas. Journal of Neurosurgery 71 687-690.[Web of Science][Medline]

Warnet A, Harris AG, Renard E, Martin D, James-Deidier A, Chaumet-Riffaud P & The French Multicenter Octreotide Study Group 1997 A prospective multicenter trial of octreotide in 24 patients with visual defects caused by nonfunctioning and gonadotropin-secreting pituitary adenomas. Neurosurgery 41 786-797.[CrossRef][Web of Science][Medline]

Wass JA, Williams J, Charlesworth M, Kingsley DP, Halliday AM, Doniach I, Rees LH, McDonald WI & Besser GM 1982 Bromocriptine in management of large pituitary tumours. BMJ 284 1908-1911.[Abstract/Free Full Text]

Wollesen F, Andersen T & Karle A 1982 Size reduction of extrasellar pituitary tumours during bromocriptine treatment. Annals of Internal Medicine 96 281-286.[Abstract/Free Full Text]

Zárate A, Morán C, Klériga E, Loyo M, González-Angulo A & Aquilar-Parada E 1985 Bromocriptine therapy as pre-operative adjunct of non-functional pituitary macroadenomas. Acta Endocrinologica 108 445-450.[Abstract/Free Full Text]

Zárate A, Fonseca ME, Mason M, Tapia R, Miranda R, Kovacs K & Schally AV 1986 Gonadotropin-secreting pituitary adenoma with concomitant hypersecretion of testosterone and elevated sperm count. Treatment with LRH agonist. Acta Endocrinologica 113 29-34.[Abstract/Free Full Text]

Zatelli MC, Piccin D, Vignali C, Tagliati F, Ambrosio MR, Bondanelli M, Cimino V, Bianchi A, Schmid HA, Scanarini M et al. 2007 Pasireotide, a multiple somatostatin receptor subtypes ligand, reduces cell viability in non-functioning pituitary adenomas by inhibiting vascular endothelial growth factor secretion. Endocrine-Related Cancer 14 91-102.[Abstract/Free Full Text]

This article has been cited by other articles:

				F. E. Gordon, C. L. Nutt, P. Cheunsuchon, Y. Nakayama, K. A. Provencher, K. A. Rice, Y. Zhou, X. Zhang, and A. Klibanski Increased Expression of Angiogenic Genes in the Brains of Mouse Meg3-Null Embryos Endocrinology, June 1, 2010; 151(6): 2443 - 2452. [Abstract] [Full Text] [PDF]

				M. C. Zatelli, M. Minoia, C. Filieri, F. Tagliati, M. Buratto, M. R. Ambrosio, M. Lapparelli, M. Scanarini, and E. C. degli Uberti Effect of Everolimus on Cell Viability in Nonfunctioning Pituitary Adenomas J. Clin. Endocrinol. Metab., February 1, 2010; 95(2): 968 - 976. [Abstract] [Full Text] [PDF]

				F. Barbieri, A. Pattarozzi, M. Gatti, C. Aiello, A. Quintero, G. Lunardi, A. Bajetto, A. Ferrari, M. D. Culler, and T. Florio Differential efficacy of SSTR1, -2, and -5 agonists in the inhibition of C6 glioma growth in nude mice Am J Physiol Endocrinol Metab, November 1, 2009; 297(5): E1078 - E1088. [Abstract] [Full Text] [PDF]

				C Hagen, H D Schroeder, S Hansen, C Hagen, and M Andersen Temozolomide treatment of a pituitary carcinoma and two pituitary macroadenomas resistant to conventional therapy Eur. J. Endocrinol., October 1, 2009; 161(4): 631 - 637. [Abstract] [Full Text] [PDF]

				D. Ferone, F. Gatto, M. Arvigo, E. Resmini, M. Boschetti, C. Teti, D. Esposito, and F. Minuto The clinical-molecular interface of somatostatin, dopamine and their receptors in pituitary pathophysiology J. Mol. Endocrinol., May 1, 2009; 42(5): 361 - 370. [Abstract] [Full Text] [PDF]

This Article Abstract Full Text (PDF) All Versions of this Article: ERC-08-0181v1 15/4/905    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (10) Citing Articles via Google Scholar Google Scholar Articles by Colao, A. Articles by Savastano, S. Search for Related Content PubMed PubMed Citation Articles by Colao, A. Articles by Savastano, S.