KDM1A genotyping and expression in 146 sporadic somatotroph pituitary adenomas.

IMPORTANCE: A paradoxical increase of growth hormone (GH) following oral glucose load has been described in ∼30% of patients with acromegaly and has been related to the ectopic expression of the glucose-dependent insulinotropic polypeptide (GIP) receptor (GIPR) in somatotropinomas. Recently, we identified germline pathogenic variants and somatic loss of heterozygosity of lysine demethylase 1A (KDM1A) in patients with GIP-dependent primary bilateral macronodular adrenal hyperplasia with Cushing's syndrome. The ectopic expression of GIPR in both adrenal and pituitary lesions suggests a common molecular mechanism. OBJECTIVE: We aimed to analyze KDM1A gene sequence and KDM1A and GIPR expressions in somatotroph pituitary adenomas. SETTINGS: We conducted a cohort study at university hospitals in France and in Italy. We collected pituitary adenoma specimens from acromegalic patients who had undergone pituitary surgery. We performed targeted exome sequencing (gene panel analysis) and array-comparative genomic hybridization on somatic DNA derived from adenomas and performed droplet digital PCR on adenoma samples to quantify KDM1A and GIPR expressions. RESULTS: One hundred and forty-six patients with sporadic acromegaly were studied; 72.6% presented unsuppressed classical GH response, whereas 27.4% displayed a paradoxical rise in GH after oral glucose load. We did not identify any pathogenic variant in the KDM1A gene in the adenomas of these patients. However, we identified a recurrent 1p deletion encompassing the KDM1A locus in 29 adenomas and observed a higher prevalence of paradoxical GH rise (P = .0166), lower KDM1A expression (4.47 ± 2.49 vs 8.56 ± 5.62, P < .0001), and higher GIPR expression (1.09 ± 0.92 vs 0.43 ± 0.51, P = .0012) in adenomas from patients with KDM1A haploinsufficiency compared with those with 2 KDM1A copies. CONCLUSIONS AND RELEVANCE: Unlike in GIP-dependent primary bilateral macronodular adrenal hyperplasia, KDM1A genetic variations are not the cause of GIPR expression in somatotroph pituitary adenomas. Recurrent KDM1A haploinsufficiency, more frequently observed in GIPR-expressing adenomas, could be responsible for decreased KDM1A function resulting in transcriptional derepression on the GIPR locus.

Surgical and non-surgical interventions for primary and salvage treatment of growth hormone-secreting pituitary adenomas in adults.

BACKGROUND: Growth hormone (GH)-secreting pituitary adenoma is a severe endocrine disease. Surgery is the currently recommended primary therapy for patients with GH-secreting tumours. However, non-surgical therapy (pharmacological therapy and radiation therapy) may be performed as primary therapy or may improve surgical outcomes. OBJECTIVES: To assess the effects of surgical and non-surgical interventions for primary and salvage treatment of GH-secreting pituitary adenomas in adults. SEARCH METHODS: We searched CENTRAL, MEDLINE, WHO ICTRP, and ClinicalTrials.gov. The date of the last search of all databases was 1 August 2022. We did not apply any language restrictions. SELECTION CRITERIA: Randomised controlled trials (RCTs) and quasi-RCTs of more than 12 weeks' duration, reporting on surgical, pharmacological, radiation, and combination interventions for GH-secreting pituitary adenomas in any healthcare setting. DATA COLLECTION AND ANALYSIS: Two review authors independently screened titles and abstracts for relevance, screened for inclusion, completed data extraction, and performed a risk of bias assessment. We assessed studies for overall certainty of the evidence using GRADE. We estimated treatment effects using random-effects meta-analysis. We expressed results as risk ratios (RR) for dichotomous outcomes together with 95% confidence intervals (CI) or mean differences (MD) for continuous outcomes, or in descriptive format when meta-analysis was not possible. MAIN RESULTS: We included eight RCTs that evaluated 445 adults with GH-secreting pituitary adenomas. Four studies reported that they included participants with macroadenomas, one study included a small number of participants with microadenomas. The remaining studies did not specify tumour subtypes. Studies evaluated surgical therapy alone, pharmacological therapy alone, or combination surgical and pharmacological therapy. Methodological quality varied, with many studies providing insufficient information to compare treatment strategies or accurately judge the risk of bias. We identified two main comparisons, surgery alone versus pharmacological therapy alone, and surgery alone versus pharmacological therapy and surgery combined. Surgical therapy alone versus pharmacological therapy alone Three studies with a total of 164 randomised participants investigated this comparison. Only one study narratively described hyperglycaemia as a disease-related complication. All three studies reported adverse events, yet only one study reported numbers separately for the intervention arms; none of the 11 participants were observed to develop gallbladder stones or sludge on ultrasonography following surgery, while five of 11 participants experienced any biliary problems following pharmacological therapy (RR 0.09, 95% CI 0.01 to 1.47; 1 study, 22 participants; very low-certainty evidence). Health-related quality of life was reported to improve similarly in both intervention arms during follow-up. Surgery alone compared to pharmacological therapy alone may slightly increase the biochemical remission rate from 12 weeks to one year after intervention, but the evidence is very uncertain; 36/78 participants in the surgery-alone group versus 15/66 in the pharmacological therapy group showed biochemical remission. The need for additional surgery or non-surgical therapy for recurrent or persistent disease was described for single study arms only. Surgical therapy alone versus preoperative pharmacological therapy and surgery Five studies with a total of 281 randomised participants provided data for this comparison. Preoperative pharmacological therapy and surgery may have little to no effect on the disease-related complication of a difficult intubation (requiring postponement of surgery) compared to surgery alone, but the evidence is very uncertain (RR 2.00, 95% CI 0.19 to 21.34; 1 study, 98 participants; very low-certainty evidence). Surgery alone may have little to no effect on (transient and persistent) adverse events when compared to preoperative pharmacological therapy and surgery, but again, the evidence is very uncertain (RR 1.23, 95% CI 0.75 to 2.03; 5 studies, 267 participants; very low-certainty evidence). Concerning biochemical remission, surgery alone compared to preoperative pharmacological therapy and surgery may not increase remission rates up until 16 weeks after surgery; 23 of 134 participants in the surgery-alone group versus 51 of 133 in the preoperative pharmacological therapy and surgery group showed biochemical remission. Furthermore, the very low-certainty evidence did not suggest benefit or detriment of preoperative pharmacological therapy and surgery compared to surgery alone for the outcomes 'requiring additional surgery' (RR 0.48, 95% CI 0.05 to 5.06; 1 study, 61 participants; very low-certainty evidence) or 'non-surgical therapy for recurrent or persistent disease' (RR 1.22, 95% CI 0.65 to 2.28; 2 studies, 100 participants; very low-certainty evidence). None of the included studies measured health-related quality of life. None of the eight included studies measured disease recurrence or socioeconomic effects. While three of the eight studies reported no deaths to have occurred, one study mentioned that overall, two participants had died within five years of the start of the study. AUTHORS' CONCLUSIONS: Within the context of GH-secreting pituitary adenomas, patient-relevant outcomes, such as disease-related complications, adverse events and disease recurrence were not, or only sparsely, reported. When reported, we found that surgery may have little or no effect on the outcomes compared to the comparator treatment. The current evidence is limited by the small number of included studies, as well as the unclear risk of bias in most studies. The high uncertainty of evidence significantly limits the applicability of our findings to clinical practice. Detailed reporting on the burden of recurrent disease is an important knowledge gap to be evaluated in future research studies. It is also crucial that future studies in this area are designed to report on outcomes by tumour subtype (that is, macroadenomas versus microadenomas) so that future subgroup analyses can be conducted. More rigorous and larger studies, powered to address these research questions, are required to assess the merits of neoadjuvant pharmacological therapy or first-line pharmacotherapy.

[Tumor predisposition in endocrinology - from MEN to FIPA]. / Tumorprädisposition in der Endokrinologie ­ von MEN bis FIPA.

Understanding genetic predisposition has a significant impact on the management of patients with endocrine tumours, including therapy, early detection and prevention. These tumours, which develop as part of a familial predisposition, often manifest early in life and frequently affect several endocrine organs. In the following article, both common syndromes, such as multiple endocrine neoplasia (MEN) syndromes, and rare syndromes, such as familial isolated pituitary adenoma (FIPA), are presented based on their indicator diseases.

Transsphenoidal hypophysectomy for the treatment of hypersomatotropism secondary to a pituitary somatotroph adenoma in a dog.

Pituitary-dependent hypersomatotropism is rarely diagnosed in dogs and surgical treatment is not reported. A 6-year-10-month male neutered Patterdale Terrier presented with polyuria, polydipsia, progressive pharyngeal stertor, excessive hair growth and widened facial features and paws. Serum insulin-like growth factor-1 concentration via radioimmunoassay was consistent with hypersomatotropism (1783 ng/mL). A pituitary mass was identified on magnetic resonance and computed tomography imaging. Six weeks later, glucosuria, starved hyperglycemia and serum fructosamine above the reference range (467.6 µmol/L, RI 177-314) were documented, consistent with diabetes mellitus. Transsphenoidal hypophysectomy was performed under general anesthesia without complications. Pituitary histopathology identified an acidophil neoplasm, with positive immunostaining for growth hormone. Postoperatively, there was rapid resolution of clinical, biochemical and morphologic changes of hypersomatotropism with persistence of diabetes mellitus. This case demonstrates successful resolution of hypersomatotropism with ongoing diabetes mellitus in a dog after surgical treatment by transsphenoidal hypophysectomy.

Analysis of Diffusion-Weighted and T2-Weighted Imaging in the Prediction of Distinct Granulation Patterns of Somatotroph Adenomas.

OBJECTIVE: The heterogeneity of the somatotroph adenomas, especially for sparsely granulated (SG) and densely granulated (DG) subtypes, has attracted great attention in identifying their imaging biomarker. The purpose of the current study was to compare the diagnostic performance of diffusion-weighted and T2-weighted magnetic resonance imaging (MRI) sequences for preoperatively distinguishing the granulation patterns of somatotroph adenomas. METHODS: Thirty-two patients with a clinical diagnosis of somatotroph adenomas from October 2018 to March 2023 were included in this study. Coronal diffusion-weighted imaging (DWI) and T2-weighted MRI sequence data were collected from 3.0T MRI and compared between SG and DG groups. The immunohistochemistry was used to confirm the electron microscopy pathologic subtypes and Ki67 expression levels of somatotroph adenomas postoperatively. RESULTS: Patients in the SG group had significantly higher signal intensity (SI) ratio of DWI (rDWI) (P < 0.001), lower SI ratio of apparent diffusion coefficient (rADC) (P < 0.001), and higher SI ratio of T2-weighted imaging (P = 0.011). The combined diagnosis index of rDWI and rADC had the highest diagnostic efficiency in predicting SG adenomas (sensitivity, 93.3%; specificity, 88.2%; P < 0.001). The rDWI and rADC values had positive and negative correlations with the Ki67 index and tumor maximum diameter, respectively. Lower rADC×103 was an independent predictor for SG adenomas. CONCLUSIONS: Our results indicated that compared with previously used T2-weighted imaging, the DWI sequence, especially the combined diagnosis index of rDWI and rADC, could more efficiently distinguish the granulation patterns of somatotroph adenomas preoperatively.

MiR-320a Acts as a Tumor Suppressor in Somatotroph Pituitary Neuroendocrine Tumors by Targeting BCAT1.

INTRODUCTION: Aberrant miR-320a has been reported to be involved in the tumorigenesis of several cancers. In our previous study, we identified the low expression of circulating miR-320a in patients with somatotroph pituitary neuroendocrine tumor (PitNET); however, the role of miR-320a in somatotroph PitNET proliferation is still unclear. METHODS: Cell viability and colony formation assays were used to detect the effect of miR-320a and BCAT1 on GH3 cells. TargetScan was used to identify the target genes of miR-320a. Dual-luciferase reporter gene assay was used to explore the relation between miR-320a and BCAT1. Transcriptome and proteome analyses were performed between somatotroph PitNETs and healthy controls. The expression level of miR-320a in somatotroph PitNETs were detected by RT-qPCR and Western blot. RESULTS: miR-320a mimics inhibit cell proliferation, while miR-320a inhibitors promote cell proliferation in GH3 cells. An overlap analysis using a Venn diagram revealed that BCAT1 is the only target gene of miR-320a overexpressed in somatotroph PitNETs compared to healthy controls, as revealed by both microarray and proteomics results. A dual-luciferase reporter gene assay showed that miR-320a may bind to the BCAT1-3'UTR. The transfection of miR-320a mimics downregulated the expression and miR-320a inhibitors and upregulated the expression of BCAT1 in GH3 cells. The interference of BCAT1 expression in GH3 cells downregulated cell proliferation and growth. Pan-cancer analyses demonstrated that high BCAT1 expression often indicates a poor prognosis. CONCLUSION: Our findings illustrate that miR-320a may function as a tumor suppressor and BCAT1 may promote tumor progression. miR-320a may inhibit the growth of somatotroph PitNETs by targeting BCAT1.

DNA Methylation Pattern in Somatotroph Pituitary Neuroendocrine Tumors.

INTRODUCTION: Growth hormone secretion by sporadic somatotroph neuroendocrine pituitary tumors (PitNETs) is a major cause of acromegaly. These tumors are relatively heterogenous in terms of histopathological and molecular features. Our previous transcriptomic profiling of somatotroph tumors revealed three distinct molecular subtypes. This study aimed to investigate the difference in DNA methylation patterns in subtypes of somatotroph PitNETs and its role in distinctive gene expression. METHODS: Genome-wide DNA methylation was investigated in 48 somatotroph PitNETs with EPIC microarrays. Gene expression was assessed with RNAseq. Bisulfite pyrosequencing and qRT-PCR were used for verifying the results of DNA methylation and gene expression. RESULTS: Clustering tumor samples based on methylation data reflected the transcriptome-related classification. Subtype 1 tumors are densely granulated without GNAS mutation, characterized by high expression of NR5A1 (SF-1) and GIPR. The expression of both genes is correlated with specific methylation of the gene body and promoter. This subtype has a lower methylation level of 5' gene regions and CpG islands than the remaining tumors. Subtype 2 PitNETs are densely granulated and frequently GNAS-mutated, while those in subtype 3 are mainly sparsely granulated. Methylation/expression analysis indicates that ∼50% genes located in differentially methylated regions are those differentially expressed between tumor subtypes. Correlation analysis revealed DNA methylation-controlled genes, including CDKN1B, CCND2, EBF3, CDH4, CDH12, MGMT, STAT5A, PLXND1, PTPRE, and MMP16, and genes encoding ion channels and semaphorins. CONCLUSION: DNA methylation profiling confirmed the existence of three molecular subtypes of somatotroph PitNETs. High expression of NR5A1 and GIPR in subtype 1 tumors is correlated with specific methylation of both genes.

A novel somatostatin receptor ligand for human ACTH - and GH -secreting pituitary adenomas.

OBJECTIVE: Somatostatin receptor ligands have come to play a pivotal role in the treatment of both ACTH- and GH-secreting pituitary adenomas. Clinical efficacy averages 30-50%, thus a considerable number of patients with Cushing's disease or acromegaly remain unresponsive to this therapeutic approach. HTL0030310 is a new somatostatin receptor ligand selective for subtype 5 over subtype 2, thus with a different receptor profile compared to clinical somatostatin receptor ligands. DESIGN: Assessment of the effect of HTL0030310 on hormone secretion in human ACTH- and GH-secreting pituitary adenomas in vitro. METHODS: Primary cultures from 3 ACTH-secreting and 5 GH-secreting pituitary adenomas were treated with 1, 10 and 100 nM HTL0030310 alone or with 10 nM CRH or GHRH, respectively. Parallel incubations with 10 nM pasireotide were also carried out. ACTH and GH secretion were assessed after 4 and 24 hour incubation; SSTR2, SSTR3, SSTR5, GH and POMC expression were evaluated after 24 hours. RESULTS: HTL0030310 reduced unchallenged ACTH and POMC levels up to 50% in 2 ACTH-secreting adenomas and blunted CRH-stimulated ACTH/POMC by 20-70% in all 3 specimens. A reduction in spontaneous GH secretion was observed in 4 GH-secreting adenomas and in 2 specimens during GHRH co-incubation. SSTRs expression was detected in all specimens. CONCLUSIONS: This first study on a novel somatostatin receptor 5-preferring ligand indicates that HTL0030310 can inhibit hormonal secretion in human ACTH- and GH-secreting pituitary adenomas. These findings suggest a potential new avenue for somatostatin ligands in the treatment of Cushing's disease and acromegaly.

A Novel Preoperative Score to Predict Long-Term Biochemical Remission in Patients with Growth-Hormone Secreting Pituitary Adenomas.

OBJECTIVE: Transsphenoidal surgery (TSS) is considered the treatment of choice in most patients with growth hormone (GH)-secreting pituitary adenomas. Several preoperative factors have been studied to predict postsurgical remission. Our objective was to design a score that could be used in the preoperative setting to identify patients that will achieve long-term biochemical remission after TSS. METHODS: A retrospective analysis of consecutive patients with GH-secreting pituitary adenomas that underwent TSS in our institution from 2000 to 2015 who fulfilled prespecified criteria were included. Logistic regression methods were used to evaluate independent preoperative variables predicting long-term remission. Beta coefficients were used to create a scoring system for clinical practice. RESULTS: Sixty-eight patients were included, with a mean follow-up time of 87 months. Twenty (29%) patients had tumors with a Knosp grade ≥ 3A. Gross-total resection was achieved in 43 (63%) patients. Thirty-three (48%) patients had long-term biochemical remission after TSS. In a multivariate analysis, the following variables were statistically significantly associated with long-term biochemical remission: age, adenoma size (diameter), Knosp grade, GH level, and insulin growth-factor 1index 1 at diagnosis. A score of <3 out of 8 total points was identified as a cutoff associated with long-term remission, with a sensitivity of 91.4% and specificity of 72.7% (AUC 0.867, OR 28.44, 95% CI 6.94-116.47, P = < 0.001). CONCLUSIONS: A novel, simple, easy-to-use scoring system was created to identify patients with the highest chances of long-term biochemical remission following TSS. This scale should be prospectively validated in a multicenter study before widespread adoption.

Prospective Integrated Individualized Clinical Decision-making and Outcome Evaluation for Surgery in Patients with Acromegaly: A New Paradigm?

BACKGROUND: Growth-hormone-producing pituitary adenomas have variable likelihood for biochemical remission (BR). During preoperative counseling, individual estimated surgical likelihoods/risks should be balanced against alternative (medical) treatments, which is necessary for accurate outcome presentation. Preoperative estimation of BR or total resection (TR) likelihoods have not been reported, resulting in extrapolation of individual outcomes. AIMS: To share an innovative outcome reporting paradigm by integrating surgical decision-making, and expected/realized results, resulting from the Value-Based Health Care (VBHC) care path with periodical performance evaluation and care innovation cycle. METHODS: Prospective cohort study of consecutive patients with acromegaly undergoing surgery (January 2016-December 2020; postoperative follow-up ≥6 months) reporting on both classic, and novel innovative outcome evaluations. RESULTS: Fifty eight patients (66 procedures) were included. Intended TR was achieved in 34/50 procedures, whereas intended debulking was achieved in 15/16 procedures. 38/66 procedures resulted in BR, and 4 procedures resulted in permanent complications. Achieving intended surgical goal was estimated preoperatively as likely in 33 (goal achieved (GA) in 28/33), potentially in 27 (GA in 19/27), and unlikely in 6 procedures (GA in 2/6). Integrated Outcome Square 1 (IOQ1) -intended effect achieved without complications- was achieved in 46/66 patients. CONCLUSION: Implementation of the developed quality process positively affects preoperative individual shared decision-making, resulting in improved (individual) outcomes, particularly in complex patients for whom preoperative chances are not fully reflected by tumor size and KNOSP grade, e.g., reoperations, or other challenging circumstances identified during preoperative counseling. Through repeated evaluations, our own team's knowledge increased, allowing for improved individualized treatment strategies.

Uric acid levels correlate with disease activity in growth hormone-secreting pituitary adenoma patients.

Objective: Few studies reported the effects of growth hormone-secreting pituitary adenoma (GHPA) on uric acid (UA) metabolism and the relationship between growth hormone (GH)/insulin-like growth factor-1 (IGF-1) levels and UA are controversial. This study aimed to evaluate the relationship between IGF-1 and UA in patients with GHPA and to further clarify whether UA levels are associated with GHPA disease activity by follow-up. Methods: A longitudinal study of 424 GHPA patients presenting to Beijing Tiantan Hospital, Capital Medical University between January 2015 and January 2023 was conducted. Spearman's correlation tests were performed to examine the relationship between IGF-1 and UA at baseline. Univariate and multivariate linear regression analysis was conducted to investigate the independent association between UA and IGF-1. Changes in postoperative IGF-1 and UA levels were followed prospectively, and the differences in UA levels between the biochemical remission and nonremission groups were compared. Results: At baseline, male patients, the lower the age, the higher the IGF-1 and body mass index (BMI), and the higher the UA levels. IGF-1 was significantly associated with UA after controlling for sex, age, and BMI (r = 0.122, P = 0.012). In adjusted multiple linear regression analysis, IGF-1 was independently associated with UA, and UA levels increased significantly with increasing IGF-1. During postoperative follow-up, UA decreased gradually as IGF-1 levels decreased. At 12 months postoperatively, UA levels were significantly lower in the biochemical remission group than in the nonremission group (P = 0.038). Conclusions: In patients with GHPA, UA levels are associated with disease activity. Changes in UA levels should be taken into account in the comprehensive treatment of GHPA, patients presenting with HUA should be given lifestyle guidance and appropriate urate-lowering treatment according to their condition to better improve their prognosis.

Clinical characteristics and therapeutic outcomes of acromegalic patients with giant growth hormone-secreting pituitary adenomas: a single-center study of 67 cases.

PURPOSE: Acromegalic patients with giant growth hormone-secreting pituitary adenomas (GHPAs) (≥ 40 mm) are relatively rare, and their clinical characteristics and treatment outcome data are limited. This study aims to analyze the clinical practice experience of giant GHPAs. METHODS: Sixty-seven acromegalic patients with giant GHPAs and 67 patients with macro GHPAs (10-39 mm), matched for age and gender from the same hospital during the same period, were retrospectively recruited. The clinical characteristics, treatment, and outcomes were analyzed. RESULTS: Enlargement of the extremities and facial features were the most common symptoms in most patients (92.5%). Compared with the macroadenoma group, more frequent visual impairment (86.6% vs. 25.4%, P < 0.001) and gonadal axis dysfunction (49.3% vs. 34.3%, P = 0.008), higher preoperative fasting GH, nadir GH after OGTT and IGF-1 levels, and a higher proportion of extrasellar tumor invasion were seen in the giant adenoma group. As the adenoma size increases, the total resection rate decreases, and postoperative complications and multimodal treatment strategies increase significantly. Fasting and nadir GH levels remained higher at 1 week postoperatively, and there were more surgical complications and cases of anterior hypopituitarism in the giant group. After a median follow-up of 36 months, 12 patients (36.4%) in the giant GHPA group and 17 (36.2%) in the macro GHPA group achieved biochemical remission. Other factors such as age of onset, age of diagnosis, delayed diagnosis time, metabolic complications, p53 positive rate, and Ki-67 index showed no significant difference between the two groups. CONCLUSIONS: With aggressive multimodal therapy, the biochemical remission rate of acromegalic patients with giant GHPAs is comparable to that of patients with macro adenoma. However, postoperative complications and hypopituitarism need to be closely monitored.

Long-term control of acromegaly after pituitary surgery in South-Eastern Norway.

PURPOSE: Sustained cure of acromegaly can only be achieved by surgery. Most growth hormone (GH) secreting pituitary adenomas are macroadenomas (≥ 10 mm) at diagnosis, with reported surgical cure rates of approximately 50%. Long-term data on disease control rates after surgery are limited. Our aim was to estimate short- and long-term rates of biochemical control after pituitary surgery in acromegaly and identify predictive factors. METHODS: Patients operated for GH-secreting pituitary adenomas between 2005-2020 were included from the local pituitary registry (n = 178). Disease activity and treatment data were recorded at one-year (short-term) and five-year (long-term) postoperative follow-up. Biochemical control was defined as insulin-like growth factor 1 (IGF-1) ≤ 1.2 × upper limit of normal value. Multivariate regression models were used to identify factors potentially predicting biochemical control. RESULTS: A total of 178 patients with acromegaly (median age at diagnosis 49 (IQR: 38-59) years, 46% women) were operated for a pituitary adenoma. Biochemical control was achieved by surgery in 53% at short-term and 41% at long-term follow-up, without additional treatment for acromegaly. Biochemical control rates by surgery were of same magnitude in paired samples (45% vs. 41%, p = 0.213) for short- and long-term follow-up, respectively. At short-term, 62% of patients with microadenomas and 51% with macroadenomas, achieved biochemical control. At long-term, the biochemical control rate was 58% for microadenomas and 37% for macroadenomas (p = 0.058). With adjunctive treatment, 82% achieved biochemical control at long-term. Baseline IGF-1 levels significantly predicted biochemical control by surgery at short-term (OR: 0.98 (95% CI: 0.96-0.99), p = 0.011), but not at long-term (OR: 0.76 (95% CI: 0.57-1.00), p = 0.053). CONCLUSION: In unselected patients with acromegaly, the long-term biochemical control rate remains modest. Our findings indicate a need to identify patients at an earlier stage and improve therapeutic methods and surgical outcomes.

Comparative effectiveness of endoscopic and microscopic adenoma removal in acromegaly.

Introduction: Somatotropinomas are the main cause of acromegaly. Surgery is the primary and most efficient method of treatment. The study aimed to compare the radicality of small-sized and medium (<30 mm) somatotropinoma removal and the incidence of postoperative complications in patients with acromegaly when using microscopic and endoscopic techniques. Methods: In this randomized controlled trial, a total of 83 patients with acromegaly underwent transspheroidal endoscopy or microscopic surgery. Somatotropinoma was the cause of acromegaly in all cases. Patients were randomly divided into two comparison groups depending on the applied surgical technique. Group 1 (n = 40) consisted of patients who underwent adenomectomy with transnasal transsphenoidal access by a microscope. Group 2 (n = 43) included patients who underwent the same surgical procedure with an endoscope. The following indicators were assessed: radicality of tumor removal, treatment effectiveness, postoperative complications, and remission rate. Results: The study has shown that removal of somatotropinoma in patients with acromegaly using endoscopic technique increases the radicality of tumor removal in comparison with microscopic technique. Total removal of somatotropinoma was successful in 88.4% of cases when using the endoscopic technique. Secondly, the segmentation of patients according to their tumor characteristics poses challenges, primarily owing to the rarity of acromegaly as a disease. The difference between groups was not statistically significant (p=1.02). There were no statistically significant differences in basal GH level and IGF-1 level between groups (p=0.546 and p=0.784, respectively). Discussion: Endonasal transsphenoidal endoscopic adenomectomy is proven efficacy, a less traumatic degree, and higher somatotropinoma removal radicality. Both surgical methods lead to disease remission.

Clinical and prognostic significance of granulation patterns in somatotroph adenomas/tumors of the pituitary: a meta-analysis.

INTRODUCTION: Sparsely granulated somatotroph adenoma/tumor (SGST) is thought to be more clinically aggressive than densely granulated somatotroph adenoma/tumor (DGST). However, the literature is not entirely consistent as to the disparate demographic and behavioral features of these subtypes. In this study, we conducted a meta-analysis to further clarify the demographic, clinicopathological, prognostic, and molecular characteristics of SGST versus DGST. METHODS: We accessed two electronic databases to search for potential data. Pooled estimates of odds ratio (OR), mean difference (MD), and corresponding 95% confidence interval (CI) were calculated using the random-effect model. RESULTS: SGST was associated with younger patient age and lower male-to-female ratio (p < 0.001) compared to DGST. Clinically, SGST had larger tumor size and high rate of cavernous sinus and suprasellar extension (p < 0.001) than DGST. During postoperative follow-up, SGST was associated with a lower endocrinological remission rate (OR 0.60; 95% CI 0.40 to 0.90; p = 0.01) and a poorer response rate to SRL (OR 0.16; 95% CI 0.08-0.35; p < 0.001) in comparison to DGST. The prevalence of GSP mutations was significantly lower in SGST (OR 0.36; 95% CI 0.17 to 0.79; p = 0.01). CONCLUSION: SGST and DGST were demographically, clinicopathologically, and molecularly different from each other with the former associated with adverse treatment outcomes and poor response to medical therapy. There are still gaps in translational studies that could help us better understand the behavior of these tumors and identify potential targets in the treatment of sparsely granulated tumors.

Neuromedin B receptor as a potential therapeutic target for corticotroph adenomas.

PURPOSE: Cushing's disease (CD) results from autonomous adrenocorticotropic hormone (ACTH) secretion by corticotroph adenomas, leading to excessive cortisol production, ultimately affecting morbidity and mortality. Pasireotide is the only FDA approved tumor directed treatment for CD, but it is effective in only about 25% of patients, and is associated with a high rate of hyperglycemia. Neuromedin B (NMB), a member of the bombesin-like peptide family, regulates endocrine secretion and cell proliferation. Here, we assessed NMB and NMB receptor (NMBR) expression in human corticotroph adenomas and the effects of NMBR antagonist PD168368 on murine and human corticotroph tumors. METHODS: To investigate NMB and NMBR expression, real-time qPCR and immunostaining on human pathological specimens of corticotroph, non-functional and somatotroph adenomas were performed. The effects of PD168368 on hormone secretion and cell proliferation were studied in vitro, in vivo and in seven patient-derived corticotroph adenoma cells. NMB and NMBR were expressed in higher extent in human corticotroph adenomas compared with non-functional or somatotroph adenomas. RESULTS: In murine AtT-20 cells, PD168368 reduced proopiomelanocortin (Pomc) mRNA/protein expression and ACTH secretion as well as cell proliferation. In mice with tumor xenografts, tumor growth, ACTH and corticosterone were downregulated by PD168368. In patient-derived adenoma cells, PD168368 reduced POMC mRNA expression in four out of seven cases and ACTH secretion in two out of five cases. A PD168368-mediated cyclin E suppression was also identified in AtT-20 and patient-derived cells. CONCLUSION: NMBR antagonist represents a potential treatment for CD and its effect may be mediated by cyclin E suppression.

[Acromegaly in the differential diagnosis of hearing loss].

Acromegaly is a multifactorial neuroendocrine disease caused by hyperproduction of growth hormone (GH). In more than 95% of cases the reason of acromegaly the GH-secreting pituitary adenoma. In patients with this neuroendocrine disease, a slowly developing complex of symptom can manifest with concomitant pathological conditions, including auditory function disordersDiagnostic difficulties of acromegaly at the ambulatory stage determine the importance of doctor`s awareness in different medical specialties.Here we demonstrate a clinical case of the improvement of the auditory function due to combined surgical and medical treatment of a patient with the pituitary macroadenoma, acromegaly and hearing loss.Anamnesis features: a patient with an active stage of acromegaly and a pituitary macroadenoma measuring 57x35x32 mm with ante-, supra-, infra-, parasellar spread, (Knosp III(D), Knosp IV(S) noted a violation of auditory function. She was consulted by an otolaryngologist, sensorineural hearing loss on the right of the 3rd degree was diagnosed, on the left of the 1st degree. The patient underwent surgical treatment of pituitary adenoma, noted a significant improvement in auditory function in the early postoperative period. Six months later, repeated audiometry was performed, marked regression of hearing damage was noted.The case described by us indicates the reversibility of a rare complication of acromegaly - hearing loss and the importance of an interdisciplinary approach in the management of patients with this pathology.

Refractory somatotroph adenomas.

Somatotroph adenomas are usually controlled with standard therapy, which can include surgery, medical treatment and radiotherapy. Some tumors have a more aggressive behavior and are refractory to standard therapy. In this review, we summarize the phenotype of these tumors and the current options for their management.