A case of hypophysitis after COVID-19 vaccination with a detection of anti-pituitary antibody, with review of literature.

COVID-19 vaccines have resulted in a remarkable reduction in both the morbidity and mortality associated with COVID-19. However, there are reports of endocrine rare clinical conditions linked to COVID-19 vaccination. In this report, we present a case of hypophysitis following COVID-19 vaccination and review the literature on this condition. This case involved a 72-year-old male with type 1 diabetes who experienced symptoms such as vomiting, appetite loss, and headaches following his fifth COVID-19 vaccine dose. He was diagnosed with secondary adrenal insufficiency; subsequent assessment revealed an enlarged pituitary gland. Unlike previous cases, our patient has partial recovery from pituitary insufficiency, and his pituitary function gradually improved over time. Anti-pituitary antibodies (APAs) against corticotrophs, thyrotrophs, gonadotrophs, and folliculo stellate cells (FSCs) were detected in serum samples taken 3 months after onset. Hypophysitis after COVID-19 vaccination is a rare clinical condition, with only eight cases reported by the end of 2023, most occurring after the initial or second vaccination. Symptoms of hypophysitis after COVID-19 vaccination are similar to those of classic pituitary dysfunction. Pituitary insufficiency is persistent, with five of the above eight patients presenting posterior pituitary dysfunction and three patients presenting only anterior pituitary dysfunction. Two of those eight patients had autoimmune diseases. Our case suggests a potential link between acquired immunity, APA production, and pituitary damage. To elucidate the etiology of hypophysitis associated with COVID-19 vaccination, detailed investigation of patients with nonspecific symptoms after vaccination against COVID-19 is necessary.

Parameters of captopril challenge test can predict results of other confirmatory tests for primary aldosteronism and propose the next test to be done.

In Japan, primary aldosteronism (PA) is diagnosed if any one of the captopril challenge test (CCT), saline infusion test (SIT), furosemide-upright test (FUP), and oral salt-loading test (OST) is positive. The present study aimed to investigate if parameters of CCT, the safest confirmatory test, could predict decisions of other tests and propose the next test to diagnose PA in CCT-negative patients. In a cross-sectional design, 142 patients, who were referred to our hospital for the scrutiny of PA and underwent at least two confirmatory tests, were enrolled. While 123 patients underwent all of the CCT, SIT, and FUP, the OST was successfully done in only six patients and excluded from further analyses. CCT parameters showing correlations of higher degrees with SIT and FUP parameters were selected, and their powers to predict SIT and FUP decisions were investigated by receiver operating characteristic analyses. Proposals of the next test based on the CCT parameters were validated with SIT and FUP decisions in subsets of CCT-negative patients divided by cut-offs of the CCT parameters. The plasma aldosterone concentration and plasma renin activity 60 min after the load of CCT (CCT60-PAC and CCT60-PRA) were selected, and CCT60-PAC ≤59.0 pg/mL and CCT60-PRA ≥1.05 ng/mL/h could predict negativities of SIT and FUP, respectively, with >95% specificities. Based on the validation, the present study suggested the SIT as the next test to be done if the CCT-negative patient belonged to the subset with CCT60-PAC >59.0 pg/mL and CCT60-PRA ≥1.05 ng/mL/h, otherwise the FUP should be selected.

Effects of sodium-glucose cotransporter 2 inhibitor (dapagliflozin) on food intake and plasma fibroblast growth factor 21 levels in type 2 diabetes patients.

The objective of this study was to investigate whether sodium-glucose cotransporter 2 inhibitors (SGLT2i) treatment in patients with type 2 diabetes induced compensatory hyperphagia by reducing fibroblast growth factor 21 (FGF21) secretion. This prospective study was performed in 26 type 2 diabetes patients treated with dapagliflozin (5 mg/day). Hormonal factors associated with glucose metabolism, dietary intakes estimated by brief self-administered diet-history questionnaire (BDHQ), body weight (BW), and body composition were measured at baseline, and 4 and 12 weeks after dapagliflozin. At 12 weeks, HbA1c levels and BW decreased significantly (both p < 0.0001). BMI at baseline was predictive to baseline log10 (FGF21) (p = 0.037). This study showed no change in FGF21, but insulin and glucagon levels decreased significantly (both p < 0.05). Although hyperphagia was found in 10 patients (38.5%), defining hyperphagia as >20% increase in carbohydrate intake, dapagliflozin treatment induced no hyperphagia, when analyzed by all subjects, and there was no significant association between changes in FGF21 levels and carbohydrate intake. On the other hand, a positive correlation between changes in FGF21 levels or carbohydrate intake and BW was observed (both p < 0.005). Taken together, this study demonstrates that the intervention to maintain the reduced levels in FGF21 is beneficial for BW reduction in type 2 diabetes patients treated with SGLT2i.

A Case of an Ectopic ACTH-Producing Tumor With Adrenal Shrinkage During Osilodrostat Administration.

Ectopic adrenocorticotropin (ACTH)-secreting tumors are among the causes of ACTH-dependent Cushing syndrome. When surgical resection of the primary lesion is not feasible, medications such as metyrapone, mitotane, and ketoconazole have been used to control hypercortisolism. This report presents a case treated with the novel drug osilodrostat, wherein the patient's adrenal glands exhibited shrinkage following the initiation of this drug. The case involves a 68-year-old man diagnosed with small cell lung cancer and ectopic ACTH-producing Cushing syndrome. Initially, metyrapone was administered to manage hypercortisolism, but its effect proved insufficient. Subsequently, osilodrostat was initiated while gradually decreasing metyrapone, leading to full suppression of blood cortisol levels. With continued osilodrostat treatment, the adrenal glands reduced in size, suggesting the potential to reduce the osilodrostat dosage.

Light and Shadow of Na-Glucose Cotransporter 2 Inhibitors in the Treatment of Diabetes Mellitus: Points for Improvement Based on Our Clinical Experience.

We analyzed the effect of Na-glucose cotransporter 2 inhibitors (SGLT2-I) in diabetic patients visiting our hospital. The study included 236 patients treated with SGLT2-I alone or with codiabetic drugs for at least two years. We analyzed overtime changes in glycosylated hemoglobin A1c (HbA1c) in the patients by repeated analyses of variance (ANOVA) and evaluated the therapeutic effect. HbA1c levels decreased significantly in the first six months after treatment. Afterward, they leveled off and increased slightly over the next two years. Six months after treatment, the mean (SD) of HbA1c was 8.19 (1.46) %; the mean difference dropped by 0.91%, and HbA1c in mild DM2 did not drop by below 8.0%. Overall, there was only a slight improvement. We performed multivariate logistic regression analysis using a model with or without improvement as the objective variable and several explanatory variables. Na and Hct were significant factors. They increased considerably over six months and then leveled off. eGFR significantly reduced in the hyperfiltration group six months after treatment. The annual decline rate in eGFR was also faster, even in the nonhyperfiltration group than in the healthy subjects, which may be a characteristic of renal clearance in SGLT2-I treatment. In conclusion, SGLT2-I is an excellent antidiabetic, nephroprotective agent to eliminate hyperfiltration, but unfortunately, SGLT2-I alone does not have enough power to reduce blood glucose levels. SGLT2-I, with insulin or insulin secretagogues, enhances insulin resistance, induces hyperinsulinemia, and exacerbates type 2 DM. In contrast, SGLT2-I, with noninsulin antidiabetic agents and a low-carbohydrate diet, may bring better results.

Complexities in Adjuvant Endocrine Therapy for Breast Cancer in Female-to-Male Transgender Patients.

Introduction: Managing breast cancer in female-to-male (FtM) transgender patients is complicated and challenging. Androgens play a crucial role in the development of secondary sexual identity in FtM transgender patients, but their effectiveness in breast cancer remains unclear. Furthermore, the considerations for adjuvant endocrine therapy in this population are highly intricate and warrant thorough discussion. Case Presentation: We describe the case of a 44-year-old FtM transgender diagnosed with breast cancer 3 years after initiating androgen receptor agonist therapy as part of his gender identity transition. After mastectomy, adjuvant endocrine therapy was initiated, consisting of a combination of an aromatase inhibitor and a gonadotropin-releasing hormone agonist, along with a cross-sex hormone. Conclusion: Estradiol levels were significantly reduced, and male-typical levels of sex hormones were attained.

An Asymptomatic Case With MEN1 Slipping Through Genetic Screening by SNV-dependent Allelic Dropout.

Context: Genetic testing is useful not only for the diagnosis of the MEN1 proband but also for determining the putative asymptomatic variant carriers to improve the prognosis or to avoid unnecessary medical intervention. However, we must be aware of the putative pitfalls of polymerase chain reaction (PCR)-based genetic testing in specific conditions that lead to medical mismanagement. Objective: To warn of the putative pitfalls of PCR-based genetic testing, we report an overlooked case of MEN1 due to PCR allelic dropout. Methods: A 69-year-old man was clinically diagnosed with MEN1, and genetic testing revealed that he had a pathogenic variant in the MEN1 gene. His 36-year-old son was completely asymptomatic. As the son was 50% at risk of MEN1, he was willing to undergo genetic testing himself after genetic counseling. Results: Genetic testing was carried out in 2 independent laboratories. Although laboratory A showed that he carried a pathogenic variant, laboratory B showed that he had the wild-type genotype of MEN1. The discrepancy in these results was due to PCR allelic dropout by single-nucleotide variations of the MEN1 gene in the 5' region. The surveillance revealed that he had asymptomatic primary hyperparathyroidism and a neuroendocrine tumor of the pancreas. Conclusion: PCR-dependent genetic analysis may be susceptible to PCR allelic dropout in an SNV-specific manner. We must be careful when genetically testing individuals of relatives with clinical MEN1 disease.

Comparisons of plasma aldosterone and renin data between an automated chemiluminescent immunoanalyzer and conventional radioimmunoassays in the screening and diagnosis of primary aldosteronism.

Determining values of plasma renin activity (PRA) or plasma active renin concentration (ARC), plasma aldosterone concentration (PAC), and aldosterone-to-renin ratio (ARR) is essential to diagnose primary aldosteronism (PA), but it takes several days with conventional radioimmunoassays (RIAs). Chemiluminescent enzyme immunoassays for PAC and ARC using the Accuraseed® immunoanalyzer facilitated the determination, but relations between Accuraseed® immunoanalyzer-based and RIA-based values in samples of PA confirmatory tests and adrenal venous sampling remained to be elucidated. We addressed this issue in the present study. This is a prospective, cross-sectional study. ARC and PAC values were measured by the Accuraseed® immunoanalyzer in samples, in which PRA and PAC values had been measured by the PRA-FR® RIA and SPAC®-S Aldosterone kits, respectively. The relations between Accuraseed® immunoanalyzer-based and RIA-based values were investigated with regression analyses. The optimal cutoff of Accuraseed® immunoanalyzer-based ARR for PA screening was determined by the receiver operating characteristic analysis. After log-log transformations, linear relations with high coefficients of determination were observed between Accuraseed® immunoanalyzer-based and RIA-based data of renin and aldosterone. Following the PA guidelines of Japan Endocrine Society, Accuraseed® immunoanalyzer-based cutoffs were calculated from the regression equations: the basal PAC for PA screening >12 ng/dL, PAC for the saline infusion test >8.2 ng/dL, ARC for the furosemide-upright test <15 pg/mL, and ARR for the captopril challenge test >3.09 ng/dL per pg/mL. The optimal cutoff of Accuraseed® immunoanalyzer-based ARR for PA screening was >2.43 ng/dL over pg/mL not to overlook bilateral PA patients. The present study provided conversion formulas between Accuraseed® immunoanalyzer-based and RIA-based values of renin, aldosterone, and ARR, not only in basal samples but also in samples of PA confirmatory tests and adrenal venous sampling. Although validation studies are awaited, the present study will become priming water of harmonization of renin and aldosterone immunoassays.

Genotype-phenotype analysis, and assessment of the importance of the zinc-binding site in PHEX in Japanese patients with X-linked hypophosphatemic rickets using 3D structure modeling.

X-linked hypophosphatemic rickets (XLH) is an inheritable type of rickets caused by inactivating variants in the phosphate regulating endopeptidase homolog X-linked (PHEX) gene, which results in the overproduction of fibroblast growth factor 23 (FGF23). The mechanism by which PHEX impairment leads to FGF23 overproduction is unknown. Because little is known regarding the genotype-phenotype correlation in Japanese XLH, we summarized the available clinical and genetic data and analyzed the genotype-phenotype relationships using 3-dimensional (3D) structure modeling to clarify the XLH pathophysiology. We retrospectively reviewed the clinical features and performed genetic analysis of 39 Japanese patients with XLH from 28 unrelated pedigrees carrying any known or novel PHEX variant. To predict changes in the 3D structure of mutant PHEX, we constructed a putative 3D model of each mutant and evaluated the effect of structural alteration by genotype-phenotype correlation analysis. Genetic analysis revealed 23 PHEX variants, including eight novel variants. They were associated with high i-FGF23 levels, hypophosphatemia, phosphaturia, high alkaline phosphatase levels, and short stature. No gene dosage effect or genotype-phenotype correlation was observed when truncating and non-truncating variants were compared. However, the conservation of the zinc-binding site and cavity in PHEX had an impact on the elevation of i-FGF23 levels. Via genotype-phenotype relationship analysis using 3D modeling, we showed that the zinc-binding site and cavity in PHEX can play a critical role in its function. These findings provide new genetic clues for investigating the function of PHEX and the pathogenesis of XLH.

ARMC5 Alterations in Primary Macronodular Adrenal Hyperplasia (PMAH) and the Clinical State of Variant Carriers.

CONTEXT: Primary macronodular adrenal hyperplasia (PMAH) is a rare type of Cushing or subclinical Cushing syndrome and is associated with bilateral multinodular formation. ARMC5 is one of the responsible genes for PMAH. OBJECTIVES: This study was performed to identify the genotype-phenotype correlation of ARMC5 in a cohort of Japanese patients. PATIENTS AND METHODS: Fourteen patients with clinically diagnosed PMAH and family members of selected patients were studied for ARMC5 gene alteration and clinical phenotype. The associated nonadrenal tumor tissues were also studied. RESULTS: Of fourteen patients with PMAH, 10 had pathogenic or likely pathogenic variants of ARMC5. We found two variants. Five unrelated patients had identical variants (p.R619*). In two patients, the variant was found in offspring with the asymptomatic or presymptomatic state. Six of ten patients who tested positive for the ARMC5 pathogenic or likely pathogenic variant carried nonadrenal tumors; however, no loss of heterozygosity (LOH) or second hit of the ARMC5 gene was evident. The ARMC5 variant-positive group showed a significantly higher basal cortisol level. Furthermore, age-dependent cortisol hypersecretion was seen in the ARMC5 variant-positive group. CONCLUSIONS: ARMC5 pathogenic variants are common (71%) in Japanese patients with PMAH. p.R619* might be a hot spot in Japanese patients with PMAH. Asymptomatic or presymptomatic pathogenic variant carriers were found among the family members of the patients. Although 50% of ARMC5 variant carriers had nonadrenal neoplastic lesions, no LOH or second hit of ARMC5 in the tumor tissues was evident. The ARMC5 variant-positive mutant group showed a higher basal cortisol level than the negative group.

Matrix metalloproteinase-1 is a crucial bone metastasis factor in a human breast cancer-derived highly invasive cell line.

Bone metastasis is one of the most severe cancer complications. To analyze the mechanism of bone metastasis, we established highly invasive cell lines from the human breast cancer cell line MDA-MB-231 using an in vitro sequential selection system. The cell lines, MDA-231-S10 and MDA-231-S5, were more invasive and more motile than the parental cell line. Moreover, MDA-231-S10 metastasized to bone more often when inoculated into the arterial circulation of nude mice. MDA-231-S10-bearing nude mice had a significantly poorer prognosis, and their bony metastatic tumors grew more rapidly than those of the mice bearing the parental cell line (MDA-231-P). Given that a high expression of matrix metalloproteinase (MMP) is reported to be associated with cancer invasiveness, we examined MMP expression. Our results showed that the expression of MMP-3, -5, -7, -9, -13 and -14 was decreased on Multiplex real-time quantitative RT-PCR analysis in the two new cell lines. The zymographic analysis showed no MMP-2 activity and a decreased MMP-9 activity in MDA-231-S10. However, the expression of MMP-1 in MDA-231-S10 was increased. We therefore concluded that MMP-1 plays a crucial role in breast cancer bone metastasis. Furthermore, our MDA-231-derived cell lines are useful analytical models of MMP-1- associated breast cancer bone metastasis.

Asymptomatic Congenital Hyperinsulinism due to a Glucokinase-Activating Mutation, Treated as Adrenal Insufficiency for Twelve Years.

Congenital hyperinsulinism (CHI) caused by a glucokinase- (GCK-) activating mutation shows autosomal dominant inheritance, and its severity ranges from mild to severe. A 43-year-old female with asymptomatic hypoglycemia (47 mg/dL) was diagnosed as partial adrenal insufficiency and the administration of hydrocortisone (10 mg/day) was initiated. Twelve years later, her 8-month-old grandchild was diagnosed with CHI. Heterozygosity of exon 6 c.590T>C (p.M197T) was identified in a gene analysis of GCK, which was also detected in her son and herself. The identification of GCK-activating mutations in hyperinsulinemic hypoglycemia patients may be useful for a deeper understanding of the pathophysiology involved and preventing unnecessary glucocorticoid therapy.

Novel germline variant of TMEM127 gene in a patient with familial pheochromocytoma.

SUMMARY: Pheochromocytomas (PCCs) and paragangliomas (PGLs) are rare tumours with a heterogeneous genetic background. Up to 40% of apparently sporadic PCC/PGL cases carry 1 of the 12 gene germline mutations conferring genetic susceptibility to PCC/PGL. Although the precise mechanisms are unclear, TMEM127 is one of the rare responsible genes for PCC/PGL. Here we report the case of a patient with familial PCC having a novel TMEM127 variant (c.119C > T, p.S40F). In silico prediction analysis to evaluate the functional significance of this variant suggested that it is a disease-causing variant. A PCC on the left side was considered to be the dominant lesion, and unilateral adrenalectomy was performed. The histopathologic findings were consistent with benign PCC. A loss of heterogeneity of the TMEM127 variant was detected in the surgically removed tumour. LEARNING POINTS: c.119C > T (p.S40F) is a novel TMEM127 variant that can cause pheochromocytoma.The tumour showed loss of heterozygosity of this TMEM127 variant.The clinical phenotype of this mutation is putative bilateral pheochromocytoma in the 4th decade.Unilateral adrenalectomy may be performed as the initial surgery in such cases.