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.

Evaluation of bromocriptine and plumbagin against the monogenean Rhabdosynochus viridisi: Computational drug repositioning and in vitro approaches.

Monogeneans are parasitic platyhelminths that can harm the health of farmed fish. Few treatments are available against monogeneans, and the incentive to develop new antiparasitic agents is similar or even lower than the incentive for neglected parasitic diseases in humans. Considering that searching for and developing new antimonogenean compounds may require enormous investments of time, money, and animal sacrifice, the use of a computer-guided drug repositioning approach is a reasonable alternative. Under this context, this study aimed to evaluate the effectiveness of plumbagin and bromocriptine against adults and eggs of the monogenean Rhabdosynochus viridisi (Diplectanidae). Plumbagin is a phytochemical compound that has recently emerged as a potent antimonogenean; however, further investigation is required to determine its effects on different monogenean species. Bromocriptine was selected through a computational approach that included molecular docking analyses of 77 receptors of monogeneans (putative drug targets) and 77 ligands (putative inhibitors). In vitro experiments showed that bromocriptine does not exhibit mortality at concentrations of 0.1, 1, and 10 mg/L whereas plumbagin at 2 and 10 mg/L caused 100% monogenean mortality after 3 h and 30 min, respectively. The most effective concentration of plumbagin (10 mg/L) did not completely inhibit egg hatching. These findings underscore plumbagin as a highly effective agent against adult monogeneans and highlight the need for research to evaluate its effect(s) on fish. Although computational drug repositioning is useful for selecting candidates for experimental testing, it does not guarantee success due to the complexity of biological interactions, as observed here with bromocriptine. Therefore, it is crucial to examine the various compounds proposed by this method.

Pemphigus Vulgaris Successfully Treated With Bromocriptine.

Pemphigus vulgaris (PV) is an autoimmune blistering skin condition primarily treated with immunosuppressive agents. We describe a case of PV successfully treated with nonconventional treatment, bromocriptine mesylate. Bromocriptine has been used in human trials showing beneficial therapeutic effects in managing autoimmune conditions. The results from experimental trials and the low toxicity of bromocriptine in comparison with immunosuppressive agents form a solid rationale for investigating its role in controlling PV.  J Drugs Dermatol. 2024;23(3):     doi:10.36849/JDD.7720e.

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.

A giant invasive macroprolactinoma with recurrent nasal bleeding as the first clinical presentation: case report and review of literature.

BACKGROUND: Giant prolactinoma (> 4 cm in dimension) is a rare disorder. Invasive macroprolactinoma has the potential to cause base of skull erosion and extend into the nasal cavity or even the sphenoid sinus. Nasal bleeding caused by intranasal tumor extension is a rare complication associated with invasive giant prolactinoma. We report a case of giant invasive macroprolactinoma with repeated nasal bleeding as the initial symptom. CASE PRESENTATION: A 24-year-old man with an invasive giant prolactinoma in the nasal cavity and sellar region who presented with nasal bleeding as the initial symptom, misdiagnosed as olfactory neuroblastoma. However, markedly elevated serum prolactin levels (4700 ng/mL), and a 7.8-cm invasive sellar mass confirmed the diagnosis of invasive giant prolactinoma. He was treated with oral bromocriptine. Serum prolactin was reduced to near normal after 6 months of treatment. Follow-up magnetic resonance imaging showed that the sellar lesion had disappeared completely and the skull base lesions were reduced. CONCLUSION: This case is notable in demonstrating the aggressive nature of untreated invasive giant prolactinomas which can cause a diagnostic difficulty with potential serious consequences. Early detection of hormonal levels can avoid unnecessary nasal biopsy. Early identification of pituitary adenoma with nasal bleeding as the first symptom is particularly important.

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.

Antipyretic Efficacy of Bromocriptine in Central Fever: an Exploratory Analysis.

BACKGROUND: 'Central' fevers are thought to result from disruption of hypothalamic thermoregulatory pathways following severe brain injuries. Bromocriptine, due to its central dopamine receptor agonism, has been hypothesized to have antipyretic effect in this setting. However, clinical evidence for this off-label use is limited to a few case reports. In this retrospective cohort study, we analyzed the effect of bromocriptine administration on body temperature in acute brain injury patients with suspected central fever. METHODS: We screened a cohort of adult patients that received bromocriptine in the neurologic-intensive care unit of a tertiary care hospital between January 2018 and December 2021. Indication of central fever was ascertained by review of clinical documentation. A generalized additive mixed model (GAMM) was used to model temperature as a function of time relative to bromocriptine initiation. We adjusted for potential confounding due to the following covariates: temperature recording method (invasive vs surface), concurrent antipyretic administration within 8 h, and surface cooling device use within 4 h of temperature measurement. Temperature-time function was modeled using a cubic spline with k = 10 knots. RESULTS: A total of 33 patients were included in the analysis (14 women; mean age: 50 y, standard deviation 14 y). Median dose of bromocriptine was 7.5 mg (range 2.5-40) for a median of 13 d (range 5-160). Age and sex did not impact the function of temperature over time. Predicted temperatures were significantly (p < 0.05) higher by 0.4 °C with invasive compared to surface recording methods, lower by 0.2 °C in the presence of cooling device use and lower by 0.1 °C with concurrent antipyretic use. On adjusted analysis with the GAMM, there was decline (p < 0.05) in temperature following bromocriptine initiation by - 0.3 °C at 24 h, - 0.5 °C at 48 h, and - 0.7 °C at 72 h. CONCLUSIONS: Bromocriptine use was associated with modest but statistically significant decline in temperature, with nadir at 72 h post initiation. The findings provide a data driven basis for prospective evaluation.

Diagnosis and Management of Pituitary Adenomas: A Review.

Importance: Pituitary adenomas are neoplasms of the pituitary adenohypophyseal cell lineage and include functioning tumors, characterized by the secretion of pituitary hormones, and nonfunctioning tumors. Clinically evident pituitary adenomas occur in approximately 1 in 1100 persons. Observations: Pituitary adenomas are classified as either macroadenomas (≥10 mm) (48% of tumors) or microadenomas (<10 mm). Macroadenomas may cause mass effect, such as visual field defects, headache, and/or hypopituitarism, which occur in about 18% to 78%, 17% to 75%, and 34% to 89% of patients, respectively. Thirty percent of pituitary adenomas are nonfunctioning adenomas, which do not produce hormones. Functioning tumors are those that produce an excess of normally produced hormones and include prolactinomas, somatotropinomas, corticotropinomas, and thyrotropinomas, which produce prolactin, growth hormone, corticotropin, and thyrotropin, respectively. Approximately 53% of pituitary adenomas are prolactinomas, which can cause hypogonadism, infertility, and/or galactorrhea. Twelve percent are somatotropinomas, which cause acromegaly in adults and gigantism in children, and 4% are corticotropinomas, which secrete corticotropin autonomously, resulting in hypercortisolemia and Cushing disease. All patients with pituitary tumors require endocrine evaluation for hormone hypersecretion. Patients with macroadenomas additionally require evaluation for hypopituitarism, and patients with tumors compressing the optic chiasm should be referred to an ophthalmologist for formal visual field testing. For those requiring treatment, first-line therapy is usually transsphenoidal pituitary surgery, except for prolactinomas, for which medical therapy, either bromocriptine or cabergoline, is usually first line. Conclusions and Relevance: Clinically manifest pituitary adenomas affect approximately 1 in 1100 people and can be complicated by syndromes of hormone excess as well as visual field defects and hypopituitarism from mass effect in larger tumors. First-line therapy for prolactinomas consists of bromocriptine or cabergoline, and transsphenoidal pituitary surgery is first-line therapy for other pituitary adenomas requiring treatment.

Effectivity of Bromocriptine Administration Towards Prolactin Positive Breast Cancer Receiving Anthracycline-Based Chemotherapy: A Literature Review.

Breast cancer is among the deadliest gynecology cancers in the world. However, the management of advanced-stage breast cancer is often harder as a result of chemoresistance. This review aimed to discover the effect of bromocriptine on prolactin-positive breast cancer patients who received anthracycline-based chemotherapy. It is known that anthracycline works by inhibiting topoisomerase IIα (TOP2A), forming free radicals, binding DNA, and altering cell homeostasis, hence stopping the cell cycle and inducing cell death. However, reduction of TOP2A expression and increased glutathione s-transferase (GST) and ATP-binding cassette (ATP) membrane activity increase anthracycline efflux from the cell membrane, hence reducing its effectivity. Prolactin is one of the most common chemoresistance agents whose complex with its receptor will induce JAK/STAT pathway to increase GST. The regulation of Bcl-2 and ERK was also determined by prolactin. Bromocriptine is an agonist of the D2 dopamine receptor that inhibits adenyl cyclase and a D1 dopamine weak antagonist. Bromocriptine could reduce prolactin serum and receptors in various cases. Some studies have found that bromocriptine could improve the effectiveness of chemotherapy regimens, including cancer-related hyperprolactinemia, breast cancer that underwent cisplatin, and taxanes. Therefore, bromocriptine offers potential as it could improve outcomes and reduce resistance in prolactin-positive breast cancer patients who are administered anthracycline-based neoadjuvant chemotherapy.

Effects of bromocriptine in peripartum cardiomyopathy: a systematic review and meta-analysis.

Peripartum cardiomyopathy (PPCM) is a rare but potentially life-threatening form of heart failure (HF). Bromocriptine, a dopamine D2 agonist, has been used as an adjunctive treatment for PPCM with controversial benefits. A comprehensive literature search was conducted through June 2021. We included studies comparing the outcomes of PPCM with or without bromocriptine use. Pooled risk ratio (RR) with 95% confidence intervals (CI) and I2 statistics were calculated. Composite major adverse outcomes were defined by a composite of death, need for advanced HF therapies, persistent New York Heart Association (NYHA) functional class III/V, or left ventricular ejection fraction (LVEF) ≤ 35% at 6-month follow-up. LVEF recovery was defined by improvement of LVEF to more than 50%. Eight studies (two randomized-controlled, six observational) involving 593 PPCM patients were included. Bromocriptine use was associated with significantly higher survival (91.6% vs. 83.9%, RR 1.11 p = 0.02). Baseline LVEF was not significantly different between the groups. LVEF at follow-up was significantly higher in the bromocriptine group (53.3% vs. 41.8%, p < 0.001). There was no significant association between bromocriptine use and lower composite major adverse outcomes (13.7% vs. 33.3%, RR 0.60 p = 0.54) or LVEF recovery (46.9% vs. 46.8%, RR 0.94 p = 0.74). In conclusion, the addition of bromocriptine to standard HF treatment in PPCM was associated with significantly higher survival and higher LVEF improvement. No association with lower composite adverse clinical outcomes or LVEF recovery was seen. The findings, although encouraging, warrant larger randomized-controlled studies.

Bromocriptine quick-release as adjunct therapy in youth and adults with type 1 diabetes: A randomized, placebo-controlled crossover study.

AIM: To evaluate the potential for glycaemic, renal and vascular benefits of bromocriptine quick release (BCQR) in adolescents and adults with type 1 diabetes. MATERIALS AND METHODS: Forty adolescents and 40 adults with type 1 diabetes aged 12-60 years old were enrolled in a double-blind, placebo-controlled, random order crossover study of 4 weeks of treatment in the morning with BCQR (titrated weekly from 0.8 mg to 1.6 mg to 3.2 mg, minimum dose 1.6 mg). Study assessments after each phase included blood pressure (BP), lipids, peripheral arterial stiffness and autonomic function, mixed meal tolerance test, continuous glucose monitoring (CGM), creatinine, estimated glomerular filtration rate, estimated insulin sensitivity, insulin dose and indirect calorimetry. RESULTS: Adolescents displayed baseline hyperglycaemia, insulin resistance, metabolic dysfunction and increased renal filtration compared with adults. In both age groups, continuous glucose monitoring measures, estimated insulin sensitivity and insulin dose did not differ with BCQR treatment. In adolescents, BCQR decreased systolic BP, diastolic BP and triangular index and increased serum creatinine. In adults, systolic BP, mean arterial pressure, systemic vascular resistance, and mixed meal tolerance test glucose and glucagon-like peptide 1 areas under the curve were lower, and the orthostatic drop in systolic BP was greater with BCQR. CONCLUSIONS: Greater hyperglycaemia, insulin resistance, metabolic dysfunction and renal hyperfiltration in adolescents argues for increased attention during this high-risk age period. Although BCQR had little impact on glycaemia or insulin sensitivity, initial vascular and renal responses suggest potential benefits of BCQR in adolescents and adults with type 1 diabetes requiring further study.

Bromocriptine-QR Therapy Reduces Sympathetic Tone and Ameliorates a Pro-Oxidative/Pro-Inflammatory Phenotype in Peripheral Blood Mononuclear Cells and Plasma of Type 2 Diabetes Subjects.

Bromocriptine-QR is a sympatholytic dopamine D2 agonist for the treatment of type 2 diabetes that has demonstrated rapid (within 1 year) substantial reductions in adverse cardiovascular events in this population by as yet incompletely delineated mechanisms. However, a chronic state of elevated sympathetic nervous system activity and central hypodopaminergic function has been demonstrated to potentiate an immune system pro-oxidative/pro-inflammatory condition and this immune phenotype is known to contribute significantly to the advancement of cardiovascular disease (CVD). Therefore, the possibility exists that bromocriptine-QR therapy may reduce adverse cardiovascular events in type 2 diabetes subjects via attenuation of this underlying chronic pro-oxidative/pro-inflammatory state. The present study was undertaken to assess the impact of bromocriptine-QR on a wide range of immune pro-oxidative/pro-inflammatory biochemical pathways and genes known to be operative in the genesis and progression of CVD. Inflammatory peripheral blood mononuclear cell biology is both a significant contributor to cardiovascular disease and also a marker of the body's systemic pro-inflammatory status. Therefore, this study investigated the effects of 4-month circadian-timed (within 2 h of waking in the morning) bromocriptine-QR therapy (3.2 mg/day) in type 2 diabetes subjects whose glycemia was not optimally controlled on the glucagon-like peptide 1 receptor agonist on (i) gene expression status (via qPCR) of a wide array of mononuclear cell pro-oxidative/pro-inflammatory genes known to participate in the genesis and progression of CVD (OXR1, NRF2, NQO1, SOD1, SOD2, CAT, GSR, GPX1, GPX4, GCH1, HMOX1, BiP, EIF2α, ATF4, PERK, XBP1, ATF6, CHOP, GSK3ß, NFkB, TXNIP, PIN1, BECN1, TLR2, TLR4, TLR10, MAPK8, NLRP3, CCR2, GCR, L-selectin, VCAM1, ICAM1) and (ii) humoral measures of sympathetic tone (norepinephrine and normetanephrine), whole-body oxidative stress (nitrotyrosine, TBARS), and pro-inflammatory factors (IL-1ß, IL-6, IL-18, MCP-1, prolactin, C-reactive protein [CRP]). Relative to pre-treatment status, 4 months of bromocriptine-QR therapy resulted in significant reductions of mRNA levels in PBMC endoplasmic reticulum stress-unfolded protein response effectors [GRP78/BiP (34%), EIF2α (32%), ATF4 (29%), XBP1 (25%), PIN1 (14%), BECN1 (23%)], oxidative stress response proteins [OXR1 (31%), NRF2 (32%), NQO1 (39%), SOD1 (52%), CAT (26%), GPX1 (33%), GPX4 (31%), GCH1 (30%), HMOX1 (40%)], mRNA levels of TLR pro-inflammatory pathway proteins [TLR2 (46%), TLR4 (20%), GSK3ß (19%), NFkB (33%), TXNIP (18%), NLRP3 (32%), CCR2 (24%), GCR (28%)], mRNA levels of pro-inflammatory cellular receptor proteins CCR2 and GCR by 24% and 28%, and adhesion molecule proteins L-selectin (35%) and VCAM1 (24%). Relative to baseline, bromocriptine-QR therapy also significantly reduced plasma levels of norepinephrine and normetanephrine by 33% and 22%, respectively, plasma pro-oxidative markers nitrotyrosine and TBARS by 13% and 10%, respectively, and pro-inflammatory factors IL-18, MCP1, IL-1ß, prolactin, and CRP by 21%,13%, 12%, 42%, and 45%, respectively. These findings suggest a unique role for circadian-timed bromocriptine-QR sympatholytic dopamine agonist therapy in reducing systemic low-grade sterile inflammation to thereby reduce cardiovascular disease risk.

Effect of dopaminergic agonist group of drugs in treatment of sleep bruxism: A systematic review.

STATEMENT OF PROBLEM: Various factors are responsible for sleep bruxism; however, whether the dopaminergic agonist group of drugs is effective in the treatment of sleep bruxism is unclear. PURPOSE: The purpose of this systematic review was to evaluate the effect of the dopaminergic agonist group of drugs in controlling sleep bruxism in comparison with no treatment or placebo-controlled treatment. MATERIAL AND METHODS: Two electronic databases, PubMed and Cochrane Central, were searched by using the keywords bruxism, sleep bruxism, dopamine, and dopamine agonist. After screening titles and abstracts, only those articles which met predefined inclusion criteria were selected for full-text assessment. Clinical trials using the dopaminergic agonist group of drugs as a treatment approach to sleep bruxism were included. RESULTS: The literature search yielded a total of 64 articles from the 2 electronic databases (PubMed, 53; Cochrane Central, 11). After removal of the duplicates (n=8), the initial screening of titles and abstracts was performed by 2 independent reviewers, removing 46 articles. A total of 10 articles were selected for full-text reading, and 4 studies were included for qualitative analysis. CONCLUSIONS: Levodopa (L-DOPA) and Bromocriptine showed decrease in root mean square value in electromyography per bruxism burst (P<.001) and 20% to 30% reduction of bruxism episodes during sleep in 2 different studies. However, treatment with bromocriptine led to conflicting result in another study in terms of frequency of bruxism episodes and amplitude of muscle contractions in electromyography (EMG). Bruxism bursts and episodes were also not significantly improved with another dopaminergic agonist group of drugs, Pramipexole (P>.001). Based on the limited evidence and conflicting results, significant conclusions cannot be generated, and further studies are required.

Treatment of Prolactinoma.

Prolactinomas are the commonest form of pituitary neuroendocrine tumor (PitNET), representing approximately half of such tumors. Dopamine agonists (DAs) have traditionally been the primary treatment for the majority of prolactinomas, with surgery considered the second line. The aim of this review is to examine the historical and modern management of prolactinomas, including medical therapy with DAs, transsphenoidal surgery, and multimodality therapy for the treatment of aggressive prolactinomas and metastatic PitNETs, with an emphasis on the efficacy, safety, and future directions of current therapeutic modalities. DAs have been the mainstay of prolactinoma management since the 1970s, initially with bromocriptine and more recently with cabergoline. Cabergoline normalizes prolactin in up to 85% of patients and causes tumor shrinkage in up to 80%. Primary surgical resection of microprolactinomas and enclosed macroprolactinomas performed by experienced pituitary neurosurgeons have similar remission rates to cabergoline. Aggressive prolactinomas and metastatic PitNETS should receive multimodality therapy including high dose cabergoline, surgery, radiation therapy (preferably using stereotactic radiosurgery where suitable), and temozolomide. DAs remain a reliable mode of therapy for most prolactinomas but results from transsphenoidal surgery in expert hands have improved considerably over the last one to two decades. Surgery should be strongly considered as primary therapy, particularly in the setting of microprolactinomas, non-invasive macroprolactinomas, or prior to attempting pregnancy, and has an important role in the management of DA resistant and aggressive prolactinomas.

The recurrence of prolactinoma after withdrawal of dopamine agonist: a systematic review and meta-analysis.

BACKGROUND: Prolactinoma is the major cause of hyperprolactinemia, and dopamine agonists (DAs) are generally the first-line treatment for them. Several studies have reviewed the recurrent rate of hyperprolactinemia after DAs withdrawal. However, few of them have concerned the recurrence risk of prolactinoma following the withdrawal of DAs. METHODS: Three medical databases, PubMed, EMBASE and Cochrane library, were retrieved up to February, 14, 2021 to identify studies related to recurrence of prolactinoma and withdrawal of DAs. Statistical analyses including meta-analysis, sensitivity analysis, meta-regression, funnel plot and Egger test were performed through software R. RESULTS: A total of 3225 studies were retrieved from the three data bases, and 13 studies consisted of 616 patients and 19 arms were finally included in this systematic analysis. There was no significant heterogeneity among the included studies, and fixed effect model was thus used. The pooled recurrence proportion of prolactinoma after withdrawal of DA was 2% with a 95% confidence interval (CI) of 1-3%. CONCLUSION: Our study showed a very low recurrent rate of prolactinomas after DAs withdrawal. Much more prospective studies with larger cases and longer follow-up period are encouraged to confirm our finding. TRIAL REGISTRATION: Registration number CRD42021245888 (PROSPERO).

Evolution of a refractory prolactin-secreting pituitary adenoma into a pituitary carcinoma: report of a challenging case and literature review.

BACKGROUND: Pituitary carcinomas (PCs), defined as distant metastases of pituitary neoplasms, are very rare malignancies. Because the clinical presentation of PCs is variable, early diagnosis and management remain challenging. PCs are always refractory to comprehensive treatments, and patients with PCs have extremely poor prognoses. CASE PRESENTATION: We describe one case of a prolactin-secreting pituitary adenoma (PA) refractory to conventional therapy that evolved into a PC with intraspinal metastasis. A 34-year-old female was diagnosed with an invasive prolactin-secreting PA in 2009 and was unresponsive to medical treatment with bromocriptine. The tumor was gross totally removed via transsphenoidal surgery (TSS). However, the patient experienced multiple tumor recurrences or regrowth despite comprehensive treatments, including medical therapy, two gamma knife radiosurgeries (GKSs), and four frontal craniotomies. In 2016, she was found to have an intradural extramedullary mass at the level of the fourth lumbar vertebra. The intraspinal lesion was completely resected and was confirmed as a metastatic PC based on histomorphology and immunohistochemical staining. The literature on the diagnosis, molecular pathogenesis, treatment, and prognosis of patients with prolactin-secreting PCs was reviewed. CONCLUSION: PCs are very rare neoplasms with variable clinical features and poor prognosis. Most PCs usually arise from aggressive PAs refractory to conventional therapy. There is no reliable marker to identify aggressive PAs with a risk for progression to PCs; thus, it is difficult to diagnose these PCs early until the presence of metastatic lesions. It is still very challenging to manage patients with PCs due to a lack of standardized protocols for diagnosis and treatment. Establishing molecular biomarkers and the pathobiology of PCs could help in the early identification of aggressive PAs most likely to evolve into PCs.

The role of MAPK11/12/13/14 (p38 MAPK) protein in dopamine agonist-resistant prolactinomas.

BACKGROUND: Prolactinoma is a functional pituitary adenoma that secretes excessive prolactin. Dopamine agonists (DAs) such as bromocriptine (BRC) are the first-line treatment for prolactinomas, but the resistance rate is increasing year by year, creating a clinical challenge. Therefore, it is urgent to explore the molecular mechanism of bromocriptine resistance in prolactinomas. Activation of the P38 MAPK pathway affects multidrug resistance in tumours. Our previous studies have demonstrated that inhibiting MAPK14 can suppress the occurrence of prolactinoma, but the role of MAPK11/12/13/14 (p38 MAPK) signalling in dopamine agonist-resistant prolactinomas is still unclear. METHODS: A prolactinoma rat model was established to determine the effect of bromocriptine on MAPK11/12/13/14 signalling. DA-resistant GH3 cells and DA-sensitive MMQ cells were used, and the role of MAPK11/12/13/14 in bromocriptine-resistant prolactinomas was preliminarily verified by western blot, RT-qPCR, ELISA, flow cytometry and CCK-8 experiments. The effects of MAPK11 or MAPK14 on bromocriptine-resistant prolactinomas were further verified by siRNA transfection experiments. RESULTS: Bromocriptine was used to treat rat prolactinoma by upregulating DRD2 expression and downregulating the expression level of MAPK11/12/13/14 in vivo experiments. The in vitro experiments showed that GH3 cells are resistant to bromocriptine and that MMQ cells are sensitive to bromocriptine. Bromocriptine could significantly reduce the expression of MAPK12 and MAPK13 in GH3 cells and MMQ cells. Bromocriptine could significantly reduce the expression of MAPK11, MAPK14, NF-κB p65 and Bcl2 in MMQ but had no effect on MAPK11, MAPK14, NF-κB p65 and Bcl2 in GH3 cells. In addition, knockdown of MAPK11 and MAPK14 in GH3 cells by siRNA transfection reversed the resistance of GH3 cells to bromocriptine, and haloperidol (HAL) blocked the inhibitory effect of bromocriptine on MAPK14, MAPK11, and PRL in MMQ cells. Our findings show that MAPK11 and MAPK14 proteins are involved in bromocriptine resistance in prolactinomas. CONCLUSION: Bromocriptine reduces the expression of MAPK11/12/13/14 in prolactinomas, and MAPK11 and MAPK14 are involved in bromocriptine resistance in prolactinomas by regulating apoptosis. Reducing the expression of MAPK11 or MAPK14 can reverse bromocriptine resistance in prolactinomas.

Dopamine agonists for preventing ovarian hyperstimulation syndrome.

BACKGROUND: Ovarian hyperstimulation syndrome (OHSS) is a potentially serious complication of ovarian stimulation in assisted reproduction technology (ART). It is characterised by enlarged ovaries and an acute fluid shift from the intravascular space to the third space, resulting in bloating, increased risk of venous thromboembolism, and decreased organ perfusion. Most cases are mild, but forms of moderate or severe OHSS appear in 3% to 8% of in vitro fertilisation (IVF) cycles. Dopamine agonists were introduced as a secondary prevention intervention for OHSS in women at high risk of OHSS undergoing ART treatment.  OBJECTIVES: To assess the effectiveness and safety of dopamine agonists in preventing OHSS in women at high risk of developing OHSS when undergoing ART treatment. SEARCH METHODS: We searched the following databases from inception to 4 May 2020: Cochrane Gynaecology and Fertility Specialised Register, CENTRAL, MEDLINE, Embase, CINAHL, and PsycINFO for randomised controlled trials (RCTs) assessing the effect of dopamine agonists on OHSS rates. We also handsearched reference lists and grey literature. SELECTION CRITERIA: We considered RCTs for inclusion that compared dopamine agonists with placebo/no intervention or another intervention for preventing OHSS in ART. Primary outcome measures were incidence of moderate or severe OHSS and live birth rate. Secondary outcomes were rates of clinical pregnancy, multiple pregnancy, miscarriage, and adverse events. DATA COLLECTION AND ANALYSIS: Two review authors independently screened titles, abstracts, and full texts of publications; selected studies; extracted data; and assessed risk of bias. We resolved disagreements  by consensus. We reported pooled results as odds ratios (OR) and 95% confidence interval (CI) by the Mantel-Haenszel method. We applied GRADE criteria to judge overall quality of the evidence. MAIN RESULTS: The search identified six new RCTs, resulting in 22 included RCTs involving 3171 women at high risk of OHSS for this updated review. The dopamine agonists were cabergoline, quinagolide, and bromocriptine. Dopamine agonists versus placebo or no intervention Dopamine agonists probably lowered the risk of moderate or severe OHSS compared to placebo/no intervention (OR 0.32, 95% CI 0.23 to 0.44; 10 studies, 1202 participants; moderate-quality evidence). This suggests that if the risk of moderate or severe OHSS following placebo/no intervention is assumed to be 27%, the risk following dopamine agonists would be between 8% and 14%. We are uncertain of the effect of dopamine agonists on rates of live birth (OR 0.96, 95% CI 0.60 to 1.55; 3 studies, 362 participants; low-quality evidence). We are also uncertain of the effect of dopamine agonists on clinical pregnancy, multiple pregnancy, miscarriage  or adverse events (very low to low-quality evidence). Dopamine agonists plus co-intervention versus co-intervention Dopamine agonist plus co-intervention (hydroxyethyl starch, human albumin, or withholding ovarian stimulation 'coasting') may decrease the risk of moderate or severe OHSS compared to co-intervention (OR 0.48, 95% CI 0.28 to 0.84; 4 studies, 748 participants; low-quality evidence). Dopamine agonists may improve rates of live birth (OR 1.21, 95% CI 0.81 to 1.80; 2 studies, 400 participants; low-quality evidence). Dopamine agonists may improve rates of clinical pregnancy and miscarriage, but we are uncertain if they improve rates of multiple pregnancy  or adverse events (very low to low-quality evidence). Dopamine agonists versus other active interventions We are uncertain if cabergoline improves the risk of moderate or severe OHSS compared to human albumin (OR 0.21, 95% CI 0.12 to 0.38; 3 studies, 296 participants; very low-quality evidence), prednisolone (OR 0.27, 95% CI 0.05 to 1.33; 1 study; 150 participants; very low-quality evidence), hydroxyethyl starch (OR 2.69, 95% CI 0.48 to 15.10; 1 study, 61 participants; very low-quality evidence), coasting (OR 0.42, 95% CI 0.18 to 0.95; 3 studies, 320 participants; very low-quality evidence), calcium infusion (OR 1.83, 95% CI 0.88 to 3.81; I² = 81%; 2 studies, 400 participants; very low-quality evidence), or diosmin (OR 2.85, 95% CI 1.35 to 6.00; 1 study, 200 participants; very low-quality evidence). We are uncertain of the effect of dopamine agonists on rates of live birth (OR 1.08, 95% CI 0.73 to 1.59; 2 studies, 430 participants; low-quality evidence). We are uncertain of the effect of dopamine agonists on clinical pregnancy, multiple pregnancy or miscarriage (low to moderate-quality evidence). There were no adverse events reported. AUTHORS' CONCLUSIONS: Dopamine agonists probably reduce the incidence of moderate or severe OHSS compared to placebo/no intervention, while we are uncertain of the effect on adverse events and pregnancy outcomes (live birth, clinical pregnancy, miscarriage). Dopamine agonists plus co-intervention may decrease moderate or severe OHSS rates compared to co-intervention only, but we are uncertain whether dopamine agonists affect pregnancy outcomes. When compared to other active interventions, we are uncertain of the effects of dopamine agonists on moderate or severe OHSS and pregnancy outcomes.

Bromocriptine for the treatment of postoperative cerebellar mutism syndrome in pediatric patients: Three case reports.

INTRODUCTION: Cerebellar mutism syndrome (CMS) is a common complication after posterior fossa tumor resection. It is characterized by a significant lack or loss of speech. Its biological origin remains unclear and there are no standardized treatments. However, bromocriptine seems to be a possible treatment for this condition. CASE REPORT: In this paper, we present three cases of pediatric patients (4, 5, and 17-year old) who developed CMS after posterior fossa tumor surgery. They were treated with bromocriptine to improve neurological symptoms.Management and outcome: Bromocriptine was started at a low dose and was progressively increased to reach the minimum effective dose. After four months of treatment, a normal and fluid speech was observed in the three patients. No discontinuation due to adverse events were reported. DISCUSSION: Bromocriptine has shown to be an effective and safe treatment for CMS in pediatric patients after posterior fossa tumor resection.

Estrogen receptor α/prolactin receptor bilateral crosstalk promotes bromocriptine resistance in prolactinomas.

Prolactinomas are the most common type of functional pituitary adenoma. Although bromocriptine is the preferred first line treatment for prolactinoma, resistance frequently occurs, posing a prominent clinical challenge. Both the prolactin receptor (PRLR) and estrogen receptor α (ERα) serve critical roles in the development and progression of prolactinomas, and whether this interaction between PRLR and ERα contributes to bromocriptine resistance remains to be clarified. In the present study, increased levels of ERα and PRLR protein expression were detected in bromocriptine-resistant prolactinomas and MMQ cells. Prolactin (PRL) and estradiol (E2) were found to exert synergistic effects on prolactinoma cell proliferation. Furthermore, PRL induced the phosphorylation of ERα via the JAK2-PI3K/Akt-MEK/ERK pathway, while estrogen promoted PRLR upregulation via pERα. ERα inhibition abolished E2-induced PRLR upregulation and PRL-induced ERα phosphorylation, and fulvestrant, an ERα inhibitor, restored pituitary adenoma cell sensitivity to bromocriptine by activating JNK-MEK/ERK-p38 MAPK signaling and cyclin D1 downregulation. Collectively, these data suggest that the interaction between the estrogen/ERα and PRL/PRLR pathways may contribute to bromocriptine resistance, and therefore, that combination treatment with fulvestrant and bromocriptine (as opposed to either drug alone) may exert potent antitumor effects on bromocriptine-resistant prolactinomas.