quinagolide and Pituitary-Neoplasms

Three dopamine agonists [bromocriptine, cabergoline, and quinagolide (CV)] have been used for hyperprolactinemia treatment for decades. Several studies have reviewed the efficacy and safety of bromocriptine and cabergoline. However, no systematic review or meta-analysis has discussed the efficacy and safety of CV in hyperprolactinemia and prolactinoma treatment.. Five medical databases (PubMed, Web of Science, Embase, Scopus, and Cochrane Library) were searched up to 9 May 2022 to identify studies related to CV and hyperprolactinemia. A meta-analysis was implemented by using a forest plot, funnel plot, sensitivity analysis, meta-regression, and Egger's test. A total of 1,211 studies were retrieved from the five medical databases, and 33 studies consisting of 827 patients were finally included in the analysis. The pooled proportions of patients with prolactin concentration normalization and tumor reduction (>50%) under CV treatment were 69% and 20%, respectively, with 95% confidence intervals of 61%-76% and 15%-28%, respectively. The pooled proportion of adverse effects was 13%, with a 95% confidence interval of 11%-16%.. Our study showed that CV is not less effective than cabergoline and bromocriptine in treating hyperprolactinemia, and the side effects were not significant. Hence, this drug could be considered an alternative first-line or rescue treatment in treating hyperprolactinemia in the future.. https://www.crd.york.ac.uk/PROSPERO, identifier CRD42022347750.

Topics: Aminoquinolines; Bromocriptine; Cabergoline; Drug-Related Side Effects and Adverse Reactions; Humans; Hyperprolactinemia; Pituitary Neoplasms

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

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

High prolactin levels can occur as a physiological condition in females who are pregnant or lactating. As a pathological condition, hyperprolactinaemia is associated with gonadal dysfunction, infertility and an increased risk of long-term complications including osteoporosis. The most frequent cause of persistent hyperprolactinaemia is the presence of a micro- (<10mm diameter) or macroprolactinoma (>/=10mm). These pituitary tumours may produce an excessive amount of prolactin or disrupt the normal delivery of dopamine from the hypothalamus to the pituitary; prolactin secretion from the pituitary is inhibited by dopamine released from neurones in the hypothalamus. Medications including anti-psychotics can induce hyperprolactinaemia, while idiopathic hyperprolactinaemia accounts for 30-40% of cases. The prevalence of hyperprolactinaemia is difficult to establish as not all sufferers are symptomatic or concerned by their symptoms and may remain undiagnosed. Symptoms of hyperprolactinaemia include signs of hypogonadism, with oligomenorrhoea, amenorrhoea and galactorrhoea frequently observed. Pharmacological intervention should be considered the first line therapy and involves the use of dopamine agonists to reduce tumour size and prolactin levels. Bromocriptine has the longest history of use and is a well-established, inexpensive, safe and effective therapy option. However, bromocriptine requires multiple daily dosing and some patients are resistant or intolerant to this therapy. The two newer dopamine agonists, quinagolide and cabergoline, provide more effective and better tolerated treatments compared with bromocriptine and may offer effective therapies for bromocriptine-resistant or intolerant patients. Quinagolide can be used until pregnancy is confirmed and may result in improved compliance in females wishing to become pregnant. For patients with hyperprolactinaemia, pregnancy is safe and can frequently be beneficial, inducing a decrease in prolactin levels. There does not appear to be any increased risk of abortion, malformations or multiple births in pregnancies achieved with bromocriptine and this dopamine agonist can be used safely during pregnancy. Surgery should be considered only in certain circumstances, and for the majority of patients, dopamine agonists will be sufficient to alleviate symptoms and restore normal prolactin levels.

Topics: Aminoquinolines; Bromocriptine; Cabergoline; Dopamine Agonists; Ergolines; Female; Humans; Hyperprolactinemia; Male; Pituitary Neoplasms; Pregnancy; Prolactinoma

Prolactinomas are the most frequent pituitary tumors. Treatment of infertility in such tumors usually is very successful. On the other hand, reports of pituitary tumor growth during pregnancy have been described since bromocriptine started to be used. Since then, dopamine agonists (DA) have been increasingly used as the first-choice treatment of prolactinomas, with surgery being reserved for resistance or persistent intolerance to DA or for special situations. More recently other DA, such as quinagolide and cabergoline have shown better tolerance than bromocriptine with similar or greater efficacy. Cabergoline is now the first choice drug but its use in pregnancy is still under evaluation. We followed 71 term pregnancies in women bearing microprolactinomas. Of the 22 patients with previous surgery, none presented symptoms of tumor growth. Of the 41 pregnant patients treated with bromocriptine alone, only one (2.4%) presented with headaches, which regressed with drug reintroduction. Fifty one term pregnancies in patients with macroprolactinomas were followed by us. Of those, 21 were in patients with previous surgery and none of them presented clinical evidence of tumor growth. On the other hand, of the 30 patients treated only with pre-gestational bromocriptine, 11 (37%) manifested complaints related to tumor growth. A non-hormonal contraceptive should be the use along with a DA drug until tumor shrinkage within sellar boundaries has been evidenced. After pregnancy has been confirmed, the DA can be withdrawn and the patient must be closely followed. If tumor expansion is suspected, confirmation can be made through MRI and by visual field testing. Reintroduction of bromocriptine in such cases can lead to tumor reduction and clinical improvement. Surgery can also be employed as treatment for symptomatic tumor growth in pregnancy.

Topics: Aminoquinolines; Bromocriptine; Cabergoline; Child; Dopamine Agonists; Ergolines; Female; Humans; Magnetic Resonance Imaging; Pituitary Neoplasms; Pregnancy; Pregnancy Complications, Neoplastic; Prolactinoma

Topics: Aminoquinolines; Bromocriptine; Cabergoline; Dopamine Agonists; Ergolines; Female; Humans; Pituitary Neoplasms; Pregnancy; Pregnancy Complications, Neoplastic; Prolactinoma

Prolactinomas are the most common hormone-secreting pituitary tumours and cause infertility and gonadal and sexual dysfunction in both sexes. The approach to prolactinomas has changed in the last 25 years thanks to the availability of dopaminergic drugs characterised by a potent prolactin-inhibitory effect, a tumour shrinking effect associated with a satisfactory tolerability. In more recent years, cabergoline 1-[(6-allelylergolin-8beta-yl)carbonyl]-1-[3-(dimethylamino) propyl]-3-ethyl-urea an ergoline derivative with potent, selective and long-lasting inhibitory activity on prolactin release, has been used to suppress prolactin secretion in women with hyperprolactinaemia. Cabergoline was shown to be significantly more effective than bromocriptine in inducing a complete biochemical response and clinical efficacy and was better tolerated than bromocriptine in the majority of patients. Notable tumour shrinkage until tumour disappearance was observed during cabergoline treatment in most patients with macroprolactinoma and it was also proven effective in patients resistant to or with a poor response to bromocriptine. In view of the limited data on cabergoline-associated pregnancies and the long half-life of the drug, it is currently recommended that women hoping to become pregnant, once ovulatory cycles have been established, should discontinue cabergoline therapy 1 month before they intend to conceive. However, no data concerning negative effects on pregnancy or offspring have been reported. The great efficacy of this compound together with its excellent tolerability makes this drug the current treatment of choice for the majority of patients with hyperprolactinaemic disorders.

Topics: Aminoquinolines; Animals; Bromocriptine; Cabergoline; Dopamine Agonists; Drug Resistance, Neoplasm; Ergolines; Ergot Alkaloids; Female; Humans; Pergolide; Pituitary Neoplasms; Pregnancy; Prolactin; Prolactinoma

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

Quinagolide is a non-ergot dopaminergic agonist recently available on the French market. The endocrine and tumoral efficacy as well as the safety and tolerability of quinagolide in the treatment of macroprolactinomas are reviewed. In this situation, plasma prolactin levels are normalized in about 60% of patients and in about one third of those who are resistant to bromocriptine. A significant decrease in pituitary tumor size is demonstrated by radiographic studies in 58 to 69% of patients. About one third of patients show more than 50% tumor shrinkage. The tolerability of quinagolide is satisfactory in most cases and clearly better than that of bromocriptine. Thus, quinagolide is a useful tool in the treatment of macroprolactinomas.

Topics: Aminoquinolines; Antineoplastic Agents; Dopamine Agonists; Drug Tolerance; Female; Humans; Male; Pituitary Neoplasms; Prolactinoma

Topics: Aminoquinolines; Bromocriptine; Dopamine Agonists; Drug Resistance, Neoplasm; Female; Humans; Pituitary Neoplasms; Pregnancy; Pregnancy Complications, Neoplastic; Prolactinoma

Hyperprolactinemic syndromes are a diverse group of disorders that present in widely different age groups. They are common disorders in both men and women and require management over a lifetime. The past 20 years have greatly increased our knowledge about these disorders and simplified their management. Yet, we have made little progress in understanding the origin and dynamics of pituitary tumors and their natural histories, and as yet we have been unable to develop effective tumoricidal therapy or medication that corrects, at the central axis level, neurotransmitter disorders that may produce hyperprolactinemia. Perhaps these issues will be the subject of such reviews in the future.

Topics: Aminoquinolines; Animals; Bromocriptine; Dopamine Agents; Female; Humans; Hyperprolactinemia; Infertility; Ovary; Pituitary Gland; Pituitary Neoplasms; Prolactin; Prolactinoma

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

To compare effectiveness and tolerability of quinagolide (CV 205-502) and cabergoline (CAB) treatments in 39 patients with prolactinoma.. All 39 patients were treated first with quinagolide for 12 months and then with cabergoline for 12 months. A wash-out period was performed in all patients after 12 months of both treatments in order to evaluate recurrence of hyperprolactinaemia.. Twenty-three patients with microprolactinoma (basal serum PRL levels 1620-18750 mU/l) and 16 patients with macroprolactinoma (basal serum PRL levels 4110-111000 mU/l), previously shown to be intolerant of bromocriptine. All patients had gonadal failure and 11 patients with macroprolactinoma had visual field defects. Five patients with macro- and one with microprolactinoma had previously undergone surgery.. The starting doses of quinagolide and CAB were 0.075 mg/day and 0.5 mg/week, respectively, subsequently increased up to 0.6 mg once daily and 1.5 mg twice weekly, respectively. Serum PRL levels were measured monthly for the first 3 months and then quarterly for 12 months. PRL levels were assayed weekly for the first month and then monthly during the wash-out period. Tumour shrinkage was evaluated by serial magnetic resonance imaging (MRI) studies of the hypothalamus-pituitary region at study entry and after 6 and 12 months of both treatments in micro- and macroprolactinomas.. After 12 months of quinagolide treatment, serum PRL levels normalized in all 23 patients with microprolactinoma (100%) and in 14 out of 16 with macroprolactinoma (87.5%). A tumour volume reduction of greater than 80% was documented by MRI studies in five of 23 (21.7%) patients with microprolactinoma and in four of 16 (25%) with macroprolactinoma. All patients had recurrence of hyperprolactinaemia after 15-60 days withdrawal of quinagolide treatment. However, before starting CAB treatment basal PRL levels were significantly lower than before quinagolide treatment both in microprolactinomas (4667.4 +/- 714.7 vs. 2636.1 +/- 262.3 mU/l, P = 0.006) and in macroprolactinomas (24853.1 +/- 7566.7 vs. 3576.6 +/- 413.0 mU/l, P = 0.013). After 12 months of CAB treatment, serum PRL levels normalized in 22 out of 23 patients with microprolactinoma (95.6%) and in 14 out of 16 with macroprolactinoma (87.5%). No difference in PRL nadir was found after quinagolide and CAB treatments both in micro 174.6 +/- 30.6 vs. 169.8 +/- 37.9 mU/l, P = 0.5) and in macroprolactinomas (277.5 +/- 68.4 vs. 341.8 +/- 95.2 mU/l, P = 0.6). A tumour volume reduction of greater than 80% was documented by MRI studies in seven other patients with microprolactinoma (30.4%) and in five other patients with macroprolactinoma (31.2%). After CAB treatment, further tumour shrinkage ranging 4-40% and 2-70% was observed in 12 micro- and seven macroprolactinomas, respectively. The percentage of tumour shrinkage after CAB was significantly higher than that observed after quinagolide in microprolactinomas (48.6 +/- 9.5 vs. 26.7 +/- 4. 5%, P = 0.046) but not in macroprolactinomas (47.0 +/- 10.6 vs. 26.8 +/- 8.4%, P = 0.2). The withdrawal from CAB treatment, induced an increase in serum PRL levels in all macroprolactinomas between 15 and 30 days, in 15 out of 23 microprolactinoma after 30 days, and in four patients after 2-4 months. In the remaining four patients serum PRL levels remained normal after 12 months of CAB withdrawal. Both compounds were tolerated satisfactorily by all patients. In the first week of quinagolide treatment, 12 patients reported nausea and postural hypotension, which spontaneously disappeared during the second-third week of treatment. None of the 39 patients reported side-effects during CAB treatment.. Both quinagolide and CAB treatments, induced the normalization of serum PRL levels in the great majority of patients with prolactinoma. Tumour shrinkage was recorded in 22-25% of patients after quinagolide and in 30-31% after CAB treatment

Topics: Adult; Aminoquinolines; Cabergoline; Cross-Over Studies; Dopamine Agonists; Ergolines; Female; Humans; Magnetic Resonance Imaging; Male; Middle Aged; Pituitary Neoplasms; Prolactin; Prolactinoma; Receptors, Dopamine D2; Treatment Outcome

This study reports a six year experience with quinagolide (CV205-502) in the treatment of 40 patients with hyperprolactinemia or prolactinoma.. Forty patients with hyperprolactinemia were treated with quinagolide (CV 205-502, Norprolac) for 2-72 months (mean 31.6 months). The patient's ages ranged from 12 to 53 years and 90% were female. Seventeen had no radiologic evidence of tumor; 11 had microadenomas; and 12 had macroadenomas.. All patients had a reduction of the serum prolactin following quinagolide therapy with normalization in 82% with no tumor, 73% with microadenomas, and 67% with macroadenomas. Fifty-five percent of microadenoma and 75% of macroadenoma patients had a decrease in tumor size when assessed by a blinded reviewer. Ten of 38 female patients became pregnant while taking quinagolide. The dosage of quinagolide ranged from 75 to 400 [mgr]g/day with a median dose of 100[mgr]g/day. A comparison of side effects in a subgroup of 35 patients who had taken bromocriptine prior to quinagolide administration showed a greater than 75% reduction in nausea, vomiting, dizziness, and drowsiness during quinagolide administration.. We conclude that quinagolide is a safe and effective long-term alternative to bromocriptine therapy, particularly in those individuals with bromocriptine intolerance.

Topics: Adolescent; Adult; Aminoquinolines; Child; Dopamine Agonists; Female; Humans; Male; Middle Aged; Pituitary Neoplasms; Prolactin; Prolactinoma

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

Quinagolide is a non-ergot dopaminergic agonist recently available on the French market. The endocrine and tumoral efficacy as well as the safety and tolerability of quinagolide in the treatment of macroprolactinomas are reviewed. In this situation, plasma prolactin levels are normalized in about 60% of patients and in about one third of those who are resistant to bromocriptine. A significant decrease in pituitary tumor size is demonstrated by radiographic studies in 58 to 69% of patients. About one third of patients show more than 50% tumor shrinkage. The tolerability of quinagolide is satisfactory in most cases and clearly better than that of bromocriptine. Thus, quinagolide is a useful tool in the treatment of macroprolactinomas.

Topics: Aminoquinolines; Antineoplastic Agents; Dopamine Agonists; Drug Tolerance; Female; Humans; Male; Pituitary Neoplasms; Prolactinoma

In the last decade, the treatment of macroprolactinomas has been significantly improved by the introduction in the clinical practice of new drugs with dopamine-agonist properties. In particular, the availability of different forms of bromocriptine (BRC) with long duration of action and slow absorption, suitable for injectable (BRC-LAR) or oral (BRC-SRO) administration, has allowed one to obtain a more constant bromocriptinemia than with standard BRC, thus reducing adverse reactions. Moreover, a selective action on dopamine D2 receptors has been achieved using a new non-ergot derivative: the quinagolide (CV 205-502). The aim of this study was to evaluate the effects of BRC-LAR, BRC-SRO and CV 205-502 in 34 patients with macroprolactinoma. PROTOCOL OF THE STUDY: BRC-LAR was given at the monthly dose of 50-100 mg for 6-24 months to 8 patients whose PRL levels were 150-700 micrograms/l. BRC-SRO was given at the daily dose of 5-20 mg for 1-24 months to 10 patients whose PRL levels were 120-900 micrograms/l. CV 205-502 was given at the daily dose of 0.075-0.6 mg for 6-12 months to 16 patients whose PRL levels were 250-2,050 micrograms/l. CT and/or MRI scans were performed before and during treatment to evaluate tumor shrinkage. Data are presented as Mean +/- SD.. Serum PRL levels normalized in 8/8 with BRC-LAR, 7/10 with BRC-SRO and 12/16 patients with CV 205-502. A significant shrinkage of tumor mass was obtained in 7/8 with BRC-LAR, 9/10 with BRC-SRO and 16/16 patients with CV 205-502, with consequent improvement of visual-field defects. Overall, the drugs were rather well tolerated: no patient stopped BRC-LAR or BRC-SRO and only 2 stopped CV 205-502. In particular, nausea, vomiting, headache, hypotension that disappeared spontaneously were observed in 5/8 with BRC-LAR, 4/10 with BRC-SRO and 4/16 with CV 205-502.. The medical approach with long-acting BRC preparations and CV 205-502 which selectively binds D2 receptors allows one to obtain rapid normalization of PRL levels and shrinkage of macroprolactinomas in a large series of patients. These drugs are rather well tolerated also by patients proven to be untolerant to standard BRC.

Topics: Administration, Oral; Adolescent; Adult; Aminoquinolines; Bromocriptine; Dopamine Agonists; Female; Humans; Injections, Intravenous; Magnetic Resonance Imaging; Male; Middle Aged; Pituitary Neoplasms; Prolactin; Prolactinoma; Radioimmunoassay; Reagent Kits, Diagnostic; Tomography, X-Ray Computed

The clinical effects of CV 205-502, a potent and non-ergot-derived dopamine agonist, were investigated in 24 selected patients with hyperprolactinemia previously treated with standard oral bromocriptine, the slow-release oral form of bromocriptine (BRC-SRO) and/or the long-acting injectable form of bromocriptine (BRC-LAR); 14 were chosen because of their resistance to treatment and ten because they were intolerant of the different forms of bromocriptine. A macroprolactinoma was present in seven patients and a microprolactinoma in ten, whereas seven had no radiological images of a pituitary tumor and were classified as having non-tumoral hyperprolactinemia. All the 24 patients were treated with CV 205-502 at a daily dose of 0.075-0.6 mg for 3-12 months. All the patients had gonadal dysfunction and galactorrhea. Basal serum prolactin values ranged from 70 to 1677 ng/ml. CV 205-502 was effective in 11 of the 14 patients resistant bromocriptine, BRC-SRO and BRC-LAR; serum prolactin levels became normal within 6 months and a tumor shrinkage was obtained in five of the seven macroprolactinomas. In general, the drug was effective and well tolerated. Only three patients (two resistant and one intolerant) manifested nausea, vomiting and postural hypotension. In conclusion, this study shows that CV 205-502 is effective in bromocriptine-resistant hyperprolactinemic patients. Furthermore, CV 205-502 has insignificant and tolerable side-effects in patients intolerant of bromocriptine. CV 205-502 can, therefore, be considered a useful and effective drug, and an interesting therapeutic alternative to the ergot-derived dopamine-agonist drugs in use today.

Topics: Administration, Oral; Adult; Aminoquinolines; Bromocriptine; Delayed-Action Preparations; Dopamine Agonists; Drug Resistance; Female; Humans; Hyperprolactinemia; Magnetic Resonance Imaging; Male; Pituitary Neoplasms; Prolactin; Prolactinoma; Time Factors; Tomography, X-Ray Computed

Prolactin-secreting pituitary adenomas are an importance cause of male and female infertility. Dopaminergic drug therapy is the cornerstone of treatment. However, the currently available drugs, particularly bromocriptine, are associated with frequent adverse effects. In this study we evaluated the efficacy and safety of long-term treatment with a new dopaminergic agent, CV 205-502 (CV) in prolactinoma patients previously intolerant of bromocriptine. Nine patients (five male, four female) were treated for up to 39 months. Six had macroprolactinomas, and three had microprolactinomas; four had had previous transphenoidal surgery. Prolactin levels, tumor size and pituitary function were determined before treatment. These parameters and indices of drug toxicity were monitored at regular intervals. Prolactin decreased from 546 +/- 381 (SE) to 19.3 +/- 9.4 micrograms/L on CV doses ranging from 75 to 600 micrograms orally, given at bedtime (percent decrease, 37-99; mean +/- SE, 87 +/- 6.5%). Levels were normalized in six patients. Twenty-four-hour prolactin profiles documented adequate suppression with a single daily dose. All clinical symptoms related to hyperprolactinemia subsided. One accidental pregnancy occurred, and two other women had normalization of menstrual function. One man regained a normal sperm count. Of the four patients who presented with arrested puberty, only the one without previous surgery completed normal puberty during CV treatment. Mild drug-related adverse effects were reported by three patients. Dose reduction eliminated the adverse effects with adequate prolactin suppression in two; the third stopped treatment. Tumor size decreased in three of six macroprolactinoma patients. Liver and kidney function, hematocrit, WBC and platelet counts, EKG and urinalysis remained normal in all.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Administration, Oral; Adolescent; Adult; Aminoquinolines; Bromocriptine; Dopamine Agonists; Female; Humans; Male; Middle Aged; Pituitary Neoplasms; Prolactin; Prolactinoma; Treatment Outcome

The long-term efficacy and tolerability of CV 205-502, a non-ergot dopamine agonist with D-2 receptor affinity, were studied for up to 36 months in 16 patients with macroprolactinomas. Prolactin values were reduced in all cases, becoming either normalized or suppressed in 12. The pituitary tumor size was reduced in the 13 patients with an obvious tumor and visual function normalized in all six patients with initial defects. Concomitantly we observed improvement in gonadal function, galactorrhea, headache, libido and general well-being. Adverse reactions were experienced by 15 patients during dosage increment and caused one patient to discontinue the medication. Seven patients had persistent adverse effects which prohibited a dosage increase of CV 205-502, sufficient to normalize PRL levels in three. Two patients experienced serious adverse events, causing the discontinuation of treatment in one case. In eight patients treatment with CV 205-502 and bromocriptine could be compared. Three patients responded better to CV 205-502 than to bromocriptine treatment. Only one patient preferred bromocriptine to CV 205-502 for long-term treatment. We conclude that CV 205-502 is an effective and in most cases well-tolerated treatment for patients with macroprolactinomas. CV 205-502 is preferable to bromocriptine as an initial treatment and should also be tried in patients where treatment with bromocriptine has failed.

Topics: Adult; Aminoquinolines; Bromocriptine; Dopamine Agents; Drug Tolerance; Erectile Dysfunction; Estradiol; Female; Humans; Libido; Longitudinal Studies; Male; Menstruation; Middle Aged; Pituitary Neoplasms; Prolactin; Prolactinoma; Radioimmunoassay; Sex Hormone-Binding Globulin; Testosterone; Visual Fields

We studied the effect of CV 205-502 in 12 patients with macroprolactinomas and 8 patients with PRL-secreting tumors, who were selected because of previous repeatedly shown intolerance to bromocriptine in even small doses. We also investigated serum insulin-like growth factor-I (IGF-I) levels before and during CV 205-502 therapy. In 12 macroprolactinoma patients followed for 1 yr, 0.075-0.450 mg CV 205-502 lowered PRL levels by 91.2 +/- 5.4%. Only 3 of the patients had transient side-effects of nausea, dizziness, or fatigue. In eight patients with PRL-secreting tumors who were bromocriptine intolerant, CV 205-502 (0.075-0.300 mg daily) lowered PRL levels by 80.2 +/- 6.3%. Four of these patients showed transient side-effects (nausea, fatigue, and/or tachycardia). None of the patients discontinued therapy. There was a close correlation between pretreatment circulating PRL levels and tumor size, expressed in cubic millimeters. The decrease in pituitary tumor size after 52 weeks of CV 205-502 therapy (-74 +/- 6%) was also correlated with the decrease in PRL levels (P less than 0.01). In four patients with hypopituitarism, lowered IGF-I levels did not change during CV 205-502 therapy. However, in seven previously untreated patients with macroprolactinoma and normal CV 205-502 is a potent dopaminergic drug, which effectively controls PRL secretion and induces tumor shrinkage. At the doses used in our study, it causes only mild and transient side-effects in a minority of patients and can also be used to treat hyperprolactinemic patients who have shown intolerance to bromocriptine therapy.

Topics: Adult; Aminoquinolines; Bromocriptine; Dopamine Agents; Dose-Response Relationship, Drug; Drug Tolerance; Female; Humans; Insulin-Like Growth Factor I; Male; Middle Aged; Pituitary Neoplasms; Prolactin; Prolactinoma; Time Factors

Eleven patients (6 men, 5 women, mean age 42 [25-65] years) with prolactinomas were treated for 4-16 months with a new dopamine agonist (CV 205-502), at a daily dose of between 0.075 and 0.45 mg. All patients had previously undergone surgery and/or been treated with bromocriptine or lisuride, but had not tolerated this therapy well, and/or had not shown sufficient suppression of serum prolactin levels. Baseline prolactin levels were between 149 and 4120 ng/ml. During treatment, levels fell significantly in all patients, to between 2.0 and 683 ng/ml, and to within the reference range in five patients. In seven patients, the adenoma size decreased by 10 to greater than 50%. Adverse reactions were less frequent and less marked than with the prior therapy. The new dopamine agonist is an alternative treatment for prolactinomas where other therapies have been unsuccessful.

Topics: Adult; Aged; Aminoquinolines; Bromocriptine; Dopamine Agents; Female; Humans; Lisuride; Male; Middle Aged; Pituitary Neoplasms; Prolactin; Prolactinoma; Time Factors

Topics: Adolescent; Adult; Aminoquinolines; Bromocriptine; Dopamine Agents; Female; Follow-Up Studies; Humans; Hyperprolactinemia; Menstruation; Pituitary Neoplasms; Pregnancy; Pregnancy Complications; Prolactin; Radiography; Sella Turcica

Seven patients with large prolactin-secreting pituitary adenomas were treated for 8 weeks with once-daily doses of the new, potent, non-ergot, long-acting dopamine agonist CV205-502. In five patients previous treatment with bromocriptine had failed to control their disease or been poorly tolerated and had therefore ceased. In all seven patients serum prolactin levels fell over the 8-week period of CV205-502 treatment with the decrease ranging from 33 to 99%. Associated with this decline in prolactin all patients showed symptomatic improvement with two of the five women beginning to menstruate and the two patients with visual field impairment showing marked improvement. Tolerance of the drug, with doses at 8 weeks ranging from 0.075 to 0.3 mg, was excellent with only minimal and transient side-effects being noted in three patients in none of whom was discontinuation of therapy necessary. In one patient noncompliance after 6 weeks of therapy was associated with a rapid return of her serum prolactin towards pretreatment levels. In all seven patients the clinical and biochemical improvement was accompanied by a marked reduction in tumour size.

Topics: Adult; Aminoquinolines; Dopamine Agents; Female; Humans; Male; Middle Aged; Pituitary Neoplasms; Prolactin; Prolactinoma; Tomography, X-Ray Computed

Eleven patients with prolactin-producing pituitary adenomas were treated with the new non-ergot, long-acting dopamine agonist, CV 205-502, for a period of 2-18 months (mean 11 months). Tumour volumes ranged from 1.9 to 64 ml in seven patients who were newly diagnosed, and from 0.1 to 3.1 ml in four patients who had been treated for macroprolactinomas by oral bromocriptine or depot bromocriptine (Parlodel LAR). Plasma prolactin values ranged from 3.5 to 360 U/l before institution of CV 205-502 treatment in these 11 patients. The following observations were made: (1) plasma prolactin values fell dramatically in all patients, and values within the normal range were obtained in five patients at once-daily doses of CV 205-502 between 0.075 and 0.300 mg; (2) tumour size reduction was obtained in all patients with macroadenomas on pretreatment CT scans. Tumour reduction was associated with the development of a partial empty sella in five patients, and with visualization of the pituitary in six cases; (3) bitemporal hemianopia (five patients) disappeared in four patients and improved in one patient. Oculomotor palsy receded in one patient; (4) signs of anterior pituitary insufficiency improved or normalized in most cases affected; (5) mild nausea or dizziness during the first days of CV 205-502 treatment and/or during several days after a dose increase were observed in three patients. We conclude that CV 205-502 in a once daily dose is an effective and safe alternative in the long-term treatment of macroprolactinomas.

Topics: Administration, Oral; Adolescent; Adult; Aged; Aminoquinolines; Dopamine Agents; Drug Administration Schedule; Female; Humans; Male; Middle Aged; Pituitary Neoplasms; Prolactin; Prolactinoma

Dopamine agonists are the first line of therapy for prolactinomas, with high rates of biochemical control and tumour shrinkage. Toxicity is considered to be low and manageable by switching of agents and dose reduction. Dopamine agonist-induced impulse control disorders are well described in the neurology setting, but further data are required regarding this toxicity in prolactinoma patients. We performed a multicenter retrospective cohort study of eight men with prolactinomas and associated central hypogonadism. The eight men had no prior history of psychiatric disease, but each developed disruptive hypersexuality whilst on dopamine agonist therapy at various doses. Cabergoline, bromocriptine and quinagolide were all implicated. Hypersexuality had manifold consequences, including relationship discord, financial loss, reduced work performance, and illicit activity. We hypothesise that this phenomenon is due to synergy between reward pathway stimulation by dopamine agonists, together with rapid restoration of the eugonadal state after prolonged hypogonadism. We refer here to this distinct drug toxicity as 'dopa-testotoxicosis'. Given the profound impact in these patients and their families, cessation of dopamine agonists should be considered in men who develop hypersexuality, and pituitary surgery may be required to facilitate this. Awareness of this distinct impulse control disorder should enable further research into the prevalence, natural history and management of dopa-testotoxicosis. The condition is likely under-reported due to the highly personal nature of the symptoms and we suggest a simple written questionnaire to screen for hypersexuality and other behavioural symptoms within the first six months of dopamine agonist treatment.

Topics: Adult; Aged; Aminoquinolines; Bromocriptine; Cabergoline; Dopamine Agonists; Ergolines; Humans; Hypogonadism; Male; Middle Aged; Pituitary Neoplasms; Prolactinoma; Retrospective Studies; Sexual Dysfunction, Physiological

Both antitumor and antisecretory efficacies of dopamine agonists (DA) make them the first-line treatment of macroprolactinomas. However, there is no guideline for MRI follow-up once prolactin is controlled. The aim of our study was to determine whether a regular MRI follow-up was necessary in patients with long-term normal prolactin levels under DA.. We conducted a retrospective multicenter study (Marseille, Paris La Pitie Salpetriere and Nancy, France; Liege, Belgium) including patients with macroprolactinomas (largest diameter: >10 mm and baseline prolactin level: >100 ng/mL) treated by dopamine agonists, and regularly followed (pituitary MRI and prolactin levels) during at least 48 months once normal prolactin level was obtained.. In total, 115 patients were included (63 men and 52 women; mean age at diagnosis: 36.3 years). Mean baseline prolactin level was 2224 ± 6839 ng/mL. No significant increase of tumor volume was observed during the follow-up. Of the 21 patients (18%) who presented asymptomatic hemorrhagic changes of the macroprolactinoma on MRI, 2 had a tumor increase (2 and 7 mm in the largest size). Both were treated by cabergoline (1 mg/week) with normal prolactin levels obtained for 6 and 24 months. For both patients, no further growth was observed on MRI during follow-up at the same dose of cabergoline.. No significant increase of tumor size was observed in our patients with controlled prolactin levels on DA. MRI follow-up thus appears unnecessary in patients with biologically controlled macroprolactinomas.

Topics: Adult; Aminoquinolines; Belgium; Bromocriptine; Cabergoline; Dopamine Agonists; Ergolines; Female; Follow-Up Studies; France; Humans; Magnetic Resonance Imaging; Male; Middle Aged; Pituitary Neoplasms; Prolactin; Prolactinoma; Retrospective Studies

The aim of this article is to investigate the phenotype and etiology of prolactinoma-associated headache as well as present and discuss the plausible pain-relieving effect of dopamine agonist treatment.. In this case-based audit we included 11 patients with prolactinomas and one patient with idiopathic hyperprolactinemia presenting with headache that subsequently improved or resolved after dopamine agonist treatment.. A significant ipsilateral location of tumor mass and reported headache symptoms was observed (p = 0.018). After dopamine agonist treatment seven out of 12 patients became pain free within 2.5 months; after one year of treatment 11 out of 12 reported headache improvement or resolution. Average tumor volume reduction after treatment was 47 ± 22% during 9.5 ± 8.4 months of follow-up. There was no significant association between headache relief and tumor shrinkage (p = 0.43) or normalization of serum prolactin (p = 1.00), respectively.. 1) The significant association between lateralization of tumor and headache suggests a mechanical origin of the headache, 2) headache responded to dopamine agonist treatment in most patients, and 3) our observations encourage future prospective controlled trials to investigate the role of hyperprolactinemia in the pathogenesis of headache as well as the therapeutic effects of dopamine agonists.

Topics: Adult; Aminoquinolines; Cabergoline; Case-Control Studies; Dopamine Agonists; Ergolines; Female; Headache; Humans; Hyperprolactinemia; Magnetic Resonance Imaging; Male; Middle Aged; Pituitary Neoplasms; Prolactinoma; Recurrence; Substance Withdrawal Syndrome

It is accepted that care must be taken in initiating testosterone replacement in hypogonadal individuals with historically low androgen levels. However less is reported about the influence of restoration of normal endogenous testosterone production on behaviour.Here we report how the adverse sequelae of successful treatment of hypogonadism secondary to hyperprolactinaemia, manifesting as irritability and low threshold to aggression, were managed through a joint approach between psychiatrist and physician.

Topics: Adult; Aminoquinolines; Behavior Therapy; Dopamine Agonists; Humans; Hyperprolactinemia; Hypogonadism; Male; Pituitary Neoplasms

We report the case of a 13-year-old prepubertal boy who presented with a left-sided proptosis, bilateral papilloedema and hydrocephalus who was subsequently diagnosed with a giant prolactinoma invading the left orbit. He was commenced on dopamine receptor agonists in the form of quinagolide and cabergoline, and made an excellent response to medical therapy alone, with resolution of hydrocephalus, restoration of normal vision and a 98% reduction in serum prolactin. The rapid improvement achieved negated the requirement for surgery and this highlights the efficacy of the dopamine agonists in the management of giant prolactinomas, even in the presence of neurological symptoms.

Topics: Adolescent; Aminoquinolines; Cabergoline; Dopamine Agonists; Ergolines; Exophthalmos; Humans; Hydrocephalus; Male; Pituitary Neoplasms; Prolactin; Prolactinoma

The patient in this case report had two severe medical conditions that require oppositional treatment: prolactinoma and psychosis. A prolactinoma is a benign tumour of the pituitary gland that produces prolactin. Dopamine agonist medication is the first-line treatment in patients with prolactinoma. The psychotic symptoms started after a dosage increase of a dopamine D2-receptor agonist. Several antipsychotic medications were tried with and without the dopamine D2-receptor agonist, but severe command hallucinations remained. Cognitive behavioural therapy (CBT) was added which reduced the impact of the hallucinations to a great extent, indicating that CBT can have an additional positive effect in prolactinoma patients with psychosis that shows incomplete recovery after antipsychotic medication. Future research should be aimed at the severe and prolonged side effects of dopamine agonists in the treatment of prolactinoma patients with multiple risk factors for a psychotic decompensation.

Topics: Adult; Aminoquinolines; Cognitive Behavioral Therapy; Dopamine Agonists; Humans; Male; Pituitary Neoplasms; Prolactinoma; Psychoses, Substance-Induced

Topics: Aminoquinolines; Antineoplastic Agents; Cabergoline; Dopamine Agonists; Embryonic Development; Ergolines; Female; Humans; Pituitary Neoplasms; Pregnancy; Pregnancy Complications, Neoplastic; Pregnancy Outcome; Prolactinoma

According to current concept, macroprolactin is biologically inactive and, therefore, its accumulation in serum has little, if any, pathological significance. Authors present the history of a 80-year-old man who proved to have, among other associated disorders, an intra- and parasellar pituitary tumor measuring 21x12x12 mm in size which was revealed by pituitary MRI. His hormonal evaluation indicated a marked hyperprolactinemia mainly due to macroprolactinemia (total prolactin, 514 ng/ml; reference range, 1.6-10.7 ng/ml; macroprolactin 436 ng/ml, monomer prolactin 78.2 ng/ml). Tests for function of the pituitary-thyroid axis showed a mild subclinical primary hypothyroidism. The function of the pituitary-adrenal axis was normal, and other hormonal tests revealed low-normal serum gonadotropins and decreased testosterone level, whereas serum insulin-like growth factor I was normal. Although the majority of current guidelines state that dopamine-agonist treatment which is successfully used in prolactin-producing pituitary tumors and in other hyperprolactinemic disorders is unnecessary in patients with macroprolactinemia, the authors introduced a dopamine-agonist, quinagolide. During prolonged treatment, plasma prolactin returned close to the upper limit of normal (12.3 ng/ml) and 9 months after the beginning of treatment pituitary MRI showed a remarkable shrinkage of the pituitary tumor. Authors propose that in this patient the pituitary tumor secreted macroprolactin, and they recommend a treatment trial with dopamine-agonist in pituitary macroadenomas associated with macroprolactinemia.

Topics: Aged, 80 and over; Aminoquinolines; Dopamine Agonists; Humans; Hyperprolactinemia; Magnetic Resonance Imaging; Male; Pituitary Neoplasms; Prolactin; Time Factors; Treatment Outcome

Topics: Aminoquinolines; Cabergoline; Diagnosis, Differential; Dopamine Agonists; Ergolines; Female; Humans; Hyperprolactinemia; Magnetic Resonance Imaging; Pituitary Gland; Pituitary Neoplasms; Pregnancy; Prolactin; Prolactinoma

Dopamine agonists (DA) may act on prolactinoma size and secretion through additional effects on adenoma vascularity that can be visualized using dynamic contrast enhanced magnetic resonance imaging (DCE-MRI).. We hypothesized that DAs may exert their effect through a change in tumour functional vascularity leading to a reduction of prolactin (PRL) levels and tumour size.. To investigate this, 23 subjects were studied comprising five with macroprolactinomas, 11 with microprolactinomas, seven with non-lesion hyperprolactinemia and 15 normal volunteers (including five females on oral contraceptive pills). Patients with macroprolactinomas were treated with cabergoline 4 mg weekly and microprolactinomas were treated with quinagolide 75 microg daily for the duration of study. DCE-MRI was performed immediately pre-treatment and at 3-4 days, 1 and 3-4 months after treatment. Normal volunteers took three 75 microg quinagolide doses and were scanned pre-treatment and at 3 days. Data were analysed using the Brix model, producing a measure of vascular permeability and leakage space.. PRL levels were significantly reduced in all patients and volunteers. Vascular parameters decreased significantly for four of five macroprolactinomas and all microprolactinomas which were maintained during the treatment period (p < 0.01). No changes were seen in normal volunteers or non-lesion hyperprolactinemia. One of five macroprolactinomas showed no change in either permeability or tumour size.. Functional prolactinoma vascularity differs from non-lesion hyperprolactinemic pituitary and normal pituitary, and is responsive to DA therapy. The reduction in vascular parameters precedes shrinkage in macroprolactinomas, and if not seen within days of treatment may indicate DA resistance requiring early surgery.

Topics: Adolescent; Adult; Aged; Aminoquinolines; Cabergoline; Contraceptives, Oral, Hormonal; Dopamine Agonists; Ergolines; Female; Humans; Immunoglobulin G; Magnetic Resonance Imaging; Male; Middle Aged; Pituitary Gland; Pituitary Neoplasms; Prolactin; Prolactinoma

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

Topics: Aminoquinolines; Anti-Inflammatory Agents; Diagnosis, Differential; Dopamine Agonists; Humans; Hydrocortisone; Male; Middle Aged; Pituitary Neoplasms; Preoperative Care; Prolactin; Prolactinoma; Thyroxine; Time Factors

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

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

Evaluation of the efficiency of somatostatin analogues in the treatment of a mixed luteinizing hormone (LH)-, alpha-subunit-, prolactin (PRL)-secreting pituitary adenoma.. A 30-year-old woman, with amenorrhaea-galactorrhaea, presented with a pituitary macroadenoma. The endocrine evaluation showed high plasma levels of PRL, LH, and alpha-subunit inhibited by 65%, 65% and 33% respectively under octreotide test (200 microg, s.c.). Long-term treatment with slow release (SR) lanreotide (30 mg/10 days, i.m.) restored menstrual cycles and normalized PRL values. Due to persisting supranormal levels of LH and alpha-subunit, and to the absence of tumoral shrinkage, the adenoma was resected by the transsphenoidal route.. In vitro characterization of the somatostatin receptor subtypes (SSTR) expression and functionality. Real-time polymerase chain reaction was performed to quantify the expression of SSTR mRNAs and functionality of the SSTRs was assessed in cell culture studies with various concentrations of native somatostatin (SRIF-14) and of analogues preferential for SSTR2 or SSTR5.. This adenoma presented with high levels of SSTR2, SSTR3 and SSTR5 mRNAs, as compared with a series of gonadotroph adenomas. In cell culture studies, PRL, LH and alpha-subunit were inhibited by 60%, 47% and 33% respectively by SRIF-14 at a concentration of 10 nmol/l. The SSTR2 (BIM-23197, lanreotide) and SSTR5 (BIM-23268) preferential analogues both produced a partial 21-38% inhibition of PRL, LH, and alpha-subunit release.. In this plurihormonal-secreting adenoma, the high efficacy of somatostatin analogues to inhibit PRL, LH and alpha-subunit secretion in vivo may be explained by the unusually high level of expression and by the functionality of both SSTR2 and SSTR5 receptor subtypes.

Topics: Adult; Aminoquinolines; Antineoplastic Agents; Dopamine Agonists; Female; Glycoprotein Hormones, alpha Subunit; Humans; Oligopeptides; Peptides, Cyclic; Piperazines; Pituitary Neoplasms; Prolactin; Prolactinoma; Receptors, Somatostatin; Reverse Transcriptase Polymerase Chain Reaction; RNA, Neoplasm; Somatostatin

To evaluate the effect of hyperprolactinaemia and its treatment with dopamine-agonists on bone mass and turnover in adolescent patients compared to adults.. Forty patients with hyperprolactinaemia (20 with disease onset during adolescence and 20 during adulthood) and 40 healthy control subjects.. Open transverse (in patients and controls) and open longitudinal (in the patients).. Bone mineral density (BMD) at lumbar spine and femoral neck, serum osteocalcin (OC) and urinary cross-linked N-telopeptides of type-1 collagen (Ntx) levels were evaluated in patients and controls. In the 40 patients, bone mass and turnover were re-evaluated after 12 and 24 months of treatment with bromocriptine (BRC, dose 2.5-10 mg daily), quinagolide (CV, dose 0.075-0.3 mg daily) or cabergoline (CAB, dose 0.5-1.5 mg weekly).. Transverse study: BMD values were significantly lower in hyperprolactinaemic patients than in controls, both at lumbar spine (0.81 +/- 0.01 vs. 1.010 +/- 0.01 g/cm2; P < 0.001) and femoral neck (0.71 +/- 0.01 vs. 0.873 +/- 0.03 g/cm2; P < 0.001). Thirty-two patients (80%) had osteoporosis and/or osteopenia at one or both skeletal sites. A significant inverse correlation was found between T score values measured at lumbar spine and femoral neck and the estimated disease duration. BMD was significantly lower in young than adult patients both at lumbar spine (T score, -2.4 +/- 0.1 vs. -1.4 +/- 0.3, P < 0.01) and at femoral neck (T score, -2.1 +/- 0.05 vs. -1.5 +/- 0.2, P < 0.05). Similarly, serum OC levels were significantly lower (2.0 +/- 0.11 vs. 9.1 +/- 2.4 micrograms/l, P < 0. 01) while Ntx levels were significantly higher in patients than in controls (129.2 +/- 1.7 vs. 80.7 +/- 2.9 nmol Bone collagen equivalent (BCE)/mmol creatinine; P < 0.001). A significant inverse correlation was found between prolactin (PRL) levels and OC levels, lumbar and femoral T score values, as well as between disease duration and OC levels, lumbar and femoral T score values. A significant direct correlation was also found between Ntx levels and PRL levels and disease duration. Longitudinal study: Normalization of serum PRL levels was obtained in all patients after 6-12 months of treatment. A significant increase of serum OC levels together with a significant decrease of Ntx levels was observed after 12 and 24 months of treatment (P < 0.01). Urinary and serum calcium, phosphorus, creatinine, and serum alkaline phosphatase and parathyroid hormone levels did not change during the study period in all patients. After 12 months of therapy OC and Ntx concentrations were restored to normal. A slight but not significant increase of BMD values was recorded after 12 and 24 months of treatment. After 12 months of treatment the percent increment of BMD values in the whole group of patients was 1.13 +/- 0.6% at lumbar spine and 1.2 +/- 0.4% at femoral neck level, whereas after 24 months, it was 2.8 +/- 0.7% at lumbar spine and 3.5 +/- 0.7% at femoral neck level. After 12 months of treatment, the percent increment of BMD values was 0.7 +/- 0.2% and 1.6 +/- 1.1% at lumbar spine and 0.9 +/- 0.5% and 1.6 +/- 0.5% at femoral neck level in the young and adult patients, respectively, whereas after 24 months, it was 2.1 +/- 0.8% and 3.4 +/- 1.3% at lumbar spine and 2.6 +/- 0.8% and 4.4 +/- 1.0% at. Adolescents with prolactinoma have osteopenia or osteoporosis, a finding that strengthens the need for a prompt diagnosis. Since normalization of PRL concentrations by dopamine agonist therapy is unable to restore the bone mass, other therapeutic approaches should be considered in order to prevent further long-term problems.

Topics: Adolescent; Adult; Aminoquinolines; Analysis of Variance; Biomarkers; Bone Density; Bone Remodeling; Bromocriptine; Cabergoline; Case-Control Studies; Collagen; Collagen Type I; Dopamine Agonists; Ergolines; Female; Femur Neck; Humans; Longitudinal Studies; Lumbar Vertebrae; Male; Middle Aged; Osteocalcin; Osteoporosis; Peptides; Pituitary Neoplasms; Prolactinoma; Regression Analysis

Three patients with psychoses and concomitant prolactin-secreting pituitary tumours are described. Patients A and B had bipolar and schizoaffective disorders, respectively. They had both been treated with neuroleptics for 20 years before the prolactinomas were revealed. Patient C developed a paranoid psychosis after two years of continuous bromocriptine treatment for a pituitary tumour. In patient A the prolactin level was successfully normalized and a good antipsychotic effect was maintained by combined therapy with haloperidol and quinagolide but not bromocriptine. In patient B the prolactinoma was removed by surgery, in view of the serious nature of the psychotic disorder, to avoid psychotic relapse by treatment with a dopamine agonist. In patient C a good result was obtained with the combination of clozapine and bromocriptine. These case reports support the view that neuroleptics being dopamine antagonists and dopamine agonistic agents which are the primary treatment of prolactinomas can cancel out each other's effects. The combination of clozapine and quinagolide is recommended as the treatment of choice for most patients.

Topics: Adult; Aminoquinolines; Antipsychotic Agents; Bipolar Disorder; Bromocriptine; Clozapine; Comorbidity; Dopamine Agonists; Dopamine Antagonists; Drug Interactions; Drug Therapy, Combination; Female; Humans; Magnetic Resonance Imaging; Male; Middle Aged; Pituitary Neoplasms; Prolactin; Prolactinoma; Psychoses, Substance-Induced; Psychotic Disorders

Quinagolide has a strong dopaminerg activity, suppresses prolactin secretion and restores gonadal function in women with hyperprolactinemic anovulation. The aim of our study was to investigate the effectiveness of quinagolide in the treatment of 16 hyperprolactinemic patients. The clinical diagnosis was functional hyperprolactinemia in 13 patients, microprolactinoma in 2 and empty sella syndrome in 1. The drug was administered orally and initially daily dose was 0.025 mg for the first three days, 0.050 mg for the next three days and 0.075 mg for the following 6 months. The serum prolactin level was measured monthly before pregnancy, three monthly during the pregnancy and six weeks after delivery. Serum prolactin levels decreased in most of the patients during the first month and only in one case remained in the pathological range after six months quinagolide++ treatment. Prolactin secretion changed (mean and range) from 3120 (780-5790) mU/l to 370 (84-1076) mU/l. Out of 16 hyperprolactinemic patients nine women were infertile. During quinagolide treatment 5 pregnancies occurred. In conclusion, our results show that quinagolide has a good efficacy on regulation of prolactin secretion and it is a well tolerated dopamin-agonist drug.

Topics: Adult; Aminoquinolines; Anovulation; Dopamine Agonists; Empty Sella Syndrome; Female; Humans; Hyperprolactinemia; Pituitary Neoplasms; Postpartum Period; Pregnancy; Prolactin; Prolactinoma; Treatment Outcome

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

A retrospective French multicenter analysis was carried out to assess changes in tumor volume and plasma prolactin concentration in order to evaluate the efficacy of quinagolide (Norprolac) in patients with prolactinoma resistant to ergot dopamine agonists.. One hundred seven patients (46 men and 61 women) from 27 centers were included in the statistical analysis. All had previously been treated with a dopamine agonist (bromocriptine). Fifty-five patients had undergone surgery before being administered quinagolide: 17 of the patients had also received radiotherapy (before and after the initiation of treatment with quinagolide in 14 and 3 cases respectively). Quinagolide was given at doses ranging from 75 to 750 microg daily and continued for more than one year for 84 patients.. The prolactin level returned to normal after a mean interval of 9.8 1.6 months (1-48) in 47 of the 107 patients (44%) using a mean dose of quinagolide of 259 32.7 microg/d (75-750). The plasma prolactin concentration had already been normalized using bromocriptine in three patients. The variation in tumor volume was assessed in 82 patients since 8 had no residual tumor post-operatively and 17 had received radiotherapy: at least partial regression of the tumor was noted in 25 (30.8%), including 16 (19.5%) with a more than 50% decrease in the remaining tumor. The mean time taken to observe the anti-tumoral effect was 16.8 3.1 months (3-78) using a mean dose of quinagolide of 255.4 37.8 microg/d d (75-750). The following predictive indicators were identified concerning the efficacy of quinagolide: a pre-quinagolide prolactin level of<300 ng/ml in the group of patients whose plasma prolactin concentration was normalized, and a mean decrease in prolactin of 619 ng/ml in the group of patients showing a reduction in tumor volume treated with quinagolide for 3 months. Side effects (nausea, vomiting, hypotension) were generally mild and were observed in 51 patients (47.6%). Only 11 (10.2%) of patients had to discontinue treatment because of adverse reactions.. An anti-tumoral effect was noted in 30.8% of patients and occurred within an interval of less than 2 years in 80% of cases at a dose of 300 microg/d. Normalization of the plasma prolactin concentration was obtained in 44% of cases and occurred in less than one year in 80% of patients at a dose of 300 microg/d. Quinagolide is a useful drug and from now on should be prescribed as first-line treatment for patients presenting with bromocriptine-resistant prolactinoma.

Topics: Aminoquinolines; Bromocriptine; Dopamine Agonists; Drug Resistance, Neoplasm; Female; Humans; Male; Pituitary Neoplasms; Prolactin; Prolactinoma; Retrospective Studies

Topics: Aminoquinolines; Cabergoline; Cross-Over Studies; Dopamine Agonists; Ergolines; Female; Humans; Magnetic Resonance Imaging; Pituitary Neoplasms; Prolactinoma; Research Design; Treatment Outcome

Recently, it was demonstrated that somatostatin analogs preferential for the SSTR5 subtype suppress PRL release from prolactinoma cell cultures by 30-40%. These data supported the idea of somatostatin receptor subtype-specific control of PRL secretion in such tumors. The present study examines the quantitative profile of SSTRs messenger ribonucleic acid (mRNA) in 10 PRL-secreting tumors and correlates the expression with the ability of native somatostatins (SS14 and SS28), SSTR2 preferential analogs (octreotide and BIM-23197), and the SSTR5 preferential analog BIM-23268 to suppress PRL secretion. RT-PCR quantitative analysis showed a large predominance of SSTR5 mRNA [5648 +/- 1918 pg/pg glyceraldehyde-3-phosphate dehydrogenase (GAPDH)] vs. SSTR2 mRNA (148 +/- 83 pg/pg GAPDH). The SSTR1 transcript was also highly expressed in prolactinomas (1296 +/- 669 pg/pg GAPDH). SSTR5 mRNA expression correlated with PRL inhibition induced by both SRIF14 and SRIF28. Among the different analogs tested, only BIM-23268 produced inhibition of PRL release similar to that achieved with the native peptides. Its EC50 for PRL suppression was 0.28 +/- 0.10 nmol/L. No additive effects on PRL suppression were achieved by cotreatment of the tumor cells with SSTR2 and SSTR5 preferential analogs. In the same tumor cell cultures, quinagolide, a potent dopamine agonist, produced a dose-dependent inhibition of PRL with an EC50 at least 10 times lower than that of BIM-23268. Coincubation of quinagolide and BIM-23268, particularly in tumor cells resistant to dopamine agonist treatment, did not produce additive effects on PRL suppression. In conclusion, prolactinomas have a specific pattern of SSTR subtype mRNA expression (SSTR5 and SSTR1). SSTR5 expression is correlated to PRL regulation. These inhibitory effects are superimposable, at a higher concentration, to those of the dopamine agonists, but are not additive, particularly in the adenomas resistant to dopaminergic suppression of PRL release.

Topics: Adult; Aminoquinolines; Dopamine Agonists; Female; Gene Expression; Hormones; Humans; Male; Middle Aged; Octreotide; Oligopeptides; Piperazines; Pituitary Neoplasms; Prolactin; Prolactinoma; Receptors, Somatostatin; RNA, Messenger; Somatostatin; Tumor Cells, Cultured

This is the case report of a girl who was diagnosed as having Ullrich-Turner mosaic at the age of 12 years. She had normal pubertal development and menarche at the age of 15 years. The patient had regular menstrual cycles for 12 months before developing secondary amenorrhea. She was started on estrogen/gestagen replacement therapy by her gynecologist. Several months later a prolactinoma was diagnosed by laboratory and imaging techiques. A second-generation dopamine agonist led to almost regular cycles. Therefore, even in patients with susceptibility to ovarian failure secondary amenorrhea necessitates thorough diagnostic investigation. Copyrightz1999S.KargerAG,Basel

Topics: Amenorrhea; Aminoquinolines; Child; Dopamine Agonists; Female; Humans; Magnetic Resonance Imaging; Mosaicism; Pituitary Neoplasms; Prolactinoma; Sex Chromosome Aberrations; Turner Syndrome

We report the case of a man with an invasive macroprolactinoma who developed resistance to bromocriptine to which he had previously responded satisfactorily for 5 years. Subsequently, hyperprolactinemia was controlled equally well with 600 microg quinagolide daily and later with 4.5 mg cabergoline weekly. This observation suggests that a loss of dopamine receptors at the tumoral cell surface might be the mechanism underlying acquired resistance to bromocriptine. In addition, no tumor growth was observed over a 10-year follow-up, which virtually excludes a malignant transformation of the prolactinoma. This case emphasizes the need for close supervision of patients with macroprolactinoma, even after the serum prolactin concentration has been normalized by bromocriptine. It furthermore illustrates the usefulness of quinagolide and cabergoline when resistance to bromocriptine develops after a prolonged period of adequate response to this drug.

Topics: Aminoquinolines; Bromocriptine; Cabergoline; Dopamine Agonists; Drug Resistance, Neoplasm; Ergolines; Humans; Male; Middle Aged; Pituitary Neoplasms; Prolactin; Prolactinoma

In this study, we report the clinical presentation, response to medical treatment, and long-term follow-up of 26 patients with prolactinoma (15 macro- and 11 micro-adenomas) diagnosed at the age of 7-17 yr. All patients were first treated with bromocriptine (BRC) at doses ranging from 2.5-20 mg/day orally. BRC was discontinued for intolerance and/or resistance to the drug and was replaced by quinagolide (CV) at doses ranging from 0.075-0.6 mg/day or by cabergoline at doses ranging from 0.5-3.5 mg/week orally. Two patients received external conventional radiotherapy after surgery. In 7 prepubertal males and 6 females with macroprolactinoma, headache and/or visual defects were the first symptoms. All females presented with primary or secondary amenorrhea. Growth arrest was observed in a male patient with microadenoma, whereas all the remaining patients had normal heights, and pubertal development was appropriate for their age. Spontaneous or provocative galactorrhea was observed in 12 patients (3 males and 9 females) and gynecomastia in 4 males. Mean serum PRL concentration (+/-SE) at the time of diagnosis was 1080 +/- 267 microg/L in patients with macroadenoma and 155 +/- 38 microg/L in patients with microadenoma. In 10 patients, BRC normalized PRL levels and caused variable, but significant, tumor shrinkage. CV normalized PRL concentrations and reduced tumor size in 5 patients. Cabergoline normalized PRL concentrations in 7 of 10 patients resistant to CV. Pregnancy occurred in 2 patients while on treatment. Pregnancies were uncomplicated, and the patients delivered normal newborns at term. Only 4 patients are still moderately hyperprolactinemic. Impairment of other pituitary hormone secretion was documented at the time of diagnosis in 7 patients, 5 of whom underwent surgery. Four patients became GH deficient in adult age. In conclusion, the medical treatment with dopaminergic compounds is effective and safe in patients with prolactinoma with onset in childhood, allowing preservation of the anterior pituitary function.

Topics: Adolescent; Amenorrhea; Aminoquinolines; Bromocriptine; Child; Dopamine Agonists; Drug Resistance; Female; Follow-Up Studies; Galactorrhea; Growth Disorders; Humans; Male; Pituitary Neoplasms; Pregnancy; Prolactin; Prolactinoma; Puberty

Topics: Aminoquinolines; Antineoplastic Agents; Cabergoline; Dopamine Agonists; Drug Resistance, Neoplasm; Ergolines; Humans; Pituitary Neoplasms; Prolactinoma

Topics: Aminoquinolines; Antineoplastic Agents; Cabergoline; Dopamine Agonists; Drug Resistance, Neoplasm; Ergolines; Humans; Pituitary Neoplasms; Prolactinoma

Prolactin (PRL) circulates as multiple molecular weight variants: glycosylated phosphorylated, deamidated and sulphated forms. The profiles of the forms, as determined by isoelectrofocusing (IEF), differ in physiological and pathological conditions. The case of a 72-year-old woman affected by an invasive prolactinoma is described. The patient had undergone surgical treatment followed by radiotherapy at the age of 71 years. Bromocriptine therapy followed (up to 10 mg/die), but the PRL levels were still extremely high (over 13,000 micrograms/l as determined by IRMA, after dilution). We therefore treated the patient with quinagolide, at increasing dosages, from 150 micrograms/die on day 0 to 600 micrograms/die on day 220. This treatment progressively lowered PRL to 23.2 micrograms/l. In addition to a decrease in PRL levels, a progressive change in the IEF profile was also noted. Indeed, on day 0, the PRL isoforms were very acidic and during treatment they progressively shifted toward a more basic range. For purpose of comparison PRL profiles were also determined in 8 women with pathological hyperprolactinaemia (group A, aged 16-50 years, PRL levels: 25.1-170.4 micrograms/l), in 6 normal women (group B, aged 25-29 years, PRL levels: 3.4-7.9 micrograms/l) and in 5 normal women during a TRH test (group C, aged 17-52 years, PRL levels: 2.7-10.3 micrograms/l). The profiles observed in group A had a single major peak at isoelectric point (pI) 6.5, while the group B and C profiles were more heterogeneous displaying multiple minor peaks, the majority of the molecules being in a more basic range (pI 6.9 for group B and pI 7.5 for group C). During treatment, the profiles of our subject at first resembled those of group A; subsequently, when the PRL levels had normalised, the profile resembled those noted in group B. Altered (immature?, more glycosilated?, less bioactive?) PRL molecules could be secreted by the tumour. These data show that quinagolide successfully reduced PRL levels, while inducing secretion of forms more similar to those found in women affected by pathological hyperprolactinaemia or in normal women.

Topics: Adolescent; Adult; Aged; Aminoquinolines; Cohort Studies; Combined Modality Therapy; Dopamine Agonists; Female; Humans; Hydrogen-Ion Concentration; Isoelectric Focusing; Middle Aged; Pituitary Neoplasms; Prolactin; Prolactinoma; Reference Values; Time Factors

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

Resistance to bromocriptine, defined as the absence of normalization of prolactin (PRL) levels despite a 15-30 mg daily dose of bromocriptine during at least 6 months, has been observed in 5-17% of the prolactinomas according to the literature. The recent availability of a new potent dopamine agonist, quinagolide, prompted us to analyze its long-term therapeutic effects in 28 patients with prolactinomas resistant to bromocriptine. Before bromocriptine, their PRL levels were 520 +/- 185 micrograms/l (mean +/- SEM) and decreased to 291 +/- 154 micrograms/l after a 6-21 month period of bromocriptine treatment. All the women (N = 20) remained amenorrheic and hypogonadism was not improved in men (N = 8). Subsequently, after 1 year of 150-300 micrograms/day quinagolide, 12/28 patients of the present series recovered normal gonadal function and their initial mean baseline PRL value (404 +/- 180 micrograms/l) was 16 +/- 2 micrograms/l after 1 year of treatment. A significant tumor shrinkage was observed in 5/8 macroadenomas (62%). During the 3-year follow-up period under quinagolide, a similar good control was achieved in these patients, with the exception of one man presenting with a secondary rise of PRL under quinagolide. In contrast, 15 other patients (one patient interrupted quinagolide at 6 months because of poor tolerance) were not normalized under 150-450 micrograms/day quinagolide. Their initial PRL levels (606 +/- 298 micrograms/l) were reduced to 343 +/- 187 micrograms/l (versus 463 +/- 265 micrograms/l under bromocriptine after the same duration of treatment). Despite such a partial inhibitory effect of quinagolide, 7/12 women resumed menstrual cycles and three pregnancies occurred. In no case was any tumor shrinkage noticed during the 3-4-year follow-up. Three patients even presented, after 2 years of quinagolide treatment, with a secondary rise of PRL values associated with a further tumor growth in two patients. During the 3-year follow-up period, nine pregnancies occurred in seven women. In five women, after quinagolide withdrawal, the plasma PRL baseline values ranged from 52 to 158 micrograms/l and from 65 to 192 micrograms/l, respectively, at the first trimester and at the end of uneventful pregnancies. In contrast, in two women a rapid increase of PRL (240-400 micrograms/l) correlated with tumor growth during the first trimester. Such a tumor progression was blocked by quinagolide treatment but not by bromocriptine. These data, although observ

Topics: Aminoquinolines; Bromocriptine; Dopamine Agonists; Drug Resistance; Female; Humans; Male; Middle Aged; Pituitary Neoplasms; Pregnancy; Pregnancy Complications, Neoplastic; Pregnancy Outcome; Prolactinoma

The aim of this study was to evaluate the effects of a chronic treatment with the non-ergot-derived dopamine agonist quinagolide (CV 205-502) on sexual and gonadal function in hyperprolactinemic males. Thirteen males with macroprolactinoma and one with microprolactinoma were treated with CV 205-502 at the dose of 0.15-0.6 mg/day for 6-24 months. Baseline prolactin (PRL) was 464 +/- 75.7 microg/l. All the patients suffered from libido impairment, five of reduced sexual potency, six had infertility and in four bilateral induced galactorrhea was shown. The semen analysis revealed a severe oligoasthenospermia with reduced sperm count, motility and forward progression, with an abnormal morphology and decreased viability. A significant reduction of serum PRL levels (nadir PRL = 12.3 +/- 5.4 microg/l) was obtained during the treatment. Normalization of prolactinemia was reached in 13 of the 14 patients after 3 months. After 1 year, a significant improvement of sperm parameters, in terms of increase of number (from 5600 +/- 111 to 20,564 +/- 587 mm3), motility at 1 h (from 24.8 +/- 0.1 to 52.6 +/- 0.5%), forward progression (from 24 +/- 1.4 to 62.3 +/- 2.9%) and normal morphology (from 53.8 +/- 2.5 to 62.2 +/- 2.4%), was recorded. In addition, a significant increase of serum follicle-stimulating hormone (from 5.3 +/- 0.6 to 7.8 +/- 0.4 U/l), luteinizing hormone (from 4.4 +/- 0.5 to 7.7 +/- 0.4 U/l) and testosterone (from 3.4 +/- 0.4 to 4.7 +/- 0.2 microg/l) was recorded. A significant increase of luteinizing hormone (9.4 +/- 0.7 U/l) and testosterone (5.2 +/- 0.4 microg/l), as well as a further improvement of sperm parameters, was found after 2 years of therapy. Sellar computed tomography and/or magnetic resonance showed a considerable shrinkage (> or = 30%) of tumoral mass in 8 out of 13 patients with macroprolacinoma. Side effects were recorded in only one patient. In conclusion, the treatment with CV 205-502 normalizing PRL levels improves gonadal and sexual function and fertility in males with prolactinoma, providing good tolerability and excellent patient compliance to medical treatment. This result demonstrates that the impairment of gonadal function in hyperprolactinemic patients is a functional modification.

Topics: Aminoquinolines; Animals; Dopamine Agonists; Humans; Hyperprolactinemia; Male; Middle Aged; Oligospermia; Pituitary Neoplasms; Prolactin; Prolactinoma; Sperm Count; Spermatozoa; Testis; Time Factors

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

Quinagolide (CV 205 502) is a dopamine D2-receptor agonist which has proved effective in the treatment of prolactinomas, reducing both serum PRL and tumour size. Some of its D2-receptor effects are mediated via alpha-adrenoceptors, which have a major influence on the control of vascular tone. The aim of this study was to examine the influence of quinagolide on in-vivo dorsal hand vein vascular responses to noradrenaline in patients with a prolactinoma.. Seven female patients with prolactinomas (age 37 (28-46) years), intolerant of bromocriptine, were studied before and after 3 months treatment with quinagolide (0.75-1.5 mg/day). Patients were otherwise disease free, were taking no other medication, and had been on no other medication (including bromocriptine) for at least 3 months prior to enrollment into the study.. Vascular responses to locally infused noradrenaline were measured in dorsal hand veins using an established technique. PRL, oestradiol, FSH, LH, blood pressure and body mass index were also measured before and after 3 months treatment.. Quinagolide significantly reduced PRL in all 7 patients (1795 (696-4680) (mean (range)) vs 488 (290-868) mU/l, P = 0.001), with no effect on the other parameters, including mean arterial pressure (88 (2) vs 87 (4) mmHg, P = 0.6). Vascular reactivity to noradrenaline was significantly increased after 3 months therapy: log10 dose estimated to cause 50% vasoconstriction (ED50) 1.37 (0.12) vs 0.85 (0.12) ng/min (P = 0.003; a lower ED50 indicates less noradrenaline is required to constrict the vein by 50%).. Vasoconstrictor responses to noradrenaline were increased in all patients after 3 months treatment with quinagolide. Peripheral veins carry alpha-adrenoceptors analogous to those of systemic resistance vessels. If this increased vasoconstrictor response in patients with prolactinomas was occurring in hypophyseal vessels, it would lead to reduced tumour blood supply. Quinagolide may therefore reduce tumour blood flow, which may be one factor responsible for its effectiveness in these patients.

Topics: Adult; Aminoquinolines; Dopamine Agonists; Dose-Response Relationship, Drug; Female; Hand; Humans; Middle Aged; Norepinephrine; Pituitary Neoplasms; Prolactin; Prolactinoma; Receptors, Dopamine D2; Vasoconstriction; Veins

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

The SMtTW tumor, a spontaneous PRL-secreting transplantable tumor, is the only available animal model sensitive to dopamine agonists. This model has been used to compare the long term in vivo effects of CV 205-502 (CV) and bromocriptine (BR) on PRL secretion and tumor growth. These two drugs were given for 2 months to female Wistar-Furth rats bearing either small or large tumors 4 and 6 months after the graft. Untreated grafted rats served as control. In all rats treated with 5 or 10 mg/kg.day BR or 0.3 mg/kg.day CV, a normalization of plasma PRL levels was observed whatever the pretreatment levels (plasma PRL or CV or BR-treated rats, < 15 ng/ml vs. 28253 ng/ml in control rats 8 months after graft). An inhibition of tumor growth was found for both small and large tumors, but the tumors never disappeared completely (mean tumor weights at autopsy, 440 and 660 mg in BR and CV groups vs. 5270 mg in control group 8 months after graft). Experiments performed with increasing doses of BR (0.15-5 mg/kg.day) or CV (0.03-0.6 mg/kg.day) indicated that CV is effective at doses 5-10 times lower than those of BR. A shrinkage under treatment and a regrowth after drug withdrawal were demonstrated for large tumors by in vivo ultrasonographic measurements of tumor size. Histological and ultrastructural effects were similar for the two drugs: decrease in hemorrhage, reduction of the cell size and secretory activity, increase in immunoreactive PRL cellular content, and inhibition of exocytosis. There was no difference in the PRL mRNA content of treated and untreated tumors, as assessed by in situ hybridization. In conclusion, CV and BR exhibit similar inhibitory effects on tumor growth and PRL secretion. These effects are rapidly and fully reversible after drug withdrawal. The present results give a complete account of the actions of the two dopamine agonists under conditions comparable to those used in the treatment of human prolactinomas.

Topics: Aminoquinolines; Animals; Bromocriptine; Dopamine Agents; Dose-Response Relationship, Drug; Female; Neoplasm Transplantation; Pituitary Neoplasms; Prolactin; Rats; Rats, Inbred WF; Ultrasonography

CV 205-502 (octahydrobenzol[g]quinoline), a non-ergot dopamine agonist drug, was administered to 40 patients with hyperprolactinemic syndrome: 16 patients with macroprolactinoma, 14 with microprolactinoma and 10 with non-tumoral hyperprolactinemia. Twenty-four out of 40 patients had previously been treated by surgery and/or bromocriptine, with variable results. All had gonadal dysfunction and 22 patients had galactorrhea. Eight patients with macroprolactinoma had defects of the visual field. Pre-treatment serum PRL levels ranged from 60 to 2050 micrograms/l. The daily dose of CV 205-502 used in this trial ranged from 0.075 to 0.600 mg. After 6-12 months of treatment, serum PRL level decreased in all the patients reaching normoprolactinemia in 31 of them (77.5%) who demonstrated restoration of menses and disappearance of galactorrhea. The remaining nine patients (22.5%) had only a decrease of PRL levels without reaching normoprolactinemia and without any clinical effect. In 12 out of 16 patients with macroprolactinoma not previously surgically treated, a significant tumor shrinkage was shown by means of Computed Tomography and/or Magnetic Resonance Imaging. The disappearance of visual defects was obtained in four out of eight patients. CV 205-502 was tolerated satisfactorily: mild side-effects occurred in four patients in the first week of treatment and spontaneously disappeared, whereas six patients (15%) needed to withdraw the therapy after 6 months because of side-effects. In conclusion CV 205-502 is a potent and well-tolerated drug in the treatment of tumoral and non-tumoral hyperprolactinemic states and is an effective alternative to other dopamine agonists in use today.

Topics: Adult; Aminoquinolines; Dopamine Agonists; Drug Administration Schedule; Female; Humans; Hyperprolactinemia; Male; Middle Aged; Pituitary Neoplasms; Prolactinoma

Macroprolactinomas are pituitary tumours which have been effectively treated medically since the introduction of bromocriptine. The visual function of 13 patients treated with a new prolactin (PRL) inhibitor CV 205-502 (Sandoz Basle), a potent and selective dopamine D2 receptor agonist, was evaluated. This is the first detailed ophthalmic report of the use of this drug in macroprolactinomas. Patients were enrolled from June 1988 to July 1990 (mean follow up 30 months). Visual function including visual acuity, ocular pressure, and visual fields was regularly controlled. Visual fields (VF) were tested with Goldmann and automatic static perimetry (Vision Monitor). Treatment was globally effective. No modifications of the visual function were observed in nine patients (six normal, three previous VF losses after surgery). In four other patients, visual function dramatically improved (regression of a III paresis, one case; disappearance of a chiasmatic syndrome, three cases). A pituitary necrosis was observed in one case and successfully cured. CV 205-502 seems to be an effective and well tolerated treatment of macroprolactinomas.

Topics: Adult; Aminoquinolines; Dopamine Agents; Female; Humans; Intraocular Pressure; Magnetic Resonance Imaging; Male; Middle Aged; Pituitary Neoplasms; Prolactin; Prolactinoma; Vision, Ocular; Visual Acuity; Visual Fields

Topics: Aminoquinolines; Bromocriptine; Dopamine Agents; Edema; Humans; Male; Middle Aged; Pergolide; Pituitary Neoplasms; Prolactinoma

The oral non-ergot D2-dopamine agonist quinagolide (CV 205-502, CAS 87056-78-8) has proven to be highly effective in suppressing elevated prolactin (PRL) levels. It was the aim of this study to search for possible interference of the drug with other endocrine systems which are partly under dopaminergic control, and to compare such effects to those of previously investigated prolactin inhibitors. Twelve patients suffering from macroprolactinoma were treated for at least 6 months with daily doses ranging from 50 up to 300 micrograms. During the first two months, individual doses were gradually increased either until serum PRL levels reached the normal range (n = 7) or until side effects made a further dose increase intolerable (n = 5). Mean basal PRL level fell from 255 +/- 65 (SEM) ng/ml before treatment to 19 +/- 8 ng/ml, after the definite dose was reached (p < 0.01). Luteinizing hormone (LH) rose from 0.6 +/- 0.8 (SD) to 1.7 +/- 1.6 mU/ml (p < 0.05). While basal levels of aldosterone, renin, follicle-stimulating hormone (FSH), triiodothyronine (T3), testosterone, and estradiol in females were not affected by the treatment, we found a significant rise in thyroxine (T4) and a decrease of estradiol in males. Blood pressure and renal clearances of creatinine, sodium, potassium, and chloride failed to show any significant change. Following stimulation with metoclopramide, aldosterone and renin rose sharply before treatment was initiated. When the test was repeated during treatment, the increase of plasma renin was slightly dampened, whereas the rise of aldosterone remained unaffected.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Aged; Aminoquinolines; Blood Pressure; Dopamine Agents; Female; Gonadal Steroid Hormones; Gonadotropins; Humans; Kidney Function Tests; Male; Metoclopramide; Middle Aged; Pituitary Gland; Pituitary Neoplasms; Prolactin; Prolactinoma; Receptors, Dopamine D2; Renin-Angiotensin System; Thyrotropin-Releasing Hormone

A patient with a macroprolactinoma and extrasellar extension was treated by incomplete transfrontal surgery, external irradiation and additional bromocriptine (Br) treatment. After 4 years, partial bromocriptine resistance developed (a rare occurrence) together with the appearance of intracranial metastases. 123I-Iodobenzamide was helpful in evaluating the dopamine D2 receptor status of the metastatic tumour both in vivo using single-photon emission computed tomography (SPECT) and in vitro. Prolactin release by the cultured metastatic tumour cells was more potently inhibited by CV 205-502 than by bromocriptine. The patient, treated by surgery, irradiation and CV 205-502, developed a ptosis of the left eye and a transient psychiatric delusional state, the latter probably an effect of the dopamine agonist. As the right frontal metastasis was markedly positive on SPECT with 111In-SMS, somatostatin treatment was added to the CV 205-502.

Topics: Aminoquinolines; Brain Neoplasms; Bromocriptine; Combined Modality Therapy; Drug Therapy, Combination; Humans; Male; Middle Aged; Pituitary Neoplasms; Prolactinoma; Radiotherapy Dosage; Somatostatin

Among 288 patients with prolactinoma (aged 12-62 years; 242 women), 27 were diagnosed as resistant to bromocriptine as their plasma prolactin (PRL) levels remained elevated despite long-term (3 months or more) treatment at high doses (> or = 15 mg daily). These 18 women and 9 men, aged 29 +/- 9 years (mean +/- SD, range 13-50), followed-up for 8 +/- 4 years, had microadenomas (n = 6) or macroadenomas. They were treated by dopamine agonists alone (n = 6) or associated with surgical or radiation therapy. In 8 cases repetitive surgical treatments were necessary. Among the 24 patients who were treated with the nonergot dopamine agonist CV 205-502 after unsuccessful bromocriptine treatment, half of them (9 women, 3 men) resumed normal PRL levels on doses ranging from 0.15 to 0.45 mg/day. Despite daily doses of CV 205-502 from 0.3 to 0.525 mg, the remaining patients were not normalized by this drug which did not prevent tumor growth in 4 of them. Two patients died from invasive cerebral extensions of their tumor and a third had vertebral metastases with positive anti-PRL immunostaining. It is concluded that bromocriptine-resistant prolactinomas represent the most severe aspect of this disease and that a more powerful dopamine agonist like CV 205-502 is effective in only a fraction of these patients.

Topics: Adolescent; Adult; Aminoquinolines; Bromocriptine; Child; Drug Resistance; Female; Humans; Male; Middle Aged; Pituitary Neoplasms; Prolactin; Prolactinoma

This study reports a case of allergy to ergot-derived drugs in a patient with a prolactin (PRL)-secreting microadenoma. The anamnesis revealed allergic reactions to the administration of analgesics and antibiotics. The administration of dopamine agonist drugs, such as bromocriptine (BRC; 2.5 mg) or lisuride (0.2 mg), induced after a few minutes the appearance of nausea, vomiting, postural hypotension, headache, edema of the glottis with dispnea and acroedema. The edemas disappeared a few hours after the administration of antihistaminic drugs while nausea, vomiting, postural hypotension and headache persisted for a few days. Therefore, the patient was tested with another dopamine agonist non-ergot-derived drug, quinagolide (CV 205-502), which did not cause side effects or allergic reactions. Furthermore, not only was the responsiveness to the drug optimal but it also normalized the PRL levels, and menses reappeared after more than a 5-year amenorrhea. This report suggests that ergot-derived drugs, such as lisuride and BRC, seldom induce allergic reactions apart from common side effects. Consequently, the feasibility of using a new drug with a different molecular structure (non-ergot derived) effective in the therapy of hyperprolactinemic syndromes represents a good alternative to conventional therapy.

Topics: Adult; Aminoquinolines; Bromocriptine; Drug Hypersensitivity; Female; Humans; Lisuride; Pituitary Neoplasms; Prolactin; Prolactinoma

In 21 patients with prolactinomas resistant to bromocriptine, we studied the effects of CV 205-502 on PRL hypersecretion and tumor mass, as assessed by consecutive computed tomography examinations. Cell culture studies were performed in 9 of such tumors. In 11 patients (group I; 52%) with a mean baseline plasma PRL level of 468 +/- 160 micrograms/L (+/- SE), normal PRL values were achieved after 1-6 months of treatment with 0.1-0.5 mg/day CV 205-502. Tumor size was reduced by 25% or more in 6 of 11 patients. In group II (n = 10), PRL levels (948 +/- 538 micrograms/L at baseline) were reduced by 48% after treatment with 0.1 mg/day CV 205-502. A progressive increase in the daily dose up to 0.5 mg did not further improve the partial reduction of PRL. No reduction in tumor size was observed in this group. The cell culture studies showed that 1) a brief exposure to both drugs provoked PRL suppression lasting 3 days; 2) in group I, CV 205-502 suppressed PRL release more efficiently than bromocriptine, with a maximal inhibition of 72% at 10(-9) mol/L; and 3) in group II, CV 205-502 only achieved a 26% inhibition of PRL release at 10(-8) mol/L, superimposable to that of bromocriptine. These data indicate that in at least half of such adenomas resistant to bromocriptine, CV 205-502, probably due to its higher affinity toward the D2 dopamine receptor, can overcome such resistance.

Topics: Adult; Aminoquinolines; Antineoplastic Agents; Bromocriptine; Dopamine Agents; Dose-Response Relationship, Drug; Drug Resistance; Female; Growth Hormone; Humans; Luteinizing Hormone; Male; Pituitary Neoplasms; Prolactin; Prolactinoma; Tomography, X-Ray Computed; Triiodothyronine; Tumor Cells, Cultured

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

We report the case of a 27-year-old woman with a prolactin-secreting macroadenoma of the pituitary gland who was under treatment with a new dopamine agonist, Sandoz CV 205-502. Immediately after diagnosis of a 12 x 10 mm intrasellar prolactinoma, treatment with CV 205-502 was begun at a daily dose of 0.075 mg. Under this low dose, prolactin in the serum normalized after 4 weeks, the initial hormone value being 189.9 ng/ml. After 6 months of therapy there was still a 6 x 6 mm tumor, and after 15 months of treatment the pathological process could no longer be observed with magnetic resonance imaging. In the 20th month of therapy the patient became pregnant. An ovulatory menstrual cycle had been present for a few months.

Topics: Adult; Aminoquinolines; Dopamine Agents; Female; Humans; Magnetic Resonance Imaging; Pituitary Neoplasms; Prolactinoma; Time Factors; Tomography, X-Ray Computed

Bromocriptine is currently and successfully used for the treatment of pituitary prolactinomas. However, bromocriptine appears unable to normalize plasma prolactin levels in about 10% and to reduce tumour size in one-third of cases. The lack of normalization of plasma prolactin levels in spite of a daily dose of bromocriptine equal to or higher than 15 mg suggests a bromocriptine resistance. We compared the long-term effects of bromocriptine and CV 205-502 (a non-ergot derivative D2 dopamine agonist) on plasma prolactin levels and tumour size in seven bromocriptine-resistant prolactinomas. Bromocriptine reduced significantly (P less than 0.001) plasma prolactin levels (from 2307 +/- 518 to 568 +/- 279 micrograms/l) (conversion to Sl units: 1 microgram/l = 20 mU/l). Visual field defects observed in five patients improved in four. However, CT scan analysis showed a decrease in tumour size in only three patients. Except for transient and minor side-effects at the beginning of the treatment, CV 205-502 was well tolerated in five of seven patients. In the remaining two patients nausea and vertigo occurred with high dosages of CV 205-502 and it was necessary to reduce the daily dose. CV 205-502 lowered plasma prolactin to levels similar to those obtained after bromocriptine therapy in four cases. In the three remaining patients, CV 205-502 was more potent than bromocriptine as demonstrated by the further 90% reduction in plasma levels obtained in one case and by the normalization of plasma prolactin levels in the two other cases. One woman became pregnant during CV 205-502 treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Aged; Aminoquinolines; Bromocriptine; Dopamine Agents; Female; Humans; Male; Middle Aged; Pituitary Neoplasms; Prolactin; Prolactinoma; Prospective Studies; Retrospective Studies

CV 205-502, a benzoquinoline, is a new nonergot dopamine agonist compound which has been shown to be effective in lowering PRL levels in normal volunteers and in hyperprolactinemic women. Seven patients (4 men and 3 women) presenting with hyperprolactinemia due to macroprolactinoma were treated with CV 205-502 given as a single daily dose at bedtime for up to 12 months. Six patients presented with impaired gonadal function and 2 with galactorrhea. All patients but one had previously been treated with bromocriptine and 4 had undergone pituitary surgery (3 with complementary radiotherapy). Six patients responded within a few weeks to CV 205-502 treatment, PRL levels being normalized (4 patients, 0.075 to 0.150 mg/day) or significantly reduced to restore normal gonadal function (2 patients, 0.225 mg/day). The seventh patient, who had previously been resistant to bromocriptine, also failed to respond to CV 205-502 treatment even after high doses (0.450 mg/day). Under CV 205-502 treatment, follow-up with magnetic resonance imaging revealed a reduction in tumor size of up to 52% of the initial volume in the "PRL-responders" whereas an increase in tumor size was observed in the "nonresponding" patient. No biological disturbance appeared during CV 205-502 treatment and the drug tolerance was very good, with mild side-effects being reported by only 2 patients. In conclusion, CV 205-502, given once daily, appears to be a safe and effective alternative to other dopamine agonists in the treatment of macroprolactinoma, by reducing hyperprolactinemia and tumor size. It was, however, of no benefit in the one patient whose macroprolactinoma had been resistant to bromocriptine.

Topics: Adult; Aminoquinolines; Bromocriptine; Dopamine Agents; Drug Resistance; Endocrine System Diseases; Female; Galactorrhea; Gonads; Humans; Magnetic Resonance Imaging; Male; Middle Aged; Pituitary Neoplasms; Prolactin; Prolactinoma

Although bromocriptine is the mainstay of treatment of macroprolactinomas, its therapeutic usefulness may be limited by poor tolerance, lack of consistent reduction in serum prolactin levels and tumour size, and the necessity for multiple dosing. Consequently new dopamine agonists have been developed, including the long acting non-ergot agonist CV205-502 which has been shown to date to be consistently effective in reducing serum PRL levels and causing tumour shrinkage. Twelve patients were treated for periods of up to 24 months with CV205-502 in doses ranging from 0.075 mg to 1.65 mg once daily. Clinical and psychiatric assessments, biochemical parameters, tumour size determination, and anterior pituitary function tests were performed regularly. Tumour shrinkage was noted in all patients, and varied from 11 per cent reduction to complete disappearance of tumour. Prolactin levels became normal in seven patients and were reduced by more than 90 per cent in the remaining five. Normal menstruation resumed in six of the eight women, one of whom conceived after one year of therapy; libido returned in all patients. Psychiatric complications occurred in three patients necessitating withdrawal of therapy in one. Significant weight loss was noted in 11 of 12 patients. Triglyceride concentrations fell from 1.5 +/- 0.1 to 1.0 +/- 0.1 mmol/l at 12 months (p = 0.006), and cholesterol fell from 6.3 +/- 0.4 to 5.3 +/- 0.3 mmol/l (p = 0.04). The mean TSH response 20 min following TRH injection fell from 14.3 +/- 2.9 to 8.7 +/- 1.3 mU/l at 2 months (p = 0.027). There was a significant increase in the peak growth hormone response to the insulin stress test from basal median (25th-75th centiles) values of 15 (4.4-25.5) mU/l to 24.5 (9-37) mU/l at 2 months (p less than 0.01) and 31 (19.3-63.5) at 12 months (p less than 0.005). CV205-502 is highly effective in the medical management of patients with macroprolactinomas, reducing prolactin levels and tumour size and restoring normal anterior pituitary function. It is, however, associated with the important side effects of weight loss and psychiatric complications which should be drawn to the attention of clinicians.

Topics: Adult; Aminoquinolines; Dopamine Agents; Female; Humans; Male; Mental Disorders; Middle Aged; Pituitary Gland, Anterior; Pituitary Neoplasms; Prolactin; Prolactinoma; Weight Loss

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

The effects of a new PRL inhibitor, CV 205-502 (CV), on human macroprolactinomas were studied in nine patients according to a prospective protocol. Five patients had undergone surgery leaving tumor remnants and persistent hyperprolactinemia. The four others were de novo patients, two of whom had received short term treatment with Parlodel. Plasma PRL levels ranged from 235-6050 micrograms/L before treatment. The doses of CV used in this trial ranged from 0.075-0.600 mg. Plasma PRL normalized in eight of the nine patients during treatment with CV. The time to normalize varied from 2 weeks to 9 months, and the doses from 0.075-0.450 mg. A tumor volume reduction of more than 50% was obtained in all four patients who had not been operated on before CV treatment. Only one of the five patients with postoperative tumor remnants had no reduction in tumor size. The drug was generally well tolerated, and no patient interrupted the treatment. Slight and short-lasting gastrointestinal symptoms were noted in several patients, and a single episode of fainting occurred in one patient when the drug was not taken at bedtime as instructed. A noticeable and persistent weight loss with anorexia was noted in two patients. Since CV 205-502, administered in a single daily dose, has tolerable side-effects and is effective in reducing PRL secretion and tumor size, it can be considered to be a useful treatment for macroprolactinomas.

Topics: Adult; Aminoquinolines; Antineoplastic Agents; Dopamine Agents; Female; Follow-Up Studies; Humans; Magnetic Resonance Imaging; Male; Pituitary Neoplasms; Prolactin

CV 205-502, a new long-acting nonergot dopamine agonist, was given to 15 patients (6 women and 9 men) with PRL-secreting pituitary macroadenomas. The compound was administered in a single daily dose for a period of 6-12 months. The treatment resulted in normalization of plasma PRL levels (less than or equal to 20 micrograms/L) in 5 of 6 women at a mean dose of 135 micrograms (range, 75-300 micrograms) and in 6 of 9 men at a mean dose of 192 micrograms (range, 75-300 micrograms). Among patients for whom computed tomographic scans were available before and after at least 6 months of therapy, definite tumor shrinkage occurred in 6 of 7 patients. Libido was improved in 5 of 6 women and in 6 of 8 men, galactorrhea disappeared in all cases (3 women and 1 man) and menses resumed in 3 of 5 women. Plasma testosterone rose to normal levels in 3 of 6 men who were not receiving testosterone injections. The PRL response to TRH was blunted in 4 of 6 patients with normalized basal PRL. Serum total cholesterol was reduced by CV 205-502 treatment in women from 5.35 +/- 0.49 to 4.63 +/- 0.51 mmol/L (P = 0.031) and in men from 5.93 +/- 0.89 to 5.28 +/- 0.82 mmol/L (P = 0.045). Side-effects included mainly headache, nausea, and dizziness. One side-effect or more occurred transiently and with mild intensity in 14 patients. No patient discontinued the therapy because of side-effects. In conclusion, CV 205-502 appears to be a safe and valuable compound in the treatment of patients with PRL-secreting macroadenomas.

Topics: Adult; Aged; Aminoquinolines; Drug Evaluation; Female; Humans; Lipids; Luteinizing Hormone; Male; Middle Aged; Pituitary Neoplasms; Prolactin; Prolactinoma; Testosterone; Thyrotropin; Tomography, X-Ray Computed

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

Two novel dopaminergic drugs, designated CV 205-502 and CQP 201-403 have recently been developed by Sandoz Pharmaceuticals Ltd (Basle, Switzerland). The effects of these drugs on PRL and GH secretion by normal rat and tumorous human pituitary cells in vitro have been investigated. Low doses of both CV 205-502 and CQP 201-403 immediately and profoundly suppressed PRL secretion, which failed to recover up to 7 h after removal of the drugs. Similarly, CQP 201-403 significantly suppressed basal GH secretion by human pituitary somatotropic tumours in culture, and both drugs significantly reduced the stimulatory effect of GHRH. These effects are more potent and longer acting than the previously described in vitro effects of bromocriptine. It is concluded that CV 205-502 and CQP 201-403 hold potential for the treatment of patients with hyperprolactinaemia and, possibly, also in patients with acromegaly.

Topics: Aminoquinolines; Animals; Ergolines; Growth Hormone; Humans; Pituitary Gland, Anterior; Pituitary Neoplasms; Prolactin; Rats; Receptors, Dopamine; Tumor Cells, Cultured