pasireotide and Pituitary-Neoplasms

Pasireotide (PAS) is a novel somatostatin receptor ligands (SRL), used in controlling hormonal hypersecretion in both acromegaly and Cushing's Disease (CD). In previous studies and meta-analysis, first-generation SRLs were reported to be able to induce significant tumor shrinkage only in somatotroph adenomas. This systematic review and meta-analysis aim to summarize the effect of PAS on the shrinkage of the pituitary adenomas in patients with acromegaly or CD.. We searched the Medline database for original studies in patients with acromegaly or CD receiving PAS as monotherapy, that assessed the proportion of significant tumor shrinkage in their series. After data extraction and analysis, a random-effect model was used to estimate pooled effects. Quality assessment was performed with a modified Joanna Briggs's Institute tool and the risk of publication bias was addressed through Egger's regression and the three-parameter selection model.. The electronic search identified 179 and 122 articles respectively for acromegaly and CD. After study selection, six studies considering patients with acromegaly and three with CD fulfilled the eligibility criteria. Overall, 37.7% (95%CI: [18.7%; 61.5%]) of acromegalic patients and 41.2% (95%CI: [22.9%; 62.3%]) of CD patients achieved significant tumor shrinkage. We identified high heterogeneity, especially in acromegaly (I. PAS treatment is effective in reducing tumor size, especially in acromegalic patients. This result strengthens the role of PAS treatment in pituitary adenomas, particularly in those with an invasive behavior, with progressive growth and/or extrasellar extension, with a low likelihood of surgical gross-total removal, or with large postoperative residual tissue.. https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42022328152, identifier CRD42022328152.

Topics: Acromegaly; ACTH-Secreting Pituitary Adenoma; Adenoma; Humans; Pituitary ACTH Hypersecretion; Pituitary Neoplasms; Somatostatin

Transsphenoidal surgery remains the primary treatment for Cushing's disease (CD). However, despite the vast improvements in pituitary surgery, successful treatment of CD remains a great challenge. Although selective transsphenoidal removal of the pituitary tumor is a safe and effective procedure, the disease persists in around 22% of CD patients due to incomplete tumor resection. The persistence of hypercortisolism after pituitary surgery may also be the consequence of a misdiagnosis, as can occur in case of ectopic ACTH secretion or pseudo-Cushing. Considering the elevated mortality and morbidity characterizing the disease, a multidisciplinary approach is needed to minimize potential pitfalls occurring during the diagnosis, avoid surgical failure and provide the best care in those patients who have undergone unsuccessful surgery. In this review, we analyze the factors that could predict remission or persistence of CD after pituitary surgery and revise the therapeutic options in case of surgical failure.

Topics: Enzyme Inhibitors; Humans; Natural Orifice Endoscopic Surgery; Neurosurgical Procedures; Outcome Assessment, Health Care; Pituitary ACTH Hypersecretion; Pituitary Neoplasms; Somatostatin; Sphenoid Sinus

Prolactinomas in men are usually large and invasive, presenting with signs and symptoms of hypogonadism and mass effects, including visual damage. Prolactin levels are high, associated with low testosterone, anemia, metabolic syndrome and if long-standing also osteoporosis.. Medical treatment with the dopamine agonist, cabergoline, became the preferred first-line treatment for male prolactinomas as well as for giant tumors, leading to prolactin normalization in ~ 80% of treated men, and tumor shrinkage, improved visual fields and recovery of hypogonadism in most patients. Multi-modal approach including surgery and occasionally radiotherapy together with a high-dose cabergoline is saved for resistant and invasive adenomas. Experimental treatments including temozolomide or pasireotide may improve clinical response in men harboring resistant prolactinomas.. Compared to other pituitary adenomas, secreting and non-secreting, where pituitary surgery is the recommended first-line treatment, men with prolactinomas will usually respond to medical treatment with no need for any additional treatment.

Topics: Cabergoline; Dopamine Agonists; Humans; Hypogonadism; Male; Pituitary Neoplasms; Prolactinoma; Somatostatin; Temozolomide

Somatostatin receptors (SSTs) are widely co-expressed in pituitary tumors. SST. Critical revision of literature data correlating SST expression with patients' response to SRLs.. SST. The assumption "more target receptor, more drug efficacy" is not straightforward for SRLs. The complex pathophysiology of SSTs, and the technical challenges faced to translate research findings into clinical practice, still need our full commitment to make receptor evaluation a worthwhile procedure for individualizing treatment decisions.

Topics: Adenoma; Antineoplastic Combined Chemotherapy Protocols; Gene Expression Regulation, Neoplastic; Human Growth Hormone; Humans; Insulin-Like Growth Factor I; Molecular Targeted Therapy; Octreotide; Pituitary Neoplasms; Receptors, Somatostatin; Somatostatin

Recent publications suggested that pasireotide could be a good therapeutic option in some dopamine-resistant or aggressive prolactinomas. We discussed the two published cases and describe another case of poorly differentiated plurihormonal PIT-1-positive adenoma with moderate SSTR2 expression and intense STTR5 expression successfully treated with PAS-LAR 40 mg/month.

Topics: Adenoma; Dopamine Agonists; Drug Resistance, Neoplasm; Female; Hormones; Humans; Middle Aged; Neuroendocrine Tumors; Pituitary Neoplasms; Prolactin; Prolactinoma; Somatostatin

In almost every patient, acromegaly is caused by a growth hormone secreting pituitary adenoma. Clinical features are the result of excessive growth hormone secretion and the consecutive excess in insulin-like growth factor I levels. This results in somatic overgrowth and metabolic disturbances with a higher morbidity and mortality than in the general population. With optimal disease management, mortality can be reduced to that seen in the general population. The current treatment of acromegaly is based on a combination of surgery, radiotherapy and medical therapy. This review provides an overview of the current and upcoming therapies with a focus on medical therapy.

Topics: Acromegaly; Adenoma; Antineoplastic Agents; Dopamine Agonists; Human Growth Hormone; Humans; Octreotide; Pituitary Neoplasms; Somatostatin

The aim of this study was to review the literature published and the most important papers presented to meetings on Cushing's disease from October 2011 to September 2012. The selection has been performed according to the authors' criteria. Articles have been classified into five groups: quality of life and perception of the disease, clinical features and pathophysiology, comorbidity conditions, diagnosis, and treatment. The results and conclusions of each publication are discussed.

Topics: ACTH-Secreting Pituitary Adenoma; Deamino Arginine Vasopressin; Endomyocardial Fibrosis; Humans; Hyperglycemia; Hypertension; Hypoglycemic Agents; Hypophysectomy; Neoplasm Proteins; Pituitary ACTH Hypersecretion; Pituitary Neoplasms; Prognosis; Quality of Life; Somatostatin; Thrombophilia

Somatostatin (SST), an inhibitory polypeptide with two biologically active forms SST14 and SST28, inhibits GH, prolactin (PRL), TSH, and ACTH secretion in the anterior pituitary gland. SST also has an antiproliferative effect inducing cell cycle arrest and apoptosis. Such actions are mediated through five G-protein-coupled somatostatin receptors (SSTR): SSTR1-SSTR5. In GH-secreting adenomas, SSTR2 expression predominates, and somatostatin receptor ligands (SRLs; octreotide and lanreotide) directed to SSTR2 are presently the mainstays of medical therapy. However, about half of patients show incomplete biochemical remission, but the definition of resistance per se remains controversial. We summarize here the determinants of SRL resistance in acromegaly patients, including clinical, imaging features as well as molecular (mutations, SSTR variants, and polymorphisms), and histopathological (granulation pattern, and proteins and receptor expression) predictors. The role of SSTR5 may explain the partial responsiveness to SRLs in patients with adequate SSTR2 density in the cell membrane. In patients with ACTH-secreting pituitary adenomas, i.e. Cushing's disease (CD), SSTR5 is the most abundant receptor expressed and tumors show low SSTR2 density due to hypercortisolism-induced SSTR2 down-regulation. Clinical studies with pasireotide, a multireceptor-targeted SRL with increased SSTR5 activity, lead to approval of pasireotide for treatment of patients with CD. Other SRL delivery modes (oral octreotide), multireceptor-targeted SRL (somatoprim) or chimeric compounds targeting dopamine D2 receptors and SSTR2 (dopastatin), are briefly discussed.

Topics: Adenoma; Adrenocorticotropic Hormone; Apoptosis; Cell Cycle Checkpoints; Dopamine; Drug Resistance, Neoplasm; Hormones; Human Growth Hormone; Humans; Ligands; Pituitary Neoplasms; Prolactin; Receptors, Somatostatin; Signal Transduction; Somatostatin; Thyrotropin

Somatostatin receptors are an important target for medical treatment of pituitary and neuroendocrine tumors. To date, five somatostatin receptor (sst) subtypes have been identified. The currently available somatostatin analogues octreotide and lanreotide have predominantly affinity for sst2. Pasireotide is a sst multireceptor ligand with affinity for sst1, sst2, sst3 and sst5 and this broader binding profile may translate into a higher efficacy with respect to suppression of hormone production and cell growth in certain tumors. Experimental animal studies and in vitro studies with cultured tumor cells have shown that pasireotide strongly suppresses growth hormone and adrenocorticotropin production. In addition, pasireotide can influence tumor cell growth via effects on apoptosis and angiogenesis. In this review, the role of somatostatin receptors in pituitary and neuroendocrine tumors is briefly discussed followed by an overview of possible applications of pasireotide based on recent trials in patients with acromegaly, Cushing's disease and neuroendocrine tumors.

Topics: Acromegaly; Humans; Ligands; Neuroendocrine Tumors; Pituitary ACTH Hypersecretion; Pituitary Neoplasms; Receptors, Somatostatin; Somatostatin

Prolonged overproduction of growth hormone, like insulin-like growth factor-1 hypersecretion leads to acromegaly in adults. This is associated with several co-morbidities and increased mortality. Despite typical clinical features and modern diagnostic tools, it often takes years to diagnose from the onset of the disease. The aims of the treatment are to reduce or control tumour growth, inhibit growth hormone hypersecretion, normalize insulin-like growth factor-1 levels, treat co-morbidities and, therefore, reduce mortality. There are three approaches for therapy: surgery, medical management (dopamine agonists, somatostatin analogues and growth hormone receptor antagonist), and radiotherapy. Efficient therapy of the disease is based on the appropriate multidisciplinary team management. The review provides a summary of medical treatment for acromegaly.. Az acromegalia a növekedési hormon, ennélfogva az inzulinszerű növekedési faktor-1 tartós túltermelése következtében kialakuló betegség felnőttekben, amely számos szövődménnyel jár és megfelelő kezelés nélkül a mortalitás növekedéséhez vezet. Jellegzetes tünetei ellenére, valamint a korszerű biokémiai és képalkotó diagnosztikai módszerek mellett is általában több év telik el a betegség kialakulásának kezdete és a diagnózis felállítása között. Terápiás lehetőségként sebészi beavatkozás, gyógyszeres (dopaminagonista, szomatosztatinanalóg és növekedésihormonreceptor-antagonista) kezelés és radioterápia áll rendelkezésre. A kezelés célja a biztonságos növekedési hormon- és inzulinszerű növekedési faktor-1-szintek elérése, a tumor eltávolítása vagy méretének csökkentése, valamint a betegség szövődményeinek kezelése, végső fokon a mortalitás csökkentése. Az eredményes kezelés több különböző diszciplína képviselőjének megfelelő együttműködésén alapszik. A közleményben a szerző az acromegalia gyógyszeres kezelési lehetőségeit tekinti át. Orv. Hetil., 2013, 154, 1527–1534.

Topics: Acromegaly; Aminoquinolines; Antineoplastic Agents, Hormonal; Bromocriptine; Cabergoline; Dopamine Agonists; Drug Administration Schedule; Drug Therapy, Combination; Ergolines; Human Growth Hormone; Humans; Insulin-Like Growth Factor I; Interdisciplinary Communication; Membrane Proteins; Octreotide; Patient Care Team; Peptides, Cyclic; Pituitary Neoplasms; Somatostatin

Hypercortisolism induced by Cushing disease causes high morbidity and mortality. The treatment of choice is pituitary surgery, but it often fails to achieve cure, and other treatment modalities (radiotherapy, bilateral adrenalectomy) may therefore be required. If these treatments are not effective or while waiting for their results, hypercortisolism should be controlled with drugs. The classical drug treatments are those that act by inhibiting cortisol secretion by the adrenal gland (ketoconazole, metyrapone, mitotane, etomidate). The preliminary results of a new drug (LCI699) which is a potent enzyme inhibitor of cortisol secretion have been reported. A clinical trial of the safety and efficacy of mifepristone, a glucocorticoid receptor antagonist, has just been published. The drugs deserving more attention today are those with a direct action on the tumor by inhibiting ACTH secretion: somatostatin analogues (pasireotide), dopamine agonists (cabergoline), PPAR-γ, and retinoic acid. A special review is made of the available clinical trials with pasireotide and cabergoline.

Topics: Adenoma; Adrenocorticotropic Hormone; Animals; Cabergoline; Clinical Trials as Topic; Clinical Trials, Phase III as Topic; Drug Evaluation, Preclinical; Ergolines; Etomidate; Humans; Hydrocortisone; Imidazoles; Ketoconazole; Metyrapone; Mice; Mifepristone; Mitotane; Multicenter Studies as Topic; Pituitary ACTH Hypersecretion; Pituitary Neoplasms; PPAR gamma; Pyridines; Rats; Somatostatin; Therapies, Investigational; Tretinoin

Topics: Acromegaly; Clinical Trials as Topic; Dopamine; Humans; Models, Biological; Pituitary ACTH Hypersecretion; Pituitary Neoplasms; Somatostatin

Acromegaly is a rare disease with typical clinical manifestations. Untreated acromegaly carries a 2-4-fold increase in mortality in long-term outcome. The goal of treatment is double, including biochemical control of the disease (normalization of serum IGF1 levels compared to age and gender matched controls, GH levels below 1 ng/ml after oral glucose load, or random GH below 2.5 ng/ml) and control of the tumor mass. The therapeutic modalities currently available for the treatment of acromegaly are: surgery, medical therapy, radiation therapy and their combinations. The cornerstones of medical therapy in acromegaly are the somatostatin receptor ligands due to their effectiveness in controlling GH excess in 60-70 % of patients and their beneficial effects on tumor volume. Somatostatin analogues have an established role as adjuvant therapy after non-curative surgery, and evidence suggests their use as primary treatment for selected patients. The long-term use of somatostatin receptor ligands is safe and they are well tolerated. Future medical therapy consists of pasireotide, a novel, universal somatostatin receptor agonist, and a new class of drugs named dopastatins. The latter so-called chimeric molecules have strong affinity for somatostatin receptors and dopamine-2 receptors, resulting in a more effective blocking of GH secretion, according to preliminary data. The authors of this paper review the current medical therapy of acromegaly, focusing on the role of somatostatin receptor ligands.

Topics: Acromegaly; Adenoma; Case-Control Studies; Dopamine; Drug Administration Schedule; Female; Human Growth Hormone; Humans; Ligands; Male; Pituitary Neoplasms; Receptors, Somatostatin; Somatostatin

Despite considerable progress, there is still no medical treatment available for some kinds of pituitary tumors, in particular hormone inactive adenomas and corticotroph pituitary tumors. Surgical removal or at least debulking of the tumor is the only option to treat these kinds of tumors apart from rarely applied radiotherapy. Moreover, treatment resistance is present in a considerable proportion of patients bearing pituitary tumors, for which medical treatment regimens are already available (prolactinomas, somatotroph adenomas). Thus, novel or improved medical treatment strategies would be desirable. Here, we summarize preclinical and clinical findings about the hormone and growth-suppressive action of various drugs, which will probably lead to novel future medical treatment concepts for pituitary tumors.

Topics: Dopamine; Dopamine Agonists; Humans; Interferon-gamma; Pituitary Neoplasms; Somatostatin; Tretinoin

Cushing's disease is Cushing's syndrome caused by an adrenocorticotropic hormone-secreting pituitary adenoma and, in the absence of adequate treatment, can be fatal. Cushing's disease represents an unmet medical need, with no approved medical therapies. Pasireotide is a novel multi-receptor-targeted somatostatin analogue with high affinity for sst(1,2,3) and sst(5). Compared with octreotide, pasireotide has an in vitro binding affinity 40-, 30- and 5-fold higher for sst(5,) sst(1) and sst(3), respectively, and 2-fold lower for sst(2). Adrenocorticotropic hormone-secreting pituitary adenomas predominantly express sst(5), followed by sst(2) and sst(1), suggesting that pasireotide may be effective in the treatment of Cushing's disease. In a 15-day phase II trial of pasireotide 600 μg s.c. b.i.d. in patients with de novo or persistent/recurrent Cushing's disease, 22 of 29 patients (76%) achieved reduced urinary free cortisol (UFC) levels, 5 of whom (17%) achieved normalized UFC. Patients who achieved normalized UFC had a significantly greater reduction in serum cortisol than those who did not (p = 0.04), and minimum pasireotide plasma concentrations appeared to be higher in responders. Based on these results, a randomized, double-blind phase III study comparing pasireotide 600 μg b.i.d. and 900 μg b.i.d. was initiated and is ongoing. This is the largest ever phase III study in patients with Cushing's disease. The primary end point of this study is normalization of UFC after 6 months of treatment. Finally, preliminary results from a study on 17 patients with Cushing's disease suggest that the combined use of pasireotide, cabergoline and low-dose ketoconazole may have additive beneficial effects in the medical treatment of Cushing's disease.

Topics: Humans; Pituitary ACTH Hypersecretion; Pituitary Neoplasms; Somatostatin

Acromegaly is a chronic disorder of enhanced growth hormone (GH) secretion and elevated insulin-like growth factor–I (IGF-I) levels, the most frequent cause of which is a pituitary adenoma. Persistently elevated GH and IGF-I levels lead to substantial morbidity and mortality. Treatment goals include complete removal of the tumor causing the disease, symptomatic relief, reduction of multisystem complications, and control of local mass effect. While transsphenoidal tumor resection is considered first-line treatment of patients in whom a surgical cure can be expected, pharmacological therapy is playing an increased role in the armamentarium against acromegaly in patients unsuitable for or refusing surgery, after failure of surgical treatment (inadequate resection, cavernous sinus invasion, or transcapsular intraarachnoid invasion), or in select cases as primary treatment. Three broad drug classes are available for the treatment of acromegaly: somatostatin analogs, dopamine agonists, and GH receptor antagonists. Somatostatin analogs are considered as the first-line pharmacological treatment of acromegaly, although efficacy varies among the different formulations. Octreotide long-acting release (LAR) appears to be more efficacious than lanreotide sustained release (SR). Lanreotide Autogel (ATG) has been shown to result in similar biological control as octreotide LAR, and there may be a benefit in switching from one to the other in some cases of treatment failure. The novel multireceptor somatostatin analog pasireotide, currently in Phase II clinical trials, also shows promise in the treatment of acromegaly. Dopamine agonists have been the earliest and most widely used agents in the treatment of acromegaly but have been found to be less effective than somatostatin analogs. In this class of drugs, cabergoline has shown greater efficacy and tolerability than bromocriptine. Dopamine agonists have the advantage of oral administration, resulting in increased use in select patient groups. Selective GH receptor antagonists, such as pegvisomant, act by blocking the effects of GH, resulting in decreased IGF-I production despite persistent elevation of GH serum levels. Thus far, tumor growth has not been a concern during pegvisomant therapy. However, combination treatment with somatostatin analogs may counteract these effects. The authors discuss the latest guidelines for biochemical cure and highlight the efficacy of combination therapy. In addition, the effects of phar

Topics: Acromegaly; Dopamine Agonists; Drug Therapy, Combination; Human Growth Hormone; Humans; Insulin-Like Growth Factor I; Octreotide; Peptides, Cyclic; Pituitary Neoplasms; Somatostatin; Treatment Outcome

Acromegaly is a multisystem disease resulting from chronic exposure to supraphysiological levels of growth hormone (GH), and is associated with significant morbidity and excess mortality. The etiology is almost exclusively an underlying pituitary adenoma. Current therapeutic interventions include surgery, radiotherapy, and medical therapy.. Despite surgery, around 50% of patients fail to achieve the biochemical targets shown to correlate with normalization of mortality rates. Radiotherapy is efficacious in controlling tumor growth and GH secretion; still, achievement of biochemical targets may take up to a decade and a number of safety issues have been raised with this treatment modality. Medical therapy, therefore, has an important role as adjuvant therapy in patients who fail to achieve control with surgery, or while awaiting the effects of radiotherapy to be realized. Furthermore, medical therapy is increasingly being used as primary therapy. Current medical therapies include dopaminergic agonists, somatostatin analogs, and GH receptor (GHR) antagonists. Dopaminergic agonists achieve biochemical targets in up to 30% of patients, and somatostatin analogs in around 60%. The currently available GHR antagonist pegvisomant effectively controls insulin-like growth factor-I levels in over 90% of patients; however, it has no effect on the tumor itself and has considerable financial implications. Research into optimizing the somatostatin and dopaminergic systems has led to promising advances in agonist development. Moieties with selectivity for various combinations of somatostatin receptor subtype receptors have been examined, along with molecules that additionally show high affinity for the dopaminergic D2 receptor. Of the molecules studied in vitro, only pasireotide (SOM230) and BIM-23A760 are currently undergoing further development. Other innovations to improve convenience of currently available drugs are also being investigated.. Significant advances in under standing of the somatostatin and dopaminergic system have aided drug development. This may lead to new clinically available therapies enabling control of acromegaly in a larger proportion of patients, and at an earlier stage in their disease management.

Topics: Acromegaly; Adenoma; Combined Modality Therapy; Dopamine; Dopamine Agonists; Drug Discovery; Drug Evaluation; Human Growth Hormone; Humans; Insulin-Like Growth Factor Binding Protein 1; Pituitary Neoplasms; Radiotherapy; Receptors, Dopamine D2; Receptors, Somatotropin; Somatostatin; Treatment Outcome

According to epidemiological studies, the prevalence of pituitary adenomas is 16.5% and the majority of them are "incidentalomas". The symptoms of pituitary disorders are often non-specific; disturbances of pituitary function, compression symptoms, hypophysis apoplexy or accidental findings may help the diagnosis. The hormonal evaluation of pituitary adenomas is different from the algorithm used in the disorders of peripheral endocrine organs. The first-line therapy of prolactinomas are the dopamine agonists, and the aims of the treatment are to normalize the prolactin level, restore fertility in child-bearing age, decrease tumor mass, save or improve the residual pituitary function and inhibit the relapse of the disease. The available dopamine agonists in Hungary are bromocriptine and quinagolide. In case of tumors with good therapeutic response, medical therapy can be withdrawn after 3-5 years; hyperprolactinemia will not recur in 2/3 of these patients. Neurosurgery is the primary therapy of GH-, ACTH-, TSH-producing and inactive adenomas. In the last decades, significant improvement has been reached in surgical procedures, resulting in low mortality rates. Acromegalic patients with unresectable tumors have a great benefit from somatostatin analog treatment. The growth hormone receptor antagonist pegvisomant is the newest modality for the treatment of acromegaly. The medical therapy of Cushing's disease is still based on the inhibition of steroid production. A new, promising somatostatin analog, pasireotide is evaluated in clinical trials. The rare TSH-producing tumor can respond to both dopamine agonist and somatostatin analog therapy. The application of conventional radiotherapy has decreased; radiotherapy is mainly used in the treatment of invasive, incurable or malignant tumors. Further studies are needed to elucidate the exact role of radiosurgery and fractionated stereotaxic irradiation in the treatment of pituitary tumors.

Topics: Acromegaly; ACTH-Secreting Pituitary Adenoma; Adenoma; Adrenocorticotropic Hormone; Aminoquinolines; Bromocriptine; Cushing Syndrome; Dopamine Agonists; Female; Growth Hormone-Secreting Pituitary Adenoma; Human Growth Hormone; Humans; Hypophysectomy; Incidental Findings; Male; Pituitary Hormones; Pituitary Neoplasms; Pregnancy; Pregnancy Complications, Neoplastic; Prolactinoma; Radiosurgery; Receptors, Somatotropin; Somatostatin; Thyrotropin

For a considerable time, somatostatin analogs have been the medical therapy of choice for the treatment of acromegaly. In addition to their well-established use as an adjunctive therapy, primary therapy with somatostatin analogs has been investigated in recent years. Adjunctive therapy with octreotide long-acting release over 12-36 months allowed for sufficient GH suppression in 47-75% of patients (average 56%), as summarized by Freda. IGF-I was normalized in 41-75% (average 66%). Tumor shrinkage was observed in about 30% of patients, with a mass reduction of 20-50% in most cases. A bias in some of these studies cannot be excluded, with patients being selected on base of their octreotide responsiveness. Regarding primary treatment of acromegaly with long-acting somatostatin analogs, our review of five published studies, that applied stringent criteria for the analysis of biochemical normalization, revealed sufficient GH and IGF-I suppression in 68% and 61% of the 107 patients included, respectively, and significant tumor reduction in 51%. Therefore, somatostatin analogs represent an effective medical therapy in a significant proportion of patients with acromegaly. Resistance to currently available somatostatin analogs in some patients may be due to reduced density of SSTR2 on the tumors of these patients. New somatostatin receptor ligands with extended binding profile may have even higher efficacy in the biochemical control of patients with acromegaly.

Topics: Acromegaly; Adenoma; Animals; Human Growth Hormone; Humans; Insulin-Like Growth Factor I; Octreotide; Peptides, Cyclic; Pituitary Neoplasms; Receptors, Somatostatin; Somatostatin

Currently available medical treatment of acromegaly includes dopamine agonists, slow release formulation of somatostatin analogues and pegvisomant, a GH-receptor antagonist. Dopamine agonists are well tolerated, not expensive but poorly effective. Somatostatin analogues are highly effective in 60-70% of patients based on the receptor profile of individual tumors. Pegvisomant is reported to normalize IGF-I levels in nearly the totality of the patients, but is devoted of tumor shrinking effect. In a preliminary study in patients with acromegaly, a new somatostatin analogue with affinity to four of the five somatostatin receptors (SOM230) was shown to be similarly effective as octreotide in some patients and more effective than octreotide in other patients. Moreover, new molecules with selective activity on the somatostatin receptor type 2, or 5, or 1 have been reported in vitro to strongly suppress GH secretion. Other new promising alternatives are the chimeric compounds with both somatostatin receptor and dopamine receptor binding. These drugs have been also shown to possess strong GH-inhibitory activity in primary cultures from GH-secreting adenomas. These drugs are the future perspectives in the treatment of patients with GH-secreting or GH/PRL-secreting tumors.

Topics: Acromegaly; Adenoma; Adult; Animals; Delayed-Action Preparations; Dopamine Agonists; Female; Human Growth Hormone; Humans; Insulin-Like Growth Factor I; Male; Middle Aged; Octreotide; Pituitary Neoplasms; Receptors, Somatostatin; Receptors, Somatotropin; Somatostatin

In recent years, somatostatin analogs have been proposed and used in the diagnosis and therapy in Cushing's syndrome (CS). In these last few years, the potential therapeutic effects of somatostain analogs have been studied in different aspects of CS. The strong expression of somatostatin receptors (SSTR) type 5 in human corticotroph cells and the demonstrated efficacy of SOM230, a novel multi-ligand somatostatin analog, in inhibiting ACTH release in vitro suggest that this new drug may be effective in the treatment of ACTH hypersecretion. Very preliminary in vivo results suggest that SOM230 could be a promising drug in medical therapy for patients with Cushing's disease (CD). Prolonged treatment and more data will be needed in order to evaluate its long-term therapeutic efficacy.

Topics: Adenoma; Adrenal Gland Neoplasms; Adrenocorticotropic Hormone; Animals; Cushing Syndrome; Humans; Hydrocortisone; Octreotide; Pituitary Neoplasms; Receptors, Somatostatin; Somatostatin

Somatostatin (SRIF) has been proposed to be of therapeutic interest in the medical treatment of Cushing's disease. While in vitro data demonstrate the presence of SRIF-receptor subtype (sst) expression in corticotroph adenomas, the current clinically available SRIF-analog Octreotide, predominantly targeting sst(2), is ineffective in lowering ACTH levels in Cushing's disease and only appears to inhibit the release of ACTH in Nelson's syndrome. In the present review, current knowledge on the physiological role of SRIF in the regulation of ACTH secretion by the anterior pituitary gland, as well as by corticotroph tumor cells is summarized. In addition, the role of glucocorticoids in regulating sst-mediated inhibition of ACTH release by corticotroph adenoma cells is discussed. Recently, it was reported that the novel multiligand SRIF-analog SOM230 might have the potential to be of therapeutic interest for Cushing's disease. On the basis of the potent suppressive effects on ACTH release by SRIF-analogs with high binding affinity to sst(5) and the observation that sst(5) expression and action is relatively resistant to glucocorticoid treatment, including the recent observation that sst(5) is the predominant sst expressed in human corticotroph adenomas, it is hypothesized that sst(5) may be a new therapeutic target for the control of ACTH and cortisol hypersecretion in patients with pituitary dependent Cushing's disease.

Topics: ACTH-Secreting Pituitary Adenoma; Adrenocorticotropic Hormone; Animals; Glucocorticoids; Humans; Hydrocortisone; Mice; Octreotide; Pituitary ACTH Hypersecretion; Pituitary Gland, Anterior; Pituitary Neoplasms; Receptors, Somatostatin; Somatostatin

Monitoring of patients with Cushing's disease on cortisol-lowering drugs is usually performed with urinary free cortisol (UFC). Late-night salivary cortisol (LNSC) has an established role in screening for hypercortisolism and can help to detect the loss of cortisol circadian rhythm. Less evidence exists regarding the usefulness of LNSC in monitoring pharmacological response in Cushing's disease.. Exploratory analysis evaluating LNSC during a Phase III study of long-acting pasireotide in Cushing's disease (clinicaltrials.gov: NCT01374906).. Mean LNSC (mLNSC) was calculated from two samples, collected on the same days as the first two of three 24-h urine samples (used to calculate mean UFC [mUFC]). Clinical signs of hypercortisolism were evaluated over time.. At baseline, 137 patients had evaluable mLNSC measurements; 91.2% had mLNSC exceeding the upper limit of normal (ULN; 3.2 nmol/L). Of patients with evaluable assessments at month 12 (n = 92), 17.4% had both mLNSC ≤ULN and mUFC ≤ULN; 22.8% had mLNSC ≤ULN, and 45.7% had mUFC ≤ULN. There was high variability in LNSC (intra-patient coefficient of variation (CV): 49.4%) and UFC (intra-patient CV: 39.2%). mLNSC levels decreased over 12 months of treatment and paralleled changes in mUFC. Moderate correlation was seen between mLNSC and mUFC (Spearman's correlation: ρ = 0.50 [all time points pooled]). Greater improvements in systolic/diastolic blood pressure and weight were seen in patients with both mLNSC ≤ULN and mUFC ≤ULN.. mUFC and mLNSC are complementary measurements for monitoring treatment response in Cushing's disease, with better clinical outcomes seen for patients in whom both mUFC and mLNSC are controlled.

Topics: ACTH-Secreting Pituitary Adenoma; Adult; Circadian Rhythm; Female; Hormones; Humans; Hydrocortisone; Male; Middle Aged; Pituitary ACTH Hypersecretion; Pituitary Neoplasms; Saliva; Somatostatin; Treatment Outcome

OBJECTIVE To evaluate clinical signs, endocrine test results, and pituitary tumor size for dogs with medically managed pituitary-dependent hyperadrenocorticism (PDH) and macroadenoma following 6 months of concurrent treatment with pasireotide. DESIGN Prospective case series. ANIMALS 9 client-owned dogs with PDH and macroadenoma in which PDH had been successfully managed with adrenal-directed treatment (trilostane or mitotane). PROCEDURES Dogs were given pasireotide (0.03 mg/kg [0.014 mg/lb], SC, q 12 h) for 6 months, while adrenal-directed treatment was continued. Physical examination, basic clinicopathologic testing, ACTH stimulation testing, and plasma ACTH concentration measurement were performed before (baseline) and 3 and 6 months after treatment began. Measurements of pituitary gland volume and pituitary gland-to-brain ratio were performed via MRI at baseline and 6 months after treatment began. RESULTS No dog developed neurologic abnormalities or signs of adverse effects during the study period. No differences from baseline were identified in clinicopathologic values, ACTH stimulation test results, or plasma ACTH concentration at the 3- or 6-month assessment points. After 6 months of pasireotide treatment, 6 dogs had decreases in MRI-measured values, and 3 had increases. CONCLUSIONS AND CLINICAL RELEVANCE Pasireotide as administered in this study had no noted adverse effects on dogs with PDH and macroadenoma successfully managed with standard treatment. Placebo-controlled, randomized studies are needed to determine whether pasireotide protects from the development of neurologic signs or improves outcome in dogs with pituitary macroadenomas.

Topics: Adenoma; Adrenocortical Hyperfunction; Animals; Dog Diseases; Dogs; Female; Hormones; Male; Pituitary ACTH Hypersecretion; Pituitary Neoplasms; Prospective Studies; Somatostatin

The aim of the present study was to evaluate the serial changes of GH and IGF-1 in seven patients with naïve, active acromegaly following presurgical treatment of the somatostatin analog pasireotide long-acting release (LAR) and octreotide LAR. The patients were treated with pasireotide LAR with or without octreotide LAR for two years and underwent transsphenoidal adenomectomy. After treatment with the somatostatin analogs, the surgical cure rate was similar to that in patients who underwent transsphenoidal surgery alone. Diabetes insipidus was not identified in any patients after the operation. Pasireotide LAR was effective on GH as well as IGF-1 suppression and tumor size decreasing when used as the primary therapy. Future large-population studies to investigate the surgical curative rate after presurgical treatment with somatostatin analogs in patients with acromegaly and macroadenomas close to the cavernous sinus are warranted. However, that hyperglycemia developed following pre-surgical treatment with pasireotide should take into consideration.

Topics: Acromegaly; Adult; Aged; Double-Blind Method; Female; Follow-Up Studies; Human Growth Hormone; Humans; Insulin-Like Growth Factor I; Magnetic Resonance Imaging; Male; Middle Aged; Octreotide; Pituitary Neoplasms; Prospective Studies; Somatostatin; Treatment Outcome; Tumor Burden

Pasireotide has a broader somatostatin receptor binding profile than other somatostatin analogues. A 16-week, Phase II trial showed that pasireotide may be an effective treatment for acromegaly. An extension to this trial assessed the long-term efficacy and safety of pasireotide. This study was an open-label, single-arm, open-ended extension study (primary efficacy and safety evaluated at month 6). Patients could enter the extension if they achieved biochemical control (GH ≤ 2.5 μg/L and normal IGF-1) or showed clinically relevant improvements during the core study. Thirty of the 60 patients who received pasireotide (200-900 μg bid) in the core study entered the extension. At extension month 6, of the 26 evaluable patients, six were biochemically controlled, of whom five had achieved control during the core study. Normal IGF-1 was achieved by 13/26 patients and GH ≤ 2.5 μg/L by 12/26 at month 6. Nine patients received pasireotide for ≥24 months in the extension; three who were biochemically controlled at month 24 had achieved control during the core study. Of 29 patients with MRI data, nine had significant (≥20%) tumor volume reduction during the core study; an additional eight had significant reduction during the extension. The most common adverse events were transient gastrointestinal disturbances; hyperglycemia-related events occurred in 14 patients. Twenty patients had fasting plasma glucose shifted to a higher category during the extension. However, last available glucose measurements were normal for 17 patients. Pasireotide has the potential to be an effective, long-term medical treatment for acromegaly, providing sustained biochemical control and significant reductions in tumor volume.

Topics: Acromegaly; Adenoma; Adolescent; Adult; Aged; Aged, 80 and over; Female; Growth Hormone; Growth Hormone-Secreting Pituitary Adenoma; Humans; Injections, Subcutaneous; Insulin-Like Growth Factor I; Magnetic Resonance Imaging; Male; Middle Aged; Pituitary Neoplasms; Somatostatin; Treatment Outcome; Tumor Burden; Young Adult

Pasireotide (SOM230) is a novel multireceptor ligand somatostatin analog with affinity for somatostatin receptor subtypes sst(1-3) and sst(5). Because most GH-secreting pituitary adenomas express sst(2) and sst(5), pasireotide has the potential to be more effective than the sst(2)-preferential somatostatin analogs octreotide and lanreotide.. Our objective was to evaluate the efficacy and safety of three different doses of pasireotide in patients with acromegaly.. We conducted a phase II, randomized, multicenter, open-label, three-way, crossover study.. Sixty patients with acromegaly, defined by a 2-h five-point mean GH level higher than 5 microg/liter, lack of suppression of GH to less than 1 microg/liter after oral glucose tolerance test, and elevated IGF-I for age- and sex-matched controls. Patients could have had previous surgery, radiotherapy, and/or medical therapy or no previous treatment.. After treatment with octreotide 100 microg s.c. three times daily for 28 d, each patient received pasireotide 200, 400, and 600 microg s.c. twice daily in random order for 28 d.. A biochemical response was defined as a reduction in GH to no more than 2.5 microg/liter and normalization of IGF-I to age- and sex-matched controls.. After 4 wk of octreotide, 9% of patients achieved a biochemical response. After 4 wk of pasireotide 200-600 microg s.c. bid, 19% of patients achieved a biochemical response, which increased to 27% after 3 months of pasireotide; 39% of patients had a more than 20% reduction in pituitary tumor volume. Pasireotide was generally well tolerated.. Pasireotide is a promising treatment for acromegaly. Larger studies of longer duration evaluating the efficacy and safety of pasireotide in patients with acromegaly are ongoing.

Topics: Acromegaly; Adolescent; Adult; Aged; Aged, 80 and over; Blood Glucose; Cross-Over Studies; Dose-Response Relationship, Drug; Double-Blind Method; Endpoint Determination; Female; Human Growth Hormone; Humans; Insulin-Like Growth Factor I; Magnetic Resonance Imaging; Male; Middle Aged; Octreotide; Pituitary Neoplasms; Somatostatin; Young Adult

Topics: Acromegaly; Female; Growth Hormone-Secreting Pituitary Adenoma; Humans; Insulin-Like Growth Factor I; Pituitary Neoplasms; Pregnancy; Somatostatin

Clinical control of corticotroph tumors is difficult to achieve since they usually persist or relapse after surgery. Pasireotide is approved to treat patients with Cushing's disease for whom surgical therapy is not an option. However, Pasireotide seems to be effective only in a sub-set of patients, highlighting the importance to find a response marker to this approach. Recent studies demonstrated that the delta isoform of protein kinase C (PRKCD) controls viability and cell cycle progression of an in vitro model of ACTH-secreting pituitary tumor, the AtT-20/D16v-F2 cells. This study aims at exploring the possible PRKCD role in mediating Pasireotide effects.. It was assessed cell viability, POMC expression and ACTH secretion in AtT20/D16v-F2 cells over- or under-expressing PRKCD.. We found that Pasireotide significantly reduces AtT20/D16v-F2 cell viability, POMC expression and ACTH secretion. In addition, Pasireotide reduces miR-26a expression. PRKCD silencing decreases AtT20/D16v-F2 cell sensitivity to Pasireotide treatment; on the contrary, PRKCD overexpression increases the inhibitory effects of Pasireotide on cell viability and ACTH secretion.. Our results provide new insights into potential PRKCD contribution in Pasireotide mechanism of action and suggest that PRKCD might be a possible marker of therapeutic response in ACTH-secreting pituitary tumors.

Topics: Adrenocorticotropic Hormone; Cell Line; Cell Line, Tumor; Corticotrophs; Humans; Neoplasm Recurrence, Local; Pituitary ACTH Hypersecretion; Pituitary Neoplasms; Pro-Opiomelanocortin; Protein Kinase C-delta

Somatostatin receptor type 5 (SST5) represents the main pharmacological target in the treatment of adrenocorticotroph hormone (ACTH)-secreting tumors. However, molecular predictors of responsiveness to pasireotide require further investigation. The cytoskeleton protein filamin A (FLNA) modulates the responsiveness to somatostatin analogs (SSA) treatment in other types of pituitary tumors by regulating somatostatin receptor type 2 (SST2)/dopamine receptor type 2 (DRD2) expression and activity. Here, we aimed to test the involvement of FLNA in the modulation of SST5 response to SSA in human and murine tumor corticotrophs. Western blot analysis of human corticotropinomas showed that FLNA and SST5 correlate. Both in human primary cultures and AtT-20 cells, FLNA genetic silencing caused a decrease of receptor expression level. Moreover, pasireotide-mediated SST5 downregulation observed in AtT-20 control cells was no further detected in FLNA silenced cells. In AtT-20 cells, in situ PLA experiments revealed an increased number of SST5-FLNA complexes following pasireotide incubation. Finally, FLNA knock down abolished pasireotide-induced SST5 actions on hormone secretion, cell proliferation and apoptosis. In conclusion, FLNA is implicated in SST5 expression modulation and signaling.

Topics: Animals; Apoptosis; Cell Line, Tumor; Cell Proliferation; Corticotrophs; Filamins; Gene Silencing; Hormones; Humans; Mice; Pituitary Neoplasms; Protein Binding; Receptors, Somatostatin; Signal Transduction; Somatostatin

About 10% of prolactinomas are resistant to dopamine-agonists (DAs). The only alternatives for tumor and prolactin control are surgery or radiotherapy. While studies on first generation somatostatin analogs have shown no efficacy against prolactinomas, no study has been conducted on the new multireceptor-targeted somatostatin receptor ligand pasireotide, which presents high affinity for 5, 3, 2 and 1 receptor subtypes.. A 41 year-old woman presented with a macroprolactinoma showing resistance to all available DAs. She was first diagnosed at 17 years old after which she had undergone two incomplete debulking surgeries. Under pasireotide long-acting release (LAR) treatment, plasma prolactin levels normalized and symptoms disappeared within one month after initiation. The clinical benefits of the monotherapy (specifically, prolactin levels within normal range and stable tumor volume) were maintained for seven years. Glucose tolerance was satisfactory. Pathological analysis of the tumor revealed high SSTR5 and low SSTR2 expression (25 and 5% of cells respectively).. This is a promising first report of a patient with a DA-resistant macroprolactinoma who achieved long-term control, in terms of prolactin normalization and tumor volume, under pasireotide treatment alone. Pasireotide could thus be an alternative in prolactinomas resistant to DA. SSTR expression analysis on pathology could guide patient selection.

Topics: Adult; Dopamine Agonists; Drug Resistance, Neoplasm; Female; Humans; Octreotide; Pituitary Neoplasms; Prolactinoma; Somatostatin

Pasireotide has been associated with tumor shrinkage in patients with Cushing's disease subjected to long term treatment. However, to date the implicated molecular mechanisms are poorly elucidated. Here, we tested pasireotide-mediated cytostatic and cytotoxic effects in ACTH-secreting primary tumor cultures and murine corticotroph tumor cell line, AtT-20 cells. We found somatostatin receptor type 5 (SST5) expressed in 17 different ACTH-secreting tumors and SST2 detectable in 15 out of the 17 tissues. Pasireotide caused a slight but significant in vitro inhibition of cell growth in 3 out of 6 ACTH-secreting primary cultures (-12.1 ± 4.3%, P < 0.01 at 10 nM), remarkably reduced phospho-ERK1/2 levels in 5 out of 8 samples (-36.4 ± 20.5%, P < 0.01 at 1 μM) and triggered an increase of caspase 3/7 activity in 2 of 4 tumors (17 ± 3.6%, P < 0.05 at 1 μM). Accordingly, in AtT-20 cells, pasireotide significantly inhibited cell proliferation (-10.5 ± 7.7% at 10 nM, P < 0.05; -13.9 ± 10.9% at 100 nM, P < 0.05; -26.8 ± 8.9% at 1 μM, P < 0.01). Similar antiproliferative actions were exerted by BIM23206 and BIM23120 (SST5&2 selective ligands, respectively), whereas octreotide was effective when used at 1 μM (-13.3 ± 9.1%, P < 0.05). Moreover, a reduction of phospho-ERK1/2 was observed upon pasireotide and BIM23206 treatment (-8.4 ± 28.6%, P < 0.01 and -51.4 ± 15.9%, P < 0.001 at 10 nM, respectively) but not after octreotide and BIM23120 incubation. Finally, pasireotide was able to induce cell apoptosis in AtT-20 cells at lower concentration than octreotide. Altogether these data indicate a downstream implication of SST5-mediated phospho-ERK1/2 inhibition by pasireotide resulting in ACTH-secreting tumor cells proliferation reduction. Moreover, we describe for the first time a pro-apoptotic effect of pasireotide in corticotrophs.

Topics: Animals; Cell Proliferation; Cell Survival; Corticotrophs; Humans; MAP Kinase Signaling System; Mice; Phosphorylation; Pituitary Neoplasms; Receptors, Somatostatin; Somatostatin; Tumor Cells, Cultured

Topics: Acromegaly; Adenoma; Aged; Humans; Magnetic Resonance Imaging; Male; Pituitary Gland; Pituitary Neoplasms; Somatostatin; Treatment Outcome

Acromegaly is a rare disease caused by excessive production of growth hormone (GH), typically by a pituitary tumour. The diagnosis is usually delayed, and patients frequently develop various complications that cause premature mortality. In patients with hypertension, heart failure, diabetes, and arthropathies that are not age-specific, attention should be paid to signs of acromegaly. Insulin-like growth factor 1 (IGF-1) assay should be used as a screening test whenever acromegaly is suspected. Further diagnostic investigations and treatment should be carried out at specialist centres. First-line treatment involves selective excision of pituitary adenoma using transsphenoidal access. Patients with chances of cure with surgical removal of the pituitary tumour should be referred to centres that have experience in this type of procedure, following pharmacological preparation. Other patients, as well as patients after failed neurosurgical treatment, should first receive chronic treatment with first-generation somatostatin analogues. For second-line treatment, pasireotide, pegvisomant, cabergoline, or combinations thereof should be considered. In every case, acromegaly sequelae require life-long monitoring and active treatment. Current recommendations, being an updated version of the recommendations published in Endokrynologia Polska in 2014, which take into account the Polish situation, should prove useful in the management of patients with acromegaly.

Topics: Acromegaly; Cabergoline; Endocrinology; Female; Human Growth Hormone; Humans; Male; Pituitary Neoplasms; Poland; Societies, Medical; Somatostatin

A phase III study has demonstrated that 6-month pasireotide treatment induced disease control with good safety in 15-26% of patients with Cushing's disease (CD). The aim of the current study was to evaluate the 6-month efficacy and safety of pasireotide treatment according to the real-world evidence. Thirty-two CD patients started pasireotide at the dose of 600 µg twice a day (bid) and with the chance of up-titration to 900 µg bid, or down-titration to 450 or 300 µg bid, on the basis of urinary cortisol (UC) levels or safety. Hormonal, clinical and metabolic parameters were measured at baseline and at 3-month and 6-month follow-up, whereas tumour size was evaluated at baseline and at 6-month follow-up. At baseline, 31 patients had very mild to moderate disease and 1 patient had very severe disease. Five (15.6%) patients discontinued treatment for adverse events; the remaining 27 patients (26 with very mild to moderate disease and 1 with very severe disease), reached 6-month follow-up. Considering the group of patients with very mild to moderate disease, responsiveness, defined by the normalization (<1 the upper limit of normal range, ULN) or near normalization (>1 and ≤1.1 ULN) of UC levels, was registered in 21 patients (full control in 19 and near control in 2), corresponding to 67.7% and 80.8% according to an "intention-to-treat" or "per-protocol" methodological approach, respectively. Weight, body mass index, waist circumference, as well as total and LDL-cholesterol significantly decreased, whereas fasting plasma glucose and glycated haemoglobin significantly increased. Hyperglycaemia was documented in 81.2%, whereas gastrointestinal disturbances in 40.6% of patients. In conclusion, in the real-life clinical practice, pasireotide treatment normalizes or nearly normalizes UC in at least 68% of patients with very mild to moderate disease, with consequent improvement in weight, visceral adiposity and lipid profile, despite the occurrence or deterioration of diabetes in the majority of cases, confirming the usefulness of this treatment in patients with milder disease and without uncontrolled diabetes.

Topics: Adult; Aged; Body Mass Index; Female; Humans; Hydrocortisone; Italy; Magnetic Resonance Imaging; Male; Middle Aged; Pituitary ACTH Hypersecretion; Pituitary Neoplasms; Somatostatin; Treatment Outcome; Waist Circumference; Young Adult

Prolactinomas are the most commonly encountered pituitary adenomas in the clinical setting. While most can be controlled by dopamine agonists, a subset of prolactinomas are dopamine-resistant and very aggressive. In such tumors, the treatment of choice is neurosurgery and radiotherapy, with or without temozolomide. Here, we report a patient with an highly aggressive, dopamine-resistant prolactinoma, who only achieved biochemical and tumor control during pasireotide long-acting release (PAS-LAR) therapy, a second-generation somatostatin receptor ligand (SRL). Interestingly, cystic degeneration, tumor cell necrosis or both was observed after PAS-LAR administration suggesting an antitumor effect. This case shows that PAS-LAR therapy holds clinical potential in selective aggressive, dopamine-resistant prolactinomas that express somatostatin (SST) receptor subtype 5 and appears to be a potential new treatment option before starting temozolomide. In addition, PAS-LAR therapy may induce cystic degeneration, tumor cell necrosis or both in prolactinomas.

Topics: Adenoma; Dopamine Agonists; Drug Resistance, Neoplasm; Female; Hormones; Humans; Middle Aged; Neoplasm Invasiveness; Pituitary Neoplasms; Prolactinoma; Somatostatin; Treatment Outcome; Tumor Burden

The treatment of acromegaly resistant to first- and second-line therapies can be extremely challenging.. We have described six patients who were successfully treated with a combination therapy of pasireotide and pegvisomant and compared them with a control group of patients resistant to conventional somatostatin analogs (SSAs), whose disease was controlled with other treatment, such as pasireotide (as monotherapy) or pegvisomant (as monotherapy or combined with conventional SSAs).. In these six patients, acromegaly was controlled with combined pasireotide and pegvisomant treatment after failure of all other treatments. Compared with the 49 patients in the control group, these six patients had giant and invasive pituitary adenomas (at both the cavernous sinus and other structures). Although not statistically significant, higher growth hormone levels, more elevated Ki-67 expression, greater somatostatin receptor (SSTR) subtype 5 expression, and lower SSTR subtype 2 expression at the diagnosis of acromegaly were detected in patients receiving combination treatment with pasireotide and pegvisomant compared with the control group.. Our data have reinforced the importance of personalized treatment of patients with acromegaly according to the clinical, biochemical, molecular, and morphological disease markers and suggest that combined treatment with pasireotide and pegvisomant can induce disease control in tumors with low SSTR2 expression, resistant to conventional SSAs (alone or combined with pegvisomant) and to new-generation SSAs alone (pasireotide).

Topics: Acromegaly; Adenoma; Adult; Drug Therapy, Combination; Female; Hormones; Human Growth Hormone; Humans; Longitudinal Studies; Male; Middle Aged; Pituitary Neoplasms; Retrospective Studies; Somatostatin; Treatment Outcome; Young Adult

Topics: Acromegaly; Adenoma; Humans; Pituitary Neoplasms; Somatostatin

Topics: Acromegaly; Adenoma; Humans; Pituitary Neoplasms; Somatostatin

Topics: Acromegaly; Adenoma; Adult; Aged; Female; Hormones; Humans; Male; Middle Aged; Pituitary Neoplasms; Precision Medicine; Somatostatin; Tumor Burden

A 22-year-old woman presented with worsening vision loss and headaches. A diagnosis of acromegaly was confirmed after detection of an invasive pituitary macroadenoma and biochemical testing. Despite two attempts of surgical debulking of the tumour and administration of long-acting octreotide and cabergoline, growth hormone (GH) and insulin-like growth factor 1 (IGF-1) levels were uncontrolled. The patient experienced persistent headaches despite surgery, gamma knife radiation and ventriculoperitoneal shunt placement; she was then enrolled in the ACCESS trial (ClinicalTrials.gov identifier, NCT01995734). Pasireotide (Signifor; Signifor LAR) was initiated, which led to reduced GH and IGF-1 levels and resolution of her intractable headaches. This highlights the use of monthly pasireotide in resolving headaches and improved biochemical control in a patient with acromegaly. We postulate that the headaches improved due to an analgesic and/or anti-inflammatory effect mediated by somatostatin receptors targeted by pasireotide. This may represent an additional benefit of pasireotide and requires further investigation.

Topics: Acromegaly; Female; Headache Disorders; Human Growth Hormone; Humans; Insulin-Like Growth Factor I; Magnetic Resonance Imaging; Pituitary Neoplasms; Somatostatin; Young Adult

A 43-year-old woman with an 8-year history of diabetes, hypertension, and dyslipidemia presented with amenorrhea and convulsion. Her MRI scan revealed a 3.5-cm T2-hyperintense pituitary macroadenoma with suprasellar extension to the frontal lobe and bilateral cavernous sinus invasion. Her serum levels of GH and insulin-like growth factor-I (IGF-I) were elevated to 9.08 ng/mL (normal range: <2.1 ng/mL) and 1,000 ng/mL (normal range: 90-233 ng/mL, SD score +10.6), respectively. Bromocriptine insufficiently suppressed her GH levels, while octreotide paradoxically increased her GH levels. Together with her characteristic features, she was diagnosed with acromegaly caused by an invasive GH-producing pituitary macroadenoma. As performing a one-stage operation would have been extremely difficult, she was first treated with pasireotide long-acting release (40 mg monthly) for 5 months followed by a successful transsphenoidal surgery. One month after the first injection, biochemical control was achieved (IGF-I, 220 ng/mL; GH, 1.26 ng/mL), and tumor shrinkage of approximately 50% was observed. The resected tumor was histologically diagnosed as a sparsely granulated somatotroph adenoma, with higher expression of somatostatin receptor subtype 5 (SSTR5) than that of SSTR2A. The germline aryl hydrocarbon receptor interacting protein (AIP) mutation was negative, and several tumor cells were weakly immunoreactive for AIP. Despite the presence of a residual tumor postoperatively, biochemical control was achieved 6 months after the final injection of pasireotide. In conclusion, this case suggests that pasireotide may be an option for preoperative first-line therapy in invasive and octreotide-resistant sparsely granulated somatotroph adenomas.

Topics: Acromegaly; Adult; Combined Modality Therapy; Female; Growth Hormone-Secreting Pituitary Adenoma; Humans; Pituitary Neoplasms; Preoperative Care; Somatostatin; Treatment Outcome

Topics: Adenoma; Humans; Male; Middle Aged; Pituitary Neoplasms; Somatostatin; Thyrotropin

We reported that a single nucleotide polymorphism (SNP) at codon 388 of the fibroblast growth factor receptor 4 (FGFR4-Gly388Arg) can result in distinct proteins that alter pituitary cell growth and function. Here, we examined the differential properties of the available therapeutic somatostatin analogs, octreotide and pasireotide, in pituitary tumor cells expressing the different FGFR4 isoforms. Consistent with their enhanced growth properties, FGFR4-R388-expressing cells show higher mitochondrial STAT3 serine phosphorylation driving basal and maximal oxygen consumption rate (OCR) than pituitary cells expressing the more common FGFR4-G388 isoform. While both somatostatin analogs reduce the OCR in FGFR4-G388 cells, pasireotide was more effective in decreasing OCR in cells expressing the variant FGFR4-R388 isoform. Down-regulation of somatostatin receptor 5 (SSTR5) abrogated the effect of pasireotide, demonstrating its involvement in mediating this action. The effects on OCR were recapitulated by introducing a constitutively active serine STAT3 but not by a tyrosine-active mutant. Moreover, pharmacologic inhibition demonstrated the role for the phosphatase PP2A in mediating the dephosphorylation of STAT3-S727 by pasireotide. Our data indicate that FGFR4 polymorphic isoforms mediate signaling that yields mitochondrial therapeutic targets of relevance to the actions of different somatostatin analogs.

Topics: Alleles; Animals; Antineoplastic Agents, Hormonal; Cell Line, Tumor; Cell Respiration; Disease Models, Animal; Drug Resistance, Neoplasm; Humans; Mice; Mice, Transgenic; Mitochondria; Octreotide; Phosphorylation; Pituitary Neoplasms; Polymorphism, Single Nucleotide; Protein Transport; Receptor, Fibroblast Growth Factor, Type 4; Signal Transduction; Somatostatin; STAT3 Transcription Factor; Xenograft Model Antitumor Assays

X-linked acrogigantism (X-LAG) syndrome is a newly described form of inheritable pituitary gigantism that begins in early childhood and is usually associated with markedly elevated GH and prolactin secretion by mixed pituitary adenomas/hyperplasia. Microduplications on chromosome Xq26.3 including the GPR101 gene cause X-LAG syndrome. In individual cases random GHRH levels have been elevated. We performed a series of hormonal profiles in a young female sporadic X-LAG syndrome patient and subsequently undertook in vitro studies of primary pituitary tumor culture following neurosurgical resection. The patient demonstrated consistently elevated circulating GHRH levels throughout preoperative testing, which was accompanied by marked GH and prolactin hypersecretion; GH demonstrated a paradoxical increase following TRH administration. In vitro, the pituitary cells showed baseline GH and prolactin release that was further stimulated by GHRH administration. Co-incubation with GHRH and the GHRH receptor antagonist, acetyl-(d-Arg(2))-GHRH (1-29) amide, blocked the GHRH-induced GH stimulation; the GHRH receptor antagonist alone significantly reduced GH release. Pasireotide, but not octreotide, inhibited GH secretion. A ghrelin receptor agonist and an inverse agonist led to modest, statistically significant increases and decreases in GH secretion, respectively. GHRH hypersecretion can accompany the pituitary abnormalities seen in X-LAG syndrome. These data suggest that the pathology of X-LAG syndrome may include hypothalamic dysregulation of GHRH secretion, which is in keeping with localization of GPR101 in the hypothalamus. Therapeutic blockade of GHRH secretion could represent a way to target the marked hormonal hypersecretion and overgrowth that characterizes X-LAG syndrome.

Topics: Antineoplastic Agents, Hormonal; Child, Preschool; Female; Genetic Diseases, X-Linked; Gigantism; Growth Hormone; Growth Hormone-Releasing Hormone; Humans; Octreotide; Pituitary Neoplasms; Prolactin; Receptors, Ghrelin; Somatostatin; Syndrome; Tumor Cells, Cultured

The hypercortisolism is a rare endocrine disease characterized by an autonomous steroid secretion or excessive adrenal stimulation by ACTH. the Surgical removal of the lesion directly responsible hypercortisolism represents the treatment of choice. When neurosurgery for pituitary adenoma is contraindicated, radiotherapy is candidate as the second line of therapy. Currently, the recent advances in medical therapy provide a viable alternative to surgery and radiotherapy, when these are not feasible or followed by relapses (present in more than one third of cases) of the underlying disease. Recently, also in Italy, are available pharmacological agents with central activity (pasireotide) specifically indicated for treating Cushing's disease together with peripherally acting drugs (metyrapone and ketoconazole) that are used in a broader spectrum of hypercortisolemic clinical pictures. In addition, drugs active in the inhibition of steroidogenesis provide a valid support to the patient's surgical preparation allowing the reduction or normalization of plasma cortisol levels.

Topics: Adenoma; Cushing Syndrome; Humans; Hydrocortisone; Italy; Ketoconazole; Metyrapone; Pituitary Neoplasms; Somatostatin

Gonadotroph pituitary adenomas (GPAs) often present as invasive macroadenomas not amenable to complete surgical resection. Radiotherapy is the only post-operative option for patients with large invasive or recurrent lesions. No medical treatment is available for these patients. The somatostatin analogs (SSAs) octreotide and lanreotide that preferentially target somatostatin receptor type 2 (SSTR2) have little effect on GPAs. It is widely accepted that the expression of specific SSTR subtypes determines the response to SSAs. Given that previous studies on mRNA and protein expression of SSTRs in GPAs have generated conflicting results, we investigated the expression of SSTR2, SSTR3, and SSTR5 (the main targets of available SSAs) in a clinically and pathologically well-characterized cohort of 108 patients with GPAs. A total of 118 samples were examined by immunohistochemistry using validated and specific MABs. Matched primary and recurrent tissues were available for ten patients. The results obtained were validated in an independent cohort of 27 GPAs. We observed that SSTR3 was significantly more abundant than SSTR2 (P<0.0001) in GPAs, while full-length SSTR5 was only expressed in few tumors. Expression of SSTR3 was similar in primary and recurrent adenomas, was high in potentially aggressive lesions, and did not change significantly in adenomas that recurred after irradiation. In conclusion, low levels of expression of SSTR2 may account for the limited response of GPAs to octreotide and lanreotide. Given the potent anti-proliferative, pro-apoptotic, and anti-angiogenic activities of SSTR3, targeting this receptor with a multireceptor ligand SSA such as pasireotide may be indicated for potentially aggressive GPAs.

Topics: Adenoma; Adult; Aged; Aged, 80 and over; Female; Humans; Male; Middle Aged; Molecular Targeted Therapy; Neoplasm Recurrence, Local; Pituitary Neoplasms; Receptors, Somatostatin; Somatostatin; Young Adult

Aggressive pituitary adenomas (PAs) are clinically challenging for endocrinologists and neurosurgeons due to their locally invasive nature and resistance to standard treatment (surgery, medical or radiotherapy). Two pituitary-directed drugs have recently been proposed: temozolomide (TMZ) for aggressive PA, and pasireotide for ACTH-secreting PA. We describe the experience of our multidisciplinary team of endocrinologists, neurosurgeons, neuroradiologists, oncologists, otolaryngologists and pathologists with TMZ and pasireotide treatment for aggressive PAs in terms of their radiological shrinkage and genetic features. We considered five patients with aggressive PA, three of them non-secreting (two ACTH-silent and one becoming ACTH secreting), and two secreting (one GH and one ACTH). TMZ was administrated orally at 150-200 mg/m(2) daily for 5 days every 28 days to all 5 patients, and 2 of them also received pasireotide 600-900 µg bid sc. We assessed the MRI at the baseline and during TMZ or pasireotide treatment. We also checked for MGMT promoter methylation and IDH, BRAF and kRAS mutations. Considering TMZ, two patients showed PA progression, one stable disease and two achieved radiological and clinical response. Pasireotide was effective in reducing hypercortisolism and mass volume, combined with TMZ in one case. Both treatments were generally well tolerated; one patient developed a grade 2 TMZ-induced thrombocytopenia. None of patients developed hypopituitarism while taking TMZ or pasireotide treatment. No genetic anomalies were identified in the adenoma tissue. TMZ and pasireotide may be important therapies for aggressive PA, alone or in combination.

Topics: Adenoma; Adult; Aged; Antineoplastic Agents, Alkylating; Dacarbazine; Drug Therapy, Combination; Female; Follow-Up Studies; Humans; Male; Middle Aged; Neoplasm Staging; Pituitary Neoplasms; Prognosis; Retrospective Studies; Somatostatin; Survival Rate; Temozolomide; Tertiary Care Centers

Somatotropinomas have unique "fingerprints" of somatostatin receptor (sst) expression, which are targets in treatment of acromegaly with somatostatin analogues (SSAs). However, a significant expression of sst is not always related to the biochemical response to SSAs. Headache is a common complaint in acromegaly and considered a clinical marker of disease activity. SSAs are reported to have an own analgesic effect, but the sst involved are unknown.. We investigated sst expression in two acromegalic patients with severe headache and no biochemical effects of octreotide, but a good response to pasireotide. We searched the literature for determinants of biochemical and analgesic effects of SSAs in somatotropinomas.. Case 1 had no biochemical or analgesic effects of octreotide, a semi-selective SSA, but a rapid and significant effect of pasireotide, a pan-SSA. Case 2 demonstrated discordance between analgesic and biochemical effects of octreotide, in that headache disappeared, but without biochemical improvement. In contrast, pasireotide normalized insulin-like growth factor 1. Both adenomas were sparsely granulated and had strong membranous expressions of sst2a in 50-75% and sst5 in 75-100% of tumor cells. The truncated sst5 variant TMD4 (sst5TMD4) showed expression in 20-57% of tumor cells.. A poor biochemical response to octreotide may be associated with tumor expression of a truncated sst5 variant, despite abundant sst2a expression, suggesting an influence from variant sst5 on common sst signaling pathways. Furthermore, unrelated analgesic and biochemical effects of SSAs supported a complex pathogenesis of acromegaly-associated headache. Finally, assessment of truncated sst5 in addition to full length sst could be important for a choice of postoperative SSA treatment in somatotropinomas.

Topics: Acromegaly; Adult; Female; Growth Hormone-Secreting Pituitary Adenoma; Headache; Human Growth Hormone; Humans; Octreotide; Pituitary Neoplasms; Receptors, Somatostatin; Somatostatin; Young Adult

Adrenocorticotropic hormone (ACTH) production by pituitary corticotroph adenomas is the main cause of Cushing's disease. A drug that targets pituitary ACTH-secreting adenomas would aid treatment of Cushing's disease. Octreotide, a somatostatin receptor type 2 (SSTR2)-preferring somatostatin analogue, has no effect on ACTH secretion in patients with Cushing's disease. The multiligand SOM230 (pasireotide) displays a much higher affinity for SSTR1 and SSTR5 than octreotide and suppresses ACTH secretion in cultures of human corticotroph tumors to a greater extent than octreotide. In the present in vitro and in vivo study, we determined the effect of SOM230 on ACTH production and cell proliferation of AtT-20 corticotroph tumor cells. SOM230 decreased proopiomelanocortin (POMC) mRNA levels in AtT-20 cells and ACTH levels in the culture medium of these cells, suggesting that SOM230 suppresses ACTH synthesis and secretion in corticotroph tumor cells. SOM230 also decreased cell proliferation and both cyclic adenosine monophosphate response element-binding protein and Akt phosphorylation in AtT-20 cells. SSTR5 knockdown inhibited the SOM230-induced decreases in cell proliferation. Fluorescence-activated cell sorting analyses revealed that SOM230 did not attenuate cell cycle progression. Tumor weight in mice xenografted with AtT-20 cells and treated with SOM230 was significantly lower than in AtT-20-xenografted control mice. SOM230 also significantly decreased plasma ACTH levels, and POMC and pituitary tumor transforming gene mRNA levels in the tumor cells. Thus, SOM230 inhibits ACTH production and corticotroph tumor cell proliferation in vitro and in vivo.

Topics: ACTH-Secreting Pituitary Adenoma; Adrenocorticotropic Hormone; Animals; Cell Line, Tumor; Cell Proliferation; Corticotrophs; Humans; Male; Mice; Mice, Nude; Neoplasm Transplantation; Pituitary Gland; Pituitary Neoplasms; Pro-Opiomelanocortin; Proto-Oncogene Proteins c-akt; Receptors, Somatostatin; RNA, Messenger; RNA, Small Interfering; Somatostatin; Tumor Burden

Somatostatin is a widely distributed polypeptide that modulates endocrine and exocrine secretion, cell proliferation, and apoptosis by 5 somatostatin receptors (SSTR1-5). The inhibitory effects of somatostatin on tumor growth may be the result of its suppressing the synthesis and/or secretion of growth factors and growth-promoting hormones.. Very little information is available on the effect of somatostatin analogs on adrenal tumors, so we examined SSTR expression in adrenocortical tumors and studied the effect of a somatostatin analog (SOM230) on hormone secretion and cell viability in adrenal cells.. SSTR expression was analyzed by real-time PCR in 13 adrenocortical carcinomas (ACC), 24 aldosterone-producing adenomas (APA), 11 cortisol-producing adenomas (CPA), and 7 normal adrenals (NA), and verified by immunohistochemistry (IHC) in 14 samples. The effect of SOM230 on cortisol or aldosterone secretion in H295R and primary cell cultures was determined by radioimmunoassay, and its effect on viability in H295R and SW13 using the MTT test.. SSTR1 and SSTR2 mRNA was expressed in 100% of adrenal tumors. Compared to NA, ACC revealed an increase in almost all SSTR, while only some APA over-expressed SSTR3 and SSTR1. CPA expressed SSTR similar to NA. IHC confirmed the mRNA expression data. At nanomolar concentrations, SOM230 inhibited hormone secretion in primary adrenal cultures and H295R cells, but had no evident effect on cell viability.. The evidence of SSTR over-expression (particularly in ACC) and of hormone secretion being inhibited by SOM230 suggests a potential therapeutic role for this broad-spectrum somatostatin analog in adrenal tumors.

Topics: Adenoma; Adrenal Cortex Neoplasms; Adrenal Glands; Aldosterone; Apoptosis; Cell Cycle; Cell Proliferation; Flow Cytometry; Humans; Hydrocortisone; Immunoenzyme Techniques; In Vitro Techniques; Pituitary Neoplasms; Real-Time Polymerase Chain Reaction; Receptors, Somatostatin; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Somatostatin; Tumor Cells, Cultured

Pituitary adenomas can cause specific syndromes due to hormone excess and/or determine sellar mass symptoms. Pituitary cell growth can sometimes be influenced by medical therapy, such as for somatotroph adenomas treated with somatostatin analogs or prolactinomas treated with dopaminergic drugs. However, nonfunctioning pituitary adenomas (NFAs) are still orphans of medical therapy. Everolimus (RAD001), a derivative of rapamycin, is a well-known immunosuppressant drug, which has been recently shown to have antineoplastic activity in several human cancers.. The objective of the study was to investigate the possible antiproliferative effects of RAD001 in human NFAs.. We collected 40 NFAs that were dispersed in primary cultures, treated without or with 1 nm to 1 microm RAD001, 10 nm cabergoline, 10 nm SOM230 (a somatostatin receptor multiligand), and/or 50 nm IGF-I. Cell viability and apoptosis were evaluated after 48 h, and vascular endothelial growth factor (VEGF) secretion was assessed after an 8-h incubation. Somatostatin and dopamine subtype 2 receptor expression was investigated by quantitative PCR.. In 28 cultures (70%), Everolimus significantly reduced cell viability (by approximately 40%; P < 0.05 vs. control), promoted apoptosis (+30%; P < 0.05 vs. control), inhibited p70S6K activity (-20%), and blocked IGF-I proliferative and antiapoptotic effects. In selected tissues cotreatment with SOM230, but not cabergoline, exerted an additive effect. Everolimus did not affect VEGF secretion but blocked the stimulatory effects of IGF-I on this parameter.. Everolimus reduced NFA cell viability by inducing apoptosis, with a mechanism likely involving IGF-I signaling but not VEGF secretion, suggesting that it might represent a possible medical treatment of invasive/recurrent NFAs.

Topics: Adenoma; Aged; Apoptosis; Cabergoline; Cell Line, Tumor; Cell Survival; Ergolines; Everolimus; Female; Humans; Immunosuppressive Agents; Male; Middle Aged; Pituitary Neoplasms; Receptors, Somatostatin; Ribosomal Protein S6 Kinases, 70-kDa; Sirolimus; Somatostatin; Vascular Endothelial Growth Factor A

Topics: Acromegaly; Adenoma; Combined Modality Therapy; Comorbidity; Cranial Irradiation; Data Collection; Disease Management; Drug Therapy, Combination; Drug Utilization; History, 20th Century; History, 21st Century; Human Growth Hormone; Humans; Hypophysectomy; Peptides, Cyclic; Pituitary Neoplasms; Receptors, Somatostatin; Registries; Retrospective Studies; Somatostatin; Spain

Pituitary carcinomas are rare and neurosurgically challenging lesions, as they commonly relapse after surgical removal. Their prognosis is dismal due to their limited response to radiotherapy and chemotherapy. In recent studies, temozolomide was administered in very few patients with partial effects. We report a patient with an ACTH-secreting pituitary carcinoma and widespread intracranial, spinal and systemic metastases despite repeated surgical treatment, bilateral adrenalectomy, medical treatment and radiotherapy. Additionally to chemotherapy with temozolomide, the patient received SOM230 as salvage therapy with an improvement of the patient's clinical status, and a reduction of ACTH levels. After 12 months of combination therapy a sustained tumor control was achieved and persisted upon monotherapy with SOM230 for more than 9 months thereafter. Thus, temozolomide in combination with SOM230 seems to be promising in patients with ACTH-secreting metastasized pituitary carcinoma.

Topics: Adrenocorticotropic Hormone; Antineoplastic Agents, Alkylating; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Carcinoma; Dacarbazine; Female; Humans; Middle Aged; Pituitary Neoplasms; Salvage Therapy; Somatostatin; Temozolomide; Treatment Outcome

Topics: Adenoma; Clinical Trials as Topic; Dacarbazine; Humans; Pituitary ACTH Hypersecretion; Pituitary Neoplasms; Somatostatin; Temozolomide; Treatment Outcome

Ten percent of patients with prolactinoma fail to respond with normalization of prolactin (PRL) and tumor shrinkage under dopamine agonist (DA) therapy. The resistance to treatment is linked to a loss of dopamine receptor 2 (D2DR). Prolactinomas express somatostatin (SST) receptor subtypes, SSTR1, 2, and 5. The aim of this study was to determine whether different SST compounds could overcome the resistance to DA in prolactinomas.. The efficacy of SSTR1, SSTR2, and SSTR5 ligands; the universal SST ligand, SOM230; and the chimeric SST-DA compound, BIM-23A760, was compared with cabergoline in suppressing PRL secretion from primary cultures of ten prolactinomas (six DA responders and four DA resistant). Receptor mRNAs were assessed by quantitative PCR.. The mean mRNA levels for D2DR, SSTR1, SSTR2, and SSTR5 were 92.3+/-47.3, 2.2+/-1.4, 1.1+/-0.7, and 1.6+/-0.6 copy/copy beta-glucuronidase (beta-Gus) respectively. The SSTR1 agonist, BIM-23926, did not suppress PRL in prolactinomas. In a DA-resistant prolactinoma, it did not inhibit [(3)H]thymidine incorporation. The SSTR5 compound, BIM-23206, produced a dose-dependent inhibition of PRL release similar to that of cabergoline in three DA-sensitive prolactinomas. BIM-23A760 produced a maximal PRL inhibition superimposable to that obtained with cabergoline with a lower EC(50) (0.5+/-0.1 vs 2.5+/-1.5 pmol/l). In DA-resistant prolactinomas, BIM-23206 and SOM230 were ineffective. Cabergoline and BIM-23A760 produced a partial inhibition of PRL secretion (19+/-6 and 21+/-3% respectively).. Although the SSTRs are expressed in prolactinomas, the somatostatinergic ligands analyzed do not appear to be highly effective in suppressing PRL. D2DR remains the primary target for effective treatment of prolactinomas.

Topics: Adult; Antineoplastic Agents; Cabergoline; Dopamine; Dose-Response Relationship, Drug; Drug Resistance, Neoplasm; Ergolines; Female; Growth Hormone-Secreting Pituitary Adenoma; Humans; Ligands; Male; Middle Aged; Pituitary Neoplasms; Prolactinoma; Receptors, Dopamine D2; Receptors, Somatostatin; RNA, Messenger; Somatostatin; Tumor Cells, Cultured

Somatostatin (SRIF) analogs have been employed in medical therapy of non-functioning pituitary adenomas (NFA), with contrasting results. Previous evidence showed that SRIF can exert its antiproliferative effects by reducing vascular endothelial growth factor (VEGF) secretion and action, and that VEGF expression may be related to pituitary tumor growth. The aim of our study was to clarify the possible effects of a multireceptor SRIF ligand on VEGF secretion and cell proliferation in human NFA primary cultures. We assessed the expression of SRIF receptors (SSTR1-5), the in vitro effects on VEGF secretion, and on cell viability of SRIF and of the stable SRIF analog pasireotide (SOM230), which activates SSTR1, 2, 3, and 5. Twenty-five NFA were examined by RT-PCR for expression of alpha-subunit, SSTR, VEGF, and VEGF receptors 1 (VEGF-R1) and 2 (VEGF-R2). Primary cultures were tested with SRIF and with pasireotide. All NFA samples expressed alpha-sub, VEGF and VEGFR-1 and 2, while SSTR expression pattern was highly variable. Two different groups were identified according to VEGF secretion inhibition by SRIF. VEGF secretion and cell viability were reduced by SRIF and pasireotide in the 'responder' group, but not in the 'non-responder' group, including NFA expressing SSTR5. SRIF and pasireotide completely blocked forskolin-induced VEGF secretion. In addition, SRIF and pasireotide completely abrogated the promoting effects of VEGF on NFA cell viability. Our data demonstrate that pasireotide can inhibit NFA cell viability by inhibiting VEGF secretion, and suggest that the multireceptor-SSTR agonist pasireotide might be useful in medical therapy of selected NFA.

Topics: Adenoma; Adult; Aged; Cell Survival; Female; Hormones; Humans; Ligands; Male; Oligopeptides; Pituitary Neoplasms; Receptors, Somatostatin; RNA, Messenger; Somatostatin; Vascular Endothelial Growth Factor A

We have previously shown that transgenic mice ubiquitously overexpressing the HMGA2 gene develop growth hormone/prolactin-secreting pituitary adenomas. This animal model has been used to evaluate the therapeutic efficacy of SOM230, a somatostatin analogue with high affinity for the somatostatin receptor subtypes 1, 2, 3, and 5, on the growth of the pituitary adenomas.. Four groups of 3- and 9-month-old HMGA2 transgenic mice were treated for 3 months with a continuous s.c. injection of two different dosages of SOM230 (5 or 50 microg/kg/h), one dose of octreotide, corresponding to that used in human therapy, and a placebo, respectively. The development of the tumor before and after therapy was monitored by magnetic resonance imaging of the pituitary region and evaluation of the serum prolactin levels.. The highest dose of SOM230 induced a drastic regression of the tumor, whereas octreotide was not able to induce any significant tumor regression, although tumor progression was significantly slowed down. No significant differences were observed between the animals treated with the lowest dose of SOM230 and those receiving placebo.. These results clearly support the efficacy of the SOM230 treatment in human pituitary adenomas secreting prolactin based on the dramatic tumor shrinkage and fall in prolactin levels. This beneficial effect could be of crucial clinical usefulness in patients bearing tumors resistant to dopaminergic drugs.

Topics: Animals; Cell Proliferation; Female; Growth Hormone-Secreting Pituitary Adenoma; HMGA2 Protein; Mice; Mice, Transgenic; Pituitary Neoplasms; Somatostatin; Treatment Outcome

Somatostatin (SST) analogues play an important role in the medical management of somatotroph pituitary adenomas and new agonists have the potential to be effective in a wider group of pituitary and other tumours. The anti-proliferative effect of SST occurs through multiple mechanisms, one of which is cell-cycle arrest, where p27, a cyclin-dependent kinase inhibitor, is an important regulator. We hypothesised that SST may upregulate p27 protein levels and downregulate the MAP kinase pathway in these tumours.. Human pituitary adenoma cells and rat pituitary cell line (GH3) were cultured and treated in vitro with octreotide and the broad-spectrum SST agonist SOM230 (pasireotide). Immunoblotting for p27 and phospho-ERK (pERK) was performed and proliferation assessed by [3H]-thymidine incorporation. Histological samples from acromegalic patients treated with octreotide before surgery were immunostained for p27 and compared to samples from untreated patients matched for sex, age, tumour size, extension and invasiveness.. We detected upregulation of p27 protein levels with SST analogue treatment in vitro in human pituitary adenoma samples. pERK1/2 was inhibited by SST analogues in both the human samples and GH3 cells. SST and its analogues inhibited the proliferation of GH3 cells. p27 immunostaining was stronger in samples from patients with longer preoperative octreotide treatment (more than 6 months) than in samples from patients with shorter treatment periods.. This study demonstrates that SST-mediated growth inhibition is associated with the downregulation of pERK and upregulation of p27. More potent and broader-spectrum SST analogues are likely to play an increasing role in the treatment of tumours, where the MAP kinase pathway is overactivated.

Topics: Adenoma; Animals; Antineoplastic Agents, Hormonal; Cell Division; Cell Line, Tumor; Cyclin-Dependent Kinase Inhibitor p27; Down-Regulation; Extracellular Signal-Regulated MAP Kinases; Growth Hormone-Secreting Pituitary Adenoma; Humans; In Vitro Techniques; MAP Kinase Signaling System; Octreotide; Pituitary Gland; Pituitary Neoplasms; Prolactinoma; Rats; Somatostatin; Thymidine; Tritium; Up-Regulation

In a series of human corticotroph adenomas, we recently found predominant mRNA expression of somatostatin (SS) receptor subtype 5 (sst5). After 72 h, the multiligand SS analog SOM230, which has a very high sst5 binding affinity, but not Octreotide (OCT), significantly inhibited basal ACTH release. To further explore the role of sst5 in the regulation of ACTH release, we conducted additional studies with mouse AtT-20 cells. SOM230 showed a 7-fold higher ligand binding affinity and a 19-fold higher potency in stimulating guanosine 5'-O-(3-thiotriphosphate) binding in AtT-20 cell membranes compared with OCT. SOM230 potently suppressed CRH-induced ACTH release, which was not affected by 48-h dexamethasone (DEX) pretreatment. However, DEX attenuated the inhibitory effects of OCT on ACTH release, whereas it increased the inhibitory potency of BIM-23268, an sst5-specific analog, on ACTH release. Quantitative PCR analysis showed that DEX lowered sst(2A+2B) mRNA expression significantly after 24 and 48 h, whereas sst5 mRNA levels were not significantly affected by DEX treatment. Moreover, Scatchard analyses showed that DEX suppressed maximum binding capacity (B(max)) by 72% when 125I-Tyr3-labeled OCT was used as radioligand, whereas B(max) declined only by 17% when AtT-20 cells were treated with [125I-Tyr11]SS-14. These data suggest that the sst5 protein, compared with sst2, is more resistant to glucocorticoids. Finally, after SS analog preincubation, compared with OCT both SOM230 and BIM-23268 showed a significantly higher inhibitory effect on CRH-induced ACTH release. In conclusion, our data support the concept that the sst5 receptor might be a target for new therapeutic agents to treat Cushing's disease.

Topics: Adrenocorticotropic Hormone; Animals; Corticotropin-Releasing Hormone; Dose-Response Relationship, Drug; Down-Regulation; Glucocorticoids; Mice; Octreotide; Pituitary Gland; Pituitary Neoplasms; Receptors, Somatostatin; RNA, Messenger; Somatostatin; Stimulation, Chemical; Tumor Cells, Cultured

Currently, there is no effective medical treatment for patients with pituitary-dependent Cushing's disease. A novel somatostatin (SS) analogue, named SOM230, with high binding affinity to SS receptor subtypes sst(1), sst(2), sst(3) and sst(5) was recently introduced. We compared the in vitro effects of the sst(2)-preferring SS analogue octreotide (OCT) and the multi-ligand SOM230 on ACTH release by human and mouse corticotroph tumour cells.. By quantitative RT-PCR the sst subtype expression level was determined in human corticotroph adenomas. In vitro, the inhibitory effect of OCT and SOM230 on ACTH release by dispersed human corticotroph adenoma cells and mouse AtT20 corticotroph adenoma cells was determined. In addition, the influence of dexamethasone on the responsiveness to OCT and SOM230 was studied.. Corticotroph adenomas expressed predominantly sst(5) mRNA (six out of six adenomas), whereas sst(2) mRNA expression was detected at significantly lower levels. In a 72 h incubation with 10 nmol/l SOM230, ACTH release was inhibited in three out of five cultures (range -30 to -40%). Ten nmol/l OCT slightly inhibited ACTH release in only one of five cultures (- 28%). In AtT20 cells, expressing sst(2), sst(3) and sst(5), SOM230 inhibited ACTH secretion with high potency (IC(50) 0.2 nmol/l). Dexamethasone (10 nmol/l) pre-treatment did not influence the sensitivity of the cells to the inhibitory effect of SOM230, suggesting that sst(5) is relatively resistant to negative control by glucocorticoids.. The selective expression of sst(5) receptors in corticotroph adenomas and the preferential inhibition of ACTH release by human corticotroph adenoma cells by SOM230 in vitro, suggest that SOM230 may have potential in the treatment of patients with pituitary-dependent Cushing's disease.

Topics: Adenoma; Adrenocorticotropic Hormone; Animals; Gene Expression; Glucocorticoids; Humans; Mice; Octreotide; Pituitary Neoplasms; Receptors, Somatostatin; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Somatostatin; Tumor Cells, Cultured

Ghrelin stimulates while somatostatin inhibits GH release and they thus serve as functional antagonists. We have compared their effects on cell proliferation. Ghrelin stimulates while somatostatin inhibits cell proliferation in most tissues and cell lines. Here we show that ghrelin and desoctanoyl ghrelin stimulate cell proliferation in rat pituitary cell line (GH3), and these effects could be inhibited with mitogen-activated protein kinase (MAPK), tyrosine kinase and protein kinase C inhibitors. Somatostatin and its analogs negatively regulate the growth of pituitary cells, and we now show that they inhibit MAPK activation. We hypothesised that one of the mechanisms involved in the somatostatin effect is a stimulation of cell cycle inhibitor p27, as pituitary adenomas have decreased p27 peptide content. Both octreotide and a new somatostatin analog SOM230 treatment resulted in an upregulation of p27 protein levels in human somatotrophinoma cells. In summary, we suggest that ghrelin and somatostatin have opposite effects on somatotroph cells not just at the level of GH release but also in terms of cell proliferation. Ghrelin may play a role in pituitary tumorigenesis via an autocrine/paracrine pathway. Our results also suggest that the antiproliferative effect of somatostatin analogs octreotide and SOM230 involve the up-regulation of p27 and down-regulation of the MAPK pathway in human somatotrophinomas.

Topics: Adenoma; Cell Division; Cell Line, Tumor; Cyclin-Dependent Kinase Inhibitor p27; Enzyme Activation; Ghrelin; Human Growth Hormone; Humans; Mitogen-Activated Protein Kinases; Octreotide; Peptide Hormones; Pituitary Neoplasms; Receptors, Somatostatin; Somatostatin

To determine the inhibitory profile of the novel somatostatin (SRIF) analog SOM230 with broad SRIF receptor binding, we compared the in vitro effects of SOM230, octreotide (OCT), and SRIF-14 on hormone release by cultures of different types of secreting pituitary adenomas. OCT (10 nM) significantly inhibited GH release in seven of nine GH-secreting pituitary adenoma cultures (range, -26 to -73%), SOM230 (10 nM) in eight of nine cultures (range, -22 to -68%), and SRIF-14 (10 nM) in six of six cultures (range, -30 to -75%). The sst analysis showed predominant but variable levels of somatostatin receptor (sst)(2) and sst(5) mRNA expression. In one culture completely resistant to OCT, SOM230 and SRIF-14 significantly inhibited GH release in a dose-dependent manner with an IC(50) value in the low nanomolar range. In the other cultures, SOM230 showed a lower potency of GH release inhibition (IC(50), 0.5 nM), compared with OCT (IC(50), 0.02 nM) and SRIF-14 (IC(50), 0.02 nM). A positive correlation was found between sst(2) but not sst(5) mRNA levels in the adenoma cells and the inhibitory potency of OCT on GH release in vivo and in vitro, and the effects of SOM230 and SRIF-14 in vitro. In three prolactinoma cultures, 10 nM OCT weakly inhibited prolactin (PRL) release in only one (-28%), whereas 10 nM SOM230 significantly inhibited PRL release in three of three cultures (-23, -51, and -64.0%). The inhibition of PRL release by SOM230 was related to the expression level of sst(5) but not sst(2) mRNA. Several conclusions were reached. First, SOM230 has a broad profile of inhibition of tumoral pituitary hormone release in the low nanomolar range, probably mediated via both sst(2) and sst(5) receptors. The higher number of responders of GH-secreting pituitary adenoma cultures to SOM230, compared with OCT, suggest that SOM230 has the potency to increase the number of acromegalic patients which can be biochemically controlled. Second, compared with OCT, SOM230 is more potent in inhibiting PRL release by mixed GH/PRL-secreting adenoma and prolactinoma cells.

Topics: Adenoma; Adult; Dose-Response Relationship, Drug; Female; Hormone Antagonists; Human Growth Hormone; Humans; Male; Middle Aged; Octreotide; Pituitary Neoplasms; Prolactin; Protein Isoforms; Receptors, Somatostatin; RNA, Messenger; Somatostatin; Tumor Cells, Cultured

Currently available somatostatin analogs predominantly bind to the somatostatin receptor subtype (SSTR)2 subtype, and control GH and IGF-I secretion in approximately 65% of patients with acromegaly, their efficacy relating to receptor density and subtype expression. SOM230 is a somatostatin ligand with high affinity to four SSTR subtypes. In primary cultures of rat pituicytes, SOM230 dose-dependently inhibited GH release (P = 0.002) with an IC50 of 1.2 nM. Ten nanomoles SOM230 inhibited GH and TSH release by 40 +/- 7% (P < 0.001) and 47 +/- 21% (P = 0.09), respectively. No effect of SOM230 was observed on prolactin (PRL) or LH release. In cultures of human fetal pituitary cells, SOM230 inhibited GH secretion by 42 +/- 9% (P = 0.002) but had no effect on TSH release. SOM230 inhibited GH release from GH-secreting adenoma cultures by 34 +/- 8% (P = 0.002), PRL by 35 +/- 4% from PRL-secreting adenomas (P = 0.01), and alpha-subunit secretion from nonfunctioning pituitary adenomas by 46 +/- 18% (P = 0.34). In contrast, octreotide inhibited GH, PRL, and alpha-subunit from the respective adenoma by 18 +/- 12 (P = 0.39), 22 +/- 4 (P = 0.04), and 20 +/- 10% (P = 0.34). In all culture systems, no significant difference in the inhibitory action of SOM230, octreotide, and somatostatin 14 on hormone release was observed. SOM230, similar to somatostatin, has high-affinity binding to SSTR1, 2, 3, and 5 and, in keeping with this, has an equivalent inhibitory effect on pituitary hormone secretion. As a consequence of its broader binding profile, SOM230 is likely to find clinical utility in treating tumors resistant to SSTR-2-preferential analogs.

Topics: Adenoma; Animals; Antineoplastic Agents, Hormonal; Fetus; Human Growth Hormone; Humans; Male; Octreotide; Pituitary Gland, Anterior; Pituitary Neoplasms; Rats; Rats, Sprague-Dawley; Receptors, Somatostatin; Somatostatin; Tumor Cells, Cultured