A Genetic Assessment of Dopamine Agonist-Induced Impulse Control Disorder in Patients With Prolactinoma.

CONTEXT: Dopamine agonist (DA)-induced impulse control disorder (ICD) represents a group of behavioral disorders that are increasingly recognized in patients with prolactinoma. OBJECTIVE: We aimed to examine the genetic component of the underlying mechanism of DA-induced ICD. METHODS: Patients with prolactinoma receiving dopamine agonist (cabergoline) treatment were included in the study. These patients were divided into 2 groups: patients who developed ICD due to DA and patients who did not. Patients were evaluated for polymorphisms of the DRD1, DRD3, COMT, DDC, GRIN2B, TPH2, OPRK1, OPRM1, SLC6A4, SLC6A3, HTR2A genes. RESULTS: Of the 72 patients with prolactinoma using cabergoline, 20 were diagnosed with ICD. When patients with and without ICD were compared according to genotype frequencies, OPRK1/rs702764, DRD3/rs6280, HTR2A/rs6313, SLC6A4/rs7224199, GRIN2B/rs7301328, TPH2/rs7305115, COMT/rs4680, DRD1/rs4532 polymorphisms significantly increased in patients with DA-induced ICD. CONCLUSION: Our results show that multiple neurotransmission systems affect DA-induced ICD in patients with prolactinoma.

The economic impact of drying off cows with a dry-off facilitator (cabergoline) compared with 2 methods of gradual cessation of lactation for European dairy farms.

An abrupt method to dry off cows has disadvantages and is considered inappropriate for current dairy cows due to welfare issues and risks for intramammary infections (IMI). A gradual cessation of lactation (by feeding or milking frequency reduction) has been the generally recommended method for drying off cows to prevent these adverse effects. However, a new alternative to the gradual approach is to abruptly stop milking at the same time as using cabergoline (CAB), a prolactin inhibitor. The aim of the study was to compare the net costs of 3 different methods of drying off cows [gradual reduction in feed (referred to as gradual feeding), gradual reduction in milking frequency (referred to as gradual milking), and abrupt cessation of milking with CAB]. A stochastic Monte Carlo simulation model, at cow level, was developed to calculate the net costs of applying these methods. All inputs for the model were based on literature information, authors' expertise, and expert knowledge. The net costs were determined by only including costs and benefits, which varied between the 3 methods. The model simulated a cow from 7 d before the day of drying off until the end of the next lactation. The likelihood of whether a cow was leaking milk early in the dry period was determined. Subsequently, it was determined whether or not the cow will get an IMI during the dry period, where the probability of getting an IMI was higher for cows leaking milk than for cows not leaking milk. If the IMI was not cured during the dry period, the cow had an IMI at calving. Also, milk production and feed requirements were modeled, and labor for applying the drying off method was included. For all methods, the net costs were calculated as the sum of costs for feed during the gradual feed reduction period, costs for applying the gradual-milking method, and the IMI costs during the dry period and lactation, minus the milk revenues during the transition from lactation to the dry period. Under default conditions, the average net cost of abrupt cessation of milking with CAB was €49.6/cow. The data showed that 90% of the net costs ranged from -€13.7 to €307.8/cow. The average net costs for gradual feeding and gradual milking were €99.1 and €71.5/cow, respectively. In conclusion, abrupt cessation of milking with CAB saved €49.5 and €21.9/cow on average compared with gradual feeding and gradual milking, respectively. This difference was mainly due to more milk returns and lower labor and IMI costs during lactation.

Cost-Effectiveness Analysis of Microscopic and Endoscopic Transsphenoidal Surgery Versus Medical Therapy in the Management of Microprolactinoma in the United States.

BACKGROUND: Although prolactinomas are treated effectively with dopamine agonists, some have proposed curative surgical resection for select cases of microprolactinomas to avoid life-long medical therapy. We performed a cost-effectiveness analysis comparing transsphenoidal surgery (either microsurgical or endoscopic) and medical therapy (either bromocriptine or cabergoline) with decision analysis modeling. METHODS: A 2-armed decision tree was created with TreeAge Pro Suite 2012 to compare upfront transsphenoidal surgery versus medical therapy. The economic perspective was that of the health care third-party payer. On the basis of a literature review, we assigned plausible distributions for costs and utilities to each potential outcome, taking into account medical and surgical costs and complications. Base-case analysis, sensitivity analysis, and Monte Carlo simulations were performed to determine the cost-effectiveness of each strategy at 5-year and 10-year time horizons. RESULTS: In the base-case scenario, microscopic transsphenoidal surgery was the most cost-effective option at 5 years from the time of diagnosis; however, by the 10-year time horizon, endoscopic transsphenoidal surgery became the most cost-effective option. At both time horizons, medical therapy (both bromocriptine and cabergoline) were found to be more costly and less effective than transsphenoidal surgery (i.e., the medical arm was dominated by the surgical arm in this model). Two-way sensitivity analysis demonstrated that endoscopic resection would be the most cost-effective strategy if the cure rate from endoscopic surgery was greater than 90% and the complication rate was less than 1%. Monte Carlo simulation was performed for endoscopic surgery versus microscopic surgery at both time horizons. This analysis produced an incremental cost-effectiveness ratio of $80,235 per quality-adjusted life years at 5 years and $40,737 per quality-adjusted life years at 10 years, implying that with increasing time intervals, endoscopic transsphenoidal surgery is the more cost-effective treatment strategy. CONCLUSIONS: On the basis of the results of our model, transsphenoidal surgical resection of microprolactinomas, either microsurgical or endoscopic, appears to be more cost-effective than life-long medical therapy in young patients with life expectancy greater than 10 years. We caution that surgical resection for microprolactinomas be performed only in select cases by experienced pituitary surgeons at high-volume centers with high biochemical cure rates and low complication rates.

Conflict acts as an implicit cost in reinforcement learning.

Conflict has been proposed to act as a cost in action selection, implying a general function of medio-frontal cortex in the adaptation to aversive events. Here we investigate if response conflict acts as a cost during reinforcement learning by modulating experienced reward values in cortical and striatal systems. Electroencephalography recordings show that conflict diminishes the relationship between reward-related frontal theta power and cue preference yet it enhances the relationship between punishment and cue avoidance. Individual differences in the cost of conflict on reward versus punishment sensitivity are also related to a genetic polymorphism associated with striatal D1 versus D2 pathway balance (DARPP-32). We manipulate these patterns with the D2 agent cabergoline, which induces a strong bias to amplify the aversive value of punishment outcomes following conflict. Collectively, these findings demonstrate that interactive cortico-striatal systems implicitly modulate experienced reward and punishment values as a function of conflict.

The role of primary pharmacological therapy in acromegaly.

BACKGROUND AND OBJECTIVES: Primary pharmacological therapy may be the only viable treatment option for many patients with acromegaly, especially those presenting with advanced disease with large inoperable tumors. Long-acting somatostatin analogs are currently the first-line treatment of choice in this setting, where they provide biochemical control and reduce tumor size in a significant proportion of patients. We herein present a brief overview of the role of primary pharmacological therapy in the treatment of acromegaly within the context of Latin America and support this with a representative case study. CASE DESCRIPTION: A 20 year old male presented with clinical and biochemical evidence of acromegaly. The glucose-suppressed growth hormone (GH) was 5.3 µg/L, his insulin-like growth factor-1(IGF-1) was 3.5 times the ULN and serum prolactin greater than 4,000 µg/L. Pituitary MRI revealed a large and invasive mass, extending superiorly into the optic chiasm and laterally into the left cavernous sinus. He was treated with a combination of octreotide and cabergoline with remarkable clinical improvement, normalization of GH and IGF-1 values and striking shrinkage of the adenoma. CONCLUSION: This case illustrates how effective the pharmacological therapy of acromegaly can be and yet at the same time, raises several important issues such as the need for life-long treatment with costly medications such as the somatostatin analogs. Access to these agents may be limited in regions where resources are restricted and clinicians face challenges in order to make the most efficient use of available options.

[Prescription of ergot derivatives for lactation inhibition in France: Current practices]. / Pratiques de prescription des dérivés de l'ergot de seigle dans l'inhibition de la lactation en France.

OBJECTIVES: To provide an overview of ergot derivatives prescription for lactation inhibition in France, either label (bromocriptine 2.5mg and lisuride 0.2mg) or off-label prescription (dihydroergocryptine and cabergoline). PATIENTS AND METHODS: Analysis based on a questionnaire sent to all 618 French maternity wards in 2009, and prescription modalities from social security reimbursement data in the Rhône-Alpes region. RESULTS: The mean response rate to the questionnaire was 43% and main characteristics of respondents in this sample were very close to those found at the national level. The use of bromocriptine (89%) was the most frequently proposed. Dihydroergocryptine and cabergoline were mentioned as first or second alternatives in 39 and 24% of cases, respectively. Lisuride, homeopathy and phytotherapy were very rarely mentioned. The analysis of social security reimbursement data in the Rhône-Alpes region between 2008 and 2009 evidenced an increase in the rate of dihydroergocryptine prescriptions (from 37 to 46%), which were more frequent in women also treated with cardiovascular or psychotropic drugs, while that of bromocriptine decreased. CONCLUSION: This study shows that, in France, the main alternative to bromocriptine for lactation inhibition is the off-label use of dihydroergocryptine followed by cabergoline, which seems to be safer.

The impact in Japan of regulatory action on prescribing of dopamine receptor agonists: analysis of a claims database between 2005 and 2008.

BACKGROUND: Use of the ergot-derived dopamine receptor agonists (cabergoline and pergolide) is associated with an increased risk of cardiac valvulopathy. Pergolide was withdrawn from the US market in 2007 because of the risk of valvular heart disease, while the European Medicines Agency (EMA) required a reduction in the maximum daily dosage of cabergoline and pergolide from 6 mg/day to 3 mg/day in 2008. In Japan, the package inserts of both drugs were revised in April 2007 to request that physicians conduct periodic ultrasonic cardiography (UCG) examinations for patients taking cabergoline or pergolide. Also, through face-to-face communication with medical representatives of drug companies, physicians were informed that use of cabergoline and pergolide has increased the risk of valvulopathy. However, cabergoline and pergolide have remained in wide use, even following the regulatory actions. OBJECTIVE: The objective of this study was to assess the impact of actions, including the package insert revision in April 2007, to encourage periodic UCG. METHODS: Data on monthly claims (January 2005-October 2008) covering 330 000 patients were obtained from a Japanese database vendor. We selected patients ≥40 years of age with Parkinson's disease. The impact of the regulatory action on the proportion of patients with Parkinson's disease prescribed cabergoline or pergolide was assessed by segmented regression analysis and by a statistical model of the rates of UCG examination in patients taking/not taking cabergoline or pergolide before and after the action. We also compared the use of cabergoline and pergolide before and after the action with that of other antiparkinson drugs. RESULTS: Of 574 patients with Parkinson's disease, the proportion of patients prescribed cabergoline or pergolide did not decrease but rather tended to increase after the action when analysed by segmented regression analysis (p = 0.13). Similarly, the proportion of the prevalent and incident users of cabergoline or pergolide did not change between two 19-month periods before and after the action. The adjusted rates of UCG examination per person-year before and after the action were both 0.02 in those not prescribed cabergoline or pergolide, but 0.02 before the action and 0.09 after the action in those taking either drug. The excess UCG examination rate of cabergoline or pergolide attributable to the action was 0.08 per person-year (95% CI 0.03, 0.11). While 1 of 49 (2%) patients taking cabergoline or pergolide had a UCG up to 19 months before the action, 9 of 36 (25%) patients taking cabergoline or pergolide had a UCG up to 19 months after the action. Annual sales from 2004 to 2008 were 195, 195, 170, 110 and 75 billion yen, respectively, and the number of valvulopathy events, including incompetence of aortic/mitral/tricuspid valves and cardiac valve disease, per annual sales from 2004 to 2008 were estimated at 0.23, 0.03, 0.08, 0.25 and 0.19 per billion yen, respectively. CONCLUSIONS: Following the actions in April 2007, no decrease in the use of cabergoline or pergolide occurred, although more patients administered the drug underwent a UCG. However, those undergoing a UCG represented one-quarter of the total number prescribed cabergoline or pergolide. To mitigate the risk, additional risk management tools such as patient registration may be needed to secure careful clinical examination (including UCG examination, if necessary) for cardiac function.

Assessment of cardiac valve dysfunction in patients receiving cabergoline treatment for hyperprolactinaemia.

OBJECTIVE: Cabergoline is a highly effective medical treatment for patients with hyperprolactinaemia. There is an increased risk of valvular heart disease in patients receiving cabergoline for Parkinson's disease. This study examined whether cabergoline treatment of hyperprolactinaemia is associated with a greater prevalence of valvulopathy. DESIGN: Cross-sectional, two-dimensional echocardiographic study performed by a single echocardiographer. PATIENTS: Seventy-two patients (median age 36 years, 19 men) receiving cabergoline for hyperprolactinaemia, and 72 controls prospectively matched for age, sex and cardiovascular risk factors. Measurements Assessment of valvular mobility, regurgitation and morphology. RESULTS: Median cumulative dose exposure for cabergoline was 126 (58-258) mg, and patients had received cabergoline for 53 (26-96) months. The frequency of mild mitral regurgitation was identical (5/72, 7%) in patient and control groups. Mild aortic regurgitation was not significantly different between groups (4/72 [controls] vs 2/72 [patients], P = 0.681). There was only one case of tricuspid regurgitation, which was mild and observed in a cabergoline-treated patient. Nodular thickening of the right coronary cusp, noncoronary cusp or left coronary cusp of the aortic valve was observed at a similar frequency in both groups. There were no cases of extensive thickening of any valvular leaflet. CONCLUSION: Our data demonstrates that there is no association between cabergoline treatment for hyperprolactinaemia and valvulopathy. This study therefore supports continued use of low-dose cabergoline for patients with hyperprolactinaemia.

Prevalence of valvular heart disease in a cohort of patients taking cabergoline for management of hyperprolactinemia.

OBJECTIVE: To determine the prevalence of valvular heart disease in a cohort of patients taking cabergoline for the management of hyperprolactinemia. METHODS: A retrospective review of medical records identified patients with hyperprolactinemia who underwent evaluation at Vanderbilt University Medical Center between January and June 2007. The medical records of those patients who were prescribed cabergoline and who underwent elective echocardiography were reviewed for details pertaining to cardiac valvular abnormalities and cabergoline use. RESULTS: Forty-five patients (mean age, 41 +/- 10 years [SD]) taking 0.91 +/- 0.96 mg of cabergoline per week for a mean duration of 39 +/- 29 months underwent echocardiography. Abnormalities of the cardiac valves were present in 3 patients (7%): 1 patient exhibited mild mitral regurgitation, 1 patient had focal aortic valve thickening, and 1 patient demonstrated mitral valve thickening. We found no significant difference in either the cumulative dose of cabergoline (P = .800) or the duration of cabergoline therapy (P = .745) between those patients with and those without these echocardiographic abnormalities. CONCLUSION: We found echocardiographic valve abnormalities in 3 of 45 patients (7%) who had been prescribed cabergoline for the management of hyperprolactinemia. This prevalence of valvular heart disease after approximately 3 years of cabergoline treatment is no different from that previously reported in normal populations as determined by echocardiography.

Assessment of valvulopathy in Parkinson's disease patients on pergolide and/or cabergoline.

OBJECTIVE: To assess the effect of ergot derivatives on cardiac valves in patients with Parkinson's disease (PD). MATERIALS AND METHODS: Echocardiography was performed on 46 PD patients who used either pergolide or cabergoline (MonoPD) or both (MixPD) for a minimum of 1 year and 49 age-matched healthy controls. Valvular regurgitation was graded as mild, moderate and severe. MonoPD and MixPD groups were compared with regard to demographic features, drug profile and valvulopathy. RESULTS: The PD group had a mean age of 63 years, agonist duration of 3.8 years and agonist equivalent dose of 3.5mg/day. Moderate regurgitation in all three valves was significantly more common in the PD group than the controls. Severe valvular regurgitation was not observed in either group, with the exception of one PD patient. The frequency of valvulopathy and doses of agonists did not differ between MixPD and MonoPD groups. CONCLUSION: PD patients on dopamine ergot agonists are prone to moderate valvular regurgitation more than age-matched controls. However, the frequency of valvulopathy was similar in patients who used either one or more agonists.

Cabergoline : a review of its use in the treatment of Parkinson's disease.

Cabergoline is a synthetic ergoline dopamine agonist with a high affinity for dopamine D2 receptors and a long elimination half-life. This agent provides continuous dopaminergic stimulation with once-daily administration. Adjuvant oral cabergoline is usually well tolerated and effective in controlling symptoms in patients with advanced Parkinson's disease experiencing response fluctuations to long-term levodopa therapy. In patients with early Parkinson's disease, cabergoline (with or without levodopa) is well tolerated and effective in controlling disease symptoms, and may reduce the risk of developing drug-induced motor complications. Data from two pharmacoeconomic analyses suggest that cabergoline may be a cost-effective treatment option versus levodopa in patients with early Parkinson's disease, and highlight the need for further evaluation of the drug in this indication.

Pharmacological approach to the treatment of acromegaly.

The treatment of patients with persistently active acromegaly has been facilitated over the past decade by the advent of highly specific and selective pharmacological agents. Somatostatin analogs, derived from the native inhibitory hormone somatostatin, are available in extended-duration preparations and are effective in reducing serum levels of growth hormone (GH) and insulin-like growth factor-I (IGF-I) as well as in improving the adverse clinical effects of acromegaly. Cabergoline, an agonist with a specificity for the dopamine D-2 receptor, has been shown to suppress IGF-I levels and induce tumor shrinkage in 35 and 50% of patients, respectively. The GH receptor antagonists compete with naturally occurring GH for binding with the GH receptor. As such, pegvisomant normalizes circulating IGF-I levels in 80 to 90% of patients with acromegaly. This last line of therapy should be considered for use in patients in whom surgery and medical therapy with somatostatin and/or dopamine agonists are either ineffective or poorly tolerated.

Cabergoline versus levodopa monotherapy: a decision analysis.

We evaluated the incremental cost-effectiveness of cabergoline compared with levodopa monotherapy in patients with early Parkinson's disease (PD) in the German healthcare system. The study design was based on cost-effectiveness analysis using a Markov model with a 10-year time horizon. Model input data was based on a clinical trial "Early Treatment of PD with Cabergoline" as well as on cost data of a German hospital/office-based PD network. Direct and indirect medical and nonmedical costs were included. Outcomes were costs, disease stage, cumulative complication incidence, and mortality. An annual discount rate of 5% was applied and the societal perspective was chosen. The target population included patients in Hoehn and Yahr Stages I to III. It was found that the occurrence of motor complications was significantly lower in patients on cabergoline monotherapy. For patients aged >/=60 years of age, cabergoline monotherapy was cost effective when considering costs per decreased UPDRS score. Each point decrease in the UPDRS (I-IV) resulted in costs of euro;1,031. Incremental costs per additional motor complication-free patient were euro;104,400 for patients <60 years of age and euro;57,900 for patients >/=60 years of age. In conclusion, this decision-analytic model calculation for PD was based almost entirely on clinical and observed data with a limited number of assumptions. Although costs were higher in patients on cabergoline, the corresponding cost-effectiveness ratio for cabergoline was at least as favourable as the ratios for many commonly accepted therapies.

The assessment of cabergoline efficacy and tolerability in patients with pituitary prolactinoma type.

Prolactinoma is the most frequent type of secreting pituitary tumours. In the treatment, pharmacotherapy with dopamine agonists is considered the first-line option. For many years bromocriptine, a D1 and D2 dopamine receptor agonist, has been the standard medicine for hyperprolactinemic patients. However, the treatment is frequently associated with intolerance or resistance. Recently cabergoline, a long acting, ergoline-derived, selective D2 agonist has become available and has been promoted as the initial treatment. Therefore the object of four studies was to assess the efficacy and tolerability of cabergoline in patients with prolactin-secreting pituitary adenomas. 17 patients, 13 women at the age of 21-55 years (average 37.1) and 4 men at the age of 29-45 years (average 36.3), with pathological hyperprolactinemia due to pituitary tumours were involved in the study. In all patients the increased pretreatment concentration of PRL was observed, ranging from 1047 to 1678 mlU/ml (mean 1369 mlU/ml). MRI scans revealed microprolactinomas in 11 (64.7%) cases and macroadenomas in 6 (35.3%) cases. None of the patients had previously undergone pituitary surgery and all of them were newly diagnosed, previously untreated. The patients were treated with cabergoline for 6 months. Cabergoline therapy was started at a dose of 0.5 mg twice a week for the first two months, then the dose was decreased to a 0.25 mg twice a week and finally maintained at 0.25 mg a week. After 6 months of the therapy, the normalization of serum PRL concentrations (from mean 1358 mlU/ml to mean 420 mlU/ml; p < 0.001) was achieved in 13 (76.5%) patients (8 with microprolactinoma and 5 with macroprolactinoma). In the remaining 4 patients PRL levels remained elevated but were decreased from mean 1403 mIU/ml to mean 812 mIU/ml. There were no differences, regarding CAB efficacy in lowering PRL levels, between patients with micro- and macroadenomas (p > 0.05). About 90% women resumed menstrual cycles in our study. All the other clinical pretreatment symptoms disappear in the course of the therapy. The tumour shrinkage, confirmed by control MRI was noted in 2 patients (33%) with macroprolactinoma. Cabergoline was tolerated satisfactorily by all our patients. The results have confirmed a high efficacy and a very good tolerability of CAB in the treatment of patients with pituitary adenomas. Together with a very convenient administration, such therapy can provide a very good patient compliance thus should be considered the first line option in patients with prolactinomas.

Detecting dose-response using contrasts: asymptotic power and sample size determination for binomial data.

Recently, Stewart and Ruberg proposed the use of contrast tests for detecting dose-response relationships. They considered in particular bivariate contrasts for healing rates and gave several possibilities of defining adequate sets of coefficients. This paper extends their work in several directions. First, asymptotic power expressions for both single and multiple contrast tests are derived. Secondly, well known trend tests are rewritten as multiple contrast tests, thus alleviating the inherent problem of choosing adequate contrast coefficients. Thirdly, recent results on the efficient calculation of multivariate normal probabilities overcome the traditional simulation-based methods for the numerical computations. Modifications of the power formulae allow the calculation of sample sizes for given type I and II errors, the spontaneous rate, and the dose-response shape. Some numerical results of a power study for small to moderate sample sizes show that the nominal power is a reasonably good approximation to the actual power. An example from a clinical trial illustrates the practical use of the results.

Assessment of cabergoline as a reproductive inhibitor in coyotes (Canis latrans).

The efficacy of three oral formulations (gelatin capsule, tablet, oil base) and five dosages (50, 100, 250, 500, 1000 microg) of cabergoline to disrupt reproduction in coyotes (Canis latrans) was evaluated. The type of formulation used had no effect on plasma progesterone and prolactin concentrations or on mean litter size. No adverse side effects (for example, vomiting, anorexia, diarrhoea) were observed despite the use of doses of up to 20 times the therapeutic dose used for domestic dogs and cats. All coyotes treated with 50, 100, 250 and 500 microg cabergoline whelped, but plasma progesterone concentrations in these coyotes were lower (P < or = 0.07) than in control animals at day 7 after treatment. Ten of 11 females treated with 1000 microg cabergoline whelped, but progesterone concentrations in these coyotes were lower than in control animals up to day 14 after treatment (P < or = 0.04). Dosages of 1000 microg cabergoline decreased blood serum prolactin (P < or = 0.10) and progesterone (P < or = 0.06) concentrations, but apparently failed to decrease progesterone below the threshold necessary to maintain pregnancy in all but one animal. However, progressive inhibition of prolactin and progesterone with increasing doses of cabergoline indicated that higher dosages might be effective in coyotes. Survival of pups born to cabergoline-treated females was not different (P < 0.001) from that of pups born to control females, but mean litter size was smaller for females treated with cabergoline (P < or = 0.073) than for the control females. Although all cabergoline treatments in this study were ineffective at preventing reproduction in coyotes, progressive inhibition of prolactin and progesterone with increasing dosages of cabergoline indicates that higher doses might be effective in preventing reproduction in coyotes. However, the physiological differences from other canine species in dopamine D2 receptors and mechanisms of luteal support may ultimately prevent the use of cabergoline for reproductive control in coyotes.

Resistance to cabergoline as compared with bromocriptine in hyperprolactinemia: prevalence, clinical definition, and therapeutic strategy.

To evaluate the prevalence of resistance to cabergoline treatment, we studied 120 consecutive de novo patients (56 macroadenoma, 60 microadenoma, 4 nontumoral hyperprolactinemia) treated with cabergoline (CAB) compared with 87 consecutive de novo patients (28 macroadenoma, 44 microadenoma, 15 nontumoral hyperprolactinemia) treated with bromocriptine (BRC) for 24 months. Resistance was evaluated as inability to normalize serum PRL levels (first end point) and to induce tumor shrinkage (second end point). After 24 months, PRL normalization and tumor shrinkage after CAB and BRC treatments, respectively, were obtained in 82.1% and 46.4% of macroprolactinomas (P < 0.001) and in 90% vs. 56.8% of microprolactinomas (P < 0.001). The median doses of CAB and BRC able to fulfill the two criteria of treatment success were 1 mg/wk and 7.5 mg/d in macroprolactinomas, 1 mg/wk and 5 mg/d in microprolactinomas, and 0.5 mg/wk and 3.75 mg/d in nontumoral hyperprolactinemia. Hyperprolactinemia persisted in 17.8% of macroprolactinomas, 10% of microprolactinomas, and after CAB at doses of 5-7 mg/wk and in 53.6% of macroprolactinomas, 43.2% of microprolactinomas, and 20% of nontumoral hyperprolactinemic patients, after BRC at doses of 15-20 mg/d. In these resistant macro- and microprolactinomas, the maximal tumor diameter was reduced by 43.7 +/- 3.6% and 22.1 +/- 3.7% and by 59.3 +/- 7.1% and 4.3 +/- 2.1% after CAB and BRC, respectively (P < 0.001). In conclusion, long-term CAB treatment induced the successful control of hyperprolactinemia associated with tumor shrinkage in a higher proportion of patients than did BRC treatment. In a small number of patients (i.e. 17.8% of macroprolactinomas and 10% of microprolactinomas), however, CAB treatment did not normalize serum PRL levels despite reducing tumor mass, even at very high doses. Therefore, an absence of tumor shrinkage cannot be considered as end point to indicate resistance to CAB, and increasing the dose of CAB higher than 3 mg/wk does not seem to be helpful in controlling PRL hypersecretion.