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Purpose A few previous basic and clinical reports implied that roxadustat, a drug recently approved for treating renal anemia, might activate thyroid hormone receptors (TRα and TRβ). We thus investigated the direct effects of roxadustat on intact TRα and TRβ in vitro. Methods U2OS, MCF-7, COS-7 and Caco-2 cells were transiently transfected with a firefly luciferase reporter plasmid highly responsive to activation of TRα and TRβ, along with a plasmid overexpressing either TRα or TRβ. Transfected cells were incubated for 3 h in 100% thyroid hormone-stripped fetal bovine serum (FBS) with or without either roxadustat or triiodothyronine (T3). Also, transfected U2OS cells were placed for 3 h in 100% unprocessed normal adult human serum with or without the addition of either roxadustat or T3. Cell lysates were measured for firefly luciferase activities. Results Roxadustat induced firefly luciferase activities when added at clinically achievable serum concentrations in TRα- or TRβ-transfected U2OS, MCF-7, COS-7 and Caco-2 cells placed in thyroid hormone-deprived FBS. The induction was comparable to or greater than that observed with T3 added at normal or even supranormal serum concentrations. Roxadustat also increased firefly luciferase activities in TRα- or TRβ-transfected U2OS cells in adult human serum. Conclusions Roxadustat does activate TRα and TRβ at clinically relevant concentrations. Physicians prescribing roxadustat should be aware of its thyromimetic activity.

Serum dehydroepiandrosterone sulfate (DHEA-S) levels reflect the state of adrenocorticotropic hormone (ACTH) secretion. However, it is difficult to use serum DHEA-S to diagnose hypothalamic-pituitary-adrenal (HPA) axis insufficiency due to its non-normal and highly skewed distribution. In this study, we focused on HPA insufficiency caused by hypothalamic and/or pituitary dysfunction and evaluated the usefulness of the standard deviation score of log-transformed DHEA-S (ln DHEA-S SD score), which was calculated from the established age-and sex-specific reference values. We retrospectively reviewed the medical records of 94 patients suspected of having HPA insufficiency, in whom serum DHEA-S measurement and the rapid ACTH stimulation test were performed, and included 65 patients who met our criteria in this study. The ln DHEA-S SD scores were distributed more normally than measured DHEA-S levels and were significantly higher in patients with a peak cortisol level ≥18 μg/dL than in those below this value, suggesting that this score is a legitimate and strong indicator of adrenocortical function. The optimal cut-off value for impaired HPA function was -0.853, with a sensitivity of 70.3% and a specificity of 100%. Among the 37 patients whose peak cortisol levels were below 18 μg/dL, 11 patients with ln DHEA-S scores ≥-0.853 exhibited significantly higher basal ACTH and basal and peak cortisol levels than the 26 patients with scores <-0.853. Thus, this score plays a supportive role in evaluating HPA axis function, particularly in patients with borderline cortisol responses to ACTH.

[Introduction] Immune checkpoint inhibitors (ICIs) are widely used for the treatment of several malignancies. Despite their effectiveness, they may cause immune-related adverse effects on endocrine organs. Here we describe three cases of isolated ACTH deficiency (IAD) that has occurred after ICI therapy. [Case presentation] Case 1: An 80-year-old female patient with advanced melanoma received nivolumab (NIVO) (3 mg/kg intravenously (IV) every two weeks) for 16 weeks, followed by ipilimumab (3 mg/kg IV every three weeks). After the third injection of ipilimumab, she was alert but complained of general fatigue and anorexia. Her laboratory tests revealed hyponatremia (Na 126 mEq/l), hypoglycemia (Glu 65 mg/dl), low ACTH (ACTH <2.1 pg/ml), hypocortisolemia (cortisol (F) 3.6 µg/dl), and inflammation (white blood cell (WBC) 9,000/µl and C-reactive protein 12.87 mg/dl). Case 2: A 52-year-old diabetic male patient on sulfonylurea for the past two years was given 13 courses of NIVO (3 mg/kg IV every two weeks) for the treatment of recurrent lung cancer but could not proceed with the 14th treatment because of general malaise, appetite loss, and slight fever (37ºC). About three weeks after the 13th injection, he went into hypoglycemic coma (Glu 32 mg/dl) and received intravenous glucose. On admission, his Glasgow Coma Scale score was 14 (E4V4M6). Laboratory tests showed hyponatremia (Na 133 mEq/l), low ACTH (ACTH <2.1 pg/ml), and hypocortisolemia (F 0.2 µg/dl), but no leukocytosis (WBC 6,000/µl). Case 3: A 67-year-old male patient received NIVO (3 mg/kg IV every two weeks) as third-line therapy for advanced gastric cancer. After the seventh course of treatment, he complained of general fatigue, anorexia, joint pain, and palpitations. His blood laboratory test was unremarkable with normal serum sodium (Na 140 mEq/l). Six days later, he returned due to persistent symptoms. Laboratory investigation revealed hyponatremia (Na 135 mEq/l), normoglycemia (Glu 88 mg/dl), low ACTH (2.7 pg/ml), and hypocortisolemia (F 0.8 µg/dl), but no inflammation (WBC 3,200/µl). In all three cases, magnetic resonance imaging showed no abnormalities and endocrinological tests confirmed the clinical diagnosis of IAD. All of them were discharged on a physiological replacement dose of hydrocortisone. [Discussion] A recent report suggested that hyponatremia can be an early manifestation of ICI-induced IAD. Indeed, in Cases 1 and 2, adrenal insufficiency was suspected due to hyponatremia and hypoglycemia, although in Case 2, sulfonylurea presumably also contributed to the development of hypoglycemia. In Case 3, however, serum sodium and glucose levels were normal when he initially became symptomatic. This case illustrates the importance of suspecting IAD in ICI-treated patients who present with non-specific symptoms, such as malaise, even in the absence of hyponatremia or hypoglycemia.

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