Prolactin-secreting tumors, dopamine agonists and pregnancy: a longitudinal experience of a tertiary neuroendocrine center.

PURPOSE: Prolactin (PRL)-secreting tumours are associated with infertility and can be reverted by dopamine agonist (DA) therapy. The suspension of DA is recommended once pregnancy is established, as all DAs cross the placenta. The aim of the study was to evaluate the rate of maternal-foetal complications in women treated with cabergoline (CAB) or bromocriptine (BRM) for prolactinoma during gestation and the effect of pregnancy on prolactinoma progression. METHODS: This was a retrospective observational study involving 43 women affected by prolactinoma who became pregnant during therapy with CAB or BRM for a total of 58 pregnancies. For each patient, medical records were analysed by integrating the data with outpatient or telephone interview. RESULTS: At the time of conception, 18 women were in the BRM group, while 40 were in CAB group. No differences were found in obstetric or neonatal outcomes between the two groups. There was a significant difference (p = 0.046) in child complications reported in maternal interview found exclusively in the CAB group. No further confounding factors were detected. Disease remission rate after the first pregnancy was 42.9% and the main predictor was a lower PRL nadir before pregnancy (p = 0.023). No difference was detected between the two groups in terms of tumor remission. Breastfeeding did not modify the outcome. CONCLUSION: Foetal exposure to DAs during the first weeks of embryogenesis is not associated with a greater risk of complications. The transient and mild developmental disorders recorded resolved spontaneously and the prevalence was substantially overlapping with that observed in the general population.

How to manage intolerance to dopamine agonist in patients with prolactinoma.

PURPOSE: Dopamine agonists (DA) are the gold-standard for prolactinoma and hyperprolactinemia treatment. Intolerance to DA leading to drug drop out occurs in 3 to 12% of cases. We provide here a review of published data about DA intolerance and present a case report concerning the use of intravaginal cabergoline. METHODS: We review the literature on the definition, the pathogenesis, frequency and management of DA intolerance. In addition, the review provides strategies to enhance tolerability and avoid precocious clinical treatment withdrawal. RESULTS: Cabergoline is often cited as the most tolerable DA and its side effects tend to ameliorate within days to weeks. Restarting the same drug at a lower dose or switching to another DA can be used in cases of intolerance. The vaginal route can be tried specifically if there are gastrointestinal side effects in the oral administration. Symptomatic treatment could be attempted, although mainly based on a strategy used in other diseases. CONCLUSIONS: Due to limited data, no guidelines have been developed for the management of intolerance in DA treatment. The most frequent management is to perform transsphenoidal surgery. Nevertheless, this manuscript provides data derived from published literature and expert opinion, suggesting new approaches to this clinical issue.

Effect of Cabergoline Treatment on Disease Control in Acromegaly Patients.

The aim of this study was to evaluate the efficacy of cabergoline in normalizing plasma IGF-I levels in acromegaly patients with elevated IGF-I levels after surgery and/or SRL therapy. Acromegaly patients (n: 143) were evaluated retrospectively. Patients with elevated IGF-I levels after surgery and/or SRLs therapy and a fixed dose of SRLs treatment for the last six months with no history of radiotherapy in the last three years were included in the study (n: 12). Previous treatment regimens, baseline PRL and IGF-I levels (ULNR), sella MRI, and immunohistochemical findings were evaluated. Cabergoline was used as an add on (n: 11) or single medical treatment (n: 1). The median duration of treatment with SRL alone was 12 months (range 6-48 months). The mean IGF-I value before cabergoline therapy was 1.45±0.4 ULNR. The mean cabergoline dose and duration of treatment were 1.55±0.75 mg/week and 9±6.3 months, respectively. IGF-I normalization was only achieved in patients with serum IGF-I concentration<1.5×ULNR before the onset of cabergoline treatment (n: 9). In some of the patients with IGF-I normalization, baseline prolactin levels were normal (n: 3). Immunopositivity for prolactin in adenoma tissue was found in three patients with IGF-I normalization. Cabergoline therapy is effective in the normalization of IGF-I levels even in normoprolactinemic acromegaly patients when IGF-I levels are mildly or moderately elevated during SRL therapy.

Safety of Cabergoline for Postpartum Lactation Inhibition or Suppression: A Systematic Review.

This study sought to perform a systematic review of adverse events reported with the use of cabergoline for postpartum lactation inhibition or suppression in women aged 15 to 50. Following registration with PROSPERO (CRD42017049894), a comprehensive search of the Ovid databases Medline, Embase, and CENTRAL, along with PubMed, was conducted from January 1, 1985 to January 25, 2018. All study designs investigating cabergoline use for postpartum lactation inhibition or suppression in women aged 15 to 50 were included. A total of 695 articles were retrieved, and 25 articles were eligible for inclusion. Adverse events were then reported in terms of frequency, with percentages calculated according to the total number of women exposed to the intervention. A bias assessment of the articles was also performed. Among a total of 757 women, 108 adverse events were observed in 96 women (14.2%). The most common adverse events were dizziness (35 of 757), headache (30 of 757), and nausea or vomiting (19 of 757). These events were described as short-lived, self-resolving, and dose dependent. One pharmacovigilance study reported 29 "serious" events from a total of 175 events in 72 case reports, which included thromboembolic and neurologic events. Four case studies specifically addressed the psychiatric population, with one half reporting psychiatric symptoms following administration of cabergoline. In conclusion, this systematic review demonstrates that adverse events were generally benign and tolerable following the administration of cabergoline. However, pharmacovigilance data reveal that vigilance is still needed given the occurrence of rare but serious events.

Pharmacological lactation suppression with D2 receptor agonists and risk of postpartum psychosis: A systematic review.

BACKGROUND: It has been suggested that D2 receptor agonists commonly used postpartum for the physiological suppression of lactation, such as bromocriptine and cabergoline, may increase the risk of illness onset or relapse in women where there is a predisposition for or history of schizophrenia, bipolar disorder or postpartum psychosis. This is based on two lines of reasoning: current models of psychosis assume episodes are triggered by dysregulation of brain dopaminergic activity and treated by medications that universally have D2 receptor antagonist properties; and limited research suggesting these agents may be associated with psychotic episodes in vulnerable individuals outside of the postpartum period. AIM: The aim of this study was to examine whether D2 agonists trigger psychosis in previously well mothers, or psychotic relapse or exacerbation of symptoms in mothers with known psychotic illnesses, when used to suppress lactation during the early postpartum period. MATERIALS AND METHODS: A systematic review of the literature was undertaken of electronic databases, including: MEDLINE, EMBASE and PsychINFO from 1950 to 2015 using keywords. RESULTS: Eight case reports, three case series and a pharmacovigilance survey were identified. CONCLUSION: Whilst D2 receptor agonists appear to increase the risk of triggering psychosis in previously well mothers and those previously diagnosed with schizophrenia, bipolar disorder and postpartum psychosis, bromocriptine appears to pose a much greater risk than cabergoline. When considering the use of pharmacological agents to suppress lactation, physicians should carefully screen patients for a history of psychosis and consider alternatives to moderate this risk.

Treating prolactinoma can prevent autoimmune diseases.

Prolactin (PRL) is a pleiotropic hormone; in addition to a wide variety of endocrine effects, PRL also exhibits immunostimulating effects. Therefore, there is increasing evidence linking PRL with a large number of systemic and organ specific autoimmune diseases. Herein, we report the case of an adolescent girl diagnosed with multiple sclerosis (MS) occurring in the context of untreated prolactinoma evolving since childhood. This raises the exciting question of the involvement of PRL in the pathogenesis of MS. It is likely that early treatment of hyperprolactinemia in this case would have significantly reduced the risk of developing MS or even prevented its occurrence.

Effectiveness of risk minimization measures for cabergoline-induced cardiac valve fibrosis in clinical practice in Italy.

On June 2008, the European Medicines Agency (EMA) introduced changes to the Summary of Product Characteristics (SPC) for cabergoline and pergolide, to reduce the risk of cardiac valvulopathy in users of these drugs. To assess the effectiveness of EMA recommendations in Italian clinical practice, we retrospectively reviewed medical charts of patients with degenerative Parkinsonism treated with cabergoline in three large Italian clinics between January 2006 and June 2012. The prevalence and the severity of cardiac valve regurgitation were assessed in patients who stopped cabergoline therapy prior to June 2008 or continued therapy after that date. In addition, the proportion of patients undergoing echocardiographic examination in each cohort was evaluated. A total of 61 patients were available for evaluation. The proportion of patients who underwent a baseline echocardiographic examination increased from 64 % in the period before the 2008 SPC changes to 71 % among those who continued treatment after that date. However, only 18 and 29 % of patients underwent at least two echocardiographic examinations during the pre-SPC and cross-SPC change period, respectively. No severe cardiac valve regurgitation was documented in any of the study patients using cabergoline either prior or after 26th June 2008. Our findings show that the 2008 changes to the SPC resulted in an increase in physicians' awareness of cabergoline-induced valvulopathy risk in Italy. However, only a small percentage of patients underwent serial echocardiography. Further efforts are needed to achieve better compliance with the prescribing guidelines for cabergoline treated patients in clinical practice.

Giant prolactinomas: clinical manifestations and outcomes of 16 Arab cases.

BACKGROUND: The management of giant prolactinomas remains a major challenge, despite dopamine agonists being the first line of treatment, owing to its efficacy to normalize prolactin levels and reduce tumor volume. The aim of this study is to characterize the therapeutic aspects, manifestations and outcomes of 16 cases of giant prolactinomas admitted at a single tertiary center in Riyadh, Saudi Arabia. METHODS: Retrospective data collection involving 16 Saudi patients diagnosed with giant prolactinoma at the Pituitary Clinic in King Fahad Medical City, Riyadh, Saudi Arabia between January 2006 and July 2012. RESULTS: A total of 16 patients (ten males; six females) with age of diagnosis between 21 and 55 years (mean 34.9 years) were included in the analysis. The most common presenting features include headache, visual defects and sexual dysfunction. Baseline mean serum prolactin level were extremely high for both sexes which eventually decreased by as much as 97% after cabergoline treatment. Serum prolactin concentrations completely normalized in six patients and significantly decreased in five patients 3-5 times that of normal range. Tumor volume also decreased by an average of 86% for males and 87% for females. Two patients had no tumor size change with cabergoline and required surgery. CONCLUSION: Findings indicate that cabergoline provides dramatic clinical improvements with excellent safety profile. Cabergoline should therefore be considered as the primary therapy for giant prolactinomas.

Current drug withdrawal strategy in prolactinoma patients treated with cabergoline: a systematic review and meta-analysis.

BACKGROUND: Cabergoline is a recommended first-line dopamine agonist for prolactinoma treatment, which is withdrawable for some cases. However, the optimal withdrawal strategy and the accurate recurrence rate associated with cabergoline withdrawal remains uncertain. OBJECTIVE: To assess the current recurrence rate of hyperprolactinemia and possible favorable factors associated with cabergoline withdrawal in prolactinoma patients. METHOD: The databases of PubMed, EMBASE, and Web of Science were searched up to May 2014 to identify studies containing data of recurrent hyperprolactinemia in prolactinoma patients after cabergoline withdrawal. Meta-analysis, including sensitivity analysis, meta-regression analysis, and subgroup analysis were performed. RESULTS: When the patients who received cabergoline withdrawal were pooled, it was found that the hyperprolactinemia recurrence rate was 65% by a random effects meta-analysis [95% confidence interval 55-74%]. In a random effects meta-regression adjusting for optimal withdrawal strategies, CAB dose reduced to the lowest level before withdrawal was associated with treatment success (p = 0.006), whereas CAB treatment longer than 2 years showed no trend of effect (p = 0.587). Patients who received the lowest CAB dose and presented a significant reduction in tumor size before withdrawal were more likely to achieve the best success (p < 0.001). CONCLUSIONS: Our meta-analysis shows that hyperprolactinemia recurs after cabergoline withdrawal in a majority of patients. The probability of success favors patients who have achieved normoprolactinemia and considerable reduction in tumor size by low dose of cabergoline treatment. In addition, our study further suggests that a beneficial strategy is associated with tapering CAB dose before withdrawal but not with CAB treatment duration longer than 2 years.

Inhibiting the onset of lactation. Is cabergoline an alternative to bromocriptine?

In late 2014, following a review by the French Health Products Agency (ANSM) and the European Pharmacovigilance Risk Assessment Committee (PRAC), the European Commission restricted the indications for bromocriptine in lactation inhibition to situations in which breastfeeding must be stopped for medical reasons. Some healthcare professionals have asked us whether bromocriptine can be replaced with cabergoline, an option that is already used in practice and authorised in some European countries.

Prolactinoma-associated headache and dopamine agonist treatment.

AIM: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Investigation of impulsivity in patients on dopamine agonist therapy for hyperprolactinemia: a pilot study.

The use of dopamine agonists (DAs) has been associated with increased impulsivity and impulse control disorders in several diseases, including Parkinson's disease. Such an effect of DAs on impulsivity has not been clearly characterized in hyperprolactinemic patients, where DAs are the mainstay of therapy. We studied the effects of DAs on impulsivity in hyperprolactinemic patients treated at a tertiary pituitary center, using validated psychometric tests. Cross-sectional study. Impulsivity was evaluated in 30 subjects, 10 hyperprolactinemic patients on DAs compared to two control groups; one comprising untreated hyperprolactinemic patients (n = 10) and a second group consisting of normoprolactinemic controls with pituitary lesions (n = 10). Measures of impulsivity included both self-report questionnaires as well as laboratory-based tasks. Hyperprolactinemic patients on DAs had a higher score (mean ± SD) in one self-report measure of impulsivity, the attention subscale of the Barratt Impulsiveness Scale (16.2 ± 2.7), as compared to the hyperprolactinemic control group (12.3 ± 2.5) and the normoprolactinemic group (14.7 ± 4.4) (p = 0.04). No statistically significant difference was found between groups with regards to the other impulsivity scales. In the DA-treated group, a correlation was observed between increased impulsivity (as assessed in the Experiential Discounting Task) and higher weekly cabergoline dose (r(2) = 0.49, p = 0.04). The use of DAs in hyperprolactinemic patients is associated with an increase in one aspect of impulsivity. This effect should be further characterized in larger, longitudinal studies.

AACE/ACE Disease State Clinical Review: Dopamine Agonists for Hyperprolactinemia and the Risk of Cardiac Valve Disease.

OBJECTIVE: To review the current literature regarding dopamine agonists (DAs) and the risk of the development of cardiac valve disease. METHODS: PubMed searches were performed to identify all of the available published data on DAs and valve disease in patients with hyperprolactinemia. RESULTS: Most of the available echocardiographic data from patients treated for hyperprolactinemia are from case-control studies, and prospective data are limited. The majority of the studies do not support an increased risk of clinically significant valve disease in hyperprolactinemic patients treated with cabergoline. Evidence for the use of echocardiography is needed to limit unnecessary procedures and healthcare costs. Based on the published literature describing Parkinson's disease (PD) patients, the daily and cumulative doses of cabergoline are important factors. Considerations to minimize exposure to cabergoline, such as surgical resection of adenomas or medication withdrawal in responders, may be appropriate depending on the clinical setting. CONCLUSION: There is no conclusive evidence that cabergoline causes clinically significant cardiac valve disease at the usual doses for the treatment of hyperprolactinemia. Although current recommendations from regulatory agencies advise routine echocardiography for patients receiving cabergoline, evidence-based criteria would be useful both to identify patients at risk and generate appropriate screening protocols.

Lesson of the month (1): cabergoline - 'i eat funny on that'.

We present the case of a patient treated for hyperprolactinaemia with weekly doses of cabergoline for 12 years. Over this time she had suffered from binge eating and compulsive shopping which impacted on her weight and made her finances precarious. We discuss the features of impulse control disorders and suggest that seeking out these side effects in patients taking such agents is important. The behaviours may be embarrassing and patients may not volunteer them, likewise if the doctor dismisses them they may continue unabated, causing significant social harm.

Reconsideration of Surgical Indication for Prolactin-producing Pituitary Tumor Focusing on Visual Impairment.

Prolactin-producing pituitary tumor (PRLoma) is the most prevalent functional pituitary tumor. If the tumor becomes large, vision can be impaired. In contrast to other pituitary tumors, cabergoline (CAB) is extremely effective for PRLoma and has become the first-line treatment. In this study, we examined our experience with the pharmacological and surgical management of PRLomas with visual impairment (VI) to determine whether VI could be a surgical indication. Further, we discussed the function of surgery in situations where the gold standard of PRLoma treatment was CAB administration. Of the 159 patients with PRLomas (age, 13-77 [mean = 36.3] years; men, 29; women, 130) at Tokyo Women's Medical University Hospital from 2009 to 2021, 18 (age, 15-67 [mean = 35.8] years; men, 12; woman, 6) had VI (subjectively, 12; objectively, 6). They started CAB treatment immediately (maximum dose: 0.5 to 6 mg/week; average: 2.17 mg/week). VI improved in 16 patients (88.9%) but did not improve in 2 (11.1%) requiring surgeries. One of the two patients had a parenchymal tumor resistant to CAB, and the other had a cystic tumor due to intratumoral bleeding. Consequently, CAB is the first-line treatment for PRLomas with VI because of its significantly high rate of improvement. However, close and rigorous surveillance is necessary for cases resistant to CAB, and the correct decision is required regarding surgical interventions at proper timing and appropriate surgical approaches considering the purpose of surgery.

Cabergoline as treatment of ovarian hyperstimulation syndrome: a review.

One of the most serious complications of assisted reproduction techniques is ovarian hyperstimulation syndrome (OHSS). OHSS not only increases morbidity and mortality in IFV cycles, but also causes significant other problems, as cancelled in vitro fertilization (IVF) cycles, prolonged hospitalization, causing emotional and sociofinancial consequences. Several treatments for OHSS have been proposed and among these Cabergoline (Cb2). Despite the above-mentioned beneficial effect, Cb2 has not been widely used in everyday's clinical practice. With our study, we try to review all studies with strong evidence examining Cb2 use for OHSS prevention.

Cabergoline use and risk of fibrosis and insufficiency of cardiac valves. Meta-analysis of observational studies.

BACKGROUND: Therapy with ergot-derivative dopamine agonists (ergot-DAs) is suspected to cause or promote the development of insufficiency and regurgitation in previously normal cardiac valves. Thus, we conducted a systematic review and meta-analysis of the literature to determine whether administration of cabergoline, i.e., an ergot-DA used to treat Parkinson's disease (PD) or hyperprolactinemia, is associated with an increased risk of valve regurgitation compared with pharmacological regimens not comprising ergot-DAs or with no therapy. METHODS: Observational studies were selected from the Pubmed and Embase databases. Studies had to have assessed the prevalence, odds, or risk of cardiac valve regurgitation in patients who underwent chronic treatment with cabergoline for PD or hyperprolactinemia compared with patients with the same diseases whose therapy did not include cabergoline or another ergot-DA. Separate meta-analyses were performed for PD and hyperprolactinemia patients. RESULTS: On the basis of five studies, 634 PD patients were taking cabergoline, while 9,120 PD patients were treated with dopa/dopamine decarboxylase inhibitor, alone or associated with a non-ergot DA. Valvular regurgitation of any degree - at one cardiac valve or more - was more frequent in PD patients who were taking cabergoline compared to those treated with a non-ergot DA agent or not treated with any dopamine agonist [adjusted (inverse variance: iv) odds ratio: 7.25 95 % CI: 3.71-14.18; p < 0.0001]. On the other hand, pooled data from seven studies showed that patients with hyperprolactinemia who were taking cabergoline (n = 444) exhibited significantly higher odds of mild- to-moderate tricuspid regurgitation compared to untreated controls (n = 954) [adjusted (iv) odds ratio: 1.92 95 % CI:1.34-2.73; p = 0.0003]. No significant differences in mitral or aortic valve regurgitation were detected between hyperprolactinemic patients taking cabergoline and controls. CONCLUSION: In PD patients, the risk of valvular regurgitation of any grade involving one or more cardiac valves was proven to be strongly associated with cabergoline treatment. Furthermore, based on our results, hyperprolactinemic patients taking cabergoline have an increased risk of mild-to-moderate tricuspid valve regurgitation.

A case of iatrogenic severe mitral regurgitation.

Bromocriptine and cabergoline, ergot derived dopamine receptor agonists used to treat Parkinson's disease and prolactinomas, have been associated with increased risk of cardiac valve disease. Here we present a case of iatrogenic symptomatic severe mitral regurgitation due to these drugs.

[Clinical comparision of alpha dihydroergocryptine against cabergoline in the treatment of the fibrocystic mastopathy]. / Comparación clínica de alfa dihidroergocriptina contra cabergolina en el tratamiento de la mastopatía fibroquística.

BACKGROUND: Fibrocystic breast disease is one of the most frequent conditions of the breast among women from 30 to 49 years, with a frequency of about 60%, hence the interest in studying and treating it with the most advanced and effective resources. OBJECTIVE: To compare the efficacy and adverse events of alpha dihydroergocryptine with cabergoline in patients with fibrocystic breast disease. MATERIAL AND METHODS: A prospective, longitudinal, open, comparative study between alpha-dihydroergocryptine and cabergoline, made in the service of Gynecology and Obstetrics at the Dr. Miguel Silva General Hospital in Morelia, Michoacán. 171 patients diagnosed with fibrocystic breast disease were randomly assigned to the alpha-dihydroergocryptine or the cabergoline group. Assessments were made at baseline and every month subsequently. The following symptoms were evaluated: breast tenderness, breast pain, lumps and nipple discharge. The concentrations of prolactin were determined and an ultrasound was performed at baseline and at 3 and 6 months, patients were questioned about adverse events. RESULTS: 171 patients were included (81treated with alpha-dihydroergocryptine and 90 with cabergoline); 156 completed the study. The age limits were 18 and 51 years. The evolution time prior to study entry was 17.71 +/- 18.3 months for the alpha-dihydroergocryptine group and 18.57 +/- 20.35 for the cabergoline group. 15 patients discontinued treatment due to adverse events (8 of the alpha-dihydroergocryptine group and 7 of the cabergoline group). The most common adverse event was headache. CONCLUSIONS: In this study alpha-dihydroergocryptine was better tolerated and had better clinical response compared with cabergoline; breast pain and breast tenderness disappeared within the first month of treatment. Adverse events were similar for both treatments.

A Case Report of Delusions in a Patient Receiving Cabergoline Therapy for Prolactinoma: Pathophysiology and Proposed Treatment With Aripiprazole.

ABSTRACT: Cabergoline is a dopamine 2 receptor agonist used as first-line treatment of pituitary prolactinomas. Here, we describe the case of a 32-year-old woman with a pituitary prolactinoma who was treated with cabergoline for 1 year, during which time she developed delusions. We also discuss the use of aripiprazole to mitigate the psychotic symptoms, while maintaining the efficacy of cabergoline treatment.