Exploring neuroadaptive cellular pathways in chronic morphine exposure: An in-vitro analysis of cabergoline and Mdivi-1 co-treatment effects on the autophagy-apoptosis axis.

The complex impacts of prolonged morphine exposure continue to be a significant focus in the expanding area of addiction studies. This research investigates the effectiveness of a combined treatment using Cabergoline and Mdivi-1 to counteract the neuroadaptive changes caused by in vitro morphine treatment. The impact of Methadone, Cabergoline, and a combination of Cabergoline and Mdivi-1 on the cellular and molecular responses associated with Morphine-induced changes was studied in human Neuroblastoma (SK-N-MC) and Glioblastoma (U87-MG) cell lines that were exposed to prolong Morphine treatment. Cabergoline and Mdivi-1 combined treatment effectively influenced the molecular alterations associated with neuroadaptation in chronic morphine-exposed neural cells. This combination therapy normalized autophagy and reduced oxidative stress by enhancing total-antioxidant capacity, mitigating apoptosis, restoring BDNF expression, and balancing apoptotic elements. Our research outlines morphine's dual role in modulating mitochondrial dynamics via the dysregulation of the autophagy-apoptosis axis. This emphasizes the significant involvement of DRP1 activity in neurological adaptation processes, as well as disturbances in the dopaminergic pathway during in vitro chronic exposure to morphine in neural cells. This study proposes a novel approach by recommending the potential effectiveness of combining Cabergoline and Mdivi-1 to modulate the neuroadaptations caused by morphine. Additionally, we identified BDNF and PCNA in neural cells as potential neuroprotective markers for assessing the effectiveness of drugs against opioid toxicity, emphasizing the need for further validation. The study uncovers diverse effects observed in pretreated morphine glioblastoma cells under treatment with Cabergoline and methadone. This highlights the potential for new treatments in the DRD2 pathway and underscores the importance of investigating the interplay between autophagy and apoptosis to advance research in managing cancer-related pain. The study necessitates an in-depth investigation into the relationship between autophagy and apoptosis, with a specific emphasis on protein interactions and the dynamics of cell signaling.

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.

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.

Dopamine receptor agonist cabergoline promotes immunogenic phenotype in human monocyte-derived dendritic cells.

Dendritic cells (DCs) are known as antigen-presenting cells that are capable of regulating immune responses. DCs and T cells can interact mutually to induce antigen-specific T-cell responses. Cabergoline, which is a dopamine (DA) receptor agonist, seems to implement anti-inflammatory properties in the immune system, and therefore in the present study the impact of a DA receptor agonist cabergoline on the monocyte-derived DCs (moDCs) was assessed. Immature moDCs were treated with lipopolysaccharide to produce mature DCs (mDCs). The expression of DCs' related surface markers namely: CD11c, HLA-DR, and CD86 was measured by utilizing of flow cytometry. Real-time PCR was the technique of choice to determine the levels at which diverse inflammatory and anti-inflammatory factors in cabergoline-treated and control mDC groups were expressed. DCs treated with cabergoline displayed a significant decrease in CD86 and HLA-DR expression, markers linked to maturation and antigen presentation, respectively. In addition, the cabergoline-mDC group showed a considerable decline in terms of the levels at which IL-10, TGF-ß, and IDO genes were expressed, and an increase in the expression of TNF-α and IL-12 in comparison to the mDC control group. Our findings revealed that cabergoline as an immunomodulatory agent can relatively shift DCs into an immunogenic state, and there is a requirement for further investigations to evaluate the effects of cabergoline-treated DCs on the T cell responses in vitro, and also in various diseases including cancer in animal models.

Cabergoline treatment for surgery-naïve non-functioning pituitary macroadenomas.

PURPOSE: The treatment strategy of non-functioning pituitary adenomas (NFPAs) includes surgery, radiotherapy, medical therapy, or observation without intervention. Cabergoline, a dopaminergic agonist, was suggested for the treatment of NFPA remnants after trans-sphenoidal surgery. This study investigates the efficacy of cabergoline in surgery-naive patients with NFPA. METHODS: Retrospective cohort study including surgery-naive patients with NFPA ≥ 10 mm, treated with cabergoline at a dose of ≥ 1 mg/week for at least 24 months. Patients with chiasmal damage were excluded. Data collected included symptoms, in particular visual disturbances, hormonal levels, tumor characteristics and size evaluated by MRI. Tumor growth was defined as an increase in maximal diameter of ≥ 2 mm, and shrinkage as reduction of ≥ 2 mm. RESULTS: Our cohort included 25 patients treated with cabergoline as primary therapy. Mean age was 63.3 ± 17.3 years, 56% (14/25) were males. Mean tumor size at diagnosis was 18.6 ± 6.3 mm (median 17 mm, range 10-36), and the average follow-up period with cabergoline was 4.6 ± 3.4 years. Out of the 25 tumors, five tumors (20%) decreased in size (mean decrease of 5.0 ± 3.0 mm), 12 tumors (48%) remained stable, and eight (32%) increased in size (mean growth of 5.0 ± 3.3 mm) with cabergoline treatment. During the first two years of cabergoline treatment, the median tumor size exhibited a reduction of 0.5 mm. Patients with an increase in tumor size had larger adenomas at diagnosis and a longer follow-up. Two patients (8%) underwent surgery due to tumor enlargement. CONCLUSION: Primary treatment with cabergoline is a reasonable approach for selected patients with NFPAs without visual threat.

Modulatory effect of vitamin B6 on sex hormone receptors, thyroid, and kisspeptin/kiss1r system in the uterus of pseudopregnant bitches.

This study evaluated whether the treatment of pseudopregnancy in bitches with vitamin B6 modulates uterine expression of receptors for progesterone (PR), oestrogen (ERα), androgen (AR), thyroid hormone (TRα) and the kisspeptin/Kiss1r system. Eighteen pseudopregnant bitches were treated for 20 days in groups receiving placebo (n = 6); cabergoline (5 µg/kg/day; n = 6); or vitamin B6 (50 mg/kg/day; n = 6). Blood was collected on the 1st day of drug administration and 120 h later to measure serum prolactin (PRL). After treatment, they were ovariohysterectomized and uterine fragments were collected for histomorphometry and immunohistochemical evaluation of PR, ERα, AR, TRα, Kiss1 and Kiss1r. After 120 h of cabergoline or vitamin B6 treatment, PRL levels were reduced in the bitches, confirming the antiprolactinemic effect of these drugs. Furthermore, regardless of treatment, the animals exhibited uterine histomorphometry consistent with dioestrus. The PR showed strong immunostaining in all regions and an increase in scores was observed for this receptor in animals treated with vitamin B6 in deep glands. In contrast, ERα and Kiss1R receptors showed weak to no immunostaining in all uterine regions and no changes between groups. Regarding AR, most animals treated with vitamin B6 showed increased trends in the deep gland and myometrium marking scores. In contrast, in both vitamin B6 and cabergoline treatments, a reduction in TRα marking scores was observed compared to the control group. In addition, on the endometrial surface, a reduction was observed in the marked area of Kiss1 after administration of cabergoline when compared to the pseudopregnant control group. These findings shed valuable insight into the use of vitamin B6 as a drug with actions similar to cabergoline in reducing PRL and uterine modulation in bitches.

Natural history of nonfunctioning pituitary macroadenomas followed without intervention: A retrospective cohort study.

OBJECTIVE: The treatment strategy for nonfunctioning pituitary adenomas (NFPA) includes surgery, radiotherapy, medical treatment, or follow-up. Prior series of patients with NFPAs followed without intervention include small numbers of patients with macroadenomas. This study investigated the natural history of patients with macroadenomas followed without treatment. DESIGN AND PATIENTS: Retrospective cohort study included patients>18 years, with a diagnosis of NFPA ≥ 10 mm who were naïve to surgery or medical treatment and followed more than 12 months after diagnosis. Patients with chiasmal threat were excluded. Follow-up terminated if the patient underwent surgery, received cabergoline or was lost to follow-up. MEASUREMENTS: Data collected included evaluation of tumour characteristics and size by MRI, symptoms including visual disturbances, and hormonal levels. Tumour growth was defined as maximal diameter increase of ≥2 mm. RESULTS: The cohort included 49 patients (30 males, mean age 68.0 ± 12.0 years). At diagnosis, the average tumour size was 17.8 ± 5.9 mm. Mean follow-up time was 4.9 ± 4.9 years. Increase in tumour size occurred in 16 patients (33%), with an average growth of 5.1 ± 4.4 mm. Reduction in tumour size occurred in 10 patients (20%), with a mean decrease of 3.5 ± 1.3 mm. Twenty-three patients remained with stable tumours. Overall, 33 patients (67%) were observed without any intervention; 3 patients were operated and 13 were treated with cabergoline. None of the parameters including age, gender, baseline tumour size, invasiveness, visual disturbances, or hypopituitarism at diagnosis, predicted tumour growth. CONCLUSION: Observation of NFPAs without surgery or medical therapy is a reasonable approach in selected patients. In our study, no parameter predicted tumour growth.

Risk of impulse control disorders in patients with Cushing's disease: do not blame cabergoline but do not give up caution.

PURPOSE: To asses risk of new-onset impulse control disorders (ICDs) in patients with Cushing's disease (CD) who initiated cabergoline (CBG) and to determine frequency of ICDs in CBG-treated patients with CD. METHODS: This naturalistic observational study had prospective and cross-sectional arms which included patients at five referral centers based in Istanbul. Patients who were scheduled for CBG were assigned to prospective arm. These patients underwent neuropsychological tests (Barratt Impulsiveness Scale, Minnesota Impulsive Disorders Interview, Questionnaire for Impulsive-Compulsive Disorders in Parkinson's Disease-Rating Scale, Go/No-Go Task, Iowa Gambling Task, and Short Penn Continuous Performance Test) for assessment of impulsivity and psychiatric evaluations at baseline, 3, 6, and 12 months of CBG treatment. Impulsivity and new-onset ICDs were prospectively assessed. Patients with CD with current CBG treatment for ≥ 3 months and matched CBG-naïve patients with CD were included in cross-sectional arm. These patients underwent the same neuropsychological and psychiatric assessments. The impulsivity and frequency of ICDs were compared between CBG-treated and CBG-naïve patients with CD. RESULTS: The follow-up duration of prospective cohort (n = 14) was 7.3 ± 2.3 months. One patient developed major depressive episode and another patient developed compulsive gambling after CBG. We observed no significant changes in impulsivity scores during follow-up. In cross-sectional arm, CBG-treated (n = 34) and CBG-naïve patients (n = 34) were similar in impulsivity scores and frequency of ICDs [3 patients (8.8%) vs. 2 patients (5.9%) respectively, p = 1.0]. CONCLUSION: CBG-treated patients with CD appeared to have a low risk of ICDs, suggesting that CBG still holds promise as a safe agent in CD.

A systematic literature review to evaluate extended dosing intervals in the pharmacological management of acromegaly.

PURPOSE: This systematic literature review investigated whether extended dosing intervals (EDIs) of pharmacological acromegaly treatments reduce patient burden and costs compared with standard dosing, while maintaining effectiveness. METHODS: MEDLINE/Embase/the Cochrane Library (2001-June 2021) and key congresses (2018-2021) were searched and identified systematic literature review bibliographies reviewed. Included publications reported on efficacy/effectiveness, safety and tolerability, health-related quality of life (HRQoL), and patient-reported and economic outcomes in longitudinal/cross-sectional studies in adults with acromegaly. Interventions included EDIs of pegvisomant, cabergoline, and somatostatin receptor ligands (SRLs): lanreotide autogel/depot (LAN), octreotide long-acting release (OCT), pasireotide long-acting release (PAS), and oral octreotide; no comparator was required. RESULTS: In total, 35 publications reported on 27 studies: 3 pegvisomant monotherapy, 11 pegvisomant combination therapy with SRLs, 9 LAN, and 4 OCT; no studies reported on cabergoline, PAS, or oral octreotide at EDIs. Maintenance of normal insulin-like growth factor I (IGF-I) was observed in ≥ 70% of patients with LAN (1 study), OCT (1 study), and pegvisomant monotherapy (1 study). Achievement of normal IGF-I was observed in ≥ 70% of patients with LAN (3 studies) and pegvisomant in combination with SRLs (4 studies). Safety profiles were similar across EDI and standard regimens. Patients preferred and were satisfied with EDIs. HRQoL was maintained and cost savings were provided with EDIs versus standard regimens. CONCLUSIONS: Clinical efficacy/effectiveness, safety, and HRQoL outcomes in adults with acromegaly were similar and costs lower with EDIs versus standard regimens. Physicians may consider acromegaly treatment at EDIs, especially for patients with good disease control.

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.

CircOMA1 modulates cabergoline resistance by downregulating ferroptosis in prolactinoma.

PURPOSE: Prolactinomas are one of the most common pituitary neuroendocrine tumors (PitNETs), accounting for approximately 50% of all pituitary tumors. Dopamine agonists are the main treatment for prolactinoma, but a small number of patients are still resistant to pharmacotherapy. Recent discoveries have revealed that ferroptosis is involved in regulating tumor drug resistance. However, the role of ferroptosis in prolactinoma has not been reported. In this study, we aimed to explore the mechanism of a circRNA in ferroptosis in prolactinoma. METHODS: The expression of circOMA1 in prolactinoma tissues was examined by quantitative reverse transcription PCR (qRT-PCR). The biological function of circOMA1 was evaluated in vitro and in vivo. To explore the role of ferroptosis in prolactinoma, we used qRT-PCR and western blotting. Glutamate-cysteine ligase, modifier subunit (GCLM) was predicted to be a direct target gene of miR-145-5p by bioinformatics analysis, which was confirmed by luciferase reporter assays. RESULTS: circOMA1 was overexpressed in drug-resistant prolactinoma tissues compared with sensitive prolactinoma samples. We further found that circOMA1 promoted MMQ cells growth in vivo and in vitro. In addition, GCLM was directly targeted by miR-145-5p and indirectly regulated by circOMA1. Importantly, circOMA1 induced ferroptosis resistance through the increased expression of Nrf2, GPX4, and xCT, and circOMA1 attenuated CAB-induced ferroptosis in MMQ cells in vivo and in vitro. CONCLUSION: The present study demonstrates that circOMA1 attenuates CAB efficacy through ferroptosis resistance and may be a new therapeutic target for the individualized treatment of DA-resistant prolactinoma patients.

Does cabergoline administration affect endometrial VEGFR-2 expression in a rat model of ovarian hyperstimulation syndrome?

OBJECTIVE: To assess the effect of cabergoline on endometrial vascular endothelial growth factor receptor-2 (VEGFR-2) immunoexpression in an ovarian hyperstimulation syndrome (OHSS) rat model. MATERIAL AND METHODS: Twenty-one immature female Wistar rats were assigned into three groups: group 1, the control group; group 2, stimulated with gonadotropins to mimic OHSS; and group 3, in which an OHSS protocol was induced and thereafter treated with cabergoline (100 µg/kg/day). Body weight, ovarian volume, corpora lutea numbers, and endometrial VEGFR-2 expression were compared between the groups. RESULTS: Weight gain and ovarian volume were highest in the OHSS-placebo group, while cabergoline administration significantly reversed those effects (p = 0.001 and p = 0.001, respectively). VEGFR-2 stained cells were significantly lower in groups 2 and 3 compared to group 1 (p = 0.002). Although VEGFR-2 expression was lowest in group 3, the difference was not statistically significant. Corpora lutea numbers were also similar (p = 0.465). CONCLUSION: While successful implantation requires a vascularized receptive endometrium, impaired expression of VEGFR-2 and disrupted endometrial angiogenesis due to cabergoline administration may be associated with IVF failure in fresh OHSS cycles. The insignificant decrease in endometrial VEGFR-2 expression observed in this research needs to be investigated by further studies involving additional techniques such as immunoblotting and/or RT-PCR analyses.

Long-term low-dose cabergoline usage: Another association with cardiac valvulopathy.

A 60-year-old patient, professor of physics, presented in 1999 with sudden-onset vitiligo associated with hyperprolactinemia and a prolactinoma. Fearful of potential surgical complications at the peak of his career, the patient declined surgery and opted for medical management with bromocriptine. The decreasing effectiveness of bromocriptine after 5 years required a switch to cabergoline. After a 15-year-course of cabergoline therapy with a cumulative dose of 572 mg, echocardiographic monitoring demonstrated aortic and mitral valve thickening and regurgitation. An additional 3 years of cabergoline treatment (cumulative dose: 649 mg) resulted in worsening valve thickening and regurgitation. It is well-recognized that such valvular changes may occur with high-dose cabergoline treatment. We report a case of mitral and aortic vavulopathy in a patient who was treated with long-term (18 years) low-dosage (.5-1 mg weekly) cabergoline. cabergoline, echocardiography, valvulopathy.

Effects of feed energy density, daily milking frequency, and a single injection of cabergoline on behavior and welfare in dairy cows at dry-off.

Drying off dairy cows may challenge animal welfare due to high milk yields. A total of 111 loose-housed Holstein cows yielding >15 kg/d of milk were included in a 2 × 2 × 2 factorial design during dry-off to investigate the effects of reduced feeding level (normal vs. reduced energy density), reduced milking frequency (twice vs. once daily), and administration of a dopamine agonist (saline i.m. injection vs. cabergoline i.m. injection) on behavior in the home pen. During the 7 d before dry-off, cows were fed and milked according to 1 of the 4 feeding level and milking frequency combinations. Within 3 h after the last milking, cows were injected i.m. with 5 mL of either saline or a dopamine agonist (5.6 mg of cabergoline; Velactis, Ceva Santé Animale, Libourne, France; labeled for use only with abrupt dry-off, i.e., no preceding reduction in feeding level or milking frequency before last milking). Cows' behavior during d -1, 0, and +1 relative to the last milking was recorded via video and leg-attached sensors. Cows on the reduced energy density diet spent more time feeding and showed more attempts to feed from other cows' bins on d -1. Throughout the period of observations, cows on the reduced diet spent a lower percentage of lying time with their head raised, a higher percentage of lying time with their legs bent, and less time standing in a vigilant posture than did cows on the normal lactation diet. Reducing the daily milking frequency from 2 to 1 did not result in any clear behavioral signs of discomfort. On d 0, cows injected with cabergoline lay down longer but had their head raised for a shorter percentage of time while lying, compared with cows injected with saline. Cows injected with cabergoline also spent less time feeding than cows injected with saline on d 0, and reduced the time spent drinking from d -1 to d 0. Finally, fewer cabergoline-injected cows used the brush for self-grooming, and, among cows that did use the brush, the cows injected with cabergoline reduced the time spent using the brush from d -1 to d 0. In conclusion, cows injected with cabergoline showed several behavioral changes compared with control cows injected with saline. The behavioral changes shown by cows injected with cabergoline may be indicative of malaise during the first 24 h after injection, raising concern for animal welfare. No behavioral evidence for reduced udder pain in cows injected with cabergoline compared with control cows injected with saline was found. Drying off by reducing the energy density of the diet caused behavioral changes indicative of hunger before dry-off, whereas reducing the milking frequency had no clear effects on behavior.

Effects of feeding level, milking frequency, and single injection of cabergoline on blood metabolites, hormones, and minerals around dry-off in dairy cows.

This study aimed to investigate the effect of the different dry-off strategies based on reducing feeding level (normal vs. reduced energy density), reducing milking frequency (twice vs. once daily), and administration of a dopamine agonist after last milking (i.e. saline vs. cabergoline injection) on blood metabolites, hormones, and minerals around dry-off. In this experiment, 119 Holstein dairy cows were used in a 2 × 2 × 2 factorial arrangement. In the last week before dry-off, cows were allocated to 1 of the 4 possible dry-off strategies based on feeding level and milking frequency. Within 3 h after last milking, cows were injected with either saline or a D2 dopamine agonist (cabergoline; Velactis, Ceva Santé Animale, Libourne, France; labeled for use only with abrupt dry-off, e.g., no preceding reduction in feeding level or milking frequency before last milking). After dry-off, all cows were fed the same dry cow diet and data collection continued for a week. Blood samples were collected from the coccygeal vein on d -9, -6, -5, -2, 1, 2, 5, and 7 relative to dry-off. Additionally, blood was sampled at 0, 3, and 6 h relative to injection of either cabergoline or saline, equivalent to d 0.125, 0.250, and 0.375 relative to last milking (dry-off). The reduced feeding level before dry-off caused reduced glucose and insulin concentrations as well as increased free fatty acid concentrations, particularly when reduced feeding level was combined with milking the cows 2× daily. The intramuscular injection of cabergoline caused the expected reduction in circulating prolactin concentrations. In addition, dopamine-agonist cabergoline induced an atypical simultaneous pattern of plasma metabolites (i.e., increased glucose and free fatty acid concentrations), hormones (i.e., reduced insulin and increased cortisol concentrations), and minerals (i.e., reduced calcium concentration), indicating that normal metabolic and mineral homeostatic regulations were hindered after the injection of ergot alkaloid cabergoline. In conclusion, reducing milking frequency seems the best management strategy to reduce milk production at dry-off among those tested in this study.

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.

Impulse control disorders in hyperprolactinemic patients on dopamine agonist therapy.

Dopamine agonists (DAs) represent a mainstay of therapy for hyperprolactinemia and prolactinomas. The widespread use of DAs, including bromocriptine, cabergoline and (in some countries) quinagolide, has led to the emergence and recognition of impulse control disorders (ICDs) that may occur in association with DA therapy.Such ICDs include pathological gambling, compulsive shopping, hypersexuality and punding (the performance of repetitive tasks), among others. These manifestations can lead to substantial harms to patients and their families, if left undiagnosed and untreated. Several risk factors that may increase the risk of ICDs have been proposed, including younger age, male gender, smoking and alcohol use and history of depression.The diagnosis of ICDs in hyperprolactinemic patients treated with DAs requires a high index of suspicion and a systematic approach, using available screening questionnaires. However, it should be noted that available test instruments, including questionnaires and computerized tasks, have not been validated specifically in hyperprolactinemic patients. Hyperprolactinemic patients who develop ICDs should be withdrawn from DA therapy or, at a minimum, undergo a DA dose reduction, and considered for psychiatric consultation and cognitive behavioral therapy. However, the role of psychopharmacotherapy in hyperprolactinemic patients with ICDs remains incompletely characterized.Patient counseling regarding the risk of ICDs occurring in association with DA therapy, early detection and prompt intervention may mitigate potential harms associated with ICDs. Additional studies are needed to fully characterize risk factors, underlying mechanisms and identify effective therapies for ICDs in patients with hyperprolactinemia receiving DAs.

The elusive role of prolactin in the sociality of the naked mole-rat.

Despite decades of research into the evolutionary drivers of sociality, we know relatively little about the underlying proximate mechanisms. Here we investigate the potential role of prolactin in the highly social naked mole-rat. Naked mole-rats live in large social groups but, only a small number of individuals reproduce. The remaining non-breeders are reproductively suppressed and contribute to burrow maintenance, foraging, and allo-parental care. Prolactin has well-documented links with reproductive timing and parental behaviour, and the discovery that non-breeding naked mole-rats have unusually high prolactin levels has led to the suggestion that prolactin may help maintain naked mole-rat sociality. To test this idea, we investigated whether urinary prolactin was correlated with cooperative behaviour and aggression. We then administered the prolactin-suppressing drug Cabergoline to eight female non-breeders for eight weeks and assessed the physiology and behaviour of the animals relative to controls. Contrary to the mammalian norm, and supporting previous findings for plasma, we found non-breeders had elevated urinary prolactin concentrations that were similar to breeding females. Further, prolactin levels were higher in heavier, socially dominant non-breeders. Urinary prolactin concentrations did not explain variation in working behaviour or patterns of aggression. Furthermore, females receiving Cabergoline did not show any behavioural or hormonal (progesterone) differences, and urinary prolactin did not appear to be suppressed in individuals receiving Cabergoline. While the results add to the relatively limited literature experimentally manipulating prolactin to investigate its role in reproduction and behaviour, they fail to explain why prolactin levels are high in non-breeding naked mole-rats, or how female non-breeding phenotypes are maintained.

Prolactin Response to Metformin in Cabergoline-Resistant Prolactinomas: A Pilot Study.

INTRODUCTION: Cabergoline is the treatment of choice for prolactinomas. However, 10-20% of prolactinomas are resistant to cabergoline. Metformin, a biguanide widely used in the treatment of diabetes mellitus, has been shown to reduce prolactin secretion in various pituitary tumor-cell lineages both in vitro and in vivo and in human pituitary adenomas in vitro. The aim of this study is to test the effects of metformin addition to cabergoline treatment on prolactin levels in patients with resistant prolactinomas. SUBJECTS AND METHODS: This is a prospective study performed in an outpatient clinic in a reference center. Ten adult patients (26-61 years) with prolactinomas (7 M), persistent hyperprolactinemia (38-386 ng/mL) under cabergoline treatment (2-7 mg/week) for at least 6 months (6-108 months), features of metabolic syndrome, and not taking metformin were included. Metformin (1.0-2.5 g v.o./day) was given according to patients' tolerance. Cabergoline doses were kept unchanged. Serum prolactin levels were measured before and after short- (30-60 days) and long-term (120-180 days) metformin treatment. RESULTS: Mean prolactin levels did not show any significant changes (148 ± 39 vs. 138 ± 42 vs. 133 ± 39 ng/mL, before, at 30-60 days, and at 120-180 days, respectively, p = 0.196) after metformin (mean dose: 1.25 g/day; range: 1.0-2.0 g/day). No patient reached a normal prolactin level during metformin treatment. Two patients were considered partial responders for exhibiting prolactin decreases ≥50% at a single time point during metformin. CONCLUSION: Metformin addition to ongoing high-dose cabergoline treatment in patients with cabergoline-resistant prolactinomas failed to show a consistent inhibitory effect in serum prolactin levels.

Effect of Cabergoline Treatment on Disease Control in Acromegaly Patients.

The aim of this study was to evaluate the efficacy of cabergoline in normalizing plasma IGF-I levels in acromegaly patients with elevated IGF-I levels after surgery and/or SRL therapy. Acromegaly patients (n: 143) were evaluated retrospectively. Patients with elevated IGF-I levels after surgery and/or SRLs therapy and a fixed dose of SRLs treatment for the last six months with no history of radiotherapy in the last three years were included in the study (n: 12). Previous treatment regimens, baseline PRL and IGF-I levels (ULNR), sella MRI, and immunohistochemical findings were evaluated. Cabergoline was used as an add on (n: 11) or single medical treatment (n: 1). The median duration of treatment with SRL alone was 12 months (range 6-48 months). The mean IGF-I value before cabergoline therapy was 1.45±0.4 ULNR. The mean cabergoline dose and duration of treatment were 1.55±0.75 mg/week and 9±6.3 months, respectively. IGF-I normalization was only achieved in patients with serum IGF-I concentration<1.5×ULNR before the onset of cabergoline treatment (n: 9). In some of the patients with IGF-I normalization, baseline prolactin levels were normal (n: 3). Immunopositivity for prolactin in adenoma tissue was found in three patients with IGF-I normalization. Cabergoline therapy is effective in the normalization of IGF-I levels even in normoprolactinemic acromegaly patients when IGF-I levels are mildly or moderately elevated during SRL therapy.