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There is uncertainty regarding the need for COVID-19 peri-vaccination glucocorticoid coverage in patients with adrenal insufficiency. In this survey conducted in a single tertiary medical institution, 167 consecutive outpatients taking physiological glucocorticoids because of adrenal insufficiency were included. The patients declared if they developed an adrenal crisis after vaccination, and the amount and duration of an increase in their glucocorticoid dosage, if any. None of the patients without preventive glucocorticoid increase suffered an adrenal crisis after COVID-19 vaccination. Only 8.3% (14 cases) and 27.5% (46 cases) of the patients needed to escalate the dose of glucocorticoids when systemic symptoms appeared after the first and second injections, respectively. Glucocorticoids were increased in patients

Background Immune checkpoint inhibitors (ICIs) as a cancer immunotherapy have emerged as a treatment for multiple advanced cancer types. Because of enhanced immune responses, immune-related adverse events (irAEs), including endocrinopathies such as hypophysitis, have been associated with the use of ICIs. Most underlying mechanisms of ICI-related hypophysitis remain unclear, especially for programmed cell death-1 (PD-1)/PD-1 ligand 1 (PD-L1) inhibitors. We hypothesized that ICI-related hypophysitis is associated with paraneoplastic syndrome caused by ectopic expression of pituitary-specific antigens. Methods Twenty consecutive patients with ICI-related hypophysitis between 2017 and 2019 at Kobe University Hospital were retrospectively analyzed. Circulating anti-pituitary antibodies were detected using immunofluorescence staining and immunoblotting. Ectopic expression of pituitary autoantigens in tumor specimens was also examined. Results Eighteen patients were treated with PD-1/PD-L1 inhibitors, and two were treated with a combination of cytotoxic T-lymphocyte antigen-4 (CTLA-4) and PD-1 inhibitors. All patients showed adrenocorticotropic hormone (ACTH) deficiency and additionally, three showed thyroid-stimulating hormone (TSH) deficiency, and one showed gonadotropin-releasing hormone (GnRH) deficiency. Among these patients, three exhibited anti-pituitary antibodies, two with anti-corticotroph antibody and one with anti-somatotroph antibody. Interestingly, the anti-corticotroph antibody recognized proopiomelanocortin (POMC) and those two patients exhibited ectopic ACTH expression in the tumor, while the patients without anti-corticotroph antibody did not. Conclusions We demonstrated 10% of PD-1/PD-L1 inhibitors-related hypophysitis were associated with the autoimmunity against corticotrophs and maybe caused as a form of paraneoplastic syndrome, in which ectopic expression of ACTH in the tumor was observed. It is also suggested that the pathophysiology is heterogenous in ICI-related hypophysitis.

Background Corticotrophs are a well-known tissue susceptible to cytotoxicity by lymphocytes, as seen in autoimmune hypophysitis, suggesting that immunological approach may be one of the therapeutic strategies for ACTH-producing adenomas. However, the efficacy of immune therapy for general ACTH-producing adenomas remains unclear. And cortisol levels expected to affect the tumor microenvironment (TME). Objectives To clarify whether ACTH-producing adenomas are sensitive to immunotherapy and if this approach can be a potential treatment for these challenging tumors. Methods TME was examined by immunostaining using pituitary adenomas specimens. This study consists of two phases: In phase 1, TME of ACTH-producing adenomas (n=29) was analyzed by comparing with GH-producing pituitary adenomas (GHomas) (n=10) and nonfunctioning pituitary adenomas (NPAs) derived from gonadotrophs origin (Gnomas) (n=10). In phase 2, corticotroph adenomas were divided into three groups that were considered to be at different cortisol exposure; naïve ACTH-producing adenomas (Naïve, n=29), treatment with metyrapone (Met, n=13), and silent corticotroph adenomas (SCAs) (n=12). These TME were analyzed and compared. To detect T-lymphocytes and M2 macrophages, antibodies to CD3, 4, or 8, and CD163 were used, respectively. The association between TME and patients’ background data including urinary free cortisol levels were analyzed. Results Phase 1: Tumor infiltrating lymphocytes (TILs) evaluated by CD3 + cells inACTH-producing adenomas were less than those in the GHomas (p Conclusions We revealed for the first time that low TILs are common features among corticotroph adenomas regardless cortisol levels. Moreover, the CD4 + cells but not CD8 + cells were higher in tumors with low cortisol status, suggesting induction of CD8 + cells are required for the immune therapy to corticotroph adenomas. Regarding with CD163 + cells, no association with tumor behavior was shown rather related to cortisol exposure status. Presentation: No date and time listed

Background Growth hormone replacement therapy (GHRT) in adults with growth hormone deficiency (AGHD) has shown to improve body composition, lipid and bone metabolism, and quality of life (QOL), but its effect on glucose tolerance can be bidirectional. Objective To investigate the long-term effect of GHRT on glucose tolerance in AGHD patients. Patients and Methods We conducted a retrospective single-center study at Kobe University Hospital. One hundred twenty-five AGHD patients who had visited our department since January 2011 to September 2021 were enrolled. The exclusion criteria was as follows: Patients 1) who never received GHRT 2) whose HbA1c was 6.5% or higher, or under antidiabetic drugs before GHRT, 3) not available data on HbA1c at baseline or after GHRT 4) with functional pituitary adenomas, 5) who had initiated GHRT at childhood and had discontinued GH for less than 1year due to transition, 6) who receiving supraphysiological doses of steroid therapy, 7) GHRT interruption period for more than 1 year or its initiation from less than 2 months. Fifty-three AGHD patients eventually met the inclusion criteria. We collected data at baseline, 3, 6, 12 months after treatment, and at each patients’ last visit. The influence of GHRT on glucose metabolism and its associated factors were analyzed. All data were presented as median [interquartile range]. Results Fifty-three patients (27 female (51. 0%), 14 childhood onset (26.4%), age at GH initiation was 45 [32 - 60] years, the duration of GHRT was 4 [2 - 6] years) were analyzed. Both IGF-I levels and IGF-I SDS increased at the last visit compared to baseline: 56 [38 - 88] to 119 [84.5 - 181] ng/mL (P Conclusions Overall, GHRT was safely used in regard with impaired glucose tolerance at least non-diabetes mellitus patients with AGHD. Among them, cases with impaired glucose tolerance during GHRT were associated with increased BMI. Presentation: No date and time listed

Context The occurrence of multiple endocrinopathies due to immune checkpoint inhibitors (ICIs) is a relatively common adverse event. However, the occurrence of a combination of hypophysitis and type 1 diabetes mellitus (T1DM) is extremely rare, and its clinical features are unclear. Objective We comparatively analyzed the clinical features of this combination and each individual ICI-induced endocrinopathy. Methods We reported 3 cases that we encountered and reviewed previously reported cases of patients with combined hypophysitis and T1DM due to ICIs. Results Anti-programmed cell death-1 (anti-PD-1) antibodies were prescribed to all 3 cases. The duration from ICI initiation to the onset of endocrine disease was 12 to 48 weeks. Several human leukocyte antigen (HLA) haplotypes that have disease susceptibility to hypophysitis were detected in all 3 patients. With the 17 previously reported cases, combined endocrinopathies were more common in men (85%). The onset age was in the 60s for both combined and single endocrinopathies. Anti-PD-1 antibodies were used in most of the cases (90%). The time from ICI initiation to the onset of endocrinopathies was 24 (8-76) weeks for hypophysitis and 32 (8-76) weeks for T1DM in patients with combined endocrinopathies, which was not significantly different from that for each single endocrinopathy. Conclusion We presented 3 cases of patients with combined endocrinopathies of hypophysitis and T1DM that may have been caused by anti-PD-1 antibodies. There was no difference in the time from ICI initiation to the onset of endocrinopathies between combined and single endocrinopathies. Further case accumulation and pathogenic investigations are required.

To clarify the characteristics of Cushing's disease (CD) patients who respond to the desmopressin (DDAVP) test and its underlying mechanisms.Forty-seven patients with CD who underwent DDAVP testing were included. Patients were divided into two groups: DDAVP test (+) (adrenocorticotropic hormone [ACTH] levels increased by ≥ 1.5-fold during the DDAVP test) and DDAVP test (-) (ACTH levels increased by 1.5-fold). AVP receptor expression levels in these tumors were quantified using quantitative RT-PCR and immunohistochemistry. AVP receptor promoter activity was analyzed using a dual-luciferase reporter assay system.Females (96.9%) and USP8 mutants (85.7%) were more prevalent in the DDAVP test (+) than in the DDAVP test (-). Indeed, the ACTH and cortisol responsiveness to DDAVP was greater in USP8 mutation positive tumors than that in USP8 wild type tumors (3.0-fold vs. 1.3-fold, 1.6-fold vs. 1.1-fold, respectively). Responsiveness to DDAVP was correlated with the expression levels of AVPR1B, but not with those of AVPR2. Comparably, Avpr1b promoter activity was enhanced by the overexpression of mutant USP8 compared to the wild type.We found that the responsiveness of ACTH to DDAVP in CD was greater in tumors with USP8 mutations. The present data suggest that USP8 mutations upregulate the AVPR1B promoter activity. Additionally, we showed that the DDAVP test can predict the presence of USP8 mutations.

Context Anti–pituitary-specific transcriptional factor-1 (anti–PIT-1) antibody syndrome is characterized by acquired and specific deficiencies in growth hormone, prolactin, and thyroid-stimulating hormone. Although PIT-1–reactive cytotoxic T lymphocytes (CTLs) have been speculated to recognize anterior pituitary cells and to cause the injury in the pathogenesis of the syndrome, it remains unclear whether endogenous PIT-1 protein is processed through the proteolytic pathway and presented as an antigen on anterior pituitary cells. Objective To examine how PIT-1 protein is processed and whether its epitope is presented by major histocompatibility complex (MHC)/HLA class I on anterior pituitary cells. Materials and Methods Immunofluorescence staining and proximity ligation assay (PLA) were performed using anti–PIT-1 antibody and patients’ sera on PIT-1–expressing cell line GH3 cells and human induced pluripotent stem cell (iPSC)-derived pituitary tissues. Results PIT-1 was colocalized with MHC class I molecules, calnexin, and GM130 in the cytosol. PLA results showed that PIT-1 epitope was presented by MHC/HLA class I molecules on the cell surface of GH3 cells and iPSC-derived pituitary cells. The number of PIT-1/HLA complexes on the cell surface of pituitary cells in the patient was comparable with that in the control subject. Conclusions Our data indicate that PIT-1 protein is processed in the antigen presentation pathway and that its epitopes are presented by in MHC/HLA class I on anterior pituitary cells, supporting the hypothesis that PIT-1–reactive CTLs caused the cell-specific damage. It is also suggested that number of epitope presentation was not associated with the pathogenesis of anti–PIT-1 antibody syndrome.

Purpose IgG4-related disease involves various organs including the pituitary and pancreas. The prevalence of IgG4-related hypophysitis is relatively rare compared with IgG4-related pancreatitis (autoimmune pancreatitis). Although several cases demonstrating both autoimmune pancreatitis and hypophysitis have been reported, the prevalence of IgG4-related hypophysitis in patients with autoimmune pancreatitis remains unknown. This study aimed at screening for IgG4-related hypophysitis to accurately determine its prevalence in patients with autoimmune pancreatitis. Methods In this cohort study, we screened IgG4-related hypophysitis via pituitary magnetic resonance imaging (MRI) and endocrinological examination in 27 patients who were undergoing follow-up for autoimmune pancreatitis at Kobe University Hospital between 2014 and 2018. Results Among 27 patients with autoimmune pancreatitis, 5 patients exhibited morphological abnormalities in the pituitary (18.5%). Among them, one patient (3.7%) met the criteria for hypophysitis with an enlarged pituitary and stalk concomitant with hypopituitarism. After glucocorticoid treatment, the enlarged pituitary shrank and became empty sella during the clinical course. Four patients (14.8%) revealed empty sella without obvious pituitary dysfunction. Four of 5 patients with morphological pituitary abnormalities showed multiple organ involvement in addition to pancreatic and pituitary involvement. Accordingly, multiple organ involvement was more prevalent in patients with morphological pituitary abnormalities (80%) compared to those without (48%). Conclusions Although a large-scale study is necessary to validate these results, these data suggest that the prevalence of hypophysitis in patients with autoimmune pancreatitis may be underestimated. Based on our findings, we recommend screening for hypophysitis, especially in patients with multiple organ involvement.

Pituitary autoimmunity is one of the principal causes of hypopituitarism. Additionally, hypophysitis is one of the immune-related adverse events associated with immunotherapy. Recent case-oriented research has revealed a novel type of autoimmune hypophysitis, anti-PIT-1 hypophysitis, related to isolated adrenocorticotropic hormone (ACTH) deficiency and immune checkpoint inhibitor-related hypophysitis, as a form of paraneoplastic syndrome. Under these conditions, the ectopic expression of pituitary antigens present in tumors evokes a breakdown of immune tolerance, resulting in the production of autoantibodies and autoreactive cytotoxic T cells that specifically harm pituitary cells. Consequently, an innovative clinical entity of paraneoplastic autoimmune hypophysitis has been purported. This novel concept and its underlying mechanisms provide clues for understanding the pathogenesis of autoimmune pituitary diseases and can be applied to other autoimmune diseases. This review discusses the etiology of paraneoplastic autoimmune hypophysitis and its future.

Anti–pituitary-specific transcription factor 1 (PIT-1) hypophysitis (anti–PIT-1 antibody syndrome) is a thymoma-associated autoimmune disease characterized by acquired growth hormone (GH), prolactin (PRL), and thyrotropin (TSH) deficiencies due to autoimmunity against PIT-1. Ectopic expression of PIT-1 in the thymoma plays a causal role in development of the disease. Here, we report 2 cases of anti–PIT-1 hypophysitis exhibiting as a form of paraneoplastic syndrome with conditions other than thymoma. A 79-year-old woman (case 1) and an 86-year-old man (case 2) were referred with a suspicion of anti–PIT-1 hypophysitis because of acquired GH, PRL, and TSH deficiencies. Case 1 was complicated by diffuse large B-cell lymphoma (DLBCL) of the bladder and case 2 was diagnosed with malignancy with multiple metastases of unknown origin. Because circulating anti–PIT-1 antibody was detected, both patients were diagnosed with anti–PIT-1 hypophysitis. Circulating PIT-1–reactive T cells were detected in case 1 via enzyme-linked immunospot (ELISPOT) assay. Interestingly, the PIT-1 protein was ectopically expressed in the DLBCL cells of case 1, whereas DLBCL tissues derived from patients without anti–PIT-1 hypophysitis were negative for PIT-1. In case 2, the materials were not available because of best supportive care was under way. These data show that anti–PIT-1 hypophysitis is associated not only with thymoma but also with other malignancies. Additionally, the ectopic expression of PIT-1 in the DLBCL tissues and presence of PIT-1–reactive T cells suggested that the underlying mechanisms were similar to those observed in thymoma. Thus, anti–PIT-1 hypophysitis is defined as a form of paraneoplastic syndrome.

Background: Anti-pituitary-specific transcription factor 1 (PIT-1) hypophysitis (anti-PIT-1 antibody syndrome) is a newly defined clinical entity, demonstrating an adult-onset hypopituitarism, and is a thymoma-associated autoimmune disease characterized by acquired GH, PRL, and TSH deficiencies due to autoimmunity against PIT-1 (1, 2). This disease is defined by an acquired specific GH, PRL, and TSH deficiencies and the presence of circulating anti-PIT-1 antibody and/or PIT-1-specific T cells (2). As the etiology, ectopic expression of PIT-1 in thymoma plays a causal role in the development of the disease (3); however, it is unknown whether this disease is involved in other conditions. Here, we report two PIT-1 hypophysitis cases, exhibiting as a form of paraneoplastic syndrome with malignancies other than thymoma. Clinical Case: A 79-year-old woman (case 1) and an 86-year-old man (case 2) were referred to us on suspicion of anti-PIT-1 hypophysitis because of acquired GH, PRL, and TSH deficiencies. In both patients, the endocrinological evaluation revealed extremely low basal levels and blunted responses of GH, PRL, and TSH to the provocative stimuli. In contrast, the secretion of HPA and HPG axis were preserved in both patients. Magnetic resonance imaging of the pituitary gland showed slight atrophy in case 1 and normal size in case 2. Interestingly, computed tomography imaging revealed no evidence for thymomas in both patients. On the other hand, case 1 was complicated with diffuse large B-cell lymphoma (DLBCL) of the bladder with multiple bilateral cervicals, axillary, para-aorta, and internal and external peri iliac lymphadenopathies. Case 2 was diagnosed with malignancy with multiple metastases of unknown origin with para-aortic and para-gastric lymphadenopathies, and vertebral body infiltrates. Because circulating anti-PIT-1 antibody was detected, both patients were diagnosed with anti-PIT-1 hypophysitis. Circulating PIT-1-reactive T cells were detected in case 1 using Enzyme-Linked Immunospot assay. Interestingly, the PIT-1 protein was ectopically expressed in the DLBCL tissue of case 1, while DLBCL tissues derived from control patients without anti-PIT-1 hypophysitis were negative for PIT-1. In case 2, the materials were not available because of the situation of the best supportive care. Conclusion: These data show that anti-PIT-1 hypophysitis is associated not only with thymoma but also with other malignancies. Additionally, the ectopic expression of PIT-1 in the DLBCL tissues and presence of PIT-1- reactive T cells suggested that the underlying mechanisms were similar to those observed in thymoma (3). Thus, anti-PIT-1 hypophysitis is defined as a form of paraneoplastic syndrome. Reference: (1) J Clin Invest. 2011;121(1):113-119., (2) Endocr Rev. 2020;41(2)., (3) Sci Rep. 2017;7:43060.

Context Luscan-Lumish syndrome (LLS) is characterized by postnatal overgrowth, obesity, Chiari I malformation, seizures, and intellectual disability. SET domain-containing protein 2 (SETD2) is a histone methyltransferase, where mutations in the gene are associated with the development of LLS. However, mechanisms underlying LLS remain unclear. Case Description A 20-year-old man was referred to our hospital because of tall stature. His body height was 188.2 cm (+3.18 SD) and he showed obesity with a body mass index of 28.4 kg/m2. He exhibited acral overgrowth, jaw malocclusion, and prognathism, but no history of seizures, intellectual disability, or speech delay. Serum growth hormone (GH), insulin-like growth factor 1 (IGF-1), and nadir GH levels after administration of 75 g oral glucose were within normal range. Pituitary magnetic resonance imaging showed no pituitary adenoma, but Chiari I malformation. Whole exome sequencing analysis of the proband revealed a de novo heterozygous germline mutation in SETD2 (c.236T>A, p.L79H). Skin fibroblasts derived from the patient grew faster than those from his father and the control subject. In addition, these cells showed enhanced tyrosine phosphorylation and transcriptional activity of signal transducer and activator of transcription 5b (STAT5b) and increased IGF-1 expression induced by GH. Conclusion This is a mild case of LLS with a novel mutation in SETD2 without neurological symptoms. LLS should be differentiated in a patient with gigantism without pituitary tumors. Although further investigation is necessary, this is the first study to suggest the involvement of aberrant GH signaling in the development of LLS.

Background: With rapid aging in the society and the improvement of prognosis in patients with acromegaly, treatment goals have been changed. In elderly patients with acromegaly, improvement in the quality of life (QoL) is one of the most important treatment goals. However, factors associated with QoL in elderly patients with acromegaly remains unclear. Objective: To clarify the differences in the QoL in patients with acromegaly between the young and elderly, and to identify the factors associated with the impairment in the elderly. Patients and Methods: This is a retrospective cross-sectional single-center study. Eighty patients with acromegaly (male 49%, the mean age 59.6±12.6 years, mean IGF-I SD score 0.7±2.3), who had been followed up in the outpatient clinic at Kobe University Hospital, were enrolled. Patients were divided into following 2 groups; Elderly group (E group); 65 years of age or more (n =34, male 41%, mean age 71.4±4.1 years), or Young group (Y group); younger than 65 years old (n =46, male 50.9%, mean age 50.9±9.2 years). We evaluated QoL using AcroQoL and analyzed the associated factors by multivariate analysis. Results: In the comparison of E and Y group, IGF-I SD score (0.4±1.6 in E group vs. 0.9±2.7 in Y group) and the way of treatment (surgery; 65% vs 72%, current medical therapy; 56% vs 43%, past radiation therapy; 15% vs 9%) were comparable, while disease duration was longer in E than Y group (13.7±10.9 vs 8.3±8.1 years, p =0.02). Arthropathy was more frequent in E group (50% vs 11%, p In total, current medical therapy and hydrocortisone replacement were associated with lower total scale (β =-0.27, p =0.01 and β =-0.35, p Conclusions: AcroQoL score was impaired both in E and Y group in patients with acromegaly. In total, current medical therapy and hydrocortisone replacement were associated with lower QoL scale as previously reported; however, when stratified by age, arthropathy and high BMI were associated with lower QoL scale in the elderly. These data clearly indicate that the factors influence on QoL are different depending on the age. Although causal relationship remains unclarified, these data suggest that when treat the patients, it may be important to avoid these complications.

In isolated adrenocorticoropic hormone (ACTH) deficiency (IAD), autoimmunity against corticotrophs has been suggested; however, the pathogenesis remains largely unknown. Large cell neuroendocrine carcinoma (LCNEC) of the lung is a pulmonary tumor of high-grade malignant neuroendocrine tumor and it reportedly caused paraneoplastic syndrome by autoimmunity in several cases. A 42-year-old woman with isolated adrenocorticotropic (ACTH) hormone deficiency (IAD) was diagnosed with large cell neuroendocrine carcinoma (LCNEC) 3 years after being diagnosed with IAD. We hypothesized that the LCNEC played a causal role in the development of IAD as a paraneoplastic syndrome and analyzed the autoimmunity. We also analyzed another case of ectopic ACTH syndrome to prove this hypothesis. The LCNEC tissue revealed an ectopic ACTH expression and lymphocyte infiltration. Interestingly, autoantibody against the proopiomelanocortin (POMC) protein was detected in the peripheral blood. Although, patient’s serum did not show any effects on cell viability, proliferation, nor pomc expression in a corticotroph cell line, AtT20 cells, patient’s lymphocytes in the peripheral blood specifically reacted toward POMC protein, indicating a presence of cytotoxic T lymphocytes (CTLs). In addition, the analysis of another case of ectopic ACTH syndrome showed lymphocyte infiltration not only in the metastatic liver tumors but also in the pituitary. Moreover, most CD8-positive cells resided adjacent to corticotrophs. These data indicate that the ectopic ACTH expression in the tumor evoked the autoimmunity to corticotrophs and caused IAD as a form of paraneoplastic syndrome.

Background: Type 1 Diabetes mellitus (T1DM) is a well-known condition associated with low bone mineral density (BMD) and bone fracture, in which one of the risk factor is impaired endogenous insulin secretion. However, the association between the rate of impaired insulin secretory capacity in T1DM and BMD remains to be elucidated. Objective: To clarify the effect of the rate of impaired insulin secretion on BMD in T1DM. Patients and Methods: This a retrospective single-center cross-sectional study, in which consecutive one-hundred seventy Japanese patients with T1DM at Kobe University Hospital were registered. According to the diagnostic criteria of The Japan Diabetes Society, patients were stratified into three subtypes; acute-onset (AO) (n =51, male 25%, 39 ± 15 years), slowly-progressive (SP) (n =37, male 37%, 57 ± 14 years), and fulminant (F) (n =12, male 33%, 51 ± 15 years) mainly by insulin secretory capacity at onset of T1DM. Lumbar spine (LS) and femoral neck (FN) BMD Z-score between three groups were evaluated. Results: The LS BMD is lower in AO than SP (p =0.03), while no differences were observed compared to F (SP/AO/F; 0.38 ± 1.08/-0.25 ± 0.96/-0.35 ± 1.01). The FN BMD also tended to be lower in AO than in SP (p =0.08) and in F (p =1.00) (SP/AO/F;0.03 ± 1.01/-0.44 ± 0.96/-0.35 ± 0.70). To identify the factors associated with decreased BMD, the multivariate regression analysis was performed using AO and SP. The LS BMD was associated with the pathogenic group (p =0.01). Since a negative correlation was seen between durations and CPR both in AO and SP group (p

Some endocrine disorders, including hypophysitis and isolated adrenocorticotropic hormone (ACTH) deficiency, are caused by an autoimmune response to endocrine organs. Although the pathogenesis of some autoimmune endocrine diseases has been elucidated, it remains obscure for most. Anti-PIT-1 hypophysitis (anti-PIT-1 antibody syndrome) is a newly described pituitary autoimmune disease characterized by acquired and specific growth hormone (GH), prolactin (PRL), and thyroid-stimulating hormone (TSH) deficiencies. This disorder is associated with a thymoma or neoplasm that ectopically expresses pituitary-specific transcription factor 1 (PIT-1) protein. Circulating anti-PIT-1 antibody is a disease marker, and PIT-1-reactive cytotoxic T cells (CTLs) play a pivotal role in disease development. In addition, isolated ACTH deficiency appears to be caused by autoimmunity to corticotrophs; however, the pathogenesis remains unclear. A recently described case of isolated ACTH deficiency with large cell neuroendocrine carcinoma (LCNEC) showed ectopically expressed proopiomelanocortin (POMC), and circulating anti-POMC antibody and POMC-reactive CTLs were also detected. As CTL infiltrations around corticotrophs were also observed, isolated ACTH deficiency may be associated at least in part with a paraneoplastic syndrome. Although several underlying mechanisms for pituitary autoimmunity have been proposed, these observations highlight the importance of paraneoplastic syndrome as a cause of pituitary autoimmune disease. In this review, we focus on the pathophysiology and connection of anti-PIT-1 hypophysitis and isolated ACTH deficiency and discuss the state-of-art knowledge for understanding pituitary autoimmunity.

Background: Desmopressin test (DT) is useful for the diagnosis of Cushing’s disease (CD). Approximately 80% of patients with CD respond in DT; however, the clinical significance remains unclear. Objective: To clarify the clinical significance of the responsiveness to DT in CD. Patients and Methods: This is a retrospective multi-center study. Thirty-five patients with CD who underwent DT (29 women and 6 men, age 40 ± 15 years) between 2014 and 2018 in Kobe university hospital or Toranomon hospital were included. A method of single intravenous injection of desmopressin (4μg) were used as previously described (1). Patients were divided into two groups by the responsiveness to DT; DT (+), whose ACTH increased to 1.5-folds or more during the DT (n = 20) and DT (-), whose response was less than 1.5-folds (n = 14). Following clinical parameters; age, gender, serum ACTH level, cortisol level (F), F in low dose dexamethasone suppression test, F in high dose dexamethasone suppression test, 24 hour urinary free cortisol (UFC), tumor diameter, Knosp grades, and USP8 mutation were compared between DT(+) and DT(-). Results: While serum ACTH, F, UFC and tumor size did not show any differences between these two groups, the responder was more predominant in women than men (68% vs. 17%, p = 0.028). Intriguingly, the responsiveness to DT was significantly greater in USP8 mutation-positive group (n = 15) than that in wild-type group (n = 6) (median (range); 3.0 (1.0-6.7) vs. 1.3 (1.1-1.6) folds, p = 0.010). When cutoff value is defined as 1.6-folds, the responsiveness to DT predicts the presence of USP8 mutation in the sensitivity of 80% and specificity of 100%. Conclusions: The responsiveness to DT was greater in female patients with CD. DT can predict the presence of USP8 mutation in a high specificity. These results suggest that the underlying mechanisms associated with USP8 mutation may affect the expression of V1b or V2 receptor. Reference (1) Y. Sakai, et al., Endocr J 1997;44:687-695.

[Background] In acquired idiopathic isolated ACTH deficiency (IAD), anti-pituitary antibodies are reportedly detected in a part of the patients; however, the significance of the antibodies remains unclarified. [Subjects and methods] Forty-six patients with IAD who diagnosed between 1992 and 2018 were retrospectively analyzed. Serum anti-corticotroph and anti-follicular stellate cell (FSC) antibody were analyzed using immunofluorescence staining in 33 patients, whose serum was available. We performed principle component and cluster analysis for the clarification of pathophysiology of IAD based on the clinical characteristics and autoantibodies. [Results] Among 46 patients, male was predominant (63%). The average age of the onset of IAD was 58.1 ± 12.3 years and that in male was significantly older (male vs. female: 62.8 ± 9.3 vs. 50.1 ± 13.0 years, P < 0.01). Forty-one % of the patients exhibited other autoimmune diseases including chronic thyroiditis. Interestingly, 58% of the patients exhibited anti-corticotroph antibody and 6% exhibited anti-FSC antibody in the serum. Principle component analysis demonstrated that 69.6% of the patients were explained by following 3 components; 1) age and gender, 2) the presence of antibody against corticotroph or FSC and the serum ACTH level, 3) the presence of other autoimmune disease. Cluster analysis demonstrated that the patients can be divided into 3 groups; A) middle-aged male (60.9 ± 10.3 years) with low ACTH values at the onset (2.2 ± 5.6 pg/mL) and positive for the anti-coricotroph antibody (73.3%), B) elderly male (72.8 ± 3.8 years) with relatively high ACTH values (21.1 ± 10.3 pg/mL), including positive for the anti-FSC antibody (50%), C) middle-aged female (45.3 ± 11.2 years) with low ACTH values at the onset (3.8 ± 5.8 pg/mL), and positive for the anti-corticotroph antibody (60%). [Discussion] These data clearly showed the clinical heterogeneity of IAD and suggested a presence of different pathogenesis. Group A and C were characterized by a high prevalence of anti-corticotroph antibody and low levels of serum ACTH, suggesting a presence of specific autoimmunity against corticotroph resulting in a severe injury of corticotrophs. Interestingly, group B was characterized by the most elderly male with relatively high ACTH levels and half of the patients exhibited anti-FSC antibody. It is suggested that anti-FSC antibody is a novel marker for IAD especially in elderly male patients. In this group, it is speculated that the corticotroph function was indirectly impaired because of the injury of FSCs. Although further investigations are necessary, our data enabled a useful classification of IAD especially for the clarification of the pathogenesis. Unless otherwise noted, all abstracts presented at ENDO are embargoed until the date and time of presentation. For oral presentations, the abstracts are embargoed until the session begins. Abstracts presented at a news conference are embargoed until the date and time of the news conference. The Endocrine Society reserves the right to lift the embargo on specific abstracts that are selected for promotion prior to or during ENDO.

Based on clinical characteristics, patients were classified using Principal Component Analysis(PCA). For this analysis, 6 clinical parameters were included. PCA could reduce these 6 clinical parameters into 3 new parameters, known as the principal components (PCs). These 3 PCs could explain approximately 70% (cumulative contribution ratio) of all data.