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Despite most of the prolactinomas can be treated with endocrine therapy and/or surgery, a significant percentage of these tumors can be resistant to endocrine treatments and/or recur with prominent invasion into the surrounding anatomical structures. Hence, clinical, pathological, and molecular definitions of aggressive prolactinomas are important to guide for classical and novel treatment modalities. In this review, we aimed to define molecular endocrinological features of dopamine agonist-resistant and aggressive prolactinomas for designing future multimodality treatments. Besides surgery, temozolomide chemotherapy and radiotherapy, peptide receptor radionuclide therapy, estrogen pathway modulators, progesterone antagonists or agonists, mTOR/akt inhibitors, pasireotide, gefitinib/lapatinib, everolimus, and metformin are tested in preclinical models, anecdotal cases, and in small case series. Moreover, chorionic gonadotropin, gonadotropin releasing hormone, TGFβ and PRDM2 may seem like possible future targets for managing aggressive prolactinomas. Lastly, we discussed our management of a unique prolactinoma case by asking which tumors' proliferative index (Ki67) increased from 5-6% to 26% in two subsequent surgeries performed in a 2-year period, exerted massive invasive growth, and secreted huge levels of prolactin leading up to levels of 1 605 671 ng/dl in blood., Competing Interests: The authors declare that they have no conflict of interest., (Thieme. All rights reserved.)

Context: Prolactinomas frequently cause amenorrhoea, galactorrhoea and infertility and require dopamine agonist (DA) treatment to normalize prolactin levels and hence, restore ovulation. The vast majority of female patients harbour microprolactinomas in whom DA treatment is usually discontinued at the time of pregnancy diagnosis and surveillance is generally limited as the symptomatic growth is considered very rare., Case Descriptions: We report five cases of women harbouring a microprolactinoma in whom symptomatic pituitary apoplexy occurred during pregnancy. Only one necessitated surgery during pregnancy, while the others were treated conservatively by reintroducing DAs in three. A systematic literature review found reports of four additional cases among 20 cases of prolactinomas (both macro- and micro-prolactinomas) complicated by apoplexy during pregnancy., Conclusion: During pregnancy, pituitary apoplexy may occur in pre-existing microprolactinomas, causing tumour enlargement and headache, which may be self-limiting but may require intervention by re-initation of dopamine agonists or surgery. Our literature review confirms that this clinical event is rare; nevertheless, physicians managing pregnant patients with microprolactinomas must be aware that symptomatic pituitary apoplexy may incidentally occur in all trimesters of pregnancy and require prompt radiological, endocrine and ophthalmological assessment and treatment.

Objective: To present the outcomes of endoscopic endonasal surgery for giant pituitary adenomas and discuss the extent of resection to minimize morbidity and mortality., Methods: We retrospectively reviewed medical records of 44 patients with giant pituitary adenomas who underwent endoscopic endonasal surgery. Clinical presentation, laboratory results, imaging studies, clinical outcomes, extent of resection, and complications were collected and analyzed. Factors affecting long-term outcome according to surgical technique were identified and analyzed., Results: Radical resection (RR) was defined as either gross total resection or near-total resection (90%-100% of the tumor). There were 28 patients (63.6%) who underwent RR, 10 patients (22.7%) who underwent subtotal resection, and 6 patients (13.6%) who underwent partial resection. Visual improvement was achieved in 27 patients (81.8%). Thirteen patients (72.2%) with pituitary dysfunction had improvement in at least 1 preoperative endocrinological dysfunction. RR rates for dumbbell and multilobular tumors were 44.4% and 28.6%, respectively. Surgical complications were observed in 14 (31.8%) patients. Major vascular injury occurred in 3 patients (6.8%). Mean follow-up period was 38.5 months (range, 1-70 months). No patients with RR had recurrence or residual tumor progression. Ten patients (22.7%) received adjuvant radiation therapy after resection. Two patients were reoperated on for tumor regrowth, and 3 patients (including the 2 patients with tumor regrowth) were lost to follow-up., Conclusions: Long-term follow-up results and low recurrence rate of tumors indicate that RR is effective to decrease morbidity and mortality., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: Although long-term dopamine agonist (DA) therapy is recommended as a first-line treatment for prolactinoma, some patients may prefer surgical treatment because of the potential adverse effects of long-term medication, or the desire to become pregnant. This study aimed to determine whether surgical treatment of prolactinomas could be an alternative to DA therapy., Methods: In this retrospective study, 96 consecutive patients (74 female, 22 male) underwent primary pituitary surgery without long-term DA treatment for prolactinomas at a single institution from 1990 to 2010. All patients underwent primary surgical treatment in the microscopic transsphenoidal approach (TSA)., Results: The median age and median follow-up period were 31 (16-73) years and 139.1 (12.2-319.6) months, respectively. An initial overall remission was accomplished in 47.9% (46 of 96 patients, 33 macroadenomas, and 13 microadenomas) of patients. DA dose reduction was achieved in all patients after TSA. A better remission rate was independently predicted by lower diagnostic prolactin levels and by a greater extent of surgical resection. Overall remission at the last follow-up was 33.3%, and the overall recurrence rate was 30.4%. The permanent complication rate was 3.1%, and there was no mortality., Conclusion: TSA can be considered a safe and potentially curative treatment for selective microprolactinomas as an alternative to treatment with a long-term DA., Competing Interests: The authors have no potential conflicts of interest to disclose., (© 2021 The Korean Academy of Medical Sciences.)

While prolactinoma patients have high bone turnover, current data are inconclusive when it comes to determining whether correction of hyperprolactinemia and associated hypogandism improves osteodensitometric data in men and women over the long term. In a large cohort of including 40 men and 60 women, we studied the long-term impact of prolactinoma treatment on bone mineral density (BMD) in men versus women, assessed adverse effects of a primary surgical or medical approach, and evaluated data for risk factors for impaired BMD at last follow-up using multivariate regression analyses. Median duration of follow-up was 79 months (range 13-408 months). Our data indicate that the prevalence of impaired BMD remained significantly higher in men (37%) than in women (7%, p < 0.001), despite the fact that hyperprolactinemia and hypogonadism are under control in the majority of men. We found that persistent hyperprolactinemia and male sex were independent risk factors for long-term bone impairment. Currently, osteoporosis prevention and treatment focus primarily on women, yet special attention to bone loss in men with prolactinomas is advised. Bone impairment as "end organ" reflects the full range of the disease and could become a surrogate marker for the severity of long-lasting hyperprolactinemia and associated hypogonadism.

Objective: To report the clinical presentation, management and outcomes of young patients with prolactinomas (<20 years) and conduct a systematic review and meta-analysis., Patients and Design: Clinical, biochemical and radiological data (1996-2018) were collected from our centre. A systematic review and meta-analysis of published literature (1994-2019) on prolactinoma (age <20 years) were conducted. Both random and fixed effects meta-analysis were used to pool outcomes across studies. RESULTS 1 CASE SERIES: Twenty-two patients (14 females) were identified; median age at diagnosis 15.7 years (range 13-19); 12 patients (6 females) had a macroprolactinoma. Seven patients (macroprolactinoma-6) had associated pituitary hormone deficiencies at presentation. Five patients (4 males) underwent surgical resection due to poor response to cabergoline or apoplexy. Patients undergoing surgery had larger tumours (p < .02) and higher serum prolactin concentration (p < .005). All patients with macroprolactinoma >20 mm required surgical intervention. RESULTS 2 SYSTEMATIC REVIEW AND META-ANALYSIS: We selected 11 studies according to strict inclusion criteria describing 275 patients. Macroprolactinoma was more common in girls (78.7% [95% CI 70.5-85.9]) than boys and was more frequent than microprolactinoma (56.6% [95% CI 48.4-64.5]). In males, only 6/57 (10.5%) of tumours were microprolactinoma as compared to 102/198 (51.5%) microprolactinoma in females (risk difference -0.460; [95% CI -0.563 to -0.357]; p < .001). Surgery was first-line therapy in 18.9% patients, with another 15.4% requiring it as a second line (overall 31.3%)., Conclusions: Macroprolactinoma, particularly if >20 mm, usually requires multimodal therapy including surgical intervention. While overall prolactinomas in <20 years age group are more common in females, the proportion of macroprolactinoma vs microprolactinoma is greater in males, particularly for large invasive tumours. Microprolactinoma is a rare diagnosis in adolescent males., (© 2020 John Wiley & Sons Ltd.)

First-line treatment of prolactinoma is usually medical, based on dopamine agonists receptors, mainly cabergoline. The classical side-effects of cabergoline (low blood pressure and nausea) have been well known since it was first introduced. Other side-effects, however, are more controversial or simply less frequent, but need to be considered during monitoring. This review will focus on these side-effects: cardiac valvular fibrosis, pleural, pericardial and retroperitoneal fibrosis, addictive/compulsive behaviors, and risks secondary to significantly decreased tumor volume. We will also describe how such side-effects should be monitored and managed. In our opinion, the low prevalence of these side-effects should not cast doubt on the role of cabergoline in the therapeutic algorithm of prolactinoma., (Copyright © 2021 Elsevier Masson SAS. All rights reserved.)

Context: Dopamine agonists (DAs) are the first-line therapy for prolactinomas. Although pituitary tumors often do not completely disappear, discontinuing DAs in patients with no visible tumor on magnetic resonance imaging is advised., Objective: To analyze biochemical remission after cabergoline (CAB) withdrawal in patients with visible remnant pituitary tumors., Design: Retrospective cohort study., Setting: Severance Hospital., Subjects: We identified 734 patients with prolactinomas undergoing CAB therapy for at least 12 months from 2005 to 2018. We selected 44 patients with prolactinomas who discontinued CAB with normal prolactin levels; they were receiving a minimal CAB dose but had visible remnant tumors., Results: Median age at diagnosis was 32 (18-58) years, and most patients were women (95.45%). Median treatment duration was 32 (12-120) months. Of 44 patients, 33 continued to have normoprolactinemia, but 11 patients developed hyperprolactinemia after drug withdrawal within 26 (12-97) months. Age, sex, maximal and remnant tumor size, and treatment duration were similar between the groups. The initial prolactin level and chances of cavernous sinus (CS) invasion were higher in the recurrence group. CS invasion at diagnosis was associated with an increased recurrence rate. Although treatment response did not correlate with the initial and final signal intensity assessments, a significant decrease in T2 intensity ratio after 6 months of CAB therapy was observed in the remission group (P = .043)., Conclusion: In patients with visible tumors, the presence of CS invasion at diagnosis may be an unfavorable predictor for biochemical remission after CAB discontinuation., (© The Author(s) 2020. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Context: Approximately 10% to 20% of prolactinomas are resistant to dopamine agonist therapy. The ErbB signaling pathway may drive aggressive prolactinoma behavior., Objective: We evaluated lapatinib, an ErbB1-epidermal growth factor receptor (EGFR)/ErbB2 or human EGFR2 (HER2) tyrosine kinase inhibitor (TKI), in aggressive prolactinomas., Design: A prospective, phase 2a multicenter trial was conducted., Setting: This study took place at a tertiary referral pituitary center., Patients: Study participants included adults with aggressive prolactinomas showing continued tumor growth despite maximally tolerated dopamine agonist therapy., Intervention: Intervention included oral lapatinib 1250 mg/day for 6 months., Main Outcome Measures: The primary end point was 40% reduction in any tumor dimension assessed by magnetic resonance imaging at study end; tumor response was assessed by Response Evaluation Criteria in Solid Tumors criteria. Secondary end points included prolactin (PRL) reduction, correlation of response with EGFR/HER2 expression, and safety., Results: Owing to rigorous inclusion criteria, of 24 planned participants, only 7 consented and 4 were treated. None achieved the primary end point but 3 showed stable disease, including 2 with a 6% increase and 1 with a 16.8% decrease in tumor diameter. PRL response was not always concordant with tumor response, as 2 showed 28% and 59% increases in PRL. The fourth participant had a PRL-secreting carcinoma and withdrew after 3 months of lapatinib because of imaging and PRL progression. EGFR/HER2 expression did not correlate with treatment response. Lapatinib was well tolerated overall, with reversible grade 1 transaminitis in 2 patients, grade 2 rash in 2 patients, and grade 1 asymptomatic bradycardia in 2 patients., Conclusions: An oral TKI such as lapatinib may be an effective option for a difficult-to-treat patient with an aggressive prolactinoma., (© The Author(s) 2020. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The reviewer CY declared a shared affiliation with the authors to the handling editor at time of review.

Objective: In pituitary macroadenomas with extensive suprasellar extension (SSE), suprasellar region can be approached by extending exposure either anteriorly by adding bone removal of the tuberculum sellae and planum sphenoidal or posteriorly from inside the sellar cavity through diaphragma sella. The later approach has been rapidly regressed in favor of the anteriorly extended approach, mainly due to the inadequate angled illumination. Benefiting from the continuous evolution of visualization, authors, in current series, tried to revive this technique in form of pure endoscopic trans-sellar trans-diaphragmatic approach (ETSDA) for extra-capsular resection of pituitary macroadenomas with extensive SSE., Methods: A prospective review including 10 patients of pituitary macroadenomas with extensive SSE more than 10 mm underwent extra-capsular resection via the ETSDA. The detailed technical nuances and surgical outcome of this approach were evaluated., Results: Six of 10 patients had SSE > 10 mm and 4 patients had SSE > 20 mm, grade B and C, respectively. Gross total resection was achieved in all cases. Postoperatively, visual field deficit was ameliorated to varying degrees in all patients. There were no serious intraoperative complications, and the clinically overt postoperative CSF rhinorrhea was not observed in any case., Conclusion: Extra-capsular resection of pituitary macroadenomas with extensive SSE can be effectively and safely achieved using the ETSDA. Thus, it may be more preferable to the anteriorly extended approach that may potentially increase the risk for postoperative CSF rhinorrhea., (Copyright © 2020 Elsevier Inc. All rights reserved.)

As hyperprolactinemia is observed in patients with bromocriptine‑resistant prolactinoma, prolactin (PRL) has been implicated in the development of bromocriptine resistance. Since PRL primarily mediates cell survival and drug resistance via the Janus kinase‑2 (JAK2)/signal transducer and activator of transcription 5A (STAT5) signaling pathway, the STAT5 inhibitor, pimozide, may inhibit cell proliferation and reverse bromocriptine resistance in prolactinoma cells. In the present study, compared with bromocriptine or pimozide alone, the combination of pimozide and bromocriptine exerted enhanced reduction in cell growth and proliferation, and increased apoptosis and cell cycle arrest in bromocriptine‑resistant prolactinoma cells. A reduction in phospho‑STAT5, cyclin D1 and B‑cell lymphoma extra‑large (Bcl‑xL) expression levels were observed in cells treated with the combination of drugs. In addition, pimozide suppressed spheroid formation of human pituitary adenoma stem‑like cells, and reduced the protein expression of the cancer stem cell markers, CD133 and nestin. Pimozide did not exert any additional antitumor activity in STAT5‑knockdown primary culture cells of human bromocriptine‑resistant prolactinomas. Furthermore, Pimozide combined with bromocriptine treatment significantly reduced human prolactinoma xenograft growth. Western blot and immunohistochemical analyses also demonstrated significant inhibition of cell proliferation and stem cell marker proteins in vivo. Collectively, these data indicated that pimozide treatment reduced prolactinoma growth by targeting both proliferating cells and stem cells, at least in part, by inhibiting the STAT5/Bcl‑xL and STAT5/cyclin D1 signaling pathways.

Pituitary neuroendocrine tumors (PitNETs) represent the neoplastic proliferation of the anterior pituitary gland. Transcription factors play a key role in the differentiation of PitNETs. However, for a substantial proportion of PitNETs, the etiology is poorly understood. According to the transcription data of 172 patients, we found the imprinting disorders of the 14q32.2 region and DLK1/MEG3 locus associated with the differentiation of PitNETs. DLK1/MEG3 locus promoted somatotroph differentiation and inhibited tumor proliferation in PIT1(+) patients, furthermore, the level of DLK1 played a critical role in the trend of somatotroph or lactotroph differentiation. Anti-DLK1 monoclonal antibody blockade or siMEG3 both indicated that the DLK1/MEG3 significantly promoted the synthesis and secretion of GH/IGF-1 and inhibited cell proliferation. In addition, loss of DLK1 activated the mTOR signaling pathway in high DLK1-expressing and PIT1(+) GH3 cell lines, a mild effect in the low DLK1-expressing and PIT1(+) MMQ cell lines and no effect in the PIT1(-) ATT20 cell line. These findings emphasize that expression at the DLK1/MEG3 locus plays a key role in the differentiation of PitNETs, especially somatotroph adenomas, and provide potential molecular target data for patient stratification and treatment in the future.

Pituitary adenomas (PAs) are slow growing and benign primary intracranial tumors that often cause occupying effects or endocrine symptoms. PAs can be classified into various subtypes according to hormone secretion. Although widespread transcriptional alterations that cause aberrant hormone secretion have been characterized, the impact of genomic variations on transcriptional alterations is unclear due to the rare occurrence of single-nucleotide variations in PA. In this study, we performed whole-genome sequencing (WGS) on 76 PA samples across three clinical subtypes (PRL-PAs; GH-PAs, and NFPAs); transcriptome sequencing (RNA-seq) of 54 samples across these subtypes was also conducted. Nine normal pituitary tissues were used as controls. Common and subtype-specific transcriptional alterations in PAs were identified. Strikingly, widespread genomic copy number amplifications were discovered for PRL-PAs, which are causally involved in transcriptomic changes in this subtype. Moreover, we found that the high copy number variations (CNVs) in PRL-PA cause increased prolactin production, drug resistance and proliferative capacity, potentially through key genes with copy number amplification and transcriptional activation, such as BCAT1. This study provides insight into how genomic CNVs affect the transcriptome and clinical outcomes of PRL-PA and sheds light on the development of potential therapeutics for aberrantly activated targets.

Purpose: Moderate hyperprolactinaemia (2-5 times upper limit of normal) occurring in a patient with a normal pituitary MRI is generally considered to be due to a lesion below the level of detection of the MRI scanner assuming macroprolactin and stress have been excluded. Most patients with mild-to-moderate hyperprolactinaemia and a normal MRI respond to dopamine agonist therapy. We present the rare case of a patient who had prolactin elevation typical of a prolactin-secreting pituitary macroadenoma,with a normal cranial MRI, and in whom the prolactin rose further with dopamine agonist treatment. Subsequent investigations revealed ectopic hyperprolactinaemia to a uterine tumor resembling ovarian sex cord tumor (UTROSCT) which resolved following tumor resection. Although mostly considered to be benign, the UTROSCT recurred with recurrent hyperprolactinaemia and intraabdominal metastases., Methods: We have systematically and critically reviewed existing literature relating to ectopic hyperprolactinaemia in general and UTROCST specifically., Results: Fewer than 80 cases of UTROSCTs have been reported globally of which about 23% have shown malignant behaviour. There are fewer than 10 cases of paraneoplastic hyperprolactinaemia originating from uterine neoplasms including one other case of ectopic hyperprolactinaemia to a UTROSCT., Conclusions: Our case demonstrates the importance of screening for extracranial hyperprolactinaemia in the context of: (1) substantially raised prolactin (10× ULN) and (2) normal cranial MRI assuming macroprolactin has been excluded. The majority of extracranial ectopic prolactin-secreting tumors occur in the reproductive organs.

Objective: To evaluate the prevalence of impulse control disorders (ICD) and psychiatric symptoms in patients with acromegaly receiving dopamine agonists (DA) in comparison with those with prolactinoma, nonfunctioning pituitary adenomas (NFA), and healthy controls (HC)., Design: Forty patients with acromegaly, 40 with prolactinoma, 38 with NFA, and 32 HCs were included. All patients and controls were evaluated using the revised version of the Minnesota Impulsive Disorders Interview (MIDI-R), Symptom Check List (SCL-90-R) questionnaire, Barratt Impulsiveness Scale (BIS-11), Beck Depression Inventory (BDI), and Beck Anxiety Inventory (BAI)., Results: We detected ICD associated with DAs in two patients with acromegaly (5%) and three patients (7.5%) with prolactinoma. All patients' symptoms resolved after discontinuation of the drug. While the mean DA dose was higher in patients with acromegaly than prolactinomas (p < 0.05), no difference was detected in terms of ICD prevalence between two groups (p > 0.05). SCL-90 depression and interpersonal sensitivity subscale positivity was higher in patients with NFA than HCs. Patients with prolactinoma had higher obsession and interpersonal sensitivity positivity and those with NFA had higher somatization, interpersonal sensitivity, and depression positivity as compared to patients with acromegaly (p < 0.05 for all)., Conclusions: Although DA dose was significantly higher in patients with acromegaly, there was no significant difference in the prevalence of DA-related ICD. The higher prevalence of positive screening in SCL-90 in patients with NFA in comparison to HCs supports the hypothesis that the presence of a pituitary adenoma per se might cause significant psychiatric symptoms., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Dopamine agonists (DAs), such as cabergoline and bromocriptine, are the first-line clinical treatment for prolactinomas. Our previous study demonstrated that long noncoding RNA H19 expression is frequently downregulated in human primary pituitary adenomas and is negatively correlated with tumor progression. However, the significance and mechanism of H19 in the DA treatment of prolactinomas are still unknown. In this study, we reported that H19 had a synergistic effect with DA treatment on prolactinomas in vitro and in vivo. Mechanistically, H19 promoted ATG7 expression in pituitary tumor cells by inhibiting miR-93a expression. In addition, a potential binding site between miR-93 and H19 was confirmed, and low expression of miR-93 was previously found in DA-resistant prolactinomas. Furthermore, we showed that miR-93a regulates ATG7 expression by targeting ATG7 mRNA. In conclusion, our study has identified the role of the H19-miR-93-ATG7 axis in DA treatment of prolactinomas, which may be a potential therapeutic target for human prolactinomas., (Copyright © 2020. Published by Elsevier B.V.)

Prolactinomas are the most common type of functional pituitary adenoma. Although bromocriptine is the preferred first line treatment for prolactinoma, resistance frequently occurs, posing a prominent clinical challenge. Both the prolactin receptor (PRLR) and estrogen receptor α (ERα) serve critical roles in the development and progression of prolactinomas, and whether this interaction between PRLR and ERα contributes to bromocriptine resistance remains to be clarified. In the present study, increased levels of ERα and PRLR protein expression were detected in bromocriptine-resistant prolactinomas and MMQ cells. Prolactin (PRL) and estradiol (E2) were found to exert synergistic effects on prolactinoma cell proliferation. Furthermore, PRL induced the phosphorylation of ERα via the JAK2-PI3K/Akt-MEK/ERK pathway, while estrogen promoted PRLR upregulation via pERα. ERα inhibition abolished E2-induced PRLR upregulation and PRL-induced ERα phosphorylation, and fulvestrant, an ERα inhibitor, restored pituitary adenoma cell sensitivity to bromocriptine by activating JNK-MEK/ERK-p38 MAPK signaling and cyclin D1 downregulation. Collectively, these data suggest that the interaction between the estrogen/ERα and PRL/PRLR pathways may contribute to bromocriptine resistance, and therefore, that combination treatment with fulvestrant and bromocriptine (as opposed to either drug alone) may exert potent antitumor effects on bromocriptine-resistant prolactinomas., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Background: The '3PAs' syndrome, associating pituitary adenoma (PA) and pheochromocytoma/paraganglioma (PPGL), is sometimes associated with mutations in PPGL-predisposing genes, such as SDHx or MAX. In '3PAs' syndrome, PAs can occur before PPGL, suggesting a new gateway into SDHx/MAX-related diseases., Objective: To determine the SDHx/MAX mutation prevalence in patients with isolated PAs and characterize PAs of patients with SDHx/MAX mutations., Design: Genes involved in PAs (AIP/MEN1/CDKN1B) or PPGLs (SDHx/MAX) were sequenced in patients with isolated PAs. We then conducted a review of cases of PA in the setting of '3PAs' syndrome., Results: A total of 263 patients were recruited. Seven (likely) pathogenic variants were found in AIP, two in MEN1, two in SDHA, and one in SDHC. The prevalence of SDHx mutations reached 1.1% (3/263). Of 31 reported patients with PAs harboring SDHx/MAX mutations (28 published cases and 3 cases reported here), 6/31 (19%) developed PA before PPGL and 8/31 (26%) had isolated PA. The age of onset was later than in patients with AIP/MEN1 mutations. PAs were mainly macroprolactinomas and showed intracytoplasmic vacuoles seen on histopathology., Conclusions: We discovered SDHx mutations in patients bearing PA who had no familial or personal history of PPGL. However, the question of incidental association remains unresolved and data to determine the benefit of SDHx/MAX screening in these patients are lacking. We recommend that patients with isolated PA should be carefully examined for a family history of PPGLs. A family history of PPGL, as well as the presence of intracytoplasmic vacuoles in PA, requires SDHx/MAX genetic testing of patients.

Background: The specific underlying pathogenesis of prolactinoma has not been clarified yet, to the best of our knowledge. p38 mitogen-activated protein kinase (MAPK) signaling including p38α MAPK (MAPK14), p38β (MAPK11), p38γ (MAPK12) and p38δ (MAPK13) is associated with the development and progression of several types of cancer., Methods: Immunofluorescence analysis was performed on the prolactin (PRL) and MAPK14 expressions of pituitary gland in C57BL/6 mice and human prolactinoma specimen. In the present study, the role of MAPK14 in prolactinoma was determined using estradiol-induced mice and dopamine D2 receptor knockout (DRD2 -/- ) mice models in C57BL/6 wild-type (WT), MAPK14 -/- and DRD2 -/- MAPK14 +/- mice. GH3 cells were transfected with different sets of MAPK14 small interfering RNA, which to study MAPK14 and PRL expression in GH3 cells., Results: Immunofluorescence analysis showed that PRL and MAPK14 expression were colocalized and increased in the pituitary gland of mice and human prolactinoma specimen compared with the control specimen. It was shown that PRL and MAPK14 expression was colocalized and increased significantly in the pituitary gland of estradiol-injected prolactinoma mice compared with the control mice. Knockout of MAPK14 significantly inhibited tumor overgrowth, and PRL expression was decreased in estradiol-induced mice. Furthermore, MAPK14 knockout of DRD2 -/- MAPK14 +/- mice significantly reduced the overgrowth of pituitary gland and PRL production and secretion compared with DRD2 -/- mice. MAPK14 knockout using siRNA inhibited PRL production in GH3 cells., Conclusion: These results suggest that MAPK14 serves a promoting role in the formation of prolactinoma, and highlights the potential of MAPK14 as a potential therapeutic target in the treatment of prolactinoma.

Pituitary adenoma (PA) is one of the most common intracranial tumors, and approximately 40% of all PAs are prolactinomas. Dopamine agonists (DAs), such as cabergoline (CAB), have been successfully used in the treatment of prolactinomas. The expression of dopamine type 2 receptor (DRD2) determines the therapeutic effect of DAs, but the molecular mechanisms of DRD2 regulation are not fully understood. In this study, we first demonstrated that DRD2 underwent proteasome-mediated degradation. We further employed the yeast two-hybrid system and identified kelch repeat and BTB (POZ) domain containing 7 (KBTBD7), a substrate adaptor for the CUL3-RING ubiquitin (Ub) ligase complex, as a DRD2-interacting protein. KBTBD6/7 directly interacted with, and ubiquitinated DRD2 at five ubiquitination sites (K221, K226, K241, K251, and K258). CAB, a high-affinity DRD2 agonist, induced DRD2 internalization, and cytoplasmic DRD2 was degraded via ubiquitination under the control of KBTBD6/7, the activity of which attenuated CAB-mediated inhibition of the AKT/mTOR pathway. KBTBD7 knockout (KO) mice were generated using the CRISPR-Cas9 technique, in which the static level of DRD2 protein was elevated in the pituitary gland, thalamus, and heart, compared to that of WT mice. Consistently, the expression of KBTBD6/7 was negatively correlated with that of DRD2 in human pituitary tumors. Moreover, KBTBD7 was highly expressed in dopamine-resistant prolactinomas, but at low levels in dopamine-sensitive prolactinomas. Knockdown of KBTBD6/7 sensitized MMQ cells and primary pituitary tumor cells to CAB treatment. Conversely, KBTBD7 overexpression increased CAB resistance of estrogen-induced in situ rat prolactinoma model. Together, our findings have uncovered the novel mechanism of DRD2 protein degradation and shown that the KBTBD6/7-DRD2 axis regulates PA sensitivity to DA treatment. KBTBD6/7 may thus become a promising therapeutic target for pituitary tumors.

There can potentially be a number of clinical interactions that could adversely affect patient outcomes in a patient with a prolactinoma and psychiatric disease that might require antipsychotic and dopamine agonist treatment. Dopamine agonists stimulate the dopamine D2 receptor, resulting in a decrease in prolactin (PRL) levels and in prolactinoma size but action on dopamine receptors in the meso-limbic system may rarely cause psychosis and more commonly cause impulse control disorders. The psychiatric benefits of antipsychotic agents involve blocking the D2 and other dopamine receptors but this blockade often also causes hyperprolactinemia. In patients with macroprolactinomas and psychosis, observation, estrogen/progestin replacement, and surgery can be considered in addition to dopamine agonists. In those who require dopamine agonists for PRL and tumor size control, the introduction of antipsychotics may blunt this effect, so that higher doses of the dopamine agonists may be needed. Alternatively, antipsychotics that have less of a blocking effect at the D2 receptor, such as aripiprazole, can be tried, if appropriate. For patients already on antipsychotic drugs who are found to have a macroprolactinoma for which dopamine agonists are required, dopamine agonists can be initiated at low dose and the dose escalated slowly. However, such patients require careful monitoring of psychiatric status to avoid the rare complication of exacerbation of the underlying psychosis. Again, if appropriate, use of antipsychotics that have less of a blocking effect at the D2 receptor may allow lower doses of dopamine agonists to be used in this situation.

Background/Purpose: A prolactinoma is the most common pituitary adenoma, but it is relatively rare in childhood and adolescence. There is only limited research about the clinical spectrum, treatment, and outcomes of prolactinomas in childhood and adolescence. In this single-center cohort study, we assessed the clinical, hormonal, and neuroradiological characteristics and therapeutic outcomes of children and adolescents with prolactinomas. Methods: This retrospective cohort study included 25 patients with prolactinomas diagnosed before 19 years of age, who presented at Samsung Medical Center during a 15-year period (March 2005 to August 2019). Results: The median age at diagnosis was 16.9 (range 10.1-18.5) years, and 80% of the patients were female. The common clinical manifestations at diagnosis were galactorrhea (10/20, 50%) and amenorrhea (9/20, 45%) among females and visual field defects (3/5, 60%) and headaches (2/5, 40%) among males. In our cohort, macroadenomas accounted for 56% of cases, and the rate of overall responsiveness to dopamine agonists (DAs) was 56% (10/18). Male gender, the prolactin (PRL) level at diagnosis, and the presence of panhypopituitarism were positively correlated with maximum tumor diameter ( r = 0.443, P = 0.026; r = 0.710, P < 0.001; and r = 0.623, P = 0.001, respectively). After the trans-sphenoidal approach (TSA), 53% (8/15) of patients showed normalization of the PRL level. Three patients, who underwent gamma knife surgery (GKS) owing to either resistance or intolerance to DAs or recurrence after the TSA, achieved a normal PRL level accompanied with marked tumor reduction and symptom remission. Conclusions: A macroprolactinoma is more prevalent than a microprolactinoma in children and adolescents than in adults. Male gender, increased PRL levels, and the presence of panhypopituitarism at diagnosis are closely related to macroprolactinomas in children and adolescents., (Copyright © 2020 Yang, Cho, Park, Kim, Kong, Shin and Jin.)

Purpose: Aggressive pituitary adenomas (APAs) and pituitary carcinomas (PCs) are challenging for their invasive nature, resistance to treatment and recurrences. Temozolomide (TMZ) is used with benefit and well-tolerated toxicity profile in APAs and PCs. In most studies patients received ≤ 12 cycles but the best length of treatment is debated since other options after discontinuation are scarce and a second course is mainly unsuccessful., Methods: We report outcomes of 8 patients with APAs and PCs treated with TMZ for more than 12 continuous cycles with a literature review. Data were retrospectively collected from Padua and Milan University Hospitals. TMZ was used as a single agent (150-200 p.o. mg/m2 daily, 5/28 days) for 14 to 45 cycles., Results: Eight patients (7 M), 7 APAs and 1 PC. Previous treatments included neurosurgery and radiotherapy in all cases except two giant masses (ACTH-silent APA and prolactinoma). No patient had progression disease (PD) during long-term treatment nor toxicities. No one had complete response (CR) but four had partial response (PR). Four ACTH+ tumors maintained stable disease (SD) but the secretion pattern improved in all. After drug withdrawal, three had delayed PD (2 after 18 and one after 29 months, all ACTH+); two are still in SD., Conclusions: TMZ may be useful and well-tolerated in APAs and PCs as a long-term therapy. PR appears within the first cycles with no escape throughout the treatment; most patients achieve SD. We suggest extended protocols particularly in responsive ACTH+  PAs and PCs, when further therapies may be unsuccessful.

Context: In patients treated with antipsychotics, the rare occurrence of a macroprolactinoma represents a therapeutic challenge., Objective: Our aim was to evaluate the efficacy and psychiatric safety of dopamine agonists (DAs) prescribed for large macroprolactinomas in patients with psychosis treated with antipsychotics., Design: This was a multicenter (France and Belgium) retrospective study., Patients: Eighteen patients treated with antipsychotics were included., Results: Under DA, median PRL levels decreased from 1247 (117-81 132) to 42 (4-573) ng/mL (P = 0.008), from 3850 (449-38 000) to 141 (60-6000) ng/mL (P = 0.037) and from 1664 (94-9400) to 1215 (48-5640) ng/mL (P = 0.56) when given alone (n = 8), before surgery (n = 7), or after surgery (n = 6), respectively. The prolactinoma median largest diameter decreased by 28% (0-57) in patients under DAs alone (P = 0.02) but did not change when given after surgery. Optic chiasm decompression was achieved in 82% of patients. Five patients (28%) were admitted for psychotic relapse while receiving DAs (but three of them had stopped antipsychotic treatment at that time). A more severe underlying psychosis, rather than the DA treatment itself, may explain such psychiatric admissions., Conclusions: Even if the DA efficacy on PRL levels and tumor volume in patients with macroprolactinoma under antipsychotic drugs is less impressive than that typically observed, it may be considered satisfactory for half of our patients, particularly in cases of optic chiasm compression. Psychotic exacerbation was unusual in these patients, occurring mostly in those with the most severe psychotic forms. DAs may therefore be used as antitumor treatment for macroprolactinoma in patients with visual involvement, severe headaches or invasion into the skull base who receive antipsychotics., (© 2020 European Society of Endocrinology.)

Background and Objective: Most patients with prolactinomas receive pharmacological treatment only, resulting in limited research on the predictors of successful prolactinoma surgery. In this study, we analyzed whether early postoperative serum prolactin concentrations and selected tumor characteristics could predict early, hormonal remission after removal of prolactinomas. Methods: We prospectively enrolled 48 consecutive patients with prolactinomas who underwent transsphenoidal resection performed by the same surgeon. Early remission, defined as a lack of hyperprolactinemia symptoms and normalization of serum prolactin concentration, was ascertained in all patients at 3 months. We evaluated the invasiveness of prolactinomas on the Knosp grading scale and measured serum prolactin concentrations on the first postoperative day. Routine immunohistochemical analysis, evaluation for plurihormonality, and assessment of the Ki-67 proliferation index (<3 or ≥3% of positive nuclei) were performed in all tumor samples. Results: Of 48 patients, 38 (79%) achieved early biochemical remission at 3 months. Patients in early remission at 3 months had lower serum prolactin concentrations on the first postoperative day than patients with recurrent or persistent hyperprolactinemia ( p < 0.001). Using univariate logistic regression, larger maximum tumor diameter ( p = 0.014), higher Knosp grade ( p < 0.001), and plurihormonality predicted remission at 3 months ( p = 0.021). However, using multivariate stepwise logistic regression, only the Knosp grade remained significant ( p < 0.001). Conclusions: Radiological assessment of prolactinoma invasiveness (Knosp grades) and early postoperative serum prolactin concentrations are important predictors of early remission following transsphenoidal prolactinoma resection., (Copyright © 2020 Zielinski, Ozdarski, Maksymowicz, Szamotulska and Witek.)

Objective: Our study aimed to investigate miR-193a-3p expression and its clinical significance in pituitary adenomas (PAs). Moreover, the correlation between miR-193a-3p expression and the invasiveness of PAs was explored., Patients and Methods: In this study, the relative expression levels of miR-193a-3p were detected via quantitative Real Time-Polymerase Chain Reaction (qRT-PCR). The correlations between miR-193a-3p and tumor size, clinical features, and prolactinomas postoperative prolactin (PRL) levels early remission were further analyzed., Results: Compared with non-invasive PAs, there was a lower miR-193a-3p expression in invasive PAs. MiR-193a-3p expression had reverse relevance to tumor size. A higher risk of postoperative residual and recurrence was found in patients with downregulated miR-193a-3p. Prolactinomas patients with postoperative PRL levels early remission were at lower risk to relapse and patients with high-expression miR-193a-3p had a higher early remission rate, suggesting that miR-193a-3p was a significant prognostic factor for prolactinomas., Conclusions: MiR-193a-3p could have potential therapeutic value for invasive pituitary adenomas.

Objective: To evaluate the maternal-fetal outcomes of CAB-induced pregnancies in patients with prolactinoma in a large cohort., Methods: The prevalence of tumor growth, miscarriage, preterm, low birth weight, congenital malformations and impairment in neuropsychological development in children among women treated with CAB were assessed in a Brazilian multicentre retrospective observational study, RESULTS: We included 194 women with a mean age of 31 (17-45) years, 43.6% presenting microadenomas and 56.4% macroadenomas, at prolactinoma diagnosis. In 233 pregnancies, CAB was withdrawn in 89%, after pregnancy confirmation. Symptoms related to tumor growth occurred in 25 cases, more frequently in macroadenomas. The overall miscarriage rate was 11%, although higher in the subgroup of patients with CAB maintainance after pregnancy confirmation (38% vs. 7.5%). Amongst the live-birth deliveries, preterm occurred in 12%, low birth weight in 6% and congenital malformations in 4.3%. Neuropsychological development impairment was reported in 7% of cases., Conclusions: Our findings confirm previous results of safety in maternal and fetal outcomes in CAB-induced pregnancies; nevertheless, CAB maintenance after pregnancy confirmation was associated with higher miscarriage rate; result that must be further confirmed.

Estrogen signaling plays an important role in pituitary development and function. In sensitive rat or mice strains of both sexes, estrogen treatments promote lactotropic cell proliferation and induce the formation of pituitary adenomas (dominantly prolactin or growth-hormone-secreting ones). In male patients receiving estrogen, treatment does not necessarily result in pituitary hyperplasia, hyperprolactinemia or adenoma development. In this review, we comprehensively analyze the mechanisms of estrogen action upon their application in male animal models comparing it with available data in human subjects. Sex-specific molecular targets of estrogen action in lactotropic (PRL) cells are highlighted in the context of their proliferative and secretory activity. In addition, putative effects of estradiol on the cellular/tumor microenvironment and the contribution of postnatal pituitary progenitor/stem cells and transdifferentiation processes to prolactinoma development have been analyzed. Finally, estrogen-induced morphological and hormone-secreting changes in pituitary thyrotropic (TSH) and adrenocorticotropic (ACTH) cells are discussed, as well as the putative role of the thyroid and/or glucocorticoid hormones in prolactinoma development, based on the current scarce literature.

Objective: Drug resistance is the main limitation for dopamine agonist therapy with prolactinoma. Transsphenoidal surgery is an additional operation that circumvents this limitation. To characterize distinctive clinical features of resistant prolactinoma in different levels of Ki-67, a retrospective analysis of 423 patients who were diagnosed and surgically treated at Shandong Provincial Hospital Affiliated to Shandong University from January 2007 to June 2017 was performed., Methods: Patients were subdivided into Ki-67≥3% group (High) and Ki-67<3% group (Low) according to Ki-67 labeling values., Results: Tumors in the High group were larger ( P =0.001), associated with more frequent headaches and dizziness ( P =0.004), more visual impairment ( P =0.008), more polyuria and polydipsia ( P =0.029), and had a higher percentage of invasion ( P =0.003) than patients in the Low group. However, the prolactin normalization rate in the High group was significantly lower ( P =0.042). More frequent recurrence was observed in the High group ( P =0.018)., Conclusions: These observations suggest the importance of investigating Ki-67 in patients with resistant prolactinoma. The treatment of resistant prolactinomas with higher level of Ki-67 is still a challenge., (© 2020 by the Association of Clinical Scientists, Inc.)

Context: The improved remission and complication rates of current transsphenoidal surgery warrant reappraisal of the position of surgery as a viable alternative to dopamine agonists in the treatment algorithm of prolactinomas., Objective: To compare clinical outcomes after dopamine agonist withdrawal and transsphenoidal surgery in prolactinoma patients., Methods: Eight databases were searched up to July 13, 2018. Primary outcome was disease remission after drug withdrawal or surgery. Secondary outcomes were biochemical control and side effects during dopamine agonist treatment and postoperative complications. Fixed- or random-effects meta-analysis was performed to estimate pooled proportions. Robustness of results was assessed by sensitivity analyses., Results: A total of 1469 articles were screened: 55 (10 low risk of bias) on medical treatment (n = 3564 patients) and 25 (12 low risk of bias) on transsphenoidal surgery (n = 1836 patients). Long-term disease remission after dopamine agonist withdrawal was 34% (95% confidence interval [CI], 26-46) and 67% (95% CI, 60-74) after surgery. Subgroup analysis of microprolactinomas showed 36% (95% CI, 21-52) disease remission after dopamine agonist withdrawal, and 83% (95% CI, 76-90) after surgery. Biochemical control was achieved in 81% (95% CI, 75-87) of patients during dopamine agonists with side effects in 26% (95% CI, 13-41). Transsphenoidal surgery resulted in 0% mortality, 2% (95% CI, 0-5) permanent diabetes insipidus, and 3% (95% CI, 2-5) cerebrospinal fluid leakage. Multiple sensitivity analyses yielded similar results., Conclusions: In the majority of prolactinoma patients, disease remission can be achieved through surgery, with low risks of long-term surgical complications, and disease remission is less often achieved with dopamine agonists., (© Endocrine Society 2019.)

Background: The prevalence of sellar masses (SMs) is reported in Europe and North America but only limited data are available from the Middle East and North Africa (MENA) region., Objectives: Assess the prevalence and characteristics of SMs in Al Ain city, United Arab Emirates., Design: Retrospective, descriptive multicenter study., Setting: Three endocrine centers in Al Ain., Patients and Methods: All patients diagnosed with SMs in the city of Al Ain, Emirate of Abu Dhabi, between 2011 and 2016 were evaluated. Cases were identified using ICD 9 and 10 codes and demographic and clinical data were collected. The prevalence rate was calculated for patients alive and residing in Al Ain city until 31 December 2016., Main Outcome Measures: Clinical presentations and prevalence rate., Sample Size: 272., Results: The mean (SD) age on presentation was 40.8 (14.3) years (range: 6-114 years, median: 40.0). The 170 (61.8%) females and 128 (46.5%) were native citizens of the United Arab Emirates. Two hundred and forty five (90%) patients had pituitary adenomas (PAs) while 27 (10%) had non-pituitary sellar lesions. The four most common SMs were prolactinoma (n=139, 51.1%), nonfunctioning adenoma (NFA) (n= 69, 25.4%), somatotroph adenoma (n=32, 11.8%) and craniopharyngioma (n=15, 5.5%). Patients with prolactinoma, corticotroph adenoma, and Rathke's cleft cyst had small sellar masses (<1 centimeter) while the majority of patients with other SMs had macroadenomas. Hypogonadism and growth hormone deficiency was present in 41.8% and 20.5% of the patients, respectively. Of 268 patients with available data, 82 patients underwent surgery while 25 patients received radiotherapy. At the end of 2016, 197 patients were residing in Al Ain city. The overall prevalence of SMs was 25.7/100 000 with PAs constituting most of these masses (n=177) for a prevalence of 23.1/100 000., Conclusions: This is the first study of SMs in the United Arab Emirates and the MENA region. Prolactinoma and NFA were the two most common SMs. Further studies are needed to explore the reasons for the lower prevalence of SMs in our region compared with other countries., Limitations: Retrospective design, relatively small sample size., Conflict of Interest: None.

Objective: The association between prolactin level variation and prolactinoma size reduction remains unclear. This study aimed to determine the prolactin level cut-off predictive of a tumor size reduction., Design: Retrospective cohort study., Methods: We reviewed medical records of patients with prolactinoma who received primary cabergoline therapy and for whom complete data on pituitary hormone assays and sellar MRI at baseline and 3 months post treatment were available. We tested whether the certain prolactin level after 3 months post treatment predicted better response., Results: Prolactin levels normalized in 109 (88.6%) of 123 included macroprolactinoma patients. The mean tumor size reduction was 22.9%, and patients in the lowest prolactin tertile (≤0.7) had the highest frequency of tumor size reductions of ≥20% (73.7 vs 52.9% and 45.9% in tertiles 2 (>0.7 to 2.6) and 3 (>2.6 to 20), P = 0.015). Patients with prolactin levels ≤1 ng/mL exhibited larger tumor size reductions vs those with prolactin levels of 1-20 (27.2 ± 18.3% vs 19.5 ± 13.9%, P = 0.014), 1-10 (19.3 ± 13.7%, P = 0.017) and 1-5 ng/mL (19.2 ± 14.3%, P = 0.039). A multivariable logistic regression analysis revealed that a prolactin level ≤1 ng/mL at 3 months and high-dose cabergoline therapy were significantly associated with tumor size reductions of ≥20% (odds ratio (OR): 2.8, 95% confidence interval (CI): 1.2-6.7, P = 0.017; OR: 2.0, 95% CI: 1.0-3.9, P = 0.043)., Conclusions: A prolactin level ≤1 ng/mL at 3 months after cabergoline treatment was correlated with a significant tumor size reduction in patients with macroprolactinoma. This finding may help clinical decision making when treating macroprolactinoma patients.

17β-estradiol (E2) is considered to be an important instigator of prolactinoma, and can positively regulate the expression of calbindin-D9k (CaBP-9k) which contains an estrogen responsive element (ERE) via estrogen receptors (ERs). However, the detailed mechanism of E2 in promoting CaBP-9k expression and their roles in prolactinoma progression remain unclear. Here, we aimed to characterize it. The luciferase gene reporter assay with luc-ERE transfection showed that E2 treatment significantly enhanced the transcriptional level of CaBP-9k, whereas CaBP-9k activity was reduced when GH3 and MMQ cells were treated with AZD9496, an antagonist of ERα. E2 treatment increased the protein expressions of CaBP-9k and ERα but not ERβ, whereas this effect was also abolished when cells were treated with AZD9496. Besides, immunoprecipitation (IP) and immunofluorescence assays demonstrated that CaBP-9k could directly interact with ERα not ERβ, and Chromatin IP (ChIP) assay showed that ERα could bind to ERE of the CaBP-9k promoter. Moreover, cell counting kit-8 (CCK-8) and flow cytometry assays showed that E2 treatment significantly enhanced cell viability and inhibited cell apoptosis, but these effects were all abolished when ERα was down-regulated by short hairpin RNA (shRNA) or inhibited by AZD9496, as well as CaBP-9K suppression in both GH3 and MMQ cell lines. Taken together, these findings indicated that E2 stimulation promoted prolactin cell proliferation and inhibited cell apoptosis through ERα-induced CaBP-9k up-regulation, which then accelerated the advanced progression of prolactinoma., (© 2020 The Author(s).)

Introduction: Approximately one third of pituitary adenomas are manifested neither by specific symptoms of hormone overproduction nor by elevated blood levels of pituitary hormones. However, these tumours, diagnosed before surgical intervention as clinically non-functioning pituitary adenomas (CNFPAs) express in majority different pituitary hormones, as can be revealed by means of immunohistochemical examination. One of the pituitary hormones which may be expressed in CNFPAs is prolactin (PRL) but the clinical and pathological data on this condition are very scarce., Material and Methods: Sixty two pituitary adenomas, diagnosed before surgery as CNFPAs, were immunoassayed with antibodies against PRL, growth hormone (GH), luteinizing hormone (LH), follicle stimulating hormone (FSH), thyrotropin (TSH), alpha subunit (alpha-SU), corticotropin (ACTH) and dopamine receptor type 2. In a proportion of the patients the presurgical concentrations of insulin-like growth factor 1 (IGF-1) were estimated by means of enzyme-amplified chemiluminescence assay., Results: Twenty-three (37.1%) of the examined CNFPAs presented the positive immunoreaction with anti-PRL antibody. Most cases concerned women. Only in two cases (one woman and one man), PRL was the unique hormone expressed in the tumour. In the remaining adenomas PRL immunopositivity was accompanied by GH expression - 17, LH or free bLH - 13, FSH - 2, free a subunit - 4 or by ACTH - 5 tumours. Seven (30.43%) of them were recurrent in comparison with 12.8% PRL-immunonegative recurrent CNFPAs. Dopamine receptors were positively immunostained in all the investigated PRL-immunopositive and all PRL-immunonegative adenomas., Conclusions: Our data confirm the observations that monohormonal silent prolactinomas are very rare but frequently silent PRL often co-expressed with GH or LH. Although in the whole population of patients with CNFPAs both sexes are equally represented, in the case of silent prolactinomas the female sex is prevalent. The observation of the higher rate of recurrent tumours within PRL-immunopositive adenomas versus PRL-immunonegative CNFPAs has to be confirmed on the larger material.

Context: Prolactinomas are the most common functional pituitary adenomas; the aggressive tumors still present challenge to clinicians. Aberrant expression of miRNAs has been functionally associated with prolactinomas., Objective: Here we explored the role of miR-137 on the proliferation, invasion, and apoptosis of prolactinomas and its possible mechanism., Results: Low expression of miR-137 was correlated with the invasive behavior of human prolactinomas and predicted high recurrence. MiR-137 inhibited cell proliferation, invasion, and survivals of MMQ and GH3 cells and reduced tumor volume in F344 rat prolactinomas. The luciferase reporter assay confirmed that microphthalmia-associated transcription factor (MITF) was the direct target of miR-137. In addition, miR-137 mimics could inhibit MITF expression in vivo and in vitro. Upregulation of MITF expression promoted cell proliferation, invasion, and survivals and reversed the antitumor effect of miR-137 in vivo and in vitro. Furthermore, miR-137 could also upregulate wnt-inhibitory factor-1 and inhibit nuclear translocation of β-catenin. Upregulation of wnt-inhibitory factor-1 with decitabine can enhance the inhibition on cell proliferation of miR-137. A glycogen synthase kinase-3 inhibitor, SB 216763, promoted cell proliferation by upregulation of total/cytoplasmic/nuclear β-catenin and reversed tumor suppression of miR-137 mimics., Conclusions: Our data suggest that miR-137 possesses a tumor invasive suppressor function with a prognostic value in prolactinomas by targeting MITF and modulating Wnt-β-catenin signaling pathway., (Copyright © 2019 Endocrine Society.)

Introduction: Pediatric pituitary adenomas are rare lesions. Incidence is reported between 1 and 10% of all childhood brain tumors and between 3 and 6% of all surgically treated adenomas. Although pituitary adenomas present with symptoms of hormone hypersecretion or neurological disruptions secondary to mass effect, they are almost constantly benign. Characteristics of patients may vary in different studies according to age, gender, size of adenoma, hormonal activity, and recurrence rates., Methods: Data on consecutive pediatric patients who were operated for pituitary adenoma with endoscopic endonasal transsphenoidal surgery (EETS) and transsphenoidal microsurgery (TMS) in the Department of Neurosurgery, Istanbul University Cerrahpasa Medical Faculty, Istanbul, Turkey, in the Neurosurgical Unit of the San Matteo Hospital, Pavia, Italy, and in the Division of Neurological Surgery Department of Biotechnology and Life Sciences, University of Insubria-Varese, ASST Sette Laghi, Ospedale di Circolo e Fondazione Macchi, Varese, Italy, between July 1997 and May 2018, were analyzed. Twenty-seven patients (11 males and 16 females), who were 18 years old or younger at the time of surgery, were included in the study. Medical records, images, and operative notes of patients were retrospectively reviewed., Results: There were 16 females (59.3%) and 11 males (40.7%). Mean age was 15.3 ± 3.3 (4-18). Thirty-two surgical procedures were performed for 27 patients (6 children required second operation). Thirteen patients (48.14%) had Cushing's disease (CD), 5 patients (18.5%) had growth hormone (GH)-secreting adenoma, 5 patients (18.5%) had prolactinoma, and 4 patients (14.8%) had non-functional adenoma. Twenty-two patients (81.4%) met remission criteria, and 5 patients (18.5%) did not meet remission criteria. Four patients met remission criteria after the second operation., Conclusion: Transsphenoidal approach affords effective release of mass effect and not only restoration but also perpetuation of normal endocrine functions in the majority of pediatric pituitary adenoma patients. Satisfactory results are reported with both EETS and TMS in the literature. Despite the technical difficulties in pediatric age, transsphenoidal resection of adenoma is still the mainstay treatment that provides cure in pediatric patients.

Context: Multiple endocrine neoplasia 1 (MEN 1) is an autosomal dominant disease presenting as hyperplasia and neoplasia of parathyroid, pituitary and enteropancreatic tissues. Over 90% of gene carriers develop phenotypic disease by age 30 years, potentially with onset of asymptomatic disease during childhood and adolescence., Objective: To describe the paediatric and young adult manifestations of MEN 1., Design: Descriptive retrospective study of 180 patients with a common MEN1 genotype. The paediatric and young adult (age <22 years) manifestations were determined using hospital records and disease surveillance data., Results: Primary hyperparathyroidism (PHPT) was identified in 42 patients (mean age 17.2 ± 3.3 years). Parathyroidectomy was performed in 16 (38.1%; mean age 17.8 ± 3.2). Four patients experienced recurrent PHPT (25%), and six (37.5%) developed permanent hypoparathyroidism. Pituitary disease was identified in 13 patients. Prolactinoma was found in nine patients (mean age 16.6 ± 2.6 years) of whom four (44.4%) had macroprolactinoma. Two patients required surgical intervention; dopamine agonists showed efficacy in six patients. Two patients with Cushing's disease were successfully treated surgically. Three patients with nonfunctioning pituitary microadenoma managed conservatively. Pancreatic neuroendocrine neoplasms (pNENs) were diagnosed in 12 patients (mean age 17.0 ± 2.6 years): three patients with insulinoma successfully resected (two resected and one exhibiting perineural invasion) and nine patients with nonfunctioning adenomas (NFAs)., Conclusion: Pituitary adenomas, PHPT and pNENs are encountered in the paediatric and young adult MEN 1 population. Successful outcomes are typically achieved using standard medical and surgical paradigms; however, parathyroidectomy was associated with a substantial complication rate., (© 2019 John Wiley & Sons Ltd.)

Background: Current standard treatment of microprolactinomas is dopamine agonist therapy. As this drug treatment is lifelong in up to 80% of cases, many patients consult pituitary surgeons regarding a surgical alternative., Objective: To identify prognostic criteria for surgical remission, we reviewed outcomes of our series of microprolactinomas treated with endoscopic transsphenoidal surgery, with a special emphasis on magnetic resonance adenoma delineation and position., Methods: Our study cohort comprises a single center series of 60 patients operated for histopathologically verified magnetic resonance imaging unequivocally identifiable endosellar microprolactinoma between 2003 and 2017. In 31 patients the adenoma was enclosed by pituitary gland (group ENC), in 29 patients the adenoma was located lateral to the gland adherent to the medial cavernous sinus wall (group LAT)., Results: After a mean follow-up of 37 mo (range 4-143 mo), remission rate was significantly higher in adenomas enclosed by pituitary gland (group ENC) than adenomas located lateral to the gland (group LAT), with 87% vs 45%, P = .01. Intraoperatively, 4 patients showed signs of invasiveness. Preoperative prolactin levels did not differ between the groups (mean 155 and 187 ng/ml in group ENC and LAT, respectively).A binary logistic regression model revealed that only the radiological criteria applied showed a significant correlation (P = .003) with endocrine remission., Conclusion: According to our results, remission rate is significantly higher in microprolactinomas enclosed by the pituitary gland. However, the decision for surgery should take into account surgeons experience and possibility of complications., (Copyright © 2018 by the Congress of Neurological Surgeons.)

Background Prolactin-secreting pituitary adenomas in childhood and adolescence are rare. First-line therapy consists of dopamine agonists (DAs) like cabergoline. Experience in treating prolactinomas in paediatric and adolescent patients is limited. Methods This study was a retrospective analysis of clinical data, laboratory data, radiological findings and medical treatment of paediatric and adolescent patients with prolactinomas between 2009 and 2018. Results Our cohort of nine patients had a median age at diagnosis of 13 years (range 5-17). Main presenting symptoms were weight gain, disorders of the pituitary-gonadal axis and headache. Treatment with cabergoline resulted in a marked reduction in prolactin concentration in all nine patients. Tumour mass reduction was confirmed by magnetic resonance imaging (MRI) scan in seven patients. Noteworthy is that cabergoline therapy triggered frequent adverse effects in a total of eight patients - seven of whom suffered from mental disorders, five of whom had neurological symptoms and five of whom had gastrointestinal problems. The adverse effects occurred at a median dose of only 0.5 mg/week (range 0.25-2.0). Most symptoms were alleviated after the cabergoline dose was lowered. Therapy discontinuation was not necessary in any patient. Conclusions Cabergoline effectively lowers prolactin levels and may reduce tumour mass in paediatric and adolescent patients with prolactinomas. Potential adverse effects may include mental disorders and behavioural problems even at low cabergoline doses. Low starting doses and careful individual dose adjustments are required to enable therapy adherence.

Objective Current recommendations for cochlear hydrops treatment include systemic glucocorticoids and diuretics. Cochlear cells express dopamine receptors, although their role is unknown in the pathophysiology of cochlear hydrops. Case Description We report the case of remission of recurrent right-sided cochlear hydrops in a young male patient treated with bromocriptine due to pituitary macroprolactinoma. Transient improvement was observed after oral steroid and diuretic treatment, but cochlear hydrops recurred until the dose of bromocriptine was increased to 10 mg daily. Conclusion Bromocriptine may stimulate dopamine receptors in cochlear cells with potential therapeutic role in patients with cochlear hydrops. There are no widely accepted and effective treatments for endolymphatic hydrops, and identifying potential new and efficacious therapeutics is of high relevance.

DEP domain-containing mechanistic target of rapamycin (mTOR)-interacting protein (DEPTOR) is an important modulator of mTOR, a highly conserved kinase whose hyperactivation is critically involved in a variety of human tumors. The role of DEPTOR playing in pituitary adenoma (PA) is largely unknown. Here, we reported that DEPTOR was downregulated in PA tissues, especially dopamine-resistant prolactinomas. Consistently, overexpression of DEPTOR inhibited pituitary tumor GH3 and MMQ cells proliferation in vitro and in vivo, and sensitized GH3 and MMQ cells to cabergoline (CAB), a dopamine agonist (DA). Conversely, knockdown of DEPTOR promoted GH3 and MMQ cells proliferation, and conferred cells resistance to CAB. Mechanistically, DEPTOR inhibited both mTOR Complex 1 (mTORC1) and 2 (mTORC2) activities in PA cells. In addition, DEPTOR expression level was increased to suppress mTOR kinase activity via decreasing E3 ubiquitin ligase, βTrCP1, in response to CAB. Furthermore, DEPTOR enhanced autophagy-dependent cell death to confer cells sensitivity to CAB. Taken together, our results suggest that DEPTOR may be a potential target for the treatment of PAs., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Objective: First-line treatment for prolactin-producing pituitary adenomas is dopamine agonist (DA) therapy. This is the first study to analyze the rate of radiographic and hormonal regression of prolactinomas in response to DA therapy to better understand what time frame we consider DA treatment failure., Methods: We searched the electronic medical records of 3 tertiary care medical institutions for patients with prolactinomas. The primary outcome was tumor volume and prolactin (PRL) levels at various time points. The secondary outcome was indicators of treatment failure. Modeling by both linear and exponential models was tested to determine potential predictors of response magnitude and treatment failure by multivariate and regression analyses respectively., Results: There were 99 patients (53% male) included in this analysis. The mean patient age was 42.7 years ± 14.5, and mean width/volume of tumor at diagnosis was 12.3 mm and 1.3 cm 3 , respectively. The mean PRL level at diagnosis was 593.2 ng/mL (79-7913). Modeling indicated a plateau at 68.2% initial volume (95% confidence interval 61.7-73.5) by 12.6 months and a PRL plateau of 21.4 ng/mL (95% confidence interval 0-92.5) by 3.3 months. Multivariate analyses revealed male sex (odds ratio 0.168; P = 0.036) to be a predictor of faster PRL response to DA therapy., Conclusions: Prolactinomas plateau in PRL levels and the rate of size regression within the first year of DA treatment. Prolactinomas with lack of size regression and failure to reach normalization of PRL levels by 12 months may be considered for other management strategies., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Prolactinoma is a common subtype of pituitary tumors. Dopamine receptor agonists are the preferred treatment for prolactinoma; however, with this therapy, drug resistance often occurs. In our previous work, we found that partial resistant prolactinomas showed increased fibrosis and that the transforming growth factor (TGF)-β1/Smad3 signaling pathway mediated fibrosis and was involved in drug resistance. Additionally, the success of surgery is known to be heavily influenced by the consistency of the pituitary adenoma. Therefore, in this study, we aimed to clarify the mechanisms of fibrosis in prolactinoma. Using high-throughput sequencing for analysis of microRNAs, we found that miR-93-5p was significantly upregulated in prolactinoma samples with a high degree of fibrosis compared with that in samples without fibrosis. Furthermore, we found that miR-93-5p was negatively correlated with the relative expression of Smad7 and positively correlated with the relative expression of TGF-β1 in clinical prolactinoma samples. In addition, luciferase reporter assays showed that miR-93-5p could downregulate the Smad7 gene, an important inhibitor of the TGF-β1/Smad3 signaling pathway, and activate TGF-β1/Smad3 signaling-mediated fibrosis in a feed-forward loop. Moreover, miR-93-5p could enhance the drug resistance of prolactinoma cells by regulation of TGF-β1/Smad3-dependent fibrosis. Taken together, our findings demonstrated that miR-93-5p may be a potential therapeutic target for inhibiting fibrosis and reducing drug resistance in prolactinoma cells., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Pituitary tumors are a heterogeneous group of lesions (usually benign) and proper understanding of the anatomy, physiology, and pathology of the hypothalamic/pituitary region is essential to make an accurate diagnosis and define the essential treatment options (i.e., surgery, medical therapies, and radiotherapy, alone or in combination). Surgery is the primary treatment for acromegaly, Cushing disease, thyroid-stimulating hormone-secreting adenomas, resistant prolactinomas, and nonfunctioning pituitary adenomas causing mass effect. Medical and radiation therapy are reserved in cases in which surgery is not possible or does not provide a complete cure. In the last decades, tremendous innovations (i.e., targeted drugs and refined surgical tools and techniques) have expanded the treatment strategies for pituitary adenomas. We herein report the current indications for and depiction of the surgical techniques in pituitary surgery, review current medical treatments, and provide a glimpse of future possibilities., (Copyright © 2019 Elsevier Inc. All rights reserved.)

As the commonest type of functional pituitary tumor, prolactinoma takes up around 40-60% of functional pituitary tumors. Despite dedications attributed to the treatment of prolactinoma, complete cure remains difficult. Hence, it is of significance to bring to light the underlying mechanism of prolactinoma. Long noncoding RNAs (lncRNAs) are a group of transcripts which can regulate various biological processes. In the present study, we explored an lncRNA that was differentially downregulated in prolactinoma samples. LncRNA clarin 1 antisense RNA 1 (CLRN1-AS1) was downregulated in 42 patient samples and inactivated the Wnt/β-catenin signaling pathway. Functionally, CLRN1-AS1 suppressed cell proliferation, promoted apoptosis, and inhibited autophagy. Subcellular fractionation assay revealed that CLRN1-AS1 was located in the cytoplasm of prolactinoma cells. Based on bioinformatics analysis and mechanism experiments, we determined that CLRN1-AS1 acted as a competing endogenous RNA (ceRNA) by sponging miR-217 to upregulate the dickkopf WNT signaling pathway inhibitor 1 (DKK1). Furthermore, Forkhead box P1 (FOXP1) was verified to be a transcription suppressor of CLRN1-AS1. In summary, this study revealed that FOXP1-induced CLRN1-AS1 regulated cellular functions in pituitary prolactinoma by sponging miR-217 to release the DKK1/Wnt/β-catenin signaling pathway.