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ObjectivePostoperative nonfunctioning pituitary tumor (NFPT) regrowth is a significant concern, but its predictive factors are not well established. This study aimed to elucidate the pathological characteristics of NFPTs indicated for reoperation for tumor regrowth.MethodsPathological, radiological, and clinical data were collected from patients who underwent repeat operation for NFPT at Moriyama Memorial Hospital (MMH) between April 2018 and September 2023. For comparison, we also gathered data from patients who underwent initial surgery for NFPT during the same period at MMH.ResultsOverall, 61 and 244 NFPT patients who respectively underwent reoperation and initial operation were evaluated. The mean period between the previous operation and reoperation was 113 months. Immunonegativity for any adenohypophyseal hormone was significantly more frequent in the reoperation group than in the initial operation group. In addition, the rate of hormone-negative but transcription factor–positive (H-/TF+) tumors among silent gonadotroph tumors was significantly higher in the reoperation group than in the initial operation group. Furthermore, seven silent corticotroph tumors (SCTs) in the reoperation group were ACTH-negative but TPIT-positive. Because most of the previous surgeries were performed in other hospitals a long time ago, we could procure the previous pathological results with immunohistochemistry (IHC) only from 21 patients. IHC for TF had not been performed in all the previous specimens. IHC for adenohypophyseal hormone was almost the same as the current results, and many H-/TF+ tumors were previously diagnosed as NCT. In addition, the reoperated patients were classified into 3 groups on the basis of the condition of the previous operation: gross total resection (GTR), 12 patients; subtotal resection (STR), 17 patients; and partial resection (PR), 32 patients. The mean Ki-67 LI in the GTR, STR, and PR subgroups were 1.82, 1.37, and 0.84, respectively, with the value being significantly higher in the GTR subgroup than in the PR subgroup (P < 0.05).ConclusionsThe ratio of H-/TF+ tumors is significantly higher in symptomatically regrown tumors than in the initial cases, which used to be diagnosed as NCT. PR cases tend to grow symptomatically in a shorter period, even with lower Ki-67 LI than GTR cases.

The genetic alterations, protein expressions, and clinical characteristics of growth hormone-producing pituitary adenomas/somatotroph pituitary neuroendocrine tumors are integrated to detect molecules associated with acromegaly characteristics.

Objective: To report a case of pituitary functioning gonadotroph microadenoma accompanied by ovarian hyperstimulation syndrome (OHSS) in a woman of reproductive age. Design: A case report. Setting: Tertiary care unit of a university hospital. Patients: A 42-year-old parous woman with bilateral ovarian enlargement presumed to be secondary to a functioning gonadotroph pituitary microadenoma. Interventions: Oral contraceptives and endoscopic transsphenoidal surgery for adenoma that initially could not be visualized on a magnetic resonance imaging (MRI) scan. Main Outcome Measures: Medical and radiographic assessment of endogenously induced OHSS and its resolution after treatment. Results: The patient was diagnosed with OHSS secondary to elevations in endogenous levels of follicle-stimulating hormone (FSH). The cranial contrast-enhanced MRI scan did not show any apparent tumor in the pituitary gland. She was, therefore, treated with oral contraceptives, which resulted in a modest resolution of ovarian enlargement; however, this treatment became ineffective 3 years later. A small pituitary adenoma (maximum diameter of 8 mm) was suspected on repeated MRI (2 years after the first MRI). Selective adenomectomy was performed, which resulted in normalization of the ovarian size and resumption of regular menstrual cycles. Conclusions: We report a case of a functional pituitary microadenoma secreting FSH in quantities significant enough to result in OHSS. The excessive FSH production was resistant to medical therapy; however, surgical treatment was ultimately successful.

Abstract Central diabetes insipidus (CDI) is a rare condition caused by various underlying diseases including inflammatory and autoimmune diseases, and neoplasms. Obtaining an accurate definitive diagnosis of the underlying cause of CDI is difficult. Recently, anti-rabphilin-3A antibodies were demonstrated to be a highly sensitive and specific marker of lymphocytic infundibuloneurohypophysitis (LINH). Here, we report a detailed case series, and evaluated the significance of anti-rabphilin-3A antibodies in differentiating the etiologies of CDI. A prospective analysis was conducted in 15 consecutive patients with CDI from 2013 to 2020 at a single referral center. Anti-rabphilin-3A antibodies were measured and the relationship between antibody positivity and the clinical/histopathological diagnoses was evaluated. Among 15 CDI patients, the positive anti-rabphilin-3A antibodies were found in 4 of 5 LINH cases, 3 of 4 lymphocytic panhypophysitis (LPH) cases, one of 2 sarcoidosis cases, and one intracranial germinoma case, respectively. Two Rathke cleft cyst cases and one craniopharyngioma case were negative. This is the first report of anti-rabphilin-3A antibodies positivity in CDI patients with biopsy-proven LPH. Measurement of anti-rabphilin-3A antibodies may be valuable for differentiating CDI etiologies.

Aggressive somatotroph pituitary tumor that causes acromegaly is extremely rare and resists conventional treatments such as multiple surgeries, radiotherapies, and various types of somatostatin analogs. Here, we propose a novel treatment option for these rare cases by discussing our case and reviewing the literature. We experienced an aggressive somatotroph tumor in a 52-year-old woman with acromegaly. Not only could a complete remission of growth hormone (GH) and insulin-like growth factor-1 (IGF-1) not be obtained, but the tumor continued to grow and eventually recurred around the brainstem despite multidisciplinary treatments. We employed immunohistochemistry and a three-dimensional (3D) spheroid ex vivo assay to determine the best treatment option for this case. Although histology showed strong O6-methylguanine DNA methyltransferase expression and high Ki-67 labeling index (22%), temozolomide (TMZ) combined with capecitabine (CAPTEM) treatment was performed based on the results of the patient-derived 3D spheroid ex vivo assay, which predicted more effective treatment with CAPTEM than with TMZ alone. Consequently, GH and IGF-1 levels were restored to normal range with remarkable tumor shrinkage after CAPTEM treatment. To the best of our knowledge, there have been even very few reports describing successful treatment for such aggressive and refractory somatotroph tumors and this is the first report showing the effectiveness of CAPTEM on refractory somatotroph tumor both ex vivo and in vivo.

Context: Desmopressin orally disintegrating tablets (ODTs) are widely used to treat arginine vasopressin deficiency (AVP-D). However, limited information is available on the dosage regimen; the dosage for each patient is selected based on their response to the initiation dose. Objective: To investigate the relationships between clinical characteristics and the daily dose of ODTs and to identify factors that affect ODT dosages. Methods: This retrospective study included 209 adult patients with AVP-D. Patients were administered ODTs sublingually and instructed to restrict eating and drinking for 30 minutes after taking ODTs using a patient leaflet. ODT dose titration was conducted during hospitalization with close monitoring of urine output, body weight, and serum sodium levels. Multivariable linear regression models were applied to identify clinical factors associated with the daily dose of ODTs at discharge. We also evaluated the dosage at 1 year in 134 patients who were followed up in our hospital. Results: The median daily dose of ODTs at discharge was 90 µg (IQR 60-120 µg). Multivariable linear regression models identified sex, age, and estimated creatinine clearance (eCCr) as significant factors associated with the daily dose of ODTs, with eCCr having the strongest effect. After excluding patients recovering from AVP-D, 71% of those followed up at our hospital took the same daily dose at 1 year after discharge. Conclusion: To achieve the safe and stable treatment of AVP-D, the daily dose of ODT needs to be selected based on a patient’s sex, age, and eCCr under appropriate sublingual administration by patient education. [ABSTRACT FROM AUTHOR]

Postoperative delayed epistaxis is a rare but serious complication following endoscopic endonasal surgery for pituitary adenoma. It usually originates in the septal branch of the sphenopalatine artery (SPA), whereas we experienced a case of postoperative delayed epistaxis from the posterior lateral nasal branch of the SPA after endoscopic endonasal approach with middle turbinectomy. A 38-year-old woman underwent an endoscopic transsphenoethimoidal approach combined with middle turbinectomy for the removal of recurrent atypical growth hormone-secreting adenoma invading to the left cavernous sinus. She suddenly showed delayed massive epistaxis two weeks after surgery. Emergency endoscopic endonasal surgery under general anesthesia confirmed bleeding from the posterior lateral nasal branch of the SPA. To our knowledge, this is the first case reporting that delayed epistaxis occurred due to the bleeding from the posterior lateral nasal branch of the SPA after endoscopic endonasal approach for pituitary adenoma. It is important for neurosurgeons to be aware of the possibility of delayed epistaxis from injury of the posterior lateral nasal branch of the SPA during endoscopic endonasal approach with middle turbinectomy to the lateral nasal wall.

Patients with acromegaly exhibit reduced life expectancy and increased prevalence of age-related diseases, such as diabetes, hypertension, and cardiovascular disease. However, the underlying mechanism has not been fully elucidated. Telomere shortening is reportedly associated with reduced life expectancy and increased prevalence of these age-related diseases.We measured telomere length in patients with acromegaly using quantitative PCR method. The effect of GH and IGF-I on telomere length and cellular senescence was examined in human skin fibroblasts.Patients with acromegaly exhibited shorter telomere length than age-, sex-, smoking-, and diabetes-matched control patients with non-functioning pituitary adenoma (0.62 ± 0.23 vs. 0.75 ± 0.35, respectively, P = 0.047). In addition, telomere length in acromegaly was negatively correlated with the disease duration (R2 = 0.210, P = 0.003). In vitro analysis revealed that not GH but IGF-I induced telomere shortening in human skin fibroblasts. Furthermore, IGF-I-treated cells showed increased senescence-associated β-galactosidase activity and expression of p53 and p21 protein. IGF-I-treated cells reached the Hayflick limit earlier than GH- or vehicle-treated cells, indicating that IGF-I induces cellular senescence.Shortened telomeres in acromegaly and cellular senescence induced by IGF-I can explain, in part, the underlying mechanisms by which acromegaly exhibits an increased morbidity and mortality in association with the excess secretion of IGF-I.

Background: Pituitary metastasis from papillary thyroid cancer (PTC) is rare and only a few cases have been reported. Case Description: We report the case of a patient who presented with visual dysfunction and panhypopituitarism. Magnetic resonance imaging revealed a pituitary tumor and hydrocephalus. Transsphenoidal surgery had been indicated, but his surgery had been postponed due to COVID-19 pandemic. During that waiting period, he showed pituitary apoplexy with consciousness disturbance, resulting in acute adrenal insufficiency and diabetes insipidus. He was urgently hospitalized and underwent transsphenoidal surgery. Rapid and permanent pathological examinations have confirmed metastasis of PTC to the pituitary. The patient also underwent serial thyroidectomy. He was also suspected to have secondary hydrocephalus and underwent lumboperitoneal shunting after excluding cerebrospinal fluid metastasis. Thereafter, his cognitive dysfunction and performance status improved dramatically. Conclusion: To the best of our knowledge, this is the first patient with PTC who developed pituitary apoplexy secondary to metastasis. [ABSTRACT FROM AUTHOR]

Context: Mechanisms underlying pituitary corticotroph adenoma ACTH production are poorly understood, yet circulating ACTH levels closely correlate with adenoma phenotype and clinical outcomes.Objective: We characterized the 5' ends of proopiomelanocortin (POMC) gene transcripts, which encode the precursor polypeptide for ACTH, in order to investigate additional regulatory mechanisms of POMC gene transcription and ACTH production.Methods: We examined 11 normal human pituitary tissues, 32 ACTH-secreting tumors, as well as 6 silent pituitary corticotroph adenomas (SCA) that immunostain for but do not secrete ACTH.Results: We identified a novel regulatory region located near the intron2/exon3 junction in the human POMC gene, which functions as a second promoter and an enhancer. In vitro experiments demonstrated that CREB binds the second promoter and regulates its transcriptional activity. The second promoter is highly methylated in SCA, partially demethylated in normal pituitary tissue, and highly demethylated in pituitary and ectopic ACTH-secreting tumors. In contrast, the first promoter is demethylated in all POMC-expressing cells and is highly demethylated only in pituitary ACTH-secreting tumors harboring the USP8 mutation. Demethylation patterns of the second promoter correlate with clinical phenotypes of Cushing's disease.Conclusion: We identified a second POMC promoter regulated by methylation status in ACTH-secreting pituitary tumors. Our findings open new avenues for elucidating subcellular regulation of the hypothalamic-pituitary-adrenal axis and suggest the second POMC promoter may be a target for therapeutic intervention to suppress excess ACTH production. [ABSTRACT FROM AUTHOR]

Background: Injury of the internal carotid artery (ICA) during transsphenoidal surgery (TSS) is a rare but critical complication. There are several reports on endovascular treatment of ICA injury during TSS. With the recent flourishing of extended TSS, injuries to the distal arteries such as the anterior cerebral artery (ACA) are more likely to occur. Case Description: In the present case, we report a pseudoaneurysm of the right ACA due to injury during extended TSS for aggressive prolactinoma. Due to the absence of collateral vessels, the pseudoaneurysm had to be obliterated while preserving the parent artery. Hence, we decided to treat the pseudoaneurysm using stentassisted coiling (SAC). The pseudoaneurysm was completely obliterated and he was discharged without any complications. Conclusion: To the best of our knowledge, this is the first case in which an ACA pseudoaneurysm caused by injury during the TSS was treated with SAC and the parent artery was preserved. [ABSTRACT FROM AUTHOR]

Context: Somatic mutations in the ubiquitin-specific peptidase USP8 gene were recently detected in one- to two-third(s) of corticotroph adenomas of Cushing's disease (CD). These mutations may lead to the deubiquitination of EGFR, thereby increasing EGFR signaling, which has been implicated in ACTH hypersecretion. Objective: Our objective was to determine the impact of USP8 mutations on the clinicopathological features of CD. Subjects and methods: USP8 mutations as well as clinicopathological characteristics were examined in 60 corticotroph adenomas including 15 Crooke's cell adenomas (CCAs), a rare histological variant presenting with generally aggressive behavior, using qRT-PCR and/or immunohistochemistry. Results: USP8 mutations were exclusively detected in women, except for one case, with a prevalence of 42.2% in non-CCA and 13.3% in CCA (overall 35%). Clinically well-behaved presentations including microadenoma and curative resection were more common in mutated cases. The expression of EGFR was not associated with the mutation status. In contrast, mutated tumors expressed significantly higher levels of POMC, SSTR5, and MGMT. Conclusions: Microadenomas that strongly express POMC were common among mutated tumors, which may lead to the mechanisms by which very small adenomas secrete excess ACTH to present overt CD. While USP8 mutations were less likely to enhance tumorous ACTH hypersecretion via EGFR-mediated activation, the presence of USP8 mutations may predict favorable responses to the somatostatin analog pasireotide, which exhibits high affinity for SSTR5. In contrast, non-mutated aggressive tumors such as CCA may respond better to the alkylating agent temozolomide because of their significantly weak expression of MGMT. [ABSTRACT FROM AUTHOR]

Bromocriptine, a potent D2-dopamine agonist, suppresses growth hormone (GH) secretion in most patients with acromegaly and has been approved for the treatment of acromegaly. Here we report a patient with acromegaly who showed increased GH secretion after administration of bromocriptine. A 70-year-old man with acromegalic manifestation was admitted to our hospital because of a pituitary tumor invading to the right cavernous sinus detected by brain magnetic resonance imaging. Serum GH and insulin-like growth factor-I (IGF-I) levels were elevated in several occasions (GH: 15.0-51.7 ng/mL, reference range: < 2.47 ng/mL; and IGF-I: 776-856 ng/mL, reference range: 57-175 ng/mL). Effect of bromocriptine on serum GH levels was then studied because pre-operative treatment with a D2-dopamine agonist was planned in order to reduce the tumor size and serum GH levels before surgery. After oral administration of 2.5 mg of bromocriptine, serum GH levels were unexpectedly increased from 30.7 ng/mL to 189 ng/mL, despite the fact that the levels of prolactin (PRL) were decreased from 4.2 ng/mL to 0.6 ng/mL. By contrast, serum GH levels were decreased by a somatostatin analogue, octreotide. Transsphenoidal surgery of the pituitary tumor was performed after treatment of octreotide. Histological analysis and immunohistochemistry revealed a GH-producing pituitary adenoma positive for D2-dopamine receptor. This case of acromegaly suggests that the preliminary test with a single administration of a short-acting D2-dopamine agonist, bromocriptine, is mandatory before the long-term therapy with a D2-dopamine agonist in patients with GH-secreting pituitary tumors. [ABSTRACT FROM AUTHOR]

Objective: Excess GH causes insulin resistance and impaired glucose metabolism. The objective of this study was to clarify the prevalence of ketoacidosis as the initial presenting symptom of acromegaly. Design and methods: Data were collected from 860 patients with acromegaly who underwent pituitary surgery at Toranomon Hospital over the last 32 years, between 1980 and 2011. Results: Nine cases had ketoacidosis before being diagnosed with acromegaly, including seven males and two females with a mean±S.D. age of 38.8±14.2 years. Serum GH and IGF1 levels were 155± 203 ng/ml and 9.86±0.68 SDS before pituitary surgery and 3.6±1.7 ng/ml and 3.72±3.40 SDS after surgery respectively. The maximum tumor diameter was 28.2±11.6 mm (ranging from 15 to 47 mm, n=8). None of the patients were diagnosed with diabetes mellitus (DM) nor were they positive for antibodies related to type 1 DM. A possible precipitating factor for ketoacidosis in six cases was excessive ingestion of sugar-containing soft drinks. All the cases had invasive pituitary adenomas. After pituitary surgery, plasma glucose levels were under control without requiring insulin in all cases. Furthermore, six patients did not need oral hypoglycemic agents. Conclusions: Approximately 1% of patients with acromegaly presented with diabetic ketoacidosis as their first clinical condition. [ABSTRACT FROM AUTHOR]

Although surgical extirpation by transsphenoidal microsurgery is a major remedy for pituitary adenomas, adjuvant therapy also plays an important role in achieving tumor growth control and endocrine normalization in hormone-secreting tumors. Historically, the treatment options for pituitary adenomas included microsurgery, medical management, and fractionated radiotherapy, but radiosurgery has recently emerged as a practical treatment option. In this paper, we will describe the indications, radiosurgical procedure, results, histological change, and complications of gamma knife radiosurgery (GKS) for pituitary adenomas based on our experience since 1991 and a review of the literature. [ABSTRACT FROM AUTHOR]