quinagolide and Acromegaly

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

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

The growth hormone (GH) inhibitory effect of CV 205-502 was evaluated during acute and 3-month administration, alone or in combination with octreotide, in 12 therapy-resistant acromegalic patients. Although these patients previously had undergone surgery and received chronic therapy with octreotide at 0.3-0.6 mg/day, they still had high GH and insulin-like growth factor I (IGF-I) levels. CV 205-502 (0.15 mg), octreotide (0.1 mg) and placebo were tested acutely. CV 205-502 at the dose of 0.15 mg caused a decrease of GH level (from 34.9 +/- 15.1 to 2.7 +/- 0.3 micrograms/l) in 4/12 (33.3%) and completely inhibited prolactin (PRL) secretion in all the patients. Octreotide caused a decrease of GH level (from 37 +/- 6.7 to 15.9 +/- 3.0 micrograms/l) without any change of PRL level. The GH and PRL levels were not changed during placebo administration. CV 205-502 at the dose of 0.3 mg/day (chronic test) normalized GH and IGF-I levels in five patients (41.6%: the four responders to the acute test and an additional patient who was a poor responder to acute CV 205-502 administration). The remaining seven patients were subjected to CV 205-502 (0.6 mg/day) and octreotide (0.6 mg/day) in combination for 3 months. In 2/7 patients the combined therapy induced a greater inhibition of GH and IGF-I levels than did each drug when administered alone. The drug was well-tolerated by the 12 patients. In conclusion, CV 205-502 is able to normalize GH and IGF-I levels and to improve clinical symptoms in certain acromegalic patients resistant to other therapeutic approaches.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Acromegaly; Adult; Aminoquinolines; Dopamine Agonists; Female; Growth Hormone; Humans; Insulin-Like Growth Factor I; Male; Middle Aged; Prolactin

GH and PRL cosecretion frequently occurs in acromegaly and the sensitivity of both hormones to somatostatin analogs (SA) and dopamine agonists (DA) alone or in combination, is still debated. This study was designed to evaluate the in vivo and in vitro sensitivity to SA and/or DA and correlate the response in terms of hormone suppression to the results of in vivo somatostatin and dopamine receptor scintigraphy and to the immunohistochemical findings.. Scintigraphy using 111In-DTPA-D-Phe(1)-OCT (111In-OCT) and 123I-methoxybenzamide (123I-IBZM) was performed in four patients with acromegaly and high circulating GH, PRL and IGF-I levels. The results were correlated with the response to long-term treatment with octreotide (OCT), quinagolide (QN) and/or cabergoline (CAB), to the in vitro hormone suppression by OCT and DA in primary cultures from the pituitary tumors and to the immunohistochemical findings.. The first patient showed high tumour uptake of 111In-OCT and 123I-IBZM, the second high uptake of only 111In-OCT, while the third one showed faint tumour uptake of only 123I-IBZM, and the fourth a faint uptake of 111In-OCT. In the first and in the fourth patients OCT or CAB administered alone failed to normalize hormone levels while the combined treatment induced circulating GH, IGF-I and PRL normalization. In the second patient OCT administered alone normalized hormone levels while QN reduced PRL levels only. In the third patient both OCT and QN, alone or in combination, failed to normalize hormone levels. However, in this patient GH and PRL suppression was significantly greater after QN than OCT treatment. After medical therapy, all the patients were operated on. Immunohistochemistry showed diffuse GH and focal PRL staining in the first patient, while diffuse GH and PRL staining in the remaining three. In vitro, OCT significantly suppressed GH secretion in the four primary pituitary tumor cultures, while PRL secretion was significantly suppressed only in the second and the fourth cases. Dopamine agonists (DA) significantly suppressed PRL release in all the cultures, while GH secretion was significantly suppressed in three out of four.. These four acromegalics, presenting similar clinical findings and comparable peripheral hormone levels, showed different responsiveness to SA and DA. Moreover, during the in vitro study on primary tumor cell cultures, OCT and DA displayed an inhibiting activity on GH and PRL secretion positively correlated with the response observed in vivo. This evidence together with the in vivo receptor imaging study suggest the existence of somatostatin and/or dopamine D2 receptor heterogeneity in this class of pituitary tumors. The new potent DA might be primarily considered in the medical treatment of hyperprolactinemic acromegalics, while SA alone or in combination with DA in case of ineffective hormone suppression.

Topics: Acromegaly; Adrenocorticotropic Hormone; Adult; Aminoquinolines; Analysis of Variance; Antineoplastic Agents, Hormonal; Cabergoline; Dopamine Agonists; Ergolines; Female; Follicle Stimulating Hormone; Growth Hormone; Humans; Immunohistochemistry; Indium Radioisotopes; Insulin-Like Growth Factor I; Iodine Radioisotopes; Luteinizing Hormone; Male; Octreotide; Pituitary Neoplasms; Prolactin; Prolactinoma; Receptors, Dopamine; Receptors, Somatostatin; Thyrotropin; Tumor Cells, Cultured

The aim of this study was to evaluate the efficacy of a 6-month treatment with lanreotide (LAN) (60-90 mg/month) alone and combined with cabergoline (CAB) (1.5-3 mg/week) in 10 acromegalic patients previously demonstrated to be poor responders to octreotide (OCT) (0.6 mg/day) alone and combined with quinagolide (CV) (0.6 mg/day). All patients had previously undergone unsuccessful surgery and none of them received radiotherapy. Immunohistochemistry showed intense positive GH staining in all adenomas, positive PRL staining in 5 adenomas and faint ACTH or FSH/LH positive staining in other 2 adenomas. Moderately elevated serum PRL levels (35 and 47 ng/ml) were recorded in two patients. Fasting plasma IGF-I and serum GH levels were assayed at baseline and 30, 60, 90 and 120 days after each treatment. Gallbladder ultrasonography and sellar MRI were performed before and after 6 months of OCT and LAN treatments. After OCT treatment circulating GH and IGF-I levels remained elevated in all patients, while after 3 months of combined OCT + CV treatment, serum GH levels were suppressed (below 2.5 ng/ml) in only 1 patient. Significant increase of the percent GH (83.9 +/- 4.3 vs. 70.3 +/- 5.6%, p < 0.01) and IGF-I suppression (54 +/- 4.4 vs. 45.3 +/- 5.7, p < 0.01) and decrease of the nadir of GH (8.5 +/- 1.2 vs. 14.6 +/- 1.9 ng/ml, p < 0.01) and IGF-I (400.9 +/- 32.8 vs. 462.1 +/- 45.1 ng/ml) were obtained with the combined treatment when compared to OCT treatment alone. After a 15-30 days wash-out, circulating GH and IGF-I levels significantly increased up to pretreatment level in all patients. After 6 months of treatment with LAN, suppression of serum GH was achieved in 1 patient, but no difference in GH (66.3 +/- 6.3%) and IGF-I (43.9 +/- 4.6%) suppression was recorded in comparison to OCT treatment. After 3 months of treatment with LAN combined with CAB, suppression of serum GH and normalization of plasma IGF-I levels was achieved in 4 and 5 patients, respectively. Percent suppression of GH (88.1 +/- 2.1%) and IGF-I (57.5 +/- 2.8%) was significantly greater with the combined treatment than with LAN treatment alone. In the 7 patients with evident residual mass no change was documented by magnetic resonance imaging (MRI). None of the patients withdrew LAN + CAB treatment for poor tolerance, one patient had mild hypotension. Sludge was shown after 6 months of LAN treatment in one patient without notable change after 3 months of LAN + CAB treatment. In conclusion, the

Topics: Acromegaly; Adult; Aminoquinolines; Cabergoline; Dopamine Agonists; Drug Synergism; Drug Therapy, Combination; Ergolines; Female; Hormones; Human Growth Hormone; Humans; Insulin-Like Growth Factor I; Male; Middle Aged; Octreotide; Peptides, Cyclic; Somatostatin; Time Factors

Medical treatment of acromegaly with dopamine agonists possesses 2 main advantages: the oral administration and the low costs. In this study, we reported on the results of chronic treatments with quinagolide (CV 205-502), cabergoline (CAB) and long-acting depot preparation of bromocriptine (BRC-LAR) in 34 acromegalics. Patients were divided into three groups on the basis of different treatment: CV 205-502 given to 16 patients at the dose of 0.3-0.6 mg/day for 6 months; CAB given to 11 patients at the dose of 1.0-2.0 mg weekly for 6 months; and BRC-LAR injected into 7 patients at the dose of 100 mg/month for 6-12 months. Basal and oral glucose tolerance test-stimulated serum GH levels, basal and TRH-stimulated PRL levels, plasma insulin-like growth factor I (IGF-I) levels, computed tomography scan, and/or magnetic resonance imaging were assessed before and quarterly during treatments. The chronic administration of CV 205-502, CAB, and BRC-LAR caused a significant decrease of circulating GH, IGF-I, and PRL levels (P < 0.005). Normalization of circulating GH and IGF-I levels was obtained in 7 of 16 (43.8%) patients treated with CV 205-502. Serum GH response to oral glucose tolerance test (oGTT) significantly improved (P < 0.005), and PRL levels were significantly suppressed during treatments. No correlation was found between basal and TRH-stimulated PRL levels and GH suppression during different therapies. Immunohistochemical staining revealed 19 GH-positive and 10 GH + PRL-positive adenomas. A significant association was found between GH/PRL staining and responsiveness to chronic treatments (chi 2 = 7.985, P < 0.005). Three patients had significant adenoma shrinkage. Slight nausea and hypotension which spontaneously disappeared within therapy progression, were referred by 5/16 patients during CV 205-502 and 2/7 during BRC-LAR. The results of this study indicate that CAB and BRC-LAR cannot be considered as useful medical approaches for acromegalics, whereas CV 205-502 normalized circulating GH and IGF-I levels in 47.8% of patients.

Topics: Acromegaly; Adult; Aminoquinolines; Bromocriptine; Cabergoline; Delayed-Action Preparations; Dopamine Agonists; Ergolines; Female; Human Growth Hormone; Humans; Male; Middle Aged; Prolactin

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

Topics: Acromegaly; Aminoquinolines; Dopamine Agonists; Humans

It was the aim of this study to test for a possible effect of the new non ergot dopamine agonist CV 205-502 on plasma growth hormone (GH) concentrations in acromegaly. 10 acromegalic patients received a single oral dose of 150 micrograms CV 205-502 after an overnight fast. As a control group 7 acromegalic patients undertook the same procedure without receiving any drug. Blood samples were drawn hourly up to 7 hours thereafter for determination of GH. Plasma growth hormone concentrations decreased by 48.8 +/- 8.7%. The nadir was observed 3 hours after CV 205-502 was administered and GH concentrations remained suppressed throughout the 7 hours of the test period. In contrast GH plasma concentrations in the control group remained stable. We conclude that acute administration of CV 205-502 suppresses GH secretion in acromegalic patients and thus could serve as an alternative therapy in acromegaly.

Topics: Acromegaly; Adult; Aminoquinolines; Dopamine Agents; Female; Growth Hormone; Humans; Kinetics; Male; Middle Aged

In a series of acromegalic patients the effects of CV 205-502, a new long-acting dopamine-agonist drug, on growth hormone (GH), insulin-like growth factor I (IGF-I) and prolactin (PRL) levels were evaluated in an open study. After acute administration of CV 205-502 (0.0375 mg, po) in 12 patients. GH levels did not change, whereas PRL values significantly decreased and remained suppressed for 24 h. In the 14 patients who underwent chronic CV 205-502 treatment (at daily doses of 0.150-0.600 mg/day given at bedtime or b.i.d. for up to 12 months). GH and IGF-I levels fell significantly from 60 +/- 17 (mean +/- SEM) micrograms/l to 28 +/- 10 micrograms/l and from 1127 +/- 84 micrograms/l to 738 +/- 57 micrograms/l, respectively (p < 0.05). A retrospective comparison with the results obtained for the same patients during a previous chronic bromocriptine treatment (at daily doses of 5-20 mg given t.i.d. or q.i.d.) did not show any significant difference in the suppression of GH levels between the two treatments; no bromocriptine-resistant patient was CV 205-502 sensitive, even at the highest CV 205-502 dose used. We conclude that in acromegaly chronic treatment with this new dopaminergic drug has a GH- and PRL-lowering effect that is similar to but more prolonged than that of bromocriptine, and normal or near-normal GH and IGF-I levels may be obtained in a few patients with b.i.d. administration. However, no GH-lowering effect is observed in bromocriptine-resistant patients.

Topics: Acromegaly; Adult; Aminoquinolines; Bromocriptine; Dopamine Agents; Female; Growth Hormone; Humans; Insulin-Like Growth Factor I; Male; Middle Aged; Pituitary Gland; Prolactin; Time Factors