OBJECTIVE: At present, various treatment strategies are available for pituitary adenomas, including medications, surgery and radiation. The guidelines indicate that pharmacological treatments, such as bromocriptine (BRC) and cabergoline (CAB), are important treatments for prolactinomas, but drug resistance is an urgent problem that needs to be addressed. Therefore, exploring the mechanism of drug resistance in prolactinomas is beneficial for clinical treatment.
METHODS: In our research, BRC-induced drug-resistant cells were established. Previous RNA sequencing data and an online database were used for preliminary screening of resistance-related genes. Cell survival was determined by Cell Counting Kit-8 (CCK-8) assay, colony formation assays and flow cytometry. Quantitative real-time polymerase chain reaction (qRT‒PCR), western blotting, immunohistochemistry, immunofluorescence and Co-immunoprecipitation (Co-IP) were used to assess the molecular changes and regulation. The therapeutic efficacy of BRC and FGFR4 inhibitor fisogatinib (FISO) combination was evaluated in drug-resistant cells and xenograft tumors in nude mice.
RESULTS: Consistent with the preliminary results of RNA sequencing and database screening, fibroblast growth factor 19 (FGF19) expression was elevated in drug-resistant cells and tumor samples. With FGF19 silencing, drug-resistant cells exhibited increased sensitivity to BRC and decreased intracellular phosphorylated fibroblast growth factor receptor 4 (FGFR4) levels. After confirming that FGF19 binds to FGFR4 in prolactinoma cells, we found that FGF19/FGFR4 regulated prolactin (PRL) synthesis through the ERK1/2 and JNK signaling pathways. Regarding the effect of targeting FGF19/FGFR4 on BRC efficacy, FISO and BRC synergistically inhibited the growth of tumor cells, promoted apoptosis and reduced PRL levels.
CONCLUSIONS: Overall, our study revealed FGF19/FGFR4 as a new mechanism involved in the drug resistance of prolactinomas, and combination therapy targeting the pathway could be helpful for the treatment of BRC-induced drug-resistant prolactinomas.

BACKGROUND: Olanzapine antagonizes dopamine receptors and is prescribed to treat multiple psychiatric conditions. The main side effect of concern for olanzapine is weight gain and metabolic syndrome. Olanzapine induces hyperprolactinemia, however its effect on the mammary gland is poorly documented.
METHODS: Rats received olanzapine by gavage or in drinking water at 1, 3, and 6 mg/kg/day for 5-40 days or 100 days, with and without coadministration of bromocriptine or aripiprazole and using once daily or continuous administration strategies. Histomorphology of the mammary gland, concentrations of prolactin, estradiol, progesterone, and olanzapine in serum, mammary gland and adipose tissue, and mRNA and protein expressions of prolactin receptors were analyzed.
RESULTS: In adult and prepubescent female rats and male rats, olanzapine induced significant development of mammary glands in dose- and time-dependent manners, with histopathological hyperplasia of mammary ducts and alveoli with lumen dilation and secretion, marked increase of mammary prolactin receptor expression, a marker of breast tissue, and with mild increase of circulating prolactin. This side effect can be reversed after medication withdrawal, but long-term olanzapine treatment for 100 days implicated tumorigenic potentials indicated by usual ductal epithelial hyperplasia. Olanzapine induced mammary development was prevented with the coaddition of the dopamine agonist bromocriptine or partial agonist aripiprazole, or by continuous administration of medication instead of a once daily regimen.
CONCLUSIONS: These results shed light on the previously overlooked effect of olanzapine on mammary development and present experimental evidence to support current clinical management strategies of antipsychotic induced side effects in the breast.

UNASSIGNED: Sexual dysfunction induced by hyperprolactinemia accompanied by reduced luteinizing hormone (LH) is common in anrology clinics. A low dose of bromocriptine is helpful for restoring penile erectile function and libido in patients.
UNASSIGNED: Sexual dysfunction is closely related to hormonal disorders, of which prolactin (PRL) and luteinizing hormone (LH) disorders are common. How to treat sexual dysfunction induced by hyperprolactinemia accompanied by reduced LH levels is worth discussing. In this study, we aimed to present the case of a 35-year-old male patient with sexual dysfunction. The treatment process and physical and laboratory examination results were recorded. Before treatment, the PRL and LH levels in this patient were 31.27 ng/mL and 1.62 mIU/mL, respectively. The International Index of Erectile Function-5 (IIEF-5) score was initially 14 points. After regular treatment with low doses of bromocriptine and tadalafil, the hormonal disorder was corrected (PRL: 11.16 ng/mL and LH: 2.28 mIU/mL) and sexual function was recovered (IIEF-5: 23 points). This case report suggested a sufficient exposure to low-dose bromocriptine for such patients. Conversely, the exogenous supplementation of human chorionic gonadotropin may not be appropriate.

As a popular antidiabetic drug, teneligliptin has been used for over 10 years, but its efficacy and safety have rarely been systematically evaluated. Therefore, a Bayesian network meta-analysis was conducted to evaluate the efficacy and safety of teneligliptin in patients with type 2 diabetes mellitus (T2DM).
We systematically searched PubMed, Web of Science, Embase, Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov. Randomized controlled trials (RCTs) comparing teneligliptin with placebo or active comparators in T2DM patients for at least 12 weeks were included in the study. Data analysis was performed using R 4.2.3 and Stata 17.0 software. Each outcome was presented as a mean difference (MD) or an odds ratio (OR) along with 95% confidence interval (CI) and the surface under the cumulative ranking curve value (SUCRA).
A total of 18 RCTs with 3,290 participants with T2DM were included in this study. Generally, compared to placebo, sitagliptin, vildagliptin, metformin, and bromocriptine, 20 mg of teneligliptin showed better efficacy in reducing HbA1c (MD [95% CI], -0.78 [-0.86 to -0.70], -0.08 [-0.36 to 0.19], -0.04 [-0.72 to 0.60], -0.12 [-0.65 to 0.42], and -0.50 [-0.74 to -0.26], respectively) and fasting plasma glucose (FPG) (MD [95% CI], -18.02 [-20.64 to -15.13], 1.17 [-9.39 to 11.70], -8.06 [-30.95 to 14.35], -2.75 [-18.89 to 13.01], and -34.23 [-45.93 to -22.96], respectively), and 40 mg of teneligliptin also showed better efficacy in reducing HbA1c (MD [95% CI], -0.84 [-1.03 to -0.65], -0.15 [-0.49 to 0.19], -0.10 [-0.81 to 0.57], -0.18 [-0.76 to 0.39], and -0.56 [-0.88 to -0.26], respectively) and FPG (MD [95% CI], -20.40 [-26.07 to -14.57], -1.20 [-13.21 to 10.38], -10.43 [-34.16 to 12.65], -5.13 [-22.21 to 11.66], and -36.61 [-49.33 to -24.01], respectively). Compared to placebo, 20 mg of teneligliptin showed no significant difference in incidences of hypoglycemia and gastrointestinal adverse events (OR [95% CI], 1.30 [0.70 to 2.19] and 1.48 [0.78 to 2.98], respectively), and 40 mg of teneligliptin showed no significant difference in incidence of hypoglycemia (OR [95% CI], 2.63 [0.46 to 8.10]). Generally, antidiabetic effect and hypoglycemia risk of teneligliptin gradually increased as its dose increased from 5 mg to 40 mg. Compared to 20 mg of teneligliptin, 40 mg of teneligliptin showed superior efficacy and no-inferior safety, which was considered as the best option in reducing HbA1c, FPG, and 2h PPG and increasing proportion of the patients achieving HbA1c < 7% (SUCRA, 85.51%, 84.24%, 79.06%, and 85.81%, respectively) among all the included interventions.
Compared to sitagliptin, vildagliptin, metformin, bromocriptine, and placebo, teneligliptin displayed favorable efficacy and acceptable safety in treating T2DM. Twenty milligrams or 40 mg per day was the optimal dosage regimen of teneligliptin. The results of this study will provide important evidence-based basis for rational use of teneligliptin and clinical decision-making of T2DM medication.

OBJECTIVE: To review experience regarding the treatment of prolactinomas by endoscopic endonasal surgery focusing on the association between presurgical dopamine agonist (DA) treatment and perioperative outcomes, surgical morbidities, endocrine outcomes, and pathological characteristics.
METHODS: A single-center series of 290 cases was analyzed retrospectively and clinical data were collected. Intratumoral collagen content was assessed by Masson trichrome staining.
RESULTS: Tenacious tumor consistency (27.8% vs 9.8%, P < .001) was more common in DA-pretreated patients compared with patients who underwent initial surgery. Moreover, DA-pretreated macroadenomas presented more intraoperative blood loss (200 [100-400] mL vs 175 [100-300] mL; P = .014), longer surgical duration (177 ± 95 minutes vs 154 ± 57 minutes; P = .043), and more surgical morbidities (19.4% vs 8.9%; P = .034). Additionally, DA-pretreated macroadenomas presented a higher collagen volume fraction than that of the initial surgery group (23.6 ± 2.2% vs 13.2 ± 2.1%; P = .001). Correlation analysis revealed a close correlation between collagen volume fraction and the cumulative dose of bromocriptine (BRC) in macroadenomas (r = 0.438, P < .001). Regarding endocrine outcomes, DA-pretreated microadenomas showed a lower proportion of initial remission compared with patients who underwent initial surgery (86.7% vs 100%, P = .047).
CONCLUSIONS: This study described increased surgical difficulty and inferior endocrine outcomes associated with tumor fibrosis secondary to presurgical BRC treatment in prolactinomas. Neurosurgeons should note that presurgical BRC treatment may render subsequent surgery more challenging.

Recent studies have revealed that lipid droplets accumulate in neurons after brain injury and evoke lipotoxicity, damaging the neurons. However, how lipids are metabolized by spinal cord neurons after spinal cord injury remains unclear. Herein, we investigated lipid metabolism by spinal cord neurons after spinal cord injury and identified lipid-lowering compounds to treat spinal cord injury. We found that lipid droplets accumulated in perilesional spinal cord neurons after spinal cord injury in mice. Lipid droplet accumulation could be induced by myelin debris in HT22 cells. Myelin debris degradation by phospholipase led to massive free fatty acid production, which increased lipid droplet synthesis, β-oxidation, and oxidative phosphorylation. Excessive oxidative phosphorylation increased reactive oxygen species generation, which led to increased lipid peroxidation and HT22 cell apoptosis. Bromocriptine was identified as a lipid-lowering compound that inhibited phosphorylation of cytosolic phospholipase A2 by reducing the phosphorylation of extracellular signal-regulated kinases 1/2 in the mitogen-activated protein kinase pathway, thereby inhibiting myelin debris degradation by cytosolic phospholipase A2 and alleviating lipid droplet accumulation in myelin debris-treated HT22 cells. Motor function, lipid droplet accumulation in spinal cord neurons and neuronal survival were all improved in bromocriptine-treated mice after spinal cord injury. The results suggest that bromocriptine can protect neurons from lipotoxic damage after spinal cord injury via the extracellular signal-regulated kinases 1/2-cytosolic phospholipase A2 pathway.

OBJECTIVE: Spontaneous abortion (SA) is a multiple-original syndrome with immune imbalance as one of its major risk factors. As Wharton\'s jelly-mesenchymal stem cells (WJ-MSCs) are considered to be able to prevent abortion, this study aims to explore the currently poorly understood underlining molecular signaling pathways and regulatory mechanisms of WJ-MSCs in pregnancy maintenance.
METHODS: Abortion mode is established by subcutaneous injection of bromocriptine in rat on day 9 and abortion prevention is achieved by WJ-MSCs injection via tail vein. WJ-MSCs were cultured with/without the inhibitors of JAK/STAT or NF-κB. The uterus was collected on the 14th day of gestation and the rate of embryo absorption was calculated. The expression of Th1/Th2/Th3 cytokines in decidual, placental tissue, and peripheral blood was analyzed.
RESULTS: WJ-MSCs treatment significantly reduced the abortion rate in bromocriptine-treated pregnancy such that it was not significantly different from a normal pregnancy. JAK/STAT inhibition abolished pregnancy preserving effects of WJ-MSCs but NF-κB inhibition did not. The levels of Th1-related cytokines and mRNA levels in the bromocriptine abortion model were significantly higher than the normal pregnancy group and ethanol control group, while levels of the Th2-related cytokines and mRNA levels significantly decreased. WJ-MSCs transfusion into the abortion model restored cytokine profiles such that they were not significantly different from the normal pregnancy group and ethanol control group. JAK/STAT inhibition of WJ-MSCs prevented their effect on cytokine and mRNA levels, but NF-κB inhibition did not.
CONCLUSIONS: WJ-MSCs significantly lower the rate of embryo resorption of spontaneous abortion by reducing Th1-related cytokines while increasing Th2 and Th3-related cytokines in JAK/STAT-dependent manner.

BACKGROUND: Compared with levodopa, dopamine agonists (DAs) as initial treatment are associated with lower incidences of motor complications in early Parkinson\'s disease (PD). There is no strong evidence that a given DA is more potent in lower incidences of motor complications than another.
OBJECTIVE: We performed a network meta-analysis of levodopa versus DAs as monotherapy in early PD to access the risk of motor complications.
METHODS: Databases were searched up to June 2022 for eligible RCTs. Levodopa and four DAs (pramipexole, ropinirole, bromocriptine and pergolide) were investigated. The incidences of motor complications and efficacy, tolerability and safety outcomes were analyzed.
RESULTS: Nine RCTs (2112 patients) were included in the current study. The surface under the cumulative ranking curve (SUCRA) indicated that levodopa ranked first in the incidence of dyskinesia (0.988), followed by pergolide, pramipexole, ropinirole, and bromocriptine (0.704, 0.408, 0.240, 0.160). Pramipexole was least prone to wearing-off (0.109) and on-off fluctuation (0.041). Levodopa performed best in improvements of UPDRS-II, UPDRS-III, and UPDRS-II + III (0.925, 0.952, 0.934). Bromocriptine ranked first in total withdrawals and withdrawals due to adverse events (0.736, 0.751). Four DAs showed different adverse events profiles.
CONCLUSIONS: In the two non-ergot DAs, ropinirole is associated with a lower risk of dyskinesia while pramipexole is associated with lower risks of wearing-off and on-off fluctuations. Our research may facilitate head-to-head research, larger sample sizes, long following-up time RCTs to confirm the findings of this network meta-analysis.

Chemoresistance is a major obstacle in the clinical management of metastatic, castration-resistant prostate cancer (PCa). It is imperative to develop novel strategies to overcome chemoresistance and improve clinical outcomes in patients who have failed chemotherapy. Using a two-tier phenotypic screening platform, we identified bromocriptine mesylate as a potent and selective inhibitor of chemoresistant PCa cells. Bromocriptine effectively induced cell cycle arrest and activated apoptosis in chemoresistant PCa cells but not in chemoresponsive PCa cells. RNA-seq analyses revealed that bromocriptine affected a subset of genes implicated in the regulation of the cell cycle, DNA repair, and cell death. Interestingly, approximately one-third (50/157) of the differentially expressed genes affected by bromocriptine overlapped with known p53-p21- retinoblastoma protein (RB) target genes. At the protein level, bromocriptine increased the expression of dopamine D2 receptor (DRD2) and affected several classical and non-classical dopamine receptor signal pathways in chemoresistant PCa cells, including adenosine monophosphate-activated protein kinase (AMPK), p38 mitogen-activated protein kinase (p38 MAPK), nuclear factor kappa B  (NF-κB), enhancer of zeste homolog 2 (EZH2), and survivin. As a monotherapy, bromocriptine treatment at 15 mg/kg, three times per week, via the intraperitoneal route significantly inhibited the skeletal growth of chemoresistant C4-2B-TaxR xenografts in athymic nude mice. In summary, these results provided the first preclinical evidence that bromocriptine is a selective and effective inhibitor of chemoresistant PCa. Due to its favorable clinical safety profiles, bromocriptine could be rapidly tested in PCa patients and repurposed as a novel subtype-specific treatment to overcome chemoresistance.

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.
METHODS: 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.
CONCLUSIONS: 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.