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Metyrapone is commonly used in the initial management of Cushing's syndrome to reduce hypercortisolemia, but its optimal dosage and timing can vary significantly between patients. Currently, there are limited guidelines on adjustment methods for its administration to individual needs. This study aimed to evaluate responsiveness of each patient to metyrapone and identify the patient characteristics associated with the indices of cortisol responsiveness following a low-dose metyrapone. This single-center retrospective observational study included 15 treatment-naïve patients, 7 of whom had Cushing's disease and 8 had adrenal Cushing's syndrome. Serum cortisol levels were measured hourly from the time of administration of 250 mg of metyrapone up to four hours afterward. Parameters analyzed included the nadir of serum cortisol levels (F nadir ), the difference between basal and nadir serum cortisol levels ( Δ F), the time to nadir, and the characteristics of the patients. As a result, cortisol suppression curves showed significant variability among patients, particularly in the time to nadir. While the median time to nadir was 2 hours, 20% of patients required 4 hours or more, and these responses were not associated with patient characteristics. F nadir was positively correlated with early-morning serum cortisol levels, serum cortisol levels after low-dose dexamethasone suppression test (LDDST), and urinary free cortisol (UFC) levels, whereas Δ F was positively correlated with late-night serum cortisol levels, serum cortisol levels after LDDST, and UFC levels. In conclusion, the duration of response to metyrapone appeared unpredictable in patients with Cushing's syndrome and did not correlate with patient characteristics at baseline. Tracking the effect of metyrapone following a single low-dose administration may explain this variability and provide insights for optimizing individual dosing regimens. Further studies are required to validate these findings and guide more personalized treatment adjustments., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Tsujimoto, Yamamoto, Bando, Yamamoto, Ohmachi, Motomura, Oi-Yo, Sasaki, Suzuki, Urai, Takahashi, Iguchi, Ogawa and Fukuoka.)

Purpose: To elucidate the long-term efficacy and safety of growth hormone replacement therapy (GHRT) in Japanese patients with adult growth hormone deficiency (AGHD)., Methods: We conducted a retrospective study. A total of 110 patients with AGHD receiving GHRT were enrolled. Clinical and laboratory data were collected annually from the beginning of the study. Statistical analysis was performed using a linear mixed-effects model., Results: Of all patients, 46.4% were males, 70.9% had adult-onset GHD, and follow-up was up to 196 months, with a median of 68 months. The insulin-like growth factor-1 standard deviation score increased after the start of GHRT and remained constant for more than 11 years. Seventeen patients were followed up for more than 11 years. The body mass index increased. Waist circumference decreased in the short term but increased in the long term. The diastolic blood pressure decreased 1-5 years after the start of GHRT, and the systolic blood pressure increased 11 years after GHRT. Moreover, a long-term decrease in low-density lipoprotein cholesterol, an increase in high-density lipoprotein cholesterol, and a decrease in aspartate aminotransferase and alanine aminotransferase levels were observed. The glycosylated hemoglobin level increased after 3 years. The bone mineral density in the lumbar spine and total hip increased significantly 3 years after the start of GHRT. Finally, the number of adverse events was eight., Conclusion: We demonstrated the metabolic effectiveness and safety of GHRT in Japanese patients with AGHD over a long follow-up period of 16 years., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Objective: To elucidate the fluctuations in glucose levels measured using CGM-metrics during the four distinct seasons of the year in individuals with type 1 diabetes mellitus (T1DM) using an intermittently scanned CGM (isCGM) device or sensor augmented pump (SAP)., Research Design and Methods: This retrospective, single-center study enrolled 93 individuals with T1DM who were equipped with an isCGM device or SAP at Kobe University Hospital. The subjects had a median age of 47.0 years [interquartile range, 37.0-62.0 years], 25 individuals (26.9%) were male, median body mass index was 22.0 kg/m 2 [20.8-23.8 kg/m 2 ], and median hemoglobin A 1c level was 7.4% [6.9-8.0%]. CGM data were reviewed from January to December 2019, and the mean sensor glucose (SG) value, time above range (TAR), time in range (TIR), time below range (TBR), and standard deviation (SD) of SG were calculated for each season (spring, March-May; summer, June-August; autumn, September-November; winter, December-February)., Results: Seasonal fluctuations were detected for mean SG, TAR, TIR, and SD, with TIR being lower and mean SG, TAR, and SD being higher in cold seasons (spring or winter) than in warm seasons (summer or autumn)., Conclusion: Seasonal fluctuations in CGM metrics should be taken into account in future studies performed to evaluate the favorable impact of CGM on glycemic management in individuals with T1DM., (© 2024. The Author(s).)

Purpose: Preoperative medical management is critical to prevent intraoperative cardiovascular complications in patients with pheochromocytomas and paragangliomas (PPGLs). Initial treatment involves α-adrenergic receptor blockers. However, while the routine use of metyrosine alongside these blockers is not strongly recommended due to a lack of evidence supporting its efficacy and associated safety concerns, there are previous studies on combination therapy with phenoxybenzamine and metyrosine. There are few reports on combination therapy with the selective α1-adrenergic receptor blocker doxazosin. Therefore, we investigated this combination treatment, which theoretically can affect perioperative outcomes in patients with PPGLs. To our knowledge, this is the first such study., Methods: This retrospective single-center observational study involved 51 patients who underwent surgical resection of PPGLs at Kobe University Hospital between 2014 and 2022. All patients received doxazosin at maximum doses. Fourteen patients received concomitant metyrosine, while 37 received doxazosin alone. Their perioperative outcomes were compared., Results: No severe event, such as acute coronary syndrome, was observed in either group. Intraoperatively, the doxazosin + metyrosine group exhibited a lower median minimum systolic blood pressure (56 [54-60] vs. 68 [59-74] mmHg, P = 0.03) and required lower median remifentanil (P = 0.04) and diltiazem (P = 0.02) doses than the doxazosin-alone group., Conclusion: The combination of metyrosine and doxazosin as a preoperative treatment for PPGLs affects intraoperative circulatory hemodynamics, such as a reduced occurrence of blood pressure elevation during surgery. Further research is necessary to identify patients who will benefit most from this combination treatment., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Immune checkpoint inhibitor (ICI)-related hypophysitis (RH) is a common immune-related adverse event. The early detection of ICI-RH prevents life-threatening adrenal insufficiency. However, good predictors of secondary adrenal insufficiency in ICI-RH have not yet been reported. We hypothesized that fluctuations in plasma adrenocorticotropic hormone (ACTH) and cortisol levels occur similarly to those in thyroid-stimulating hormone and thyroid hormone (thyroxine and triiodothyronine) levels in ICI-related thyroiditis. Here, we sought to test this hypothesis. Patients who used ICI and had a history of measurement of plasma ACTH and serum cortisol concentrations were retrieved from electronic medical records, and those with a history of glucocorticoid use were excluded from the analysis. We evaluated fluctuations in plasma ACTH and serum cortisol concentrations and the development of ICI-RH. For patients with ICI-RH, data at three points (before ICI administration (pre), maximum ACTH concentration (peak), and onset of ICI-RH) were analyzed to evaluate hormone fluctuations. A total of 202 patients were retrieved from the medical record. Forty-three patients were diagnosed with ICI-RH. Twenty-six out of 43 patients had sufficient data to evaluate fluctuations in plasma ACTH and serum cortisol concentrations and no history of glucocorticoid use. ACTH concentrations changed from 37.4 (29.9–48.3) (pre) to 64.4 (46.5–106.2) (peak) pg/mL (1.72–fold increase, p=0.0026) in the patients with ICI-RH before the onset. There were no differences in cortisol concentrations between the pre and peak values in patients with ICI-RH. We also evaluated the fluctuations in plasma ACTH and serum cortisol levels in patients who did not receive ICI-RH (62 cases). However, elevation of plasma ACTH levels was not observed in patients without ICI-RH, suggesting that transient elevation of plasma ACTH levels is a unique phenomenon in patients with ICI-RH. In conclusion, plasma ACTH levels were transiently elevated in some patients with ICI-RH before the onset of secondary adrenal insufficiency. Monitoring the ACTH levels and their fluctuations may help predict the onset of ICI-RH., Competing Interests: Competing interests: No, there are no competing interests., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)