Heart valve disease among patients with hyperprolactinemia: a nationwide population-based cohort study.
- The Journal of clinical endocrinology and metabolism
- Published about 9 years ago
Increased risk of heart valve disease during treatment with certain dopamine agonists, such as cabergoline, has been observed in patients with Parkinson’s disease. The same compound is used to treat hyperprolactinemia, but it is unknown whether this also associates with heart valve disease.
Safety of Long-term Treatment with Cabergoline on Cardiac Valve Disease in Patients with Prolactinomas
- European journal of endocrinology / European Federation of Endocrine Societies
- Published almost 8 years ago
Cabergoline (CAB) has been found to be associated with increased risk of cardiac valve regurgitation in Parkinson’s disease (PD), whereas several retrospective analyses failed to detect a similar relation in hyperprolactinemic patients. The current study aimed at investigating cardiac valve disease before and after 24 and 60 months of continuous treatment with CAB only in patients with hyperprolactinemia.
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.
This mixed treatment comparison is used to compare the adverse effects of eleven different drugs used to treat Parkinson’s disease (PD). The drugs that we compare include the following: ropinirole, rasagiline, rotigotine, entacapone, apomorphine, pramipexole, sumanirole, bromocriptine, piribedil, pergolide, and levodopa.
The aim of this study is to compare the efficacy of bromocriptine (BRC) versus cabergoline (CAB) in patients with giant prolactinomas. We searched MEDLINE, EMBASE, CENTRAL and Clinical Trials.gov for studies dated before March 1st, 2016, that used BRC or CAB for the treatment of patients with giant prolactinomas. Specific eligibility criteria were set to identify articles and cases. The selected articles were reviewed, and the data were extracted for analysis. The compared outcomes included tumor shrinkage, tumor response, normalization of prolactin (PRL) level, and visual field defect (VFD) improvement. Gender differences were also considered. Differences between the groups were assessed using Student’s t test and the chi-square test. Two hundred and forty-five records were identified, and 10 articles and 104 cases met the inclusion criteria. Based on our analysis, CAB is significantly better than BRC in normalizing PRL levels in patients, especially males, with giant prolactinomas (69.4% versus 31.7%, p = 0.01). However, there was no significant difference between the two drugs in terms of tumor shrinkage, tumor response and VFD improvement (p > 0.05) in male or female patients. CAB exhibits significantly better efficacy than BRC in the normalization of PRL levels in male patients with giant prolactinomas. Regarding tumor reduction and VFD improvement, both drugs are comparably effective for patients of both genders. This quantitative and systematic review provides preliminary evidence in favor of CAB as a medical therapy for treating giant prolactinomas in male patients, especially those with extremely high PRL levels.
The dopaminergic treatment represents the primary treatment in prolactinomas which are the most common pituitary adenomas and account for about 40% of all pituitary tumours with an annual incidence of six to ten cases per million population. The dopaminergic treatment includes ergot and non ergot derivatives with high affinity for the dopamine receptors D1 or/and D2. Through the activation of the dopaminergic pathway on pituitary lactotrophs, the dopamine agonists inhibit the prolactin synthesis and secretion, therefore normalizing the prolactin levels and restoring eugonadism, but also lead to tumour shrinkage. Treatment with dopamine agonists has been associated - apart from the common side effects such as gastrointestinal symptoms, dizziness and hypotension - with neuropsychiatric side effects such as impulse control disorders (e.g. pathological gambling, compulsive shopping, hypersexuality and binge eating) both in patients with prolactinomas but also in patients with Parkinson’s disease and restless leg syndrome. They usually have de novo onset after initiation of the dopaminergic treatment and have been mainly reported in patients with Parkinson’s disease, who are being treated with higher doses of dopamine agonists. Moreover, dopamine and prolactin seem to play an essential role in the metabolic pathway. Patients with hyperprolactinemia tend to have increased body weight and an altered metabolic profile with hyperinsulinemia and increased prevalence of diabetes mellitus in comparison to healthy individuals and patients with non-functioning pituitary adenomas. Treatment with dopamine agonists in these patients in short term studies seems to lead to weight loss and amelioration of the metabolic changes. Together these observations provide evidence that dopamine and prolactin have a crucial role both in the regard and metabolic system, findings that merit further investigation in long-term studies.
Presently, the standard of care for prolactinomas, a type of pituitary adenoma, is dopaminergic agents such as bromocriptine and cabergoline. However, dopaminergic agents may induce fibrosis of cardiac valves leading to valvular insufficiency, necessitating surgical treatment of prolactinoma. Fibrosis of prolactinoma can be induced by prolonged medical treatment with bromocriptine, and this usually occurs after years of treatment. In comparison to bromocriptine, there have been no reports of cabergoline-induced fibrosis of prolactinoma. There is a potential for greater emphasis to be placed on assessing the tumour consistency from preoperative MRI scans, or even preoperative contrast-enhanced 3D Fast Imaging Employing Steady-state Acquisition imaging to allow better planning of the surgery. We report a rare case of fibrosis of prolactinoma after cabergoline treatment resulting in its subsequent difficult surgical removal. This patient had early MRI changes of fibrosis of prolactinoma after a short period of 6 months of cabergoline treatment.
Prolactinomas are pituitary tumors with a very low prevalence in childhood and adolescence compared to adulthood. This condition is preferentially treated with dopamine agonists. Resistance to these drugs is rare.
Octamethylcyclotetrasiloxane (D4) and decamethylcyclopentasiloxane (D5) are used as intermediates or monomers in the synthesis of silicon-based polymers for industrial or consumer applications. D4 and D5 may remain as residual monomer in these polymers at less than 1000ppm and may therefore be present as a minor impurity in consumer products. For D5, in addition to the manufacture of polymers, its uses include intentional addition to consumer products, personal care products and some dry- cleaning solvents. Two-year rodent chronic bioassays were conducted with both substances and borderline increases in the incidence of uterine tumors were observed, specifically, benign uterine adenoma with D4 and adenocarcinoma with D5. The effects profile and induction of uterine tumors share some similarity with that seen with chronic exposure to dopamine agonists. The current study investigated the potential for D4 and D5 to elicit dopamine agonist-like effects on estrous cyclicity. Separate groups of reproductively senescent female Fischer 344 rats (F344) were exposed via vapor inhalation to D4 (700ppm, 9.3mg/L) or D5 (160ppm, 2.1mg/L) or to a diet containing 0.0045, 0.045, or 4.5ppm pergolide mesylate (PM), a potent dopamine agonist used here as a reference substance, from 11 through 24 months of age. The primary focus was to characterize the effects of D4 and D5 exposure on estrous cyclicity relative to that observed with PM. As a monitoring effort, circulating endogenous estradiol, progesterone, prolactin and corticosterone levels were evaluated monthly. A blood sample from each rat was obtained via tail vein in the afternoon after the daily inhalation exposure period once every 4 weeks. Histomorphologic examination of the major organs including the reproductive tract was conducted on all animals at study termination. This study has shown that chronic exposure to D4 and D5 can affect cyclicity in the reproductively senescent F344 rat. For each substance the effect on cyclicity involved reduction in the incidence of pseudopregnancy with a shift toward cycles more typical of younger animals. D4 and D5 induced an increase in estrous cycle repetition whereas D4 also increased the incidence of extended estrus. These shifts resulted in animals entering proestrus/estrus significantly more times over the duration of the study than seen in the control group. Similar effects were observed with the reference substance, PM. However, distinct differences in the timing and magnitude of the effects on the estrous cycle and impact on prolactin, progesterone, estradiol, and corticosterone suggest that D4 and D5 are not classical dopamine agonists even though a similar increased incidence of proestrus/estrus was also observed with PM. These results may prove important with respect to understanding D4- and D5-induced uterine tumor response in the F344 rat, given the relationship between increased incidence of uterine endometrium stimulation by endogenous estrogen as a consequence of extended or more frequent proestrus/estrus, uterine tumor risk, and questions of relevance to humans. Recent publications have summarized the existing data on D4 and D5, with emphasis on exploring the biological relevance of the uterine tumors (Klaunig et al., 2016a,b; Franzen et al., 2017; Dekant and Klaunig, 2016; Dekant et al., 2017). The authors concluded that although the mode of action has not yet been fully established, the data, including the findings from this study, indicate that the D4- and D5-induced uterine tumors observed in the rodent chronic bioassays have no relevance for human risk characterization based not only on the distinct species differences in regulation of the reproductive systems, but also the high exposure levels and duration required for expression in rats.
Prolactinomas are the most common functional pituitary tumour. Dopamine agonists (DA) are its principal treatment. The criteria that should guide therapy withdrawal and the factors that influence disease remission or relapse are not yet fully established. Our purpose is to evaluate the proportion of patients who attempted DA withdrawal, and to identify the factors that influence clinicians to try it. In addition, we aim to study the factors that are involved in prolactinoma remission/relapse after therapy withdrawal.