Anterior Pituitary Cells Research Articles

Pituitary carcinoma with multiple metastases: A case report and literature review

Pituitary carcinoma is traditionally defined as a tumor of adenohypophyseal cells that metastasizes systemically or craniospinally. They account for approximately 0-2% of all pituitary tumors. Their diagnosis and treatment is challenging. We report the case of a woman who was initially diagnosed with adenoma and scheduled for surgery. An MRI of the brain three weeks later showed metastatic lesions. The patient died ten days after surgery due to adrenal crisis. The development of pituitary carcinoma is extremely unusual. It could be misdiagnosed with an invasive pituitary adenoma. Until recently, treatment of pituitary carcinoma was mainly palliative and did not appear to increase overall survival.

7815 Pembrolizumab-Induced Autoimmune Hypophysitis with “Isolated” ACTH Deficiency: Need for Heightened Awareness and Action Among Medical Fraternity

Abstract Disclosure: S. Shankar: None. S.S. Sundar: None. M.S. Vaishnav: None. L. Lekkala: None. K. Thummala: None. S. Srikanta: None. T. Deepak: None. R.B. Vijay: None. K. Muniraj: None. V. Nath: None. C. Siddlingappa: None. P. Ravikumar: None. M.D. Chitra: None. Introduction: Autoimmune hypophysitis caused by immune checkpoint inhibitors [ICIs; anti-CTLA-4 (Ipilimumab alone 7.9%), anti-PD-1 (Pembrolizumab alone 1.7%; nivolumab alone 0%)] are being increasingly documented, with anterior hypopituitarism affecting corticotrophs more commonly than thyrotrophs and gonadotrophs (large time span of onset; different recovery patterns). Clinical Case 2021 Sep Age 65 years (type 2 diabetes, hypertension). Renal Cell Carcinoma S/P radical nephrectomy. 2023 Jul PET-CT= Metastatic pleuropulmonary nodules. Four admissions to Specialist Oncology Hospital [Four 2 weekly cycles of Inj Pembrolizumab 200 mg (with Tab Axitinib 10 mg/day)]. After first cycle: progressive fatigue, body aches, drowsiness. S Sodium= Pre-pembrolizumab= 137 mEq/L (135-145); Post-pembrolizumab= 124, 134, 132, 124; T3= 1.63 to 0.60 to 1.24 to 1.35 ng/mL (0.97-1.69); T4= 6.83 to 4.93 to 10.44 to 11.44 mcg/dL (5.53-11); TSH= 10.46 to 6.28 to 5.39 to 9.48 mIU/mL (0.46-4.68); S Cortisol 8 am= 1.54 mcg/dL (5-25); S Potassium= 4.59 mEq/dL (3.5-5.1)]. One episode of loss of consciousness; EEG= abnormal; MRI Brain= normal. During every hospital admission, oncology, medical, endocrinology and nephrology teams attributed the same to “illness” (no specific diagnosis) and provided symptomatic treatment (IV 3% saline, tolvaptan and sodium bicarbonate tablets).2023 Nov Medicine: Very severe nausea, anorexia, generalised weakness, myalgia, hiccoughs, and inability to walk. Frustrated family members sought admission in “new” General Hospital. S Sodium= 119, 120; S Potassium= 4.8; S Creatinine= 1.67 mg/dL (0.7-1.3); S Uric acid= 4.5 mg/dL (4.40-7.60); Urine spot Sodium= 84 mmol/L; ESR= 144 mm. Endocrinology: S Cortisol 8 am= 0.09 mcg/dL;S Cortisol post 250 mcg Inj Synacthen= 3.76 (>20);Plasma ACTH= 5.4 pg/ml (9-52). S T3= 1.35; S T4= 11.44; S TSH= 9.48; LH= 3.61mIU/mL (1.5-9.3); FSH= 1.4mIU/mL (1.4-18.1); PRL= 30.1 (2.6-13.3); Testosterone total= 314 ng/dL (241-827); TPO antibodies negative. MRI-Pituitary: Partial empty sella; infundibulum neurohypophysis normal; mild asymmetric enhancement (5.5 mm) left cavernous sinus. Treatment: Tab Hydrocortisone 25 mg/day, with complete clinical and biochemical response [Suggestion of gonadotroph dysfunction and partial recovery of thyrotrope dysfunction/ injury. Hence, not on thyroxine replacement]. Clinical Lessons: Mechanisms for differential cellular vulnerability for ICI induced autoimmune pathologies [thyroid (destructive versus stimulatory), islet beta cells, adrenal cortical cells, various anterior pituitary cells (corticotrophs vs thyrotrophs and gonadotrophs] need elucidation. Specific molecular and cellular immunopathogenic pathways in different autoimmune endocrinopathies appear distinct and disparate. Presentation: 6/2/2024

8744 Genomic Variant Landscape In Aggressive & Treatment Resistant Prolactin-Secreting Tumors

Abstract Disclosure: D. Marrero-Rodríguez: None. K. Taniguchi-Ponciano: None. F. Martinez-Mendoza: None. E. Peña-Martinez: None. S. Vela-Patiño: None. S. Hinojosa-Alvarez: None. J. Hernandez-Perez: None. R. Chavez-Santoscoy: None. E. Sosa-Eroza: None. P.E. Espinosa Cardenas: None. M. Mercado: None. Pituitary tumors (PT) represent the second most frequent intracranial tumor and this neoplasm arises from adenohypophyseal cells. Prolactin-secreting tumor (PRL-tumors) are the most commonly neoplasm of the pituitary gland and arises from lactotrophs, and account for 50% of all pituitary tumors. Pituitary tumors are highly heterogeneous lesions and many of them are invasive in up to 45%, with up to 15% being clinically aggressive. Aggressive PRL-tumors are defined as invasive tumors with unusually rapid growth rate despite maximal tolerated dopamine agonist dose and requiring additional therapy and presenting multirecurrent potential. Predicting pituitary tumor behavior remains a challenge, therefore we performed whole exome sequencing to identify genomic variant landscape from aggressive and treatment-resistant prolactin-secreting pituitary tumors. Interestingly one tumor showed one hotspot mutation in splicing factor gene SF3B1 (c.C1873T:p.R625C), a second tumor showed an stop codon in SF3B1 (c.C496T:p.R166*). We then evaluated known hereditary-related pituitary tumor genes, identifying three patients with two different GNAS allelic variants the first one showed c.A3059G:p.N1020S and two tumors with c.C1307A:p.A436D variants. PRKAR1A gene did not showed any allelic variants in our cohort, while all tumors presented c.A1636G:p.T546A variant in MEN1 gene, in AIP gene allelic variant c.C682A:p.Q228K was present in all tumors. PAX6 gene is related to pituitary gland development and function, we found a deletion (c.980delA:p.K327Rfs*29) causing frameshift present in all tumors. The target coding-gene for cabergoline, first line of treatment, DRD2 di not showed any allelic variant. Also XRCC1 and ABCB1 genes, which are related to drug and therapy response showed c.A1196G:p.Q399R and c.T2887G:p.S963A allelic variants in 100% and 88% of tumors, respectively. Together this genomic landscape could represent higher risk to harbor aggressive non-responsive PRL secreting tumor. Presentation: 6/1/2024

8144 Hypertension in Sheehan Syndrome: A Diagnostic Challenge

Abstract Disclosure: E. Ahsan: None. F.F. Foo: None. C. Lesniak: None. M. Akula: None. K. Hu: None. R. Ong: None. K. Chalasani: None. J. Cheng: None. S. Holland: None. Introduction: Postpartum pituitary necrosis, commonly known as Sheehan syndrome (SS), is the term used to describe the necrosis of anterior pituitary gland cells that occurs after significant postpartum bleeding, hypovolemia, and shock. This typically occurs after delivery, during which the mother suffers significant blood loss. The pituitary gland fails to produce hormones due to this blood loss. Depending on the degree of tissue damage, SS can have an acute or chronic course, and patients may present with a wide range of clinical symptoms at diagnosis. Acute SS is associated with postpartum pituitary infarction, which can result in hypotension, shock, hypoglycemia, hyponatremia, headache, vision disturbances, unconsciousness, and an inability to lactate. We present a rare case of SS where the patient experienced hypertension instead of classic hypotension due to postpartum preeclampsia. Clinical Case: A 40-year-old female with no significant medical history presented to the hospital for scheduled induction of labor for polyhydramnios and underwent vacuum-assisted vaginal delivery and postpartum hysterectomy due to severe postpartum hemorrhage secondary to DIC. The postpartum course was also complicated by preeclampsia with severe features. Patients developed features like excessive fatigue, hypoglycemia, hyponatremia, hypothyroidism, polyuria, and failure of lactation, which were consistent with panhypopituitarism secondary to Sheehan syndrome. However, the patient was hypertensive to 145/91 before steroids were given. Labs were significant for serum sodium 116 mmol/L (135-145 mmol/L), FSH <0.7 mIU/mL (Follicular Phase: 2.5-10.2, Mid-cycle Peak: 3.1-17.7, Luteal Phase: 1.5-9.1, Postmenopausal: 23.0-116.3), LH <0.2 mIU/m (Follicular Phase: 1.9-12.5, Mid-Cycle Peak: 8.7-76.3, Luteal Phase: 0.5-16.9, Postmenopausal: 10.0-54.7), Prolactin: 2.4 ng/mL (Non-pregnant: 3.0-30.0, Pregnant: 10.0-209.0, Postmenopausal: 2.0-20.0), PM Cortisol on admission: 1.10 ug/dL (3.44-16.76 ug/dL), plasma ACTH 7 pg/mL( 6 - 50 pg/mL), TSH 0.430 uIU/mL (0.550 - 4.780 uIU/mL), FT4 0.59 ng/dL - 1.76 ng/dL). MRI of the brain pituitary showed- A 1.5 cm region of hypoenhancement and an additional 2 mm focus of hypoenhancement in the sella, findings represent evolving pituitary necrosis. The patient received 24 units of blood transfusion and hormone replacement therapy, followed by outpatient endocrinology follow-up. Clinical lessons: Although considerable blood loss causes hypotension in patients with SS, additional postpartum medical issues can sometimes result in atypical presentations. In our patient, postpartum preeclampsia caused hypertension. Identifying the atypical symptoms of SS is just as vital as identifying its typical features to prevent potentially fatal consequences. Presentation: 6/2/2024

8184 A Case With Primary Hyperparathyroidism Caries A New Variant Of Uncertain Significance (VUS) Of The Multiple Endocrine Neoplasia Type 1 (MEN1) Gene

Abstract Disclosure: E. Caliskan Guzelce: None. E. Fieg: None. C. Pallias: None. Background: Multiple endocrine neoplasia type 1 (MEN1) is a rare, autosomal dominant disorder caused by mutations in the MEN1 tumor suppressor gene. MEN1 syndrome is classically characterized by a predisposition to tumors of the parathyroid glands, anterior pituitary, and pancreatic islet cells. However, the clinical spectrum of this disorder has been expanded: carcinoid tumors,adrenal adenomas and lipomas are more common than in the general population.We report a case whose personal and family history is highly suggestive of and consistent with a monogenic disorder such as MEN1, also found to be a carrier of a new variant of uncertain significance (VUS) of the MEN1 gene. A study performed with the French Universal Mutation Database (UMD) for the MEN1 gene showed that one-third of the missense MEN1 variants were VUSs, mainly due to the lack of clinical and segregation data. Therefore, it is very important to identify and report the subjects with VUS of the MEN1 gene. Case report: 68-year-old female with a past medical history significant for hypertension, type 2 diabetes mellitus, hyperlipidemia, CKD stage 4, and nephrolithiasis, GERD who presented with chief complaints of nausea and upper abdominal/epigastric pain and dark stools and found to have moderate hypercalcemia c/w primary hyperparathyroidism, several pancreatic cystic lesions most likely branch duct intraductal papillary mucinous neoplasms, and multinodular goiter and adrenal adenoma. Family history significant for recurrent hyperparathyroidism and nephrolithiasis; her daughter and brother had nephrolithiasis; her daughter has undergone parathyroidectomy twice. The patient's mother died at a young age because of gastric ulcer-related complications. Hyperparathyroidism-related genes were analyzed; AP2S1, CASR, CDC73, CDKN1B, GNA11, RET, MEN1, and only a Variant of Uncertain Significance, c.247_249dup (p.Leu83dup), was identified in MEN1 gene. The patient’s daughter and granddaughter are found to have the same mutation. Conclusion: This variant, c.247_249dup, results in the insertion of 1 amino acid(s) of the MEN1 protein (p. Leu83dup), but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (gnomAD no frequency). The literature has not reported this variant in individuals affected with MEN1-related conditions. Presentation: 6/3/2024

8342 A Rare Case of a Corticotropic and Gonadotropic Pituitary Double Adenoma

Abstract Disclosure: S. Gruber: None. D. Kirschenbaum: None. T. Hortobagyi: None. C. Serra: None. A. Bink: None. F. Beuschlein: None. Z. Erlic: None. Background: Pituitary adenomas account for about 15% of all intracranial neoplasms and typically arise from monoclonal proliferation of anterior pituitary cells. While lactotropic and clinically hormone-inactive adenomas make up by far the largest proportion, somatotropic and corticotropic adenomas have a significantly lower prevalence. This case describes the very rare finding of a corticotropic and gonadotropic double adenoma. Clinical Case: A 63-year-old Caucasian man (BMI 36.7 kg/m2) presented in the obesity clinic. Hypercortisolism was suspected by repeated lack of cortisol suppression in low-dose dexamethasone suppression tests [minimal 87 nmol/l] and disrupted circadian rhythm of cortisol secretion according to salivary cortisol profile. Cortisol levels in a 24-hour sample of urine were normal. ACTH levels were elevated [73 ng/l; n<61 ng/l] leading to suspicion of Morbus Cushing. Concomitant diseases include sleep apnea, arterial hypertension and newly diagnosed type 2 diabetes mellitus. Medical history was notable for deep vein thrombosis and pulmonary embolism. Other stigmata of hypercortisolism were not evident. The rest of endocrine work up confirmed partial secondary hypothyroidism and hypogondotropic hypogonadism. An MRI of the pituitary gland revealed a pituitary macroadenoma with a maximum dimension of 20 mm. The patient underwent an endoscopic transnasal adenomectomy with post-operative corticotropic insufficiency. Contrary to our expectations, the histological examination of the surgical resection revealed a gonadotrophic pituitary adenoma with SF1 and focal FSH expression. The discrepancy between clinical, biochemical and histological findings led to subsequent examinations of the specimen with detection of an small fragment accounting for less than 5% of the total sample with expression of T-Pit and ACTH but neither SF1 nor Pit-1, corresponding to an additional corticotropic adenoma with densely granulated pattern. The tumor cells did not show overlapping expression patterns of transcription factors or hormones, which indicates the coincidence of two distinct adenomas. Three months postoperatively, the patient is biochemically cured. Partial anterior pituitary insufficiency remained. Conclusion: Pituitary double adenomas are found in 0.5-1.5% of all surgical specimens. They are characterized by their origin from different cell lines, which distinguishes them from plurihormonal adenomas, which originate from one single cell line. Here we demonstrate a SF1-T-Pit lineage combination resulting in a neighboring ACTH and FSH-adenoma. In this particular case, the clinically relevant corticotropic adenoma was comparatively tiny, making it easy to miss. This illustrates well the importance of careful correlation of clinical, laboratory and histologic findings as correct diagnosis is crucial for postoperative patient management. Presentation: 6/2/2024

Structural Basis for Antagonist Binding to Vasopressin V1b Receptor Revealed by the Molecular Dynamics Simulations.

The human V1b receptor (V1bR) is primarily expressed in the corticotropic cells of the anterior pituitary where it is involved in the regulation of the hypothalamic-pituitary-adrenal (HPA) axis. The activation of V1bR induces the secretion of adrenocorticotropin hormone (ACTH) from the anterior pituitary cells which, in turn, stimulates the production of cortisol via the adrenal cortex. Clinical studies have demonstrated the chronic dysfunction of the HPA axis in patients with several psychiatric disorders. Thus, the inhibition of the V1b receptor and normalizing the HPA axis hyperactivity is a promising approach to the treatment of many stress-related disorders such as anxiety and depression. Nelivaptan is a selective V1bR antagonist that can be used for this purpose and an excellent molecule to study how antagonists interact with V1bR, especially since in recent years the experimental structures of vasopressin V2 and oxytocin receptors were solved, providing high-similarity templates for homology modeling of V1bR. Therefore, in this work, six independent molecular dynamics simulations of a V1bR-nelivaptan complex in a fully hydrated lipid bilayer, yielding a total simulation time of 6.0 μs, have been conducted. In the lowest-energy complexes obtained in this work and proposed to be the most probable structure of the V1bR-nelivaptan complex, the location of the ligand inside the receptor pocket is very similar to that of the other ligands observed in the experimental structures of the vasopressin/oxytocin receptor family. The receptor-ligand interaction has been analyzed and described, revealing the details of the molecular mechanism of this antagonist binding to V1bR and a probable contribution of L2005×40 and T2035×43 to binding selectivity.

The role of AdipoQ on proliferation, apoptosis, and hormone Secretion in chicken primary adenohypophysis cells

Adiponectin (AdipoQ), an adipokine secreted by adipocytes, has been reported to exist widely in various cell types and tissues, including the adenohypophysis of chickens. However, the molecular mechanism by which AdipoQ regulates the function of chicken adenohypophysis remains elusive. In this study, we investigated the effects of AdipoQ on proliferation, apoptosis, secretion of related hormones (FSH, LH, TSH, GH, PRL and ACTH) and expression of related genes (FSHβ, LHβ, GnRHR, TSHβ, GH, PRL and ACTH) in primary adenohypophysis cells of chickens by using real-time fluorescent quantitative PCR (RT-qPCR), cell counting kit-8 (CCK-8), flow cytometry, enzyme-linked immunosorbent assay (ELISA) and Western blot (WB) assays. Our results showed that AdipoQ promoted the proliferation of chicken primary adenohypophysis cells, up-regulated the mRNA expression of proliferation-related genes CDK1, PCNA, CCND1 and P21 (P < 0.05), as well as the increased protein expression of CDK1 and PCNA (P < 0.05). Furthermore, AdipoQ inhibited apoptosis of chicken primary adenohypophysis cells, resulting in down-regulation of pro-apoptotic genes Caspase3, Fas, and FasL mRNA expression, and decreased Caspase3 protein expression (P < 0.05). Moreover, there was an up-regulation of anti-apoptotic gene Bcl2 mRNA and protein expression (P < 0.05). Additionally, AdipoQ suppressed the secretion of FSH, LH, TSH, GH, PRL, and ACTH (P < 0.05), as well as the mRNA expression levels of related genes (P < 0.05). Treatment with AdipoRon (a synthetic substitute for AdipoQ) and co-treatment with RNA interference targeting AdipoQ receptors 1/2 (AdipoR1/2) had no effect on the secretion of FSH, LH, TSH, GH, PRL, and ACTH, as well as the mRNA expression levels of the related genes. This suggests that AdipoQ's regulation of hormone secretion and related gene expression is mediated by the AdipoR1/2 signaling axis. Importantly, we further demonstrated that the mechanism of AdipoQ on FSH, LH, TSH and GH secretion is realized through AMPK signaling pathway. In conclusion, we have revealed, for the first time the molecular mechanism by which AdipoQ regulates hormone secretion in chicken primary adenohypophysis cells.

Autoimmune Thyroiditis Mitigates the Effect of Metformin on Plasma Prolactin Concentration in Men with Drug-Induced Hyperprolactinemia.

Metformin inhibits the secretory function of overactive anterior pituitary cells, including lactotropes. In women of childbearing age, this effect was absent if they had coexisting autoimmune (Hashimoto) thyroiditis. The current study was aimed at investigating whether autoimmune thyroiditis modulates the impact of metformin on the plasma prolactin concentration in men. This prospective cohort study included two groups of middle-aged or elderly men with drug-induced hyperprolactinemia, namely subjects with concomitant Hashimoto thyroiditis (group A) and subjects with normal thyroid function (group B), who were matched for baseline prolactin concentration and insulin sensitivity. Titers of thyroid peroxidase and thyroglobulin antibodies, levels of C-reactive protein, markers of glucose homeostasis, concentrations of pituitary hormones (prolactin, thyrotropin, gonadotropins, and adrenocorticotropic hormone), free thyroxine, free triiodothyronine, testosterone, and insulin growth factor-1 were measured before and six months after treatment with metformin. Both study groups differed in titers of both antibodies and concentrations of C-reactive protein. The drug reduced the total and monomeric prolactin concentration only in group B, and the impact on prolactin correlated with the improvement in insulin sensitivity and systemic inflammation. There were no differences between the follow-up and baseline levels of the remaining hormones. The results allow us to conclude that autoimmune thyroiditis mitigates the impact of metformin on prolactin secretion in men.

Visfatin (NAMPT) affects global gene expression in porcine anterior pituitary cells during the mid-luteal phase of the oestrous cycle

BackgroundThe pituitary belongs to the most important endocrine glands involved in regulating reproductive functions. The proper functioning of this gland ensures the undisturbed course of the oestrous cycle and affects the female’s reproductive potential. It is believed that visfatin, a hormone belonging to the adipokine family, may regulate reproductive functions in response to the female’s metabolic state. Herein we verified the hypothesis that suggests a modulatory effect of visfatin on the anterior pituitary transcriptome during the mid-luteal phase of the oestrous cycle.ResultsRNA-seq analysis of the porcine anterior pituitary cells revealed changes in the expression of 202 genes (95 up-regulated and 107 down-regulated in the presence of visfatin, when compared to the non-treated controls), assigned to 318 gene ontology terms. We revealed changes in the frequency of alternative splicing events (235 cases), as well as long noncoding RNA expression (79 cases) in the presence of the adipokine. The identified genes were associated, among others, with reproductive system development, epithelial cell proliferation, positive regulation of cell development, gland morphogenesis and cell chemotaxis.ConclusionsThe obtained results indicate a modulatory influence of visfatin on the regulation of the porcine transcriptome and, in consequence, pituitary physiology during the mid-luteal phase of the oestrous cycle.

Anterior and Posterior Pituitary Function in Patients with Sheehan Syndrome - Combining the use of Insulin Tolerance Test and Copeptin Assay.

Sheehan syndrome (SS) typically involves the loss of anterior pituitary cells and rarely affects the posterior pituitary. The water deprivation test (WDT) is the gold standard for diagnosing central diabetes insipidus (CDI), but it is cumbersome. Serum copeptin measurements are an alternative for CDI diagnosis. In this study, we measured hypoglycaemia-stimulated serum copeptin in SS patients to assess posterior pituitary function alongside anterior pituitary hormone levels. This study recruited 43 patients with SS on stable hormonal replacement except for growth hormone (GH), 18 patients with CDI, and 19 body mass index (BMI) and parity-matched controls. All patients with SS and four patients with CDI underwent an insulin tolerance test (ITT), and hypoglycaemia-stimulated copeptin levels were measured at 0, 30, 45, and 90 minutes after insulin injection. The mean serum copeptin level among patients with SS (26.01 ± 12.41 pmol/L) was significantly lower than that in healthy controls (31.92 ± 7.85 pmol/L) and higher than that in patients with CDI (1.81 ± 0.14 pmol/L). Using pre-defined cut-offs for CDI, basal serum copeptin <2.69 pmol/L and stimulated levels <4.92 pmol/L for complete central DI, and basal copeptin levels >2.69 pmol/L and stimulated copeptin <4.92 pmol/L for partial central DI, 9.2% (n = 4) of patients with SS had CDI, of which half had complete CDI and half had partial CDI. A significant number of patients with SS who are on hormone replacement therapy show involvement of the posterior pituitary, despite not displaying symptoms.

How to standardize the diagnostic approach to pituitary neuroendocrine tumors.

Pituitary tumors present heterogeneous biochemical, clinico-radiological, and histological features. Although histologically benign, a non-negligible number of cases present an unpredictable aggressive behavior with local invasiveness, partial/complete resistance to treatment and/or recurrence after surgery, and, rarely, metastasize, overall leading to a significant increase of morbidity, and, thus, requiring skilled multidisciplinary management in referral Centers. Histopathological diagnosis is essential to stratify cancer patient risk and uniform follow-up among Centers. Classification of pituitary neoplasia is continuously evolving in relation to the increased knowledge of mechanisms underlying adenohypophyseal cell tumorigenesis, and the attempts of combining clinico-radiological, biochemical, intraoperative, histological, and molecular elements, with the aim of identifying aggressive forms through. An integrated standardized histopathological report has been proposed in 2019 by the European Pituitary Pathology Group, based on the indications of the 2017 WHO classification of pituitary tumors. The last edition of the WHO Classification of Central Nervous System Tumors and of Endocrine and Neuroendocrine Tumors brought substantial novelties: 1) the replacement of the term "adenoma" with "Pituitary Neuroendocrine Tumor" (PitNET), and of "carcinoma" with "metastatic PitNET," and the consequent ICD-11 recoding from benign to malignant disease; and 2) the pivotal role of lineage restricted pituitary transcription factors for histological typing and subtyping. However, this approach does not reflect the spectrum of tumor phenotypes based on hormone secretion, nor include molecular features. Efforts of interdisciplinary groups of pituitary experts should be strongly encouraged to better understand factors involved in PitNETs evolution and, consequently, standardize diagnosis and reporting based on the most recent knowledges, essential to stratify cancer patient risk and uniform follow-up among centers.

Improvement of metabolic syndrome and its components in patients who underwent transsphenoidal resection for pituitary adenoma.

Pituitary adenomas (PA) are neoplasms of pituitary adenohypophyseal cell lineage, which are the third most common cause of brain tumors among adults. Due to hormone secretion, PAs are closely related to metabolic syndrome (MetS). However, the relationship between these two entities has been scarcely studied to date. This paper aims to evaluate changes in the metabolic status of patients with PA before and after surgical treatment and to look for differences in metabolic outcomes among patients according to the adenoma type and the surgery success rate. We assessed patients with PA who went through transsphenoidal surgery for its treatment, documenting metabolic parameters before and after surgery, analyzed whole sample changes, and then stratified them according to adenoma type (nonfunctioning, somatotroph, lactotroph, and corticotroph), and surgery success (total resection, near-total resection, partial resection, subtotal resection). A total of 214 patients were enrolled for this study. The prevalence of MetS with AACE criteria went from 51.52% before surgery to 28.99% after surgery (P < 0.001). Hyperglycemia (HG) was the most beneficial component; it went from 56% pre-surgery to 40.51% post-surgery (P = 0.03). The total resection group had the best improvement, with a significant decrease of prevalence in MetS from 83 to 16% (P < 0.001), and every component, except hypoalphalipoproteinemia (HA): obesity went from 96 to 67% (P < 0.001), arterial hypertension (AH) 59 to 24% (P < 0.001), HG 74 to 23% (P < 0.001), and hypertriglyceridemia (HTG) from 81 to 54% (P < 0.001). According to MetS prevalence, there was no difference in the improvement according to PA type. Surgical treatment in patients with PA is associated with MetS improvement.

Comparing redo surgery and stereotactic radiosurgery for recurrent, residual, and/or tumors showing progression in nonfunctioning pituitary adenomas: A systematic review and meta-analysis.

Non-functioning pituitary adenomas (NFPAs) are well-differentiated benign tumors originating from the adenohypophyseal cells of the pituitary gland. They present with headaches, visual disorders, or cranial nerve deficits. NFPAs can recur, progress, or present as residual tumors. We, therefore, conducted this review to compare the effects of both revision surgery and stereotactic surgery on tumor size, visual status, endocrine status, and complications. A systematic review of published literature on recurrent, residual, or progressing NFPAs that underwent redo surgery or stereotactic radiosurgery from the inception till June 2020 was conducted as per Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Thirteen records (1209 patients) were included, and risk ratio (RR) and 95% confidence intervals (CIs) estimated from each study were pooled using a random-effects meta-analysis model. Redo surgery was the preferred intervention in patients presenting with larger tumor sizes and was more effective in reducing the tumor size as compared to stereotactic radiosurgery (SRS) (risk ratio [RR] 56.14; 95% CI, 16.45-191.58). There was more visual loss with revision surgery as compared to SRS (risk ratio [RR] 0.08; 95% CI, 0.03-0.20). However, SRS was associated with fewer complications, such as new diabetes insipidus, as compared to the redo surgery (risk ratio [RR] 0.01; 95% CI 0.01-0.03). Redo surgery is the superior choice in the treatment of recurrent/residual or progressing NFPAs if the tumor size is large and an immediate reduction in tumor burden through debulking is warranted. However, redo surgery is associated with a higher risk of visual loss, new endocrinopathies, and other complications, in contrast to SRS.

Anterior Pituitary Transcriptomics Following a High-Fat Diet: Impact of Oxidative Stress on Cell Metabolism.

Anterior pituitary cell function requires a high level of protein synthesis and secretion which depend heavily on mitochondrial adenosine triphosphate production and functional endoplasmic reticula. Obesity adds stress to tissues, requiring them to adapt to inflammation and oxidative stress, and adding to their allostatic load. We hypothesized that pituitary function is vulnerable to the stress of obesity. Here, we utilized a 10- to 15-week high-fat diet (HFD, 60%) in a thermoneutral environment to promote obesity, testing both male and female FVB.129P mice. We quantified serum hormones and cytokines, characterized the metabolic phenotype, and defined changes in the pituitary transcriptome using single-cell RNA-sequencing analysis. Weight gain was significant by 3 weeks in HFD mice, and by 10 weeks all HFD groups had gained 20 g. HFD females (15 weeks) had increased energy expenditure and decreased activity. All HFD groups showed increases in serum leptin and decreases in adiponectin. HFD caused increased inflammatory markers: interleukin-6, resistin, monocyte chemoattractant protein-1, and tumor necrosis factorα. HFD males and females also had increased insulin and increased TSH, and HFD females had decreased serum prolactin and growth hormone pulse amplitude. Pituitary single-cell transcriptomics revealed modest or no changes in pituitary cell gene expression from HFD males after 10 or 15 weeks or from HFD females after 10 weeks. However, HFD females (15 weeks) showed significant numbers of differentially expressed genes in lactotropes and pituitary stem cells. Collectively, these studies reveal that pituitary cells from males appear to be more resilient to the oxidative stress of obesity than females and identify the most vulnerable pituitary cell populations in females.

The Effect of Visfatin on the Functioning of the Porcine Pituitary Gland: An In Vitro Study.

Visfatin (VIS), also known as nicotinamide phosphoribosyltransferase (NAMPT), is the rate-limiting enzyme in the biosynthesis of nicotinamide adenine dinucleotide (NAD+). Recently, VIS has been also recognized as an adipokine. Our previous study revealed that VIS is produced in the anterior and posterior lobes of the porcine pituitary. Moreover, the expression and secretion of VIS are dependent on the phase of the estrous cycle and/or the stage of early pregnancy. Based on this, we hypothesized that VIS may regulate porcine pituitary function. This study was conducted on anterior pituitary (AP) glands harvested from pigs during specific phases of the estrous cycle. We have shown the modulatory effect of VIS in vitro on LH and FSH secretion by porcine AP cells (determined by ELISA). VIS was also found to stimulate cell proliferation (determined by Alamar Blue) without affecting apoptosis in these cells (determined using flow cytometry technique). Moreover, it was indicated that VIS may act in porcine AP cells through the INSR, AKT/PI3K, MAPK/ERK1/2, and AMPK signaling pathways (determined by ELISA or Western Blot). This observation was further supported by the finding that simultaneous treatment of cells with VIS and inhibitors of these pathways abolished the observed VIS impact on LH and FSH secretion (determined by ELISA). In addition, our research indicated that VIS affected the mentioned processes in a manner that was dependent on the dose of VIS and/or the phase of the estrous cycle. Thus, these findings suggest that VIS may regulate the functioning of the porcine pituitary gland during the estrous cycle.

ED-1 PITUITARY TUMORS IN 5TH WHO CLASSIFICATION 2022: WHAT DO YOU MEAN BY PITNET?

Abstract It has been well known that the terminology has been changed from pituitary adenoma(4th WHO) which means benign epithelial tumors to pituitary neuroendocrine tumor(5th WHO 2022). It is apparent that the anterior pituitary cells and derived tumors contain intracytoplasmic neurosecretory granules and belong to neuroendocrine cells, and naturally neuroendocrine tumors. The pancreatic and gastrointestinal neuroendocrine neoplasms(NEN) are composed of well differentiated neuroendocrine tumors(NET) and poorly differentiated neuroendocrine carcinoma(NEC). NETs are potentially malignant(metastatic) tumors and are further graded to G1,G2,G3 by proliferative activities(mitoses or Ki-67 indices) showing correlation with prognosis . PitNET which means pituitary NET is now classified by transcription factors(PIT1,TPIT,SF1) and some tumors show clinical symptoms,(hormone production) invasive growth and rarely metastasize indicating potential malignant behavior. From this broad biological spectrum of PitNET, ICD-O coding /3(primary malignancy) has been proposed(5th WHO CNS, Pediatrics and Endocrine volumes). It has been known that some histological patterns (Sparsely granulated somatotroph PitNET, Crooke cell PitNET and others) are related more aggressive growth of PitNETs, but metastatic behavior is very hard to predict histologically. So in WHO 4th edition, the term pituitary carcinoma was used only after confirming metastasis or remote spread. The metastatic tumors are now called metastatic PitNETs. Five tiered grading by proliferation and invasion has been also proposed(Trouillas). Now we need more updated genomic studies such as single cell RNA sequencing to clarify biologic behavior of the individual PitNET cells to further clarify the their nature. . In my talk, several points of interests regarding PitNETs will be discussed by demonstrating histology and biology of representative cases.

Preliminary investigation reveals novel pathological consequences of bluetongue virus-1 infection in the endocrine glands of pregnant Indian sheep

Bluetongue virus (BTV), a major peril to the sheep industry, infects a wide range of the cells in the infected animals including mononuclear, dendritic and epithelial cells. However, little is known about its tropism for the secretory epithelial cells of endocrine glands and the pathogenesis it induces. The aim of the study was to assess the BTV load, antigen distribution in the tissue of the pituitary, thyroid as well as adrenal glands and associated histopathological consequences. BTV antigens were localized using immunohistochemistry in the thyroid’s epithelial cells, zona fasciculata and zona reticularis cells and the anterior pituitary epithelial cells. The real-time PCR portrayed the high viral load in adrenals at 7th days postinoculation (DPI) and in thyroid and pituitary glands at 15th DPI. Serum examination revealed variation in the T-3 and T-4 of infected animals in comparison to the control group. Caspase-3 immunolocalization revealed BTV-1 induces apoptosis in the affected cells of endocrine gland of infected animals. Further, this study signifies the tropism of BTV in the novel sites (endocrine glands) of the host that might be one of the reasons for the poor performance of infected animals.

Plasma level of omentin-1, its expression, and its regulation by gonadotropin-releasing hormone and gonadotropins in porcine anterior pituitary cells

Omentin-1 (OMNT1) is an adipokine involved in the regulation of energy metabolism, insulin sensitivity, and reproduction. The present study was the first to investigate the plasma levels and expression of OMNT1 in the anterior pituitary (AP) gland on days 2–3, 10–12, 14–16, and 17–19 of the estrous cycle of normal-weight Large White (LW) and fat Meishan (MS) pigs. Next, we determined the effect of GnRH, LH, and FSH on the OMNT1 levels in cultured AP cells. The gene and protein expression of OMNT1 in AP fluctuated during the estrous cycle, with a higher expression in MS than in LW (except on days 10–12). However, plasma levels of OMNT1 were higher in LW than in MS. OMNT1 was localized in somatotrophs, lactotrophs, thyrotrophs, and gonadotrophs. In LW pituitary cells, GnRH and gonadotropins stimulated OMNT1 protein expression (except FSH on days 14–16) and had no effect on OMNT1 levels in the culture medium. In MS pituitary cells, we observed that GnRH and LH increased while FSH decreased OMNT1 protein expression. These findings showed OMNT1 expression and regulation in the porcine AP and suggested that OMNT1 could be a new player modifying the pituitary functions.

SAT272 Insulin Signaling In Hyperactivation Of The HPA Axis In Metabolic Diseases

Abstract Disclosure: D. Cozma: None. P. Siatra: None. I. Oikonomakos: None. D. Kalra: None. U.A. Friedrich: None. A. Dahl: None. S.R. Bornstein: None. S. Zeissig: None. C.L. Andoniadou: None. C. Steenblock: None. Stress can lead to an increase in body fat and obesity as main clinical conditions preceding the metabolic syndrome [1]. In metabolic stress, hyperactivation of the hypothalamic-pituitary-adrenal (HPA) axis has been observed, resulting in increased steroidogenesis and alteration of cortisol secretion [1]. This increased sensitivity of the HPA axis may be related to the development of comorbidities or severe illness in patients with metabolic diseases and vice versa. Disorders of the HPA axis, e.g., Cushing’s disease, resulting from overproduction of ACTH, share similar clinical symptoms with metabolic diseases [1]. The molecular signaling mechanisms that cause such changes in the HPA axis under metabolic stress remain elusive. Previous studies indicate a role of insulin in the regulation of adrenal steroidogenesis by upregulating the transcriptional activity of NR5A1 [2]. Here, we study the molecular mechanisms to insulin-induced hyperactivation of the HPA axis and characterize the molecular changes that lead to altered cortisol secretion. We generated non-adherent spheroids from primary adrenocortical cells in vitro and treated these with insulin. This resulted in an increase of spheroid diameter over time [Slope: 5.163 ± 0.994; P=0.0139; n=11], compared to control [Slope: -4.058 ± 0.987; P=0.0261; n=10], indicating greater cell expansion following insulin treatment. Similarly, repeating this experiment with adherent primary anterior pituitary stem cell colonies showed an increase in colony size when treated with insulin compared to control [Diameter: 1221.0 ± 290.9 µm vs. 914.5 ± 256.2 µm; P=0.0079; n=3]. This indicates that the stem cell populations of the adrenal and pituitary gland are responsive to insulin stimulation, likely leading to increased proliferation. This is complementary to our previous studies where we revealed increased secretion of aldosterone in insulin-stimulated adrenocortical cultures [3]. To identify signaling pathways related to insulin stimulation, we performed bulk RNA sequencing of in vitro primary cultures of adrenocortical and pituitary cells with and without insulin treatment. Analysis of these data sets reveals specific signaling pathways that are candidates in regulation of metabolic stress in vivo. Using mouse models of obesity and diabetes along with genetic lineage-tracing studies, we aim to decipher the role of these pathways on HPA axis stem/progenitor cells during metabolic stress. The outcomes will pave the way for a better understanding of HPA axis activity during metabolic stress adaption, and the role of the HPA axis in patients suffering from metabolic diseases.