Ultrasound-Guided Jugular Vein Access for Inferior Petrosal Sinus Sampling: A Safe and Feasible Technique

Posted on December 11, 2025 by MaryO

Abstract

Pituitary Cushing’s disease (CD) results from excessive adrenocorticotropic hormone (ACTH) secretion, usually due to a pituitary adenoma. This report describes the diagnostic approach and management of a complex case of CD in a patient with multiple comorbidities, highlighting a hybrid technique for inferior petrosal sinus sampling (IPSS) when standard access fails.

A woman with poorly controlled diabetes, obesity, chronic kidney disease (CKD), and hypertension presented with suspected Cushing’s syndrome. Despite normal urinary free cortisol (UFC) levels (likely influenced by renal dysfunction), clinical suspicion prompted further testing, which revealed an inverted cortisol rhythm and lack of suppression on low-dose dexamethasone. High-dose suppression indicated a pituitary source. MRI findings were inconclusive. To confirm the diagnosis, bilateral IPSS was attempted. Right petrosal sinus catheterization via femoral access was successful; however, left-sided access failed. An alternative, ultrasound-guided direct left internal jugular puncture was performed, allowing complete sampling. A central-to-peripheral ACTH gradient >2 at baseline and >3 after desmopressin confirmed a pituitary source. The patient subsequently underwent successful transsphenoidal resection, achieving postoperative biochemical remission.

IPSS remains the gold standard for distinguishing central from ectopic ACTH production. While bilateral femoral access is standard, anatomical variants may necessitate alternative routes. This case demonstrates the feasibility and safety of combining femoral and direct jugular access to complete IPSS when conventional approaches are limited.

This is the first reported case of IPSS performed using a hybrid right femoral and left ultrasound-guided jugular approach, offering a practical alternative when femoral access is not feasible and reinforcing the diagnostic value of IPSS in challenging cases.

Introduction

Pituitary Cushing’s disease (CD) is caused by excessive secretion of adrenocorticotropic hormone (ACTH), typically due to a pituitary adenoma. It represents the most common cause of endogenous Cushing’s syndrome, accounting for approximately 70% of ACTH-dependent cases [1,2]. The diagnostic approach often requires dynamic hormonal testing and neuroimaging; however, distinguishing pituitary from ectopic ACTH secretion remains a clinical challenge [3].

Inferior petrosal sinus sampling (IPSS), first described by Oldfield EH and Doppman JL in 1977, is considered the gold standard for confirming a pituitary origin when biochemical and imaging findings are inconclusive [4-6]. Bilateral catheterization via femoral venous access is the usual approach, guided by digital subtraction angiography (DSA) [4,5]. However, anatomical variants, thrombosis, and technical difficulties can impede standard catheterization, necessitating alternative strategies such as direct ultrasound-guided internal jugular puncture [7].

This report presents a patient with multiple comorbidities and suspected CD in whom a hybrid IPSS approach was successfully performed after failed standard access.

Case Presentation

A female patient with a history of poorly controlled diabetes, obesity, chronic kidney disease (CKD), and hypertension was admitted with suspected Cushing’s syndrome. Initial evaluation revealed normal urinary free cortisol (UFC), likely underestimated due to renal dysfunction. Because of high clinical suspicion, circadian cortisol rhythm was assessed, showing inversion with higher evening than morning levels, supporting hypercortisolism.

A low-dose dexamethasone suppression test (LDDST; 1 mg) failed to suppress cortisol, confirming endogenous hypercortisolism. A high-dose dexamethasone suppression test (HDDST; 8 mg) demonstrated 80% cortisol suppression, suggesting a pituitary source of ACTH overproduction.

Pituitary MRI revealed a poorly defined hypointense nodular area, inconclusive for microadenoma (Figure 1A). To confirm the central origin, bilateral inferior petrosal sinus sampling (IPSS) was performed (Figures 1B–1E).

(A)-Contrast-enhanced-pituitary-MRI-showing-a-hypointense-nodule-in-the-left-half-of-the-gland,-which-was-inconclusive;-(B)-right-internal-jugular-vein-access-achieved,-while-left-jugular-access-was-not-possible-via-this-route;-(C-and-D)-dual-inferior-petrosal-sinus-catheterization-with-right-sided-access-via-the-femoral-vein-and-left-sided-access-via-direct-jugular-puncture;-(E)-ultrasound-guided-placement-of-the-venous-sheath.
Figure 1: (A) Contrast-enhanced pituitary MRI showing a hypointense nodule in the left half of the gland, which was inconclusive; (B) right internal jugular vein access achieved, while left jugular access was not possible via this route; (C and D) dual inferior petrosal sinus catheterization with right-sided access via the femoral vein and left-sided access via direct jugular puncture; (E) ultrasound-guided placement of the venous sheath.

Initial access was established via the bilateral femoral veins with placement of 5 Fr introducer sheaths in both. Due to anatomical complexity and inability to access the left internal jugular vein via the femoral route, a direct ultrasound-guided left jugular puncture was performed. A separate 5 Fr introducer sheath was placed directly into the left internal jugular vein under ultrasound guidance (US guidance). Catheterization was performed using 5 Fr vertebral diagnostic catheters, facilitated by a micro-guidewire.

Correct positioning within the petrosal sinuses was subsequently confirmed by contrast injection. The results demonstrated accurate catheter placement in the inferior petrosal sinuses (adequate prolactin levels), with an ACTH central-to-peripheral gradient greater than 2 at baseline and greater than 3 after desmopressin, thus confirming a pituitary source for the pathology (Tables 1–2).

Peripheral Right IPS Left IPS
16.5 ng/mL 41.2 ng/mL 63.7 ng/mL
Table 1: Prolactin concentrations obtained via inferior petrosal sinus sampling at baseline.

IPS: Inferior Petrosal Sinus.

Time Point Peripheral Right IPS Left IPS
Basal 27.5 pg/mL 77.1 pg/mL 106 pg/mL
Desmopressin 5 min 28.3 pg/mL 168 pg/mL 221 pg/mL
Desmopressin 10 min 27.9 pg/mL 32 pg/mL 80 pg/mL
Table 2: ACTH concentrations obtained via inferior petrosal sinus sampling at baseline and at 5 and 10 minutes after desmopressin stimulation.

IPS: Inferior Petrosal Sinus; ACTH: Adrenocorticotropic hormone.

The patient underwent endonasal transsphenoidal resection of an ACTH-secreting pituitary microadenoma. Postoperatively, serum cortisol fell to <5 µg/dL, indicating secondary adrenal insufficiency, and physiologic glucocorticoid replacement was initiated. Urine output remained normal (no evidence of vasopressin deficiency), and steroid replacement was titrated without adrenal crisis.

Discussion

Diagnostic considerations

CKD can lead to falsely normal UFC values due to impaired renal clearance of cortisol metabolites [8]. Therefore, alternative biochemical tests such as late-night serum cortisol or dexamethasone suppression are recommended in these patients [1,3]. The high-dose dexamethasone suppression observed here supported a pituitary origin, but confirmation by IPSS was critical given the inconclusive MRI findings.

Inferior petrosal sinus sampling

Since its introduction, IPSS has become the reference standard for distinguishing pituitary from ectopic ACTH production, with reported sensitivity and specificity of approximately 96% and 100%, respectively [4-6,9]. The test involves measuring ACTH gradients between central (petrosal) and peripheral samples, values ≥2 at baseline or ≥3 after corticotropin-releasing hormone (CRH) or desmopressin stimulation indicate a central source [5,9].

Desmopressin stimulation

Although CRH has traditionally been used, desmopressin is an effective and safe alternative that achieves comparable diagnostic accuracy [10]. In our case, desmopressin successfully elicited a diagnostic gradient, confirming the pituitary source.

Technical challenges and hybrid approach

Although the conventional IPSS technique uses bilateral femoral access, the procedure was originally performed via direct jugular puncture [2]. Variations in venous anatomy, hypoplasia, or catheterization failure may necessitate alternative routes. Direct ultrasound-guided jugular puncture offers an effective solution, minimizing procedural time and radiation exposure, and reducing the risk of complications such as cervical hematoma. Our case illustrates that combining femoral and direct jugular access allows complete bilateral sampling without compromising safety.

Conclusions

This case demonstrates the feasibility and safety of a hybrid IPSS approach combining right femoral and ultrasound-guided direct left jugular access. This method enabled successful completion of bilateral sampling when standard femoral catheterization failed. The case reinforces IPSS as a critical diagnostic tool for confirming pituitary Cushing’s disease, even in technically challenging circumstances.

References

  1. Nieman LK, Biller BM, Findling JW, Newell-Price J, Savage MO, Stewart PM, Montori VM: The diagnosis of Cushing’s syndrome: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2008, 93:1526-1540. 10.1210/jc.2008-0125
  2. Perlman JE, Johnston PC, Hui F, et al.: Pitfalls in performing and interpreting inferior petrosal sinus sampling: personal experience and literature review. J Clin Endocrinol Metab. 2021, 106:e1953-e1967. 10.1210/clinem/dgab012
  3. Findling JW, Raff H: Diagnosis and differential diagnosis of Cushing’s syndrome. Endocrinol Metab Clin North Am . 2021, 30:729-747. 10.1016/s0889-8529(05)70209-7
  4. Oldfield EH, Doppman JL, Nieman LK, et al.: Petrosal sinus sampling with and without corticotropin-releasing hormone for the differential diagnosis of Cushing’s syndrome. N Engl J Med. 1991, 325:897-905. 10.1056/NEJM199109263251301
  5. Zampetti B, Grossrubatscher E, Dalino Ciaramella P, Boccardi E, Loli P: Bilateral inferior petrosal sinus sampling. Endocr Connect. 2016, 5:R12-R25. 10.1530/EC-16-0029
  6. Vassiliadi DA, Mourelatos P, Kratimenos T, Tsagarakis S: Inferior petrosal sinus sampling in Cushing’s syndrome: usefulness and pitfalls. Endocrine. 2021, 73:530-539. 10.1007/s12020-021-02764-4
  7. Yeh CH, Wu YM, Toh CH, Chen YL, Wong HF: A safe and efficacious alternative: sonographically guided internal jugular vein puncture for intracranial endovascular intervention. AJNR Am J Neuroradiol. 2012, 33:E7-E12. 10.3174/ajnr.A2416
  8. Kidambi S, Raff H, Findling JW: Limitations of nocturnal salivary cortisol and urine free cortisol in the diagnosis of mild Cushing’s syndrome. Eur J Endocrinol. 2007, 157:725-731. 10.1530/EJE-07-0424
  9. Wind JJ, Lonser RR, Nieman LK, DeVroom HL, Chang R, Oldfield EH: The lateralization accuracy of inferior petrosal sinus sampling in 501 patients with Cushing’s disease. J Clin Endocrinol Metab. 2013, 98:2285-2293. 10.1210/jc.2012-3943
  10. Malerbi DA, Mendonça BB, Liberman B, et al.: The desmopressin stimulation test in the differential diagnosis of Cushing’s syndrome. Clin Endocrinol (Oxf). 1993, 38:463-472. 10.1111/j.1365-2265.1993.tb00341.x

From https://www.cureus.com/articles/429423-ultrasound-guided-jugular-vein-access-for-inferior-petrosal-sinus-sampling-a-safe-and-feasible-technique#!/

Filed under: Cushing's, Diagnostic Testing, pituitary | Tagged: , , , | Leave a comment »

Metyrapone Benefits Blood Pressure in Mild Hypercortisolism

Posted on November 7, 2025 by MaryO

TOPLINE:

A notable proportion of patients with mild hypercortisolism achieved blood pressure (BP) control with low-dose evening metyrapone, without requiring the intensification of antihypertensive therapy. The treatment was particularly beneficial for those with higher baseline systolic BP and was well tolerated, with no adverse events reported.

METHODOLOGY:

  • This prospective observational study assessed the impact of low-dose evening metyrapone on 24-hour ambulatory BP, glucose metabolism, and the cortisol circadian rhythm in 20 patients with mild hypercortisolism (median age, 70.5 years; 65% women).
  • Eligible patients had cortisol levels > 1.8 μg/dL after a 1-mg dexamethasone suppression test on at least two separate occasions, fewer than two specific Cushing syndrome‑related symptoms, and either hypertension or impaired glucose metabolism.
  • Patients received evening metyrapone 250 mg/d, with dose adjustments on the basis of clinical response and cortisol secretion; in 12 patients who showed no signs of hypoadrenalism after week 12, an additional 250-mg afternoon dose was given.
  • The primary endpoint was BP control, defined as a reduction in mean 24-hour systolic BP of ≥ 5 mm Hg without increasing antihypertensive medication; ambulatory BP monitoring was done at baseline and weeks 12 and 24.

TAKEAWAY:

  • At 24 weeks, 40% of patients had a clinically significant improvement in BP control without escalation of therapy, with reductions in both daytime and nighttime systolic BP; benefits were more pronounced in those with elevated baseline systolic BP.
  • Glucometabolic control improved in four patients at 24 weeks; those with poorly controlled type 2 diabetes at baseline achieved the most pronounced glycaemic benefits.
  • Salivary cortisol levels remained unchanged from baseline; no significant changes in hormonal, metabolic, or anthropometric parameters were observed from baseline, except for testosterone levels in women.
  • The treatment was well tolerated, with no side effects or reports of adrenal insufficiency.

IN PRACTICE:

“Our findings support the notion that metyrapone may offer clinical benefits in patients with mH [mild hypercortisolism], particularly those with uncontrolled comorbidities. The observed improvements in BP and glycaemic control, despite minimal changes in UFC [urinary free cortisol] levels, underscore the need to re-evaluate traditional therapeutic targets and to adopt a more holistic approach to disease management,” the authors of the study wrote.

SOURCE:

This study was led by Antonio Musolino, University of Milan, Milan, Italy. It was published online on October 16, 2025, in the European Journal of Endocrinology.

LIMITATIONS:

This study was limited by its relatively short treatment duration, potential adherence bias, and an older cohort age, which may have limited generalisability. The sample size, although adequate for the primary endpoint, was limited. The absence of a control group restricted the ability to definitively attribute improvements to metyrapone therapy.

DISCLOSURES:

This study received financial support through an investigator-initiated study grant from ESTEVE (formerly HRA RD). Two authors reported receiving speaker or consultancy fees or honoraria from Corcept Therapeutics.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication

https://www.medscape.com/viewarticle/metyrapone-benefits-blood-pressure-mild-hypercortisolism-2025a1000szc?form=fpf

Filed under: Cushing's, Diagnostic Testing, symptoms | Tagged: , , , , , | Leave a comment »

Cushing Syndrome Test Choice Should Fit Patient Factors & Disease Stage

Posted on October 20, 2025 by MaryO

Caused by excessive exposure to the hormone cortisol, endogenous Cushing syndrome (CS) is difficult to diagnose. Currently available biochemical tests that assess cortisol production have limited diagnostic specificity and sensitivity, and their performance can vary depending on the patient, according to a review article in Current Opinion in Endocrinology, Diabetes and Obesity.

“Whether performed on blood, urine, saliva, or hair, all biochemical tests for CS have advantages and disadvantages. It is therefore essential to select them based on the individual characteristics of the patient and the stage of the disease in order to improve their diagnostic performance,” wrote corresponding author Antoine Tabarin, MD, and coauthor Amandine Ferriere, MD, of the University Hospital of Bordeaux in Pessac, France.

The Endocrine Society recommends initial screening of patients with suspected CS using 24-hour urinary-free cortisol (UFC), late-night salivary cortisol (LNSC), or the overnight dexamethasone suppression test (ONDST). To avoid false negatives from variability in cortisol production, UFC and LNSC tests should be performed twice.

Among the three screening options, meta-analysis findings suggest comparable diagnostic performance, the authors reported.

“However, they also concluded that these investigations should not be used indiscriminately,” the review continued, “and should be selected according to various circumstances.”

ONDST results can be affected by medications, age, a history of bariatric surgery, and even individual differences in dexamethasone metabolism, according to the review. UFC requires patient education and a complete 24-hour urine collection. LNSC testing, which biochemically assesses the loss of circadian rhythmicity consistent in CS, may not be appropriate for people with highly variable sleep schedules, including shift workers.

For early detection of Cushing disease (CD) recurrence after pituitary surgery, LNSC is the recommended first-line procedure for biochemical follow-up. LNSC is also the tool of choice for monitoring patients with CS treated with medication, the article reported.

For patients with adrenocorticotropic hormone (ACTH)-dependent CS, UFC offers high accuracy for assessing the likelihood of CD and ectopic adrenocorticotropin. However, for the diagnosis of cyclical or intermittent CS, repeat UFC tests are “cumbersome and nearly impossible,” the authors wrote.

LNSC, on the other hand, allows for frequent daily assessment of cortisol secretion which is helpful for identifying cyclical CS. Similarly, measurements of cortisol and cortisone levels in the hair can assess mid- to long-term tissular exposure to cortisol and signal cyclical CS as well, the review explained.

References

Ferriere A, et al. Curr Opin Endocrinol Diabetes Obes. 2025;32(5):233-239. doi:10.1097/MED.0000000000000923

From https://www.physiciansweekly.com/post/cushing-syndrome-test-choice-should-fit-patient-factors-disease-stage

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The Reflex Dexamethasone Suppression Test: Development and Assessment of Reflexed Serum Dexamethasone Measurement for the Diagnosis of Cushing Syndrome

Posted on August 23, 2025 by MaryO

Abstract

Background

Screening for Cushing syndrome (CS; endogenous overproduction of ACTH or cortisol) is performed by the low-dose overnight serum dexamethasone suppression test (oDST) with the measurement of serum dexamethasone concentration to assure an effective dose.

Objective

We evaluated the utility of only measuring serum dexamethasone in samples with nonsuppressed serum cortisol using a conservative serum cortisol cutoff.

Methods

This retrospective study included 261 oDSTs completed before Reflex implementation (Pre-Reflex-oDST) and 281 oDSTs completed after (Post-Reflex-oDST). Serum cortisol and serum dexamethasone data were paired to the diagnosis and analyzed with comparative statistical tests and receiver operating characteristic curve (ROC) analysis.

Results

Endogenous hypercortisolism was diagnosed in 38 of 261 Pre-Reflex-oDSTs (14%) and 40 of 281 (14%) Post-Reflex-oDSTs. In oDSTs with SerCort >1.8 mcg/dL, there were 9% and 6% false positives in the Pre-vs Post-Reflex-oDST group, respectively. In the Pre-Reflex-oDST group, the median SerCort was 1.1 mcg/dL (95% CI: 0.8–1.5) in patients without CS and 3.9 mcg/dL (95% CI: 2.6–7.9) in those with CS (P < 0.001). The optimal ROC cutoff of SerCort in the Pre-Reflex-oDST group was 2.1 mcg/dL (sensitivity 92%, specificity 93%). In the Post-Reflex-oDST group, the median SerCort was 1.1 mcg/dL (95% CI: 0.8–1.5) in patients without CS and 2.9 mcg/dL (95% CI: 2.6–7.9) in those with CS (P < 0.001). The optimal ROC cutoff of SerCort in the Post-Reflex-oDST group was 2.1 mcg/dL (sensitivity 95%, specificity 93%; not different from Pre-Reflex-oDST group).

Conclusion

Reflex measurement of the serum dexamethasone did not affect oDST test performance while reducing costs.

Abbreviations

CS

Cushing syndrome
oDST

low-dose overnight serum dexamethasone suppression test
ROC

receiver operating characteristic
NH

neoplastic hypercortisolism
NNH

non-neoplastic hypercortisolism
HPA

hypothalamic pituitary adrenal
SerCort

serum cortisol
SerDex

serum dexamethasone
WDL

Wisconsin Diagnostic Laboratories
LOQ

limit of quantification
UFC

urine free cortisol

Highlights

  • •
    Reflexing only nonsuppressed serum cortisol samples for the measurement of serum dexamethasone does not negatively affect the performance of the overnight low-dose DST (oDST)
  • •
    Reflex implementation greatly reduced the number of serum dexamethasone measurements thereby decreasing unnecessary costs
  • •
    The oDST appeared to be valid as long as there was a measurable serum dexamethasone result (>50 ng/dL)

Clinical Relevance

We report a novel Reflex overnight dexamethasone suppression test (oDST) serum dexamethasone measurement protocol with the benefit of greatly lowering costs without loss of oDST performance supporting its implementation in screening for Cushing syndrome.

Introduction

Endogenous Cushing syndrome (CS) includes neoplastic hypercortisolism either due to autonomous cortisol production or excessive ACTH secretion.1 Non-neoplastic hypercortisolism (NNH) is also an important clinical entity that is characterized as bona fide cortisol excess caused by conditions such as depression, chronic kidney disease, and poorly controlled diabetes.2, 3, 4 Chronically elevated cortisol levels contribute to significant morbidity and mortality due to cardiovascular, metabolic, musculoskeletal, and immunologic effects, including hypertension, diabetes, osteoporosis, and increased susceptibility to infections5,6 leading to prolonged disease burden and worsening clinical outcomes.2,3
Biochemical evaluation is indicated for individuals presenting with features of hypercortisolism, as well as for those with adrenal incidentalomas, regardless of symptoms, in accordance with current guidelines.7 However, the workup is complicated by varying severities of hypercortisolism and diurnal rhythm of endogenous cortisol requiring screening tests to take advantage of predictable nadirs and negative feedback.1 One of the current first-line screening tests for CS is the 1 mg (low dose) overnight dexamethasone suppression test (oDST).8 Positive oDST results require additional testing such as late-night salivary cortisol and 24 h urine free cortisol measurements.8, 9, 10
The oDST takes advantage of decreased HPA negative feedback sensitivity in CS.11 An oral 1 mg dexamethasone dose is given between 2300 hours and 2400 hours and serum cortisol (SerCort) is then measured at 0800 h the following morning with levels <1.8 mcg/dL (50 nmol/L) representing normal suppression.8 A clinical sensitivity of 95% highlights the oDST as a useful screening tool; however, a specificity of ∼80% indicates a greater potential for false-positive results.10,12 A higher burden of false-positive results complicates diagnosis, leading to further testing, delays in diagnosis and treatment, and increased costs and resource utilization for both patients and the health care system. Therefore, the measurement of a serum dexamethasone (SerDex) in the next morning SerCort sample should identify insufficient SerDex levels that may result from factors such as mistiming of, or altogether missing the dexamethasone dose, differences in dexamethasone metabolism, variation in gastrointestinal absorption, increased cortisol binding globulin (eg, due to oral contraceptives), and medications that alter CYP3A4 activity.13, 14, 15, 16, 17
To reduce unnecessary and costly SerDex measurements, our institution implemented in 2023 a Reflex protocol in which SerDex is only measured if post-oDST SerCort is ≥ 1.6 mcg/dL (ie nonsuppressed). This approach was suggested but not evaluated by Genere et al.18 Since the purpose of this study was not to validate the concept of the oDST, we chose 1.6 mcg/dL as a conservative cutoff so that borderline SerCort with small variations around the accepted 1.8 mcg/dL cutoff would not bias the results. This study assessed equivalency in test performance between Pre- and Post-Reflex-oDST implementation and estimated the associated cost savings. As a secondary outcome, we evaluated therapeutic SerDex levels necessary for valid testing.

Materials and Methods

Study Design

A retrospective cohort study was performed on all oDSTs completed at Froedtert & the Medical College of Wisconsin and the affiliated Wisconsin Diagnostic Laboratories between May 2023 and April 2024. This study was approved by the Medical College of Wisconsin Institutional Review Board as a Quality Improvement Project under PRO00050802. All data in the database were de-identified and coded.

Study Population

The study population included patients aged ≥18 years who completed a oDST in the outpatient setting through the system with serum samples processed through Wisconsin Diagnostic Laboratories. Cohorts were divided into Pre- and Post-Reflex-oDST groups based on the date of Reflex implementation described below (October 31, 2023), with the Pre-Reflex-oDST group consisting of tests performed in the 6 months prior and the Post-Reflex-oDST group including tests from the 6 months following implementation. The ordering clinician still had the option to choose oDST AM cortisol alone without ordering a SerDex measurement. Exclusion criteria included repeat oDST for the same patient within the same 6-month period (Pre- or Post-Reflex-oDST groups); however, results from patients who underwent oDST during both the Pre- and Post-Reflex-oDST periods were included. Patients with SerDex <50 ng/dL were also excluded. At this time, all patients included in the analysis had either a confirmed hypercortisolism diagnosis or were determined not to have pathophysiological hypercortisolism based on clinical and biochemical evaluation.8 A combination of biochemical tests (24-hour free urine cortisol, late-night salivary cortisol, oDST), imaging (adrenal and pituitary CT/MRI), and other testing (DDVAP testing, surgical outcome, biopsy) were used to confirm the diagnosis of CS per the current guidelines.8 Hypercortisolism included both neoplastic causes (CS) and non-neoplastic causes (NNH).2 In our study, NNH included patients with chronic nausea and weight loss, chronic kidney disease, poorly controlled diabetes, excess alcohol intake, obesity with physiological stress, chronic pain, and opioid withdrawal. For simplicity, all hypercortisolism patients are abbreviated “CS” whether neoplastic or non-neoplastic.

Procedures

Patients were instructed to take 1 mg of dexamethasone at 11:00 pm and then had their blood sampled the next morning between 8:00 and 9:00 am SerCort level was measured using the Roche Elecsys Cortisol II Electrochemiluminescence immunoassay performed on a Cobas e801 module.19 In the Pre-Reflex-oDST group, individual orders for serum cortisol and dexamethasone were placed by the provider. Both tests were performed, regardless of the subsequently reported oDST serum cortisol value. In the Post-Reflex-oDST group, a single “Dexamethasone Suppression Cortisol Reflex” order was placed, that prompted a SerCort measurement. If SerCort was ≥1.6 mcg/dL (ie, nonsuppressed), an electronic order for a SerDex send-out measurement was automatically placed by the laboratory information system. The laboratory’s automated processing line removed the serum sample from storage, created an aliquot and placed it in a queue for samples to be sent to ARUP Laboratories. ARUP Laboratories measured SerDex by liquid chromatography-mass spectrometry (limit of quantitation [LOQ] = 50 ng/dL; reference interval: 140 – 295 ng/dL; https://ltd.aruplab.com/Tests/Pub/2003248).

Data Collection

Data acquired from each oDST, including date and time of collection, SerCort, and SerDex, were extracted from the laboratory information system. Additional data, including demographics, CS diagnosis, and treatment were collected from the electronic health record and securely stored in RedCAP (version 15.0.2; Nashville, TN). Patients with inconclusive test results were followed for several months after oDST until a diagnosis was established through additional testing and/or clinical evaluation.

Outcomes Assessment

The primary outcome of this study was to quantify the number of SerDex tests avoided while assessing whether implementation of the Reflex oDST affected overall test performance in the screening for endogenous hypercortisolism. Equivalency between Pre- and Post-Reflex-oDSTs was defined by the similarities in prevalence of a new diagnosis, average SerCort by diagnosis, and SerCort cutoffs by receiver operating characteristic (ROC) curve AUC, and optimal cutoff values. Secondary outcomes included quantification of avoided SerDex measurements to estimate the cost savings associated with Reflex implementation using the US Medicare Reimbursement Rate [20 Accessed 4/1/2025; CPT code 80 299)]. We also evaluated suppressed oDST’s SerDex concentrations to determine if there was a correlation between SerDex level achieved and the degree of suppression of SerCort.

Statistical Analysis

All statistical analyses were performed using Sigmaplot 15.0 (RRID:SCR_003210; https://scicrunch.org/resolver/SCR_003210; Systat Software, Inc, Inpixon, Palo Alto, CA). Continuous variables that were not normally distributed are presented as the median and interquartile ranges. Demographic data were analyzed by two-way analysis of variance and chi-square. Differences in SerCort and SerDex between Pre- and Post-Reflex-oDST groups and CS diagnosis were tested by Mann-Whitney U test and t-test. Optimal cutoff values for each group were determined by ROC analysis using Youden’s index and AUCs were compared with a DeLong test. A P value <0.05 was considered statistically significant. Post-hoc power analyses results are provided where appropriate.

Results

Study Population Characteristics

A total of 616 oDSTs (308 in the Pre-Reflex-oDST and 308 in the Post-Reflex-oDST groups) were screened for eligibility (Fig. 1). After excluding oDSTs with SerDex below the LOQ (n = 12) and repeated oDSTs in the same patient (n = 62), a total of 542 oDSTs were included for analysis. Demographic data are presented in Table 1. The without CS group was younger than the patients with CS group in both Pre- and Post-Reflex-oDST groups. There were no differences in the distribution of race between the groups with and without CS groups and the Pre-vs Post-Reflex-oDST groups. There were more females regardless of diagnosis, but the sex distribution was not different Pre vs Post-Reflex-oDST implementation.

  1. Download: Download high-res image (445KB)
  2. Download: Download full-size image

Figure 1. Flowchart of participants selection from 616 completed oDSTs completed 6 months before (n = 308) and after (n = 308) Reflex implementation. Subsequent oDSTs for the same patient and unmeasurable post-oDST serum dexamethasone (SerDex) (<50 ng/dL [Lower quantifiable limit]) were excluded from analysis. A total of 542 oDSTs were included for analysis and breakdown of CS diagnosis and etiology are shown. ACTH-dependent CS is further broken down to differentiate neoplastic (NH) versus non-neoplastic (NNH) etiologies. CS = Cushing Syndrome; NH = neoplastic hypercortisolism; NNH = nonneoplastic hypercortisolism; oDST = overnight dexamethasone suppression test; SerDex = serum dexamethasone.

Table 1. Demographic Characteristics of Patients Who Underwent oDST Before and After Reflex Implementation

Empty Cell Pre-Reflex Post-Reflex
Yes CS with NNH Yes CS without NNH No CS Yes CS with NNH Yes CS without NNH No CS
N 38 34 223 40 38 241
Age
 Mean (SD) 63.6 (13.8) 63.8 (14.4) 56.0 (15.1)a 63.8 (13.2) 63.1 (13.1) 55.3 (15.5)b
Sex
 Male (%) 6 (15.8) 4 (11.8) 57 (25.6) 11 (27.5) 11 (28.9) 67 (27.8)
 Female (%) 32 (84.2) 30 (88.2) 166 (74.4) 29 (72.5) 27 (71.1) 174 (72.2)
Race
 American Indian or Alaskan Native (%) 0 0 1 (0.4) 0 0 1 (0.4)
 Asian (%) 0 0 3 (1.3) 0 0 1 (0.4)
 Black or African American (%) 5 (13.2) 5 (14.7) 27 (12.2) 6 (15.0) 6 (15.8) 23 (9.5)
 Other (%) 2 (5.3) 1 (2.9) 8 (3.6) 1 (2.5) 1 (2.2) 9 (3.8)
 White (%) 31 (81.5) 28 (82.4) 184 (82.5) 33 (82.5) 31 (82.0) 207 (85.9)
Data are further stratified by Cushing syndrome (CS) diagnosis. Age is presented as mean (SD); sex and race as counts (percentages).
a
Age different from group with CS within Pre-Reflex-oDST (P = 0.005).
b
Age different from group with CS within Post-Reflex-oDST (P < 0.001) regardless of whether NNH cases are included. Male vs female distribution NS (χ2 = 2.533, 3 df, P = 0.469). Race distribution NS (χ2 = 4.37733, 12 df, P = 0.976).
Within the Pre-Reflex-oDST group, 38 patients (14%) were diagnosed with endogenous hypercortisolism (CS) with 13 being ACTH-dependent (9 pituitary and 4 non-neoplastic hypercortisolism) and 25 being ACTH-independent. Within the Post-Reflex-oDST group, 40 patients (14%) were diagnosed with CS with 11 being ACTH-dependent (8 pituitary, 2 non-neoplastic, and 1 ectopic ACTH) and 25 being ACTH-independent.

Prereflex-oDST vs Post-reflex-oDST Analysis

In the Pre-Reflex-oDST group, out of the 261 included subjects, 172 oDSTs (65%) suppressed to <1.6 mcg/dL, meaning that only 89 tests would have undergone reflex SerDex measurements after implementation of Reflex testing. Among these, 51 were determined not to have CS. In the Post-Reflex-oDST group, out of 281 subjects, 191 oDSTs (68%) suppressed to <1.6 mcg/dL, resulting in 90 reflexed SerDex measurements, of which 50 did not have CS. Within the Pre-Reflex-oDST group, there were 38 patients who had CS and in the Post-Reflex-oDST group 40 patients were found to have CS. There was no difference in CS prevalence between the Pre- and Post-Reflex-oDST groups (P = 0.52). Among oDSTs with SerCort levels >1.8 mcg/dL [the conventional cutoff 8], 24/262 (9% false positive) in the Pre-Reflex-oDST group and 21/281 (7% false positive) in the Post-Reflex-oDST group were later determined not to have CS by standard guidelines criteria.8 Reflex implementation resulted in a reduction of the number of SerDex measurements by 68% resulting in cost savings of at least $18.64 per ordered oDST.
In the Pre-Reflex-oDST group, the median SerCort was 1.1 mcg/dL (95% CI: 0.8–1.5) in patients who did not have CS and 3.9 mcg/dL (95% CI: 2.6–7.9) in those who had CS (P < 0.001). In the Post-Reflex-oDST group, the median SerCort was also 1.1 mcg/dL (95% CI: 0.8–1.5) in patients who did not have CS and 2.9 mcg/dL (95% CI: 2.6–7.9) in those who had CS (P < 0.001) (Fig. 2). There was no difference comparing the CS diagnosis status between Pre- and Post-Reflex-oDST groups. There was still no difference in median SerCort in patients with CS when comparing the Pre- and Post-Reflex-oDST groups with NNH cases excluded (P = 0.269). Furthermore, the NNH patients were biochemically indistinguishable from patients with neoplastic hypercortisolism (NH). In fact, when we compared post-oDST cortisol between NH (3.6 [2.4-7.7; N = 72) and NNH (3.4 [2.7-8.5; N = 6]), the P value was 0.729. There was also no difference between CS NH with NNH included vs CS NH excluding NH within the Pre-Reflex-oDST group and within the Post-Reflex-oDST group.

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Figure 2. Comparison of oDST serum cortisol (SerCort) levels Pre-vs Post-Reflex-oDST implementation. The medians are further stratified based on whether the patient did not have Cushing Syndrome (No CS – red) and those who had CS (Yes CS – blue). Each box represents the interquartile range and the horizontal line within represents the median. The error bars represent the 10th-90th percentiles and dots represent results outlying the 10th-90th percentiles. a, denotes significant difference of median SerCort levels between no CS vs CS in both Pre- and Post-Reflex-oDST groups (P < 0.001). There was no difference in medians following exclusion of NNH from Yes CS in both Pre- and Post-Reflex-oDST groups (P = 0.269). CS = Cushing Syndrome; NH = neoplastic hypercortisolism; NNH = nonneoplastic hypercortisolism; oDST = overnight dexamethasone suppression test; SerDex = serum dexamethasone.

A power analysis was performed to compare Pre-reflex oDST to Post-Reflex oDST SerCort values in patients with CS with the null hypothesis that there was no effect of implementing the reflex approach. Assuming a clinically significant effect of implementing the reflex test (a difference of oDST serum cortisol of 2 mcg/dL with a conservative SD of the difference of 2.5 mcg/dL) with sample sizes of 38 Pre-Reflex and 40 Post-Reflex in our study, the power was 0.937 with an alpha of 0.050. With an expected difference in serum cortisol of 0.8 mcg/dL and an SD of the difference of 1.0 mcg/dL, the power was 0.937 with an alpha of 0.05. Considering that the patients before and after reflex implementation were from the same population, institution, and ordering clinicians, we are confident that the Reflex testing did not influence the oDST performance and the laboratory data outcomes.
There was also no difference in SerCort between Pre- and Post-Reflex-oDST tests in the predictive performance for CS. The ROC curve AUC of SerCort in both the Pre- and Post-Reflex periods was 0.97. The optimal ROC cutoff of SerCort in the Pre-Reflex-oDST group was 2.1 mcg/dL (sensitivity 92%, specificity 93%). The optimal ROC cutoff of SerCort in the Post-Reflex-oDST group was 2.1 mcg/dL (sensitivity 95%, specificity 93%; not different from Pre-Reflex-oDST group) (Table 2). When NNH cases were excluded and ROC curves were rerun, there was no difference in ROC curve area, optimal SerCort cutoff values, or sensitivity and specificity in Pre- and Post-Reflex-oDST groups.

Table 2. Receiver operating characteristic (ROC) analysis of oDST SerCort results for Pre-vs Post-Reflex-oDST groups. A. Analysis including NNH patients are at the top; B. Analysis excluding NNH patients are at the bottom

Empty Cell Pre-Reflex Post-Reflex
A. Including NNH patients
 ROC Curve Area (SE) 0.97 (0.01) 0.97 (0.01)
 95% confidence interval 0.96-0.99 0.95-0.99
 P value P < 0.0001 P < 0.0001
 Sample size: No CS/Yes CS 223/38 241/40
Cutoff Sensitivity Specificity Cutoff Sensitivity Specificity
 Optimal 8 AM SerCort Cutoff (mcg/dL) 2.1 92% 93% 2.1 95% 93%
Empty Cell Pre-Reflex without NNH Post-Reflex without NNH
B. Excluding NNH patients
 ROC curve area (SE) 0.97 (0.01) 0.97 (0.01)
 95% confidence interval 0.96-0.99 0.95-0.99
 P Value P < 0.0001 P < 0.0001
 Sample size: No CS/Yes CS 223/34 241/38
Cutoff Sensitivity Specificity Cutoff Sensitivity Specificity
 Optimal 8 AM SerCort Cutoff (mcg/dL) 2.1 91% 92% 2.1 95% 93%
Area under the curve (AUC) was calculated and compared with a DeLong test (AUC = 0.97, P < 0.0001, for both). Using Youden’s Index, optimal cutoff values were determined by maximizing sensitivity and specificity. When ROC rerun without NNH, the sensitivity and specificity did not change in both Pre- and Post-oDST-Reflex groups.

Prereflex-oDST Comparison of SerDex vs SerCort

In comparing the Pre-Reflex-oDST group SerDex results of <140 ng/dL versus >140 ng/dL (the lower reference limit of the SerDex assay), median SerCort was 1.2 mcg/dL and 1.1 mcg/dL, respectively (P = 0.621) (Fig. 3A). The scatter regression plot illustrates that there was no relationship between SerDex (ng/dL) and SerCort (mcg/dL) by CS diagnosis (Fig. 3B). Each point represents an individual oDST, with red indicating patients who did not have CS (n = 223) and blue indicating those who had CS (n = 38). In patients who did not have CS, SerDex ranged from 61.5 to 908.9 ng/dL whereas in patients who had CS, SerDex ranged from 96.3 to 646.0 ng/dL. Theoretical linear regression lines are shown. In fact, no significant correlation between SerDex and SerCort was found in the group who did not have CS (r = 0.002; P = 0.972) nor the group who had CS (r = 0.114; P = 0.494) so the regression lines are only provided for visual clarity. When NNH cases were excluded, there was still no correlation between SerDex and SerCort in patients with CS (P = 0.432). Furthermore, analysis of only NNH cases also showed no correlation between SerDex and SerCort (P = 0.871).

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Figure 3. Comparison of post-oDST serum cortisol (SerCort) to serum dexamethasone (SerDex) in Pre-Reflex-oDST group. (A) Comparison of post-oDST SerCort and SerDex for no CS patients in the Pre-Reflex-oDST group. SerCort in the No CS patients stratified by the ARUP Lower limit of the reference range for SerDex (140 ng/dL). There was no significant difference in median SerCort with the SerDex <140 ng/dL (N = 20) and >140 ng/dL (N = 203) groups (1.2 vs 1.1 mcg/dL, respectively, P = 0.621). (B) Comparison of all Pre-Reflex-oDST group oDSTs stratified by patients with (blue) and without (red) CS. The black vertical solid line represents the limit of quantitation (LOQ) of SerDex (50 ng/dL). There was no correlation of SerDex and SerCort achieved in either group (see text for specifics). There was no correlation when NNH cases were removed as well (P = 0.432). CS = Cushing Syndrome; NH = neoplastic hypercortisolism; NNH = nonneoplastic hypercortisolism; oDST = overnight dexamethasone suppression test; SerDex = serum dexamethasone.

Discussion

The purpose of this study was to assess the usefulness of implementing a protocol to only reflex samples for the measurement of SerDex that do not suppress post-oDST SerCort (the “Reflex-oDST”) using a very conservative 8 AM cortisol cutoff. The major findings were as follows: (a) There was no detrimental effect on oDST-suppressed SerCort levels with the implementation of Reflex testing. That is, the SerCort levels in patients without CS were not different from each other Pre- and Post-Reflex-oDST. The same was found in the group who had CS. (b) There were comparable optimal SerCort ROC cutoff values in the Pre- and Post-Reflex-oDST groups, which also demonstrated a lack of a detrimental effect on test performance. (c) The Reflex protocol eliminated the need for SerDex measurement in 68% of oDSTs ordered without reducing the accuracy of the oDST. (d) No correlation was found between SerCort and SerDex indicating that the SerDex concentration achieved may not be an important factor in assessing the accuracy of the oDST; rather the presence of a detectible SerDex may be sufficient (ie, a Boolean function).
When comparing the Pre- and Post-Reflex-oDST groups, we observed no difference in patient population characteristics, including the prevalence of positive oDSTs, CS diagnosis, and CS etiology. Notably, patients who had CS were older than those who did not have CS in both groups. Ueland et al demonstrated a positive correlation between age and oDST SerCort, which may partially explain the significantly higher age in patients with CS.17 Age-related changes in HPA axis dynamics likely contributed to an increased prevalence of unsuppressed results.21 Additionally, older patients often have more comorbidities, which may lead clinicians to have a lower threshold for further evaluation, increasing the likelihood of identifying CS in this population.
To demonstrate that implementation of oDST Reflex protocol did not negatively affect diagnostic performance, we compared SerCort levels and false positive rates defined by unsuppressed SerCort later determined not to have CS through further testing. We found no difference in SerCort levels before and after implementation of Reflex testing (within the patients who did not have CS and within the patients who had CS). We observed a 7% false positive rate in the Pre-Reflex-oDST group that was comparable to 10% to 14% in previous studies.17,22 We found a comparable 9% false positive rate in the Post-Reflex-oDST group demonstrating preservation of test performance with Reflex implementation. These data are similar to those theorized by Genere et al18 and we have now validated the approach.
Implementation of reflex SerDex testing reduced the number of oDST SerDex measurements by ∼68% and resulted in a cost savings of $18.64 per ordered oDST using Medicare Clinical Diagnostic Laboratory Test reimbursement data, though this likely underestimates the true financial burden as patients are often billed at higher rates.20 Therefore, the Reflex protocol not only did not have a detrimental effect on test performance but also improved efficiency by reducing unnecessary costs and resource utilization. It is also important to point out that the approach is likely to save additional costs like avoiding additional analysis such as unnecessary plasma ACTH, salivary cortisols, UFCs, and even MRIs.
For the purposes of diagnosis of CS, we used accepted oDST SerCort cutoff of ≤1.8 mcg/dL (50 nmol/L) that yields a sensitivity of 95% and a specificity of ∼80%.10,12 We, like most clinicians, utilize a ≤1.8 mcg/dL SerCort diagnostic cutoff with concomitant measurement of SerDex to improve specificity by reducing false positives due to subtherapeutic dexamethasone levels. For the current study, we used the cutoff of 1.6 mcg/dL to determine when to reflex samples for SerDex in the Post-Reflex-oDST group to be as conservative as possible particularly when considering biological variability around a value of 1.8 mcg/dL.
To demonstrate equivalency, we found SerCort cutoff values that maximize specificity based on oDSTs performed similarly in both Pre- and Post-Reflex-oDST groups. Our calculated cutoff value for SerCort Pre- and Post-Reflex-oDST validated that a small increase in SerCort oDST cutoffs results in an increase in specificity to >95% (utilizing Youden’s index). However, given that the oDST is a screening test, sensitivity should be prioritized. While higher specificity reduces false positives, it may also increase the risk of missing mild CS cases. Notably, it has been shown that concomitant SerDex measurement reduces false positives by 20%,17 reinforcing the benefit of its inclusion.
To be conservative, we reanalyzed all of the data excluding the 6 patients with NNH. This had no effect on any of the outcomes. In fact, the oDST 8AM cortisol was almost identical when comparing NH to NNH patients further emphasizing the clinical challenge of distinguishing these highly overlapping groups in terms of their laboratory results.
Similar to previous studies, we found a broad range of SerDex levels across all oDSTs with minimal or no correlation to SerCort.9,23,24 To maximize specificity, Ueland et al proposed a SerDex cutoff value of 130 ng/dL [0.130 mcg/dL (3.3 nmol/L)], while Ceccato et al proposed a SerDex cutoff of 180 ng/dL [0.180 mcg/dL (4.5 nmol/L)] prioritizing specificity.17,25 SerCort levels the morning after taking 1 mg of dexamethasone (8 AM–9 AM) reflects delayed glucocorticoid negative feedback at the pituitary and hypothalamus that takes at least 1-2 h to be fully expressed.26 Therefore, differences in measured SerDex at 8 AM the morning after the 1 mg dose ingestion reflect the variability of HPA axis feedback sensitivity and the timing of the pharmacokinetics of dexamethasone metabolism that can be influenced by several factors, such as age, BMI, and concomitant medications.11,13,27,28 Our findings suggest that any detectible SerDex level (>50 ng/dL in our study), even if below the established reference interval (eg,140–295 ng/dL), is sufficient for a valid test and probably does not require repetition. That said, it may still be prudent to repeat the test if the SerCort does not suppress to <1.8 mcg/dL and the SerDex is < 100 ng/dL particularly with a high index of suspicion for CS.24 oDSTs with SerDex values below the laboratory’s detectable limits (LOQ) should still be considered invalid, most likely due to dexamethasone noncompliance or differences in absorption and/or pharmacokinetics as described above. It is also important to point out that the LOQ for some serum dexamethasone assays are higher than the assay we used, which makes this point even more important.18
An important final point is the practicability of the approach. Why not just store the serum cortisol sample and only test it for serum dexamethasone if requested18? This is very challenging for clinicians in practice who work with a variety of reference laboratories and are often not aware of the SerCort oDST results until after the sample has been discarded. By building the reflex approach into the ordering system, this problem is avoided as it does not require the intervention of the ordering clinician, thereby reducing the administrative burden while reducing laboratory costs. The significance of our novel study is confirmed by the fact that, subsequent to our implementation, a major reference laboratory has recently established a similar Reflex oDST test (https://www.labcorp.com/tests/503990/cortisol-dexamethasone-suppression-test-with-reflex-to-dexamethasone). Others are likely to follow. Our study, which is the first of its kind to our knowledge, should give the clinician assurance that this approach is appropriate. At our relatively small laboratory, this results in annual cost savings of $11,500 per year just for the dexamethasone levels not needed. The savings for each institutional and provider would obviously be different depending on their patient mix and test volumes.

Conclusion

We demonstrated that the implementation of the Reflex protocol avoided unnecessary SerDex measurements without affecting test performance, highlighting its utility from both a resource and cost standpoint. Additionally, our findings suggest that any quantifiable SerDex level, even if below the established reference interval, does not invalidate the oDST.

Disclosure

Dr Carroll is an Editorial Board Member of this journal and was not involved in the editorial review or the decision to publish this article. Dr Nerenz receives research funding from Abbott Laboratories.

Acknowledgment

The authors thank the personnel at Wisconsin Diagnostic Laboratories for their work to develop and implement the Reflex Testing protocol. J.D.K. is a recipient of the 2024 Research Experience for Graduate and Medical Students (REGMS) award from the Endocrine Society (US).

References

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Improved Noninvasive Diagnostic Evaluations in Treatment-Naïve Adrenocorticotropic Hormone (ACTH)-Dependent Cushing’s Syndrome

Posted on July 24, 2025 by MaryO

Abstract

Background

Bilateral inferior petrosal sinus sampling (BIPSS) is important in the differential diagnosis of adrenocorticotropic hormone (ACTH)-dependent Cushing’s syndrome, but BIPSS is invasive and is not reliable on tumor lateralization. Thus, we evaluated the noninvasive diagnostic evaluations, high-dose dexamethasone suppression test (HDDST) combined with different pituitary MRI scans (conventional contrast-enhanced MRI [cMRI], dynamic contrast-enhanced MRI [dMRI], and high-resolution contrast-enhanced MRI [hrMRI]), by comparison with BIPSS.

Methods

We retrospectively analyzed 95 patients with ACTH-dependent Cushing’s syndrome who underwent HDDST, preoperative MRI scans (cMRI, dMRI and hrMRI) and BIPSS in our hospital between January 2016 and December 2021. The diagnostic performance of HDDST combined with cMRI (HDDST + cMRI), HDDST + dMRI and HDDST + hrMRI, and BIPSS was evaluated, including the sensitivity of identifying pituitary adenomas and the tumor lateralization accuracy.

Results

Compared with BIPSS (AUC, 0.98; 95%CI: 0.93, 1.00), the diagnostic performance of HDDST + hrMRI was comparable in both neuroradiologist 1 (AUC, 0.95; 95%CI: 0.89, 0.99; P = 0.129) and neuroradiologist 2 (AUC, 0.98; 95%CI: 0.92, 1.00; P = 0.707). For tumor lateralization accuracy, HDDST + hrMRI (90.6-95.3%) were significantly higher than that of BIPSS (24.7%, P < 0.001).

Conclusions

In patients with ACTH-dependent Cushing’s syndrome, HDDST + hrMRI, as noninvasive diagnostic evaluations, achieves high diagnostic performance comparable with gold standard (BIPSS), and it is superior to BIPSS in terms of tumor lateralization accuracy.

Peer Review reports

Background

Cushing’s syndrome is associated with debilitating morbidity and increased mortality [1]. Adrenocorticotropic hormone (ACTH)-dependent Cushing’s syndrome is characterized by ACTH hypersecretion. Bilateral inferior petrosal sinus sampling (BIPSS) is regarded as the gold standard to distinguish pituitary ACTH secretion (also known as Cushing’s disease) from ectopic ACTH syndrome (EAS) [1, 2]. However, BIPSS is invasive and is not reliable on tumor lateralization [3, 4]. Thus, it is important to improve the diagnostic performance of noninvasive evaluations with high sensitivity and tumor lateralization accuracy.

Current noninvasive evaluations in the differential diagnosis of ACTH-dependent Cushing’s syndrome include high-dose dexamethasone suppression test (HDDST), the CRH stimulation test and pituitary MRI. However, due to the non-availability of CRH for testing, the sensitivities of current available noninvasive evaluations in identifying ACTH-secreting pituitary adenomas cannot satisfy the clinical needs. Conventional contrast-enhanced MRI (cMRI) and dynamic contrast-enhanced MRI (dMRI) with two-dimensional (2D) fast spin echo (FSE) sequence is routinely used, and only 50–66% of the ACTH-secreting pituitary adenomas can be correctly detected [5, 6]. Recently, by using 3D spoiled gradient recalled (SPGR) sequence, high-resolution contrast-enhanced MRI (hrMRI) has increased the sensitivity to up to 80% [7,8,9]. However, these noninvasive evaluations are still inferior to BIPSS, the sensitivity and specificity of which is about 90–95% [10,11,12,13]. With the development of 3D FSE sequence, superior image quality with diminished artifact has been achieved, providing a reliable alternative to detect pituitary adenomas [14]. Previous studies have shown that hrMRI using 3D FSE sequence has high diagnostic performance for identifying pituitary adenomas [15, 16]. To our knowledge, no study has investigated the diagnostic performance of HDDST combined with hrMRI using 3D FSE sequence (HDDST + hrMRI) in patients with Cushing’s syndrome, and whether it can avoid unnecessary BIPSS procedure.

The aim of this study is to evaluate the diagnostic performance of HDDST + hrMRI by comparison with BIPSS in patients with ACTH-dependent Cushing’s syndrome.

Methods

This study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by the Institutional Review Board of Peking Union Medical College Hospital. Informed consent was waived in this study because it was a retrospective, non-interventional, and observational study. Clinical trial number is not applicable.

Study design and patient population

We retrospectively reviewed the medical records and imaging studies from January 2016 to December 2021, and 232 consecutive patients with ACTH-dependent Cushing’s syndrome, who underwent HDDST, cMRI, dMRI, hrMRI and BIPSS, were enrolled in the current study. A total of 137 patients were excluded from the study because of prior pituitary surgery (n = 122) or lack of histopathology due to no pituitary surgery in our hospital (n = 15). Finally, 95 patients were included in the current study (Fig. 1) and all the patients included were confirmed by histopathology or by clinical remission after surgical resection of the ACTH-secreting lesion. In the current study, all the patients with Cushing’s disease achieved clinical remission after surgical resection of the ACTH-secreting lesion. All the patients with EAS underwent contrast-enhanced thoracic and abdominal CT to identify the ACTH-secreting lesion. The clinical decision-making process was consistent with the previous study [1].

Fig. 1
figure 1

Flowchart of patient inclusion/exclusion process. ACTH = adrenocorticotropic hormone, BIPSS = bilateral inferior petrosal sinus sampling; cMRI = conventional contrast-enhanced MRI, dMRI = dynamic enhanced MRI, HDDST = high-dose dexamethasone suppression test, hrMRI = high-resolution contrast-enhanced MRI, NPV = negative predictive value, PPV = positive predictive value

HDDST

As previously described [17], the average 24-hour urinary free cortisol (24hUFC) level of 2 days before HDDST was recorded as baseline. Then, 2 mg dexamethasone was administered orally every 6 h for 2 days, and the 24hUFC level of the second day was measured. When the ratio of 24hUFC on the second day after HDDST to 24hUFC at baseline was less than 50%, the suppression in HDDST was marked as positive in the current study.

BIPSS

BIPSS was performed according to Doppman et al. [18]. Blood samples were collected from peripheral veins and bilateral inferior petrosal sinuses (IPSs) at multiple time points (0, 3, 5 and 10 min) after the introduction of 10 µg desmopressin [19]. An IPS to peripheral ACTH ratio of ≥ 2.0 at baseline or ≥ 3.0 after desmopressin stimulation at any time point [20] was marked as positive in the current study. Furthermore, tumor lateralization was predicted by an intersinus ratio of ≥ 1.4 [20].

Imaging

All the images were acquired on a 3.0 Tesla MR scanner (Discovery MR750w, GE Healthcare) using an 8-channel head coil. Detailed acquisition parameters and sequence order before and after contrast injection (gadopentetate dimeglumine [Gd-DTPA] at 0.05 mmol/kg [0.1 mL/kg] with a flow rate of 2 mL/s followed by a 10-mL saline solution flush) were as follows: coronal 2D FSE T2WI (field of view [FOV] = 20 cm × 20 cm, slice thickness = 4 mm, slice spacing = 1 mm, repetition time/echo time [TR/TE] = 4100/90 ms, number of excitation [NEX] = 1.2, matrix = 320 × 320, scan time = 49s), coronal 2D FSE T1WI (FOV = 18 cm × 16.2 cm, slice thickness = 3 mm, slice spacing = 0.6 mm, TR/TE = 400/12 ms, NEX = 2, matrix = 256 × 192, scan time = 49s), sagittal fat-saturated 3D FSE T1WI (FOV = 16.5 cm × 16.5 cm, slice thickness = 3 mm, slice spacing = 0, TR/TE = 460/16 ms, NEX = 2, matrix = 256 × 224, scan time = 60s), dynamic contrast-enhanced coronal 2D FSE T1WI (FOV = 19 cm × 17.1 cm, slice thickness = 2 mm, slice spacing = 0.5 mm, TR/TE = 375/14 ms, NEX = 1, matrix = 288 × 192, scan time = 23s/phase × 6 phases), contrast-enhanced coronal 2D FSE T1WI, contrast-enhanced sagittal fat-saturated 3D FSE T1WI, and contrast-enhanced coronal fat-saturated 3D FSE T1WI (FOV = 15.2 cm × 15.2 cm, slice thickness = 1.2 mm, slice spacing = -0.6 mm, TR/TE = 390/15 ms, NEX = 6, matrix = 256 × 256, scan time = 4 min 30s).

Images were independently evaluated by two experienced neuroradiologists (with 25 and 16 years of experience in neuroradiology, respectively). Both neuroradiologists were blinded to the clinical information of the patients. The image order of cMRI, dMRI and hrMRI was randomized. The detection of pituitary adenomas was scored using a 3-point scale (0 = poor, 1 = fair, 2 = excellent). Scores of 1 or 2 represented a successful pituitary adenoma detection. The gold standard was the histopathology, and the diameter and the location of lesions were recorded on the sequence where identified.

The signal-to-noise ratio (SNR) and contrast-to-noise ratio (CNR) were calculated as follows: SNR = SIadenoma / SDbackground, CNR = |SIpituitary – SIadenoma| / SDbackground. SIpituitary and SIadenoma were defined as the mean signal intensity of the pituitary gland and the pituitary adenoma, respectively. SDbackground was defined as the standard deviation of the signal intensity of the background. CNR was recorded as 0 when no pituitary adenoma was identified. Figure 2 showed the calculation of SNR and CNR using an operator defined region of interest.

Fig. 2

figure 2

The calculation of SNR and CNR using an operator defined region of interest. CNR = contrast-to-noise ratio, SD = standard deviation, SI = signal intensity, SNR = signal-to-noise ratio

Statistical analysis

The κ analysis was conducted to assess the interobserver agreements. The κ value was interpreted as follows: below 0.20, slight agreement; 0.21–0.40, fair agreement; 0.41–0.60, moderate agreement; 0.61–0.80, substantial agreement; greater than 0.80, almost perfect agreement.

To assess the diagnostic performance of different evaluations, the receiver operating characteristic curves were plotted and the area under curves (AUCs) were compared between noninvasive and invasive evaluations for each neuroradiologist by using the DeLong test. Sensitivity, specificity, positive predictive value, and negative predictive value were calculated. The Friedman’s test was used to evaluate the SNR and CNR measurements as well as conspicuity scores of pituitary adenomas between MR protocols, and the Wilcoxon signed-rank test was used for pairwise comparison. The McNemar’s test was used to evaluate the tumor lateralization accuracy. A P value of less than 0.05 was considered statistically significant. A stricter P value of less than 0.017 was considered statistically significant after Bonferroni correction. Statistical analysis was performed using MedCalc Statistical Software (version 23.0.2) and SPSS Statistics (version 22.0).

Results

Clinical characteristics

The clinical characteristics of the 95 patients with Cushing’s syndrome were shown in Table 1. There were 85 patients (median age, 38 years; interquartile range [IQR], 29–51 years; 55 females [65%]) with Cushing’s disease and 10 patients (median age, 39 years; IQR, 30–47 years; 5 females [50%]) with EAS. Of the 85 patients with Cushing’s disease, the median diameter of pituitary adenomas was 5 mm (IQR, 4–5 mm), ranging from 3 to 28 mm. Among them, 80 patients had microadenomas (less than 10 mm in size). Of the ten patients with EAS, one patient had an ovarian carcinoid tumor found by abdominal CT, others had pulmonary carcinoid tumors found by thoracic CT as the cause of Cushing’s syndrome. None of the patients with EAS had a lesion in the pituitary.

Table 1 Clinical characteristics of the patients

Diagnostic performance noninvasive and invasive evaluations

The inter-observer agreements between two neuroradiologists were moderate on cMRI (κ = 0.597), moderate on dMRI (κ = 0.595), and almost perfect on hrMRI (κ = 0.850), respectively.

The diagnostic performance of noninvasive and invasive evaluations was shown in Table 2. Compared with BIPSS (AUC, 0.98; 95%CI: 0.93, 1.00), the diagnostic performance of HDDST + hrMRI was comparable in both neuroradiologist 1 (AUC, 0.95; 95%CI: 0.89, 0.99; P = 0.129) and neuroradiologist 2 (AUC, 0.98; 95%CI: 0.92, 1.00; P = 0.707). However, the diagnostic performance of HDDST + cMRI and HDDST + dMRI was inferior to BIPSS (P ≤ 0.001 for all). No difference was found between HDDST + cMRI and HDDST + dMRI in neuroradiologist 1 (P = 0.050) and neuroradiologist 2 (P = 0.353).

Table 2 The diagnostic performance of noninvasive and invasive evaluations

Figures 3 and 4 showed that microadenomas were correctly diagnosed on hrMRI, but missed on cMRI or dMRI.

Fig. 3

figure 3

Images in a patient with Cushing’s disease. The lesion is missed on (a) coronal contrast-enhanced T1-weighted image and (b) coronal dynamic contrast-enhanced T1-weighted image obtained with two-dimensional (2D) fast spin echo (FSE) sequence. (c) Coronal contrast-enhanced T1-weighted image on high-resolution MRI obtained with 3D FSE sequence shows a round pituitary microadenoma measuring approximately 4 mm with delayed enhancement on the left side of the pituitary gland

Fig. 4

figure 4

Images in a patient with Cushing’s disease. The lesion is missed on (a) coronal contrast-enhanced T1-weighted image and (b) coronal dynamic contrast-enhanced T1-weighted image obtained with two-dimensional (2D) fast spin echo (FSE) sequence. (c) Coronal contrast-enhanced T1-weighted image on high-resolution MRI obtained with 3D FSE sequence shows a round pituitary microadenoma measuring approximately 5 mm with delayed enhancement on the left side of the pituitary gland

Further, subgroup analysis was conducted in 85 patients with Cushing’s disease. The conspicuity scores of pituitary adenomas on cMRI, dMRI and hrMRI were shown in Table 3. Significant differences between three MR protocols were found in neuroradiologist 1 and neuroradiologist 2 (P < 0.001 for both). Pairwise comparison showed no difference between cMRI and dMRI in neuroradiologist 1 (P = 0.732) and neuroradiologist 2 (P = 0.130). However, hrMRI had significantly higher scores than cMRI and dMRI in neuroradiologist 1 and neuroradiologist 2 (P < 0.001 for all). The SNR on cMRI, dMRI and hrMRI were 64.8 (IQR, 50.8–97.0), 42.4 (IQR, 30.2–57.0) and 65.1 (IQR, 51.9–92.4), respectively. The SNR on cMRI and hrMRI were similar (P = 0.759), but they were higher than that of dMRI (P < 0.001 for both). The CNR on cMRI, dMRI and hrMRI were27.0 (IQR, 17.8–43.8), 26.4 (IQR, 17.7–37.5), and 29.7 (IQR, 21.1–45.1), respectively. The CNR were comparable (P = 0.159).

Table 3 Conspicuity scores of pituitary adenomas on MRI

The comparison of tumor lateralization accuracy was shown in Table 4. Because HDDST has no role to identify the tumor lateralization, the tumor lateralization of noninvasive evaluations was only based on MRI. The sensitivity of BIPSS was 96.5% (82/85), comparable to those of hrMRI in neuroradiologist 1 (90.6%, P = 0.227) and neuroradiologist 2 (95.3%, P > 0.99). However, for tumor lateralization accuracy, 36 patients had BIPSS lateralization predicted by an intersinus ratio of ≥ 1.4 [20], and 21 patients had BIPSS lateralization that were concordant in laterality with surgery. The tumor lateralization accuracy was 58.3% (21/36).

Table 4 Tumor lateralization accuracy comparison

In the whole population, the tumor lateralization accuracy of BIPSS in total was 24.7% (21/85), which is significantly lower than those of hrMRI in neuroradiologist 1 (90.6%, P < 0.001) and neuroradiologist 2 (95.3%, P < 0.001).

Discussion

In patients with ACTH-dependent Cushing’s syndrome, it is crucial but challenging to distinguish pituitary secretion from ectopic ACTH secretion. In the current study, the diagnostic performance of noninvasive evaluations, HDDST + hrMRI, is comparable to BIPSS. Moreover, it is superior to BIPSS in terms of tumor lateralization.

No consensus agreement has been made that whether BIPSS should be performed in all the patients with suspected Cushing’s disease, although BIPSS is the gold standard with high sensitivity and specificity, which is about 90–95% [10,11,12,13]. On the one hand, about 10–40% of the population harbor nonfunctioning pituitary adenomas [13, 21], which may lead to false-positive results without centralizing BIPSS results. On the other hand, BIPSS is invasive and is not reliable on tumor lateralization. BIPSS will be bypassed when the tumor is greater than 6 mm in pituitary MRI and the patient has a classical presentation and dynamic biochemical results consistent with Cushing’s disease [13].

Noninvasive evaluations have comparable sensitivity to BIPSS for identifying pituitary adenomas in patients with Cushing’s disease. With the development of MRI technology, 3D FSE sequence provides a reliable alternative to detect pituitary adenomas [14]. The 3D FSE sequence overcomes the disadvantages of 3D SPGR sequence, such as bright blood and magnetic susceptibility [22, 23]. By using black blood in 3D FSE sequence, an obvious contrast between the pituitary and the cavernous sinus can be observed. By using fat saturation after enhancement, the hyperintensity of adjacent fat-containing tissue can be suppressed. All these mentioned above can facilitating the identification of pituitary adenomas. The sensitivity of hrMRI using 3D FSE sequence ranges from 87.7 to 93.8%, depending on radiologists with different experience levels [16]. Compared with traditional 2D FSE sequence acquiring images with 2- to 3-mm slice thickness, hrMRI using 3D FSE sequence acquiring images with 1.2-mm slice thickness can dramatically reduce the partial volume averaging effect, improving the identification of the microadenomas [15]. The trade-off between spatial resolution and image noise is challenging in pituitary MRI [24]. Previous studies have proved that hrMRI has high signal-to-noise ratio and contrast-to-noise ratio [15, 16], and sufficient contrast between pituitary adenomas and the pituitary gland could help to improve the identification of pituitary adenomas. In the current study, the conspicuity scores of hrMRI are significantly higher than those of cMRI and dMRI, supporting that hrMRI is reliable on identifying pituitary lesions. Besides, the diagnosis of Cushing’s disease cannot be made depending on the results of hrMRI alone. Given that there is a population with accidental adenomas when imaging, most of which are nonfunctioning pituitary adenomas, the results of HDDST will help rule out. In the current study, all the patients who underwent surgery had positive histopathology results, which means that no pituitary incidentalomas were found in this population. This might be caused by the relatively small sample size. Eighty patients with Cushing’s disease have microadenomas, and the median diameter at surgery is about 5 mm, consistent with previous studies [25, 26]. All these mentioned above makes it more difficult to identify the lesions in the current study. However, the sensitivity of HDDST + hrMRI in the current study is up to 95.3%, comparable to the gold standard.

Noninvasive evaluations have significantly higher tumor lateralization accuracy than BIPSS. According to the guideline, surgery is the first-line treatment [3]. Precise location of the pituitary adenoma before surgery can dramatically improve the postoperative remission rate [27]. However, the tumor lateralization accuracy of BIPSS, less than 80% in previous studies [19, 28, 29], cannot satisfy the clinical need. According to previous studies, the cut-off value for tumor lateralization was set as an intersinus ratio of ≥ 1.4 [20], and the accuracy of lateralization by BIPSS ranged from 48.0 to 78.7% [19, 28, 29]. In the current study, 36 patients had BIPSS lateralization and 21 patients had BIPSS lateralization that were concordant in laterality with surgery. The tumor lateralization accuracy was 58.3%, consistent with previous studies [19, 28, 29]. However, the aim of our study is to evaluate the diagnostic performance of BIPSS in all the patients underwent BIPSS, therefore, the tumor lateralization accuracy of BIPSS in total was only 24.7% (21/85). In our study, many patients have positive BIPSS results with an intersinus ratio of < 1.4, resulting in the low tumor lateralization accuracy of BIPSS. One possible reason might be that desmopressin is not so effective. Another possible reason for low tumor lateralization accuracy of BIPSS is that IPSs have considerable anatomy variations. A previous study suggests that BIPSS results are much improved when venous drainage is symmetric [30]. Patients with asymmetric IPSs have dominant venous drainage, and when the dominant side of venous drainage is discordant with the side of the lesion, BIPSS will fail in tumor lateralization [30]. Failure in tumor lateralization will result in multiple incisions into the pituitary in search of adenoma or hemi- or subtotal hypophysectomy, increasing the risk of complications and reducing the remission rate [31]. In total, only 24.7% of the patients have a BIPSS lateralization that were concordant in laterality with surgery, whereas the tumor lateralization accuracy of HDDST + hrMRI is superior to BIPSS with statistical significance.

Limitations of the study included its retrospective nature. The bias may be introduced during the patient inclusion/exclusion process. Patients lack of any of preoperative MRI scans, HDDST, or BIPSS have not been included in the current study. Some patients will bypass hrMRI as well as BIPSS when they have obvious pituitary adenomas on cMRI and dMRI. The diagnostic performance of these evaluations might be better with the inclusion of these patients. Second, the sample size in our current study is relatively small. Because this is a single institutional study and Cushing’s syndrome is a rare disease. The relatively small sample size may limit the conclusions regarding the diagnostic performance of hrMRI for differentiating ectopic from pituitary sources of ACTH. A larger population from multicenter is needed for future study. Besides, a large portion of patients with prior pituitary surgery have been excluded. The imaging findings of these patients are more complicated and hrMRI may show more advantages than routine sequences in this population.

Conclusions

In conclusion, as noninvasive diagnostic evaluations, HDDST + hrMRI achieves high diagnostic performance comparable with gold standard (BIPSS), and it is superior to BIPSS in terms of tumor lateralization accuracy in patients with ACTH-dependent Cushing’s syndrome.

Data availability

The datasets used and analyzed during the current study are available from the corresponding author upon reasonable request.

Abbreviations

24hUFC:
24-hour urinary free cortisol
2D:
Two-dimensional
3D:
Three-dimensional
ACTH:
Adrenocorticotropic hormone
AUC:
Area under curve
BIPSS:
Bilateral inferior petrosal sinus sampling
cMRI:
Contrast-enhanced MRI
CNR:
Contrast-to-noise ratio
dMRI:
Dynamic contrast-enhanced MRI
EAS:
Ectopic adrenocorticotropic hormone syndrome
FSE:
Fast spin echo
HDDST:
High-dose dexamethasone suppression test
hrMRI:
High-resolution contrast-enhanced MRI
IPS:
Inferior petrosal sinus
IQR:
Interquartile range
SNR:
Signal-to-noise ratio
SPGR:
Spoiled gradient recalled

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Acknowledgements

We thank Dr. Kai Sun, Medical Research Center, Peking Union Medical College Hospital, for his guidance on the statistical analysis in this study. We thank all the patients who participated in this study.

Funding

This study was supported by the National Natural Science Foundation of China (grants 82371946 and 82071899), the Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences (grant 2021-I2M-1-025), and the National High Level Hospital Clinical Research Funding (grants 2022-PUMCH-B-067 and 2022-PUMCH-B-114). The funding played no role in the design of the study and collection, analysis, and interpretation of data and in writing the manuscript.

Author information

Authors and Affiliations

  1. Department of Radiology, Peking Union Medical College Hospital, Chinese Academe of Medical Sciences and Peking Union Medical College, No.1 Shuaifuyuan Wangfujing Dongcheng Distinct, Beijing, 100730, China

    Zeyu Liu, Bo Hou, Hui You, Mingli Li & Feng Feng

  2. Department of Endocrinology, Peking Union Medical College Hospital, Chinese Academe of Medical Sciences and Peking Union Medical College, No.1 Shuaifuyuan Wangfujing Dongcheng Distinct, Beijing, 100730, China

    Lin Lu, Lian Duan & Huijuan Zhu

  3. Department of Neurosurgery, Peking Union Medical College Hospital, Chinese Academe of Medical Sciences and Peking Union Medical College, No.1 Shuaifuyuan Wangfujing Dongcheng Distinct, Beijing, 100730, China

    Kan Deng & Yong Yao

  4. State Key Laboratory of Complex Severe and Rare Disease, Peking Union Medical College Hospital, Chinese Academe of Medical Sciences and Peking Union Medical College, No.1 Shuaifuyuan Wangfujing Dongcheng Distinct, Beijing, 100730, China

    Yong Yao, Huijuan Zhu & Feng Feng

Contributions

All authors have participated sufficiently in this submission to take public responsibility for its content. H.Y. and F.F. proposed research ideas, revised the paper, and reviewed it academically. B.H. and Z.L. were responsible for literature review, data analysis and writing the manuscript. M.L. revised the paper. L.L., L.D. and H.Z. collected the clinical data. K.D. and Y.Y. collected the surgical and histopathology data. All authors reviewed the manuscript.

Corresponding authors

Correspondence to Hui You or Feng Feng.

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Ethics approval and consent to participate

This study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by the Institutional Review Board of Peking Union Medical College Hospital. Informed consent was waived by Institutional Review Board of Peking Union Medical College Hospital, because it was a retrospective, non-interventional, and observational study.

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The authors declare no competing interests.

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Liu, Z., Hou, B., You, H. et al. Improved noninvasive diagnostic evaluations in treatment-naïve adrenocorticotropic hormone (ACTH)-dependent Cushing’s syndrome. BMC Med Imaging 25, 252 (2025). https://doi.org/10.1186/s12880-025-01786-y

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