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Context There are inconsistent results and insufficient evidence as to whether an association exists between the size and aldosterone-producing ability of aldosterone-producing adenomas. Objective We further investigated this possible association retrospectively. Methods A total of 142 cases of primary aldosteronism diagnosed as unilateral by adrenal venous sampling at 2 referral centers between 2009 and 2019 were included. We classified these individuals into small and large tumor groups using a diameter of 14 mm as a cutoff. This size was the median diameter of the tumor on the affected side of the adrenal gland. We compared plasma aldosterone concentration (PAC), plasma renin activity (PRA), PAC to PRA ratio, PAC from a saline infusion test (SIT), urinary aldosterone secretion (uAld), and serum potassium as indices of aldosterone-producing ability between the 2 groups. In some cases, we conducted histopathological evaluations and detection of the KCNJ5 mutation. Results PAC, PAC to PRA ratio, PAC from SIT, and uAld were higher and serum potassium was lower in the large tumor group. PAC, PAC from SIT, uAld, and serum potassium significantly correlated with tumor diameter. PRA was not associated with tumor diameter. Clear cell–dominant cases were more common in the large tumor group, while cases showing a strong expression of CYP11B2 were not significantly different between the groups. KCNJ5 mutations tended to be more common in the large tumor group. Conclusion The higher aldosterone-producing ability in larger adenomas can be used to infer the responsible lesion and disease type.

To establish real-world evidence about the safety and efficacy of bexarotene for Japanese patients with cutaneous T-cell lymphoma, we conducted a nationwide cohort study using data from post-marketing surveillance for bexarotene treatment. In total, 294 patients with cutaneous T-cell lymphoma were identified between June 2016 and June 2018. Of these, 267 patients were included as the safety analysis set. Of the 267 patients, 175 were included in the efficacy analysis set. Of these, 139 patients had mycosis fungoides, including 46 with early stage disease and 93 with advanced stage disease. Among the 139 patients with mycosis fungoides, the objective response rate was 46.8%. A significant difference in objective response rate was detected between patients who started with bexarotene at 300 mg/m2 (61.6%) and patients who started with bexarotene at less than 300 mg/m2 (22.6%, p < 0.001). Of the 139 patients with mycosis fungoides, 92 were treated with a combination of bexarotene plus photo(chemo)therapy. A significant difference in objective response rate was seen between bexarotene with a combination of photo(chemo)therapy (57.6%) and bexarotene without a combination of photo(chemo)therapy (25.5%, p < 0.001). Starting bexarotene at 300 mg/m2 and combination with photo(chemo)therapy were detected as independent factors influencing response. Common treatment-related adverse events included hypothyroidism (85.8%), hypertriglyceridemia (68.5%), hypercholesterolemia (43.8%), and neutropenia (21.3%). Hypertriglyceridemia, hypercholesterolemia, and neutropenia occurred more frequently in patients who started with bexarotene at 300 mg/m2 than patients who started with bexarotene at less than 300 mg/m2 (hypertriglyceridemia, 76.4% vs. 57.0%, p = 0.001; hypercholesterolemia, 49.0% vs. 36.4%, p = 0.045; neutropenia, 28.0% vs. 12.1%, p = 0.002; respectively). The present study indicates that starting bexarotene at 300 mg/m2 and combination of photo(chemo)therapy offer a promising efficacy for the treatment of patients with mycosis fungoides. Efficacy of low-dose bexarotene plus photo(chemo)therapy should be evaluated in future.

Immune checkpoint inhibitors (ICIs) are potent therapeutic options for many types of advanced cancer. The expansion of ICIs use however has led to an increase in immune-related adverse events (irAEs). Secondary adrenal insufficiency (AI) can be life-threatening especially in patients with delayed diagnosis. We retrospectively investigated secondary AI in ICI-treated patients. A total of 373 cancer patients treated with ICIs were included and evaluated. An adrenocorticotropic hormone (ACTH) deficiency was described in 13 patients. Among 24 patients with a combination of nivolumab and ipilimumab therapy, 7 patients (29%) developed secondary AI in a median time of 8 weeks during the combination therapy and 2 of 15 patients (13%) developed isolated ACTH deficiency during maintenance nivolumab monotherapy following the combination therapy. More than half of the patients (4/7) with a combination therapy-induced multiple anterior hormone deficiencies was diagnosed as secondary AI based on regular ACTH and cortisol tests with slight subjective symptoms. Secondary AI can arise frequently and rapidly in cancer patients receiving a combination ICI therapy, and thus we speculate active surveillance of AI using regular ACTH and cortisol tests during the combination therapy might be useful for avoiding life-threatening conditions due to secondary AI.

In the largest retrospective study of adrenal incidentalomas (AIs) in Japan between 1999 and 2004, adrenal tumors detected during secondary hypertension (HT) screening were included. The characteristics of patients with adrenal tumors detected during HT screening may differ from those of patients with AIs. This study aimed to compare the characteristics of patients with AIs with those of patients with adrenal tumors detected during HT screening. We retrospectively analyzed patients referred to our division for detailed examination of adrenal tumors between April 2009 and April 2017. When the purposes of imaging tests included HT screening, we defined adrenal tumors as HT associated, otherwise as strictly defined AIs. We reviewed data on age, sex, purpose and modality of imaging, location of tumor, tumor diameter, and hormonal evaluation. We identified 104 patients with HT-associated adrenal tumors and 413 with AIs. Patients with HT-associated adrenal tumors were younger (54.2 years vs. 61.7 years, p < 0.001) and had smaller tumor diameters (1.3 cm vs. 1.9 cm, p < 0.001), lower prevalence of nonfunctioning tumors (24.0% vs. 67.6%, p < 0.001), and higher prevalence of primary aldosteronism (58.7% vs. 4.8%, p < 0.001) than those with AIs. There were no differences in terms of tumor location and prevalence of subclinical Cushing's syndrome, Cushing's syndrome, and pheochromocytoma (18.3% vs. 16.0%, 7.7% vs. 8.0%, and 2.9% vs. 4.6%, respectively). In conclusion, patients with HT-associated tumors were younger and had a smaller tumor with higher prevalence of primary aldosteronism than those with AIs.

Neuroendocrine manifestations are common in Erdheim-Chester disease (ECD) patients. ECD is a rare non-Langerhans form of histiocytosis with multisystemic infiltration. The involvement of the hypothalamo-pituitary axis is common and central diabetes insipidus (CDI) is one of the most common endocrine manifestations in ECD patients. CDI is the first manifestation of ECD in 25%-48% of the cases. Suprasellar region extension, due to the infiltration of ECD lesions, can cause neurologic manifestations by mass effects, such as headache, visual disturbance, and cranial nerve palsies. Recent studies have revealed that disorders affecting anterior pituitary hormones are common in ECD patients. Secondary adrenal insufficiency, secondary hypothyroidism, (adult) growth hormone deficiency, hypogonadotropic hypogonadism, hyperprolactinemia, and hypoprolactinemia can develop as the neuroendocrine manifestations of ECD. Since the symptoms of anterior pituitary hormone deficiencies tend to be nonspecific, the diagnosis of anterior pituitary hormone dysfunctions can be delayed. Some anterior pituitary dysfunctions such as adrenocorticotropic hormone and/or thyroid-stimulating hormone deficiencies can be life-threatening without adequate hormone supplementation therapies. An endocrinological evaluation of the function of the pituitary gland should be performed at the initial diagnosis of ECD. It is important to recognize that endocrine dysfunctions can develop later during the follow-up of ECD.

The incidence of thyroid carcinoma has been increasing worldwide. This is interpreted as an increase in the incidental detection of papillary thyroid microcarcinomas (PTMCs). However, mortality has not changed, suggesting overdiagnosis and overtreatment. Prospective clinical trials of active surveillance for low-risk PTMC (T1aN0M0) have been conducted in two Japanese institutions since the 1990s. Based on the favorable outcomes of these trials, active surveillance has been gradually adopted worldwide. A task force on the management of PTMC in adults organized by the Japan Thyroid Association therefore conducted a systematic review and has produced the present position paper based on the scientific evidence concerning active surveillance. This paper indicates evidence for the increased incidence of PTMC, favorable surgical outcomes for low-risk PTMC, recommended criteria for diagnosis using fine needle aspiration cytology, and evaluation of lymph node metastasis (LNM), extrathyroidal extension (ETE) and distant metastasis. Active surveillance has also been reported with a low incidence of disease progression and no subsequent recurrence or adverse events on survival if conversion surgery was performed at a slightly advanced stage. Active surveillance is a safe and valid strategy for PTMC, because it might preserve physical quality of life and reduce 10-year medical costs. However, some points should be noted when performing active surveillance. Immediate surgery is needed for PTMC showing high-risk features, such as clinical LNM, ETE or distant metastasis. Active surveillance should be performed under an appropriate medical team and should be continued for life.

Context Insulinoma is the most common pancreatic functional neuroendocrine neoplasm, yet little information on recent clinical practice in patients with insulinoma, especially malignant insulinoma, is available. Objective This work aims to clarify the characteristics and practice patterns in patients with insulinoma using a national inpatient database. Methods Using the Japanese Diagnosis Procedure Combination database, we retrospectively identified patients with insulinoma admitted between 2010 and 2018. We compared background characteristics and therapeutic interventions between patients with benign and malignant insulinoma. We also estimated the incidence of insulinoma using the number of patients with newly diagnosed insulinoma in 2012. Results We identified 844 patients with benign insulinoma and 102 patients with malignant insulinoma. Patients with malignant insulinoma were younger (median, 55.5 vs 66.0 years, P Conclusion The present study using a nationwide database had a larger sample size than previous studies and revealed definitive differences in patient characteristics and therapeutic patterns between benign and malignant insulinoma.

Neuroendocrine manifestations are common in Erdheim-Chester disease (ECD) patients. ECD is a rare non-Langerhans form of histiocytosis with multisystemic infiltration. The involvement of the hypothalamo-pituitary axis is common and central diabetes insipidus (CDI) is one of the most common endocrine manifestations in ECD patients. CDI is the first manifestation of ECD in 25%-48% of the cases. Suprasellar region extension, due to the infiltration of ECD lesions, can cause neurologic manifestations by mass effects, such as headache, visual disturbance, and cranial nerve palsies. Recent studies have revealed that disorders affecting anterior pituitary hormones are common in ECD patients. Secondary adrenal insufficiency, secondary hypothyroidism, (adult) growth hormone deficiency, hypogonadotropic hypogonadism, hyperprolactinemia, and hypoprolactinemia can develop as the neuroendocrine manifestations of ECD. Since the symptoms of anterior pituitary hormone deficiencies tend to be nonspecific, the diagnosis of anterior pituitary hormone dysfunctions can be delayed. Some anterior pituitary dysfunctions such as adrenocorticotropic hormone and/or thyroid-stimulating hormone deficiencies can be life-threatening without adequate hormone supplementation therapies. An endocrinological evaluation of the function of the pituitary gland should be performed at the initial diagnosis of ECD. It is important to recognize that endocrine dysfunctions can develop later during the follow-up of ECD.

Ectopic ACTH syndrome (EAS) due to a prostate small cell carcinoma (SCC) is very rare with only 26 cases reported to date and has a poor prognosis. We here describe another case of this disorder that was clinically typical based on prior reports as it showed hypercortisolemia and severe hypokalemia with multiple metastasis. However, our current case of prostate SCC causing EAS is the first to display negative immunostaining for ACTH despite detectable POMC mRNA expression in the primary lesion. ACTH immunonegativity is thought to be associated with a more aggressive disease course and a poorer prognosis although there are few studies of the underlying mechanisms. We explored two possibilities for this finding in our current patient: aberrant POMC processing prevented immunodetection with an anti-ACTH antibody; and the ACTH content per cell was below the threshold for immunodetection due to its rapid secretion or low synthesis. The aberrant processing theory was thought to be less likely because of immunonegative findings even using anti-POMC/ACTH antibodies. As the plasma ACTH levels in our patient were comparable with those reported for previous immunopositive prostate EAS cases, we speculated that the depletion of ACTH may be caused not only by rapid secretion but also by low production levels as a sign of de-differentiation. De-differentiation may therefore explain the mechanism underlying the negative correlation between immunoreactivity for ACTH in EAS and disease aggressiveness. We believe that our present findings will be of use in future prospective studies aimed at confirming the mechanism of immunonegativity.

V2 vasopressin receptor (V2R) is a member of the G protein-coupled receptor (GPCR) family in which many disease-causing mutations have been identified and thus generated much interest. Loss-of-function V2R mutations cause nephrogenic diabetes insipidus (NDI) whereas gain-of-function mutations cause nephrogenic syndrome of inappropriate antidiuresis (NSIAD). The mechanisms underlying a V2R loss-of-function can be theoretically classified as either protein expression, localization (ER retention) or functional disorders. Functional analyses have revealed however that these mechanisms are likely to be complex. Strikingly, V2R mutations at the same site can result in opposite phenotypes, e.g., R137H and R137L/C cause NDI and NSIAD, respectively. These findings support the notion that the constitutive activation of GPCRs might be often associated with their instability and denaturation. Thus, functional analysis of disease-causing V2R mutations may not only reveal potential new treatment strategies using pharmacochaperones for NDI and inverse agonists for NSIAD, but also provide a greater understanding of the physiological functions of GPCRs and highlight the new paradigms, i.e., biased agonism and protean agonism.

V2 vasopressin receptor (V2R) is a member of the G protein-coupled receptor (GPCR) family in which many disease-causing mutations have been identified and thus generated much interest. Loss-of-function V2R mutations cause nephrogenic diabetes insipidus (NDI) whereas gain-of-function mutations cause nephrogenic syndrome of inappropriate antidiuresis (NSIAD). The mechanisms underlying a V2R loss-of-function can be theoretically classified as either protein expression, localization (ER retention) or functional disorders. Functional analyses have revealed however that these mechanisms are likely to be complex. Strikingly, V2R mutations at the same site can result in opposite phenotypes, e.g., R137H and R137L/C cause NDI and NSIAD, respectively. These findings support the notion that the constitutive activation of GPCRs might be often associated with their instability and denaturation. Thus, functional analysis of disease-causing V2R mutations may not only reveal potential new treatment strategies using pharmacochaperones for NDI and inverse agonists for NSIAD, but also provide a greater understanding of the physiological functions of GPCRs and highlight the new paradigms, i.e., biased agonism and protean agonism.

Biased agonism is a paradigm that may explain the selective activation of a signaling pathway via a GPCR that activates multiple signals. The autoantibody-induced inactivation of the calcium-sensing receptor (CaSR) causes acquired hypocalciuric hypercalcemia (AHH). Here, we describe an instructive case of AHH in which severe hypercalcemia was accompanied by an increased CaSR antibody titer. These autoantibodies operated as biased allosteric modulators of CaSR by targeting its Venus flytrap domain near the Ca(2+)-binding site. A positive allosteric modulator of CaSR, cinacalcet, which targets its transmembrane domain, overcame this autoantibody effect and successfully corrected the hypercalcemia in this patient. Hence, this is the first study to our knowledge that identifies the interaction site of a disease-causing GPCR autoantibody working as its biased allosteric modulator and demonstrates that cinacalcet can correct the AHH autoantibody effects both in vitro and in our AHH patient. Our observations provide potentially new insights into how biased agonism works and how to design a biased allosteric modulator of a GPCR. Our observations also indicate that the diagnosis of AHH is important because the severity of hypercalcemia may become fatal if the autoantibody titer increases. Calcimimetics may serve as good treatment options for some patients with severe AHH.

Objective Central hypothyroidism (CH) is a well-known adverse effect of bexarotene treatment for cutaneous T-cell lymphoma (CTCL). While concomitant levothyroxine therapy is recommended in these cases, associations between ethnic variation or susceptibility and bexarotene-induced CH have not yet been reported. This study aimed to characterize the kinetics and dose dependency of bexarotene-induced CH in Japanese patients. Design and patients Sixty-six Japanese patients with CTCL were retrospectively investigated by evaluating thyroid function during the early phase of bexarotene therapy. Results At one week after bexarotene initiation, TSH and FT4 values significantly declined. However, this effect was not bexarotene dose-dependent at least at the dose of 96-320 mg/m2 . Approximately 1 month later, 61 patients exhibited hypothyroidism at a relatively low dose of bexarotene (average 251 mg/m2 /day). Forty-five study cases showed this effect at 1 week. Simple regression analyses indicated that higher pretreatment TSH values (at a cut-off value of 1.30:73% sensitivity, 57% specificity) or lower normal (within the lower half of the reference range) pretreatment FT4 values (84% sensitivity, 57% specificity) were predictive of hypothyroidism at 1 week. The remaining 21 cases showed euthyroidism at 1 week, at which TSH values may roughly predict their thyroid function at 1 month (at a cut-off value of 0.05:100% sensitivity, 80% specificity). Conclusions Preventive treatment with levothyroxine is recommended for Japanese CTCL patients prior to bexarotene therapy. Minimally, it should be considered for patients with a pretreatment TSH above 1.30, a lower normal pretreatment FT4, or a TSH below 0.05 at 1 week.

Disease-causing mutations in G protein-coupled receptor (GPCR) genes, including the V2 vasopressin receptor (V2R) gene, often cause misfolded receptors, leading to a defect in plasma membrane trafficking. A novel V2R mutation, T273M, identified in a boy with partial nephrogenic diabetes insipidus (NDI), shows intracellular localization and partial defects similar to the two mutants we described previously (10). Although non-peptide V2R antagonists have been shown to rescue the membrane localization of V2R mutants, their level of functional rescue is weak. Interestingly, it has been reported that a non-peptide agonist, OPC51803, activates misfolded V2R mutants intracellularly without degradation, thus potentially serving as a therapeutic agent against NDI (14). In our current experiments, however, a peptide antagonist blocked arginine vasopressin (AVP)- or OPC51803-stimulated cAMP accumulation both in COS-7 and MDCK cells, suggesting that OPC51803 mainly stimulates cell surface V2R mutants. In addition, our analyses revealed that OPC51803 works not only as a non-peptide agonist that causes activation/β-arrestin-dependent desensitization of V2R mutants expressed at the plasma membrane but also as a pharmacochaperone that promotes the endoplasmic reticulum-retained mutant maturation and trafficking to the plasma membrane. The ratio of the pharmacochaperone effect to the desensitization effect likely correlates negatively with the residual function of the tested mutants, suggesting that OPC5 has a more favorable effect on the V2R mutants with a less residual function. We speculated that the canceling of the desensitization effect of OPC51803 by the pharmacochaperone effect after long-term treatment may produce sustainable signaling, and thus pharmacochaperone agonists such as OPC51803 may serve as promising therapeutics for NDI caused by misfolded V2R mutants.

Inactivating mutations of the V2 vasopressin receptor (V2R) cause cross-linked congenital nephrogenic diabetes insipidus (NDI), resulting in renal resistance to the antidiuretic hormone AVP. In two families showing partial NDI, characterized by an apparently normal response to diagnostic tests and an increase in the basal ADH levels suggesting AVP resistance, we have identified two V2R mutations, Ser-333del and Y128S. Both mutant V2Rs, when expressed in COS-7 cells, show partial defects in vasopressin-stimulated cAMP accumulation and intracellular localization. The inhibition of internalization does not rescue their localization. In contrast, the non-peptide V2R antagonists OPC41061 and OPC31260 partially rescue the membrane localization and basal function of these V2R mutants, whereas they inhibit the basal activity of the wild-type V2R. These results indicate that a partial loss of function of Ser-333del and Y128S mutant V2Rs results from defective membrane trafficking. These findings further indicate that V2R antagonists can act as protean agonists, serving as pharmacological chaperones for inactivating V2R mutants and also as inverse agonists of wild-type receptors. We speculate that this protean agonism could underlie the possible dual beneficial effects of the V2R antagonist: improvement of hyponatremia with heart failure or polycystic kidney disease and potential rescue of NDI.

For elderly hemodialysis patients with diabetes, the treatment options are restricted, and insulin therapy plays an important role. However, sometimes it might be difficult for them to inject insulin by themselves because of technical and/or social problems. The recently introduced basal insulin analog degludec has a longer half life than the previous basal insulin analogs such as glargine or detemir. Here we report an elderly hemodialysis patient with type 2 diabetes who was successfully treated with insulin degludec injection by the medical staff at every hemodialysis clinic visit. Throughout this treatment, he did not experience any side effects due to degludec, including hypoglycemia. There are few reports of using degludec for HD patients. In addition, this is the first report showing the validity of a three-times-a-week degludec regimen as a basal supported oral therapy for a hemodialysis patient with diabetes who could not inject insulin by himself. The inferiority of the three-times-a-week degludec regimen compared with the once-a-day glargine regimen in non-hemodialysis patients has already been reported. Based on this, this three-times-a-week degludec regimen should also not be considered as a standard regimen in hemodialysis patients. However, this three-times-a-week degludec regimen may be useful as an alternative for hemodialysis patients who cannot inject insulin once a day by themselves to achieve good and safe glycemic control, improving the prognosis and avoiding problems with hyperglycemia.

Rationale:Heart failure is relatively common in patients with hyperthyroidism, but thyrotoxic cardiomyopathy with poor left ventricular (LV) systolic function is very rare.Patient concerns:We experienced a representative case of a patient who presented with severe LV dysfunction related to t

An early thirties man diagnosed with Erdheim-Chester disease (ECD) was simultaneously disclosed to have hypogonadotropic hypogonadism, central adrenal insufficiency, and GH deficiency in addition to central diabetes insipidus (CDI). Pituitary magnetic resonance imaging (MRI) showed swelling in the stalk, enlargement of the anterior lobe with delayed enhancement, and loss of high intensity of the posterior lobe on T1-weighted images, suggesting of pituitary involvement of ECD. Three months after starting treatment with interferon α and zoledronic acid, polyuria and polydipsia were ameliorated without DDAVP, accompanied with improvement of MRI. Simultaneously technetium-99m bone scintigraphy showed improvement, accompanied with a relief of bone pain and high fever. In contrast, he developed secondary hypothyroidism with slight enlargement of anterior pituitary gland without relapse of CDI, suggesting of different responses to treatment with interferon α between anterior pituitary lobe and posterior one. So far he continues to be replaced with deficient hormone replacement therapy. As for bone pain, it remains to be controlled with the decreased levels of bone resorption marker with decreased abnormal uptake in bone scintigraphy although zoledronic acid was discontinued for osteonecrosis of the jaw. For four years, he has not showed new involvement at other organs besides bones and the pituitary. While CDI is known to be very common in ECD, improvement of CDI has been reported in a few cases. Other endocrine manifestations, especially with detailed endocrine status, have been also reported in limited cases. Thus we report this case and review the literature.

The seven-spanning calcium-sensing receptor (CaSR) activates multiple G proteins including Gq and Gi, and thereby activates a variety of second messengers and inhibits parathyroid hormone (PTH) secretion. However, the exact signaling mechanisms underlying the functional activity of CaSR are not yet fully understood. The heterozygous inactivation of CaSR or its inhibition by antibody blocking results in either familial hypocalciuric hypercalcemia or acquired hypocalciuric hypercalcemia (AHH), respectively. Here, we report the identification of a unique CaSR autoantibody in an AHH patient. Paradoxically, we find that this autoantibody potentiates the Ca 2+ /Gq-dependent accumulation of inositol phosphates by slightly shifting the dose dependence curve of the Ca 2+ mediated activation of phosphatidylinositol turnover to the left, whereas it inhibits the Ca 2+ /Gi-dependent phosphorylation of ERK1/2 in HEK293 cells stably expressing human CaSR. Treatment of these same cells with a calcimimetic, NPS-R-568, augments the CaSR response to Ca 2+ , increasing phosphatidylinositol turnover and ERK1/2 phosphorylation, and overcoming the autoantibody effects. Our observations thus indicate that a calcium-stimulated CaSR primed by a specific autoantibody adopts a unique conformation that activates Gq but not Gi. Our findings also suggest that CaSR signaling may act via both Gq and Gi to inhibit PTH secretion. This is the first report of a disease-related autoantibody that functions as an allosteric modulator and maintains G protein-coupled receptors (GPCRs) in a unique active conformation with its agonist. We thus speculate that physiological modulators may exist that enable an agonist to specifically activate only one signaling pathway via a GPCR that activates multiple signaling pathways.