Functional Pituitary Adenomas Research Articles

T5224, RSPO2 and AZD5363 are novel drugs against functional pituitary adenoma.

We tested whether the drugs T5224, RSPO2, and AZD5363 exert therapeutic effects against functioning pituitary adenoma (FPA). We analysed the gene expression profiles of four FPA mRNA microarray datasets (GSE2175, GSE26966, GSE36314, and GSE37153) from the Gene Expression Omnibus database and identified genes differentially expressed in FPA vs control tissues. We then carried out Gene Ontology, Kyoto Encyclopedia of Genes and Genomes (KEGG), and protein-protein interaction network analyses. We also measured the difference in expression of hub genes between human normal pituitary cells and FPA cells using qRT-PCR. Our in vitro colony-formation and MTT assays showed that cell viability, number, and the size of clonogenicities were all lower in the presence of T5224, RSPO2, or AZD536 than in controls. Moreover, flow cytometry experiments showed that the incidence of apoptosis was higher in the presence of T5224, RSPO2, or AZD5363 than among controls, and was increased by increasing the doses of the drugs. This suggests these drugs could be used as therapeutic agents to treat FPA. Finally, we found that cFos, WNT5A, NCAM1, JUP, AKT3, and ADCY1 are abnormally expressed in FPA cells compared to controls, which highlights these genes as potential prognostic and/or therapeutic targets.

Association of Acromegaly and Central Sleep Apnea Syndrome.

Acromegaly is usually characterized by the excessive secretion of growth hormone (GH) after the closure of epiphyseal plaques, resulting from functional pituitary adenomas. The most common manifestations of acromegaly are acral and soft tissue overgrowth, diabetes mellitus, hypertension, and heart and respiratory failure. In patients, obstruction of the upper airway may develop due to enlargement of the tongue and thickening of the tissues of the larynx; consequently, obstructive sleep apnea syndrome (OSAS) occurs commonly in acromegaly. Previous studies have shown an association between acromegaly and central sleep apnea syndrome (CSAS). Some of these described patients described showed that an elevation in the GH level may cause a defect in the respiratory drive. Most systemic diseases seen in acromegaly require effective treatment. We believe that it is necessary to perform effective treatments by examining respiratory disorders in sleep.

Development and validation of an MRI-based radiomic signature for the preoperative prediction of treatment response in patients with invasive functional pituitary adenoma

PurposeThe preoperative prediction of treatment response is important for determining individual treatment strategies for invasive functional pituitary adenoma (IFPA). This study aimed to develop and validate a magnetic resonance imaging (MRI)-based radiomic signature for preoperative prediction of treatment response in IFPA. MethodOne hundred and sixty-three patients with IFPA were enrolled and divided into primary (n = 108) and validation cohorts (n = 55) according to time point. IFPA patients were divided into remission and non-remission according to postoperative hormone levels. Radiomic features were extracted from their MR images and a radiomic signature was built using a support vector machine. Subsequently, multivariable logistic regression analysis was used to select the most informative clinical features, and a radiomic model incorporating the radiomic signature and selected clinical features was constructed and used as the final predictive model. ResultsSeven radiomic features were selected to construct the radiomic signature, which achieved an area under the curve (AUC) of 0.834 and 0.808 on the primary and validation cohorts respectively. The radiomic model incorporating the radiomic signature and Knosp grade showed good discrimination abilities and calibration, with AUCs of 0.832 and 0.811 for the primary and validation cohorts respectively. The radiomic signature and radiomic model better estimated the treatment responses of patients with IFPA than our clinical features model. Decision curve analysis showed the radiomic model was clinically useful. ConclusionsThis radiomic model may help neurosurgeons predict the treatment responses of patients with IFPA before surgery and determine individual treatment strategies.

Peel-off resection of the pituitary gland for functional pituitary adenomas: pathological significance and impact on pituitary function.

Functional pituitary adenomas (FPAs) lacking a well-defined pseudocapsule can invade the adjacent pituitary gland. In such situations, peel-off resection of the adjacent pituitary gland after selective adenomectomy might lead to complete tumor removal, resulting in optimal endocrinological outcomes. Here, we present the significance of peel-off resection of the pituitary gland in patients with FPA in whom complete extracapsular tumor removal cannot be achieved. We performed a retrospective review of 21 patients with FPA who underwent transsphenoidal surgery (TSS). After selective adenomectomy, peel-off resection of the adjacent pituitary gland was performed in 13 patients because complete extracapsular resection could not be achieved, while peel-off resection was not performed in the remaining 8 patients because complete extracapsular resection was accomplished. The clinical outcomes of these groups were compared. The pituitary tissues obtained by peel-off resection were pathologically examined for tumor cells. Early postoperative biochemical remission was achieved in 20 patients (95.2%). Anterior pituitary functions were not aggravated postoperatively in any patient: however, transient diabetes insipidus (DI) occurred in 2 patients. There were no statistically significant differences in the clinical outcomes of the two groups. A pseudocapsule was pathologically detected in the adjacent anterior pituitary even in patients in whom no pseudocapsule was intraoperatively detected. Tumor cells were pathologically detected in 7 (58.3%) of 12 pituitary tissues examined. Peel-off resection of the pituitary gland, which can remove a small tumor cell remnant in the adjacent pituitary, might maximize the effectiveness of TSS with minimal impact on postoperative pituitary function.

Up-regulation of 15-lipoxygenase enzymes and products in functional and non-functional pituitary adenomas

BackgroundPituitary adenoma accounts as a complex and multifactorial intracranial neoplasm with wide range of clinical symptoms which its underlying molecular mechanism has yet to be determined. The bioactive lipid mediators received attentions toward their contribution in cancer cell proliferation, progression and death. Amongst, 15-Lipoxygense (15-Lox) enzymes and products display appealing role in cancer pathogenesis which their possible effect in pituitary adenoma tumor genesis is perused in the current study.MethodsThe 15-Lipoxygenses isoforms expression level was evaluated in tumor tissues of prevalent functional and non-functional pituitary adenomas and normal pituitary tissues via Real-Time PCR. The circulating levels of 15(S) HETE and 13(S) HODE as 15-Lox main products were assessed in serum of patients and healthy subjects using enzyme immunoassay kits.ResultsOur results revealed that 15-Lox-1 and 15-Lox-2 expression levels were elevated in tumor tissues of pituitary adenomas comparing to normal pituitary tissues. The elevated levels of both isoforms were accompanied with 15(S) HETE and 13(S) HODE elevation in the serum of patients. The 15-Lox-1 expression and activity was higher in invasive tumors as well as tumors with bigger size indicating the possible pro-tumorigenic role of 15-Lox-1, more than 15-Lox-2 in pituitary adenomas. The diagnostic value of 15-Lipoxygense isoforms and products were considerable between patients and healthy groups.ConclusionThe possible involvement of 15-Lipoxygense pathway especially 15-Lox-1 in the regulation of pituitary tumor growth and progression may open up new molecular mechanism regarding pituitary adenoma pathogenesis and might shed light on its new therapeutic strategies.

Near-Infrared Optical Contrast of Skull Base Tumors During Endoscopic Endonasal Surgery.

Near-infrared (NIR) tumor contrast is achieved through the "second-window ICG" technique, which relies on passive accumulation of high doses of indocyaninegreen (ICG) in neoplasms via the enhanced permeability and retention effect. To report early results and potential challenges associated with the application of second-window ICG technique in endonasal endoscopic, ventral skull-base surgery, and to determine potential predictors of NIR signal-to-background ratio (SBR) using endoscopic techniques. Pituitary adenoma (n=8), craniopharyngioma (n=3), and chordoma (n=4) patients received systemic infusions of ICG (5 mg/kg) approximately 24 h before surgery. Dual-channel endoscopy with visible light and NIR overlay were photodocumented and analyzed post hoc. All tumors (adenoma, craniopharyngioma, chordoma) demonstrated NIR positivity and fluoresced with an average SBR of 3.9±0.8, 4.1±1.7, and 2.1±0.6, respectively. Contrast-enhanced T1 signal intensity proved to be the single best predictor of observed SBR (P=.0003). For pituitary adenomas, the sensitivity, specificity, positive predictive value, and negative predictive value of NIR-guided identification of tumor was 100%, 20%, 71%, and 100%, respectively. In this preliminary study of a small set of patients, we demonstrate that second-window ICG can provide NIR optical tumor contrast in 3 types of ventral skull-base tumors. Chordomas demonstrated the weakest NIR signal, suggesting limited utility in those patients. Both nonfunctional and functional pituitary adenomas appear to accumulate ICG, but utility for margin detection for the adenomas is limited by low specificity. Craniopharyngiomas with third ventricular extension appear to be a particularly promising target given the clean brain parenchyma background and strong SBR.

MiR-137's Tumor Suppression on Prolactinomas by Targeting MITF and Modulating Wnt Signaling Pathway.

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. Here we explored the role of miR-137 on the proliferation, invasion, and apoptosis of prolactinomas and its possible mechanism. 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. 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.

Predicting the regrowth of clinically non-functioning pituitary adenoma with a statistical model

BackgroundCompared with clinically functioning pituitary adenoma (FPA), clinically non-functioning pituitary adenoma (NFPA) lacks of detectable hypersecreting serum hormones and related symptoms which make it difficult to predict the prognosis and monitoring for postoperative tumour regrowth. We aim to investigate whether the expression of selected tumour-related proteins and clinical features could be used as tumour markers to effectively predict the regrowth of NFPA.MethodTumour samples were collected from 295 patients with NFPA from Beijing Tiantan Hospital. The expression levels of 41 tumour-associated proteins were assessed using tissue microarray analyses. Clinical characteristics were analysed via univariate and multivariate logistic regression analyses. Logistic regression algorithm was applied to build a prediction model based on the expression levels of selected proteins and clinical signatures, which was then assessed in the testing set.ResultsThree proteins and two clinical signatures were confirmed to be significantly related to the regrowth of NFPA, including cyclin-dependent kinase inhibitor 2A (CDKN2A/p16), WNT inhibitory factor 1 (WIF1), tumour growth factor beta (TGF-β), age and tumour volume. A prediction model was generated on the training set, which achieved a fivefold predictive accuracy of 81.2%. The prediction ability was validated on the testing set with an accuracy of 83.9%. The area under the receiver operating characteristic curves (AUC) for the signatures were 0.895 and 0.881 in the training and testing sets, respectively.ConclusionThe prediction model could effectively predict the regrowth of NFPA, which may facilitate the prognostic evaluation and guide early interventions.

Impacts of Surgery on Symptom Burden and Quality of Life in Pituitary Tumor Patients in the Subacute Post-operative Period.

Background: Pituitary tumors are rare but are associated with significant symptoms that impact patients' quality of life (QOL). Surgery remains one of the most effective treatment options for long term disease control and symptom benefit, but symptom, and quality of life recovery in the subacute period has not been previously reported. This study aimed to better understand the impact of surgery on patients' symptom burden and QOL in the subacute post-surgical period.Methods: Twenty-three adult patients with pituitary tumors undergoing surgical resection at University of North Carolina Cancer Hospital were enrolled in this study. M.D. Anderson Symptom Inventory Brain Tumor Module, European Organization for Research and Treatment of Cancer QLQ-C30 and QLQ-BN20 questionnaires were collected pre- and 1-month post- surgical resection and differences were analyzed for individual and groups of symptoms and QOL using Wilcoxon signed-rank tests.Results: Twenty adult patients had both pre-operation and post-operation follow-up visits; 60% had functional pituitary adenomas. Seven symptoms including fatigue, memory, vision, numbness, speaking, appearance, and weakness were significantly improved at the 1-month post-operation visit while one symptom, sleep, worsened. Global Health Status/QOL measurements was improved minimally from 63 (SD 25) at pre-operation to 67 (SD 22) at 1-month post-operation without statistical significance.Conclusions: This study demonstrated a rapid improvement of many symptoms in the subacute post-operative period in pituitary tumor patients. Disturbed sleep was identified as the only symptom to worsen post-operatively, encouraging potential prospective interventions to improve sleep, and subsequently improve the QOL in pituitary tumor patients following surgical intervention.

MON-440 Cyberknife Radiosurgery for Functional and Non-Functional Pituitary Adenomas: Long-Term Single-Center Experience

Background: In recent years, CyberKnife radiosurgery (CKRS) has become an accepted adjuvant treatment modality when surgery has failed to achieve biochemical control of functional pituitary adenomas or after subtotal removal of non-secretory and secretory adenomas. However, long-term experience and clinical follow-up is limited. We present a retrospective review of our institutional experience with CKRS in patients with functional and non-functional pituitary adenomas. Methods: Forty-eight patients (23M/25F, age range 24-83 years) with pituitary adenomas received CKRS. Median follow-up period was 50 months (range 1 to 123 months). Patients consisted of 31 with non-functioning adenomas, 10 with acromegaly, 5 with Cushing disease (CD) and 2 with prolactinomas. Changes in hormonal function and treatment complications were analyzed in each case. Results: The ranges of radiation doses administered and prescription isodose line were 2500-3500 cGy/5 fractions and 62-78%, respectively. Pituitary hormone secretion improved in all 17 functioning adenomas, with hormonal normalization observed in 11/17 (65%) patients over median of 14 months. In patients with nonfunctioning adenomas, 4/31 (13%) patients subsequently developed panhypopituitarism over a median duration of 16 months. Radiological data was available in 42 patients, and 11/42 (26%) patients had reduction in tumor size over median of 16.5 months, 4/42 (10%) patients had local tumor recurrence over median of 41.5 months, and 27/11 (64%) patients had stable and unchanged tumor size. Of those with local tumor recurrence, 1 patient that had CD was treated with a low dose of 2500 cGy of salvage radiation therapy, 1 patient had Crooke’s changes after a dose of 2500 cGy salvage surgery, and 2 patients had high MIB scores (> 10). Post-treatment complications included temporal radiation-induced changes (n=2), 6th nerve palsy (n=1), and secondary malignancy (n=1). No patients developed visual field deficits. Five- and 7-year local progression free survival rates were 90% and 83%, respectively. Four patients died due to the following reasons: suicide, unknown reason, previously diagnosed testicular malignancy and infield neuroendocrine malignancy. Conclusion: We describe the long-term efficacy, safety and complication profile of CKRS in the treatment of functional and non-functional pituitary adenomas in our cohort of patients. Our data demonstrated that CKRS is a safe and effective adjunct for salvage therapy in patients with pituitary adenomas that have failed first-line therapy. In functioning pituitary adenomas, hormone hypersecretion improved in all patients, with the majority of patients achieving biochemical remission. Post-radiosurgery pituitary hormone deficiencies resulting in panhypopituitarism was observed in only a minority of patients. Overall, local tumor control and survival rates were relatively high.

Removal of the Medial Wall of the Cavernous Sinus for Functional Pituitary Adenomas: A Technical Report and Pathologic Significance

Removal of the medial wall of the cavernous sinus (MW) is challenging for neurosurgeons. We describe a practical method of endoscopic MW removal via endonasal transsphenoidal approach to minimalize intraoperative blood loss and postoperative morbidities. We also present the pathologic significance of this technique for functional pituitary adenomas (FPAs). We performed MW removal in patients with FPA with no well-defined pseudocapsule and a tumor in direct contact with the MW. The MW was judged to have tumor invasion based on the intraoperative appearance, and it was removed regardless of the appearance of MW involvement. Intraoperative findings and postoperative clinical, endocrinologic, and pathologic outcomes were retrospectively reviewed. Fourteen patients underwent MW removal for FPA, including 12 patients with acromegaly and 2 with Cushing disease. Mean intraoperative blood loss was 170 mL (range, 32-400 mL), and none of the patients required blood transfusion. Among the 7 patients without intraoperative apparent MW involvement, 4 (57.1%) had pathologically confirmed tumor invasion into the MW (occult invasion). Biochemical remission by surgery alone was achieved in 13 patients (92.9%). Transient oculomotor palsy occurred in 1 patient (7.1%). Occult tumor invasion into the MW was often detected in patients with FPA without a well-defined pseudocapsule but in direct contact with the MW. Our technique can enhance the effectiveness of surgery with minimal postoperative morbidities.

Various Strategies of Transsphenoidal Pseudocapsule-Based Extracapsular Resection in Noninvasive Functional Pituitary Adenomas and their Effectiveness and Safety.

Increasing attention has been paid to the pseudocapsule-based extracapsular resection in transsphenoidal surgery for pituitary adenomas. Prior reports focused more on Cushing disease or nonfunctional pituitary adenomas. In this study we present systematic research, especially concerning all kinds of noninvasive functional pituitary adenomas (NIFPAs) adopting various strategies of extracapsular resection, in order to evaluate the effectiveness and safety of these surgical methods for NIFPAs. From October 2008 to November 2014, 116 patients suffering from NIFPAs underwent pseudocapsule-based extracapsular resection (ER) with different surgical strategies; that is, by a microscope or endoscope via the endonasal transsphenoidal approach. During the same period, 90 patients suffering NIFPAs also underwent traditional transsphenoidal intracapsular resection (IR). In different postoperative periods, we re-examined the endocrine series and recorded the complications. Enhanced magnetic resonance imaging examination was also performed three months later. In the ER and IR group, the tumors were completely removed in 97 (83.7%) and 62 (68.9%) cases, whereas the endocrine disorders were remitted in 89 (76.7%) and 53 (58.9%) cases, respectively. Statistical analyses to compare the overall complete resection rates and the overall endocrine remission rates in both groups showed significant differences (P = 0.028 and 0.006, respectively). Intraoperative rhinorrhea occurred in 26.7% patients of the ER group and 13.3% of the IR group, showing a significant difference (P = 0.019). Transient diabetes insipidus occurred in 73.3% patients of the ER group and 63.3% of the IR group, with no difference between groups (P = 0.126). There was no case with intracranial hematoma or pituitary crisis in both the groups. With our various surgical strategies of ER, the patients can achieve content imaging resection, high and sustained endocrine remission, which are effective and safe for NIFPAs.

Hypopituitarism after Gamma Knife radiosurgery for pituitary adenomas: a multicenter, international study.

Recurrent or residual adenomas are frequently treated with Gamma Knife radiosurgery (GKRS). The most common complication after GKRS for pituitary adenomas is hypopituitarism. In the current study, the authors detail the timing and types of hypopituitarism in a multicenter, international cohort of pituitary adenoma patients treated with GKRS. Seventeen institutions pooled clinical data obtained from pituitary adenoma patients who were treated with GKRS from 1988 to 2016. Patients who had undergone prior radiotherapy were excluded. A total of 1023 patients met the study inclusion criteria. The treated lesions included 410 nonfunctioning pituitary adenomas (NFPAs), 262 cases of Cushing's disease (CD), and 251 cases of acromegaly. The median follow-up was 51 months (range 6-246 months). Statistical analysis was performed using a Cox proportional hazards model to evaluate factors associated with the development of new-onset hypopituitarism. At last follow-up, 248 patients had developed new pituitary hormone deficiency (86 with NFPA, 66 with CD, and 96 with acromegaly). Among these patients, 150 (60.5%) had single and 98 (39.5%) had multiple hormone deficiencies. New hormonal changes included 82 cortisol (21.6%), 135 thyrotropin (35.6%), 92 gonadotropin (24.3%), 59 growth hormone (15.6%), and 11 vasopressin (2.9%) deficiencies. The actuarial 1-year, 3-year, 5-year, 7-year, and 10-year rates of hypopituitarism were 7.8%, 16.2%, 22.4%, 27.5%, and 31.3%, respectively. The median time to hypopituitarism onset was 39 months.In univariate analyses, an increased rate of new-onset hypopituitarism was significantly associated with a lower isodose line (p = 0.006, HR = 8.695), whole sellar targeting (p = 0.033, HR = 1.452), and treatment of a functional pituitary adenoma as compared with an NFPA (p = 0.008, HR = 1.510). In multivariate analyses, only a lower isodose line was found to be an independent predictor of new-onset hypopituitarism (p = 0.001, HR = 1.38). Hypopituitarism remains the most common unintended effect of GKRS for a pituitary adenoma. Treating the target volume at an isodose line of 50% or greater and avoiding whole-sellar radiosurgery, unless necessary, will likely mitigate the risk of post-GKRS hypopituitarism. Follow-up of these patients is required to detect and treat latent endocrinopathies.

DICER1 mutation and pituitary prolactinoma

SummaryA young woman carrying germline DICER1 mutation was discovered to have a pituitary microprolactinoma when she became amenorrhoic. The mutation was identified as a result of family screening following the early death of the patient’s daughter with ovarian cancer. The patient was in follow-up screening for thyroid disease, and investigations were initiated when she became amenorrhoic. MR scan revealed a 6 mm diameter pituitary microadenoma and raised prolactin. The prolactin was efficiently suppressed with low-dose cabergoline, and her menstrual cycles resumed. Dicer is an RNase enzyme, which is essential for processing small non-coding RNAs. These molecules play pleiotropic roles in regulating gene expression, by targeting mRNA sequences for degradation. DICER1 plays different roles depending on cell context, but is thought to be a functional tumour suppressor gene. Accordingly, germline mutation in one DICER1 allele is insufficient for oncogenesis, and a second hit on the other allele is required, as a result of postnatal somatic mutation. Loss of DICER1 is linked to multiple tumours, with prominent endocrine representation. Multinodular goitre is frequent, with increased risk of differentiated thyroid cancer. Rare, developmental pituitary tumours are reported, including pituitary blastoma, but not reports of functional pituitary adenomas. As DICER1 mutations are rare, case reports are the only means to identify new manifestations and to inform appropriate screening protocols.Learning points:DICER1 mutations lead to endocrine tumours.DICER1 is required for small non-coding RNA expression.DICER1 carriage and microprolactinoma are both rare, but here are reported in the same individual, suggesting association.Endocrine follow-up of patients carrying DICER1 mutations should consider pituitary disease.

Role of TGF-β1/Smad3-mediated fibrosis in drug resistance mechanism of prolactinoma

Prolactinomas are the most common functional pituitary adenomas. While dopamine agonists are a primary method of therapeutic treatment, the rate of resistance to these drugs continues to increase each year. During previous long-term clinical investigations, we found that partial resistant prolactinomas exhibited significantly more fibrosis than did sensitive adenomas, suggesting a role of fibrosis in their drug resistance. Furthermore, resistant adenomas with extensive fibrosis mainly express type I and type III collagens. Since TGF-β1 is the key factor in the initiation and development of tissue fibrosis, including in the pituitary, in this study, we aimed to determine whether TGF-β1 mediated fibrosis in prolactinomas and whether fibrosis was related to prolactinoma drug resistance. Using immunochemistry and western blotting, we found that the TGF-β1/Smad3 signaling pathway-related proteins were elevated in resistant prolactinoma specimens with high degrees of fibrosis compared to levels in sensitive samples, suggesting that this pathway may play a role in prolactinoma fibrosis. In vitro, TGF-β1 stimulation promoted collagen expression in normal HS27 fibroblasts. Furthermore, the sensitivity of rat prolactinoma MMQ cells to bromocriptine decreased when they were co-cultured with HS27 cells treated with TGF-β1. The TGF-β1/Smad3 signaling-specific inhibitor SB431542 counteracted these effects, indicating that TGF-β1/Smad3-mediated fibrosis was involved in the drug-resistant mechanisms of prolactinomas. These results indicate that SB431542 may serve as a promising novel treatment for preventing fibrosis and further improving the drug resistance of prolactinomas.

Long-term follow-up of female prolactinoma patients at child-bearing age after transsphenoidal surgery

Prolactinoma is the most common subtype of functional pituitary adenoma. Effective therapy is required for women of child-bearing age to achieve remission at serum prolactin level and regain reproductive function. To evaluate long-term outcomes, including menstrual recovery, after transsphenoidal surgery on female prolactinoma patients by experienced neurosurgeons. Observational study. Consecutive female prolactinoma patients aged from 16 to 45 years were included. Histological analysis after surgery revealed adenoma with positive staining for prolactin. Plurihormonal cell adenomas were excluded. Clinical manifestations, surgical indications, serum prolactin level before and after surgery, surgical complications, pituitary fuctions, drug maintenance, the status of menstruation, and pregnancy. Sixty-three consecutive female patients with a mean age of 29.5 ± 1.1 years were included. Based on magnetic resonance imaging findings before surgery, 31 (49.2%) patients had microadenoma, and the remaining 32 (50.8%) had macroadenoma. The median follow-up after transsphenoidal surgery was 53 (33-74) months, and long-term surgical remission was achieved in 50 (79.37%) patients with 28 (90.32%) microadenomas and 22 (68.75%) macroadenomas. No meningitis or persistent cerebrospinal fluid leaks occurred. Only one case suffered from persistent diabetes insipidus at follow-up. No severe pituitary dysfunction was observed in microprolactinoma patients. Of patients with menstrual disorders, 85% regained regular menstrual cycles after surgery. Nineteen patients in this cohort desired pregnancy and 15 of them successfully gave birth after surgery. All 17 microadenoma patients with modern surgical indications achieved normal prolactin levels and regular menstrual cycles with only one patient on drug therapy at follow-up. Long-term follow-up showed a high remission rate in female prolactinoma patients, especially in microadenoma patients, after surgery. Transsphenoidal surgery performed by experienced neurosurgeons may offer a valuable approach to treat female microprolactinoma patients of child-bearing age with modern indications for surgery.

Stereotactic radiation therapy for the treatment of functional pituitary adenomas associated with feline acromegaly.

BackgroundConventional fractionated radiotherapy has been shown to be partially effective for management of pituitary tumors in cats that cause acromegaly and diabetes mellitus (DM), but, the efficacy and safety of stereotactic radiation therapy (SRT) as a treatment for acromegalic cats has not been described.HypothesisStereotactic radiation therapy is an effective and safe treatment for controlling acromegaly associated with pituitary adenomas in cats. Additionally, SRT‐treated acromegalic cats with DM will experience a decrease in insulin requirements after radiation therapy.AnimalsFifty‐three client‐owned cats referred to Colorado State University for SRT to treat pituitary tumors causing poorly controlled DM secondary to acromegaly.MethodsRetrospective study of cats treated for acromegaly with SRT between 2008 and 2016 at Colorado State University. Diagnosis of acromegaly was based on history, physical examination, laboratory results, and cross‐sectional imaging of the pituitary. Signalment, radiation protocol, insulin requirements over time, adverse effects, and survival were recorded.ResultsMedian survival time was 1072 days. Of the 41 cats for which insulin dosage information was available, 95% (39/41) experienced a decrease in required insulin dose, with 32% (13/41) achieving diabetic remission. Remission was permanent in 62% (8/13) and temporary in 38% (5/13) cats. Median duration to lowest insulin dose was 9.5 months. Of the treated cats, 14% developed hypothyroidism and required supplementation after SRT.ConclusionsStereotactic radiation therapy is safe and effective for treating cats with acromegaly. Cats treated with SRT have improved survival time and control of their DM when compared to previously reported patients treated with non‐SRT.

The prolactin-release inhibitor paeoniflorin suppresses proliferation and induces apoptosis in prolactinoma cells via the mitochondria-dependent pathway.

Prolactinomas are the most prevalent functional pituitary adenomas that cause chronic pathological hyperprolactinemia. Prolactin is known to promote cell growth and inhibit apoptosis in cells. Paeoniflorin is the principal component of radix Paeoniae alba (the main ingredient in some traditional herbal formulas clinically used for hyperprolactinemia-associated disorders). Recent findings from intensive studies have suggested that paeoniflorin regulates cell proliferation and apoptosis in many cell lines. However, the effects of paeoniflorin in pituitary tumor cells remain unknown. Here the results by the Cell Counting Kit-8 and colony formation assays showed that paeoniflorin concentration-dependently decreased cell viability in both MMQ and GH3 cells and colony formation in GH3 cells, suggesting inhibition of cell proliferation by paeoniflorin. By flow cytometry, paeoniflorin was found to increase apoptotic rate in MMQ cells. Mechanistically, Western blot results revealed that paeoniflorin enhanced protein expression of cleave caspase-9 and -3, and Bax, whereas it suppressed Bcl-2 protein expression in MMQ cells. Furthermore, paeoniflorin upregulated phosphorylated p53 protein expression, but it decreased prolactin concentration and prolactin protein expression in both MMQ and GH3 cells. Thus, the present results demonstrate that paeoniflorin inhibits cell proliferation and induces the mitochondrial pathway-mediated apoptosis in prolactinoma cells. These antitumor property is associated with inhibition of prolactin secretion. Our findings may provide new insight into the mechanisms underlying improving prolactinoma-associated disorders of paeoniflorin-enriched herbs and formulas.

Clinicopathological significance of baseline T2-weighted signal intensity in functional pituitary adenomas.

To assess baseline T2-weighted signal intensity (T2-WSI) of functional pituitary adenomas (FPA), and to investigate the relationship of baseline T2-WSI with clinical features, histopathological granulation patterns, and response to treatment in patients with acromegaly, prolactinoma and Cushing's disease (CD). Somatotroph adenomas (n = 87), prolactinomas (n = 78) and corticotroph adenomas (n = 29) were included in the study. Baseline T2-WSI findings (grouped as hypo-, iso- and hyperintense) were compared with hormone levels, tumor diameter, granulation patterns and response to treatment. Somatotroph adenomas were mostly hypointense (53%), prolactinomas were dominantly hyperintense (55%), and corticotroph adenomas were generally hyperintense (45%). Hyperintense somatotroph adenomas were larger in size with sparsely granulated pattern and tumor shrinkage rate was lower after somatostatin analogues (SSA) (p = 0.007, p = 0.035, p = 0.029, respectively). T2 hypointensity was related with higher baseline IGF-1% ULN (upper limit of normal) levels and a better response to SSA treatment (p = 0.02, p = 0.045, respectively). In female prolactinomas, hyperintensity was correlated with a smaller adenoma diameter (p = 0.001). Hypointense female prolactinomas were related to younger age at diagnosis, higher baseline PRL levels and dopamine agonist (DA) resistance (p = 0.009, p = 0.022, p < 0.001, respectively). Hyperintense corticotroph adenomas were related to larger adenoma size and sparsely granulated pattern (p = 0.04, p = 0.017, respectively). There was no significant difference in the recurrence with T2WSI in CD. Baseline hypointense somatotroph adenomas show a better response to SSA, whereas hypointensity was related to DA resistance in female prolactinomas.

Functional versus Nonfunctional Pituitary Adenomas: A Review of Surgical Outcomes

Functional versus Nonfunctional Pituitary Adenomas: A Review of Surgical Outcomes