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.

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.

Real-World Evidence of the Incidence of and Risk Factors for Type 1 Diabetes Mellitus and Hypothyroidism as Immune-Related Adverse Events Associated With Programmed Cell Death-1 Inhibitors.

OBJECTIVE: The incidence of type 1 diabetes mellitus (T1DM) and hypothyroidism as immune-related adverse events (irAEs) after programmed cell death-1 inhibitor (PD-1i) administration has not yet been sufficiently evaluated in a real clinical setting. To assess the incidence of T1DM and hypothyroidism among PD-1is and to identify the risk factors associated with hypothyroidism using a large claims database. METHODS: This cohort study used the Shizuoka Kokuho database in Japan from 2012 to 2018, including approximately 2.2 million people. We enrolled 695 PD-1i-treated patients. T1DM and hypothyroidism as irAEs were identified using International Classification of Diseases 10th Revision and Anatomical Therapeutic Chemical classification codes. Risk factors for hypothyroidism were explored using the multivariable Fine and Gray regression model after adjusting for age group and sex, treating death as a competing risk. RESULTS: The cumulative incidences of T1DM and hypothyroidism were 0.3% and 8.3%, respectively. We described the detailed onset timing of irAEs in patients with T1DM and hypothyroidism; hypothyroidism was observed evenly within 1 year of the PD-1i prescription. Sex and certain cancer types, such as lung and urothelial cancers, were significantly associated with subdistribution hazard ratio (sHR) (female: sHR, 2.04 [95% CI, 1.20-3.47]; lung cancer: sHR, 0.55 [95% CI, 0.32-0.95]; and urothelial carcinoma: sHR, 2.40 [95% CI, 1.05-5.49]). CONCLUSION: The incidence of T1DM and hypothyroidism as irAEs and associated risk factors identified in this analysis were comparable to those found in previous studies. The use of a large claims database to detect irAEs, such as T1DM and hypothyroidism, may lead to safer use of PD-1is.

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.

A case of type B insulin resistance syndrome treated with low-dose glucocorticoids.

SUMMARY: Type B insulin resistance syndrome is characterized by the presence of autoantibodies to the insulin receptor. We present a 57-year-old male admitted to a hospital due to body weight loss of 16 kg and hyperglycemia of 13.6 mmol/L. He was diagnosed with type B insulin resistance syndrome because the anti-insulin receptor antibodies were positive. We informed him that some hyperglycemic cases of this syndrome had been reported to be spontaneously remitted in 5 years, and he did not agree to be treated with high-dose glucocorticoids and/or immunosuppressive agents due to his concern for their adverse effects such as hyperglycemia and immunosuppression. He chose to be treated with insulin and voglibose, but fair glucose control could not be obtained. Six years later, he agreed to be treated with low-dose glucocorticoids practicable in outpatient settings. One milligram per day of betamethasone was tried orally and reduced gradually according to the values of glycated hemoglobin. After 30 months of glucocorticoid treatment, the anti-insulin receptor antibodies became undetectable and his fasting plasma glucose and glycated hemoglobin were normalized. This case suggests that low-dose glucocorticoids could be a choice to treat type B insulin resistance syndrome in outpatient settings. LEARNING POINTS: Type B insulin resistance syndrome is an acquired autoimmune disease for insulin receptors. This case suggested the possibility of long-lasting, low-dose glucocorticoid therapy for the syndrome as an alternative for high-dose glucocorticoids or immunosuppressive agents. Since the prevalence of autoimmune nephritis is high in the syndrome, a delay of immunosuppressive therapy initiation might result in an exacerbation of nephropathy.

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.

Plasma kisspeptin levels in lactational amenorrhea.

The kisspeptin is a neuropeptide to play physiological roles in regulating gonadotropin-releasing hormone secretion in the hypothalamus. In human plasma, the kisspeptin concentration is measured, but gonadotropin-releasing hormone is not. This study aims to understand the physiological roles of the circulating kisspeptin in lactational amenorrhea in humans because prolactin reduces the kisspeptin expression and luteinizing hormone secretion resulting in anovulations in rodent brains. Plasma kisspeptin levels were measured in 11 subjects in lactational amenorrhea and in four cases with pathological amenorrhea by different etiologies for comparison using the enzyme immunoassay specific for human kisspeptin. The plasma kisspeptin levels in the 11 women with lactational amenorrhea were 15.2 ± 2.5 fmol/mL (mean ± SD) which were not significantly different as compared with 16.5 ± 4.8 fmol/mL (mean ± SD) in four age-matched women with menstrual cycles as we reported previously. In the four cases with pathological amenorrhea, their plasma kisspeptin levels were from 5.8 to 13.7 fmol/mL. This study demonstrated that the plasma kisspeptin levels were not totally reduced in lactational or pathological amenorrhea. These results suggest the physiological roles of the circulating kisspeptin are different from the role in the brain.

The relationship between circulating kisspeptin and sexual hormones levels in healthy females.

The kisspeptin (metastin) is an endogenous peptide, which regulates human reproduction by modulating gonadotropin-releasing hormone (GnRH) secretion. Kisspeptin was detected in peripheral blood, although GnRH was not. Previously, we measured plasma kisspeptin levels in male healthy subjects and patients with hypogonadism using enzyme immunoassay (EIA) to elucidate a normal range in healthy males and clinical implications of kisspeptin in male hypogonadism. We suggested that the plasma kisspeptin levels were received feedback from testosterone. In this study, we focused female subjects and elucidated the relationship between menstrual cycle and plasma kisspeptin levels to understand kisspeptin-hypothalamic-pituitary-gonadal axis. We measured plasma kisspeptin levels in eight female volunteers. The plasma kisspeptin levels in female are significantly higher than those in male. There are no significant correlation between plasma kisspeptin levels and sexual hormones. We revealed that the kisspeptin might stimulate a start of menstruation as a trigger, and progress menstruation covered for weakened ovarian function. We suggest that kisspeptin may be closely related with menstrual cycle and that the measurement of plasma kisspeptin levels is useful for understanding of reproductive system.

Plasma kisspeptin levels in male cases with hypogonadism.

The hypothalamic hormone kisspeptin (metastin) regulates human reproduction by modulating gonadotropin-releasing hormone (GnRH) secretion. Kisspeptin is detected in peripheral blood, although GnRH is not. In this study, we measured plasma kisspeptin levels in four male cases with hypogonadism and seven normal male controls using enzyme immunoassay (EIA) to elucidate the clinical implications of kisspeptin levels in male hypogonadism. The results showed a variety of plasma kisspeptin levels: 6.0 fmol/mL in a male with isolated hypogonadotropic hypogonadism (IHH), 43.2 fmol/mL in a male with Kallmann's syndrome, 40.7 fmol/mL in a male with azoospermia, 323.2 fmol/mL in a male with hypergonadotropic hypogonadism, and 12.3 ± 2.5 fmol/mL (mean ± SD) in seven normal controls. Except for the case with IHH, the plasma kisspetin levels were elevated in the three cases with Kallmann's syndrome, azoospermia, and hypergonadotropic hypogonadism. The reason why the three cases had high values was their lesions were downstream of the kisspeptin neuron in the hypothalamic-pituitary-gonadal axis, suggesting that elevated kisspeptin levels were implicated in hypothalamic kisspeptin secretion under decreased negative feedback of gonadal steroids. The result that the plasma kisspeptin levels were decreased by gonadotropin therapy in the case with Kallmann's syndrome supported this hypothesis. In conclusion, to measure plasma kisspeptin levels could be useful for better understanding of male hypogonadism.

Plasma kisspeptin levels in male cases with hypogonadism.

The hypothalamic hormone kisspeptin (metastin) regulates human reproduction by modulating gonadotropin-releasing hormone (GnRH) secretion. Kisspeptin is detected in peripheral blood, although GnRH is not. In this study, we measured plasma kisspeptin levels in four male cases with hypogonadism and seven normal male controls using enzyme immunoassay (EIA) to elucidate the clinical implications of kisspeptin levels in male hypogonadism. The results showed a variety of plasma kisspeptin levels: 6.0 fmol/ml in a male with isolated hypogonadotropic hypogonadism (IHH), 43.2 fmol/ml in a male with Kallmann's syndrome, 40.7 fmol/ml in a male with azoospermia, 323.2 fmol/ml in a male with hypergonadotropic hypogonadism, and 12.3 ± 2.5 fmol/ml (mean ± SD) in seven normal controls. Except for the case with IHH, the plasma kisspetin levels were elevated in the three cases with Kallmann's syndrome, azoospermia, and hypergonadotropic hypogonadism. The reason why the three cases had high values was their lesions were downstream of the kisspeptin neuron in the hypothalamic-pituitary-gonadal axis, suggesting that elevated kisspeptin levels were implicated in hypothalamic kisspeptin secretion under decreased negative feedback of gonadal steroids. The result that the plasma kisspeptin levels were decreased by gonadotropin therapy in the case with Kallmann's syndrome supported this hypothesis. In conclusion, to measure plasma kisspeptin levels could be useful for better understanding of male hypogonadism.

Pharmacological characterization of human NPFF(1) and NPFF(2) receptors expressed in CHO cells by using NPY Y(1) receptor antagonists.

Neuropeptide FF (NPFF) belongs to an opioid-modulatory system including two precursors (pro-NPFF(A) and pro-NPFF(B)) and two G-protein coupled receptors (NPFF(1) and NPFF(2)). The pharmacological and functional profiles of human NPFF(1) and NPFF(2) receptors expressed in Chinese hamster ovary (CHO) cells were compared by determining the affinity of several peptides derived from both NPFF precursors and by measuring their abilities to inhibit forskolin-induced cAMP accumulation. Each NPFF receptor recognizes peptides from both precursors with nanomolar affinities, however, with a slight preference of pro-NPFF(A) peptides for NPFF(2) receptors and of pro-NPFF(B) peptides for NPFF(1) receptors. BIBP3226 ((R)-N(2)-(diphenylacetyl)-N-[(4-hydroxyphenyl)-methyl]-argininamide) and BIBO3304 ((R)-N(2)-(diphenylacetyl)-N-[4-(aminocarbonylaminomethyl)-benzyl]-argininamide trifluoroacetate), two selective neuropeptide Y (NPY) Y(1) receptor antagonists, display relative high affinities for NPFF receptors and exhibit antagonist properties towards hNPFF(1) receptors. The structural determinants responsible for binding of these molecules to NPFF receptors were investigated and led to the synthesis of hNPFF(1) receptor antagonists with affinities from 40 to 80 nM. Our results demonstrate differences in pharmacological characteristics between NPFF(1) and NPFF(2) receptors and the feasibility of subtype-selective antagonists.