Dopamine Agonist Therapy Research Articles

FRI336 A Case Of Pituitary Apoplexy In Late Pregnancy

Abstract Disclosure: H. Abdelrahman: None. S. Rasiah: None. S. Braunthal: None. L. Mahoney: None. R.M. Carneiro: None. K.K. Chen: None. Case: A 20-year-old primigravida presented at 36 weeks gestation due to persistent left-sided headache of 4 weeks duration. MRI brain demonstrated pituitary enlargement (15x17x14 mm) with hemorrhage as well as suprasellar extension and mass effect upon the optic chiasm, consistent with pituitary apoplexy (PA). She has no known medical history or prior endocrinopathies. Serum prolactin was appropriately elevated for pregnancy (299 ng/mL). She was started on levothyroxine for secondary hypothyroidism (TSH 3.4 mcg/dL, free T4 0.8ng/dL (0.7-1.5 ng/dL)) and hydrocortisone for prevention of adrenal insufficiency. She was admitted for semi-urgent induction of labor following the discovery of visual field defects on formal perimetry testing by ophthalmology. After discussion with neurosurgery and maternal fetal medicine, she was permitted to have a trial of vaginal delivery with a brief period of Valsalva but she ended up requiring an emergency C-section due to failure to progress. Her delivery was complicated by significant blood loss (∼5000ml), resulting in bilateral uterine artery embolization followed by an emergency hysterectomy. Repeat MRI brain with contrast following delivery demonstrated a cystic pituitary lesion, possibly a Rathke’s cleft cyst. She underwent endoscopic transnasal exploration and resection two days following delivery. Discussion: Pituitary apoplexy is a rare cause of acute headache in pregnancy. The majority of PA occurs in the setting of undiagnosed pituitary adenomas. Rapid treatment of possible adrenal insufficiency is imperative. Conservative versus surgical treatment plans are tailored to the patient’s obstetric care and neurological status. The earliest reported PA occurrence is at 7 weeks gestation (associated with subsequent miscarriage). Coordination of care between different specialists is paramount especially in late pregnancy. It is theoretically possible that Valsalva during vaginal delivery may increase intracranial pressure and exacerbate hemorrhage. Women with pituitary adenomas are recommended to undergo standard obstetric care with close surveillance, as C-section deliveries can also be associated with increased blood loss. Timing of surgery in gestational pituitary apoplexy is variable; it may be up to one month after delivery. Dopamine agonist therapy may be started during pregnancy for confirmed prolactinomas. The European Society of Endocrinology recommends transsphenoidal surgery in the second trimester for symptomatic adenomas. In the third trimester, preterm delivery may be considered. Post-operative adverse events are not uncommon due to the high risk nature of these pregnancies. After surgery, most patients should experience some degree of vision improvement but many will continue to need hormone replacement. Presentation: Friday, June 16, 2023

THU060 Time To First Remission, Medical Therapy And Survival In Acromegaly: UK Acromegaly Register (UKAR) Study

Abstract Disclosure: H. Deshmukh: None. E. Ssemmondo: None. K. Adeleke: None. L. Batten: None. M. Aye: None. T. Sathyapalan: None. Introduction: There are limited data on the effect of time to remission of acromegaly and survival in people living with acromegaly Methods: The UK Acromegaly Register collected routine biochemical and clinical data on patients with acromegaly. We defined remission of acromegaly as Growth hormone (GH) controlled at ≤2 μg/l following the diagnosis of acromegaly. Time to first remission was defined as the difference between the date of diagnosis and the first GH date ≤2 μg/l in the longitudinal follow-up data (following surgery and/or medical therapy). We used a t-test to compare the mean survival and used the cox-proportional hazard model to assess the effect of time to remission on survival in acromegaly. Results: The study consisted of 3750 participants in the UK acromegaly register with complete data, of which 2472 (65%) participants achieved remission of acromegaly. The mean time to remission with somatostatin analogs (SA) and dopamine agonist (DA) therapy was 4.5 yrs and 7.3 years, respectively (P<0.001). The mean survival was significantly higher in those who achieved remission of acromegaly as compared to those who did not (25.5 yrs vs 21.9yrs P<0.001) achieve remission. In those who achieved remission, (median follow-up period of 23.9 years), there was 15% mortality in those who achieved remission within 1 year and 23% mortality in those who needed more than 1 year to achieve remission. In the cox-proportional hazard model adjusted for, baseline GH, age at diagnosis, and gender, a shorter time to regression of acromegaly was associated with improved survival (HR=0.92(0.91-0.93) P<0.001). Conclusion: This large population-based study of acromegaly showed that a shorter time to remission is associated with improved survival. Presentation: Thursday, June 15, 2023

FRI323 Prolactinoma Recurrence With Testosterone Treatment In Transgender Male

Abstract Disclosure: N. Arnouk: None. P.R. Schroeder: None. Introduction: We present a case of recurrent hyperprolactinemia due to testosterone treatment for gender-affirming hormonal therapy in a transgender male after being controlled on cabergoline for more than a year. Case: A 27-year-old female with history of HTN and polycystic ovary syndrome was diagnosed with pituitary microadenoma after hospital admission for headache and blurry vision. MRI brain showed a mass in the sella and right parasella measuring 36 mm W x 36 mm D x 44 mm H. Hormonal workup showed prolactin (PRL) >999 ng/mL in the diluted assay. The patient was treated medically with cabergoline and discharged home. PRL level improved to 22 ng/mL on treatment. Cabergoline was continued at 0.5 mg twice weekly. The patient was lost to follow-up but returned to clinic after 8 months with PRL level of 58 ng/mL. Cabergoline 0.5 mg twice weekly was continued. PRL level monitoring every ∼6 weeks showed an increase to 184 ng/mL and then 199 ng/mL. Cabergoline was increased to 1 mg twice weekly. PRL level 1 month later was 222 ng/mL. Repeat brain MRI showed markedly decreased microadenoma 4.8 X 2.6 mm. The patient was asymptomatic with no headache, blurry vision, or galactorrhea. On further questioning, the patient reported starting transgender female to male testosterone cypionate 200 mg/mL once weekly for the past 6 months. After discussion with the primary care provider who was managing testosterone treatment, he was started on 60 mg weekly, and the dose was gradually increased to 80 mg weekly to stop the menstrual period. With the 60-mg weekly cypionate dose, the testosterone level was 346 pg/mL, and PRL level was 184 ng/mL. With the cypionate dose of 80 mg weekly, PRL increased to 194 ng/mL and 222 ng/mL. The cypionate dose was decreased to 60 mg weekly, based on literature noting elevated PRL level with testosterone replacement in patients with prolactinoma and hypogonadism. Based on repeat blood work showing elevated testosterone 366 pg/mL with PRL 318 ng/mL, the plan is to start an aromatase inhibitor. Discussion: Testosterone treatment as hormonal affirming therapy in some transgender female to male patients may exacerbate pre-existing hyperprolactinemia or induce PRL secretion, thus close monitoring is required. Testosterone is aromatized to estradiol, which then stimulates the release of PRL from the pituitary gland. The serial measurement of estradiol may serve as an index of aromatization. Hyperprolactinemia in this setting is resistant to dopamine agonist therapy, as noted in multiple case reports. There are no established reference ranges for PRL levels for transgender patients on gender-affirming hormone therapy and no current guidelines regarding routine imaging or biochemical assessment during follow-up. Transgender patients with prolactinoma may require additional treatment with non-aromatizable androgens or the concomitant administration of aromatase inhibitors. Presentation: Friday, June 16, 2023

FRI317 Simultaneous Occurrence Of A Pineal Germ Cell Tumor And Pituitary Macroprolactinoma In A Young Male

Abstract Disclosure: E.P. Monsour: None. S. Badour: None. J.M. Munoz Pena: None. W.T. Donahoo: None. Background: Germ Cell Tumors (GCTs) are a group of heterogeneous tumors that derive from pluripotent germ cells and originate in the yolk sac of the embryo in early gestation. They account for 10% of all central nervous system (CNS) GCTs, primarily occurring in the pediatric and adolescent populations. The co-existence of macroprolactinoma and a mixed CNS GCT is extremely rare, with an unknown worldwide prevalence. Here we report a case of a pituitary macroprolactinoma occurring with a separate primary CNS mixed GCT. Clinical Case: A 19-year-old male presented with a 2-month history of headaches associated with nausea and vomiting. Relevant physical exam findings included decreased visual acuity, absent facial and axillary hair, and prominence of the left testis. Brain MRI demonstrated a pituitary adenoma measuring 3.5 x 2.3 x 3.2 cm extending into the cavernous sinus and an enhancing necrotic lesion in the third ventricle measuring 5.0 x 3.7 x 4.9 cm. Testicular ultrasound revealed two sub-centimeter ill-defined masses in the left testis. Pre-operative labs showed intact thyroid, adrenal, and growth hormone axis. He had a low total testosterone [14.2 ng/dl, reference range (RR): 230-800 ng/dL] with inappropriately normal gonadotrophins and markedly elevated prolactin (PRL) level (2,517 ng/mL, RR <14 ng/mL). Testicular tumor marker, alpha-fetoprotein, was elevated (15.3 ng/dL, RR <9 ng/dL). He was started on glucocorticoids for vasogenic edema and cabergoline twice weekly. He underwent left orchiectomy and subsequent pineal tumor resection. Testicular tumor pathology was consistent with teratoma and a well-differential neuroendocrine tumor with negative margins. Pineal tumor pathology was diagnostic of a mixed GCT. Despite optimal medical therapy, the patient ultimately opted to pursue transsphenoidal tumor resection. Pituitary mass pathology was compatible with a pituitary adenoma, immunoreactive for PRL. Post-operative PRL levels decreased to 6 ng/dL. He achieved a surgical cure without the need to restart dopamine agonist therapy. Conclusion: Simultaneous occurrence of primary brain tumors with different pathologies is estimated to be ∼0.9% of all brain tumors. To our knowledge, only one other case report described an adolescent with a craniopharyngioma and intracranial GCT. This is the first report in the literature of a pituitary macroprolactinoma synchronous with a mixed CNS GCT, and testicular well-differential neuroendocrine tumor with teratoma. Presentation: Friday, June 16, 2023

THU077 Differences In Clinicopathological Features Of Acidophil Stem Cell Adenomas Compared To Other Subtypes Of Acromegaly: A Retrospective Study

Abstract Disclosure: K.C. Yuen: Advisory Board Member; Self; Novo Nordisk, Ascendis, Corcept Therapeutics, Ipsen, Amryt, Strongbridge, Crinetics, Recordati, Xeris. Grant Recipient; Self; Corcept Therapeutics, Crinetics, Ascendis, Amryt. Speaker; Self; Corcept Therapeutics, Novo Nordisk, Recordati. E. Smith: None. F. Bernabe: None. J.M. Eschbacher: None. M. Rodriguez: None. A.S. Little: None. Background: Acidophil stem cell adenomas (ASCAs) are tumors derived from a precursor of somatotrophs and lactotrophs. Often presenting clinically like prolactinomas that respond to dopamine agonist therapy, some may also present with subtle clinical symptoms and biochemical features of acromegaly. Because ASCAs are so rare, their clinicopathological features have not been well-studied. Aims: Clinicopathological features of ASCAs were analyzed and compared with mixed somatotroph-lactotroph adenomas (MSLAs), mammosomatotroph adenomas (MSAs) and pure somatotroph adenomas (PSAs). Methods: We retrospectively reviewed the medical records of acromegaly patients from a single institution presenting from 2001 to 2022. All growth hormone-secreting adenomas were categorized into ASCAs, MSLAs, MSAs and PSAs based on their histopathological findings in surgically treated patients, and their pre- (preop) and post-operative (postop) clinical data were analyzed. Results: Among 135 patients within this cohort, ASCAs, MLSAs, MSAs and PSAs accounted for 21 (15.5%), 11 (8.1%), 59 (43.7%) and 44 (32.6%) cases, respectively. ASCA patients were younger (mean age ASCA: 48.6 vs MLSA 56.5, MSA 59.0, PSA 63.4 years; P < 0.05), had higher preop prolactin levels (ASCA: 1190 ± 639.0 vs MSLA: 44.9 ± 23.2, MSA: 39.7 ± 6.8, PSA: 23.8 ± 5.5 µg/L; P < 0.01), had higher rates of MIB-1 labeling indices (ASCA 76.2% vs MSLA 39.0%, MSA 45.5%, PSA 43.2%; P < 0.05) and preop visual field defect (VFD) (ASCA 32.3% vs MSLA 13.6%, MSA 27.3%, PSA 29.6%; P < 0.05), and had lower rates of preop hypertension (HTN) (ASCA 14.3% vs MSLA 52.5%, MSA 36.4%, PSA 31.8%; P < 0.05) and diabetes mellitus (DM) (ASCA 14.3% vs MSLA 27.2%, MSA 54.5%, PSA 20.5%; P < 0.05). ASCA tumors were larger than MSAs (2.3 ± 1.0 vs 1.6 ± 0.7 cm; P < 0.01), but comparable to MSLAs and PSAs. Rates of cavernous sinus invasion and preop GH levels were similar between groups. Postop GH levels were higher in ASCA (8.6 ± 5.3 µg/L) compared to MSLAs (2.4 ± 0.5 µg/L) and MSAs (1.1 ± 0.7 µg/L) (P < 0.05). ASCA preop IGF-I levels were lower than PSA (ASCA: 466.7 ± 118.5 vs PSA: 803.7 ± 56.5 µg/L; P < 0.05), while postop IGF-I levels were comparable to MLSAs, MSAs and PSAs. ASCAs also had lower postop remission rates compared to MLSAs, MSAs and PSAs (ASCA 19.0% vs MLSA 45.5%, MSA 38.6% and PSA 54.2%; P < 0.05). Most ASCA (85.7%), MLSA (81.4%), MSA (100%) and PSA (77.2%) patients underwent one surgery and more ASCA (23.8%), MLSA (25.4%) and PSA (22.7%) patients underwent radiation therapy than MSA (9.1%) patients. Conclusions: Our data demonstrated important insights into the differences of clinicopathological features of ASCAs compared to other acromegaly subtypes. Notably, ASCAs occurred in younger patients, had larger and more aggressive tumors, had lower postop remission rates and had higher VFD rates. In addition, ASCAs had higher rates of preop hyperprolactinemia and lower rates of preop HTN and DM. Presentation: Thursday, June 15, 2023

SAT620 Dopamine Challenge: Treatment Of Pituitary Macroadenoma/Prolactinoma In Patient On Antipsychotic Medication

Abstract Disclosure: A. Bazhenov: None. I. Alpertunga: None. Background When hyperprolactinemia is a well-known side effect of antipsychotic medications1, the link between prolonged treatment with dopamine antagonist and the development of lactotroph adenomas is still unclear4. Treating a patient with prolactinoma and psychotic disorder may pose a challenge. Antipsychotic agents can cause increases in prolactin levels. Additionally, treatment of prolactinoma with dopamine agonists may worsen psychotic symptoms. Case presentation We present a case of 56 yo male with a PMH of bipolar disorder with psychotic features who was found to have a macroprolactinoma after 18 years of treatment with antipsychotic medications. At age 30, the patient was diagnosed with Bipolar Disorder with psychotic features. The course of the disease was complicated by numerous hospitalizations and frequent changes to the treatment plan, with different combination of second-generation antipsychotic, haloperidol and antiseizure medications. The patient’s prolactin level was 50 ng/ml at the time. 18 years after the diagnosis, the patient developed severe headaches. An MRI revealed a pituitary macroadenoma measuring 1.3 cm, and a repeat prolactin level resulted in 729 ng/ml. He was started on cabergoline 0.5 mg twice a week. As a result, the prolactin level dropped to 32 ng/ml and the macroprolactinoma size decreased to 1.1 cm. Unfortunately, the patient was lost to follow up. Once he re-established his care, he was started on Olanzapine 15 mg daily, Lamotrigine 200 mg daily and cabergoline 0.5 mg twice a week. After reinitiating cabergoline, the patient developed three maniac episodes, two of which required hospitalization. The dose of the cabergoline was decreased to avoid future maniac episodes. Neurosurgery will be consulted for possible surgery treatment. Discussion The treatment of a patient with prolactinoma and a psychotic disorder poses a particular challenge. We believe that care of these patients requires a multidisciplinary approach, and surgical treatment should be considered for those who cannot tolerate dopamine-agonist therapy. Literature 1. Bostwick JR, et al. Antipsychotic-induced hyperprolactinemia. Pharmacotherapy. 2009;29(1):64-73. 2. Lertxundi U et al. Antipsychotics and pituitary tumors. Int Clin Psychopharmacol. 2019;34(2)89. 3. Andrade EH, et al. Insights in the management of antipsychotics. Case Rep Med. 2010;2010. 4. McCarren M,et al. Follow-up study of a pharmacovigilance signal. J Clin Psychopharmacol. 2012;32(6)743. 5. Bakker IC, et al. Successful treatment of a prolactinoma on antipsychotic drug. Endocrinol Diabetes Metab Case Rep. 2016. 6. The challenges in managing prolactinomas SFEBES2009 Accessed April 11 2023. https://endocrine-abstracts.org 7. Howes OD et al. The role of dopamine in schizophrenia. Biol Psychiatry. 2017;81(1)9. 8.Bamarinejad A, et al. Schizophrenia and Macroprolactinoma: Adv Biomed Res. 2020;9(1)38. Presentation: Saturday, June 17, 2023

Macroprolactinoma and empty sella: Swinging pendulum and lessons for dopamine agonists therapy

Abstract Prolactinomas account for nearly 40% of all pituitary tumors with a remarkable response to dopamine agonist (DA) therapy, rendering surgical intervention unnecessary in most cases. Clinical guidelines recommend discontinuing DA therapy two years after achieving normalized prolactin levels and without tumor visibility on MRI. We report a middle-aged man with a macroprolactinoma who presented with apoplexy and panhypopituitarism. The patient responded remarkably to cabergoline with normalization of prolactin and complete tumor disappearance with radiological empty sella within 18 months, and subsequently, he discontinued cabergoline. The patient presented lately (after 10 years) with a recurrence of macroprolactinoma, for which he was reinitiated on cabergoline therapy. Patients with an empty sella remain susceptible to tumor recurrence, as pituitary adenomas may arise from residual pituitary tissue or microscopic tumor remnants may persist, which is not discernible radiologically. This case is a poignant reminder of the importance of diligent and long-term clinical and biochemical monitoring in patients with prolactinomas.

Diagnosis and management of prolactin-secreting pituitary adenomas: a Pituitary Society international Consensus Statement.

This Consensus Statement from an international, multidisciplinary workshop sponsored by the Pituitary Society offers evidence-based graded consensus recommendations and key summary points for clinical practice on the diagnosis and management of prolactinomas. Epidemiology and pathogenesis, clinical presentation of disordered pituitary hormone secretion, assessment of hyperprolactinaemia and biochemical evaluation, optimal use of imaging strategies and disease-related complications are addressed. In-depth discussions present the latest evidence on treatment of prolactinoma, including efficacy, adverse effects and options for withdrawal of dopamine agonist therapy, as well as indications for surgery, preoperative medical therapy and radiation therapy. Management of prolactinoma in special situations is discussed, including cystic lesions, mixed growth hormone-secreting and prolactin-secreting adenomas and giant andaggressive prolactinomas. Furthermore, considerations for pregnancy and fertility are outlined, as well as management of prolactinomas in children and adolescents, patients with an underlying psychiatric disorder, postmenopausal women, transgender individuals and patients with chronic kidney disease. The workshop concluded that, although treatment resistance is rare, there is a need for additional therapeutic options to address clinical challenges in treating these patients and a need to facilitate international registries to enable risk stratification and optimization of therapeutic strategies.

Clinical guidelines ‘Hyperprolactinemia’ (draft)

Hyperprolactinemia is a persistent excess of the blood serum prolactin. The syndrome contains various symptoms, the most characteristic is a violation of the reproductive system. There are multiple endogenous and exogenous causes of hyperprolactinemia. The main treatment method is dopamine agonist therapy, in case of prolactinoma existence, surgical and radiation methods can be applied. About 15% of patients are resistant to dopamine agonist therapy, which determines creation of individual management tactics. The article presents a draft of clinical guidelines for the diagnosis and treatment of hyperprolactinemia, which provides a modern examination algorithm, discusses the basic principles of diagnostics and treatment approaches.

Dopamine agonist therapy in Parkinson’s disease: Spanish expert consensus on its use in different clinical situations

BackgroundDifferent types of therapies were proven effective for the medical management of motor and non-motor symptoms in Parkinson’s disease (PD). We aimed to gain consensus on the dopamine agonist (DA) therapy use in different clinical scenarios of Parkinson’s disease (PD) patients. MethodsThis consensus study was based on the nominal group technique. Initially, a consensus group comprising 12 expert neurologists in the PD field identified the topics to be addressed and elaborated different evidence-based preliminary statements. Next, a panel of 48 Spanish neurologists expressed their opinion on an internet-based systematic voting program. Finally, initial ideas were reviewed and rewritten according to panel contribution and were ranked by the consensus group using a Likert-type scale. The analysis of data was carried out by using a combination of both qualitative and quantitative methods. The consensus was achieved if the statement reached ≥ 3.5 points in the voting process. ResultsThe consensus group produced 76 real-world recommendations. The topics addressed included 12 statements related to DA therapy in early PD, 20 statements concerning DA treatment strategy in patients with motor complications, 11 statements associated with DA drugs and their side effects, and 33 statements regarding DA therapy in specific clinical scenarios. The consensus group did not reach a consensus on 15 statements. ConclusionThe findings from this consensus method represent an exploratory step to help clinicians and patients in the appropriate use of DA in different stages and clinical situations of PD.

Modern concepts of genetic and immunohistochemical features of prolactin-secreting pituitary adenomas

Prolactinomas are the most common secreting adenomas of the pituitary. In 20% of cases resistance to dopamine-agonists treatment is observed. Medical therapy resistance causes progression of pathological symptoms of hyperprolactinemia and negative topographic and anatomical changes of prolactinoma. The causes of ineffectiveness of dopamine agonists therapy are not fully understood as well as approaches to managing patients require clarification. Current concepts of resistance are based on the data obtained as a result of surgery or after a period of long-term ineffective therapy. Thus, it is very important to find methods of assessing the sensitivity of prolactin-secreting adenomas to drug therapy before surgical treatment. Genetic and immunohistochemical studies find special place among these methods, making it possible to predict adenoma's response to drug therapy at early diagnostic stage. Obtained results will allow us to form personalized algorithm for managing patients.

Operative treatment of cystic prolactinomas: a retrospective study

BackgroundThe optimal therapeutic approach for cystic prolactinomas remains unclear. This study aimed to evaluate the remission rates of prolactinoma patients after surgical treatment and the risk factors affecting postoperative remission in cystic prolactinoma patients.MethodsThe clinical data were retrospectively compiled from 141 patients with prolactinomas (including 41 cases of cystic prolactinomas, 21 cases of solid microprolactinomas and 79 cases of solid macroprolactinomas) who underwent transsphenoidal surgery (TSS) between April 2013 and October 2021 at the First Affiliated Hospital of Sun Yat-sen University.ResultsEarly postoperative remission was achieved in 65.83% (n = 27/41) of cystic prolactinomas, 80.95% (n = 17/21) of solid microprolactinomas and 40.51% (n = 32/79) of solid macroprolactinomas. The mean length of follow up in all patients was 43.95 ± 2.33 months (range: 6-105 months). The follow-up remission rates were 58.54%, 71.43% and 44.30% in cystic, solid micro- and solid macroprolactinomas, respectively. For cystic prolactinomas, the early postoperative remission rates in the patients with preoperative dopamine agonists (DA) treatment were significantly higher than those without preoperative DA treatment (p = 0.033), but the difference in the follow-up remission rates between these two groups was not significant (p = 0.209). Multivariate stepwise logistic regression analysis indicated that tumor size and preoperative prolactin (PRL) levels < 200 ng/ml were independent predictors for early postoperative remission in cystic prolactinomas.ConclusionFor cystic prolactinomas, tumor size and preoperative PRL levels were independent predictors of early postoperative remission. Preoperative DA therapy combined with TSS may be more beneficial to cystic prolactinoma patients.

Abstract #1413579: Rathke Cleft Cyst Unveiling Incidental Prolactin Producing Adenoma

Rathke cleft cysts (RCCs) are benign sellar and or/suprasellar lesions that arise from remnants of Rathke's pouch. Pituitary hormonal dysfunction associated with RCCs most often present as hormonal deficiencies due to compression. However pituitary hyper-secretion may coexist with RCC challenging diagnosis and management. A 37-year-old female presented with worsening headache, bilateral blurry vision and pressure-like eye pain for two weeks. She denied any galactorrhea or irregular periods. Her medications included as-needed butalbital-acetaminophen-caffeine and alprazolam. CT Head without IV contrast revealed a pituitary lesion measuring 1.9 cm extending near the inferior margin of the optic chiasm. Subsequent MRI Pituitary with and without IV contrast revealed an enhancing sellar/suprasellar solid lesion measuring 1.6 x 2.7 x 1.9 cm with small hypoenhancing components associated with expansion of the sella, rightward infundibulum deviation, mass effect on the optic chiasm and left cavernous sinus invasion. Pituitary secretion workup revealed an elevated serum prolactin level of 50.4 ng/mL (range 4.8 - 23.3 ng/mL). Repeat prolactin level was 75.7 mg/ml. Dilution studies 1:10 and 1:100 revealed prolactin levels of 78.3 ng/mL and 75.9 ng/mL respectively; absence of hook effect. Her elevated prolactin was attributed to stalk effect given the large size of her sellar mass and relatively minimally elevated prolactin level. Serum Alpha Subunit, ILGF-1, TSH, FT4, LF, FSH, AM cortisol and ACTH level were all normal. She underwent endoscopic transsphenoidal pituitary mass resection with pathology results revealing prolactin producing adenoma and RCC. Immunostains were strongly positive for chromogranin A and prolactin while negative for FSH, ACTH, TSH, beta hCG, GH. Prolactin levels 11 days post-resection remained elevated at 50.7 ng/mL. She continued to have regular periods without galactorrhea. Additionally, she expressed desire to attain pregnancy. This case illustrates the presence of a secreting pituitary prolactinoma in the setting of an RCC. Whether these two entities share a common pathophysiology or simply co-exist is unknown. In one study of 33 surgically treated RCC at presentation, 60% had gonadotroph deficiency, 36% had ACTH deficiency, 36% had TSH deficiency, 18% had ADH deficiency and 31% had hyperprolactinemia (1). It is possible that the majority of this patient 's sellar mass was comprised of RCC as a much higher prolactin level would have been expect for the size of her mass. Interesting, her sellar mass exhibited enhancement which is uncharacteristic for RCC, classical described as cystic lesions without calcification or enhancement. Given that her post-resection prolactin level remained elevated and she desires pregnancy, she may require dopamine agonist therapy.

Elevated insulin-like growth factor-1 in patients without clinical evidence of acromegaly.

To 1) identify the frequency of IGF-1 elevation in a cohort of patients without clinically suspected GH excess, in a state-based reference laboratory over a 24-month period, and 2) to examine potential differences in comorbidities and relevant medications between people with an elevated IGF-1 compared to a matched control group. All IGF-1 measurements at Pathology Queensland between 1/12/2018 - 1/12/2020 were identified. The medical records of those with IGF-1 ≥1.1x the upper limit of the reference range were appraised to determine: 1) documentation of acromegalic features, 2) relevant comorbidities and medication use, and 3) further investigations to exclude pathological GH excess. There were 2759 IGF-1 samples measured in 1963 people ≥18 years, over the specified period. Of these, 204 had IGF-1 ≥1.1x the upper limit of the age-matched reference range; 102 cases (61M, 41F) met inclusion criteria, and were matched to 102 controls with a normal IGF-1 based on age, sex, gonadal status and pituitary anatomy on MRI. There were significant differences in the frequency of dopamine agonist use (19/102 cases vs 6/102 controls, OR=3.66, 95%CI: 1.45-9.29, P=0.009) and chronic kidney disease (CKD) (14/102 cases vs 4/102 controls, OR = 3.90, 95%CI: 1.28-11.14, P=0.024). Out of 1963 patients having IGF-1 measured, 102 (5.2%) had an elevated IGF-1 where there was no known acromegaly, GH replacement or endogenous glucocorticoid excess. Intra-individual biological variability, assay imprecision and physiological factors are known contributors to falsely elevated IGF-1, dopamine agonist therapy and CKD should also be considered. This article is protected by copyright. All rights reserved.

Surgical Management of Giant Prolactinomas: A Descriptive Study.

Giant prolactinoma (GP) is a rare pituitary lactotropic cell tumor larger than 4 cm in its widest dimension, and is less likely than a smaller prolactinoma to achieve prolactin normalization on dopamine agonist (DA) monotherapy. There is a paucity of data on the circumstances and outcomes of second-line management of GP with surgery. Herein, our institution's experience with the surgical management of GPs is described. A single-center retrospective analysis was conducted of patients who underwent surgery for giant prolactinoma from 2003 to 2018. A chart review was conducted for demographic data, clinical features, laboratory and radiographic findings, operative and pathology reports, perioperative management, and clinical outcomes in follow-up. Descriptive statistics were used. Of 79 prolactinoma cases, 8 patients had GP with a median age of 38 years (range 20-53), 75% (6/8) were male, with a median largest tumor dimension of 6 cm (range 4.6-7.7), and a median prolactin level of 2,500 μg/L (range 100->13,000). Six patients had transsphenoidal surgery for dopamine agonist (DA) resistance or intolerance. Two patients had a craniotomy for a missed diagnosis; one was due to the hook effect. No tumor resections were complete by either surgical approach; all had persistent hyperprolactinemia requiring postoperative DA therapy, and two patients had an additional craniotomy procedure for further tumor debulking. There was no recovery of pituitary axes and postoperative deficits were common. Remission as defined by prolactin normalization occurred in 63% (5/8) at a median time of 36 months (range 14-63 months) on DA therapy after surgery with a follow-up of 3-13 years. GPs infrequently require surgical resection, which is generally incomplete and requires adjuvant therapy. Given the rarity of surgery for GPs, multi-institutional or registry studies would yield clearer guidance on optimal management.

Effect of Dopaminergic Therapy on Impulse Control Disorders in Patients With a Prolactinoma.

Studies have reported an increase in the incidence of impulse control disorders (ICDs) in patient groups treated with dopamine agonists (DAAs), especially in Parkinson disease (PD). However, very few studies have reported on ICDs in individuals with a prolactinoma who were treated with DAAs. To see whether a DAA by itself causes ICDs in individuals with a prolactinoma by controlling the susceptibility to impulsivity by excluding individuals with other risk factors for ICDs. We compared the performance of 31 individuals with a prolactinoma receiving DAA therapy (DAA+) on various behavioral scales and the Iowa gambling task (IGT), a neuropsychological instrument that measures risky decision-making, with the performance of 20 individuals with a prolactinoma who were not on DAA therapy (DAA-) and 30 healthy controls (HC). There was no significant difference among the groups concerning performance on the Zuckerman Sensation Seeking Scale-V, Minnesota Impulse Disorders Interview, Barratt Impulsiveness Scale-11, or IGT. No correlation was found between the scores on these scales and the duration or dose of DAA in the DAA+ group. The incidence of ICDs was 25.8% in the DAA+ group, 15% in the DAA- group, and 16.7% in the HC. The differences among the groups did not reach statistical significance. Individuals who are under treatment with low-dose, D 2 -selective DAAs for a prolactinoma do not face an increased risk for ICDs, especially when they are carefully screened for any psychiatric comorbidity that may also display impulsivity.

Prolactinomas in adolescent and elderly patients-A comparative long-term analysis.

Prolactinomas represent the most common type of secreting pituitary adenomas, yet are rarely encountered in adolescent-onset (AO; i.e. <18 years) or elderly-onset (EO; i.e. ≥65 years) cohorts. As a result, it is not clear whether long-term strategies should be focused differently at both age extremes when comparing their therapeutic outcomes. We aimed at investigating long-term endocrinological outcomes, looking for differences between the two cohorts and evaluating the dependence on continued dopamine agonist (DA) therapy. Retrospective cross-sectional comparative study analyzing prolactinoma patients with a follow-up of ≥4 years. Clinical, radiological and biochemical characteristics were assessed at diagnosis and last follow-up. Longitudinal endocrinological outcomes between groups of extreme ages (i.e. AO and EO) and middle age (i.e. ≥18 years to 65 years) were compared. Independent risk factors for long-term dependence on DAs were calculated. Follow-up at ≥4 years was recorded for 108 prolactinoma patients; 10 patients with AO and 10 patients with EO. Compared to AO patients, EO patients were predominantly men (p = 0.003), and presented with significantly higher prolactin (PRL) levels (p = 0.05) and higher body mass index (p = 0.03). We noted a significant positive correlation between patients' PRL values and their age (r = 0.5, p = 0.03) or BMI (r = 0.6, p = 0.03). After a median follow-up of 115 months, remission was noted in 87 (83%) patients; 9 (90%) in AO patients, and 7 (70%) in EO patients (p = 0.58). Continuation of DAs was required in 4 patients (40%) with AO and 7 patients (70%) with EO (p = 0.37). Patients with elderly-onset were an independent predictor of long-term dependence on DAs (HR 2.8, 95% CI 1.1-7.2, p = 0.03). Long-term control of hyperprolactinemia and hypogonadism does not differ between members of the AO and EO cohorts, and can be attained by the majority of patients. However, adjuvant DAs are often required, independent of the age of onset. Considering the clinical significance of persistent DA therapy for the control of hyperprolactinemia in many patients at both extremes of age, long-term monitoring may become recommended, in particular in patients with elderly-onset.

TEMPORAL LOBE HERNIATION AND CHIASMOPATHY DURING DOPAMINE AGONIST THERAPY FOR PROLACTINOMA.

Dopamine agonists (DA) are first line treatment for prolactinomas. Optic chiasm herniation can rarely occur during therapy, while brain herniation is very uncommon. A 34 yo woman presented with headaches and vision changes. Prolactin (PRL) was 4300 ng/mL. MRI showed a 4.5 cm pituitary adenoma with chiasm compression. After 3 months, PRL decreased to 201 ng/mL while patient was taking CAB 0.75 mg twice a week. MRI showed ~30% tumor reduction with medial temporal lobe herniation and encephalocele. CAB was stopped and she underwent surgical debulking and encephalocele repair. Histopathology confirmed prolactin tumor. CAB 0.75 mg twice a week was resumed.A 50 yo man had incidental detection of a sellar mass after trauma. MRI showed 3.6 cm tumor with minimal contact of right optic nerve, and PRL 3,318 ng/ml. He received CAB 0.5mg twice a week with PRL improvement to 26 ng/mL after 1 month. After 2 months ophthalmology exam showed new left superotemporal depression. PRL was 68 ng/mL and MRI showed 35% mass reduction and new inferior displacement tethering of the chiasm. CAB dose was decreased to 0.25 mg twice a week. Our cases illustrate that rapid biochemical and radiographic response to DA therapy in large prolactinomas warrants close clinical and neuro-ophthalmologic follow-up. We recommend repeating the MRI 3 months after initiation of DA therapy or sooner in case of new mass effect manifestations. Decision regarding DA dose reduction or chiasmopexy for visual field deficits needs to be multi-disciplinary and on a case-to-case basis.

Non‐ergot dopamine agonist therapy for Parkinson's disease in Japan: A claims database analysis

AbstractBackgroundLevodopa monotherapy and combination therapy with non‐ergot dopamine agonists (DAs; pramipexole, ropinirole, and rotigotine) are commonly used in patients with Parkinson's disease (PD). Changes in prescription preferences for each DA were reported previously; however, information regarding the selection of individual DAs is insufficient.AimTo investigate the reasons for selecting each DA.MethodsThis observational study used a Japanese claims database (April 2008–July 2017). The percentage of patients prescribed each DA was analyzed by year (2010–2017). The change in DA prescriptions and prevalence of comorbidities before DA initiation or before replacement with another DA were analyzed from 2013.ResultsThe database included 50,408 patients with PD who received ≥1 levodopa and/or DA prescriptions. Pramipexole was the most popular DA; however, its prescription has decreased since 2012. Ropinirole prescriptions remained relatively unchanged, while that of rotigotine tended to increase since its launch in 2013 and recently surpassed that of ropinirole. The most frequent pattern of change (both in addition and replacement) was from pramipexole to rotigotine. Differences were observed in the prevalence of comorbidities among DAs.ConclusionPramipexole was often prescribed at the beginning of the study period; the decrease in its prescription frequency might be mainly related to new DA options. The frequent change from pramipexole to rotigotine might be associated with the different DA characteristics, which may be a factor influencing the choice of a specific DA.

D2/3 Agonist during Learning Potentiates Cued Risky Choice.

Impulse control and/or gambling disorders can be triggered by dopamine agonist therapies used to treat Parkinson's disease, but the cognitive and neurobiological mechanisms underlying these adverse effects are unknown. Recent data show that adding win-paired sound and light cues to the rat gambling task (rGT) potentiates risky decision-making and impulsivity via the dopamine system, and that changing dopaminergic tone has a greater influence on behavior while subjects are learning task contingencies. Dopamine agonist therapy may therefore be potentiating risk-taking by amplifying the behavioral impact of gambling-related cues on novel behavior. Here, we show that ropinirole treatment in male rats transiently increased motor impulsivity but robustly and progressively increased choice of the high-risk/high-reward options when administered during acquisition of the cued but not uncued rGT. Early in training, ropinirole increased win-stay behavior after large unlikely wins on the cued rGT, indicative of enhanced model-free learning, which mediated the drug's effect on later risk preference. Ex vivo cFos imaging showed that both chronic ropinirole and the addition of win-paired cues suppressed the activity of dopaminergic midbrain neurons. The ratio of midbrain:prefrontal cFos+ neurons was lower in animals with suboptimal choice patterns and tended to predict risk preference across all rats. Network analyses further suggested that ropinirole induced decoupling of the dopaminergic cells of the VTA and nucleus accumbens but only when win-paired cues were present. Frontostriatal activity uninformed by the endogenous dopaminergic teaching signal therefore appeared to perpetuate risky choice, and ropinirole exaggerated this disconnect in synergy with reward-paired cues.SIGNIFICANCE STATEMENT D2/3 receptor agonists, used to treat Parkinson's disease, can cause gambling disorder through an unknown mechanism. Ropinirole increased risky decision-making in rats, but only when wins were paired with casino-inspired sounds and lights. This was mediated by increased win-stay behavior after large unlikely wins early in learning, indicating enhanced model-free learning. cFos imaging showed that ropinirole suppressed activity of midbrain dopamine neurons, an effect that was mimicked by the addition of win-paired cues. The degree of risky choice rats exhibited was uniquely predicted by the ratio of midbrain dopamine:PFC activity. Depriving the PFC of the endogenous dopaminergic teaching signal may therefore drive risky decision-making on-task, and ropinirole acts synergistically with win-paired cues to amplify this.