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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 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

Multidisciplinary team meetings (MDMs) to address various clinical problems have become common, especially for cancer care. However, the impact of MDMs on adrenal tumor care has rarely been reported. We organized an endocrine tumor MDM including adrenal tumors in August 2014. The objective of this study was to assess the impact of our adrenal tumor MDMs on patient clinical outcomes. We compared several parameters measuring clinical outcomes before and after MDMs were instituted. The adrenal tumor MDMs included an endocrinologists, urologists, radiologists, pathologists, and residents. We analyzed 128 consecutive cases of functioning adrenal tumors (primary aldosteronism (PA), n = 53; Cushing’s syndrome (CS), n = 24; pheochromocytoma (PCC), n = 51) who underwent surgery in Kobe University Hospital from 2008 to 2019, and compared clinical parameters before (n = 68) and after (n = 60) MDMs were instituted. Twenty-one selected cases including PA, CS, PCC, adrenocortical carcinoma, and metastatic adrenal tumor were discussed in the MDM. In the analysis of 128 cases, the difference between pre- and postoperative systolic BP (ΔBP) in patients with PA after MDMs were instituted was smaller compared with those before (p = 0.02). In CS, preoperative steroid synthesis inhibitors were used more often (33 vs. 100%, p

Aim Primary aldosteronism, which is usually caused by an aldosterone-producing tumour, affects glucose metabolism. The effects of this condition on insulin secretion and insulin sensitivity have remained unclear, however. To gain insight into the influence of primary aldosteronism on glucose tolerance, various parameters related to insulin secretion or insulin sensitivity in patients with an aldosterone-producing tumour were comprehensively analyzed. Methods To assess 14 patients with an aldosterone-producing tumour, hyperglycaemic and hyperinsulinaemic–euglycaemic clamp tests as well as oral glucose tolerance tests (OGTTs) were performed before and after tumour excision. Time between presurgical analysis and surgery was 27–559 (194 ± 132) days, and 14–142 (51 ± 38) days between surgery and postsurgical analysis. Various parameters related to insulin secretion or sensitivity as determined by OGTT as well as hyperglycaemic and hyperinsulinaemic–euglycaemic clamp analyses were evaluated. Results Surgical treatment of tumours ameliorated hypokalaemia and reduced plasma aldosterone levels. First and second phases of insulin secretion during the hyperglycaemic clamp, as well as the insulinogenic index and total insulin secretion measured during OGTT, were also improved after surgery. In addition, the insulin sensitivity index determined during the hyperinsulinaemic–euglycaemic clamp was reduced after surgery. Conclusion Primary aldosteronism impairs insulin secretion.

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.

Familial neurohypophyseal diabetes insipidus (FNDI) is a degenerative disease of vasopressin (AVP) neurons. Studies in mouse in vivo models indicate that accumulation of mutant AVP prehormone is associated with FNDI pathology. However, studying human FNDI pathology in vivo is technically challenging. Therefore, an in vitro human model needs to be developed. When exogenous signals are minimized in the early phase of differentiation in vitro, mouse embryonic stem cells (ESCs) differentiate into AVP neurons, whereas human ESCs/induced pluripotent stem cells (iPSCs) die. Human ES/iPSCs are generally more similar to mouse epiblast stem cells compared to mouse ESCs, which are termed as primed and naive, respectively. In this study, we converted human FNDI-specific iPSCs from primed to naive cells, and found improved cell survival under minimal exogenous signals and differentiation into rostral hypothalamic organoids. Overall, this method provides a simple and straightforward differentiation direction, which may improve the efficiency of hypothalamic differentiation.

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.

Pituitary develops from oral ectoderm in contact with adjacent ventral hypothalamus. Impairment in this process results in congenital pituitary hypoplasia (CPH); however, there have been no human disease models for CPH thus far, prohibiting the elucidation of the underlying mechanisms. In this study, we established a disease model of CPH using patient-derived induced pluripotent stem cells (iPSCs) and 3D organoid technique, in which oral ectoderm and hypothalamus develop simultaneously. Interestingly, patient iPSCs with a heterozygous mutation in the orthodenticle homeobox 2 (OTX2) gene showed increased apoptosis in the pituitary progenitor cells, and the differentiation into pituitary hormone-producing cells was severely impaired. As an underlying mechanism, OTX2 in hypothalamus, not in oral ectoderm, was essential for progenitor cell maintenance by regulating LHX3 expression in oral ectoderm via FGF10 expression in the hypothalamus. Convincingly, the phenotype was reversed by the correction of the mutation, and the haploinsufficiency of OTX2 in control iPSCs revealed a similar phenotype, demonstrating that this mutation was responsible. Thus, we established an iPSC-based congenital pituitary disease model, which recapitulated interaction between hypothalamus and oral ectoderm and demonstrated the essential role of hypothalamic OTX2.

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.

Although acromegaly has been reported in patients with Neurofibromatosis type 1 (NF1), these cases have not been associated with growth hormone (GH)-producing somatotroph adenoma, but with optic pathway glioma. A 68 year-old Japanese woman, who had been clinically diagnosed with NF1, was referred to our hospital due to a thyroid tumor and hypercalcemia. Acromegaly was suspected due to her facial features, and subsequent examinations revealed the presence of GH excess with a pituitary tumor, leading to the diagnosis of acromegaly. Histological and immunohistochemical analysis demonstrated an eosinophilic pituitary adenoma with diffuse positivity for GH, indicating typical somatotroph adenoma. In addition, her thyroid tumor was diagnosed histologically as follicular thyroid carcinoma (FTC) with primary hyperparathyroidism (PHPT). To investigate the pathogenesis of this untypical multiple endocrine tumor case of NF1, genetic analysis was performed using peripheral leukocytes and tissue of resected tumors. A heterozygous novel germline nonsense mutation (p.Arg1534*) in exon 35 of the NF1 gene was detected from peripheral leukocytes, which results in a truncated protein lacking the critical domain for GTPase activity, strongly suggesting its causal role in NF1. The loss of heterozygosity (LOH) in exon 35 of the NF1 gene was not detected in the somatotroph adenoma, parathyroid adenoma, and FTC. Although any mutations of the following genes; MEN1, CDKN1B, and PAX8-PPARγ were not detected, a heterozygous GNAS R201C mutation was detected in the somatotroph adenoma. To our knowledge, this is the first rare MEN1-like case of genetically diagnosed NF1 complicated with acromegaly caused by a somatotroph adenoma.

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.

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 Plasma renin activity (PRA) is generally increased in patients with pheochromocytoma (PCC) due to low circulating plasma volume and activation of β-1 adrenergic receptor signaling. However, there has been no study on the aldosterone renin ratio (ARR) in patients with PCC. To elucidate the issue, this study aimed to determine the PRA, plasma aldosterone concentration (PAC), and ARR in patients with PCC and compare them with those in patients with subclinical Cushing’s syndrome (SCS) and non-functioning adrenal adenoma (NFA). Methods In this retrospective single-center, cross-sectional study, 67 consecutive patients with adrenal tumors (PCC (n = 18), SCS (n = 18), and NFA (n = 31)) diagnosed at Kobe University Hospital between 2008 and 2014 were enrolled. Results PRA was significantly higher in patients with PCC than in those with SCS and NFA (2.1 (1.3 ~ 2.8) vs. 0.7 (0.5 ~ 1.8) and 0.9 (0.6 ~ 1.4) ng/mL/h; p = 0.018 and p = 0.025). Although PACs were comparable among the three groups, ARR was significantly lower in patients with PCC than in those with SCS and NFA (70.5 (45.5 ~ 79.5) vs. 156.0 (92.9 ~ 194.5) and 114.9 (90.1 ~ 153.4); p = 0.001 and p 1.55 ng/mL/h showed a sensitivity of 70.0% and specificity of 80.6%. Interestingly, ARR Conclusions ARR decreased in patients with PCC, which was a more sensitive marker than PRA. Further study is necessary to understand the usefulness of this convenient marker in the detection of PCC. Trial registration This study was not registered because of the retrospective analysis.

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.

Background Plasma renin activity (PRA) is generally increased in patients with pheochromocytoma (PCC) due to low circulating plasma volume and activation of β-1 adrenergic receptor signaling. However, there has been no study on the aldosterone renin ratio (ARR) in patients with PCC. To elucidate the issue, this study aimed to determine the PRA, plasma aldosterone concentration (PAC), and ARR in patients with PCC and compare them with those in patients with subclinical Cushing’s syndrome (SCS) and non-functioning adrenal adenoma (NFA). Methods In this retrospective single-center, cross-sectional study, 67 consecutive patients with adrenal tumors (PCC (n =18), SCS (n =18), and NFA (n =31)) diagnosed at Kobe University Hospital between 2008 and 2014 were enrolled. Results PRA was significantly higher in patients with PCC than in those with SCS and NFA (2.1 (1.3~2.8) vs. 0.7 (0.5~1.8) and 0.9 (0.6~1.4) ng/mL/h; p =0.018 and p =0.025). Although PACs were comparable among the three groups, ARR was significantly lower in patients with PCC than in those with SCS and NFA (70.5 (45.5~79.5) vs. 156.0 (92.9~194.5) and 114.9 (90.1~153.4); p =0.001 and p 1.55 ng/mL/h showed a sensitivity of 70.0% and specificity of 80.6%. Interestingly, ARR

To evaluate the advantages of intraprocedural CT during adrenal venous sampling (AVS) to confirm accurate catheterization of the right adrenal vein (RAV). This single-institution study included 106 patients (mean age 52.4 years; range 28–74 years) with primary aldosteronism who performed contrast-enhanced CT (CECT) before AVS following AVS between January 2011 and March 2018. After catheterization of the RAV under fluoroscopic guidance, unenhanced CT images were obtained to confirm catheter position on unified CT angiography system. Catheter repositioning was performed when the catheter was inaccurately positioned. Venography findings were classified into two groups: (1) presumably cannulated in the RAV (presumed RAV group) and (2) obscured visualization of the RAV because of collateral vessels (obscured RAV group). Success rates of AVS were compared using Fisher’s exact test. The overall success of AVS was achieved in 104 patients (98.1%). Catheter was deviated into the IVC during intraprocedural CT in four patients. Fourteen patients (14.0%) required catheter repositioning by intraprocedural CT images, and accurate catheterization in the RAV was eventually accomplished. The success rate of AVS was significantly higher in the presumed RAV group (90.1% [73/81]) than that in the obscured RAV group (68.4% [13/19]) (p = 0.024). If intraprocedural CT was not acquired during AVS, the success rate of AVS would have been significantly lower (84.9% [90/106]) compared with that use of intraprocedural CT (98.1% [104/106]) (p

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: 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:Pheochromocytoma and paraganglioma are catecholamine-producing tumors that oftenimpair glucose tolerance. The effects of these tumors on insulin sensitivity and insulin secretion inpatients have remained unclear, however.Objective:To characterize the influence of pheochromocytoma or paraganglioma on glucosetolerance, we comprehensively analyzed various parameters related to insulin secretion or insulinsensitivity in patients with these tumors.Design:Hyperglycemic and hyperinsulinemic-euglycemic clamps, as well as an oral glucose tolerancetest (OGTT), were performed in patients before and after tumor excision.Setting:Patients underwent metabolic analyses on admission to Kobe University Hospital.Patients:Eleven patients with pheochromocytoma and two with paraganglioma were examined.Intervention:None.Main Outcome Measures:We evaluated various parameters related to insulin secretion or insulinsensitivity as determined by an OGTT and by hyperglycemic and hyperinsulinemic-euglycemicclamp analyses.Results:Surgical treatment of the tumor reduced urinary catecholamine excretion and improvedglucose tolerance. The insulinogenic index, but not total insulin secretion, measured during theOGTT as well as the first phase, but not the second phase, of insulin secretion during the hyper-glycemic clamp were improved after surgery. The insulin sensitivity index determined during thehyperinsulinemic-euglycemic clamp remained unchanged after surgery.Conclusion:These results suggest pheochromocytoma and paraganglioma impair glucose toleranceprimarily through impairment of insulin secretion—in particular, that of the early phase of theinsulin secretory response. A prospective study with more patients is warranted to further confirmthese results.(J Clin Endocrinol Metab102: 3400–3405, 2017)

Acromegaly is a disease associated with an increased risk for several kinds of neoplasms including colon and thyroid cancer. Although the association between acromegaly and pancreatic neoplasms has not been elucidated, it has recently been reported that GNAS gene mutations were found in 58% of intraductal papillary mucinous neoplasms (IPMNs), which are representative pancreatic cystic lesions, suggesting a link between IPMNs and acromegaly. To assess the prevalence of pancreatic cystic lesions in patients with acromegaly, we performed a retrospective cross-sectional single institute study. Thirty consecutive acromegalic patients (20 females and 10 males; mean age, 60.9 ± 11.9 years) who underwent abdominal contrast-enhanced computed tomography or magnetic resonance imaging between 2007 and 2015 at Kobe University Hospital were recruited. We also analyzed the relationship between presence of pancreatic cystic lesions and somatic GNAS mutations in pituitary tumors. Seventeen of 30 (56.7%) patients studied had pancreatic cystic lesions. Nine of 17 patients (52.9%) were diagnosed with IPMNs based on imaging findings. These results suggest that the prevalence of IPMNs may be higher in acromegalic patients in acromegalic patients than historically observed in control patients (up to 13.5%). In patients with pancreatic cystic lesions, the mean patient age was higher and the duration of disease was longer than in those without pancreatic cystic lesions (67.0 ± 2.3 vs. 53.0 ± 2.7 years, p

Context Germline mutations in fumarate hydratase (FH) gene are known to cause hereditary leiomyomatosis and renal cell carcinoma (HLRCC) and are occasionally accompanied with cutaneous and uterine leiomyoma or cortisol-producing adrenocortical hyperplasia. However, the association between FH mutations and cardiac or adrenocortical tumors has remained unknown. Here, we identified a novel deletion in FH, exhibiting cardiac myxoma and subclinical Cushing syndrome due to adrenocortical tumor. Case Description A 44-year-old man was referred to our hospital for cardiac and adrenal tumor evaluation. He had a history of multiple painful, dermal papules and nodules diagnosed as cutaneous leiomyoma. The surgically resected cardiac tumor was diagnosed as myxoma. The adrenal tumor was clinically diagnosed as subclinical Cushing syndrome. Laparoscopically resected adrenal tumor was pathologically diagnosed as adrenocortical adenoma harboring unique histological findings similar to primary pigmented nodular adrenocortical disease (PPNAD). DNA analysis revealed a germline deletion in FH c0.737delT (p. Phe225Leufs*31) and loss of heterozygosity (LOH) in cardiac myxoma. As a functional analysis of FH in cardiac myxoma, low FH protein expression with elevated 2-succinocysteine (2SC), a marker of FH dysfunction, was immunohistochemically detected. However, in adrenocortical tumor, LOH of FH was not detected, and FH or 2SC expression was not altered. Conclusions This is the first case of HLRCC complicated by cardiac myxoma. LOH of FH deletion and its dysfunction were identified in cardiac myxoma. The association between FH deletion and adrenocortical lesion, however, needs to be further clarified.

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.

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

Objective Various organs are known to be affected by the comorbidities of acromegaly. However, the involvement of renal structural comorbidities, such as cysts, has so far remained largely unknown. In this single-center study, we aimed to determine the prevalence and factors associated with simple renal cysts in Japanese patients with acromegaly. Methods A total of 71 consecutive patients with acromegaly were analyzed, who all underwent abdominal ultrasonography at diagnosis between 1986 and 2012 at Kobe University Hospital. Results Of these 71 patients, 23 (32.4%) exhibited simple renal cysts. Acromegalic patients with renal cysts tended to be significantly older, had a higher prevalence of smoking- and higher nadir growth hormone (GH) levels during the oral glucose tolerance test (OGTT) than did those without renal cysts. A multivariate logistic regression analysis showed age, smoking, and nadir GH to be independent factors associated with renal cysts. Interestingly, the number of renal cysts positively correlated with both the basal GH levels and nadir GH levels during OGTT (r=0.66, p

Most of acromegaly is caused by a sporadic somatotropinoma and a couple of novel gene mutations responsible for somatotropinoma have recently been reported. To determine the cause of sporadic somatotropinoma in Japanese patients, we analyzed 61 consecutive Japanese patients with somatotropinoma without apparent family history. Comprehensive genetic analysis revealed that 31 patients harbored guanine nucleotide-binding protein, alpha stimulating (GNAS) mutations (50.8%) and three patients harbored aryl hydrocarbon receptor interacting protein (AIP) mutations (4.9%). No patients had G protein-coupled receptor 101 (GPR101) mutations. The patients in this cohort study were categorized into three groups of AIP, GNAS, and others and compared the clinical characteristics. The AIP group exhibited significantly younger age at diagnosis, larger tumor, and higher nadir GH during oral glucose tolerance test. In all patients with AIP mutation, macro- and invasive tumor was detected and repetitive surgery or postoperative medical therapy was needed. One case showed a refractory response to postoperative somatostatin analogue (SSA) but after the addition of cabergoline as combined therapy, serum IGF-I levels were controlled. The other case showed a modest response to SSA and the switching to cabergoline monotherapy was also effective. These data suggest that although resistance to SSA has been reported in patients with AIP mutations, the response to dopamine agonist (DA) may be retained. In conclusion, the cause of sporadic somatotropinoma in Japanese patients was comparable with the previous reports in Caucasians, patients with AIP mutations showed unique clinical characteristics, and DA may be a therapeutic option for patients with AIP mutations.

Measuring salivary cortisol is both convenient and non-invasive for patients; however, its usefulness as a marker for monitoring medical therapy has not yet been established. The aim of this study was to assess the utility of multiple salivary cortisol measurements in patients with Cushing's syndrome (CS) during medical therapy. Six patients with CS (three with cortisol-secreting adrenocortical adenoma and three with ACTH-secreting pituitary adenoma) were recruited. Samples for morning serum cortisol, urinary free cortisol (UFC), and multiple salivary cortisol levels were collected before and during metyrapone treatment. The area under the curve (AUC) and mean value (MV) of daily salivary cortisol levels were calculated. In five out of six patients, UFC were normalized; however, multiple salivary cortisol measurements revealed an impaired diurnal cortisol rhythm in these patients. To verify the usefulness of multiple salivary cortisol measurements, we performed a prospective case study of a patient in whom the excess secretion of cortisol was not controlled (UFC 211 μg/day) with 2,250 mg/day in four divided doses of metyrapone. Multiple measurements of salivary cortisol revealed that cortisol levels elevated before the next administration. Accordingly, we shortened the interval by increasing the number of administration from four to five times per day, with a slight increment of daily dose of 2,500 mg. These optimizations resulted in a drastic improvement of diurnal pattern as well as UFC level (101 μg/day). Changes in both the MV and AUC of salivary cortisol levels were more correlated with those in UFC levels (Correlation coefficient 0.75, p = 0.007, and 0.70, p = 0.017) than those in the morning serum cortisol levels (0.42, p = 0.200), indicating that multiple salivary cortisol measurements reflect more precisely the excess secretion of cortisol. Our preliminary data suggest that multiple salivary cortisol measurements can be a useful tool to visualize the diurnal cortisol rhythm and to determine the dose and timing of metyrapone during the treatment in patients with CS.

Purpose To develop a Japanese version of the acromegaly quality of life (QoL) questionnaire (AcroQoL) and investigate the factors associated with impaired QoL in patients with acromegaly. Methods We developed a Japanese version of the AcroQoL by a forward-backward method and evaluated QoL in 38 patients with acromegaly who had been followed up at an outpatient clinic at Kobe University Hospital. Its reliability was examined with Cronbach's alpha and item-total correlations. Second examination was performed for concurrent validity by assessment of correlations with the Short Form-36 (SF-36) and longitudinal analysis of the AcroQoL in 25 patients. Results Cronbach's alpha and item-total correlations showed a range of 0.76-0.93 and 0.20-0.84, respectively, and significant correlations were found between the AcroQoL and the SF-36. Younger age and a history of radiotherapy were associated with worse total score by the multivariate linear regression analysis (p = 0.020 and p = 0.042, respectively). Intriguingly, in the biochemically-controlled group after the exclusion of patients who received radiotherapy, patients who underwent surgery alone exhibited a higher psychological (75.0 vs. 65.7 %, p = 0.036) and appearance (64.3 vs. 53.6 %, p = 0.036) score than those who are treating with pharmaceutical therapy. Conclusions The reliability of the Japanese version of the AcroQoL was satisfactory. Younger age and a history of radiotherapy were associated with lower QoL in patients with acromegaly. In biochemically-controlled acromegaly, patients who underwent surgery alone exhibited better QoL than those under pharmaceutical therapy.

Background Most of circulating IGF-I is derived from the liver and circulating IGF-I levels are decreased in several pathological conditions, such as liver cirrhosis, uncontrolled diabetes, renal failure, and malnutrition. However, it has not fully been elucidated which factors modify IGF-I level in a physiological condition. Objective To identify the factors which are associated with circulating IGF-I levels. Design Cross-sectional study. Methods This study included 428 subjects who undertook health check-up. Subjects diagnosed with non-alcoholic fatty liver disease (NAFLD) by ultrasonography were analyzed separately. Univariate and multivariate regression analyses were conducted to identify the factors associated with circulating IGF-I levels. Results Regression analyses revealed that serum albumin levels, total-bilirubin levels, calcium levels, and HOMA-IR were positively correlated with IGF-I levels. Serum transaminase levels and habitual drinking (ethanol intake >20 g/day) were negatively correlated with serum IGF-I levels. Although serum IGF-I standard deviation scores (SDS) in subjects with and without NAFLD were comparable, after adjusting confounding factors clarified by multivariate regression analysis, IGF-I SDS negatively correlated with the presence of NAFLD. Conclusion In this study, we demonstrated that serum bilirubin and calcium levels are correlated with serum IGF-I levels. Although further study is necessary, these data suggest a presence of interaction between GH-IGF-I axis and bilirubin and calcium metabolism.

Pituitary-specific transcription factor 1 (PIT-1; POU domain, class 1, transcription factor 1 (POU1F1)) is an essential transcription factor for the differentiation of somatotrophs, lactotrophs, and thyrotrophs, and for the expression of growth hormone (GH), prolactin (PRL), and thyroid-stimulating hormone (TSH). Mutations in PIT-1 cause congenital defects in GH and PRL secretion and severe TSH insufficiency. Anti-PIT-1 antibody syndrome, firstly reported in 2011, is characterized by acquired GH, PRL, and TSH deficiencies without PIT-1 mutation and is associated with the presence of the circulating antibody against PIT-1 protein as a marker. Various autoantibodies are detected with multiple endocrine organopathies in this syndrome; therefore, it meets the criteria of autoimmune polyglandular syndrome. Mechanistically, cytotoxic T lymphocytes specifically reacting with PIT-1 protein play an important role in the development of this syndrome.

Pituitary-specific transcription factor 1 (PIT-1; POU domain, class 1, transcription factor 1 (POU1F1)) is an essential transcription factor for the differentiation of somatotrophs, lactotrophs, and thyrotrophs, and for the expression of growth hormone (GH), prolactin (PRL), and thyroid-stimulating hormone (TSH). Mutations in PIT-1 cause congenital defects in GH and PRL secretion and severe TSH insufficiency. Anti-PIT-1 antibody syndrome, firstly reported in 2011, is characterized by acquired GH, PRL, and TSH deficiencies without PIT-1 mutation and is associated with the presence of the circulating antibody against PIT-1 protein as a marker. Various autoantibodies are detected with multiple endocrine organopathies in this syndrome; therefore, it meets the criteria of autoimmune polyglandular syndrome. Mechanistically, cytotoxic T lymphocytes specifically reacting with PIT-1 protein play an important role in the development of this syndrome.