2025 年 72 巻 10 号 p. 1079-1088
Osilodrostat dosage is adjusted based on 24-h urinary free cortisol (UFC) levels. However, approximately 1 week is required to obtain the results. In contrast, serum cortisol levels are available soon after sampling, allowing the determination of osilodrostat doses promptly. However, this issue remains poorly understood. Therefore, this study aimed to determine whether a simultaneous assay of serum cortisol and UFC concentrations is useful in patients with Cushing syndrome (CS) receiving osilodrostat. This was a retrospective cross-sectional study. A total of 71 paired samples in six patients with CS during osilodrostat treatment were analyzed in this study. The 24-h urine sample collection was started from the day before blood sampling, and UFC and morning serum cortisol levels were measured on the same day. Commercially available immunoassay kits were used for the hormone measurements. A significant positive correlation between morning cortisol levels and UFC levels was observed. Receiver operating characteristic analysis showed a cut-off of 21.5 μg/dL for serum cortisol as the best indicator to predict high UFC levels. The cut-off secured UFC samples >3× the upper limit of normal. However, the positive predictive value of serum cortisol levels in predicting low UFC was considerably low. A serum cortisol level <5.0 μg/dL, which is often used to suggest adrenal insufficiency, captured patients with hypocortisolism even when the serum cortisol and UFC results were discordant. Simultaneous measurements of single morning serum cortisol and UFC levels on the same day will promote safety in patients with CS who are being treated with osilodrostat.
Overt Cushing syndrome (CS) remains a life-threatening endocrine disorder [1]. Achieving eucortisolim is indispensable to patients with CS to protect the development and/or the progression of various related complications and improve mortality [2-5]. Regardless of the subtype of CS, surgery is the only cure. However, medical treatments are required in patients with CS with severe hypercortisolism before surgery, those with postoperative recurrence or persistence, or those who are not candidates for surgery or refuse surgical treatment [6, 7].
Osilodrostat, a novel 11β-hydroxylase inhibitor, has shown high efficiency in CS [8]. However, it causes hypocortisolism or glucocorticoid withdrawal syndrome in a significant percentage of the patients, even under rigorous monitoring [9]. In most clinical trials, the dose of osilodrostat has been adjusted by means of three 24-h urinary free cortisol (UFC) levels [9-12], which represents the best way to determine the integrated daily cortisol production [13]. However, obtaining UFC results typically requires approximately 1 week. This cumbersome method is likely unsuitable for daily clinical practice. Moreover, UFC levels are deemed insensitive for diagnosing hypocortisolism [14]. Conversely, serum cortisol levels are available within a few hours after blood sampling, suggesting that they could facilitate timely adjustments in osilodrostat dosing. Nonetheless, it remains unclear how serum cortisol levels should be used as a complementary or alternative index to UFC in CS during osilodrostat administration. Therefore, the present study aimed to determine whether simultaneous assays of single morning serum cortisol and UFC concentrations can provide useful information for safety management in patients with CS receiving osilodrostat.
We retrospectively obtained data on eight patients who were diagnosed with overt CS and were treated with osilodrostat between July 2021 and June 2023 at our center. The inclusion criteria were as follows: presence of overt CS; age ≥20 years; osilodrostat administered to maintain or achieve eucortisolism. The biochemical and subtype diagnosis of overt CS adheres to the clinical guidelines issued by the Endocrine Society [15]. In brief, overt CS is diagnosed by the presence of typical Cushingoid features, elevated UFC and midnight serum cortisol levels, and failure to suppress cortisol secretion following the standard 1-mg dexamethasone suppression test (i.e., serum cortisol ≥1.8 μg/dL). Subtype diagnosis of CS is established as follows: adrenal CS, indicated by low morning plasma adrenocorticotropic hormone (ACTH) levels (<10 pg/mL) and the presence of an adrenal tumor with a diameter exceeding 1.0 cm on computed tomography; pituitary CS (Cushing disease, CD), indicated by normal to elevated morning plasma ACTH levels and a pituitary tumor detected on magnetic resonance imaging; ectopic ACTH syndrome (EAS), indicated by normal to elevated morning plasma ACTH levels, absence of pituitary tumor on imaging, negative cavernous sinus sampling results, and incomplete suppression of cortisol secretion by 8-mg dexamethasone [13, 15].
The 24-h urine specimen collection to measure UFC levels was started from the day before blood sampling to determine morning serum cortisol levels. Urine collection generally took place from 07:00 to 07:00 the next morning, and the volume was noted. Blood sampling for serum cortisol and plasma ACTH was performed at around 08:30 after an overnight fast. We instructed all patients to collect urine samples completely over 24 h and requested them to discard the first morning urine void. Patients were also asked to avoid excessive or insufficient water intake because the urine volume could be affected by UFC results [16]. In accordance with the package insert, our patients took osilodrostat twice daily in the morning and evening. The dosage of the drug was generally titrated no more than 1 week. Blood samples were consistently collected at least 8 h after the last osilodrostat dose and usually 7 days after initiating or adjusting the medication. However, during hospitalization, some of the samples were collected within a week after the procedures.
Samples obtained from a patient treated with pasireotide plus osilodrostat were included in the present study. In addition, we did not include a wash-out period after transitioning from metyrapone to osilodrostat, as the aim of this study was not to assay the effect of osilodrostat on cortisol production.
If the two types of samples were collected on separate days, we excluded the data from this study due to the inadequacy of correlation analysis. Furthermore, all samples collected during glucocorticoid replacement therapy were also excluded owing to their interference with the cortisol assays. Therefore, two of the eight patients were excluded. Finally, a total of 71 paired samples in six patients with CS were analyzed in this study (Table 1).
| Patient | No. of samples | Sex/Age | CS Subtype | Duration after diagnosis (months) | Previous treatments | eGFR (mL/min/1.73 m2) |
Baseline mean UFC (×ULN) |
Maximum UFC (×ULN) |
Maximum dose of osilodrostat (mg) | Maintenance dose of osilodrostat (mg) | Duration of osilodrostat administration (weeks) | Duration of UFC normalization (weeks) |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 1 | 27 | M/79 | EAS | 51 | Surgery metyrapone | 28.2 ± 5.7 | 8.4 ± 10.4 | 20.3 | 28 | 1 | 84 | 17 |
| 2 | 3 | F/85 | EAS | 3 | Metyrapone | 36.7 ± 0.8 | 7.3 ± 11.2 | 16.2 | 2 | 1 | 94 | 2 |
| 3 | 4 | F/84 | CD | 180 | Surgery metyrapone | 81.1 ± 8.7 | 0.2 ± 0.2 | 1.3 | 2 | 2 | 88 | 1 |
| 4 | 11 | F/48 | CD | 33 | Surgery metyrapone trilostane pasireotide |
70.0 ± 6.6 | 1.8 ± 0.8 | 3.0 | 10 | 8 | 104 | 10 |
| 5 | 14 | F/58 | Adrenal | 1 | Metyrapone | 64.5 ± 3.7 | 0.9 ± 1.2 | 53.5 | 22 | 6 | 4 | 1 |
| 6 | 12 | M/59 | Adrenal | 0.3 | None | 45.9 ± 4.1 | 1.4 ± 0.3 | 2.2 | 4 | 2 | 8 | 3 |
| All | 71 | 69 ± 16 | 44.7 ± 69.4 | 48.2 ± 19.4 | 3.3 ± 3.5 | 16.1 ± 20.0 | 11.3 ± 11.1 | 3.3 ± 2.9 | 63.6 ± 45.1 | 5.7 ± 6.5 |
The clinical research ethics committee of the St. Marianna University School of Medicine (no. 6113) approved this study protocol, which complied with the revised ethical guidelines of the Declaration of Helsinki. The ethics committee approved the use of the opt-out method of obtaining consent; therefore, informed consent was obtained via an opt-out option on the website of St. Marianna University Yokohama Seibu Hospital.
2.2. MeasurementsThe following data were collected: patient demographics, including sex, age at the time of CS diagnosis, and duration of CS; biochemical and hormonal profiles before and during osilodrostat administration, including estimated glomerular filtration rate (eGFR), serum cortisol, UFC, and plasma ACTH; osilodrostat treatment, including applied dose, adverse events, and the reason for switching to osilodrostat. The eGFR was calculated using the equation established for the Japanese population by the Japanese Society of Nephrology: eGFR (mL/min/1.73 m2) = 194 × serum creatinine – 1.094 × age – 0.287 (×0.739 for female patients) [17]. Because of a change in the assay method for UFC, we generally expressed the UFC levels as a multiple of the upper limit of normal (ULN) or the lower limit of normal (LLN) for the assay used. Hypocortisolism during osilodrostat administration was diagnosed if serum cortisol levels were <5 μg/dL [18, 19]. Furthermore, we obtained the maximum UFC levels throughout the clinical course in each participant.
2.3. Hormone assay methodsCommercially available assay kits were used for hormone measurements. UFC levels were measured by radioimmunoassay (Cortisol kit FR; Fuji Rebio Co. Ltd, Tokyo, Japan) before April 2020 and then by chemiluminescent Immunoassay (Cortisol Abbott; Abbott, Chiba, Japan), with reference ranges of 11.2–80.3 and 5.5–66.7 μg/24 h, respectively. Serum cortisol levels in the supine position were measured by chemiluminescent enzyme immunoassay (Accuraseed cortisol; FUJIFILM Wako Pure Chemical Co., Osaka, Japan), with reference ranges of 4.0–18.3 μg/dL. Plasma ACTH levels were determined by electro-chemiluminescent immunoassay (Elecsys ACTH kit; Roche Diagnostics, Tokyo, Japan) with reference ranges, in the supine position, of 7.2–63.3 pg/mL.
2.4. Statistical analysesResults are presented as mean ± standard errors and frequencies (positive/total observation) unless otherwise indicated. Spearman’s correlation was used to study the relationship between serum cortisol levels and UFC levels. Receiving operating characteristic (ROC) analysis was performed to assess possible threshold values for the serum cortisol levels to predict high or low UFC levels. The area under the curve and its 95% confidence interval (CI) were calculated to provide the best sensitivity and specificity value combination. SPSS version 26 (IBM Corp., Armonk, NY, USA) was used for all statistical analyses, and p < 0.05 was considered significant.
The mean age of six studied patients with CS was 69 ± 16 years (range, 48–79 years), and two-thirds were women. Of the six patients, two had CD, two had EAS, and two had adrenal CS (Table 1). The number of analyzed samples varied among the patients because of differences in the duration after starting osilodrostat treatment or until initiating glucocorticoid replacement therapy and/or the aim of osilodrostat administration (i.e., preoperative short-term management in adrenal CS, controlling hypercortisolism in inoperative EAS, or postoperative recurrence of CD). The mean UFC levels at baseline (i.e., before starting osilodrostat administration) were approximately 3 × ULN. However, the mean maximum UFC value throughout the clinical course was >1.5 × ULN.
In five of six patients, metyrapone was used before switching to osilodrostat. The reasons for the switching were nausea, heartburn, and/or dizziness caused by metyrapone in four patients (patients 1, 3, 4, and 5). One patient (patient 2) who had difficulty swallowing preferred osilodrostat to metyrapone because the tablet size of the former drug was much smaller than that of the latter. Pasireotide continued to be used during osilodrostat treatment in one patient (patient 4). The mean maximal daily dose of osilodrostat to ameliorate hypercortisolism was >10 mg; subsequently, the mean maintenance dose was reduced by approximately 30%. The mean eGFR in 71 samples was 48.2 ± 19.4 mL/min/1.73 m2, and chronic kidney disease, defined as eGFR <60 mL/min/1.73 m2, was observed in half the patients. One of the three patients had complicated nephritic syndrome due to diabetic nephropathy.
During the study period, neither severe nor common adverse events, including tumor enlargement, prolonged QT interval, or blood pressure elevation, were identified. However, five of six patients experienced hypocortisolism at least once. Hypokalemia was observed in one patient who required a high dose of osilodrostat to achieve eucortisolism (patient 1). In all patients who switched from metyrapone to osilodrostat, gastrointestinal symptoms, dizziness, and/or virilization disappeared or were ameliorated.
3.2. Morning cortisol levels to predict high UFC and the clinical usefulnessA significant correlation was found between single morning cortisol levels and UFC levels (×ULN) collected on the same day (r = 0.77, p < 0.0001) (Fig. 1). The mean daily urine volume from 71 samples for UFC determination was 1,978 ± 718 mL (range, 750–4,930 mL). Neither polyuria, defined as a daily urine volume >5,000 mL/day, nor oliguria, defined as <400 mL/day, was observed. Table 2 presents ROC analysis to identify the optimal cut-off of serum cortisol for predicting UFC at 1.0 × ULN, 1.5 × ULN, and 2 × ULN. The three cut-off values were close to the ULN for serum cortisol in our assay (18.3 μg/dL). The primary concern of this study was to prevent missing cases of hypocortisolism, followed by severe or moderate hypercortisolism, during osilodrostat treatment. Therefore, we determined the cut-off of 21.5 μg/dL for serum cortisol as the best marker for safety management, as it demonstrated the highest specificity and negative predictive value for detecting elevated UFC levels. As illustrated in Figs. 1 and 2, serum cortisol levels in 40 samples with UFC < ULN remained consistently <21.5 μg/dL, whereas those in five samples with UFC >3 × ULN were at least 21.5 μg/dL. In 26 samples where UFC ranged from ULN to 3 × ULN, paired serum cortisol levels varied widely. However, serum cortisol levels of at least 21.5 μg/dL corresponded with UFC levels between 1.5 × ULN and 3 × ULN. Although four samples exhibited serum cortisol levels <21.5 μg/dL with UFC >2 × ULN (green closed circle in Fig. 2), these UFC levels did not exceed 3 × ULN, indicating that the selected cut-off (i.e., 21.5 μg/dL) could prevent overlooking cases of moderate-to-severe hypercortisolism. In six of 12 samples with serum cortisol levels >21.5 μg/dL, we increased the osilodrostat dosage prior to obtaining the UFC levels on the same day. We found no case of adrenal insufficiency.
The panel shows the distribution of morning serum cortisol and UFC levels. The two types of samples studied were always collected on the same day. Because of the change in the assay method for UFC, the levels (μg/day) were converted to a multiple of the ULN for the assay used. Vertical broken (blue) lines represent UFC levels of 1 × ULN, 3 × ULN, and 5 × ULN. The horizontal broken line (black) indicates the serum cortisol level (21.5 μg/dL).
| UFC (×ULN) | Cutoff value of serum cortisol (μg/dL) | AUC (95%CI) | sensitivity (%) | specificity (%) | PPV (%) | NPV (%) |
|---|---|---|---|---|---|---|
| ×2.0 | 21.5 | 0.91 (0.82–0.96) | 71.4 | 96.5 | 83.3 | 93.2 |
| ×1.5 | 18.5 | 0.92 (0.86–0.98) | 75.0 | 93.6 | 85.7 | 88.0 |
| ×1.0 | 18.5 | 0.87 (0.78–0.95) | 61.3 | 95.0 | 90.5 | 76.0 |
Vertical broken lines (blue) represent UFC levels of 2 × ULN and 3 × ULN. The horizontal broken line (black) indicates the serum cortisol level (21.5 μg/dL). Green closed circles show discordant samples between the UFC and serum cortisol levels.
The significant correlation between morning serum cortisol levels and UFC (×ULN) was maintained in participants with chronic renal failure (i.e., patients 1, 2, and 6; r = 0.86, p < 0.0001, data not shown) or those with CD whose cortisol overproduction was relatively lower compared to that of other CS subtypes (i.e., patients 3 and 4; r = 0.72, p < 0.0001, data not shown).
3.3. Morning cortisol levels to predict low UFC and the clinical usefulnessWe found a significant correlation between morning cortisol levels and UFC levels (×LLN) collected on the same day (r = 0.70, p < 0.001) (Fig. 3). ROC analysis indicated that the optimal cut-offs for serum cortisol in UFC of LLN and 2 × LLN prediction were 10.4 and 11.1 μg/dL, respectively (Table 3). The two cut-off values for serum cortisol levels were substantially higher than 5.0 μg/dL, which strongly suggests hypocortisolism [18, 19]. Indeed, the positive predictive value for each cut-off was considerably low.
The panel shows the distribution of morning serum cortisol and UFC levels. The two types of samples studied were always collected on the same day. Because of the change in the assay method for UFC, the levels (μg/day) were converted to a multiple of the LLN for the assay used.
| UFC (×LLN) | Cutoff value serum cortisol (μg/dL) | AUC (95%CI) | sensitivity (%) | specificity (%) | PPV (%) | NPV (%) |
|---|---|---|---|---|---|---|
| ×2.0 | 11.1 | 0.940 (0.88–1.00) | 100 | 73.3 | 40.7 | 100 |
| ×1.0 | 10.4 | 0.784 (0.65–0.92) | 100 | 87.3 | 69.6 | 100 |
We observed two paired samples where serum cortisol levels were <5.0 μg/dL and UFC levels exceeded LLN (blue closed circle in Fig. 4). Patients presenting these discordant samples reported general fatigue, muscle pain, and/or arthralgia, leading to a diagnosis of adrenal insufficiency. Conversely, we identified three UFC samples with values below or near LLN despite serum cortisol levels approximately 10.0 μg/dL (red closed circle in Fig. 4). Considering their symptoms, serum sodium and potassium levels, and plasma glucose levels, the possibility of hypocortisolism was dismissed.
The vertical broken line (back) represents the serum cortisol level (5.0 μg/dL), which is defined as hypocortisolism. The horizontal broken line (red) indicates the UFC level (1 × LLN). Blue and red closed circles show discordant samples between the UFC and serum cortisol levels.
The significant correlation between morning serum cortisol levels and UFC (×LLN) was observed even in patients with chronic renal failure (i.e., patients 1, 2, and 6; r = 0.85, p < 0.0001, data not shown) or those with CD (i.e., patients 3 and 4; r = 0.71, p < 0.0001, data not shown).
In patients with CS, concomitant monitoring for therapeutic response and side effects of steroid synthase inhibitors is quite challenging for physicians. Overdosing of the drugs must be caused by adrenal insufficiency, and underdosing cannot reduce the risk of acute life-threatening complications such as infections [20] and venous thromboembolisms [21]. Thus, accurate and timely reactions are always required during the treatment. In major osilodrostat clinical trials, UFC concentrations have been used as the determinant to assess the efficacy of treatment [9-12]. In contrast to UFC, serum cortisol levels are readily available after blood sampling. Therefore, we investigated whether the index promotes safety management in CS treated with osilodrostat.
First, in this study, we found a significantly positive correlation between single morning serum cortisol levels and UFC levels collected on the same day. The results indicate that the serum cortisol concentrations can be used as an alternative and/or complementary indicator for 24-h UFC. During osilodrostat administration, cortisol production in patients with CS can vary from hypercortisolism to hypocortisolism. Furthermore, we calculated serum cortisol levels to predict high and low UFC separately using ROC analysis.
We demonstrated that when single morning serum cortisol levels are ≥21.5 μg/dL (1.2 × ULN), paired UFC levels consistently exceed ULN, suggesting that this cut-off value could prevent inappropriate reductions in osilodrostat dosage under hypercortisolism conditions. Furthermore, when UFC levels surpass 3 × ULN, paired morning serum cortisol levels invariably reach or exceed 21.5 μg/dL, indicating that this threshold may lead to the neglect of moderate or severe CS. Upon meeting these serum cortisol criteria, physicians should contemplate increasing the osilodrostat dosage based on the patient’s Cushingoid features, serum potassium levels, and eosinophil counts prior to receiving UFC results.
The cut-off value of serum cortisol levels herein is different from that in previous reports [9-12, 22]. A possible explanation for the difference is that the calculated target serum cortisol levels included the values measured at a time other than morning. Moreover, serum cortisol levels in the morning are higher than those at other times of day [23]; therefore, target cortisol levels calculated by multiple measurements in a day are inevitably lower than those obtained by a single measurement in the morning. In fact, Trainer et al. have described that the mean of six serum cortisol values in a day should be reduced to <10.8 μg/dL [24]. Haissaguerre et al. have reported that the target mean morning plasma cortisol concentrations determined from 3-day time samples is 18.1 μg/dL [25]. These results support our interpretation.
Osilodrostat has effectively corrected cortisol overproduction even in patients with severe CS [12], whereas the risk of developing adrenal insufficiency during the treatment may be higher than that with conventional steroid synthase inhibitors. Based on recent reports, the incidence or prevalence of adrenal insufficiency reached nearly 30%; thus, we must pay special attention to therapy development [9-12, 22]. Although a significant correlation between single morning cortisol and UFC (×LLN) was also observed, ROC analysis did not identify a useful cut-off value of serum cortisol levels to predict low UFC. The positive predictive value on the cut-off point of morning serum cortisol levels (10.4 or 11.1 μg/dL) was low. Therefore, it was unsuitable for practical use. Thus, we used a serum cortisol cut-off of <5.0 μg/dL set forth by the Japan Endocrine Society [19] to examine the risk regarding dose adjustment based on UFC. Conversely, our results show that morning cortisol levels >10.0 μg/dL help exclude adrenal insufficiency. Moreover, symptoms such as nausea, joint pain, or fatigue in these patients indicate steroid withdrawal syndrome, not adrenal insufficiency. This approach can prevent unnecessary discontinuation or reduction of the medication.
In over one-third of samples with low or borderline UFC, paired morning serum cortisol levels were within normal ranges. Conversely, approximately 30% of samples with morning serum cortisol levels <5.0 μg/dL exhibited paired UFC levels >1.5 × ULN. Based on symptoms, signs, and laboratory findings at each instance, diagnoses derived from serum cortisol levels proved consistently accurate. Although the exact cause of the discrepancies between serum and urinary cortisol levels was not determined, our findings suggest that adjusting the dosage of osilodrostat according to UFC levels may be inadvisable when hypocortisolism cannot be ruled out. Previous studies have suggested a lower target range for serum cortisol levels, from 5.0 to 8.0 μg/dL, during medical treatments for hypercortisolism [24-26]. This target is aligned with our findings, but further research is necessary to establish the ideal serum cortisol threshold for diagnosing adrenal insufficiency during osilodrostat treatment.
Assessment of adrenocortical function, based on serum cortisol and UFC levels, does not always yield consistent results. Challenges with UFC measurements may include incorrect urine collection, renal dysfunction, or intra-individual variability, as reported [27]. Similarly, serum cortisol levels can be influenced by alterations in its transporter protein, increase in response to various conditions such as stress, or reflect acute changes at a single point in time [23, 27, 28]. Moreover, cortisol measurements in blood and urine by immunoassay are susceptible to interference from cortisol metabolites during the use of steroidogenic enzyme inhibitors [29]. Therefore, it is crucial to consider these factors when encountering discordant serum and urinary cortisol results.
The main limitation of this study is the relatively small number of samples from six patients and the retrospective study design. However, in the report from Trainer et al., which has been often cited as showing the usefulness of mean serum cortisol for biochemical targets during medical treatment in CS, the relationship between UFC and mean serum cortisol levels was determined by using results from 29 paired samples [24]. Furthermore, the correlation coefficient between UFC levels and serum cortisol levels in our study was the same as that in their study (r = 0.77). However, assessment methods of serum cortisol between the two studies were different (i.e., single morning cortisol vs. mean cortisol from five or six samples obtained on a single day). Nearly half of the paired samples were collected within 8 days of starting or changing the dose of osilodrostat in this study. Therefore, the samples were divided into two groups: those collected within 8 days of initiating or adjusting the medication (n = 35) and those collected after 8 days (n = 36). Although both groups showed a significant correlation between serum cortisol and UFC levels, the former group had a higher relationship (serum cortisol and UFC [×ULN], r = 0.90, p < 0.001; serum cortisol and UFC [×LLN], r = 0.77, p < 0.001) than the latter group (serum cortisol and UFC [×ULN], r = 0.62, p < 0.001; serum cortisol and UFC [×LLN], r = 0.65, p < 0.001). The results indicate that clinical judgment can reliably be made as early as 8 days after dose adjustment. However, we should be aware of overestimating the correlation between the two test results when rapidly titrating osilodrostat. In addition, whether our results can apply to other steroidogenesis enzyme inhibitors or different assay kits for cortisol concentrations in blood or urine remains to be evaluated.
In conclusion, simultaneous measurements of single morning serum cortisol and UFC levels on the same day enhance the safety of osilodrostat-treated patients with CS. Morning serum cortisol levels ≥21.5 μg/dL (1.2 × ULN) may ensure that UFC levels exceed 1.5 × ULN (Graphical Abstract). It is the cortisol levels in the blood, rather than those in urine, that serve as a reliable biochemical indicator for diagnosing hypocortisolism. Morning serum cortisol levels <5.0 μg/dL appear to be the optimal criteria for this adverse event.
The authors appreciate Mariko Yoko for her work as a secretary and would like to thank Honyaku Center Inc. for English language editing.
Takuyuki Katabami declares grants and/or personal fees from Astellas Pharma Inc., MSD Corporation, Mitsubishi Tanabe Pharma Corporation, Eli Lilly Japan K.K., Novo Nordisk Pharma Ltd., Daiichi Sankyo Co., Ltd., Taisho Pharma Co., Ltd., Sumitomo Dainippon Pharma Co., Ltd., Kowa Pharmaceutical Co., Ltd., Nippon Boehringer Ingelheim Co., Ltd., Novartis Pharma K.K., Kyowa Kirin Co., Ltd., Recordati Rare Diseases Japan K.K., and Terumo Co., Ltd. The other authors declare that there is no conflict of interest. Takuyuki Katabami and Masakatsu Sone are members of Endocrine Journal’s Editorial Board.
T.K.: Writing – original draft, conceptualization, investigation, and formal analysis. R.M. and T.N.: Writing – original draft, investigation, and formal analysis. Y.Y., K.S., and M.S.: Writing – review & editing, investigation, and formal analysis. All the authors co-wrote and reviewed the manuscript, provided feedback, and approved the final version.
This study was supported by the Ministry of Health, Labour and Welfare of Japan (grant number: Nanbyo-Ippan-23FC0201) and the National Center for Global Health and Medicine, Japan (grant numbers: 27-1402 and 30-1008).
The datasets are not freely available because of restrictions imposed by the authors’ institutes. However, they may be available from the corresponding author upon reasonable request.
Adrenocorticotropic hormone
CDCushing disease
CIConfidence interval
CSCushing syndrome
EASEctopic adrenocorticotropic hormone syndrome
eGFREstimated glomerular filtration rate
LLNLower limit of normal
ROCReceiving operating characteristic
UFCUrinary free cortisol
ULNUpper limit of normal
