Drug resistance mechanisms in dopamine agonist-resistant prolactin pituitary neuroendocrine tumors and exploration for new drugs.

BACKGROUND: The treatment of dopamine agonists (DA) resistant prolactinomas remains a formidable challenge, as the mechanism of resistance is still unclear, and there are currently no viable alternative drug therapies available. This study seeks to investigate the mechanism of DA resistance in prolactinomas and identify new potentially effective drugs. METHODS: To explore the mechanism of DA resistance in prolactinomas, this study conducted transcriptome sequencing analysis on 27 cases of DA-resistant prolactinomas and 10 cases of sensitive prolactinomas. In addition, single-cell sequencing analysis was performed on 3 cases of DA-resistant prolactinomas and 3 cases of sensitive prolactinomas. Furthermore, to screen for potential therapeutic drugs, the study successfully established an organoids model for DA-resistant prolactinomas and screened 180 small molecule compounds using 8 organoids. The efficacy of the identified drugs was verified through various assays, including CCK-8, colony formation, CTG, and flow cytometry, and their mechanisms of action were confirmed through WB and IHC. The effectiveness of the identified drugs was evaluated both in vitro and in vivo. RESULTS: The results of transcriptome sequencing and single-cell sequencing analyses showed that DA resistance in prolactinomas is associated with the upregulation of the Focal Adhesion (FA) signaling pathway. Additionally, immunohistochemical validation revealed that FAK and Paxillin were significantly upregulated in DA-resistant prolactinomas. Screening of 180 small molecule compounds using 8 organoids identified Genistein as a potentially effective drug for DA-resistant prolactinomas. Experimental validation demonstrated that Genistein inhibited the proliferation of pituitary tumor cell lines and organoids and promoted apoptosis in pituitary tumor cells. Moreover, both the cell sequencing results and WB validation results of the drug-treated cells indicated that Genistein exerts its anti-tumor effect by inhibiting the FA pathway. In vivo, experiments also showed that Genistein can inhibit subcutaneous tumor formation. CONCLUSION: DA resistance in prolactinomas is associated with upregulation of the Focal Adhesion (FA) signaling pathway, and Genistein can exert its anti-tumor effect by inhibiting the expression of the FA pathway.

Management of Impulse Control and Related Disorders in Parkinson's Disease: An Expert Consensus.

BACKGROUND: Impulse-control and related behavioral disorders (ICBDs) significantly impact the lives of Parkinson's disease (PD) patients and caregivers, with lasting consequences if undiagnosed and untreated. While ICBD pathophysiology and risk factors are well-studied, a standardized severity definition and treatment evidence remain elusive. OBJECTIVE: This work aimed to establish international expert consensus on ICBD treatment strategies. To comprehensively address diverse treatment availabilities, experts from various continents were included. METHODS: From 2021 to 2023, global movement disorders specialists engaged in a Delphi process. A core expert group initiated surveys, involving a larger panel in three iterations, leading to refined severity definitions and treatment pathways. RESULTS: Experts achieved consensus on defining ICBD severity, emphasizing regular PD patient screenings for early detection. General treatment recommendations focused on continuous monitoring, collaboration with significant others, and seeking specialist advice for legal or financial challenges. For mild to severe ICBDs, gradual reduction in dopamine agonists was endorsed, followed by reductions in other PD medications. Second-line treatment strategies included diverse approaches like reversing the last medication change, cognitive behavior therapy, subthalamic nucleus deep brain stimulation, and specific medications like quetiapine, clozapine, and antidepressants. The panel reached consensus on distinct treatment pathways for punding and dopamine dysregulation syndrome, formulating therapy recommendations. Comprehensive discussions addressed management strategies for the exacerbation of either motor or non-motor symptoms following the proposed treatments. CONCLUSION: The consensus offers in-depth insights into ICBD management, presenting clear severity criteria and expert consensus treatment recommendations. The study highlights the critical need for further research to enhance ICBD management. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Paradoxical effect of dopamine-agonists on IGF-1 in patients with prolactinoma: the role of weight.

PURPOSE: An increase of IGF-1 has been reported during therapy with dopamine agonists (DA) for prolactinomas; in such cases a correct diagnosis is pivotal to avoid an unnecessary reduction or withdrawal of DA, which are needed to maintain normal prolactin levels. This study was aimed to measure IGF-1 levels, at baseline and during follow-up, in a cohort of patients with prolactinoma, treated with cabergoline, stratified by body mass index. METHODS: We retrospectively enrolled 35 patients (15 F/20 M; age m ± SD, years: 43.4 ± 13.7) with prolactinoma (21 microadenomas and 14 macroadenomas) who were followed-up at the Endocrinology Unit, in Siena, and with available pituitary hormone assessment at baseline and during follow-up (m ± SD, years: 2.74 ± 0.55). RESULTS: IGF-1 increased in the whole cohort, but remaining within normal range, except two patients, in whom acromegaly was ruled out with oral glucose tolerance test. After dividing patients by weight, this trend was confirmed only in subjects with overweight and obesity (OV/OB) (p = 0.04). Interestingly, the reduction of prolactin levels was significantly greater in the OV/OB compared to normal-weight patients (median decrease of 97.5% versus 88.2%, p = 0.04). CONCLUSIONS: Since DA and normalization of prolactin are known to improve insulin sensitivity, we speculated they have favored the increase of IGF-1 in OV/OB. Our results should be confirmed and the hypothesis proven by further studies.

Risk of Suicidal Ideation and Behavior Following Early-Onset Idiopathic Restless Legs Syndrome Treatment.

PURPOSE: To estimate incidence rates of suicidal ideation and behavior following treatment initiation with gabapentinoids or dopamine agonists (DAs) in patients with newly diagnosed early-onset idiopathic restless legs syndrome (RLS) and to examine suicidal behavior risk, comparing between those receiving gabapentinoids and DAs. METHODS: A new user retrospective cohort study using MarketScan claims data from 2012 to 2019 was conducted. Exposures were monotherapy gabapentinoids or DAs initiated within 60 days of new RLS diagnosis. Three varying outcome measures of suicidality were examined and incidence rates were calculated for each. A log-binomial regression model the estimated relative risk (RR) of the outcomes with gabapentinoids. Propensity score weighting adjusted for baseline covariates, including age, substance use disorders, hyperlipidemia, antipsychotic use, hypnotic/sedative use, and mood stabilizer use, which were most imbalanced before weighting. RESULTS: The cohort included 6672 patients, with 4986 (74.7%) initiating a DA and 1686 (25.3%) initiating a gabapentinoid. Incidence rates for all outcome measures were higher in the gabapentinoid group (suicidality: 21.6 vs. 10.7 per 1000 person-years; suicidality with self-harm: 23.0 vs. 11.1 per 1000 person-years; overdose- and suicide-related events: 30.0 vs. 15.5 person-years). Associated risk of suicidality (adjusted RR, 1.27 [95% CI, 0.86-1.88]); suicidality with self-harm (adjusted RR, 1.30 [95% CI, 0.89-1.90]); or overdose- and suicide-related events (adjusted RR, 1.30 [95% CI, 0.93-1.80]) was not significant with gabapentinoids. CONCLUSIONS: Incidence rates for suicidal ideation and behavior were higher among the gabapentinoid group, although increased risk was not detected after adjustment. A possible signal cannot be ruled out given limitations of the data and rarity of the outcome.

Quality of life in Prolactinoma: A systematic review.

BACKGROUND: Prolactinomas are common tumours that significantly reduce quality-of-life (QOL) due to sellar mass effect, secondary hypogonadism, and the peripheral effects of prolactin. Understanding the factors that influence QOL would provide insights into therapeutic targets to optimise patient outcomes and improve wellbeing in prolactinoma. METHODS: A systematic review was performed in accordance with the PRISMA statement. Studies that reported patient QoL using validated metrics were included. Bias and methodological rigour were assessed using the MINORS criteria. RESULTS: A total of 18 studies were identified studies were available for review, comprising 877 patients. Most were small cross-sectional studies at high risk of bias. Prolactinoma exhibit worse QOL than healthy controls, particularly mental and psychosocial wellbeing. QOL is also worse than patients with non-functional adenomas, but better than those with Cushing's disease and acromegaly. QOL correlates with prolactin levels, and approaches population baseline with prolonged biochemical control. Dopamine agonists and surgery both improve overall QOL, however improvements are more rapid with surgery. CONCLUSION: Poor quality of life in prolactinoma is multifactorial, related to biochemical control, side effects of therapy, and sellar mass effect. Targeting persistent symptoms, reducing healthcare costs, and reducing side-effects of therapy are avenues to improving QOL in patients with prolactinoma.

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.

Characteristics and outcomes of men with erectile dysfunction as the presenting symptom due to a lactotroph adenoma.

PURPOSE: Erectile dysfunction (ED) is frequently underreported in men suffering from prolactinomas and can be challenging to manage. Both dopamine agonists (DAs) and transsphenoidal surgery (TSS) correct hyperprolactinemia and restore gonadal function. However, there is scarce data regarding their effectiveness in correcting ED over the long term. METHODS: This study is a retrospective single-center comparative cohort study analyzing men diagnosed with prolactinomas, both with and without confirmed erectile dysfunction (ED) at diagnosis. Independent risk factors for persistent ED over the long term were examined using multivariate logistic regression. RESULTS: Among the 39 men with lactotroph adenomas, ED was one of the presenting symptoms in 22 (56%). The mean age at diagnosis was 45 ± 12 years. Surgery was the primary treatment in 6 (27%) ED patients and 8 (47%) non-ED patients. After a mean follow-up of 74 ± 48 months, remission from hyperprolactinemia was achieved in the majority (76%) of men: 71% in the non-ED cohort and 81% in the ED group (p = 0.70), regardless of the primary treatment strategy (surgical 84% versus medical 72%, p = 0.46). Long-term remission of ED was noted in 16 (73%) patients. Interestingly, high baseline BMI levels emerged as potential risk factors for persistent ED over the long term (OR 1.4, 95%CI 1.0-1.9; p = 0.04), while neither the initial adenoma size nor the primary treatment strategy (i.e., TSS vs. DAs) reached statistical significance. CONCLUSIONS: Correcting hyperprolactinemia and its associated hypogonadism significantly improves ED in the majority of men with prolactinomas over the long term, regardless of the primary treatment strategy employed. In addition to addressing endocrine deficiencies, the early initiation of weight control programs may be considered for men with lactotroph adenomas and ED. Although our study suggests an association between BMI and the risk of persistent ED, further research is needed to establish any causal relationships.

Preoperative treatment with dopamine agonist therapy influences surgical outcome in prolactinoma: a retrospective single-center on 159 patients.

INTRODUCTION: Prolactinoma account to the most common pituitary adenomas and current therapy regime constitutes of dopamine agonist therapy (DA) and surgery in selected cases [17]. Due to tumor fibrosis induced by previous DA therapy, surgical removal can be challenging though. Therefore, this study investigates how preoperative DA usage influences perioperative treatment and surgical outcome in prolactinoma and aims to ascertain whether a specific subgroup of prolactinoma patients could derive greater benefit from exclusive surgical intervention. METHODS: We retrospectively analyzed n = 159 surgically treated and histologically confirmed prolactinomas in the sella region from 2013-2022 in our institution. Clinical, radiological and surgical features were analyzed. Univariate and multivariate analyses were performed. RESULTS: Out of total of 159 prolactinoma patients, 83.6% received previous treatment with DA followed by surgery, while only 16.4% received exclusive surgery. Both groups presented similar initial tumor volumes (1.9cm3 vs. 1.5cm3, p = 0.59) and equal preoperative prolactin levels (PRL) (199.7 µg/l vs. 191.0 µg/l, p = 0.44). Surgical procedures took significantly longer when patients received prior DA treatment (79 min. vs. 70 min., p = 0.0479). Six months after surgery, pretreated patients revealed significantly higher PRL compared to non-treated (107 g/l vs. 8.64 µg/, p = 0.0009). Additionally, untreated microprolactinoma presented a remission of 100%, whereas pretreated exhibited a remission rate of 88.75%. CONCLUSION: The current study demonstrates that prior DA treatment is associated with significantly longer surgeries, higher recurrence rates and lower rates of normalization of PRL levels after surgery, particularly in microprolactinomas and support the latest recommendations of the Pituitary Society's Consensus Statement 2023, which favors the option of surgery alone as first-line therapy for microprolactinomas.

Clinical experience with bromocriptine for central hyperthermia after brain insult.

INTRODUCTION: Bromocriptine is a dopamine receptor agonist used for central hyperthermia with limited data. We describe our single-center experience utilizing bromocriptine for central hyperthermia, including the population treated, most common dosing regimens, adverse events, and discontinuation reasons. METHODS: A retrospective study was conducted screening patients who were admitted to intensive care units for acute neurological insults and administered bromocriptine for central hyperthermia between April 2016 and September 2022. Baseline characteristics, disease severity markers, and bromocriptine doses were collected. Body temperatures prior to the first dose of bromocriptine, at the time of dose, and after each dose were recorded. Co-administration of additional hyperthermia management therapies was noted. RESULTS: Thirty patients were included. The most common diagnosis was traumatic brain injury (TBI) (N = 14). The most common reason for discontinuation was resolution of indication (N = 14). Discontinuation due to mild adverse effects occurred in four patients; hepatotoxicity was the most common. There was a paired mean difference of -0.37°C (p = 0.005) between temperatures before and after bromocriptine initiation. CONCLUSION: Bromocriptine is a potential therapy for the management of central hyperthermia in patients with severe acute neurologic insults who have failed other therapies. Bromocriptine was well tolerated and associated with a low incidence of adverse events.

Tyrosine Hydroxylase Inhibitors and Dopamine Receptor Agonists Combination Therapy for Parkinson's Disease.

There are currently no disease-modifying therapies for Parkinson's disease (PD), a progressive neurodegenerative disorder associated with dopaminergic neuronal loss. There is increasing evidence that endogenous dopamine (DA) can be a pathological factor in neurodegeneration in PD. Tyrosine hydroxylase (TH) is the key rate-limiting enzyme for DA generation. Drugs that inhibit TH, such as alpha-methyltyrosine (α-MT), have recently been shown to protect against neurodegeneration in various PD models. DA receptor agonists can activate post-synaptic DA receptors to alleviate DA-deficiency-induced PD symptoms. However, DA receptor agonists have no therapeutic effects against neurodegeneration. Thus, a combination therapy with DA receptor agonists plus TH inhibitors may be an attractive therapeutic approach. TH inhibitors can protect and promote the survival of remaining dopaminergic neurons in PD patients' brains, whereas DA receptor agonists activate post-synaptic DA receptors to alleviate PD symptoms. Additionally, other PD drugs, such as N-acetylcysteine (NAC) and anticholinergic drugs, may be used as adjunctive medications to improve therapeutic effects. This multi-drug cocktail may represent a novel strategy to protect against progressive dopaminergic neurodegeneration and alleviate PD disease progression.

Levodopa versus levodopa sparing in early parkinson's disease: can we meet halfway?

Monotherapy is the recommended initial treatment for early Parkinson's disease. The pharmacological options for initial treatment include dopaminergic agonists, monoamine oxidase B inhibitors, and levodopa formulations. Several factors should be considered when selecting the optimal treatment, such as disease severity, disease duration, age, activity level, and the risk of developing motor and non-motor complications. Early evidence on the potential role of levodopa formulations in the risk of dyskinesia led to levodopa aversion in the late 1990s and early 2000s, favoring the use of levodopa-sparing options like dopamine agonists. This shift resulted in an increase in behavioral adverse effects, such as impulse control disorders, leading to a subsequent dopamine agonist aversion in the mid-2000s. This review aims to provide a comprehensive evaluation of the existing literature regarding the benefits and drawbacks of levodopa versus levodopa-sparing strategies in drug-naive early-stage Parkinson's disease.

A decision support system based on recurrent neural networks to predict medication dosage for patients with Parkinson's disease.

Using deep learning has demonstrated significant potential in making informed decisions based on clinical evidence. In this study, we deal with optimizing medication and quantitatively present the role of deep learning in predicting the medication dosage for patients with Parkinson's disease (PD). The proposed method is based on recurrent neural networks (RNNs) and tries to predict the dosage of five critical medication types for PD, including levodopa, dopamine agonists, monoamine oxidase-B inhibitors, catechol-O-methyltransferase inhibitors, and amantadine. Recurrent neural networks have memory blocks that retain crucial information from previous patient visits. This feature is helpful for patients with PD, as the neurologist can refer to the patient's previous state and the prescribed medication to make informed decisions. We employed data from the Parkinson's Progression Markers Initiative. The dataset included information on the Unified Parkinson's Disease Rating Scale, Activities of Daily Living, Hoehn and Yahr scale, demographic details, and medication use logs for each patient. We evaluated several models, such as multi-layer perceptron (MLP), Simple-RNN, long short-term memory (LSTM), and gated recurrent units (GRU). Our analysis found that recurrent neural networks (LSTM and GRU) performed the best. More specifically, when using LSTM, we were able to predict levodopa and dopamine agonist dosage with a mean squared error of 0.009 and 0.003, mean absolute error of 0.062 and 0.030, root mean square error of 0.099 and 0.053, and R-squared of 0.514 and 0.711, respectively.

A comprehensive update on the ADMET considerations for α2δ calcium channel ligand medications for treating restless legs syndrome.

INTRODUCTION: Restless legs syndrome/Willis-Ekbom disease (RLS/WED) is a sleep-related sensory-motor disorder associated with poor sleep quality and impaired daily functioning. In patients affected by chronic RLS/WED, a pharmacological therapy is recommended. International guidelines suggest to start the treatment with a α2δ calcium channel ligand in most cases, unless contraindicated. AREAS COVERED: The present review is based on an extensive Internet and PubMed search from 1986 to 2024. Our purpose is to describe the absorption, distribution, metabolism, and toxicology (ADMET) of the α2δ ligands, with common consideration for the therapeutic class, specificities of different compounds, efficacy, and safety in relation to other treatment options. EXPERT OPINION: α2δ ligands are quite similar in their ADMET profiles, sharing most of the pharmacokinetics and potential adverse effects. However, we highlight the linear kinetic of gabapentin enacarbil and pregabalin, differently from gabapentin. α2δ ligands are safe and effective for the treatment of RLS/WED. Additional benefits can be obtained in comorbid insomnia, chronic pain syndromes, history of impulse control disorder, and comorbid anxiety. The use of α2δ ligands is associated with poor risk of augmentation. We still need new long-term safe and effective treatments, which could be developed along with our knowledge of RLS/WED pathophysiology.

Connectome-guided initiation of dopamine agonists facilitates cognitive recovery after frontal lobe resection: A case report.

Abulia is a common problem that manifests following various brain conditions, including brain surgeries. Abulia is felt to be related to dysfunction with the brain's dopamine-dependent circuitry. The role of default mode network (DMN) in its pathogenesis is crucial. In this case report, we detail the presentation of abulia in an elderly woman following surgical resection of a right frontal glioblastoma involving the DMN. Connectomic imaging was used pre-operatively and post-operatively, demonstrating disruption of regions integral to the DMN and the central executive network. We observed a significant cognitive improvement following the administration of levodopa and carbidopa. Preoperative assessment of both anatomical and functional networks can help ensure surgical safety and predict postoperative deficits. This evaluation not only enhances preparedness and facilitates early case diagnosis but also expedites the initiation of prompt and potentially targeted treatments. This case highlights the potential efficacy of levodopa and carbidopa in addressing DMN dysfunction and broadly suggests the potential for connectomics-guided post-operative therapies.

Medication refractory restless legs syndrome: Real-world experience.

BACKGROUND: Restless Legs Syndrome (RLS), impacting 5-13% of the population, poses challenges in long-term management. A knowledge gap exists in predicting resistance to first-line therapies. OBJECTIVE: To identify demographic and clinical factors predictive of refractory cases. METHODS: This retrospective study, conducted at the Parkinson's Disease Center and Movement Disorders Clinic, Baylor College of Medicine, Houston, Texas (January 2018 to September 2023) identified all patients with RLS evaluated during the pre-specified period and compared clinical and demographic data between medication-refractory ("malignant") group and "benign" cohort. RESULTS: Among 132 patients with RLS, 23 (17.4%) were categorized as medication-refractory. This cohort was characterized by a significantly lower mean age at onset (39.3 vs. 53.5 years, p = 0.0005), longer disease duration (26.7 vs. 14.0 years), and a higher prevalence of a positive family history of RLS among first-degree relatives compared to the "benign" group (56.5% vs. 15.5%, p = 0.003). Furthermore, compared to the "benign" group, in the refractory group dopamine agonists were initiated as the primary medication at a significantly higher rate (p = 0.006). CONCLUSION: Our study found that a younger age at disease onset, prolonged disease duration, initial use of dopamine agonists, and a positive family history increased the likelihood of refractory RLS. We caution against the use of dopamine agonists, especially in young patients with RLS. Additionally, botulinum toxin might be considered a viable second-line treatment, especially for patients with otherwise medically-refractory RLS.

Comparing pyridoxine with dopaminergic agonists (cabergoline and bromocriptine): Unveiling the strategy for lactation inhibition - A systematic review of clinical trials.

This systematic review aims to evaluate the efficacy and safety of Pyridoxine compared to Dopaminergic agonists (cabergoline and bromocriptine) in post-partum lactation inhibition. Cochrane Central, PubMed/MEDLINE, Cochrane Central, ScienceDirect, ClinicalTrials.gov, Web of Science, CINAHL and Google Scholar, covering the period from inception to November 2023. Additionally, the bibliographies of included articles and previous meta-analyses were screened for any relevant articles. The systematic review was conducted according to the Cochrane Handbook for Systematic Reviews of Interventions. The outcomes of interest encompassed inhibition of lactation, breast pain/tenderness, breast engorgement, milk secretion, fever, mastitis, prolactin level and adverse events related to pyridoxine, cabergoline and bromocriptine. Methodological quality assessment was conducted using the Cochrane risk of bias assessment tool for rigorous evaluation. Three clinical trials assessed the effectiveness of pyridoxine and dopaminergic agents (cabergoline and bromocriptine) for lactation inhibition. It was assessed by using different assessment methods such as a scale for milk secretion, serum prolactin levels, and questionnaires for assessing breast engorgement, breast pain, and milk leakage. On the global assessment of the therapeutic efficacy of dopaminergic agents, it was found that there was significant inhibition of lactation as compared to pyridoxine (p < 0.001). In conclusion, this systematic review contributes significant insights into lactation inhibition interventions. Dopaminergic agonists, specifically cabergoline and bromocriptine, stand out as more effective and tolerable choices compared to Pyridoxine. These findings provide a foundation for informed clinical decisions and underscore the need for careful consideration of lactation inhibition strategies in diverse clinical contexts.

Dopamine agonists in restless leg syndrome treatment and their effects on sleep parameters: A systematic review and meta-analysis.

BACKGROUND: Dopamine agonists (DAs) constitute the standard therapeutic scheme for restless leg syndrome (RLS) because they have been proven to be effective. However, DAs may change sleep parameters, thus having adverse effects on patient condition. This meta-analysis clarified the effects of DAs used in RLS treatment on the sleep architecture. METHODS: PubMed, Embase, and Cochrane Central databases were searched for randomized control trials (RCT) (up to October 2023) that discussed the effects of DAs on sleep architecture in patients with RLS. A meta-analysis employing a random-effects model was conducted. The patients were divided into subgroups according to individual DAs and treatment duration (1 day or ≥4 weeks). RESULTS: Thirteen eligible randomized placebo-controlled trials were included in the assessment. The effects of three DAs (i.e., pramipexole, ropinirole, and rotigotine) on rapid eye movement (REM) sleep, slow-wave sleep (SWS), and sleep efficiency (SE) were analyzed. Overall, pramipexole significantly improved SE but decreased the percentage of REM sleep among treated patients. Ropinirole also enhanced SE compared with the placebo group. Rotigotine did not affect SE and REM sleep. Subgroup analysis found that pramipexole used for 1 day and ≥4 weeks significantly diminished the percentage of REM sleep. Ropinirole used for 1 day showed similar REM sleep patterns. Finally, none of the three DAs affected SWS. CONCLUSIONS: This meta-analysis demonstrated that DAs significantly affect sleep parameters.

Real-world value of cabergoline in the treatment of acromegaly.

Cabergoline is an ergot derivative long-acting dopamine receptor 2 (DR2) selective agonist administered orally and widely used for the treatment of prolactin-secreting adenomas and Parkinson's disease. DR2 is expressed in most somatotroph adenomas. In acromegaly, cabergoline is used off-label and its role is limited by the relatively modest efficacy for achieving hormonal remission and thus, it is largely indicated in patients with mild elevation of GH/IGF-I postoperatively. It can be given as monotherapy, usually at a higher weekly dose than usually required to treat prolactinomas, but also as an add-on treatment in patients partially responding to the somatostatin receptor ligands octreotide or lanreotide. IGF-1 normalization with cabergoline can be achieved in about a third of the patients. Low baseline IGF-1 level (below 1.5 x ULN) before cabergoline initiation is a good predictor for remission. Combination treatment with the GH receptor antagonist pegvisomant can also be beneficial. The inexpensive, well-tolerated and convenient oral administration of cabergoline makes it an attractive medical therapy for active acromegaly.

Prolactinoma in postmenopausal women: a systematic review.

IMPORTANCE: Prolactinomas occurring during the reproductive period exhibit a characteristic behavior. There are, however, gaps in the literature regarding the behavior of these tumors after menopause. OBJECTIVE: This study aimed to review and characterize the influence of menopause on prolactinoma behavior. EVIDENCE REVIEW: A systematic review of observational prospective or retrospective studies and clinical trials on prolactinomas was conducted in two situations: tumors diagnosed in the reproductive period (before menopause), with follow-up in the postmenopausal period, or prolactinomas diagnosed in the postmenopausal period, without language or date restrictions. Data extracted from the articles included patient and tumor characteristics (prolactinoma type, previous treatment, symptoms, and serum prolactin [PRL] levels). FINDINGS: This study included five studies comprising 180 participants. Prolactinomas diagnosed in women of reproductive age are treated with dopaminergic agonists (DAs), with indications of treatment withdrawal after menopause, exhibited stable tumor behavior and PRL levels. Considering the diagnosis during the postmenopausal period, macroprolactinomas were more prevalent and showed tumor shrinkage when DAs were used. Cabergoline, the most commonly used drug, lowers PRL levels and reduces symptoms associated with adenoma. CONCLUSIONS AND RELEVANCE: Microadenomas diagnosed before menopause can be followed up without treatment. Prolactinomas diagnosed after menopause are typically macroadenomas. Cabergoline remains the treatment of choice in the presence of clinical or compressive symptoms. We recommend at least one annual follow-up for such patients.

Prolactinomas: Preconception and During Pregnancy.

Prolactinomas are a common cause of infertility in women. Medical treatment with dopamine agonists (DAs) has an excellent efficacy at restoring fertility and a reassuring safety profile in early pregnancy. Surgical treatment before conception is required in some cases of large macroadenomas and incomplete treatment response. In women with microprolactinomas, the pregnancy course is usually uneventful. In women with macroprolactinomas that are near/abut the optic chiasm, symptomatic tumor enlargement can occur during pregnancy and require a multidisciplinary team approach. This review provides an update regarding outcomes and management of prolactinomas before conception, during pregnancy, and postpartum.