Immune checkpoint inhibitors (ICIs) have become a promising treatment for advanced malignancies. However, these drugs can induce immune-related adverse events (irAEs) in several organs, including skin, gastrointestinal tract, liver, muscle, nerve, and endocrine organs. Endocrine irAEs comprise hypopituitarism, primary adrenal insufficiency, thyroid dysfunction, hypoparathyroidism, and type 1 diabetes mellitus. These conditions have the potential to lead to life-threatening consequences, such as adrenal crisis, thyroid storm, severe hypocalcemia, and diabetic ketoacidosis. It is therefore important that both endocrinologists and oncologists understand the clinical features of each endocrine irAE to manage them appropriately. This opinion paper provides the guidelines of the Japan Endocrine Society and in part the Japan Diabetes Society for the management of endocrine irAEs induced by ICIs.

Abstract. New diagnostic criteria and the treatment policy for adrenal subclinical Cushing's syndrome (SCS) are proposed on behalf of the Japan Endocrine Society. The Japanese version has been published, and the essential contents are presented in this English-language version. The current diagnostic criteria for SCS have elicited two main problems: (i) the relatively low reliability of a low range of serum cortisol essential for the diagnosis by an overnight 1-mg dexamethasone suppression test (DST); (ii) different cutoff values for serum cortisol after a 1-mg DST compared with those of other countries. Thus, new criteria are needed. In the new criteria, three hierarchical cortisol cutoff values, 5.0, 3.0 and 1.8 μg/dL, after a 1-mg DST are presented. Serum cortisol ≥5 μg/dL after a 1-mg DST alone is considered sufficient to judge autonomous cortisol secretion for the diagnosis of SCS, and the current criterion based on serum cortisol ≥3 μg/dL after a 1-mg DST can continue to be used. Clinical evidence suggests that serum cortisol ≥1.8-2.9 μg/dL after a 1-mg DST is not always normal, so cases who meet the cutoff value as well as a basal adrenocorticotropic hormone (ACTH) level <10 pg/mL (or poor ACTH response to corticotropin-releasing hormone (CRH)) and nocturnal serum cortisol ≥5 μg/dL are proposed to have SCS. We suggest surgery if cases show serum cortisol ≥5 μg/dL after a 1-mg DST (or are disheartened by treatment-resistant problems) or suspicious cases of adrenal cancer according to tumor imaging. [7,8] and a reduction in bone quality when evaluated by the Spinal Density Index [9]. However, with changes in the measurement system (from radioimmunoassay to enzyme immunoassay) of cortisol in blood, four main discussions have arisen: (i) the relatively low reliability of a low range of cortisol concentrations (<3 μg/dL) essential for the diagnosis after an overnight 1-mg DST [10]; (ii) the inconsistency of the screening criteria of SCS with those proposed by the American Endocrine Society (serum cortisol ≥1.8 μg/dL after a 1-mg DST) [11] or other countries [1]; (iii) the "globalization" of diagnostic criteria; (iv) the necessity of a 8-mg DST for the SCS diagnosis [12]. Thus, new diagnostic criteria for adrenal SCS have become an important agenda for the Japan Endocrine Society (JES).The current task force was organized officially in 2012 and multicenter collaborative research was done to collect evidence for a revision. Based on the results of the research and peer reviews of articles focusing on SCS, the final new diagnostic criteria for adrenal SCS and the treatment policy were proposed. These evidence-based diagnostic criteria and the treatment policy for adrenal SCS were reviewed by a JES subcommittee and approved. These documents were also approved by Research Committee on Disorders of Adrenal Hormones from the MHLW, Japan and Japan Hormonal Steroid Association. The Japanese version has been published and the English-language version has been described here. The new diagnostic criteria for adrenal SCS ...

Urocortin (Ucn), a new mammalian member of the CRF family, is a candidate endogenous ligand for type 2 CRF receptors. In a survey of peripheral tissues from adult male rats, we found that Ucn messenger RNA (mRNA) was abundant in the gastrointestinal tract and immune tissues such as thymus and spleen. We next tested the hypothesis that levels of Ucn mRNA levels in thymus and spleen would be altered after immune activation. As measured by ribonculease protection assay, lipopolysaccharide (LPS) induced a 2-fold time-dependent increase in thymic Ucn mRNA levels within 6 h. By contrast, splenic Ucn mRNA levels decreased after LPS. Because LPS activates the hypothalamus-pituitary-adrenal (HPA) axis, we examined whether the effects of LPS on Ucn mRNA might be mediated through changes in HPA axis hormones. Ucn mRNA in thymus, but not spleen, was significantly increased after ACTH injection; however, LPS did not increase Ucn expression in the thymus of adrenalectomized rats with corticosterone replacement, despite substantial increases in ACTH. Finally, sc injection of corticosterone stimulated Ucn mRNA comparably to that of LPS. Together, these results suggest that Ucn mRNA expression can increase after immune activation in a corticosterone-dependent manner, and that such changes in Ucn mRNA may be an additional consequence of HPA axis activation.

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Abstract. The hypothalamic-pituitary-adrenal (HPa) axis is activated under various stressors. Corticotropin-releasing factor (CRF) plays a central role in controlling stress response, and regulating the HPa axis. CRF, produced in the hypothalamic paraventricular nucleus (PVN), stimulates adrenocorticotropic hormone (aCTH) production via CRF receptor type 1 (CRF 1 receptor) from the corticotrophs of the anterior pituitary (aP). Cyclic amP (camP)-protein kinase a (PKa) pathway takes a main role in stimulating CRF gene transcription. Forskolin and pituitary adenylate cyclaseactivating polypeptide (PaCaP) stimulate adenylate cyclase, intracellular camP production, and then CRF and arginine vasopressin (aVP) gene expression in hypothalamic 4B cells. Interleukin (IL)-6, produced in the PVN, both directly and indirectly stimulates CRF and aVP gene expression. estradiol may enhance the activation of CRF gene expression in response to stress. The HPa axis is regulated by a negative feedback mechanism, because glucocorticoids inhibit both CRF production in the hypothalamic PVN and aCTH production in the pituitary. Hypothalamic parvocellular neurons in the PVN are known to express glucocorticoid receptors, and glucocorticoids are able to regulate CRF gene transcription and expression levels directly in the PVN. glucocorticoids-dependent repression of camP-stimulated CRF promoter activity is mainly localized to promoter sequences between -278 and -233 bp. Both negative glucocorticoid regulatory element (ngRe) and serum response element (SRe) are involved in the repression of the CRF gene in the hypothalamic cells. Stimulation of crF gene in the hypothalamus Involvement of cAMP on CRF gene transcriptionCyclic amP (camP)-protein kinase a (PKa) pathway takes a main role in stimulating CRF synthesis [3][4][5]. There are several candidates for activating CRF neurons. For example, pituitary adenylate cyclase-activating polypeptide (PaCaP), a member of the secretin/glucagon/vasoactive intestinal peptide (VIP) family, is one of the putative hormones. Both PaCaP and the PaCaP-selective PaCaP receptor type 1 (PaC1 receptor) are known to be highly expressed in the hypothalamus, including the parvocellular and magnocellular subdivisions of the PVN, and the supraoptic nucleus (SON) [6,7]. PaCaP has shown to stimulate camP production in the aP [8]. PaCaP also increases CRF mRNa levels in the parvocellular region of the PVN, suggesting that PaCaP is involved in the positive regulation of CRF gene expression [9].

CRF receptor type 2 (CRF R2) messenger RNA (mRNA) expression in the rodent heart is modulated by exposure to both the bacterial endotoxin lipopolysaccharide (LPS) and glucocorticoids. In this study we examined the roles of glucocorticoids, cytokines, and CRF R2beta ligands in the regulation of CRF R2beta expression in the cardiovascular system both in vivo and in vitro. Using ribonuclease protection assays, we found that, in addition to the injection of LPS or corticosterone, physical restraint caused a decrease in CRF R2beta mRNA levels in the rat heart and aorta. Adrenalectomy with corticosterone replacement at constant levels partially blocked LPS-induced decreases in CRF R2beta mRNA expression in the heart. Thus, elevations of endogenous circulating corticosterone could contribute to the down-regulation of CRF R2beta mRNA expression in heart. To identify other putative modulating factors, we examined CRF R2beta expression in the aorta-derived A7R5 cell line. Incubation with CRF R2 ligands or dexamethasone reduced CRF R2beta mRNA levels. In addition, incubation with a variety of cytokines, proteins released during immune challenge, also reduced CRF R2beta mRNA expression. The multifactorial regulation of CRF R2beta mRNA expression in the cardiovascular system may serve to limit the inotropic and chronotropic effects of CRF R2 agonists such as urocortin during prolonged physical or immune challenge.

Glucocorticoids (GCs) are well known to induce insulin resistance. However, the effect of GCs on insulin secretion has not been well characterized under physiological conditions in human. We here evaluated the effect of GCs on insulin secretion/ß-cell function precisely in a physiological condition. A population-based study of 1,071 Japanese individuals enrolled in the 2014 Iwaki study (390 men, 681 women; aged 54.1 ± 15.1 years), those excluded individuals taking medication for diabetes or steroid treatment, were enrolled in the present study. Association between serum cortisol levels and insulin resistance/secretion assessed by homeostasis model assessment using fasting blood glucose and insulin levels (HOMA-R and HOMA-ß, respectively) were examined. Univariate linear regression analyses showed correlation of serum cortisol levels with HOMA-ß (ß = -0.134, p <0.001) but not with HOMA-R (ß = 0.042, p = 0.172). Adjustments for age, gender, and the multiple clinical characteristics correlated with HOMA indices showed similar results (HOMA-ß: ß = -0.062, p = 0.025; HOMA-R: ß = -0.023, p = 0.394). The correlation between serum cortisol levels and HOMA-ß remained significant after adjustment for HOMA- R (ß = -0.057, p = 0.034). When subjects were tertiled based on serum cortisol levels, the highest tertile was at greater risk of decreased insulin secretion (defined as lower one third of HOMA-ß (≤70)) than the lowest tertile, after adjustment for multiple factors including HOMA- R (odds ratio 1.26, 95% confidence interval 1.03–1.54). In conclusion, higher serum cortisol levels are significantly associated with decreased insulin secretion in the physiological cortisol range in a Japanese population.

because of the Cushingoid appearance, with the characteristic features of central obesity, moon face, skin atrophy, purple striae and buffalo hump, and the clinical criteria are clear, a debate exists in the literature over the biochemical diagnosis of this disease [3]. Recently, the diagnostic criteria for Cushing's disease have been reported by the Ministry of Health, Labour, and Welfare of Japan [4]. In the guideline, the following endocrinological findings were considered as diagnostic criteria: 1) The presence of a Cushingoid appearance; 2) Evidence of autonomic or abnormal secretion of ACTH, such as (a) normal-high ACTH and cortisol levels, and (b) high levels of urinary excretion of free cortisol; 3) Screening tests show (a) incomplete suppression of cortisol (> 5 µg/dl) by a lowdose (0.5 mg) overnight dexamethasone suppression test (DST), (b) high cortisol levels (> 5 µg/dl) during night time sleeping, and (c) response of plasma ACTH levels to the desmopressin (DDAVP) test; 4) The dif- Abstract. We evaluated the usefulness and accuracy of diagnostic tests for adrenocorticotropic hormone (ACTH)-dependent Cushing's syndrome, based on our experience of 88 cases, including 73 cases with Cushing's disease, and 15 cases with ectopic ACTH syndrome (EAS). In our study, 0.5 mg of dexamethasone failed to suppress the morning cortisol secretion in 100% of cases with Cushing's disease and EAS. Plasma ACTH levels were significantly increased by desmopressin (DDAVP) in 86% of cases with Cushing's disease, especially in microadenomas (90%), while these levels were not affected in normal subjects. In EAS, 44% responded to DDAVP. Plasma ACTH levels were increased in response to the human corticotropin-releasing hormone (CRH) test in 100% of microadenomas and 73% of macroadenomas with Cushing's disease, but only in 27% of cases with EAS. A high dose (8 mg) of dexamethasone suppressed the morning cortisol secretion in 89% of microadenomas with Cushing's disease, and in 82% of all cases with Cushing's disease, while it did in only 20% of cases with EAS. Taken together, the 0.5 mg dexamethasone suppression test (DST) and DDAVP test are considerably useful for the screening of ACTH-dependent Cushing's syndrome. The CRH test and 8 mg DST would be effective for the diagnosis of Cushing's diseases, because our study shows a sensitivity of 81% in cases with Cushing's disease when these tests are considered together. These data were submitted to prepare the diagnostic criteria for Cushing's disease, suggested by the working group of the Ministry of Health, Labour, and Welfare of Japan.