Growth Hormone-secreting Adenomas Research Articles

The Application of Pneumatic Arm in Neuroendoscopic Transsphenoidal Pituitary Adenoma Resection.

To summarize the application experience of the pneumatic arm in transnasal sphenoidal pituitary adenoma resection under neuroendoscope. A retrospective analysis was conducted on the clinical data of 52 patients with pituitary adenoma who underwent endoscopic transsphenoidal surgery with pneumatic arm fixation in the Neurosurgery Department of the First Affiliated Hospital of Anhui Medical University from July 2021 to March 2024. Among them, there were 5 cases of pituitary microadenoma, 35 cases of macroadenoma, and 12 cases of giant adenoma. Head CT and a full set of hormones were re-examined within 24 hours after surgery to evaluate the surgical effect. Follow-up was conducted by the outpatient department after surgery to assess the clinical symptoms, hormone level, and imaging of all patients. Among 52 patients, gross total resection was achieved in 48 cases (92.3%), subtotal resection in 3 cases (5.8%), and partial resection in 1 case (1.9%). Preoperatively, 43 patients had diminished vision, with 40 showing improvement postoperatively, 1 worsening, and 2 having no significant improvement. Thirty-eight patients had headaches preoperatively, and all showed varying degrees of improvement postoperatively. Routine hormone examination within 24 hours after surgery showed that all 20 prolactinoma patients had restored normal hormone levels, 10 of 12 growth hormone-secreting adenoma patients normalized, and 4 of 6 cases of adrenocorticotropic hormone-secreting adenoma immediately relieved after surgery. Postoperative complications included intracranial hematoma in 1 case, cerebrospinal fluid leakage in 2 cases, transient diabetes insipidus in 6 cases, intracranial infection in 1 case, and no death cases. The median follow-up time of 52 patients was 18.6 months (range: 1-32 mo). During the follow-up period, the initial clinical symptoms of all patients improved to varying degrees, and they were able to work and live normally. At the last follow-up, 1 patient had recurrent tumor and 1 patient had progression. Transnasal sphenoidal resection of pituitary adenoma using a pneumatic arm-fixed neuroendoscope allows the operator to perform the surgery with both hands, resulting in satisfactory overall tumor resection and fewer surgical complications. This technique has good clinical value for promotion.

Comparative study on clinicopathological characteristics of functional and non-functional subtypes in pituitary adenomas

BackgroundPituitary adenomas comprise clinical and pathological characteristics of functional and non-functional subtypes. To enhance our understanding of diagnostic presentations, our study aimed to know the clinicopathological characteristics of pituitary adenomas of both functional and non-functional subtypes. The purpose of our study was to investigate the clinicopathological characteristics of pituitary adenomas, including demographic characteristics, clinical presentations, hormone secretion patterns, invasiveness, and cellular characteristics.MethodsA total of 41 cases of pituitary adenomas were analyzed, with 63.4% classified as non-functional adenomas (NFPA) and 36.6% as functional adenomas (FPA). Clinical presentations vary, with vision loss and headaches commonly occurring in both NFPA and FPA. In FPAs, serum hormone levels varied and were categorized into growth hormone-secreting (53.3%), ACTH-secreting (26.7%), PRL-secreting (13.3%), and FSH-secreting (6.7%) subtypes. Moreover, clinical presentations in FPA included diplopia, giddiness, vomiting, ptosis, and limb weakness. Clinical features varied across subtypes, with acromegaly in growth hormone-secreting adenomas, moon facies and weight gain in ACTH-secreting adenomas, poor facial growth in PRL-secreting adenomas, and vision loss in FSH-secreting adenomas. Meanwhile, NFPA were predominantly macroadenomas (88.5%) and exhibited various morphological patterns.ResultsThe proliferation index is higher in functional adenomas (mean 1.32) as compared to non-functional (mean 0.91). Clinical presentations varied across functional and non-functional adenomas. Growth hormone-secreting adenomas were the most common functional subtype, while LH and null cell adenomas were common non-functional subtypes. Two cases were invasive adenomas with a low Ki67 index. Sheets were the most common morphological pattern. PCA analysis revealed significant differences between the two groups, with PC 1 explaining 92.111% of the variance.ConclusionsOur study elucidates the clinicopathological characteristics of pituitary adenomas, highlighting significant differences between functional and non-functional subtypes. These findings underscore the importance of tailored diagnostic and management strategies to optimize outcomes for patients with pituitary adenomas.

Pituitary Adenoma Prevalence and Characteristics of Omani Patients: A Single Center Experience.

To estimate the incidence of pituitary adenomas (PA) in adult Omani patients and describe its epidemiological, clinical, and radiological characteristics. In this longitudinal, descriptive study, we reviewed the records of all PA patients from January 2015 to January 2020 who presented at the endocrinology facilities at Sultan Qaboos University Hospital, Muscat. The participants comprised of 112 Omani patients with PA. The incidence of PA among all adult patients at Sultan Qaboos University Hospital (inpatient and outpatient) over five years (2015-2020) was 0.23%. The cohort had a mean age of 41.0±15.0 years. Of the 112 patients included in this study, 79 (70.5%) were women. Nearly half (51; 45.5%) of adenomas were prolactinomas while 46 (41.1%) were non-functioning adenomas, and seven (6.3%) were growth hormone-secreting adenomas while six (5.4%) were adrenocorticotropic hormone secreting adenomas. Headache was present in 67 (59.8%) patients, followed by visual field defects (40; 35.7%), galactorrhea (26; 23.2%), and fatigue (19; 17.0%). The majority of women (45/79; 57.0%) presented with menstrual cycle abnormalities. Radiological appearances were nearly equally distributed between micro- and macroadenomas. Most cases (58/112; 52.0%) of PA were treated medically by cabergoline, octreotide, and replacement therapies such as hydrocortisone and thyroxin, 38 (33.9%) were treated surgically (mainly by trans-sphenoidal pituitary resection), and the remaining 10 (8.9%) cases were subjected to radiotherapy. Medical treatment combined with surgery was employed for 15 (13.4%) patients. In our investigation, PA was primarily prevalent among Omani female patients, and the most common subtype of pituitary tumors was prolactinomas. The most common presentation symptom was headaches; most female patients had menstrual irregularities. Medical treatment was the primary approach for the applicable types of PAs, while surgery and radiotherapy were found to be secondary and tertiary treatment options, respectively.

P-50 Plurihormonal cystic pituitary adenoma: Case report

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

Pediatric pituitary neuroendocrine tumors-a 13-year experience in a tertiary center.

Pediatric pituitary neuroendocrine tumor is a rare condition, and despite previous research focusing on this specific group, the main factors influencing the surgical cure rate have not been identified. We conducted a single-center retrospective study on pediatric pituitary neuroendocrine tumor patients who visited Peking Union Medical College Hospital between 2010 and 2023. We collected data on their clinical characteristics, imaging features, surgical outcomes, and follow-up information. Additionally, we used multiple-factor logistic regression to investigate the factors affecting the surgical cure rate of pediatric pituitary neuroendocrine tumor. 232 patients were diagnosed with pediatric pituitary neuroendocrine tumors, with a higher incidence in females. The most common type was ACTH-secreting adenoma (90/232), followed by prolactin-secreting adenoma (63/232), and growth hormone-secreting adenoma (41/232). The majority of pediatric adenomas were macroadenomas (139/232), and some tumors were associated with cystic changes or hemorrhage (58/232), while a few exhibited invasion of the cavernous sinus (33/232). The results of the multivariate analysis indicated that the different hormone secretion types, macroadenoma or the presence of cystic changes or hemorrhage were not significant risk factors for the cure rate after the first surgery. However, the invasion of the cavernous sinus was found to be an important factor influencing the postoperative cure rate. Most pediatric pituitary neuroendocrine tumors with cavernous sinus invasion were macroadenomas, and some displayed characteristics of refractory pituitary neuroendocrine tumors, with some patients experiencing irreversible complications after surgery. Pediatric pituitary neuroendocrine tumors are complex, and the postoperative cure rate is particularly poor for tumors with cavernous sinus invasion. Although macroadenoma itself does not significantly impact the postoperative cure rate, it is still recommended to diagnose and treat early to avoid unnecessary surgery or surgical complications.

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

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

Multidisciplinary management of difficult/aggressive growth-hormone pituitary neuro-endocrine tumors.

Growth Hormone-secreting adenomas exhibits variable biological behavior and heterogeneous natural history, ranging from small adenomas and mild disease, to invasive and aggressive neoplasms with more severe clinical picture. Patients not cured or controlled after neurosurgical and first-generation somatostatin receptor ligands (SRL) therapy could require multiple surgical, medical and/or radiation treatments to achieve disease control. To date, no clinical, laboratory, histopathological, or neuroradiological markers are able to define the aggressiveness or predict the disease prognosis in patients with acromegaly. Therefore, the management of these patients requires careful evaluation of laboratory assessments, diagnostic criteria, neuroradiology examinations, and neurosurgical approaches to choose an effective and patient-tailored medical therapy. A multidisciplinary approach is particularly useful in difficult/aggressive acromegaly to schedule multimodal treatment, which includes radiation therapy, chemotherapy with temozolomide and other, recent emerging treatments. Herein, we describe the role of the different members of the multidisciplinary team according to our personal experience; a flow-chart for the therapeutic approach of difficult/aggressive acromegaly patients is proposed.

Abstract #1413664: A Case of Familial Isolated Pituitary Adenoma Emphasizing an Often-Overlooked Aspect of Medical History

Familial Isolated pituitary adenoma (FIPA) is a rare cause of pituitary adenoma and underscores the importance of family history and the knowledge of screening guidelines in these patients. A 26-year-old female presented with secondary amenorrhea, galactorrhea, headaches and dizziness. Labs showed Prolactin 501 ng/ml (3.3-26.7 ng/mL) and IGF 391 ng/ml (96-301 ng/mL). MRI of the brain showed a 12 x 14 x 15 mm pituitary mass. Acromegaly was confirmed with glucose suppression test with growth hormone (GH) lowering to 1.08 ng/ml (< 0.8 ng/ml). Further history revealed a paternal cousin with gigantism diagnosed at the age of 17. She underwent transsphenoidal resection of the adenoma which stained positive for GH and prolactin. Post operative labs show improved levels: Prolactin 31 ng/mL (3.3-26.7 ng/mL) and IGF 317 ng/mL (96-301 ng/mL). Genetic evaluation showed a pathogenic mutation in AIP (aryl hydrocarbon receptor-interacting protein). Labs 4 months later- Prolactin 36.1 ng/mL (3.3-26.7 ng/mL), IGF 209 ng/mL (96-301 ng/mL), and GH 0.1 ng/mL (0.05-8.00 ng/mL). She was amenorrheic post surgery and with hormone replacement therapy, regular menstrual cycles ensued. Surveillance showed consistently normal IGF but prolactin levels were trending upwards. Prolactin: 80 ng/mL (3.3-26.7 ng/mL). A repeat MRI brain did not show any adenoma. She was started on Cabergoline and that helped with normalization of prolactin levels. FIPA is a rare hereditary disorder responsible for less than 2% of pituitary adenomas. Mutation of AIP is seen in 20% cases and associated with worse outcomes. The peak age of onset is between 10-30 years of age. Affected patients tend to have larger tumors than non-FIPA which increases the risk of pituitary apoplexy. GH secretion is the most common; followed by prolactin, GH-Prolactin co-secretion, non-functional and rarely TSH secreting. It has an autosomal dominant transmission but with incomplete penetrance often skipping generations making the diagnosis even more challenging. Obtaining detailed family history in any patient with pituitary adenoma is essential in uncovering the inheritance pattern of this disease. Screening for FIPA and AIP is recommended if patients are noted to have- 1. GH secreting adenoma diagnosed before the age of 18 2. Pituitary macroadenoma (>10 mm) diagnosed before the age of 30 3. Any pituitary adenoma with a family history of pituitary adenoma in more than one member First degree family members of patients with FIPA and AIP need to be tested for the mutation. Patients with positive mutation are recommended to undergo screening evaluation as follows- 1. Growth assessment and evaluation for signs and symptoms of pituitary adenoma with pituitary function tests a. Age 4-30 years: annually b. Age 30-50 years: every 5 years 2. Pituitary MRI a. Age 10-30 years: every 5 years Prospective observational data shows genetic testing followed by clinical screening leads to early detection of pituitary disease which results in early interventions and better outcomes. This highlights the importance of recognition of FIPA in patients presenting with any kind of pituitary adenomas.

Pituitary microadenoma in children and adolescents: Minireview of literature and symptomatic case series

Pituitary microadenomas in children and adolescents represent a rare yet clinically significant entity, with a prevalence of up to 1 per million children and constituting only a small fraction of pediatric intracranial neoplasms. This minireview synthesizes current literature to provide an insightful overview of the epidemiology, clinical presentation, management, and outcomes of these tumors. Pituitary microadenomas are categorized as either functioning or nonfunctioning, with the former being less common in children than adults. Functioning microadenomas, such as prolactinomas, growth hormone-secreting adenomas, and ACTH-secreting adenomas, present with symptoms linked to hormonal overproduction, while nonfunctioning adenomas are often asymptomatic. Clinical presentations vary with tumor type, with common symptoms including amenorrhea, galactorrhea, gynecomastia, and headaches. Diagnosis relies heavily on hormonal assessments and MRI, with stable courses often observed in non-functioning microadenomas. We report 6 cases which were presented with variable endocrine abnormalities. Management strategies are tailored based on the tumor’s functionality and size. Medical therapy, primarily dopamine agonists, is preferred for functioning adenomas, while transsphenoidal surgery is reserved for symptomatic or non-responsive cases. Radiotherapy is considered as a third-line option. Outcomes are generally favorable, with high response rates to medical therapy and successful surgical resections. However, recurrence and long-term hormonal imbalances pose challenges, necessitating vigilant long-term follow-up. Current research is oriented towards enhancing diagnostic accuracy, understanding genetic contributions, and optimizing treatment to minimize long-term developmental impacts. This review underscores the necessity for a nuanced approach in the diagnosis and management of pediatric pituitary microadenomas, highlighting the importance of ongoing research and follow-up for optimal patient care.

154 Pituitary Adenomas Evade Apoptosis via Noxa Degradation in Cushing’s Disease

INTRODUCTION: Cushing’s disease (CD) arising from ACTH-secreting pituitary adenomas is associated with severe morbidity and mortality. Pathogenic mechanisms of sporadic CD are poorly understood. Using novel syngeneic, pairwise transcriptomic analysis of surgical tissues, we identified transcriptional upregulation of PMAIP1 (encoding pro-apoptotic noxa) in CD adenomas compared to adjacent normal gland. METHODS: We investigated noxa protein levels by immunohistochemistry in 10 CD adenoma/normal pairs and by Western blotting in two syngeneic pairs of primary human cell lines from CD adenomas. We validated our key findings in ATT20 murine pituitary corticotroph tumor cells and in corticotroph-enriched murine cell lines mCortEFGF. Proteasomal-mediated degradation was assessed by cycloheximide chase assay. Bortezomib was used for proteasomal inhibition. Cell viability was assessed using CellTiterGlo (Promega). RESULTS: Despite PMAIP1 mRNA overexpression in CD, we found consistently low noxa protein in CD adenomas compared to surrounding normal glands but not in growth hormone secreting adenomas or prolactinomas. A cycloheximide assay demonstrated proteasomal-mediated noxa degradation mCortEFGF cells, which was rescued by proteasomal inhibition using bortezomib. Bortezomib treatment decreased cell viability and induced apoptosis in mCortEFGF cells, and also inhibited growth with apoptosis induction in CD adenoma primary cells. CONCLUSION: We identified proteasomal-mediated noxa degradation as a mechanism of escape from apoptosis in CD adenomas despite PMAIP1 transcriptional upregulation. Proteasomal inhibition using bortezomib rescued noxa protein levels and induced apoptosis in a dose-dependent fashion. Bortezomib, an FDA approved medication for mantle cell lymphoma, may represent a novel therapeutic target for patients with CD.

Multivariable Diagnostic Prediction Model to Detect Hormone Secretion Profile From T2W MRI Radiomics with Artificial Neural Networks in Pituitary Adenomas.

Objective:This study aims to develop neural networks to detect hormone secretion profiles in the pituitary adenomas based on T2 weighted magnetic resonance imaging (MRI) radiomics.Methods:This retrospective model-development study included a cohort of patients with pituitary adenomas (n=130) from January 2015 to January 2020 in one tertiary center. The mean age was 46.49±13.69 years, and 76/130 (58.46%) were women. Three observers segmented lesions on coronal T2 weighted MRI, and an interrater agreement was evaluated using the Dice coefficient. Predictors were determined as radiomics features (n=851). Feature selection was based on intraclass correlation coefficient, coefficient variance, variance inflation factor, and LASSO regression analysis. Outcomes were identified as 7 hormone secretion profiles [nonfunctioning pituitary adenoma, growth hormone-secreting adenomas, prolactinomas, adrenocorticotropic hormone-secreting adenomas, pluri-hormonal secreting adenomas (PHA), follicle-stimulating hormone and luteinizing hormone-secreting adenomas, and thyroid-stimulating hormone adenomas]. A multivariable diagnostic prediction model was developed with artificial neural networks (ANN) for 7 outcomes. ANN performance was presented as an area under the receiver operating characteristic curve (AUC) and accepted as successful if the AUC was >0.85 and p-value was <0.01.Results:The performance of the ANN distinguishing prolactinomas from other adenomas was validated (AUC=0.95, p<0.001, sensitivity: 91%, and specificity: 98%). The model distinguishing PHA had the lowest AUC (AUC=0.74 and p<0.001). The AUC values for the other five ANN were >0.85 and p values were <0.001.Conclusions:This study was successful in training neural networks that could differentiate the hormone secretion profile of pituitary adenomas.

Novel Classification of Acromegaly in Accordance with Immunohistochemical Subtypes: Is There Really a Clinical Relevance?

According to the recent studies, immunohistochemical subtypes of growth hormone (GH) secreting adenomas have been considered as a predictive factor in determining the clinical outcomes including biochemical, radiologic, and endocrine remission. In a 20 year-of time period, acromegaly patients who were treated and followed at the Endocrinology Department of our University Hospital were screened for the study. Of total 98 patients, 65 patients who had been operated by transsphenoidal surgery and having postoperative specimens were included. Postoperative specimens of the surgery of the patients were classified into 3 groups based on the histochemical characteristics (densely, sparsely, and mixed). Parasellar extensions of pituitary tumors were classified into the five grades according to Knosp classification. The patients were investigated and evaluated for postoperative clinical progress, remission rates, comorbidities regarding with the histopathological patterns. Of total 65 patients, 31 were classified as densely granulated (group 1), 32 were classified as sparsely granulated (group 2), and 2 patients were assessed as mixed granulated (group 3). There was no difference between groups for age and gender. Pre-treatment of adenoma size in all groups was correlated with each other and the frequency of macroadenoma (1 vs. 2, 77.4 vs. 84.3%) was higher in two groups. Although mean initial GH levels in group 1 was higher than the other groups (p=0.03), IGF1 levels (age and gender matched) were similar in each group. Adenomas in all groups demonstrated noninvasive radiological characteristics (Knosp grade 0-1-2). Ki-67 proliferation index of both groups (64.5 vs. 50%) was predominantly 1%. With a similar follow-up period, the endocrine remission rates (GH<1 μg/l) in groups were 64 vs. 69%, respectively. In conclusion, classification according to immunohistochemical subtypes of growth hormone secreting adenomas may not be a qualified parameter to evaluate patients with patterns of aggressiveness, clinical outcomes, or treatment response.

METTL3-mediated RNA m6A Hypermethylation Promotes Tumorigenesis and GH Secretion of Pituitary Somatotroph Adenomas.

Pituitary growth hormone-secreting (GH) pituitary adenomas (PAs) cause mass effects and dysregulated hypersecretion of GH. However, somatic mutation burden is low in PAs. While progress has been made in identifying the epigenetic changes involved in GH-PA initiation, the precise details of its tumorigenesis in GH-PA patients remains to be elucidated. As N6-methyladenosine (m6A) has been shown to often play a critical role in various tumors, it represents a possible initiation point for the tumorigenesis of pituitary adenomas. However, the role of RNA methylation in GH adenomas remains unclear. Protein expression of m6A regulators was measured by immunohistochemistry. Global levels and distribution of m6A methylation were separately analyzed by m6A enzyme-linked immunosorbent assay and m6A sequencing (m6A-seq). RNA interference and lentivirus knockdown system were used to investigate the role of methyltransferase-like 3 (METTL3) and its m6A- dependent regulatory mechanism in tumor progression and GH secretion. We show that both METTL3 messenger RNA and protein expression are elevated in GH-PA samples when compared with both normal pituitary tissue specimens and nonsecreting pituitary adenomas. Levels of m6A modification increased in GH-PAs, and hypermethylated RNAs are involved in hormone secretion and cell development. Knockdown of METTL3 in GH3 cell line resulted in decreased cell growth and GH secretion. Importantly, we found that GNAS and GADD45γ act as the downstream targets in this process. Our findings strongly suggest that m6A methyltransferase METTL3 promotes tumor growth and hormone secretion by increasing expression of GNAS and GADD45γ in a m6A-dependent manner. Thus, METTL3 and the methylated RNAs constitute suitable targets for clinical treatment of GH-PAs.

Trans-Sphenoidal Surgery for "Growth Hormone-secreting adenoma; Revisiting Surgical Outcome

Objective: The purpose of this research is to review our clinical experience in transsphenoidal surgery for pituitary adenomas performed by Recep Tayyip Erdogan University Faculty of Medicine, Department of Neurosurgery and contribute to the literature in this way.Methods: This is a case review of Growth Hormone secreting pituitary adenoma operated in the Recep Tayyip Erdogan University Faculty of Medicine Department of Neurosurgery from January 2014 to May 2021. All patients underwent a microscopic transnasal approach. It was aimed gross total excision of adenoma. For functioning adenomas, hormonal assessment was done on follow-up (8 weeks) and remission was said to be achieved if normal hormonal levels were achieved along with gross total tumor removal. Surgical complications were evaluated, and postoperative follow-up with laboratory and imaging studies were performed.Results: 78 patients were operated by trans nasal route in our hospital between January 2014-June 2021. Of these 78 pituitary tumors, 22 were growth hormone secreting adenoma. The study population consisted of 22 people, 11 men and 11 women, and the average age of the population was calculated as 60.45 years ± 18.4. Statistical analysis showed that the difference between the pre-operative and post-operative somamedine and growth hormone level was statistically significantConclusions: Microscopic Trans-Sphenoidal Surgery for Acromegalic patients is a minimally invasive, safe, and efficacious choice

Evaluation of clinical, laboratory and treatment modalities of pituitary adenomas: Single center experience

Pituitary adenomas are a group of disease with broad different clinical characteristics and complications. We aimed to present the data of patients being followed in a single center and discuss the pituitary adenomas based on the literature. Two hundred and twenty patients followed at Department of Endocrinology and Metabolism, Medical School of Ondokuz Mayis University, were included into study. Clinical characteristics, laboratory findings and treatment modalities were examined retrospectively. 59% of patients were female and 41% were male. Mean age during the diagnosis was 43.7 years. Pituitary macroadenomas were 62% of all adenomas and 73% of pituitary adenomas were functional. Among the functional adenomas, the most frequently seen types were prolactin-secreting adenoma and growth-hormone secreting adenoma. Treatment options were surgical treatment (67%), medical treatment (20%) and radiotherapy (7%). Post-operative complications were developed in 27 (13.2%) of patients. In patients with non-functional adenoma, the cure after surgery was detected as 19.6% and the remission after the surgery was detected as 8.9%. In this study, the characteristics of the pituitary adenomas were found similar to the literature in general. The early diagnosis of the disease has a significant importance in terms of treatment and the response to the treatment.

Final Outcome in Growth Hormone–Secreting Adenomas After Combination of Maximal Tumor Resection and Medical Treatment

Gross total resection (GTR) is not always possible in acromegalic patients, especially in patients with invasive growth hormone-secreting adenomas. We analyzed the biochemical remission outcome in relation to extent of tumor resection and effectiveness of medical treatment in cases of remnant tumor. Retrospective analysis was performed of acromegalic patients operated on between 2002 and 2017. Preoperative imaging, tumor invasiveness, extent of resection, and biochemical remission were collected. Patients with tumor remnant not amenable to second surgery began medical treatment. The relationship between pituitary adenoma remnant volume and final biochemical outcome was analyzed. Of 120 acromegalic patients operated on, 82 underwent transsphenoidal microsurgery and 38 underwent endonasal endoscopic approach. GTR was achieved in 72 cases (60%); subtotal resection (STR), 21 (17.5%) cases; and partial resection, 27 (22.5%) cases. There was a nonsignificant higher rate of GTR/STR in patients who underwent endonasal endoscopic approach. However, a significantly higher remission rate (89.45% vs. 67.1%) was achieved in these patients (P < 0.01). Greater tumor volume and invasiveness were associated with a lower remission (P < 0.05). Patients with tumor remnant who achieved biochemical remission with added medical therapy had a significantly smaller tumor volume (P < 0.001). The more aggressive surgical resection is, the greater the chance of attaining final biochemical remission, whether or not GTR is achieved. Medical therapy effectiveness is enhanced in cases with STR. Invasive growth hormone-secreting macroadenomas that are not surgically amenable to total resection are best managed with a combination of safe STR and medical treatment.

A single-center experience of transsphenoidal endoscopic surgery for acromegaly in 73 patients: results and predictive factors for remission

Background Transsphenoidal endoscopic surgery is the first-line treatment for growth hormone-secreting adenomas. Objective To analyse the results of the transsphenoidal endoscopic approach for acromegaly and to determine the predictive factors of remission. Methods A single-centre retrospective review was performed in patients who underwent endoscopic transsphenoidal surgery for acromegaly between January 2009 and January 2019. Demographic features, clinical presentation, histopathology records, complications and pre- and postoperative radiologic and endocrinological assessments were evaluated. The factors that influenced the remission rates were investigated. Results A total of 73 patients underwent surgery via the transsphenoidal endoscopic approach. Cavernous sinus invasion was detected in 32 patients (43.8%); and macroadenoma, in 57 (78%). The pathology specimens of the 27 patients (36.9%) showed dual-staining adenomas with prolactin. A total of 51 patients (69.8%) attained biochemical remission 1 year after surgery. A second operation was performed in 10 patients (13.6%) with residual tumours without biochemical remission in the first year. Six (60%) of the patients attained remission at the last follow-up. Transient diabetes insipidus was observed in 18 patients (24.6%); and rhinorrhoea, which was resolved with conservative treatment, in 4 (5.4%). None of the patients developed panhypopituitarism. The presence of cavernous sinus invasion and preoperative IGF-1, immediate postoperative GH and third-month IGF-1 levels were predictive of remission. Conclusion Transsphenoidal endoscopic surgery is a safe and effective treatment for acromegaly. Reoperation should be considered in patients with residual tumours without remission.

Endoscopic endonasal lateral transellar approach for growth hormone-secreting adenomas with cavernous sinus invasion: Technical note and surgical results

BackgroundCavernous sinus (CS) invasion is found in 15–20% of pituitary adenomas; it represents a poor prognosis factor and a surgical challenge even in experienced pituitary centers. We present our experience and technical note description for surgical management of pituitary adenomas with CS invasion in acromegaly by the transsellar lateral approach with an endoscopic endonasal transsphenoidal route. Methodprospective case series of patients who underwent endoscopic endonasal surgery for Growing Hormone (GH) producing adenomas with CS invasion treated at the Neurosurgery departments of National Institute of Neurology and Neurosurgery in Mexico City, and of Toluca Medical Center of Social Security Institute of the State of Mexico and Provinces between January 2014 and March 2019. ResultsThirty-two of 94 patients with diagnosis of pituitary adenoma treated at our institutions (34%) had acromegaly; thirteen of patients with acromegaly diagnosis met the inclusion criteria for CS invasion. Postoperative images reported gross total resection in 10 patients (76.9%). Mean follow-up time was 28.3 months. Remission criteria were achieved in nine patients (69.2%), with one of these patients (11.1%) having recurrence during follow up. All patients with no biochemical remission had improvement in GH and IGF profiles. Three patients without remission underwent radiosurgery (14Gy), and one patient had remission after the procedure. ConclusionsWe consider this to be a safe and efficient approach for tumors invading CS, when surgical team have good experience in endoscopy of the skull base and reconstruction techniques, appropriate instruments are available, and tumor has soft consistency.

Growth Hormone (GH) and Thyroid Stimulating Hormone (TSH) Co-Secreting Pituitary Macroadenoma

Background: TSH secreting pituitary adenomas are rare and accounts for 0.5-3% of all pituitary adenomas. Only 20-25% of those adenomas co-secrete other hormones like growth hormone or prolactin. Mixed GH and TSH secreting adenomas present with symptoms from tumor growth and features of both acromegaly and hyperthyroidism. Clinical Case: A 57 years old woman with a past medical history of chronic joint pains and bilateral knee swelling presented to her PCP with complaints of chronic fatigue. Evaluation revealed a normal TSH level and MNG and patient did not have any further work-up. She reported undergoing periodic knee arthrocentesis which gave her only temporary pain relief. Two years later, patient presented with complaints of unintentional weight loss, tremors and palpitations. She also reported enlargement in the size of hands, feet and forehead and no improvement in the knee swelling after multiple arthrocentesis. Lab evaluation revealed high free T4 2.31ng/dl (0.58-1.64), high free T3 6.44pg/ml (2.50-4.30), non-suppressed TSH 1.32mU/L (0.34-5.00), elevated IGF-1 415ng/ml (47-236), GH 7.76ng/ml (0.01-3.61) and prolactin 6.69ng/mL (2.74-26.72). Neck USG showed multiple nodules and 24hr radioactive iodine uptake scan showed increased uptake at 43%. 75gm OGTT showed non-suppression of GH level. MRI of brain showed 1.8 cm pituitary macroadenoma. Patient underwent transsphenoidal pituitary resection in January 2018 and the final pathology showed positive tumor staining for GH and TSH. Following surgery, patient reported improvement in symptoms. Lab work-up from October 2018 showed normal IGF 189 ng/ml (47-236), normal GH 0.35(0.01-3.61), Free T4 0.80(0.58-1.64), Free T3 2.41(2.50-4.30), TSH 0.06(0.34-5.00) and MRI from August 2020 showed no evidence of residual pituitary tumor. Conclusion: This is a rare case of a GH and TSH co-secreting pituitary macroadenoma. This case highlights the importance of considering acromegaly early in the differential diagnosis of patients presenting with chronic musculoskeletal symptoms and to pursue work up for central hyperthyroidism in a hyperthyroid patient presenting with a non-suppressed TSH level.

Deployment of a bioabsorbable plate as the rigid buttress for skull base repair after endoscopic pituitary surgery.

Bioresorbable alloplastic implants have become desirable as a rigid buttress for reconstructing skull base defects. This study aimed to describe the use of a biodegradable plate (PolyMax RAPID) in skull base repair of endoscopic endonasal pituitary surgery and to investigate the clinical outcome and safety of this novel method. Between January 2019 and January 2020, 22 patients with pituitary adenomas who underwent endoscopic skull base repair with a Polymax RAPID plate were included. After endonasal transsphenoidal surgery, a trimmed bioresorbable plate was placed in the position between the dura and the bone of the skull base to reconstruct the sellar floor and buttress the pituitary gland and sellar packing. The patient demographics, radiologic imaging, and postoperative outcomes were carefully reviewed. All patients were followed up by a routine nasal endoscopic assessment and radiologic examinations. The present study comprised 10 (45.5%) males and 12 (54.4%) females with an average age of 51.9 years. There were 7 (31.8%) growth hormone (GH) secreting adenomas, 2 (9.1%) thyroid stimulating hormone (TSH) secreting adenomas, and 13 (59.1%) non-functioning adenomas. Enlarged sellar floor and paranasal sinusitis were seen in 13 (59.1%) and 11 (50.0%) cases shown by preoperative computed tomography (CT) or magnetic resonance imaging (MRI), respectively. There were 6 (27.3%) grade-1 and 16 (72.7%) grade-0 cases by intraoperative cerebrospinal fluid (CSF) leak grading. None of these patients received lumbar drains postoperatively and no postoperative CSF rhinorrhea was detected in our series. The PolyMax RAPID plates which could be clearly identified on postoperative CT or sagittal T1-weighted MRI were shown to provide an ideal rigid buttress for sellar repair. The Polymax RAPID plate can be an optimal implant to achieve rigid repair of sellar floor defects after endonasal transsphenoidal pituitary surgery.