quinagolide and Adenoma

Pituitary neuroendocrine tumors (PitNET) are commonly benign tumors accounting for 10-25% of intracranial tumors. Prolactin-secreting adenomas represent the most predominant type of all PitNET and for this subtype of tumors, the medical therapy relies on the use of dopamine agonists (DAs). DAs yield an excellent therapeutic response in reducing tumor size and hormonal secretion targeting the dopamine receptor type 2 (D2DR) whose higher expression in prolactin-secreting adenomas compared to other PitNET is now well established. Moreover, although DAs therapy does not represent the first-line therapy for other PitNET, off-label use of DAs is considered in PitNET expressing D2DR. Nevertheless, DAs primary or secondary resistance, occurring in a subset of patients, may involve several molecular mechanisms, presently not fully elucidated. Dopamine receptors (DRs) expression is a prerequisite for a proper DA function in PitNET and several molecular events may negatively modify DR membrane expression, through the DRs down-regulation and intracellular trafficking, and DR signal transduction pathway. The current mini-review will summarise the presently known molecular events that underpin the unsuccessful therapy with DAs.

Topics: ACTH-Secreting Pituitary Adenoma; Adenoma; Aminoquinolines; beta-Arrestins; Bromocriptine; Cabergoline; Dopamine Agonists; Drug Resistance, Neoplasm; Filamins; Growth Hormone-Secreting Pituitary Adenoma; Humans; Lisuride; MicroRNAs; Pergolide; Pituitary Neoplasms; Prolactinoma; Receptors, Dopamine D2

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 In case of tumors with good therapeutic response, medical therapy can be withdrawn after 3-5 years; hyperprolactinemia will not recur in 2/3 of these patients.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

The primary aim of therapy should be to remove symptoms, reduce tumor bulk, prevent relapse, and improve long-term outcome. Surgery, radiotherapy and medical therapies are used to achieve these aims. Post-treatment mean "safe" serum growth hormone values of < 2.5 ng/ml should be the therapeutic goal. Transsphenoidal surgery remains the first line treatment for acromegaly. Patients with microadenoma can expect 85%, while those with macroadenoma 50% chance to achieve safe serum growth hormone levels. Less than 20% of acromegalics respond to treatment with bromocriptine, while quinagolide and cabergoline may show better clinical response; the success rate is higher for tumors secreting both growth hormone and prolactin. Dopamine agonists may be considered either in combination with somatostatin-analogues or as monotherapy in selected patients, and in those with co-secretion of prolactin. Octreotide (Sandostatin, Novartis) is a synthetic somatostatin-analogue, which is administered subcutaneously in doses between 100 and 250 micrograms 3 times daily. Long-acting octreotide (Sandostatin LAR, Novartis) contains octreotide incorporated into microspheres of biodegradable polymer. To effectively lower serum growth hormone levels, monthly injections of 10-30 mg of long-acting octreotide are needed, serum growth hormone falls to 2.5 ng/ml in 70% of cases, and serum insulin-like growth factor I normalizes in 67%. Slow release lanreotide (Somatuline SR, Ipsen) is an alternative depot long-acting somatostatin-analogue, which is administered in a dose of 30 mg intramuscularly every 14, 10 or 7 days. Both compounds are equally, if not more, effective than subcutaneous octreotide, and significantly improve patient compliance. Pegvisomant (Sensus Drug Development Corporation) is a genetically engineered growth hormone receptor antagonist, which inhibits growth hormone action. When given subcutaneously in a dose of 20 mg/day, serum insulin-like growth factor I levels return to normal in 90% of patients. Theoretical concerns of tumor expansion have not been a problem to date, but long term studies are needed. Primary medical--somatostatin-analogue--therapy is recommended if surgery fails, if the patient refuses or unsuited for surgery and it may be also considered in patients with macroadenoma with extra--but not suprasellar extension, since the surgical "cure" rates of these tumors are low.

Topics: Acromegaly; Adenoma; Aminoquinolines; Antineoplastic Agents, Hormonal; Cabergoline; Dopamine Agonists; Drug Administration Schedule; Ergolines; Hormones; Human Growth Hormone; Humans; Octreotide; Peptides, Cyclic; Pituitary Neoplasms; Prolactin; Receptors, Somatotropin; Somatostatin

Dopamine agonists are indicated as primary therapy for PRL-secreting pituitary adenomas, while controversial results have been reported in nonfunctioning adenomas (NFA).. To evaluate whether the in vivo visualization of dopamine D2 receptor expression detected by pituitary scintigraphy using 123I-methoxybenzamide (123I-IBZM) was correlated with the response to chronic treatment with quinagolide or cabergoline.. 10 patients affected with NFA (5 men and 5 women, age ranging between 25 and 50 years), and 10 with PRL-secreting naive macroadenomas (3 men and 7 women, age ranging between 22 and 59 years), serving as control.. All patients underwent an acute test with quinagolide: at 3-day intervals and in random order all patients received the drug (0.075 mg at 0800 h), or placebo. Blood samples were taken 15 and 5 minutes before and every 30 minutes for 6 h after drug or placebo administration. The test was considered positive when PRL and/or alpha-subunit levels decreased >/=50% as compared to baseline levels. After 6 months of treatment, 10 patients were randomised to continue the treatment with quinagolide and the remaining 10 received cabergoline for the remaining 6 months. The doses of quinagolide and cabergoline ranged from 0.075 to 0.6 mg/day and from 0.5 to 3 mg/week, respectively. At study entry, a magnetic resonance imaging (MR) study of the pituitary region and 123I-IBZM pituitary scintigraphy were performed. MR was repeated after 12 months of treatment to evaluate tumour shrinkage: reduction of tumour volume = 80% in prolactinomas and = 50% in NFA was considered significant. Basal PRL levels were 9495.0 +/- 1131.6 mU/l in prolactinomas and 602.4 +/- 50.5 mU/l in NFA.. The scintigraphy was negative in 6 out of 10 patients with NFA. Moderate uptake was observed in 3 patients with prolactinoma and 2 patients with NFA whereas intense uptake was observed in the remaining 7 patients with prolactinoma and 2 patients with NFA. Among the 8 patients with NFA and high circulating alpha-subunit levels, the acute test was negative in 5 while it was positive in the remaining 3 patients. The acute test was positive in all 10 patients with prolactinoma. After 12 months of treatment with quinagolide and cabergoline, circulating PRL levels were decreased in all 10 patients with prolactinoma (571.8 +/- 255.9 mU/l), being normalized in 7 patients. Suppression of PRL levels was found in all 10 patients with NFA (89.5 +/- 2.3 mU/l). A significant reduction of alpha-subunit levels was obtained in 9 out of 10 patients with NFA: in 4 out of 8 patients alpha-subunit levels were normalized. Significant adenoma shrinkage was recorded in 4 patients with prolactinoma among the 7 with intense pituitary uptake of 123I-IBZM. Significant adenoma shrinkage was recorded only in the 2 out of 10 patients with NFA with intense pituitary uptake of 123I-IBZM. A significant positive correlation was found between the degree of uptake (considered as score) and the response to quinagolide or cabergoline treatment (considered as percent hormone suppression) either in patients affected with PRL-secreting adenoma (r = 0.856, P < 0.005) or in those affected with NFA (r = 0.787, P < 0.05).. An intense 123I-IBZM uptake in patients with non-functioning adenomas was predictive of a good response to a chronic treatment with quinagolide and cabergoline. This result suggests that a pituitary 123I-IBZM scintigraphy could be considered in selected patients with non-functioning adenomas before starting medical treatment with dopamine agonists.

Topics: Adenoma; Adult; Aminoquinolines; Benzamides; Cabergoline; Dopamine Agonists; Ergolines; Female; Humans; Iodine Radioisotopes; Magnetic Resonance Imaging; Male; Middle Aged; Patient Selection; Pituitary Neoplasms; Predictive Value of Tests; Prolactin; Prolactinoma; Radionuclide Imaging

The efficacy of dopaminergic agents in the medical treatment of pituitary adenomas is well known. Quinagolide is a nonergot derivative dopamine agonist, which binds dopamine D2 receptors with high affinity. The treatment with this drug is reported to suppress hormone levels and to cause tumor shrinkage in prolactinomas and in a few GH-secreting pituitary adenomas. In clinically nonfunctioning pituitary adenomas (NFPA), the efficacy of quinagolide treatment is controversial. The scintigraphy of the pituitary region using 123I-methoxybenzamide (123I-IBZM) allows us to visualize in vivo the expression of dopamine D2 receptors on pituitary tumors. In this study, the pituitary scintigraphy with 123I-IBZM was performed in 14 patients with macroadenoma before starting a long-term treatment with quinagolide: 6 NFPA with high circulating alpha-subunit levels, 4 PRL-secreting, and 4 GH-secreting adenomas. A 3-point score was used to grade the ligand accumulation within the pituitary adenomas: 0 = negative, 1 = moderate uptake (equal to that recorded in the cerebral cortex), and 2 = intense uptake (equal to that recorded in the basal nuclei). The treatment with quinagolide was carried out at the dose of 0.3-0.6 mg/day for 6-12 months. Clinical, biochemical and hormonal assessment was repeated monthly during the first 3 months, then quarterly. Sellar magnetic resonance imaging was performed before and after 6 and 12 months of quinagolide treatment, to evaluate tumor shrinkage (> 25% of baseline size). In all 14 patients, a significant positive correlation was found between the degree of 123I-IBZM uptake and the clinical response to quinagolide treatment (r = 0.90; P < 0.001). In particular, the normalization of serum alpha-subunit and PRL levels, respectively, was achieved in 3 patients with NFPA and in 2 patients with prolactinoma, who showed intense 123I-IBZM uptake in the pituitary region. In 4 of these 5 patients with positive scan, a significant tumor shrinkage occurred between 6 and 12 months after the beginning of quinagolide treatment. In all patients with GH-secreting adenoma, no significant uptake of 123I-IBZM was found and no significant decrease of circulating GH and/or insulin-like growth factor-I levels, and tumor shrinkage was obtained during long-term treatment with quinagolide. In conclusion, the pituitary scintigraphy with 123I-IBZM can be considered a useful tool to indicate adenomas with significant expression of functioning D2 receptors. This inn

Topics: Adenoma; Aminoquinolines; Benzamides; Biomarkers; Dopamine Agonists; Glycoprotein Hormones, alpha Subunit; Human Growth Hormone; Humans; Insulin-Like Growth Factor I; Iodine Radioisotopes; Magnetic Resonance Imaging; Pituitary Neoplasms; Prolactin; Pyrrolidines; Tomography, Emission-Computed, Single-Photon

Twenty-four pituitary adenomas from acromegalic patients (13 females, 11 males; age range 19-65 yr) were characterized for somatostatin receptor subtype 2A (sst(2A)), dopamine D(2) receptor (D(2)R), GH, and prolactin (PRL) expression by immunohistochemistry, and results correlated with the in vitro and in vivo hormone responses to octreotide and quinagolide. In nine cases, GH and PRL content was further studied by immunoelectron microscopy.. Immunoreactivity was semiquantitatively scored as 2 (>50% stained cells), 1 (10-50% stained cells), and 0 (<10% stained cells). Sst(2A) was scored as 2 in 13 cases, 1 in 10, and 0 in one; D(2)R was scored as 2 in 13 cases, 1 in nine, and 0 in 2; GH was 2 in 15 cases and 1 in nine; PRL was 2 in six cases, 1 in 13, and 0 in 5. Sst(2A) was positively correlated with in vitro (P = 0.003) and in vivo (P = 0.006) percent GH suppression by octreotide and with the chronic suppression of IGF-I by somatostatin analogs (P =0.008). D(2)R was positively correlated with in vitro percent GH (P =0.000) and PRL (P =0.005) suppression by quinagolide. Electron microscopy revealed two pure somatotroph adenomas, five somatomammotrophs with a variable coexpression of GH and PRL in the same cells, and two tumors consisting of mixed cell types, which were less sensitive to quinagolide and octreotide.. Sst(2A) and D(2)R are frequently coexpressed in adenomas from acromegalic patients, and immunohistochemistry may be helpful in characterizing receptor expression in pituitary adenomas to select patients responsive to different treatments.

Topics: Adenoma; Adult; Aminoquinolines; Dopamine Agonists; Female; Growth Hormone-Secreting Pituitary Adenoma; Human Growth Hormone; Humans; Immunohistochemistry; Male; Microscopy, Electron; Middle Aged; Octreotide; Prolactin; Receptors, Dopamine D2; Receptors, Somatostatin

Clinically non-functioning pituitary adenomas (NFPAs) can express functional dopamine D2 receptors. Therapy with dopamine (DA) agonists may result in a NFPA size reduction. However, DA agonist-sensitive and -resistant NFPAs are clinically indistinguishable. We have studied the correlation between in vivo imaging of D2 receptors using (123)I-epidepride and the radiological response of NFPA to DA in 18 patients.. Patients were treated with either cabergoline (1-2 mg/week) or quinagolide (150-300 mug/day) for a mean period of 89.7 months (range, 34-187 months).. Pituitary uptake of (123)I-epidepride varied from slight uptake classified as grade 0 to very high classified as grade 3. Grade 0 uptake was found in four patients; grade 1 in three; grade 2 in ten, and grade 3 in one. NFPA stabilization or shrinkage with DA agonist therapy showed no significant difference between grade 0, 1, and 2 tumors (mean tumor stabilization or shrinkage: 31, 30, and 36% respectively). However, when we considered a decrease in tumor size ranging from 0 to 20% as tumor stabilization and >20% decrease in tumor size as true shrinkage, one out of four NFPAs with grade 1 uptake, two out of three with grade 1 uptake, and eight out of ten with grade 2 uptake showed tumor shrinkage.. In conclusion, there is limited clinical usefulness of dopamine D2 receptor imaging for predicting the clinical efficacy of DA agonist in selected patients with NFPAs. DA agonist therapy in NFPAs can result in tumor stabilization and shrinkage.

Topics: Adenoma; Adult; Aged; Aged, 80 and over; Aminoquinolines; Benzamides; Cabergoline; Dopamine Agonists; Ergolines; Female; Humans; Iodine Radioisotopes; Magnetic Resonance Imaging; Male; Middle Aged; Pituitary Neoplasms; Pyrrolidines; Receptors, Dopamine D2; Tomography, Emission-Computed, Single-Photon

The clinical characteristics of 84 patients with pituitary tumour who had troublesome headache were investigated. The patients presented with chronic (46%) and episodic (30%) migraine, short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT; 5%), cluster headache (4%), hemicrania continua (1%) and primary stabbing headache (27%). It was not possible to classify the headache according to International Headache Society diagnostic criteria in six cases (7%). Cavernous sinus invasion was present in the minority of presentations (21%), but was present in two of three patients with cluster headache. SUNCT-like headache was only seen in patients with acromegaly and prolactinoma. Hypophysectomy improved headache in 49% and exacerbated headache in 15% of cases. Somatostatin analogues improved acromegaly-associated headache in 64% of cases, although rebound headache was described in three patients. Dopamine agonists improved headache in 25% and exacerbated headache in 21% of cases. In certain cases, severe exacerbations in headache were observed with dopamine agonists. Headache appears to be a significant problem in pituitary disease and is associated with a range of headache phenotypes. The presenting phenotype is likely to be governed by a combination of factors, including tumour activity, relationship to the cavernous sinus and patient predisposition to headache. A proposed modification of the current classification of pituitary-associated headache is given.

Topics: Adenoma; Adult; Aminoquinolines; Antineoplastic Agents, Hormonal; Bromocriptine; Cabergoline; Disability Evaluation; Dopamine Agonists; Ergolines; Female; Headache; Humans; Male; Migraine Disorders; Octreotide; Peptides, Cyclic; Pituitary Neoplasms; Severity of Illness Index; Somatostatin; Time Factors

In acromegaly, the combination of somatostatin (SS) and dopamine (DA) agonists has been shown to enhance suppression of GH secretion. In the present study, a new chimeric molecule, BIM-23A387, which selectively binds to the SS subtype 2 receptor (sst(2); K(i) = 0.10 nM) and to the DA D2 receptor (D2DR; K(i) = 22.1 nM) was tested in cultures prepared from 11 human GH-secreting tumors for its ability to suppress GH and prolactin (PRL) secretion. The chimeric compound was compared with individual sst(2) and D2DR agonists of comparable activity at the individual receptors. All tumors expressed both sst(2) and D2DR mRNAs (0.8 +/- 0.2 and 4.7 +/- 0.7 copy/copy beta-glucuronidase mRNA, respectively). In cell cultures from seven octreotide-sensitive tumors, the maximal inhibition of GH release induced by the individual sst(2) and D2DR analogs and by BIM-23A387 was similar. However, the mean EC(50) for GH suppression by BIM-23A387 (0.2 pM) was 50 times lower than that of the individual sst(2) and D2DR analogs, either used individually or combined. Similar data were obtained in four tumors that were only partially responsive to octreotide. The inhibition of GH release by BIM-23A387 was only partially reversed by the D2R2 antagonist, sulpiride, or by the sst(2) antagonist, BIM-23454. Only when both antagonists were combined was the GH suppressive effect of BIM-23A387 totally reversed. Finally, BIM-23A387 produced a mean 73 +/- 6% inhibition of PRL in six mixed GH plus PRL tumors. These data demonstrate an enhanced potency of the chimeric molecule, BIM-23A387, in suppressing GH and PRL secretion from acromegalic tumors, which cannot be explained merely on the basis of binding affinity for SS and/or DA receptors.

Topics: Adenoma; Adult; Aminoquinolines; Cells, Cultured; Dopamine Agonists; Dopamine D2 Receptor Antagonists; Drug Synergism; Female; Hormones; Human Growth Hormone; Humans; Male; Octreotide; Peptides, Cyclic; Pituitary Neoplasms; Prolactin; Protein Isoforms; Receptors, Dopamine D2; Receptors, Somatostatin; RNA, Messenger; Somatostatin

To evaluate the volume of micro- and macroadenomas in quinagolide-treated patients with resistance to or intolerance of bromocriptine.. The effect of the prolactin inhibitor quinagolide on the volume of pituitary adenoma was evaluated retrospectively in 11 female patients. Prolactin levels before and after the treatment were also recorded. The indications for quinagolide therapy were side-effects of bromocriptine in 5 cases, a poor response to bromocriptine in 5 cases and both in 1 case. MR imaging with a 1.0-T magnet was performed to determine the volume reduction of the adenomas.. The average volume reduction of macroadenomas was 324 mm3 (46%) and that of microadenomas 73 mm3 (57%). The level of prolactin secreted by macroadenomas was reduced by an average of 163 microg/l (65%) and that by microadenomas of 113 microg (73%). In 2 microadenomas and in 1 macroadenoma, signal intensity changed during the treatment in T1-weighted images. In follow-up no changes in signal intensity were seen in 8 adenomas in non-contrast T1-weighted images. A haemorrhagic lesion was seen in 1 macroadenoma before treatment, but it disappeared during treatment.. Quinagolide was found to be an effective alternative to bromocriptine in cases with drug intolerance or resistance, and MR imaging a suitable method for the follow-up of macro- and microadenomas.

Topics: Adenoma; Adult; Aminoquinolines; Dopamine Agonists; Female; Humans; Magnetic Resonance Imaging; Pituitary Neoplasms; Retrospective Studies

This study was performed to evaluate the effect of prolonged treatment with the dopamine agonist quinagolide on serum gonadotropin and alpha-subunit concentrations and tumor volume in patients with clinically non-functioning pituitary adenomas (CNPA).. Ten patients with CNPA were treated with quinagolide (0.3 mg daily). The median duration of treatment was 57 months (range 36-93 months). Blood samples for measurement of serum gonadotropin and alpha-subunit concentrations were drawn before treatment, after 5 days, and at each outpatient visit. Computerized tomography or magnetic resonance imaging of the pituitary region and Goldmann perimetry were done before and at regular intervals during treatment.. A significant decrease of serum FSH, LH or alpha-subunit concentrations was found in nine patients. The levels remained low during the entire treatment period. In two out of three patients with pre-existing visual field defects a slight improvement was shown during the first months of treatment, but eventually deterioration occurred in all three patients. A fourth patient developed unilateral ophthalmoplegia during treatment. During the first year tumor volume decreased in three patients, but in two of them regrowth occurred after a few months. In six patients progressive tumor growth occurred despite sustained suppression of gonadotropin or alpha-subunit levels.. Long-term treatment of patients with CNPA with high doses of the dopamine agonist quinagolide could not prevent progressive increase in tumor size in most patients. It remains unproven whether quinagolide retards CNPA growth. Additional studies are needed to investigate whether subgroups of patients, e.g. those with positive dopamine receptor scintigraphy or those with marked hypersecretion of intact gonadotropins or subunits, will respond more favorably to treatment with dopamine agonists.

Topics: Adenoma; Aged; Aminoquinolines; Dopamine Agonists; Female; Follicle Stimulating Hormone; Gonadotropins; Humans; Luteinizing Hormone; Magnetic Resonance Imaging; Male; Middle Aged; Pituitary Neoplasms; Tomography, X-Ray Computed

The effects of somatostatin (SS-14 and/or SS-28) and of the three octapeptide SS-analogs that are available for clinical use (octreotide, BIM-23014 and RC-160) on hormone release by primary cultures of 15 clinically nonfunctioning pituitary adenomas (NFA), 7 prolactinomas, and 2 insulinomas were investigated. In the pituitary adenoma cultures, a comparison was made with the effects of the dopamine (DA) agonists bromocriptine and/or quinagolide. In 5 NFAs, 2 prolactinomas and 1 insulinoma somatostatin receptor (subtype) expression was determined by ligand binding studies and by in situ hybridization to detect sst1, sst2, and sst3 messenger RNAs (mRNAs). Four NFA cultures did not secrete detectable amounts of alpha-subunit, FSH, and/or LH. In the other cultures, hormone and/or subunit release was inhibited by DA-agonists (10 nM) in 9 of 11, by SS (10 nM) in 7 of 11, and by octapeptide SS-analogs (10 nM) in 3 of 10 cultures. In three NFA cultures, hormone release was sensitive to SS but not to SS-analogs. In all cultures, except for one, DA-agonists were the most effective in inhibiting hormone release. In the prolactinoma cultures, PRL release was inhibited by DA-agonists (10 nM) in 7 of 7, by SS in 4 of 4, and by octapeptide SS-analogs in 3 of 7 cultures. A dissociation between the effects of SS and SS-analogs was found in 3 cases. In the cultures sensitive to both bromocriptine and SS-28, bromocriptine was the most potent compound in 2 out of 4 cultures. In the 2 other cultures, both compounds were equally effective. In 2 insulinoma cultures, insulin release was inhibited by SS, and by octapeptide SS-analogs in only one. The presence or absence of an inhibitory effect by octreotide was in all cases in parallel with the presence or absence of the inhibitory effect by BIM-23014 and RC-160. Autoradiographic studies using [125I-Tyr0]SS28 showed specific binding in 4 of 5 NFAs, 1 of 2 prolactinomas, and 1 of 1 insulinoma. Specific [125I-Tyr3]octreotide binding was found in 2 of 5 NFAs, in 1 of 2 prolactinomas, and in the insulinoma. Two NFAs showed binding of SS28, but not of the sst2.5 specific ligand octreotide. The tumors showed variable sst1 and/or sst3 mRNA expression, whereas no sst2 expression was found. In conclusion, a dissociation between the inhibitory effects of SS on the one hand and of the octapeptide SS-analogs octreotide, BIM-23014 and RC-160 on the other hand, is observed in a small subgroup of NFAs, prolactinomas, and insulinomas, suggesting

Topics: Adenoma; Adenoma, Islet Cell; Aminoquinolines; Bromocriptine; Dopamine Agonists; Endocrine Gland Neoplasms; Hormone Antagonists; Hormones; Humans; Insulinoma; Pancreatic Neoplasms; Pituitary Neoplasms; Prolactinoma; Receptors, Somatostatin; Somatostatin; Tumor Cells, Cultured

Topics: Acromegaly; Adenoma; Aminoquinolines; Bromocriptine; Dopamine Agonists; Drug Therapy, Combination; Humans; Octreotide; Pituitary Neoplasms; Somatostatin

Knowledge of the dopamine D2 receptor status of pituitary tumours may play a predictive role in differential diagnosis and therapeutic decisions. This study was performed to evaluate the value of pituitary dopamine D2 receptor scintigraphy with (S)-2-hydroxy-3-123I-iodo-6-methoxy-N-[(1-ethyl-2-pyrrolidinyl) methyl]benzamide (123I-IBZM) in the diagnostic evaluation of patients with pituitary tumours.. Scintigraphy using 123I-IBZM was performed in 5 patients with PRL-secreting macroadenomas, 2 patients with PRL-secreting microadenomas, 17 patients with clinically non-functioning pituitary adenomas (NFPAs), 12 patients with GH-secreting adenomas and 1 patient with a TSH-secreting macroadenoma.. Single-photon emission tomography (SPECT) showed significant uptake of 123I-IBZM in the pituitary region in 3/5 macroprolactinoma patients. These results closely correlated with the response of plasma PRL levels to the dopamine D2 receptor agonist quinagolide. In two scan-positive prolactinoma patients, repeated SPECTs during therapy with quinagolide showed a reduction in the pituitary uptake of 123I-IBZM. Pituitary SPECT was negative in the 2 microprolactinoma patients, who responded to quinagolide administration. In 4/17 patients with NFPA, significant uptake of the radioligand in the pituitary region was observed. In 2/3 scan-positive NFPA patients, who were treated with quinagolide, shrinkage of the pituitary tumours was observed. Treatment with quinagolide resulted in stabilization of tumour growth in the other scan-positive patients. Four out of 17 patients with NFPA and a negative SPECT were treated with quinagolide. Tumour growth was observed in 1 patient, and tumour size did not change in the other 3 patients. The pituitary region of none of the 12 acromegaly patients showed significant uptake of 123I-IBZM. Sensitivity of the GH-secreting adenomas to quinagolide was demonstrated in 8/12 patients in vivo by an acute test, and in 6/9 of the tumours in vitro. Pituitary SPECT was negative in the patient with the TSH-secreting macroadenoma and this tumour also showed no sensitivity to quinagolide in vivo or in vitro.. We conclude that 123I-IBZM is a ligand for in vivo imaging of dopamine agonist- sensitive macroprolactinomas, but not for microprolactinomas or GH-secreting adenomas. The technique potentially provides a means of predicting the dopamine agonist-responses of non-functioning pituitary adenomas in vivo.

Topics: Adenoma; Adolescent; Adult; Aminoquinolines; Benzamides; Contrast Media; Dopamine Agonists; Dopamine Antagonists; Female; Growth Hormone; Humans; Male; Middle Aged; Pituitary Gland; Pituitary Neoplasms; Prolactin; Prolactinoma; Pyrrolidines; Receptors, Dopamine D2; Thyrotropin; Tomography, Emission-Computed, Single-Photon

A 14-year-old girl presented with a rapidly growing, invasive prolactin-producing pituitary tumor that failed to respond to dopamine agonist medication. Histological, immunocytochemical, and ultrastructural studies of the surgically removed tissue revealed a pleomorphic, chromophobic, or slightly acidophilic pituitary tumor that was immunoreactive for prolactin and that, according to electron microscopy, consisted of atypical lactotrophs showing no evidence of cell shrinkage. In situ hybridization demonstrated large amounts of prolactin messenger ribonucleic acid (mRNA), moderate amounts of estrogen receptor mRNA and dopamine (D2) receptor mRNA, and an absence of growth hormone mRNA in the tumor cells. Because D2 receptor mRNA was present in the tumor, causes other than D2 receptor loss may have been responsible for the resistance of the lactotrophs to dopamine agonist administration.

Topics: Adenoma; Adolescent; Aminoquinolines; Bromocriptine; Dopamine Agonists; Drug Resistance; Female; Humans; Microscopy, Electron; Pituitary Neoplasms; Prolactin; Receptors, Dopamine; Receptors, Dopamine D2; Receptors, Estrogen; RNA, Messenger

We aimed to assess the effects of prolonged treatment with the dopamine agonist CV 205-502 on tumour volume, visual field defects, and serum gonadotrophin and alpha-subunit concentrations in patients with gonadotroph, alpha-subunit secreting, or clinically non-functioning pituitary adenomas.. The patients were treated with CV 205-502 in a final daily dose of 300 micrograms for at least 1 year. The patients were seen at 2 or 3-week intervals during the first 3 months of treatment, and thereafter every 1 or 2 months. Computerized tomography and Goldmann perimetry were performed before treatment and during follow-up. Blood samples were drawn before treatment and at each out-patient visit.. One patient with gonadotroph, two with alpha-subunit secreting, and two with clinically non-functioning pituitary adenomas were studied.. Computerized tomography showed tumour shrinkage in one patient. In two other patients an improvement of visual field defects was observed. In four patients, a significant decrease in serum FSH and/or alpha-subunit concentrations occurred within the first 3 months of treatment. In the remaining patient, a significant decrease of serum FSH and alpha-subunit concentrations was found after more than 3 months of treatment.. In patients with clinically non-functioning, gonadotroph, or alpha-subunit secreting pituitary tumours, long-term treatment with the dopamine agonist CV 205-502 decreases serum FSH and/or alpha-subunit concentrations. This decreased secretory activity from the pituitary tumour may be accompanied by an improvement of visual field defects, or tumour shrinkage on computerized tomography. Therefore, treatment with CV 205-502 may be useful in patients with clinically non-functioning, gonadotroph, or alpha-subunit secreting pituitary tumours, who cannot be operated upon.

Topics: Adenoma; Aged; Aged, 80 and over; Aminoquinolines; Dopamine Agents; Female; Follicle Stimulating Hormone; Humans; Luteinizing Hormone; Male; Middle Aged; Pituitary Neoplasms; Tomography, X-Ray Computed; Visual Fields

Evaluation of the effects of an experimental long-acting non-ergot dopamine agonist, CV 205-502, on serum prolactin, tumor size, gonadal function, visual abnormalities, and tolerability in patients with macroprolactinomas.. Prospective, unblinded, dose escalation as needed.. Four university medical centers; patients referred for treatment.. Twenty-six hyperprolactinemic patients (prolactin greater than 150 micrograms/L) with a pituitary macroadenoma were treated for 24 weeks with CV 205-502 given once daily.. Serum prolactin was measured at regular intervals. Prolactin levels decreased in all patients during treatment (mean pretreatment level, 2051.7 +/- 1077 micrograms/L [+/- SE]; 24 weeks, 39.0 +/- 11.3 micrograms/L; P = 0.0001); normal prolactin levels were achieved in 15 (58%). Tumor size decreased in 21 of 26 patients and ranged from 6% to 67% (mean, 19.2% +/- 3.4%). Onset or return of regular menses occurred in 11 of 15 premenopausal women, accompanied by an increase in estradiol concentrations (pretreatment, 186.5 +/- 25.0 pmol/L; on treatment, 690.9 +/- 104.3 pmol/L; P = 0.0003). Serum testosterone increased in 6 of 8 men; sexual function improved in 5 of 7 with pretreatment abnormalities. Two patients with reversible visual abnormalities improved within 2 weeks of starting treatment. Side effects occurred in 11 patients and abated over 1 to 2 weeks or after the dose was reduced. There was no evidence of toxicity as indicated by serial serum chemistries, liver function tests, hematologic profiles, thyroxine levels, and electrocardiogram studies.. CV 205-502 reverses hyperprolactinemia and promotes reduction in tumor size with reversal of visual abnormalities and restoration of gonadal function in most patients. This compound will probably be useful in treating prolactinomas.

Topics: Adenoma; Adolescent; Adult; Aged; Aminoquinolines; Dopamine Agents; Erectile Dysfunction; Female; Humans; Libido; Magnetic Resonance Imaging; Male; Menstrual Cycle; Middle Aged; Pituitary Neoplasms; Prolactin

A 39-year-old woman with secondary amenorrhea and visual field defects underwent craniotomy for a large pituitary tumor that was hormonally silent according to measurement of plasma hormone levels and immunohistochemical analysis. During the preoperative investigation, bromocriptine was administered for 1 month, but there was no change in the tumor size as seen on computed tomographic scans. One month after surgery, visual field defects recurred, and a tumor mass comparable to the preoperative state was found on computed tomographic scan. The tumor size gradually diminished during treatment with CV 205-502, a tricyclic benzoquinoline which stimulates mainly D2 receptors and is better tolerated than bromocriptine. The visual fields were completely normalized after 3 months of treatment with the drug, and surgical management of the tumor mass was no longer considered to be necessary. Thus, as in many similar cases, the hormonally silent pituitary tumor in this patient proved unresponsive to bromocriptine treatment. In contrast, the tumor was reduced by therapy with CV 205-502, a drug that is better tolerated and might permit a more intense stimulation of D2 receptors.

Topics: Adenoma; Adult; Aminoquinolines; Female; Humans; Pituitary Neoplasms; Radiography; Receptors, Dopamine; Receptors, Dopamine D2