Cabergoline Research Articles

Prolactinoma: Clinical Characteristics, Management and Outcome.

Aim Prolactinoma, a prolactin (PRL) secreting functioning pituitary tumor, is the most common of all pituitary adenomas (PA) accounting for 40-60% and dopamine agonists (DA) are the cornerstone of treatment. The aim of this study was to review the clinical presentation, treatment modalities and therapeutic outcomes of patients with prolactinomas in the South Asia region. Methods This retrospective study was conducted in the Endocrinology Department of Shaukat Khanum Memorial Cancer Hospital and Research Centre from December 2011 till December 2019. Medical records were used to retrieve for patient's demographics, clinical features at diagnosis, PRL levels and size of prolactinoma on MRI at diagnosis and after start of dopamine agonists and outcome of medical management. Results A total of 107 patients were included in this study. Mean age at diagnosis was 35 (22-54) years for men and 32 (18-50) years for women and 66.4% (71) of the patients were females. Our study included 38 (35.5%) microadenoma, 50 (46.7%) macroadenoma and 19 (17.8%) giant adenomas. At presentation, the most common symptom among females was menstrual irregularity/amenorrhea seen in 73.2% of females and among males was visual disturbance (80.6%). A significant reduction in PRL levels was seen within six to 12 months of treatment. Mean PRL levels decreased from 3162.8 ng/ml to 1.52 ng/ml. A notable decrease in tumor size was seen with medical management, mean adenoma size decreased from 2.18 cm to 1.04 cm. With cabergoline (CAB) 83.3% biochemical cure was seen compared to bromocriptine (BRC) which has 60.4%. The radiological response rate in CAB and BRC groups was 65.45% and 60%, respectively. Complete resolution of adenoma was seen in 13 patients (nine were microadenoma, two macro and two giant adenomas). The prolactin level at diagnosis was positively correlated with maximum tumor diameter (r = 0.469, P = 0.001). Two patients developed cerebrospinal fluid (CSF) rhinorrhea and the defect was repaired in both patients. Median follow-up duration was 40 (12-288) months. Conclusion Clinical presentation and demographics of prolactinoma are the same in our region when compared to the rest of the world. Cabergoline is superior to bromocriptine in prolactin normalization and tumor shrinkage but still bromocriptine is being used in a significant number of patients in low-income countries as first-line due to its low cost.

A validated LC–MS/MS method for analysis of Cabergoline in human plasma with its implementation in a bioequivalent study: investigation of method greenness

Cabergoline (CAB) is effective prolactin lowering drug. Evaluation of the bioequivalence for the new test product (0.5 mg CAB film-coated tablets) in Egypt is strongly needed for approval of the drug by the official health authority. Therefore, a highly sensitive and rapid (LC–MS/MS) method was validated for CAB analysis in human plasma. CAB was extracted from plasma via diethyl ether using Quetiapine (QUE) as an internal standard. Multiple reaction monitoring (MRM) in positive ion mode was used, m/z 452.3 → 381.2 for CAB and 384.2 → 253.1 for QUE. Separation was accomplished on a reversed-phase C18. FDA procedures for the bio-analytical method were followed. The method was used in the bioequivalence study to compare the test product (0.5 mg CAB) versus Dostinex tablets, on 24 healthy Egyptian volunteers. The total analysis time was 5.5 min for each sample which permits analysis of various samples per day. The linearity range was from 2.00 to 200.00 pg/mL for CAB. LOD and LOQ were found to be 0.5 and 1.6 pg/mL, respectively. The final greenness numerical value was 0.63 using AGREE tool. The results of pharmacokinetic parameter Tmax were 2.17, and 2.33 h; for test and reference products, respectively. The generic formulation of test product is considered bioequivalent to the reference product Dostinex 0.5 mg tablets and satisfies the requirements of the Egyptian market. The merits of the method over the previous published methods are low cost; availability of cheap internal standard; rapidness; use of acetonitrile-free solvents mobile phase.

Coenzyme Q10 improves ovarian histology and attenuates the expression of angiogenesis-associated proteins in the ovary of rats with experimental hyperstimulation syndrome.

Objective(s):Ovarian hyperstimulation syndrome (OHSS) is an iatrogenic complication characterized by many side effects. Coenzyme Q10 (CoQ10) is a protective lipophilic molecule with an extensive range of biological functions, but its possible protective effect on the ovary in OHSS has not as yet been studied. The present study aimed to investigate the potential protective effects of CoQ10 on ovarian histological and molecular alterations in an experimental model of OHSS in rats. Materials and Methods:Thirty female (2 months old) Wistar rats were randomly divided into 6 equal groups: control, OHSS, OHSS+CoQ10 (OHSS+ 200 mg/kg CoQ10 for 10 days), OHSS+ cabergoline (CAB) (OHSS+ 100 µg/kg CAB for 6 days), and CoQ10 and CAB (rats receiving similar doses to treatment groups.( In the end, the effects of treatments were assessed by measuring expressions of vascular endothelial growth factor (VEGF) and cyclooxygenase-2 (COX-2) in the ovary via western blotting, ovarian histomorphological alterations assessments, and serum estradiol and progesterone levels via ELISA. Results:There were histological alterations in OHSS groups, including the elevation of diameter and numbers of the corpus luteum and atretic follicles, and decreasing follicular reserve count, hyperemia, and hemorrhage at ovarian stroma. Treatment of OHSS groups with CAB and CoQ10 could decrease histological changes, serum estrogen and progesterone, and overexpression of VEGF and COX-2 proteins.Conclusion:Our results showed that ovarian histological and molecular alterations observed in experimental OHSS can be ameliorated by administration of CoQ10, indicating that CoQ10 can be used as new supportive care for OHSS patients.

Treatment of non-functioning pituitary adenoma with cabergoline: a systematic review and meta-analysis.

To make a systematic review and meta-analysis of studies evaluating the effect of cabergoline (CBG) in the treatment of non-functioning pituitary adenomas (NFPAs). The primary outcome was tumor shrinkage, using as cut-off a reduction of at least 20% of the NFPA size from baseline. The secondary outcomes were prevention of tumor progression, clinically required additional interventions and adverse events (AE). Search strategies were applied to MEDLINE, EMBASE, LILACS and CENTRAL. Independent reviewers assessed the study eligibility, extracted data, and evaluated risk of bias. Random meta-analysis for the proportion of tumor shrinkage, prevention of tumor progression, clinically required additional interventions and frequency of AE were conducted. Five studies were included. The meta-analysis of proportion was 19% for tumor shrinkage (95% CI 8-38%, 4 studies, 108 participants), 50% for prevention of tumor progression (95% CI 35-64%, 5 studies, 187 participants), 14% for clinically required additional interventions (95% CI 6-30%, 4 studies, 128 participants) and 2% for adverse events (95% CI 1-6%, 3 studies, 157 participants). Effect of CBG to promote tumor shrinkage in NFPAs was low, while prevention of tumor progression after surgery was seen in half of the cases, with a low frequency of adverse events. PROSPERO CRD42020206778.

Efficacy of cabergoline therapy in patients with non-functioning pituitary adenomas: A single center clinical experience.

To evaluate the response to cabergoline (CBG) treatment in patients with non-functioning pituitary adenomas (NFPA). Retrospective, single tertiary care center study. A total of 44 patients were treated with 3 mg/week of CBG, 32 after surgical treatment (transsphenoidal surgery [TSS] in 27 and TC in 5 patients) and 12 as primary therapy. Mean age was 59.2 ± 12 years and 23 (52.2%) were women. Response to therapy was ascertained by serial magnetic resonance imaging. The median duration of CBG therapy was 30 months (IQR 24-48). Response to CBG therapy was defined as a greater than 20% reduction in tumor size and volume. A significant reduction in tumor size was documented in 29 patients (66%), whereas in 11 patients (25%) the tumor increased in size and in 4 (9%), it remained stable. Significant tumor shrinkage was documented in 4 (33.3%) of 12 patients treated primarily and in 23 (71.8%) of those treated secondarily. The three-year progression-free survival was 0.61. Cabergoline therapy is effective in reducing tumor growth in over two thirds of patients with NFPA, however 16% of patients will escape to this beneficial effect and will require alternative forms of treatment to halt tumor progression.

Resistant prolactinomas: a case series of 26 patients.

Prolactin (PRL)-secreting tumors are the most common functional pituitary adenomas. They usually respond to dopamine agonist (DA) treatment, with PRL normalization and adenoma shrinkage. Our aim was to characterize patients with prolactinoma resistant to DA treatment. This retrospective case series included patients diagnosed with DA-resistant prolactinomas between 1993-2017 in three medical centers. Resistance was defined as PRL levels above three times the upper limit of normal (ULN) despite a weekly dose of ≥2 mg cabergoline (CAB). Clinical and biochemical information, and response to treatment, were retrieved from medical records. Twenty-six patients were identified; 20 males. Of 25 macroadenomas, three were giant tumors (>40 mm) and 15 (57.7%) were invasive. The mean age at diagnosis was 31.8 ± 14.9 years (range: 13-62). The median maximal CAB dose was 3.5 mg/week (IQR, 2.5-5). Half the patients received only CAB in escalating doses, nine received CAB and underwent transsphenoidal surgery, and four underwent surgery and radiotherapy in addition to CAB treatment. PRL levels at baseline between patients treated only with CAB and those operated were (91.6 [51.1-296.7] vs. 73.1 [22.6-170.9] XULN p = 0.355), and under maximal CAB dose PRL levels between patients treated only with CAB and those operated were similar (5.77 [1.27-11.27] vs 5.27 (2.9-26) XULN p = 0.317). At the last visit patients who received combined therapy achieved lower PRL levels than those treated with DA only (5.22 [1.7-21.6] vs 1.1 [0.44-3.99] XULN p = 0.017) PRL normalization was attained in seven patients and levels below 3 × ULN in fourteen patients; the overall response was 56%. Resistant prolactinomas usually require a multi-modal treatment strategy. We were able to control 14/25 (56%) of resistant tumors.

Dopamine agonist for the rapid improvement of visual field defects in giant and macro-prolactinomas

To evaluate effect of first-line dopamine agonist (DA) therapy as an alternative to surgery for visual field defect (VFD) recovery in giant and macro-prolactinoma. In this retrospective study, 125 patients with giant and macro-prolactinoma, except those with a history of previous surgery or radiotherapy, were evaluated. Those who underwent visual field examinations using the Humphrey Visual Field analyser upon initial assessment and after treatment were included for analysis. Twelve patients with VFD were included. The effects of DA therapy on both VFD and tumor size were evaluated within the first three months. There were twelve patients analysed: three females and nine males, five giant and seven macroprolactinomas; eight patients received cabergoline (CAB) and four patients received bromocriptine (BRC). The mean adenoma diameter was 35±13mm (range 15-60), and the mean PRL level was 3,523ng/dL (range 312-11,703). Eight patients (67%) complained of blurred vision, while four patients (33%) reported no visual symptoms. After a median duration of three weeks, the VFD completely resolved in ten patients (83%) but only partially improved in two (17%). The mean initial doses of CAB and BRC that provided VFD improvement were 0.5±0.2mg/week and 6.3±1.4mg/day, respectively. After a mean duration of 2.2±0.9months, the mean decrease in adenoma size was 43.6±24.5% (range 10-95%). The use of DA as a first-line treatment for at least one month before deciding on surgery is recommended in giant and macro-prolactinomas with VFD. Surgery should be considered only in cases with DA resistance or persistent visual impairment despite medical therapy.

Effects of changes in diet energy density and milking frequency and a single injection of cabergoline at dry-off on feeding behavior and rumination time in dairy cows

Dry-off is a typical management practice, but research on the effects of dry-off on feeding behavior in high-yielding cows is limited. The present study investigated the effects of 2 diet energy densities: lactation diet (normal energy density, NORM) versus a lactation diet diluted with 30% straw (reduced energy density, REDU), both offered ad libitum, and 2 daily milking frequencies (2× vs. 1×) during the 7 d before dry-off day (d 0), and the effects of an injection of either a dopamine agonist [cabergoline (CAB); Velactis, Ceva Santé Animale; labeled for use only with abrupt dry-off; i.e., no reduction in feeding level or milking frequency before the last milking] or saline (SAL) following the last milking on d 0 (2 × 2 × 2 factorial arrangement), on automatically monitored feeding behavior and rumination time in 119 clinically healthy, loose-housed, pregnant, lactating Holstein cows during the week before and after d 0. From d 0, all cows were fed the same dry-cow diet ad libitum. Data were analyzed in R using mixed-effects models. Over the days before d 0, REDU cows spent 30% more time feeding at a 50% lower feeding rate, visited both assigned and unassigned feed bins more frequently, and spent more time ruminating than NORM cows. No clear behavioral effects of reduced milking frequency were found. Within 24 h following injection, CAB cows spent approximately 40% less time feeding at a lower feeding rate, visited their feed bin 28% less often, and spent 40% less time ruminating than SAL cows, irrespective of treatment before dry-off. The current study demonstrates that reducing diet energy density for 1 wk before dry-off led to clear behavioral changes in high-yielding cows. Administering CAB after the last milking induced decreased feeding behavior lasting approximately 24 h, indicating collateral effects other than reduced prolactin secretion.

ACT001 reverses resistance of prolactinomas via AMPK-mediated EGR1 and mTOR pathways.

Dopamine agonist (DA) is the first choice for the treatment of prolactinomas, and drug resistance is unavoidable during treatment due to the heterogeneity of tumors. The two prolactinoma cell lines (GH3 cells and MMQ cells) were found to have different sensitivity and responding modes to the cabergoline (CAB) and bromocriptine (BRC). In this research, we disclosed the capability of ACT001, a derivative of parthenolide analogs, to activate AMPK by increasing the intracellular reactive oxygen species (ROS) level and AMP/ATP ratio to reverse DA resistance through dual pathways in prolactinoma cells. The results indicated that ACT001 could reverse the CAB resistance in GH3 cells by inhibiting the mTOR signaling pathway, inducing cell death through autophagy, and reverse the BRC resistance in MMQ cells by activating the EGR1 signaling pathway, inducing cell death through apoptosis. Our results suggested that ACT001 is a promising therapeutic compound for treating DA-resistant prolactinomas.

Effects of dietary and milking frequency changes and administration of cabergoline on clinical udder characteristics in dairy cows during dry-off

We investigated the effects of 2 diet energy densities [normal lactation diet (NORM) vs. energy-reduced diet (REDU), both fed for ad libitum intake] and 2 daily milking frequencies [twice (2×) vs. once (1×)] during 1 week before the dry-off day, as well as effects of an injection of either a dopamine agonist [cabergoline (CAB); Velactis, Ceva Santé Animale, Libourne, France; labelled for use only with abrupt dry-off, e.g. no reduction in diet energy density or milking frequency before the last milking] or saline (SAL) following the last milking, on clinical udder characteristics of Holstein cows. During a week before and after the last milking, the following measures were recorded: palpation-based udder firmness and soreness; image-based hock-hock distance; responsiveness to mechanical udder stimulation and degree of udder fill measured with a dynamometer. Before the last milking, REDU cows displayed lower odds of having a firm udder and lower degree of udder fill, as well as lower responsiveness to mechanical udder stimulation, than NORM cows. After the last milking, REDU cows displayed shorter hock-hock distance compared with NORM cows. The effects of milking frequency on the clinical udder characteristics were unclear. Within 24 h following injection, CAB cows showed lower odds of having a firm udder, shorter hock-hock distance, and lower degree of udder fill than SAL cows, irrespective of treatment group before dry-off. In this study, reducing diet energy density prior to dry-off, and to some extent administering the dopamine agonist cabergoline after the last milking, resulted in fewest clinical udder changes.

The effects of cabergoline in the presurgical and recurrence periods of Cushing's disease patients.

The dopaminergic agonist cabergoline (CAB) has been used in the pharmacological treatment of Cushing's disease (CD). The effect is attributed to the frequent expression of the dopamine receptor subtype 2 in corticotroph tumors. However, in vivo studies have demonstrated the normalization of 24-h urinary cortisol (24-h UC) in approximately 30-40% of patients over the long term, mainly after surgical failure. To evaluate the effect of CAB as monotherapy in the early preoperative period and on the recurrence of CD. A single-center retrospective study was conducted in a tertiary referral center. Twenty-one patients with confirmed CD were included. The median age was 32 years (13-70), 86% were female, 10 had microadenomas, and 11 had macroadenomas. They were diagnosed from 1986 to 2016 and used CAB as monotherapy either in the preoperative period (n=7, CABi) or upon recurrence before any other treatment (n=14, CABr). A 'complete response' was considered 24-h UC normalization and a 'partial response' was considered a 24-h UC reduction of >50%. UC was obtained at the last follow-up evaluation. The normalization of late-night salivary cortisol (LNSC) after CAB use was evaluated in most patients, as well as the tumor diameter by pituitary MRI, before and after CAB treatment. Complete response was achieved in 29% (6/21) of subjects after 14.9±16.4 months of treatment, with an average dose of 2.2±1.0 mg/week. Partial response occurred in 9.5% (2/21). LNSC normalized in 35% (6/17) of patients, and no variation in tumor diameter before and after CAB use was observed (n=13): 6.8±6.8 vs. 7.2±7.1 mm. There was no normalization of 24-h-UC in the CABi subgroup at the end of the treatment, whereas 43% (6/14) of patients in the CABr subgroup reached complete response. The CABi subgroup was treated for 4.7±1.9 months, and the CABr subgroup was treated for 20.1±18.1 months. Both groups were administered similar doses of CAB (CABi 2.1±0.9 and CABr 2.3±1.1 mg/week). Interestingly, the difference between the subgroups' complete response was evident early on in the three months of treatment: no patients in the CABi subgroup vs. 6/10 (60%) in the CABr subgroup (p=0.035), despite a lower dose in the CABr subgroup (1.1 vs. 1.6; p=0.008). The normalization of LNSC occurred in 20% of the CABi subgroup and in 42% of the CABr subgroup. The normalization of 24-h UC and LNSC occurred in approximately 30% of all patients, mainly in those who used CAB for the recurrence of CD. Despite the small number of subjects in the CABi subgroup, the absence of hormone control in this subgroup discourages the use of this medication as primary therapy or as a preoperative treatment option.

Клинико-гормональные критерии оценки эффективности супрессивной терапии каберголином у больных с органической гиперпролактинемией

Актуальность. В современных международных рекомендациях не выделены критерии оценки клинических симптомов, в том числе со стороны соматического, неврологического статуса, хотя практически все нейроэндокринологи признают наличие именно неспецифических жалоб и симптомов у больных с органической гиперпролактинемией. Лечение органической гиперпролактинемии направлено на достижение восстановления нормального уровня биологически активного пролактина (ПРЛ) и уменьшение объема аденомы. Цель исследования — изучить клинико-гормональную эффективность разных режимов супрессивной терапии каберголином у больных с пролактиномами за период 12 месяцев. Материалы и методы исследования. Обследованы и прошли 12-месячный курс лечения селективным агонистом дофамина (АгДоф) каберголином (САВ) 61 пациент с пролактиномой (ПРОЛ) (52 женщины и 9 мужчин) в возрасте 16–66 лет. Общая длительность заболевания составляла от 1 до 60 мес., средняя — 12,3 ± 10,1 мес. Среди женщин, получавших терапию САВ, у 40 была микроПРОЛ, у 12 макро- и гигантская ПРОЛ. Среди мужчин у 2 была микроаденома, у 7 макроаденома. ПРОЛ верифицировали с помощью магнитно-резонансной томографии (МРТ). Уровень ПРЛ в крови (нг/мл) определяли иммуноферментным методом на автоматическом анализаторе Stat Fax 2100 (Awareness Technology, США) с помощью коммерческого набора реактивов ELISA (DRG Diagnostics, США). Применяли два режима терапии: первый — режим постепенного наращивания дозы САВ, начиная с 0,5 мг в неделю с последующим контролем уровня ПРЛ в крови каждые 4 нед. и титрацией дозы препарата при необходимости (увеличение недельной дозы на 0,25–0,5 мг). Второй — режим высоких стартовых доз из расчета: количество таблеток САВ (0,5 мг) соответствовало кратности повышения уровня ПРЛ в крови по отношению к верхней границе возрастной нормы, но не более 4 мг (8 таблеток) в неделю. Статистический анализ полученных данных проводили с использованием программного комплекса Statgraphics Plus for Windows 3.0 (Manugistic Inc. USA). Результаты. Предложена интегральная балльная система оценки клинико-гормональной эффективности супрессивной терапии САВ у больных с органической гиперпролактинемией, которая позволяет на всех этапах динамического наблюдения проводить коррекцию схемы лечения, оценить возможный риск от применения больших доз препарата и оптимизировать подбор адекватной дозы препарата. Оптимальным режимом терапии каберголином у пациентов с микропролактиномой является режим постепенного увеличения дозы, положительный клинико-гормональный эффект которого наблюдается у 80 % пациентов через 3 месяца после начала лечения. Выводы. Назначение режима высоких стартовых доз каберголина пациентам с макро- и гигантскими пролактиномами позволяет в более короткие сроки (через 1 мес.) добиться достоверной позитивной динамики показателей неврологического, общесоматического и гормонального статуса по сравнению с группой больных, получавших терапию в режиме постепенного увеличения дозы препарата.

Shrinkage by the third month predicts long-term response of macroprolactinoma after cabergoline

Transsphenoidal surgery (TSS) is mainly indicated in prolactinomas when dopamine agonist treatment fails. However, there is no established early predictor of cabergoline (CBG) response. The present study was aimed to identify predictors of CBG resistance in order to select patients who may benefit from early TSS. Retrospective longitudinal study. We reviewed the medical record of patients diagnosed with prolactinoma after 2010. Inclusion criteria: macroprolactinomas under CBG treatment with serial prolactin levels and MRI before treatment and 3 and 12 months afterwards. The main outcome was tumour size shrinkage ≥ 50% (using the two largest diameters in sagittal view) after 12 months of CBG (TS_50). The capacity of the most important clinical and biochemical variables in predicting the main outcome was examined. A total of 185 prolactinomas where included: 124 (67.0%) were microadenomas and 61 (33.0%) were macroadenomas of which 27 patients meet de inclusion criteria; median age (42.5 years; (IQR: 28.0)). The median follow-up was (67.5 months; (IQR: 30.2)). Ten patients (37.0%) underwent surgery after more than 1 year of CBG. The volume reduction at the first MRI (3-4 months) was the unique valuable predictor: (OR: 1.16 (95% CI: 1.02-1.32)) of TS_50. A tumour volume shrinkage of ≥ 30% in the first 3-4 months of CBG therapy predicts TS_50 with an AUC (0.95 (CI: 0.76-0.99)). Tumour shrinkage in the first 3-4 months after starting treatment with CBG is a good tool for predicting the long-term response and can help clinicians to take more appropriated and personalized decisions.

Ovulation Induction in Patients with Polycystic Ovarian Syndrome (PCOS) & Hyperprolactinemia (HPRL): Efficacy of Letrozole (LE) Combined with Cabergoline (CE) in Comparison to (LE) Alone

Objectives: (PCOS) is the most common cause of anovulatory infertility, with majority of patients having mild (HPRL). (CE), a dopamine receptor agonist, inhibits prolactin secretion, leading to better ovulatory response. (LE), an aromatase inhibitor, without adverse effects on endometrium & induces fewer mature follicles with less risk of OHSS. Our aim was to investigate effects of combined (LE) & (CE) in comparison to (LE) alone on ovulation & clinical pregnancy rates in (PCOS) patients with (HPRL). Patients & Methods: 180 women with (PCOS) and of 22-38 years old, were enrolled in a hospital based clinical trial. Patients randomly allocated into 2 groups, (A&B). All with a serum prolactin > 32 ng/ml. Patients in (A): (92) were given (LE), 5mg for 5days: (3 – 7 of the cycle)/3 cycles and (CE), 0.5mg weekly for 12 weeks. Those in (B): (88) received only (LE), same dose & duration as in (A). All patients were matched for their age and BMI. Exclusion criteria: other causes of (HPRL). Outcome measure: ovulation rate & detection of both chemical & clinical pregnancies by βhCG and ultrasound of fetal cardiac activity, 2-4 weeks after missed period. Follow-up for 6 months. Data analysis by using SPSS version for windows, P-value significant if (< 0.05). Results: 3 patients from (A) & 5 from (B) had drug side effects and were excluded. None of patients were lost during the follow-up period. In (A), difference between mean serum prolactin level before & after treatment was statistically significant (P<0.001): 48.3±4.2ng/ml and 8.1±5.2ng/ml, respectively. No significant decrease of prolactin level in (B) (P >0.05). After treatment, BMI in (A) 24.1± 3.2, & 24.2 ± 3.6 in (B) (P=0.567). (56.2%) of women in (A) became regularly menstruating but only (30.1%) in (B) (P< 0.05). Ovulation rate was higher in (A) (50.6%) in comparison to (B) (26.5%), (P<0.05). Clinical pregnancy rate in (A) (41.6%) and (21.6%) in (B) (P<0.05). Neither twin pregnancy, nor OHSS were recorded in both groups. Conclusions: The combination of (LE) & (CE) is superior to (LE) alone in management of anovulatory patients with (PCOS) and should be used as the first-line treatment for them

Abstract #1003713: Cabergoline Induced Psychosis During Medical Therapy of Macroprolactinoma

Dopamine agonist (DA) treatment is the mainstay of therapy for prolactinomas and in many tumors can result in significant decreases in tumor size. DA therapy is not without its risks however, with some patients reporting adverse effects such as nausea, lightheadedness, and rarely increased impulsivity or even psychosis. Here we present a case involving a patient with macroprolactinoma on DA therapy with cabergoline (CBG) who developed psychosis requiring discontinuation of CBG, and eventually transsphenoidal surgery (TPS) as well as stereotactic radiotherapy (STRT) to diminish the effects of his giant prolactinoma.

Ovulation Induction in Patients with Polycystic Ovarian Syndrome (PCOS) & Hyperprolactinemia (HPRL): Efficacy of Letrozole (LE) Combined with Cabergoline (CE) in Comparison to (LE) Alone

Ovulation Induction in Patients with Polycystic Ovarian Syndrome (PCOS) & Hyperprolactinemia (HPRL): Efficacy of Letrozole (LE) Combined with Cabergoline (CE) in Comparison to (LE) Alone

Ovulation Induction in Patients with Polycystic Ovarian Syndrome (PCOS) & Hyperprolactinemia (HPRL): Efficacy of Letrozole (LE) Combined with Cabergoline (CE) in Comparison to (LE) Alone

Objectives: (PCOS) is the most common cause of anovulatory infertility, with majority of patients having mild (HPRL). (CE), a dopamine receptor agonist, inhibits prolactin secretion, leading to better ovulatory response. (LE), an aromatase inhibitor, without adverse effects on endometrium & induces fewer mature follicles with less risk of OHSS. Our aim was to investigate effects of combined (LE) & (CE) in comparison to (LE) alone on ovulation & clinical pregnancy rates in (PCOS) patients with (HPRL). Patients & Methods: 180 women with (PCOS) and of 22-38 years old, were enrolled in a hospital based clinical trial. Patients randomly allocated into 2 groups, (A&B). All with a serum prolactin > 32 ng/ml. Patients in (A): (92) were given (LE), 5mg for 5days: (3 – 7 of the cycle)/3 cycles and (CE), 0.5mg weekly for 12 weeks. Those in (B): (88) received only (LE), same dose & duration as in (A). All patients were matched for their age and BMI. Exclusion criteria: other causes of (HPRL). Outcome measure: ovulation rate & detection of both chemical & clinical pregnancies by βhCG and ultrasound of fetal cardiac activity, 2-4 weeks after missed period. Follow-up for 6 months. Data analysis by using SPSS version for windows, P-value significant if (< 0.05). Results: 3 patients from (A) & 5 from (B) had drug side effects and were excluded. None of patients were lost during the follow-up period. In (A), difference between mean serum prolactin level before & after treatment was statistically significant (P<0.001): 48.3±4.2ng/ml and 8.1±5.2ng/ml, respectively. No significant decrease of prolactin level in (B) (P >0.05). After treatment, BMI in (A) 24.1± 3.2, & 24.2 ± 3.6 in (B) (P=0.567). (56.2%) of women in (A) became regularly menstruating but only (30.1%) in (B) (P< 0.05). Ovulation rate was higher in (A) (50.6%) in comparison to (B) (26.5%), (P<0.05). Clinical pregnancy rate in (A) (41.6%) and (21.6%) in (B) (P<0.05). Neither twin pregnancy, nor OHSS were recorded in both groups. Conclusions: The combination of (LE) & (CE) is superior to (LE) alone in management of anovulatory patients with (PCOS) and should be used as the first-line treatment for them.

Treatment of Postsurgical Clinically Nonfunctioning Pituitary Adenomas Remnants With Cabergoline

Background: The standard first-line therapy for clinically nonfunctioning adenomas (NFPA) is transsphenoidal surgery, however there is no consensus of the optimal postsurgical treatment for residual adenoma. Medical therapy, such as cabergoline (CAB), may be an alternative for preventing growth of postoperative pituitary tumor remnants. The moment of introduction dopamine agonist (DA) is still uncertain. Objective: To assess tumor behavior in patients who used CAB in the postoperative period. Design and methods: A retrospective cross-sectional study was performed with twenty one patients with NFPA treated surgically. All patients stayed with residual tumor and were divided in two groups: patients who received CAB early in postoperative period (Group A, n=6) and when tumor growth were detected during follow-up (Group B, n=15). CAB dosage was 1.5mg or 3.5mg per week. A change in tumor size was considered significant and recorded as such if a difference of at least 5 mm in major diameter was observed. MRI was performed four months after surgery and yearly thereafter in all patients. Subjects in treatment groups also underwent MRI 6 months following medical therapy. No patients were treated by irradiation before or during the follow-up. Statistical analysis was performed using the Fisher’s exact test. Results: From 21 patients, 11 were men and 10 women with similar mean age in two groups (p=0.651). MRI in group A showed stabilization of residual tumor in 50% (3/6) and tumor reduction in 50% (3/6) in group A. In group B, tumor shrinkage was observed in 47% (7/15), stabilization in 27% (4/15) and enlarged in 27% (4/15). No statistical difference between groups was obtained regarding tumor shrinkage and stabilization with the treatment (Group A n=6 versus Group B n=11, p=0.281). In contraste Batista et al., 2016, have already shown that CAB was effective alternative in residual tumor reduction in a study with 74 patients. Conclusion: A multicenter study is necessary to define the role of CAB in the treatment of residual tumor in postsurgical patients with NFPA.

Characterization of the ability of a, second-generation SST-DA chimeric molecule, TBR-065, to suppress GH secretion from human GH-secreting adenoma cells.

Somatostatin (SST) and dopamine (DA) inhibit growth hormone (GH) secretion and proliferation of GH-secreting pituitary adenomas (GHomas) through binding to SSTR2 and D2R receptors. Chimeric SST-DA compounds (Dopastatins) display increased potency in inhibiting GH secretion, as compared with individual SST or DA analogs (alone or combined). To assess the efficacy of a second-generation dopastatin, TBR-065, in suppressing GH secretion from human GH- and GH/prolactin(PRL)-omas. We compared the ability of TBR-065 to inhibit GH secretion from primary cultures of human GH- or GH/PRLoma cells to that of the first generation dopastatin, TBR-760 (formerly BIM-23A760), octreotide (OCT) and cabergoline (CAB), the later either alone or combined. We investigated whether there was any impact of BIM-133, the metabolite of TBR-065, on the ability of TBR-065 to inhibit GH in these cultures. 17 GH- and GH/PRLomas were included in this study. Inhibition of GH secretion by TBR-065, TBR-760, OCT and CAB (0.1pM to 0.1µM) was assessed over a period of 8h. All tumors expressed SSTR2 and D2R mRNAs. GH suppression was higher with TBR-065 as compared with TBR-760 (Emax = 57 ± 5.6% vs. 41.1 ± 12.5%, respectively, p < 0.001) or with OCT + CAB (Emax = 56.8 ± 7.2% vs. 44.4 ± 9.4%, p < 0.001). BIM-133 did not have any impact on the activity of TBR-065. TBR-065 has significantly improved efficacy in suppressing GH secretion as compared to current available therapies and may represent a new promising option for the treatment of acromegaly.

Brusatol Inhibits Tumor Growth and Increases the Efficacy of Cabergoline against Pituitary Adenomas

Cabergoline (CAB) is the first choice for treatment of prolactinoma and the most common subtype of pituitary adenoma. However, drug resistance and lack of effectiveness in other pituitary tumor types remain clinical challenges to this treatment. Brusatol (BT) is known to inhibit cell growth and promote apoptosis in a variety of cancer cells. In our present studies, we investigate the effects of BT on pituitary tumor cell proliferation in vitro and in vivo. BT treatment resulted in an increase in Annexin V-expressing cells and promoted the expression of apoptosis-related proteins in rat and human pituitary tumor cells. Investigation of the mechanism underlying this effect revealed that BT increased the production of reactive oxygen species (ROS) and inhibited the phosphorylation of 4EBP1 and S6K1. Furthermore, treatment with a combination of BT and CAB resulted in greater antitumor effects than either treatment alone in nude mice and pituitary tumor cells. Collectively, our results suggest that the BT-induced ROS accumulation and inhibition of mTORC1 signaling pathway leads to inhibition of tumor growth. Combined use of CAB and BT may increase the clinical effectiveness of treatment for human pituitary adenomas.