Dose Of Cabergoline Research Articles

Increased Cardiometabolic Risk in Men with Hypoprolactinemia: A Pilot Study

Low prolactin levels in men predispose them to mood disturbances, sexual dysfunction, and diabetes. The purpose of the current study was to assess cardiometabolic risk in males with hypoprolactinemia. This prospective study included three age-matched groups of young and middle-aged men: individuals with cabergoline-induced hypoprolactinemia (n = 15), cabergoline-treated subjects with prolactin levels within the reference range (n = 20), and untreated men with normal prolactin levels (n = 31). In men with hypoprolactinemia, the cabergoline dose was reduced in order to normalize prolactin concentration. Anthropometric parameters, blood pressure, QRISK3 score; plasma concentrations of prolactin, glucose, insulin, lipids, uric acid, high-sensitivity C-reactive protein (hsCRP), fibrinogen, homocysteine, and testosterone; whole-blood levels of glycated hemoglobin (HbA1C); urinary albumin-to-creatinine ratio (UACR); and carotid intima–media thickness were assessed at baseline and six months later. Men with hypoprolactinemia were characterized by higher body mass index, fat content, waist circumference, systolic blood pressure, fasting and 2 h post-load glucose, HbA1C, HOMA1-IR, uric acid, hsCRP, fibrinogen, homocysteine, and UACR; by lower HDL cholesterol and testosterone; by greater intima–media thickness; and by a higher QRISK3 score than their peers with normal prolactin levels. There were no statistically significant differences in the measured parameters between both groups of men with normal prolactin levels. Normalization of prolactin concentration was accompanied by normalization of biochemical variables, systolic blood pressure, and QRISK3 score. Although cabergoline dose reduction did not cause statistically significant changes in the remaining anthropometric parameters and intima–media thickness, six months later, they did not differ from those observed in the remaining study groups. Our findings suggest that iatrogenic hypoprolactinemia is associated with increased cardiometabolic risk, which is reversible and resolves after the normalization of prolactin levels.

7220 Menopause Has a Beneficial Influence on the Evolution of Prolactinomas: a Study in 95 Patients

Abstract Disclosure: S. Constantinescu: None. C. Nava: None. F. Chasseloup: None. P. Chanson: Consulting Fee; Self; Eli Lilly & Company, Recordati, Ipsen, Novo Nordisk. O. Alexopoulou: None. D.M. Maiter: Consulting Fee; Self; Ipsen, Recordati, Pfizer, Inc. The natural occurrence of menopause is considered to have beneficial effects in women with a prolactinoma and represents a window of opportunity for successful dopamine agonist (DA) withdrawal. Strong evidence for these effects remains however scarce. We retrospectively analyzed data from 95 women undergoing menopause (Mp) (FSH>35 U/L) while still treated with DA (cabergoline (CAB) in 82) for a prolactinoma diagnosed at a mean age of 38.0 ± 8.0 years. The pituitary tumor was a microadenoma in 66 and a macroadenoma in 29 (invasive in 12). Our objectives were to identify the influence of menopause on the evolution of treated prolactinomas and on the risk of recurrence after DA withdrawal. In post-menopausal women still treated with DA (median dose of 0.50 mg CAB/week or equivalent), a significant decrease in median prolactin (PRL) was observed from a premenopausal value of 15.1 µg/L to 10.7 µg/L 3-6 months after Mp (n=64, P=0.05) and to 7.7 µg/L 24 months after Mp (n=43, P < 0.001). There was also a significant reduction in median coronal tumor surface at 24 months, from 12.6 to 7.1 mm² (p < 0. 01). DA treatment was withdrawn in 53 women (56%) after a median interval of 26 months after menopause (range: 3-262). Strict criteria for discontinuation were fulfilled in 52 of them: a normal PRL for at least 24 months under a cabergoline dose ≤ 0.50 mg/week and a more than 50%-reduction in tumor surface area for macroadenomas. Among them, 37 women (71%) remained in remission during a median follow-up period of 26 months (range: 6-176), while 15 (29%) had an asymptomatic biological recurrence after a median duration of 6 months (range: 2-47). Only one woman showed minimal tumor regrowth. 12/15 of the biological recurrences of hyperprolactinemia occurred within the first year after withdrawal and the estimated probability of remission at 5 years was 66%. Multivariate analysis showed that the only independent predictor of recurrence was the PRL value observed 3 to 6 months after DA discontinuation (p = 0.028). Estrogen-progestin replacement therapy, given in 21 women, did not influence these outcomes. In conclusion, we confirm that menopause has a beneficial effect on the evolution of treated and untreated prolactinomas. When using strict criteria for DA withdrawal in the post-menopausal period, a sustained clinical and biological remission can be expected in two-thirds of women, and when recurrence occurs, it is usually mild and asymptomatic. Presentation: 6/2/2024

6555 Cabergoline-induced psychiatric symptoms in a patient with a pituitary macroadenoma

Abstract Disclosure: G.S. Patel: None. J. Prater: None. Cabergoline is a long-acting dopamine agonist that is used for the treatment of hyperprolactinemia, especially in pituitary macroadenomas. It reduces the levels of prolactin (PRL) but is also effective in reducing the tumor size and allows patients to avoid undergoing surgical resection of the mass. It commonly causes side effects such as abdominal pain, bloating, dizziness, and headaches. It rarely can cause new onset psychological side effects or an exacerbation of pre-existing mood and behavioral disorders. We present the case of a male on cabergoline therapy who had new-onset psychiatric symptoms that persisted even after treatment was discontinued. The patient is a 40-year-old male who was found to have a pituitary macroadenoma measuring 2.2 x 1.8 x 1.6 cm on brain MRI after a one-year history of headaches, dizziness, and hearing loss. His vital signs and physical examination were unremarkable. Laboratory investigations revealed a PRL of 1,072 ng/mL. He was started on cabergoline 0.25 mg twice a week which reduced levels of PRL to 465.3 ng/dL. Throughout the next year, his PRL levels remained persistently elevated to >100 ng/dL and the cabergoline dose was steadily increased to 1 mg three times per week. About a year into treatment he began experiencing significant emotional lability, a tendency to cry, and bursts of temper which required the addition of multiple psychiatric medications. After two years of continued psychiatric symptoms, there was an attempt to both reduce cabergoline doses and switch to escalating doses of bromocriptine, both of which resulted in a reduction of psychiatric symptoms but also significant increases in PRL levels. The patient’s mood symptoms returned shortly after switching back to cabergoline, especially with increased doses. He eventually underwent trans-sphenoidal resection for his treatment-resistant pituitary macroadenoma. He was taken off cabergoline before surgery with a significant reduction in his mood symptoms but continues to require psychiatric medications for lasting emotional lability. Although rare, psychiatric side effects of cabergoline have been documented and must be addressed if a patient develops them while receiving treatment. Our patient had a severe presentation of mood symptoms from cabergoline therapy that required multiple psychiatric medications in escalating doses to control. It not only affected his quality of life but also resulted in long-term consequences. It is recommended that patients with similar presentations should be continued on cabergoline with the addition of clozapine as it has less of an effect on PRL levels. Other treatment options also include aripiprazole and quetiapine. However, when patients have treatment resistant macroprolactinomas and are unable to tolerate cabergoline, one would have to consider surgical treatment options for the treatment of hyperprolactinemia from pituitary macroadenomas. Presentation: 6/1/2024

12612 Chiasmal Herniation - A Rare Complication Of Prolactinoma Treatment

Abstract Disclosure: A. Syeda: None. V. Kantorovich: None. Introduction: Primary treatment of symptomatic prolactinomas is medical therapy with dopamine agonists (DA). Herniation of optic chiasm is a rare complication of tumor shrinkage induced by DA therapy which causes secondary deterioration in visual fields. Case:A 26-year-old man presented to our hospital after a syncopal episode. He had headaches and blurry vision in the left eye for the past 4 months. He was diagnosed with a 4 cm x 3.6 cm x 2.6 cm pituitary macroprolactinoma compressing the optic chiasm, his prolactin (PRL) was 4700 ng/mL (N: 4.0-15.2 ng/mL) and testosterone was suppressed to 10 ng/dL (N: 249-836 ng/dL). Other hormonal workup was unremarkable. Ophthalmologic evaluation was consistent with left optic nerve pallor and neural rim thinning suggestive of a guarded prognosis. Immediate neurosurgical intervention was deemed unnecessary. Cabergoline 0.25 mg twice a week was initiated. Subsequently, the PRL levels improved but remained elevated to 414.2 ng/mL and cabergoline dose was increased to 0.5 mg twice a week. MRI Brain after 10 months revealed significant tumor reduction to 2.1 cm x 2.1cm x 1.2 cm. He was inconsistent with his endocrinology follow up appointments and was also non-adherent to cabergoline intermittently. After 14 months of starting DA therapy, he presented with worsening blurriness in his left eye. A repeat brain MRI showed stable appearance of the large pituitary macroadenoma with inferior bowing of the optic chiasm. Significant distortion, tented appearance, and attenuation of the left prechiasmatic optic nerve was also noted. He was evaluated by neuro ophthalmology and a diagnosis of secondary visual deterioration due to optic chiasmal herniation was made. Cabergoline therapy was promptly discontinued. Two weeks post-cabergoline cessation, he underwent trans-sphenoidal resection reporting vision improvement pre-surgery. Post-operative MRI depicted changes with no residual tumor and improved optic chiasm position. Discussion:Various theories explain chiasmal herniation with dopamine agonist (DA) treatment for prolactinomas. Pre-existing chiasm-tumor tethering may exacerbate downward pull during tumor reduction caused by DA therapy. Some case series have suggested that not all patients with chiasmal herniation have visual field defects and that despite improvement in visual fields with decrease in DA dosage, there are no appreciable radiographic changes/reversal of chiasmal herniation. One of the explanations for this lack of correlation is that visual impairment is rather a consequence of vascular compression. This case underscores the need for regular perimetry in macroprolactinoma patients on medical treatment. Adjusting dopamine agonist dosage to allow controlled tumor regrowth, monitored closely with frequent visual field and prolactin assessments, is crucial for relieving optic chiasm tension. Presentation: 6/3/2024

9281 Menopause Has a Beneficial Influence on the Evolution of Prolactinomas: a Study in 95 Patients

Abstract Disclosure: S. Constantinescu: None. C. Nava: None. F. Chasseloup: None. P. Chanson: Consulting Fee; Self; Eli Lilly & Company, Recordati, Ipsen, Novo Nordisk. O. Alexopoulou: None. D.M. Maiter: Consulting Fee; Self; Ipsen, Recordati, Pfizer, Inc. The natural occurrence of menopause is considered to have beneficial effects in women with a prolactinoma and represents a window of opportunity for successful dopamine agonist (DA) withdrawal. Strong evidence for these effects remains however scarce. We retrospectively analyzed data from 95 women undergoing menopause (Mp) (FSH>35 U/L) while still treated with DA (cabergoline (CAB) in 82) for a prolactinoma diagnosed at a mean age of 38.0 ± 8.0 years. The pituitary tumor was a microadenoma in 66 and a macroadenoma in 29 (invasive in 12). Our objectives were to identify the influence of menopause on the evolution of treated prolactinomas and on the risk of recurrence after DA withdrawal. In post-menopausal women still treated with DA (median dose of 0.50 mg CAB/week or equivalent), a significant decrease in median prolactin (PRL) was observed from a premenopausal value of 15.1 µg/L to 10.7 µg/L 3-6 months after Mp (n=64, P=0.05) and to 7.7 µg/L 24 months after Mp (n=43, P < 0.001). There was also a significant reduction in median coronal tumor surface at 24 months, from 12.6 to 7.1 mm² (p < 0. 01). DA treatment was withdrawn in 53 women (56%) after a median interval of 26 months after menopause (range: 3-262). Strict criteria for discontinuation were fulfilled in 52 of them: a normal PRL for at least 24 months under a cabergoline dose ≤ 0.50 mg/week and a more than 50%-reduction in tumor surface area for macroadenomas. Among them, 37 women (71%) remained in remission during a median follow-up period of 26 months (range: 6-176), while 15 (29%) had an asymptomatic biological recurrence after a median duration of 6 months (range: 2-47). Only one woman showed minimal tumor regrowth. 12/15 of the biological recurrences of hyperprolactinemia occurred within the first year after withdrawal and the estimated probability of remission at 5 years was 66%. Multivariate analysis showed that the only independent predictor of recurrence was the PRL value observed 3 to 6 months after DA discontinuation (p = 0.028). Estrogen-progestin replacement therapy, given in 21 women, did not influence these outcomes. In conclusion, we confirm that menopause has a beneficial effect on the evolution of treated and untreated prolactinomas. When using strict criteria for DA withdrawal in the post-menopausal period, a sustained clinical and biological remission can be expected in two-thirds of women, and when recurrence occurs, it is usually mild and asymptomatic. Presentation: 6/2/2024

7173 Cabergoline Induced Psychosis in a Patient with no Previous History of Psychiatric Disorder

Abstract Disclosure: B. Aryal: None. K. Kim: None. A. Shafi: None. M. Ganesh: None. Introduction: Cabergoline is a dopamine agonist (DA) used to treat prolactinomas. It is well established that DAs may cause psychotic symptoms. However, very few cases report cabergoline-associated psychosis in patients without personal or family history of psychiatric disorders. We report a rare case of cabergoline-induced psychosis in a patient with a prolactinoma without any underlying psychiatric disorder, which was managed with the addition of olanzapine. Case: A 41 year old male with no history of psychiatric disorder was started on cabergoline 0.5mg twice a week for a newly diagnosed prolactinoma. 4 weeks later, he presented to the emergency room for aggressive behavior and confusion for the past 2 weeks. He endorsed visual and auditory hallucinations. Cabergoline was discontinued. During hospitalization, he attempted suicide and required 1:1 observation. He was started on olanzapine per the inpatient psychiatry team. Surgical resection of the prolactinoma was considered given his acute psychosis associated with cabergoline. However, complete resection of the tumor was deemed impossible given encasement of the internal carotid arteries. After discussion with the patient, he underwent re-challenge with cabergoline 0.25mg weekly while on olanzapine under 1:1 observation in the ICU. He was monitored for 2 weeks and eventually discharged home on cabergoline 0.25mg twice a week and olanzapine with improvement in prolactin levels to 4973.7 ng/mL after 4 weeks. He continued to remain free of psychotic symptoms upon follow up as an outpatient. Discussion: Psychosis is a rare side effect of DA mediated via D2/D3 receptors in the mesocortical and mesolimbic pathways. Several cases report psychosis associated with cabergoline in patients with a history of psychiatric disorders. However only one case reports de novo psychosis. Our patient developed severe psychosis while on low-dose cabergoline for 4 weeks. This rare case of de novo cabergoline-associated psychosis re-emphasizes that psychosis may occur regardless of previous history of psychiatric disorder and independent of the dose or duration of cabergoline. Treatment of a prolactinoma in the setting of cabergoline-associated psychosis requires a multidisciplinary approach. Alternative treatment of surgical resection was considered for our patient. However surgical resection was not plausible given difficult surgical anatomy. Therefore he was monitored closely to re-initiate cabergoline while on olanzapine. Several cases report successful use of clozapine, aripiprazole, and quetiapine for patients with psychiatric symptoms while on cabergoline. Patients who are on cabergoline should be closely monitored for any psychotic symptoms. Further studies are warranted to identify patients at risk of developing psychosis while on cabergoline to tailor an individualized approach to therapy and monitoring. Presentation: 6/2/2024

12342 Retrospective Multicenter Study Of Prolactinomas In Men

Abstract Disclosure: M.A. Guitelman: None. G. Cardenas: None. A. Rogozinski: None. C. Ballarino: None. M.F. Battistone: None. K. Danilowicz: None. S. Diez: None. P. Fainstein-Day: None. A. Furioso: None. V. Garcia Roel: None. M.S. Gonzalez Pernas: None. D.A. Katz: None. M.G. Loto: None. S. Mallea Gil: None. M.P. Manavela: None. M.S. Martinez: None. K.A. Miragaya: None. P. Slavinsky: None. S. Sosa: None. J. Tkatch: None. G. Tubert: None. M. Vitale: None. M. Glerean: None. Prolactinomas in men: a retrospective multicenter study Introduction and Objectives: prolactinomas in men have recently been included by the World Health Organization as a more aggressive tumor category due to their size, invasiveness and response to treatment. Our objective was to evaluate clinical, biochemical, and imaging characteristics, therapeutic response, and long-term evolution (outcome) of a cohort of men with prolactinoma. Patients and Methods: multicenter retrospective study including 311 men with prolactinoma. Initial clinical parameters, therapeutic modalities, PRL normalization rate and gonadal recovery, as well as tumor reduction were analyzed. The results were expressed as median (min-max range). Results: 35 micro (Mi) and 276 macroadenomas (Ma) were found (199 invasive, 71 Giant ≥4 cm). The median age at diagnosis was 41 (13-84) and 40 y-old (15-73) for micro and macro respectively. The most frequent reasons for consultation were symptoms of hypogonadism in patients with Mi, while visual disturbances, headache, and incidental findings were seen in patients with Ma. Apoplexy as presentation was observed in two patients with Ma. Hypogonadotrophic hypogonadism was present in 90 % of patients in whole cohort. Median basal PRL was 144 in Mi and 1633 ng/ml in Ma. Treatment with cabergoline (CAB) was indicated in all but one patient with Ma who remitted after surgery. Normalization of PRL was achieved in 85.7% and 65.7% of Mi and Ma respectively. The median follow-up time was 48 months (6-240). Sixty-three Ma and only one Mi were submitted to surgery, 2 patients achieved remission criteria (Mi/Ma); a patient with micro experienced recurrence after 3 years, the remaining patients continued or started CAB after surgery. Ki-67 ≥3% was reported in 17/46 available pathologies. The maximum dose of CAB was 4.5 and 12 mg/wk , with a median of 0.5 and 1.5 mg/wk for Mi and Ma, respectively. Resistance to CAB (dose ≥3mg/week) occurred in 5.7% Mi and 35.4% Ma. Gonadal function recovery without testosterone requirement was achieved in 80% of Mi and 63% of Ma. Tumor remnant was observed in 34% and 49% of Mi and Ma respectively Ten patients with Ma received radiotherapy. Five patients presented CSF fistula during treatment with CAB, and another 3 impulse control disorder. One patient with carcinomatous transformation was treated with temozolomide. Conclusions: In our series of 311 men with prolactinomas, majority Ma consulted for neuro-ophthalmological symptoms, while hypogonadism was the most frequent initial symptom in Mi, despite the fact that 90% of the total population showed it at presentation. Giant, invasive and proliferative tumor were highly prevalent in Ma. Pharmacological treatment continues to be the first line of choice, with a high rate of normalization of PRL and recovery of gonadal function, but a low rate of long-term remission. Presentation: 6/2/2024

7768 Hereditary Phaeochromocytoma/Paraganglioma And Aortopathy In A Patient With Known Macroprolactinoma: A Series Of Incidental Findings

Abstract Disclosure: J.R. Kelly: None. S. Soule: None. P.J. Hunt: None. Background: The three P association (3PAs) describes the combination of pituitary adenoma and phaeochromocytoma/paraganglioma. Recent case series describe a range of underlying genetic causes, including SDH mutations. We describe a patient with a macroprolactinoma and their subsequent incidental diagnoses of phaeochromocytoma and paraganglioma, with a pathogenic SDHA mutation. Clinical Case: A 58-year-old man had previously received a combination of medical therapy with cabergoline and transsphenoidal debulking surgery for a histologically confirmed macroprolactinoma. Due to a small risk of valvulopathy associated with cumulative doses of cabergoline, screening echocardiogram was requested after seven years of treatment. This showed a calcified bicuspid aortic valve and severe dilatation of the ascending aorta at 58mm. Prior to surgical repair, CT aorta was requested, which showed an incidental left adrenal lesion. Formal adrenal imaging and functional assessment confirmed a 50mm phaeochromocytoma, with a right para-aortic paraganglioma subsequently revealed on Ga-68 DOTATATE-PET scan. He described symptoms of catecholamine excess, with episodic palpitations, chest pain, and increasing anxiety over the previous year, on a background of hypertension. Hereditary phaeochromocytoma/paraganglioma gene panel revealed a pathogenic mutation in SDHA (c.1663+1G>T) – a splicing variant, likely resulting in nonsense decay. Screening was recommended for his three children. He initiated alpha blockade with doxazosin, then beta blockade with metoprolol, prior to open adrenalectomy and excision of paraganglioma. Histology confirmed a left phaeochromocytoma (Ki67 0.1%, PASS score 8, no vascular or capsular invasion) and a paraganglioma. Post-operative plasma normetanephrine normalised (406 pmol/L, pre-operative 6776 pmol/L, normal <1200 pmol/L) and the patient described resolution of symptoms. He subsequently underwent tissue aortic valve replacement and Bentall’s procedure. Histology showed severe atherosclerosis with diffuse medial degeneration of the aorta. Repeat Ga-68 DOTATATE-PET seven months later showed no evidence of residual or recurrent disease. Ongoing management includes cabergoline, annual plasma metanephrine measurement, and intermittent MRI of pituitary and base of skull to coccyx. Conclusion: Macroprolactinomas are relatively common, with only a small proportion associated with underlying genetic abnormalities. This case describes a patient with 3PAs, initially presenting with a macroprolactinoma, with incidental detection of phaeochromocytoma and paraganglioma and subsequent identification of a pathogenic SDHA mutation. In the context of a calcified bicuspid aortic valve and severe aortic dilatation, pre-operative alpha blockade allowed successful surgical management of both potentially life-threatening conditions. Presentation: 6/3/2024

Aftercare following second trimester abortion procedures.

The purpose of this review is to examine patient experiences following second-trimester abortion care to identify clinical interventions to improve aftercare. Early validation of a five-question Reproductive Grief Screen suggests that this instrument may be useful for clinicians to identify patients with maladaptive grief responses following a second-trimester abortion. Patients want to talk with their healthcare providers about grief following abortion and desire frequent mental health check-ins. Most people will have breast symptoms following a second-trimester abortion; a one-time dose of cabergoline at time of abortion appears to be an effective intervention to prevent bothersome breast symptoms. As patient desires vary regarding disposition of fetal remains, clinicians should be prepared to discuss donation for research or cremation/ burial as alternatives to routine disposal. With significant variation in availability and cost of ceremonial disposition, clinicians and healthcare systems should identify local resources to facilitate this aspect of aftercare. Clinical practices and healthcare systems should prioritize the aftercare experience including the management of breast symptoms, bereavement, disposition of fetal remains, and follow-up care.

P-678 Cabergoline has inhibitory effects on FSH-induced cell differentiation and estrogen secretion in a primary culture system of rat ovarian granulosa cells

Abstract Study question How does cabergoline have effects on cell differentiation and hormone secretion induced by FSH stimulation in ovarian granulosa cells? Summary answer Cabergoline suppresses LH receptor expression and Estradiol (E2) secretion in primary cultures of rat ovarian granulosa cells by inhibiting cAMP production induced by FSH stimulation. What is known already Cabergoline is a dopamine receptor 2 agonist that has been used to treat hyperprolactinemia and, more recently, to prevent ovarian hyperstimulation syndrome. Although it has been previously reported that cabergoline suppresses E2 and Progesterone secretion induced by FSH stimulation in a primary culture system of rat ovarian granulosa cells, but the effect on LH receptor expression has not been investigated. It has also been reported that the activation of dopamine receptor 2 suppresses VEGF secretion and reduces the incidence of early-onset OHSS by inhibiting the VEGF/VEGFR2 pathway in research using human luteinized granulosa cells. Study design, size, duration We used a primary culture system of ovarian granulosa cells obtained from immature female rats treated with diethylstilbestrol to examine the effect of cabergoline addition on the changes in ovarian granulosa cells induced by FSH stimulation. Participants/materials, setting, methods FSH and cabergoline were added alone or co-added to a primary culture system of rat ovarian granulosa cells, and the changes induced by them were measured and compared. (1) mRNA expression of Lhcgr, Cyp19a1, and Fshr by RT-qPCR (2) E2 concentration in the culture medium (3) Measurement of hCG binding on the cell surface (4) cAMP concentration Main results and the role of chance Co-addition of cabergoline suppressed each of the changes induced by FSH stimulation as follows. (1) The mRNA expression levels of Lhcgr, Cyp19a1, and Fshr decreased in a concentration-dependent manner (0.01-10 µM) of co-added cabergoline compared to FSH alone. In the 10 µM of co-added cabergoline group, they decreased to 14%, 9%, and 49% of FSH alone, respectively. (2) E2 concentration in the culture media also decreased in a concentration-dependent manner (1-10 µM) of co-added cabergoline compared to FSH alone. In the 10 µM of co-added cabergoline group, it decreased to 49% of FSH alone. (3) The amount of hCG binding on the cell surface also decreased in a concentration-dependent manner (0.1-10 µM) of co-added cabergoline compared to FSH alone. In the 10 µM of co-added cabergoline group, it decreased to 7% of FSH alone. (4) FSH-stimulated cAMP production decreased in a concentration-dependent manner (0.01-1µM) of co-added cabergoline compared to FSH alone. In the 1µM of co-added cabergoline group, it decreased to 50% of FSH alone. These results suggest that cabergoline suppresses LH receptor and aromatase expression and E2 production by inhibiting cAMP production induced by FSH stimulation. Limitations, reasons for caution Since this is an in vitro experiment using a rat primary culture system, the results of this research cannot be considered directly applicable to humans. Wider implications of the findings Our findings imply that cabergoline administration during the follicular phase may inhibit ovarian granulosa cell differentiation and estrogen secretion. In women taking relatively high doses of cabergoline, attention may need to be paid regarding the effects of cabergoline on follicular development and estrogen secretion. Trial registration number not applicable

Successful medical management of a pituitary macroadenoma with features of resistant acromegaly and hyperprolactinemia using pasireotide.

The somatostatin analog, pasireotide, is used for the treatment of acromegaly after the failure of surgery and/or first-line medical treatment. A 48-year-old male reported that during a workup for obesity in his home country, hyperprolactinemia was diagnosed and a 3.5 × 3.5 cm pituitary macroadenoma was identified on pituitary MRI. He received cabergoline for 6 months; then he was lost to follow-up. He presented at our Endocrine clinic 2 years later for treatment of obesity (BMI 49.5 kg/m2). Biochemical workup revealed that in addition to hyperprolactinemia (7,237 [normal: 85-323 mIU/L), he had acromegaly, evident by elevated insulin-like growth factor 1 (IGF-1) level (450 [normal: 88-210 µg/L]), and a positive growth hormone suppression test, secondary hypothyroidism, and secondary hypogonadism. Pituitary MRI showed that the adenoma encased parts of the left and right internal carotid arteries and encroached on the optic chiasm. Surgical excision was therefore not feasible. He was treated with cabergoline and later, long-acting release (LAR) octreotide. Prolactin levels were reduced with cabergoline, but IGF-1 levels did not respond to octreotide, and it was discontinued. The patient abandoned radiotherapy after two sessions. He was started on LAR pasireotide 40 mg every 4 weeks and continued on cabergoline 0.5 mg per week. His biochemical response was dramatic, with a near normalization of IGF-1 levels in 3 months. After 6 months from starting pasireotide, we increased cabergoline dose from 0.5 mg/week to 3 mg/week. Three months later, IGF-1 level was normalized. The patient developed type 2 diabetes as a side effect of pasireotide; however, this was well-controlled with medications. The case suggests that pasireotide can provide marked biochemical improvement in acromegaly after the failure of both cabergoline monotherapy and cabergoline plus octreotide. This further confirms a potentially efficacious treatment regimen in treatment-resistant acromegaly with hyperprolactinemia.

Risk Assessment of Diabetes Mellitus during and after Pregnancy in Women with Prolactinomas.

Prolactin (PRL) is a crucial mediator of gluco-insulinemic metabolism. Dissecting glucose metabolism during and after pregnancy in patients with prolactinomas. 52 patients treated with cabergoline (CAB) were evaluated before conception, during pregnancy and up to 10 years after delivery. During pregnancy, CAB was discontinued, while it was restarted in 57.7 % of patients after delivery, due to recurrent hyperprolactinemia (RH). Hormonal (serum PRL) and metabolic (HbA1c, fasting glucose/FG, glucose tolerance) parameters were assessed. During pregnancy, PRL gradually increased, while FG remained stable. An inverse correlation between PRL and FG was found in the first (p=0.032) and third (p=0.048) trimester. PRL percent increase across pregnancy was inversely correlated with third trimester FG. Serum PRL before conception emerged as predictive biomarker of third trimester FG (τ=2.603; p=0.048). Elderly patients with lower HbA1c at first trimester and lower FG at 3 years postpartum, delivered infants with reduced birth weight. Breastfeeding up to 6 months correlated with lower FG at 4 and 10 years postpartum. A positive correlation between BMI and FG at 10 years after delivery (p=0.03) was observed, particularly in overweight/obese patients requiring higher CAB doses. Patients with RH who had to restart CAB showed shorter breastfeeding duration and higher FG at 2 years postpartum. Low PRL levels before pregnancy may be detrimental to FG during pregnancy. CAB duration and dose may influence long-term glucose tolerance, besides family history and BMI. Pre-conceptional metabolic management should be recommended to reduce the risk of gestational and type 2 diabetes mellitus.

Impulse Control Disorders in Southern Iraqi Patients Medicated With Cabergoline for Prolactinoma.

Among the patient population in Basrah, Iraq, prolactinoma is the most commonly found pituitary tumor. Impulse control disorders (ICDs) were reportedly associated with these patients being treated with cabergoline. This study aimed to assess the prevalence of ICDs in cabergoline-treated prolactinoma patients versus healthy, matched controls. This cross-sectional case-control study was conducted at the Faiha Specialized Diabetes, Endocrine and Metabolism Center (FDEMC) in Basrah, southern Iraq, from January 2023 to May 2023. It included 30 cabergoline-treated prolactinoma patients and 30 healthy, matched controls. The questionnaire for ICDs in Parkinson's disease was used as a screening tool. Following this, positively screened patients were evaluated using validated criteria accordingly to diagnose impulse control disorders. The ICDs were diagnosed in nine (30%) cabergoline-treated prolactinoma patients versus two (6.7%) in control (p = 0.02). The most frequent ICD types were hypersexuality and binge eating, while no patient reported pathological gambling. Three patients reported multiple types of ICDs. The patients' sociodemographic characteristics, prolactinoma duration and size, and cabergoline dose did not correlate significantly with ICD diagnosis. Treatment with cabergoline is associated with the development of ICDs. Therefore, clinicians should be aware of this disabling side effect to ensure its early detection and treatment.

Resistance to dopamine agonists in the treatment of prolactinomas: diagnostic criteria, mechanisms and ways to overcome it

The priority treatment approach for prolactinomas is therapy with dopamine agonists, which allows for elimination of clinical symptoms, normalization of prolactin levels, reduction of the adenoma size and prevention of metabolic abnormalities in the majority of patients. Nevertheless, 10 to 20% of patients are resistant to dopamine agonists. The aim of this review is to analyze literature data on the source mechanisms and potential ways to overcome the resistance of prolactinomas to dopamine agonists. The criteria of a prolactinoma's resistance to dopamine agonists are as follows: 1) no normalization of serum prolactin levels and/or 2) no reduction of the adenoma volume by at least 50% after treatment of bromocriptine at a dose of ≤ 15 mg/day or cabergoline at a dose of ≤ 3 mg/week for at least 6 months. Full resistance is characterized by both no biochemical and no anti-tumor effects, whereas in partial resistance, prolactin levels can be decreased but not normalized, or the adenoma size can be reduced by less than 50% of the initial. The clinical and morphological predictors of prolactinoma resistance to dopamine agonists are male gender, young age, big size of the adenoma and its invasion into the sinus cavernosus, hypointensive and/or heterogeneous MRI signal on Т2 weighed images, and cystic components within the tumor. The main molecular genetic markers are: decreased expression of dopamine and estrogen receptors, higher proliferation index Ki-67 ≤ 3%, as well as the MENIN, AIP, SF3B1, PRDM2 gene mutations. In case of resistance to bromocriptine, it is recommended to switch the patient to cabergoline. In partial resistance to standard doses of cabergoline, it is possible to increase the dose up to a maximally tolerated. Neurosurgery and/or radiation surgery is recommended in cases of full resistance to dopamine agonists or an aggressive tumor. For very aggressive/malignant tumors, or in the event of their extended growth after surgery, temozolomide is recommended as adjuvant therapy.

P-50 Plurihormonal cystic pituitary adenoma: Case report

Abstract Introduction Pituitary adenomas account for 10-15% of all intracranial neoplasms. Around 1/3 of cases are cystic pituitary adenomas presented by non-staining tumors, usually being prolactinomas and rarely – somatotropinomas. Combined prolactin and growth hormone-secreting adenomas are uncommon and clinical diagnosis can be deferred due to symptoms specific for only one of the excess secreted hormones. Clinical Case A 47-years-old woman was referred to our clinic in November 2022, her only complaint being headaches in the occipital region that persisted for the last 7 years. The patient had a history of taking various SSRI/SNRI antidepressants and benzodiazepines continuously for the same period of time (7 years). She presented outpatient prolactin test results from August 2022 showing a level of 3180 µUI/ml [N 17-637 µUI/ml], 10 fold dilution - 2947 µUI/ml and a pituitary scan that revealed a 13.3×9.6×11.1 mm tumor with a cystic component, invading the suprasellar cistern and the left cavernous sinus. Anamnesis determined that she had two children, a regular menstrual cycle and no heredocolateral antecedents. Clinical examination revealed milky white breast discharge and mild changes in the face, hands, and feet structure that were suggestive of acromegaly. Before admission the patient was started on 0.5 mg cabergoline weekly. On admission, prolactin levels were still elevated, and the cabergoline dose was increased. Of all the pituitary axes the only out-of-range value was IGF-1 – which was elevated to 53.1 nmol/l [N 10.3-28.57]. The patient refused surgery for the moment, and no pharmacological treatment options were available in the country. The patient was lost to follow up and had returned in August 2023 with complaints of general fatigue and malaise. History revealed that in May 2023 she suffered from severe headaches and was admitted to the neurosurgery department of a local hospital, where she underwent transsphenoidal surgery for the pituitary adenoma. The histology showed chromophobe adenoma tissue, no follow-up immunohistology was done. After the surgery, cabergoline was stopped. During our exploration of the pituitary function – there were no deficits or excesses registered. Considering that co-secreting pituitary adenomas are common for MEN syndromes, she was tested for presence of thyroid, parathyroid, adrenal tumors, but no imagistic or laboratory findings were detected. Conclusion In the light of global increased use of antidepressant and anxiety relieving medication, this clinical case underlines the importance of a thorough assessment in these patients, before and during treatment. Additionally, prolactin and growth hormone co-secreting pituitary adenomas often have a silent clinical presentation and may be challenging in diagnosis. A multimodal management is necessary as plurihormonal adenomas require both control of hormone excess and tumor growth.

P-53 Resistant macroprolactinoma

Abstract Introduction Dopamine agonists (DAs) are considered to be the mainstay treatment for prolactinomas. Primary DA-resistance has been reported in approximately 20–30% of the patients on bromocriptine, and in around 10% of those on cabergoline. The DA-resistance is usually defined as a failure to achieve normal prolactin levels on maximally tolerated doses of DAs for at least 3-6 months and failure to achieve 30-50% reduction in tumor size in case of macroprolactinoma. Most of resistant prolactinomas have shown to be large and/or invasive tumors. We present a clinical case of microprolactinoma, resistant to cabergoline. Clinical Case A 21-year old woman reported of a 2-year history of amenorrhea. Primary examination revealed hyperprolactinemia up to 361 ng/ml (bioactive prolactin 256 ng/ml). MR imaging with contrast enhancement showed the ovoid microadenoma in the right half of the adenohypophysis up to 10 mm without invasion to cavernous sinus (Figure 1). Hormone tests excluded the overproduction of ACTH, GH and TSH by the tumor (Table 1), and revealed no signs of hypopituitarism. The patient was prescribed cabergoline (0.5 mg per week), which was followed by the initial decrease of prolactin level to 116 ng/ml. However, subsequent increase of cabergoline dose up to 4,5 mg per week did not lead to further prolactin decrease and normoprolactinemia and there was no resumption of menstrual function. On the follow-up MR images (6 months after the first one) no dynamics was revealed: the tumor was up to 10 mm in size without invasive spreading to cavernous sinus or chiasm. Taking into account the resistance to cabergoline, young age and pregnancy planning, the patient underwent transnasal debulking of the tumor. A week after the operation, normalization of prolactin level was noted, and there were no any signs of hypopituitarism. Within a month after operation, the patient reported of resumption of regular menstrual cycle. r4 months later the woman got pregnant. The pregnancy proceeded without complications and ended in timely delivery.Figure 1.MR image of pituitary microadenoma (contrast enhanced) Table 1.Primary hormone examination

O-01 Case report: Temozolomide treatment of refractory prolactinoma

Abstract Introduction Treatment of refractory prolactinoma is challenging. Temozolomide (TMZ), an oral chemotherapeutic agent, has been recommended as an effective drug for refractory pituitary adenomas or carcinomas. Clinical Case We report a 53-year-old male who presented with diplopia, left eye proptosis, conjunctival congestion, and headache. Magnetic resonance imaging (MRI) showed a macroadenoma 20×17 mm in diameter with compression of the optic chiasm and invasion of both cavernous sinuses. Hormonal evaluation revealed hyperprolactinemia of 2382 ug/L, 120x above the upper limit of normal (ULN), with central hypothyroidism and hypogonadism. Cabergoline was recommended as an initial treatment. Despite the maximum cabergoline dose of 1.5 g daily, tumor volume increased with visual disturbances and headaches. Prolactin (PRL) remained 60x above ULN so the patient underwent transsphenoidal surgery. Tumor histology was consistent with an atypical pituitary adenoma, positively stained for prolactin and sporadically for growth hormone, Ki-67 of 6.4%, no mitosis and negative p53. Postoperatively, the PRL level was still high (25x above ULN) with tumor remnants in both cavernous sinuses. Due to the tumor resistance to dopamine agonist treatment and uncomplete surgical resection, patient underwent stereotactic gamma knife radiosurgery (GK prescription dose 22 Gy, isodose 49%) simultaneously with TMZ treatment. After 2 cycles of TMZ (1. cycle TMZ 300mg/5days, 2. cycle TMZ 400 mg/5days), the PRL level decreased significantly (126 ug/L). The plan is to apply a total of 6 cycles of temozolomide. Conclusion Clinical evidence for the efficacy of TMZ in refractory prolactinoma remains limited, but early use of this agent may be helpful in some cases.

Efficacy of cabergoline in non-irradiated patients with acromegaly: a multi-centre cohort study.

Elucidate the efficacy (as per current biochemical criteria) of cabergoline monotherapy or as addition to long-acting somatostatin receptor ligand (SRL) in patients with acromegaly and no previous pituitary radiotherapy. Multi-centre, retrospective, cohort study (four UK Pituitary centres: Birmingham, Bristol, Leicester, Oxford). Clinical, laboratory, imaging data were analysed. Sixty-nine patients on cabergoline monotherapy were included [median IGF-1 xUpper Limit of Normal (ULN) pre-cabergoline 2.13 (1.02-8.54), median treatment duration 23 months, median latest weekly dose 3 mg]. 31.9% achieved normal IGF-1 (25% GH-secreting, 60% GH+prolactin co-secreting tumours); median weekly cabergoline dose was similar between responders and non-responders. IGF-1 normalisation was related with GH+prolactin co-secreting adenoma (B 1.50, p=0.02) and lower pre-cabergoline IGF-1 xULN levels (B -0.70, p=0.02). Both normal IGF-1 and GH<1 mcg/L were detected in 12.9% of cases and tumour shrinkage in 29.4% of GH-secreting adenomas.Twenty-six patients on SRL+cabergoline were included [median IGF-1 xULN pre-cabergoline 1.7 (1.03-2.92), median treatment duration 36 months, median latest weekly dose 2.5 mg]. 23.1% achieved normal IGF-1 (15.8% GH-secreting, 33.3% GH+prolactin co-secreting tumours). Normal IGF-1 and GH<1 mcg/L were detected in 17.4%. In non-irradiated patients, cabergoline normalises IGF-1 in around one-third and achieves both IGF-1 and GH targets in approximately one out of ten cases. SRL+cabergoline is less efficient than previously reported possibly due to differences in studies methodology and impact of confounding factors.

Complementary health education and clinical guidance for treating women experiencing infertility along with unexplained resistant hyperprolactinemia

This study prospective randomized controlled trial aims to test the impact of adding health education, awareness of some contributing factors and clinical guidance to therapeutic cabergoline given to infertile women with unexplained resistant hyperprolactinemia. It comprised 120 infertile women with unexplained persistent hyperprolactinemia not responding to therapeutic doses of cabergoline 1.5-2 mg/week who were subjected to proper history taking to exclude concomitant drug intake or possible brain problems in all cases. They were classified into group A (60 cases) who received health education and clinical guidance to search for possible contributing factors and were instructed to avoid them in addition to proper therapeutic doses of cabergoline, while group B (60 cases) received proper therapeutic doses of cabergoline only without clinical guidance. After 1 month, serum prolactin (PRL) was measured for all cases. All cases had high PRL level at the start of the study (79.9±28.4 [39-195] and 78.2±19.9 [42-189] in group A and B, respectively) without any significant difference. Pretreatment counselling revealed that lifestyle factors, sexual behaviors or feeding habits may contribute to resistant hyperprolactinemia in all cases without a significant difference between both groups. Serum PRL dropped significantly more in group A (20.14±10.31 [11-45] vs. 49.32±37.03 [12-100]) after combined health education, clinical guidance of the couple and proper treatment. It is concluded that lifestyle factors, sexual behaviors, and feeding habits would affect the response of hyperprolactinemia to treatment. Health education and clinical guidance with some advice to avoid them, would concomitantly improve the response of resistant hyperprolactinemia to therapeutic doses of dopamine agonists.

Effects of cabergoline and dimethylcabergoline on the sexual behavior of male rats.

Cabergoline (CAB) is an ergot derivative typically prescribed for the treatment of hyperprolactinemia. It suppresses the release of prolactin through agonist actions on dopamine (DA) D2 receptors; however, it possesses binding affinity for other DA and 5-HT receptors. Side effects that exacerbate valvular heart disease can occur with high doses. The present study examined the acute, subchronic, and chronic dose-response effects of CAB and a derivative dimethylcabergoline (DMC) which acts as an antagonist instead of agonist at 5-HT 2B receptors, on appetitive and consummatory sexual behaviors of male rats. CAB (0, 0.03, 0.15, or 0.3mg/kg/ml) was administered daily to sexually experienced male rats (N = 10/dose) by oral gavage for a total of 68days. Sexual behavior was tested every 4days during this period for a total of 16 trials. On the 17th trial, rats were administered their dose of CAB, and 4h after were overdosed with sodium pentobarbital, perfused intracardially, and their brains processed for Fos immunohistochemistry. DMC (0, 0.03, 0.15, 0.3mg/kg/ml) was administered daily to sexually experienced male rats (N = 10/dose) by oral gavage for a total of 36days. Sexual behavior was tested every 4days for a total of 9 trials. CAB increased anticipatory level changes, intromissions, and ejaculations significantly across all timepoints, with the medium and high doses being most potent. The medium and high doses also increased Fos protein significantly within the medial preoptic area, whereas in the nucleus accumbens shell, the low and medium doses decreased Fos protein but the high dose increased it significantly from control. Similar to CAB, the medium and high doses of DMC increased the number of ejaculations significantly. Rats in all drug dose groups appeared healthy for the duration of the experiments. Both CAB and DMC facilitate ejaculations, and CAB further facilitates measures of anticipatory sexual motivation and intromissions. These data suggest that both could be used as treatments for sexual arousal disorders and ejaculation/orgasm disorders with little or no untoward side effects at low doses.