Cabergoline In Patients Research Articles

7173 Cabergoline Induced Psychosis in a Patient with no Previous History of Psychiatric Disorder

Abstract Disclosure: B. Aryal: None. K. Kim: None. A. Shafi: None. M. Ganesh: None. Introduction: Cabergoline is a dopamine agonist (DA) used to treat prolactinomas. It is well established that DAs may cause psychotic symptoms. However, very few cases report cabergoline-associated psychosis in patients without personal or family history of psychiatric disorders. We report a rare case of cabergoline-induced psychosis in a patient with a prolactinoma without any underlying psychiatric disorder, which was managed with the addition of olanzapine. Case: A 41 year old male with no history of psychiatric disorder was started on cabergoline 0.5mg twice a week for a newly diagnosed prolactinoma. 4 weeks later, he presented to the emergency room for aggressive behavior and confusion for the past 2 weeks. He endorsed visual and auditory hallucinations. Cabergoline was discontinued. During hospitalization, he attempted suicide and required 1:1 observation. He was started on olanzapine per the inpatient psychiatry team. Surgical resection of the prolactinoma was considered given his acute psychosis associated with cabergoline. However, complete resection of the tumor was deemed impossible given encasement of the internal carotid arteries. After discussion with the patient, he underwent re-challenge with cabergoline 0.25mg weekly while on olanzapine under 1:1 observation in the ICU. He was monitored for 2 weeks and eventually discharged home on cabergoline 0.25mg twice a week and olanzapine with improvement in prolactin levels to 4973.7 ng/mL after 4 weeks. He continued to remain free of psychotic symptoms upon follow up as an outpatient. Discussion: Psychosis is a rare side effect of DA mediated via D2/D3 receptors in the mesocortical and mesolimbic pathways. Several cases report psychosis associated with cabergoline in patients with a history of psychiatric disorders. However only one case reports de novo psychosis. Our patient developed severe psychosis while on low-dose cabergoline for 4 weeks. This rare case of de novo cabergoline-associated psychosis re-emphasizes that psychosis may occur regardless of previous history of psychiatric disorder and independent of the dose or duration of cabergoline. Treatment of a prolactinoma in the setting of cabergoline-associated psychosis requires a multidisciplinary approach. Alternative treatment of surgical resection was considered for our patient. However surgical resection was not plausible given difficult surgical anatomy. Therefore he was monitored closely to re-initiate cabergoline while on olanzapine. Several cases report successful use of clozapine, aripiprazole, and quetiapine for patients with psychiatric symptoms while on cabergoline. Patients who are on cabergoline should be closely monitored for any psychotic symptoms. Further studies are warranted to identify patients at risk of developing psychosis while on cabergoline to tailor an individualized approach to therapy and monitoring. Presentation: 6/2/2024

Efficacy and side effects of subcutaneous pasireotide alone or in combination with cabergoline in patients with cushing's disease whithout postoperative remission

Efficacy and side effects of subcutaneous pasireotide alone or in combination with cabergoline in patients with cushing's disease whithout postoperative remission

Pharmacokinetic profile of cabergoline in patients with dopamine agonist resistant prolactinomas: a pilot study

Pharmacokinetic profile of cabergoline in patients with dopamine agonist resistant prolactinomas: a pilot study

A Brazilian multicentre study evaluating pregnancies induced by cabergoline in patients harboring prolactinomas.

To evaluate the maternal-fetal outcomes of CAB-induced pregnancies in patients with prolactinoma in a large cohort. The prevalence of tumor growth, miscarriage, preterm, low birth weight, congenital malformations and impairment in neuropsychological development in children among women treated with CAB were assessed in a Brazilian multicentre retrospective observational study, RESULTS: We included 194 women with a mean age of 31 (17-45) years, 43.6% presenting microadenomas and 56.4% macroadenomas, at prolactinoma diagnosis. In 233 pregnancies, CAB was withdrawn in 89%, after pregnancy confirmation. Symptoms related to tumor growth occurred in 25 cases, more frequently in macroadenomas. The overall miscarriage rate was 11%, although higher in the subgroup of patients with CAB maintainance after pregnancy confirmation (38% vs. 7.5%). Amongst the live-birth deliveries, preterm occurred in 12%, low birth weight in 6% and congenital malformations in 4.3%. Neuropsychological development impairment was reported in 7% of cases. Our findings confirm previous results of safety in maternal and fetal outcomes in CAB-induced pregnancies; nevertheless, CAB maintenance after pregnancy confirmation was associated with higher miscarriage rate; result that must be further confirmed.

SUN-445 A Brazilian Multicentric Study Evaluating Pregnancies Induced by Cabergoline in Patients Harboring Prolactinomas

BACKGROUND: Prolactinoma is the most common pituitary tumor and a frequent cause of infertility. Treatment with dopamine agonists (DA) usually reverse hyperprolactinemia and hypogonadism, subsequently allowing pregnancy. Cabergoline (CAB) presents a higher affinity to dopamine receptor type 2, better tolerance and more effectiveness than bromocriptine (BCR). Nevertheless, due to the larger experience and its shorter half-life, comparing to CAB, BRC is still the drug of choice to induce pregnancy. Although studies did not show higher rates of maternal and fetal complications in CAB induced-pregnancies, an increase in published data is needed to confimr the drug safety. OBJECTIVE: To evaluate maternal-fetal outcomes of CAB-induced pregnancies in patients with prolactinoma in a large Brazilian cohort. PATIENTS AND METHODS: A Brazilian multicentric retrospective study assessed the outcomes regarding tumor expansion, abortion, preterm, low birth weight, congenital malformations and neuropsychological development of children from women with prolactinomas treated with CAB at the time of conception and/or during pregnancy. Breastfeeding safety and tumor remission after delivery were also reported. RESULTS: We included 194 women, median age of 31 (17-45) yrs, with prolactinomas, 46% microadenomas (MIC) and 54% macroadenomas (MAC), resulting in 233 pregnancies in which CAB was used. The drug was withdrawal after pregnancy confirmation in 89% of patients at a median gestation age of 6 (2-36) weeks. Symptoms secondary to tumor growth occurred in 22 cases, more frequently in MAC (23%) than MIC (7%) (p=0.005), being DA reintroduced in 21 patients. Neurosurgery was performed in six patients, five without tumor control with medical treatment. Abortion rate was 11%. From live-birth deliveries, preterm occurred in 12%, low birth weight in 6% and congenital malformations in 3%. Impared neuropsychological development was reported in 7% of 145 children, one to 228 months of age. Twenty-two pregnancies are still ongoing. After one year of delivery, tumor imaging and prolactin reassessment showed remission in 22% of cases, unrelated to breastfeeding or tumor size. DISCUSSION: Due to its longer half-lime, as compared to BRC, CAB use in pregnancy is stiil a matter of concern. Our findings are in agreement with previous studies evaluating maternal and fetal outcomes in pregnancies induced by CAB. In our cohort and in the majority of cases in those studies, CAB was usually withdrawal after pregnancy confirmation. Additionally, tumor remission rate was similar to literature data. CONCLUSIONS: Our multicentric study, including 233 pregnancies, significantly increased the number of reported cases, reassuring CAB safety for pregnancy, induction in women harboring prolactinomas.

Echocardiography and monitoring patients receiving dopamine agonist therapy for hyperprolactinaemia: a joint position statement of the British Society of Echocardiography, the British Heart Valve Society and the Society for Endocrinology

This is a joint position statement of the British Society of Echocardiography, the British Heart Valve Society and the Society for Endocrinology on the role of echocardiography in monitoring patients receiving dopamine agonist (DA) therapy for hyperprolactinaemia. (1) Evidence that DA pharmacotherapy causes abnormal valve morphology and dysfunction at doses used in the management of hyperprolactinaemia is extremely limited. Evidence of clinically significant valve pathology is absent, except for isolated case reports around which questions remain. (2) Attributing change in degree of valvular regurgitation, especially in mild and moderate tricuspid regurgitation, to adverse effects of DA in hyperprolactinaemia should be avoided if there are no associated pathological changes in leaflet thickness, restriction or retraction. It must be noted that even where morphological change in leaflet structure and function may be suspected, grading is semi-quantitative on echocardiography and may vary between different machines, ultrasound settings and operators. (3) Decisions regarding discontinuation of medication should only be made after review of serial imaging by an echocardiographer experienced in analysing drug-induced valvulopathy or carcinoid heart disease. (4) A standard transthoracic echocardiogram should be performed before a patient starts DA therapy for hyperprolactinaemia. Repeat transthoracic echocardiography should then be performed at 5 years after starting cabergoline in patients taking a total weekly dose less than or equal to 2 mg. If there has been no change on the 5-year scan, repeat echocardiography could continue at 5-yearly intervals. If a patient is taking more than a total weekly dose of 2 mg, then annual echocardiography is recommended.

Echocardiography and monitoring patients receiving dopamine agonist therapy for hyperprolactinaemia: A joint position statement of the British Society of Echocardiography, the British Heart Valve Society and the Society for Endocrinology.

This is a joint position statement of the British Society of Echocardiography, the British Heart Valve Society and the Society for Endocrinology on the role of echocardiography in monitoring patients receiving dopamine agonist (DA) therapy for hyperprolactinaemia. Evidence that DA pharmacotherapy causes abnormal valve morphology and dysfunction at doses used in the management of hyperprolactinaemia is extremely limited. Evidence of clinically significant valve pathology is absent, except for isolated case reports around which questions remain. Attributing change in degree of valvar regurgitation, especially in mild and moderate tricuspid regurgitation, to adverse effects of DA in hyperprolactinaemia should be avoided if there are no associated pathological changes in leaflet thickness, restriction or retraction. Note must be taken that even where morphological change in leaflet structure and function may be suspected, grading is semi-quantitative on echocardiography and may vary between different machines, ultrasound settings and operators. Decisions regarding discontinuation of medication should only be made after review of serial imaging by an echocardiographer experienced in analysing drug-induced valvulopathy or carcinoid heart disease. A standard transthoracic echocardiogram should be performed before a patient starts DA therapy for hyperprolactinaemia. Repeat transthoracic echocardiography should then be performed at 5years after starting cabergoline in patients taking a total weekly dose less than or equal to 2mg. If there has been no change on the 5-year scan, repeat echocardiography could continue at 5-yearly intervals. If a patient is taking more than a total weekly dose of 2mg, then annual echocardiography is recommended.

Improvement in cognitive abilities following cabergoline treatment in patients with a prolactin-secreting pituitary adenoma.

Hyperprolactinaemia may affect sexual and reproductive functioning. However, recent studies suggest that increased prolactin levels may also have negative effects on cognition. We aimed to study whether the reduction in prolactin levels by cabergoline in patients with hyperprolactinaemia is followed by an improvement in cognitive tasks. We studied seven patients with hyperprolactinaemia caused by a prolactinoma that had an indication to start treatment with cabergoline. All patients were assessed twice (baseline and 6-12 months after cabergoline treatment) with a cognitive battery. Plasma prolactin levels were determined. We found a significant improvement in the speed of processing, working memory, visual learning and reasoning and problem-solving domains after cabergoline treatment. Improvements in speed of processing and reasoning and problem solving were greater in patients with baseline prolactin levels above the median. In summary, a reduction in prolactin levels by cabergoline in patients with hyperprolactinaemia is followed by an improvement in cognitive abilities. This finding suggests that prolactin may be involved in cognitive processes, although cabergoline could also have procognitive effects that are independent of prolactin changes. Further clinical trials are needed to confirm the potential cognitive-enhancement properties of cabergoline in patients with chronic hyperprolactinaemia.

A pilot phase II trial of cabergoline in the treatment of metastatic breast cancer.

e12568 Background: The prolactin receptor can be overexpressed in breast cancer, and pre-clinical data indicate that it contributes to the pathobiology of breast cancer. Cabergoline is a potent dopamine receptor agonist of D2 receptors and has a direct inhibitory effect on pituitary prolactin secretion resulting in reduced serum prolactin levels. Methods: A pilot phase II study of cabergoline in patients with metastatic breast cancer was conducted with primary end point of best overall response rate (ORR) among patients with measurable disease. Eligible patients had metastatic breast cancer, any receptors status was allowed, and there was no limit of prior lines of therapy. Both measurable and unmeasurable diseases (RECIST 1.1) were allowed. Cabergoline 1mg orally, twice weekly (1 cycle = 4 weeks) was given until disease progression or unacceptable toxicity. Immunohistochemistry prolactin receptor staining was performed on available baseline tumor tissue, and serum prolactin levels were serially assessed. Results: A total of 20 women were enrolled, 19 of whom were evaluable for response (one patient died on C1D7 of unrelated causes). Mean age was 62 (range 42-83); 15 (75%) were Caucasian; mean number of prior lines of therapy 5 (range 0-14). Tumor receptor statuses were distributed as follows: HR+/HER2+ 1(5%), HR+/HER2- 18 (80%), HR-/HER2+ 1 (5%). Analysis was performed after a median follow-up of 6.8 months (0.2-26.2). Best ORR was 8.3% among 12 patients with measurable disease. Results for secondary endpoints were as follows: 4-month CBR = 26% (including patients with measurable and non-measurable disease), median PFS = 1.9 months, and median OS = 10.4 months. Most common treatment related AEs were nausea (30%), fatigue (25%), and elevation in alkaline phosphatase (15%). The highest-grade AE was a single grade 3 treatment-related pain in extremity. Nine patients had sufficient baseline tissue for analysis, there was no correlation between baseline tumor prolactin receptor expression and clinical benefit ( p= 0.24). Additional correlative work is ongoing. Conclusions: Cabergoline was well tolerated and associated with modest anti-tumor activity. Clinical trial information: NCT01730729.

Anti-proliferative effects of high doses cabergoline in patients with prolactinoma

Anti-proliferative effects of high doses cabergoline in patients with prolactinoma

Alternative Treatment Strategies in Women Poorly Tolerating Moderate Doses of Bromocriptine.

Background: Metformin as well as dopaminergic agents exert a beneficial effect on glucose and lipid metabolism, often impaired in patients with hyperprolactinemia. Objective: The aim of this study was to compare metabolic- and prolactin-lowering effects of low-dose bromocriptine/metformin combination therapy and cabergoline in patients with elevated prolactin levels. Methods: The study included 27 women with hyperprolactinemia and impaired glucose tolerance who were treated with moderate doses of bromocriptine but experienced adverse effects of this treatment. In 12 of these patients bromocriptine was replaced with cabergoline (group A), while the remaining ones continued treatment with bromocriptine, the dose of which was halved, and administered together with metformin (group B). Plasma lipids, glucose homeostasis markers, as well as serum levels of prolactin, thyrotropin and insulin-like growth factor-1 (IGF-1) were assessed before and after 4 months of metformin treatment. Results: Both groups did not differ in baseline levels of plasma glucose and lipids, in insulin sensitivity, as well as in circulating levels of all measured hormones. All patients from group A and 12 patients from group B completed the study. Cabergoline reduced prolactin levels, while no effect on plasma prolactin was found in group B. Neither cabergoline nor bromocriptine plus metformin affected circulating levels of thyrotropin and IGF-1. Both treatment options, particularly low-dose bromocriptine plus metformin, improved glucose and lipid homeostasis. Conclusions: Low-dose bromocriptine combined with metformin may be an interesting alternative to cabergoline in patients with mild hyperprolactinemia and early glucose metabolism abnormalities, in whom moderate doses of bromocriptine are poorly tolerated.

Long-term results of cabergoline therapy for macroprolactinomas and analyses of factors associated with remission after withdrawal.

Withdrawal of cabergoline is generally challenging, especially in patients with large or invasive macroprolactinomas. Therefore, we aimed to assess long-term results of cabergoline therapy for macroprolactinomas and remission achievement results after withdrawal in patients with macroprolactinomas. We also investigated clinical characteristics and factors related to remission after withdrawal. This was an institutional review board-approved retrospective analysis. We studied 46 macroprolactinoma patients who had taken cabergoline during the period from 2003 through 2013. Administration of cabergoline was maintained for 5 years before withdrawal. Median follow-up after the initiation of cabergoline therapy was 54·3 (range 5·3 to 137·2) months. Recurrences of hyperprolactinaemia were observed in 3 of 11 (27%) postwithdrawal patients at a median time of 3·0 (range; 2·9-11·2) months, indicating that a high percentage (73%) maintained remission for at least 12 months after cabergoline cessation. Factors significantly associated with remission were analysed in 21 patients receiving long-term cabergoline administration. On multivariate analysis, the absence of cavernous sinus invasion on pretreatment MRI (≥3/4 tumour encasement of the intracavernous internal carotid artery) (HR; 21·94, 95% CI; 2·06-1071·0, P = 0·006), initial PRL <132·7 ng/ml (HR; 8·28, 95% CI; 1·24-199·6, P = 0·03) and nadir PRL <1·9 ng/ml during cabergoline therapy (HR; 5·14, 95% CI; 1·10-39·02, P = 0·04) showed statistically significant correlations with remission after withdrawal. Cabergoline therapy can achieve a high percentage (73% in this series) of remission maintenance for at least 12 months after cessation of a 5-year course of therapy, even in patients with macroprolactinomas. The absence of cavernous sinus invasion, serum PRL level lower than 132·7 ng/ml before cabergoline therapy or nadir serum PRL below 1·9 ng/ml were related to more frequent remission after withdrawal of cabergoline in patients receiving this medication for 5 years.

Mean platelet volume in patients with prolactinoma.

Prolactin is a multifunctional pituitary hormone. The effect of prolactin on platelet activation is not well understood. Prolactinomas are the most common type of pituitary adenomas, and they are medically responsive to dopamine agonists. Mean platelet volume (MPV) is a marker of platelet function and activation. The aim of this study was to evaluate MPV values before and 6 months of cabergoline treatment when normoprolactinemia was achieved. A total of 101 newly diagnosed prolactinoma patients and 102 healthy control subjects were included in the study. Patients with hematological disorders that affect MPV and those on medications were excluded. Prolactin, platelet count and MPV levels were recorded before and 6 months after the initiation of cabergoline treatment (0.5 to 1 mg, two times a week). There was no significant difference in platelet count and MPV before and after 6 months of treatment with cabergoline in patients with prolactinoma compared with the control group (p > 0.05). Our results showed that MPV, a marker of platelet function, was unchanged in patients with prolactinoma.

Anti-proliferative effects of high doses cabergoline in patients with organic hyperprolactinemia

The aim of the study – to inestigate the antiproliferative effect of cabergoline (CAB) which was used in different regimes of suppressive therapy during 12 months in patients with prolactinomas.Materials and methods. It was examined and underwent a 12 month course of treatment by selective dopamine agonist (AgDof) CAB 61 patients with prolactinoma (PROL) (52 women and 9 men) aged 16–66 years. The total duration of the disease ranged from 1 to 60 months, average (12,3±10,1) months. Among the women, treated with CAB, it was mikroPROL 40, macro&amp;giant PROL-12. Among men it 2 was microadenoma, 7 macroadenoma. PROL was verified using magnetic resonance imaging (MRI). Pituitary volume was calculated by the formula Di Chiro-Nelson using the correction coefficient. Were estimated total and partial secretory activity (PSA) in PROL for VS Pronin. PRL blood levels (ng/mL) were determined by commercial reagent kit ELISA (DRG Diagnostics, USA) on automated analyzer Stat Fax 2100 (Awareness Technology, USA). Applied two modes of therapy: 1 – the mode of gradual increase of a CAB dose, since 0,5 mg a week with the subsequent control of the PRL blood level in each 4 weeks and titration CAB dose if necessary (increase in a week dose by 0,25–0,5 mg); 2 – the mode of high starting doses from calculation: the quantity of tablets CAB (0,5 mg) corresponded to frequency rate of increase of the PRL blood level in relation to the upper limit of age norm, but no more than 4 mg (8 tablets) a week. The statistical data analysis was carried out with the certified program package Statgraphics Plus for Windows 3.0 (Manugistic Inc. USA).Results and discussion. At purpose of high starting doses of CAB after 1 month of treatment PRL level in 58.1% of patients decreased to the reference values, including in patients with macroPROL after 1 month at 26.3% of patients had achieved target levels, after 3 months – at 84.2%, and by 6 months of treatment – at 100% patients. In all patients it was a statistically significant decreasing the pituitary volum after 12 months of treatment (p&lt;0,001), but only in patients who were treated high starting high dose CAB recorded decrease in the size of adenoma by 50% or more of the basal volume: at 9 microPROL and 4 macroPROL. It was a positive correlation between the total and the average cumulative therapeutic CAB dose during the treatment period with the volume of the pituitary gland and PSA indicates whether the use of high starting doses in patients with both micro- and macro&amp;giant PROL.Conclusions. The most expressed anti-proliferative effect is noted at application of high starting doses of CAB. Optimum therapeutic average and cumulative doses of CAB for achievement of the maximum therapeutic effect at patients with microPROL are doses of 0,8 mg/week and 33,8 mg/year, respectively; for patients with macro&amp;giant PROL – 1,3 mg/week and 67,6 mg/year, respectively. At patients with microPROL the positive therapeutic effect is reached on a smaller cumulative CAB dose which is associated with a lower risk of complications in the long term period.

Study Design of a Phase II trial of pasireotide s.c. alone or in combination with cabergoline in patients with Cushing's disease

Study Design of a Phase II trial of pasireotide s.c. alone or in combination with cabergoline in patients with Cushing's disease

Early prediction of long-term response to cabergoline in patients with macroprolactinomas.

BackgroundCabergoline is typically effective for treating prolactinomas; however, some patients display cabergoline resistance, and the early characteristics of these patients remain unclear. We analyzed early indicators predicting long-term response to cabergoline.MethodsWe retrospectively reviewed the cases of 44 patients with macroprolactinomas who received cabergoline as first-line treatment; the patients were followed for a median of 16 months. The influence of various clinical parameters on outcomes was evaluated.ResultsForty patients (90.9%) were treated medically and displayed tumor volume reduction (TVR) of 74.7%, a prolactin normalization (NP) rate of 81.8%, and a complete response (CR; TVR >50% with NP, without surgery) rate of 70.5%. Most patients (93.1%) with TVR ≥25% and NP at 3 months eventually achieved CR, whereas only 50% of patients with TVR ≥25% without NP and no patients with TVR <25% achieved CR. TVR at 3 months was strongly correlated with final TVR (R=0.785). Patients with large macroadenomas exhibited a low NP rate at 3 months, but eventually achieved TVR and NP rates similar to those of patients with smaller tumors. Surgery independently reduced the final dose of cabergoline (β=-1.181 mg/week), and two of four patients who underwent surgery were able to discontinue cabergoline.ConclusionDetermining cabergoline response using TVR and NP 3 months after treatment is useful for predicting later outcomes. However, further cabergoline administration should be considered for patients with TVR >25% at 3 months without NP, particularly those with huge prolactinomas, because a delayed response may be achieved. As surgery can reduce the cabergoline dose necessary for successful disease control, it should be considered for cabergoline-resistant patients.

Prevention of ovarian hyperstimulation syndrome in GnRH agonist IVF cycles in moderate risk patients: randomized study comparing hydroxyethyl starch versus cabergoline and hydroxyethyl starch

ObjectiveTo assess whether, in GnRH agonist IVF cycles where there is a risk of ovarian hyperstimulation syndrome (OHSS), the addition of cabergoline to the hydroxyethyl starch (HES) infusion could decrease OHSS incidence and severity. Materials and methodsProspective randomized study. The population under study consisted of women undergoing IVF cycles with GnRH agonist protocols, at risk of OHSS (more than 20 follicles observed larger than 12mm in diameter and/or estradiol levels of 3000–5000pg/mL). Women received a slow infusion of 500mL of 6% HES during follicular aspiration alone or combined with 0.5mg cabergoline administration for 8 days, starting on the day of hCG administration. ResultsThe rates of OHSS (both early and late) were very similar in the HES alone group (3.19% (3/94)) and in the HES plus cabergoline group (5.68% (5/88)), as were the rates of severe cases of OHSS (1.06% and 2.27%). Pregnancy rates (PR) were also similar in the two groups (ongoing PR per transfer, 47.56% and 47.50%). CommentsThe co-administration of cabergoline in patients receiving HES due to OHSS risk did not reduce the rate or severity of OHSS in GnRH agonist IVF cycles.

A comparison between intensive and conventional cabergoline treatment of newly diagnosed patients with macroprolactinoma

Intensive treatment with cabergoline may lead to earlier reduction in prolactin and tumour volume in comparison to conventional schedule. To compare the efficacy and safety of two different dosing schedules of cabergoline in patients with macroprolactinoma. Prospective, randomized trial in drug naive patients assigned to conventional (4 weekly escalation by 0·5 mg per week, group A) or intensive (weekly increase by 1 mg per week followed by 4 weekly escalation, group B) treatment with cabergoline. The duration required to achieve normoprolactinemia and tumour shrinkage of >50% as a composite end-point. 38 patients (19 in each group) completed the study with a mean follow-up of 64·3 ± 24·9 weeks. More subjects (22%) achieved the composite end-point in group B (18/19) as compared to the group A (14/19) (P = 0·18). The duration of cabergoline treatment required to achieve the composite end-point was 13·1 ± 9·5 weeks vs 19·3 ± 15·7 weeks (P = 0·34) in the group A and B, respectively. A reduction in prolactin of ≥90% by the fourth week of cabergoline therapy predicted subsequent normalization of prolactin (AUC 0·78; P = 0·04). A further increase in cabergoline dosage after normalization of prolactin in patients with tumour reduction of <50%, led to further tumour shrinkage by 31·2% in an additional 26·3% of patients. Intensive treatment with cabergoline is not superior to the conventional recommended dosage schedule in respect to the time necessary to achieve normoprolactinemia and ≥50% tumour shrinkage. NCT 01143584.

Polymorphisms of the drug transporter gene ABCB1 predict side effects of treatment with cabergoline in patients with PRL adenomas

Treatment with dopamine agonists in patients with prolactin (PRL) adenomas and Parkinson's disease is associated with central side effects. Central side effects may depend on a substance's ability to pass the blood-brain barrier, which can be actively controlled by transporter molecules such as the P-glycoprotein (P-gp) encoded by the ABCB1 gene. We aimed to determine whether cabergoline is transported by the P-gp and whether polymorphisms of its encoding ABCB1 gene predict central side effects of cabergoline therapy in patients with PRL adenomas. i) In an experimental mouse model lacking the homologues of the human ABCB1 gene (Abcb1ab double knockout mouse model), we examined whether cabergoline is a substrate of the P-gp using eight mutant and eight wild-type mice. ii) In a human case-control study including 79 patients with PRL adenomas treated with cabergoline at the Max Planck Institute of Psychiatry in Munich, we investigated the association of four selected ABCB1 gene single nucleotide polymorphisms (SNPs) (rs1045642, rs2032582, rs2032583 and rs2235015), with the occurrence of central side effects under cabergoline therapy. i) In the experimental mouse model, we observed that brain concentrations of cabergoline were tenfold higher in the mutant mice compared with their wild-type littermates, implying that cabergoline is indeed a substrate of the transporter P-gp at the blood-brain barrier level. ii) In the human study, we observed significant negative associations under cabergoline for the C-carriers and heterozygous CT individuals of SNP rs1045642 with two central side effects (frequency of fatigue and sleep disorders) and for the G-carriers of SNP rs2032582 with the enhancement of dizziness. For the SNPs rs2235015 and rs2032583, no associations with central side effects under cabergoline were found. This is the first study demonstrating that individual ABCB1 gene polymorphisms, reflecting a different expression and function of the P-gp, could predict the occurrence of central side effects under cabergoline. Our findings can be viewed as a step into personalised therapy in PRL adenoma patients.

Cabergoline therapy for prolactinomas: is valvular heart disease a real safety concern?

Dopamine agonists (DAs) are the first-line therapy for the treatment of hyperprolactinemia, with cabergoline, an ergot-derived selective D2-receptor agonist, being the preferred and most widely used drug. Recent studies reported cardiac valve regurgitations in patients with Parkinson’s disease treated with high doses of DA, raising concerns about the safety of cabergoline in patients with hyperprolactinemia. To date, seven case–control studies have examined the potential association between cardiac valvular abnormalities and cabergoline therapy in patients with hyperprolactinemia. Overall, a total of 463 patients exposed to low doses of cabergoline (mean cumulative doses: 204–443 mg) for a mean duration of 45–79 months have been included in these studies. Patients in all the studies were asymptomatic without clinical signs of cardiac disease. Six studies did not show any association between cabergoline therapy and clinically relevant valvular regurgitation, whereas one study found an increased rate of moderate tricuspid regurgitation. In this report, we review and discuss the results of these studies and emphasize the limitations of the methodology used in the published literature. The clinical significance of the present findings has yet to be confirmed by future larger prospective studies with rigorous echocardiographic protocols and prolonged duration of follow-up.