Xeris Presents New Post Hoc Analysis on Effects of Levoketoconazole (Recorlev®) in Cushing’s Syndrome Patients at ENDO 2024

Posted on June 6, 2024 by MaryO

In patients with Cushing’s syndrome maintained on Recorlev, a lower baseline mUFC was associated with higher cortisol normalization rate.

Lower mUFC at baseline was also associated with lower maintenance dose requirements and lower rates of potentially clinically important liver-related adverse events and liver test abnormalities.

The SONICS study previously showed that Recorlev treatment was effective at normalizing cortisol across the spectrum of Cushing’s syndrome severity.

Xeris Biopharma Holdings, Inc. (Nasdaq: XERS), a growth-oriented biopharmaceutical company committed to improving patients’ lives by developing and commercializing innovative products across a range of therapies, today announced it presented a post-hoc analysis from its previously published SONICS study on the effects of levoketoconazole (Recorlev®) in adults with Cushing’s syndrome at ENDO 2024 in Boston, June 1-4, 2024.

“The results of this analysis suggest that patients with Cushing’s syndrome/disease with lower mUFC(s) normalize at a higher rate than those with more severe disease and may require lower doses of Recorlev and experience lower rates of liver-related adverse events. This exploratory analysis brings further perspective to the importance of individualizing and tailoring medical management,” said James Meyer, PharmD, Xeris’ Senior Director, Publications and Medical Communications.

Title: Effects of Levoketoconazole on 24-hour Mean UFC (mUFC) in the SONICS Study: Relation to Baseline mUFC in Adults with Cushing’s Syndrome: A Post-hoc Analysis (SAT-085)

This post-hoc exploration included all enrolled patients in SONICS who were treated and had a post-baseline mUFC, aiming to further elucidate relationships between baseline biochemical disease severity, drug dose, and intermediate-term mUFC response. For the current analyses, 92 patients treated with levoketoconazole and with baseline mUFC measurement (modified ITT) were stratified into 3 baseline mUFC subgroups: Group 1 (≤ 2.5x upper limit of normal (ULN)); Group 2 (>2.5x to ≤ 5x ULN); or Group 3 (>5x ULN) and analyzed in respect to mUFC response, average daily dose, and adverse events following 6 months of maintenance therapy. Groups 1 and 2 were similar in baseline characteristics; whereas Group 3 differed with younger age, fewer female participants, more recently diagnosed, and more frequently on prior therapy.

Group 2 (Baseline mUFC 267.9 nmol/D) had the highest apparent mUFC response rate (12/33 [36.4%]), 95% CI 0.20, 0.54) as compared with Group 1 (Baseline mUFC 498.7 nmol/D) (12/38 [31.6%], 95% CI 0.16, 0.47) or Group 3 (Baseline mUFC 1672.8 nmol/D) (5/21 [23.8%]; 95% CI 0.01, 0.55); Group 3 having a notably lower response.

Daily doses of levoketoconazole were related to baseline mUFC. Thus, Group 3 used a nominally higher average daily dose (631 mg and 741 mg) during maintenance therapy and at the last dose in the 6-month maintenance phase (regardless of completion status) than Group 1 (475 mg and 545 mg) or Group 2 (548 mg and 611 mg).

Group 3 had more liver-related AEs of special interest than Group 1 or 2 (14% vs 7.9% or 3.0%) and more AEs leading to discontinuation (24% vs 12% or 16%). Group 3 had a higher incidence of liver test (ALT, AST, GGT) abnormalities compared to Group 1 and Group 2.

This post hoc analysis demonstrated:

  • Normalization of mUFC with levoketoconazole in Cushing’s syndrome patients maintained on levoketoconazole in the SONICS study for up to 6 months appeared to vary inversely with baseline mUFC.
  • Lower mUFC at baseline was also associated with lower maintenance dose requirements and lower rates of potentially clinically important liver-related AEs and liver test abnormalities.
  • Whether observed baseline characteristic differences between the highest tertile of baseline mUFC and the 2 lower tertiles were simply coincidental to or confounders or mediators of the described relationships with mUFC remains to be explored.

About Cushing’s Syndrome

Endogenous Cushing’s syndrome is a rare, serious, and potentially fatal endocrine disease caused by chronic elevated cortisol exposure–often the result of a benign tumor of the pituitary gland. This benign tumor tells the body to overproduce high levels of cortisol for a sustained period of time, which often results in characteristic physical signs and symptoms that are distressing to patients. The disease is most common among adults between the ages of 30–50, and it affects women three times more often than men. Women with Cushing’s syndrome may experience a variety of health issues including menstrual problems, difficulty becoming pregnant, excess male hormones (androgens), primarily testosterone, which can cause hirsutism (growth of coarse body hair in a male pattern), oily skin, and acne.3

Additionally, the multisystem complications of the disease are potentially life threatening. These include metabolic changes such as high blood sugar or diabetes, high blood pressure, high cholesterol, fragility of various tissues including blood vessels, skin, muscle, and bone, and psychological disturbances such as depression, anxiety, and insomnia.3 Untreated, the five-year survival rate is only approximately 50%.4

About Recorlev®

Recorlev® (levoketoconazole) is a cortisol synthesis inhibitor for the treatment of endogenous hypercortisolemia in adult patients with Cushing’s syndrome for whom surgery is not an option or has not been curative.1 Endogenous Cushing’s syndrome is a rare but serious and potentially lethal endocrine disease caused by chronic elevated cortisol exposure.2 Recorlev is the pure 2S,4R enantiomer of ketoconazole, a steroidogenesis inhibitor.1 Recorlev has demonstrated in two successful Phase 3 studies to significantly reduce mean urine free cortisol.1

The Phase 3 program for Recorlev included SONICS and LOGICS, two multinational studies designed to evaluate the safety and efficacy of Recorlev when used to treat endogenous Cushing’s syndrome. The SONICS study met its primary and secondary endpoints, significantly reducing and normalizing mean urinary free cortisol concentrations without a dose increase.1,2 The LOGICS study, which met its primary endpoint and key secondary endpoint, was a double-blind, placebo-controlled randomized-withdrawal study of Recorlev that was designed to supplement the efficacy and safety information provided by SONICS.1 The ongoing open-label OPTICS study will gather further useful information related to the long-term use of Recorlev.

Recorlev was approved by the US FDA in December 2021 and received orphan drug designation from the FDA and the European Medicines Agency for the treatment of endogenous Cushing’s syndrome.

Indication & Important Safety Information for Recorlev®

BOXED WARNING: HEPATOTOXICITY AND QT PROLONGATION
HEPATOTOXICITY

Cases of hepatotoxicity with fatal outcome or requiring liver transplantation have been reported with oral ketoconazole. Some patients had no obvious risk factors for liver disease. Recorlev is associated with serious hepatotoxicity. Evaluate liver enzymes prior to and during treatment.

QT PROLONGATION

Recorlev is associated with dose-related QT interval prolongation. QT interval prolongation may result in life-threatening ventricular dysrhythmias such as torsades de pointes. Perform ECG and correct hypokalemia and hypomagnesemia prior to and during treatment.

INDICATION

Recorlev is a cortisol synthesis inhibitor indicated for the treatment of endogenous hypercortisolemia in adult patients with Cushing’s syndrome for whom surgery is not an option or has not been curative.

Limitations of Use

Recorlev is not approved for the treatment of fungal infections.

CONTRAINDICATIONS

  • Cirrhosis, acute liver disease or poorly controlled chronic liver disease, baseline AST or ALT > 3 times the upper limit of normal, recurrent symptomatic cholelithiasis, a prior history of drug induced liver injury due to ketoconazole or any azole antifungal therapy that required discontinuation of treatment, or extensive metastatic liver disease.
  • Taking drugs that cause QT prolongation associated with ventricular arrythmias, including torsades de pointes.
  • Prolonged QTcF interval > 470 msec at baseline, history of torsades de pointes, ventricular tachycardia, ventricular fibrillation, or prolonged QT syndrome.
  • Known hypersensitivity to levoketoconazole, ketoconazole or any excipient in Recorlev.
  • Taking certain drugs that are sensitive substrates of CYP3A4 or CYP3A4 and P-gp.

WARNINGS AND PRECAUTIONS

Hepatotoxicity

Serious hepatotoxicity has been reported in patients receiving Recorlev, irrespective of the dosages used or the treatment duration. Drug-induced liver injury (peak ALT or AST greater than 3 times upper limit of normal) occurred in patients using Recorlev. Avoid concomitant use of Recorlev with hepatotoxic drugs. Advise patient to avoid excessive alcohol consumption while on treatment with Recorlev. Routinely monitor liver enzymes and bilirubin during treatment.

QT Prolongation

Use Recorlev with caution in patients with other risk factors for QT prolongation, such as congestive heart failure, bradyarrythmias, and uncorrected electrolyte abnormalities, with more frequent ECG monitoring considered. Routinely monitor ECG and blood potassium and magnesium levels during treatment.

Hypocortisolism

Recorlev lowers cortisol levels and may lead to hypocortisolism with a potential for life-threatening adrenal insufficiency. Lowering of cortisol levels can cause nausea, vomiting, fatigue, abdominal pain, loss of appetite, and dizziness. Significant lowering of serum cortisol levels may result in adrenal insufficiency that can be manifested by hypotension, abnormal electrolyte levels, and hypoglycemia. Routinely monitor 24-hour urine free cortisol, morning serum or plasma cortisol, and patient’s signs and symptoms for hypocortisolism during treatment.

Hypersensitivity Reactions

Hypersensitivity to Recorlev has been reported. Anaphylaxis and other hypersensitivity reactions including urticaria have been reported with oral ketoconazole.

Risks Related to Decreased Testosterone

Recorlev may lower serum testosterone in men and women. Potential clinical manifestations of decreased testosterone concentrations in men may include gynecomastia, impotence and oligospermia. Potential clinical manifestations of decreased testosterone concentrations in women include decreased libido and mood changes.

ADVERSE REACTIONS

Most common adverse reactions (incidence > 20%) are nausea/vomiting, hypokalemia, hemorrhage/contusion, systemic hypertension, headache, hepatic injury, abnormal uterine bleeding, erythema, fatigue, abdominal pain/dyspepsia, arthritis, upper respiratory infection, myalgia, arrhythmia, back pain, insomnia/sleep disturbances, and peripheral edema.

DRUG INTERACTIONS

  • Consult approved product labeling for drugs that are substrates of CYP3A4, P-gp, OCT2, and MATE prior to initiating Recorlev.
  • Sensitive CYP3A4 or CYP3A4 and P-gp Substrates: Concomitant use of Recorlev with these substrates is contraindicated or not recommended.
  • Atorvastatin: Use lowest atorvastatin dose possible and monitor for adverse reactions for dosages exceeding 20 mg daily.
  • Metformin: Monitor glycemia, kidney function, and vitamin B12 and adjust metformin dosage as needed.
  • Strong CYP3A4 Inhibitors or Inducers: Avoid use of these drugs 2 weeks before and during Recorlev treatment.
  • Gastric Acid Modulators: See Full Prescribing Information for recommendations regarding concomitant use with Recorlev.

USE IN SPECIFIC POPULATIONS

Lactation: Advise not to breastfeed during treatment and for one day after final dose.

To report SUSPECTED ADVERSE REACTIONS, contact Xeris Pharmaceuticals, Inc. at 1-877-937-4737 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

Please see Full Prescribing Information including Boxed Warning.

About Xeris

Xeris (Nasdaq: XERS) is a growth-oriented biopharmaceutical company committed to improving patient lives by developing and commercializing innovative products across a range of therapies. Xeris has three commercially available products; Gvoke®, a ready-to-use liquid glucagon for the treatment of severe hypoglycemia, Keveyis®, a proven therapy for primary periodic paralysis, and Recorlev® for the treatment of endogenous Cushing’s syndrome. Xeris also has a robust pipeline of development programs to extend the current marketed products into important new indications and uses and bring new products forward using its proprietary formulation technology platforms, XeriSol™ and XeriJect®, supporting long-term product development and commercial success.

Xeris Biopharma Holdings is headquartered in Chicago, IL. For more information, visit www.xerispharma.com, or follow us on X, LinkedIn, or Instagram.

Forward-looking Statement

Any statements in this press release other than statements of historical fact are forward-looking statements. Forward-looking statements include, but are not limited to, statements about future expectations, plans and prospects for Xeris Biopharma Holdings, Inc. including statements regarding expectations for the release of clinical data, post hoc analyses or results from clinical trials, including the SONICS study, the market and therapeutic potential of its products and product candidates, including the levoketoconazole (Recorlev®), the potential utility of its formulation platforms and other statements containing the words “will,” “would,” “continue,” “expect,” “should,” “anticipate” and similar expressions, constitute forward-looking statements within the meaning of The Private Securities Litigation Reform Act of 1995. These forward-looking statements are based on numerous assumptions and assessments made in light of Xeris’ experience and perception of historical trends, current conditions, business strategies, operating environment, future developments, geopolitical factors, and other factors it believes appropriate. By their nature, forward-looking statements involve known and unknown risks and uncertainties because they relate to events and depend on circumstances that will occur in the future. The various factors that could cause Xeris’ actual results, performance or achievements, industry results and developments to differ materially from those expressed in or implied by such forward-looking statements, include, but are not limited to, its financial position and need for financing, including to fund its product development programs or commercialization efforts, whether its products will achieve and maintain market acceptance in a competitive business environment, its reliance on third-party suppliers, including single-source suppliers, its reliance on third parties to conduct clinical trials, the ability of its product candidates to compete successfully with existing and new drugs, and its and collaborators’ ability to protect its intellectual property and proprietary technology. No assurance can be given that such expectations will be realized and persons reading this communication are, therefore, cautioned not to place undue reliance on these forward-looking statements. Additional risks and information about potential impacts of financial, operational, economic, competitive, regulatory, governmental, technological, and other factors that may affect Xeris can be found in Xeris’ filings, including its most recently filed Annual Report on Form 10-K filed with the Securities and Exchange Commission, the contents of which are not incorporated by reference into, nor do they form part of, this communication. Forward-looking statements in this communication are based on information available to us, as of the date of this communication and, while we believe our assumptions are reasonable, actual results may differ materially. Subject to any obligations under applicable law, we do not undertake any obligation to update any forward-looking statement whether as a result of new information, future developments or otherwise, or to conform any forward-looking statement to actual results, future events, or to changes in expectations.

1. Recorlev [prescribing information]. Chicago, IL: Xeris Pharmaceuticals, Inc.; 2021. 2. Fleseriu M, et al. Lancet Diabetes Endocrinol. 2019;7(11):855-865. 3. Pivonello R et al. Lancet Diabetes Endocrinol. 2016; 4: 611-29. 4. Plotz CM, et al. Am J Med. 1952 November;13(5):597-614.

Recorlev®, Xeris Pharmaceuticals®, Xeris CareConnectionTM, Keveyis®, Gvoke®, and Ogluo® are trademarks owned by or licensed to Xeris Pharmaceuticals, Inc. PANTHERx Rare Pharmacy is a service mark of PANTHERx Rare, LLC. All other trademarks referenced herein are the property of their respective owners. All rights reserved. US-PR-22-00001 1/22

From https://www.morningstar.com/news/business-wire/20240603311134/xeris-presents-new-post-hoc-analysis-on-effects-of-levoketoconazole-recorlev-in-cushings-syndrome-patients-at-endo-2024

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Cardiac Magnetic Resonance Reveals Biventricular Impairment In Cushing’s Syndrome

Posted on June 4, 2024 by MaryO

Purpose

Cushing’s syndrome (CS) is associated with severe cardiovascular (CV) morbidity and mortality. Cardiac magnetic resonance (CMR) is the non-invasive gold standard for assessing cardiac structure and function; however, few CMR studies explore cardiac remodeling in patients exposed to chronic glucocorticoid (GC) excess. We aimed to describe the CMR features directly attributable to previous GC exposure in patients with cured or treated endogenous CS.

Methods

This was a prospective, multicentre, case-control study enrolling consecutive patients with cured or treated CS and patients harboring non-functioning adrenal incidentalomas (NFAI), comparable in terms of sex, age, CV risk factors, and BMI. All patients were in stable condition and had a minimum 24-month follow-up.

Results

Sixteen patients with CS and 15 NFAI were enrolled. Indexed left ventricle (LV) end-systolic volume and LV mass were higher in patients with CS (p = 0.027; p = 0.013); similarly, indexed right ventricle (RV) end-diastolic and end-systolic volumes were higher in patients with CS compared to NFAI (p = 0.035; p = 0.006). Morphological alterations also affected cardiac function, as LV and RV ejection fractions decreased in patients with CS (p = 0.056; p = 0.044). CMR features were independent of metabolic status or other CV risk factors, with fasting glucose significantly lower in CS remission than NFAI (p < 0.001) and no differences in lipid levels or blood pressure.

Conclusion

CS is associated with biventricular cardiac structural and functional impairment at CMR, likely attributable to chronic exposure to cortisol excess independently of known traditional risk factors.

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Introduction

Cushing’s syndrome (CS), or chronic hypercortisolism, is associated with increased mortality mostly due to cardiovascular disease [1, 2], with infectious diseases and coexisting comorbidities also playing a role [1,2,3,4,5,6,7,8,9]. Older age at diagnosis, longer disease activity, uncontrolled hypertension, and diabetes mellitus are the main factors increasing mortality in CS [1, 2].

The higher cardiovascular risk in CS has traditionally been attributed to chronic hypertension, vascular atherosclerosis, and increased thromboembolism [2, 10,11,12,13,14], ultimately leading to an increased risk for myocardial infarction, cardiac failure, and stroke [2, 15].

Prompt and effective treatment of cortisol excess is crucial for reversing comorbidities and reducing the mortality risk associated with CS [1, 2]. However, concomitant treatment for cardiovascular comorbidities should also be provided to mitigate cardiovascular damage [1, 2, 16]. Despite improved treatment modalities, comorbidities can persist in a significant proportion of patients even after remission of CS [2, 17], suggesting that the consequence of prolonged exposure to glucocorticoid (GC) excess can produce irreversible alteration in cardiac structure.

Alterations in cardiac kinetics and structure include abnormal relaxation patterns (decreased systolic strain and impaired diastolic filling) and concentric left ventricle hypertrophy [2, 18,19,20], the latter being more severe in CS patients when compared to hypertensive controls [2, 20]. Increased myocardial fibrosis, caused by enhanced responsiveness to angiotensin II and activation of the mineralocorticoid receptor in response to cortisol excess, further complicates the scenario [2].

Albeit myocardial fibrosis and cardiac abnormalities might improve [21], cardiovascular alterations can persist for up to 5 years since remission of GC excess [2, 22, 23], underscoring the importance of prompt diagnosis and treatment, but also monitoring of increased risk.

Most studies rely on 2D echocardiography to characterize cardiac alterations in patients with CS [24]. Still, cardiac magnetic resonance (CMR) is now the established non-invasive gold standard method for measuring left ventricle (LV) volume, LV mass (LVM), and cardiac function due to its higher accuracy, reproducibility, and lower variability [25]. Few controlled studies assess cardiac dysfunction in CS patients by CMR, with preliminary data confirming the 2D-echocardiography observation of altered LV function and structure [18, 24, 26,27,28,29].

Therefore, our study aims to provide a detailed characterization of cardiac alterations in patients who have been exposed to chronic GC excess using a CMR-based approach and help clarify which are directly attributable to GC excess by matching the CS cohort with randomly selected adrenal patients with proven intact hypothalamic-pituitary-adrenal-axis, but similar traditional cardio-metabolic risk factors.

Materials and methods

Study design and population

We performed a prospective, multicentric, case-control study. From September 2014 to January 2020, consecutive adult (>18 years) patients diagnosed with CS as per current criteria [30] (either cured or with an active drug-treated disease) were recruited from the endocrinology outpatient clinics of the Department of Experimental Medicine at “Sapienza” University of Rome and the Department of Clinical Medicine and Surgery at “Federico II” University of Naples. Disease remission following surgery was defined by urinary free cortisol (UFC) levels per upper limit of normal (ULN) < 1.0 and by serum morning cortisol levels <50 nmol/L following overnight 1 mg dexamethasone suppression, in the absence of any cortisol-lowering treatment. Disease control under chronic medical therapy was defined by UFC xULN <1.0 [16, 31]. Patients with contraindications (or unwilling to undergo) to CMR were excluded from the study. The control group consisted of randomly selected patients with non-functioning adrenal incidentalomas (NFAI) diagnosed according to current criteria [32] undergoing follow-up imaging for the adrenal lesion, comparable with patients in terms of sex, age, BMI, and traditional cardiovascular risk factors. Sixteen patients with CS and 15 NFAI entered the study. All patients must have been in stable condition, including hormonal control, for at least 6 months before entering the study. All patients provided written informed consent after fully explaining the purpose and nature of all procedures used. The study was approved by the Ethical Committee of Policlinico Umberto I (ref. number 4245). The study has been performed according to the ethical standards of the 1964 Declaration of Helsinki and its later amendments. This study adhered to the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines for reporting.

Study procedures

Clinical and laboratory assessment

All patients underwent an accurate medical history review, including drugs used, hormonal assessment at diagnosis (UFC xULN, serum cortisol after dexamethasone suppression test), comorbidities (hypertension, glucose metabolism impairment, dyslipidemia, obesity), and cardiovascular risk factors (e.g., smoking habit). Subsequently, they were submitted to physical examination with measurement of anthropometric parameters and vital signs. Blood sampling for the assessment of biochemistry and hormones was performed at the local laboratory of each participating center; to better standardize results about disease activity, UFC levels were normalized by the upper limit of normal of each center’s laboratory. Clinical and laboratory findings and the prevalence of cardiometabolic complications have been compared between patient groups (CS vs NFAI) and cured and drug-treated patients (cured CS vs controlled CS). All patients were followed up for a minimum of 24-month timeframe.

Cardiac evaluation

All subjects underwent cardiac evaluation with CMR imaging performed as previously described [33] with a 1.5-T clinical magnetic resonance imaging system (Avanto, Siemens, Healthcare Solutions, Erlangen, Germany). During the examination, an ECG device was used for cardiac gating, and all acquisitions were made in apnea at the end of inspiration. In all cases, CMR imaging was performed by the same radiologist expert in cardiac imaging (N.G.) using the same acquisition protocol. CMR was performed at study entry, but not earlier than 6 months from any previous severe acute disease, event, or procedure.

T1-mapping for the evaluation of fibrosis

The T1-mapping technique has been used to quantify the degree of myocardial fibrosis non-invasively. The measured extracellular volume fraction (ECV) is highly sensitive and indicates diffuse myocardial fibrosis [34]. T1-mapping is automatically calculated as the average of the intensity of the individual pixels with and without contrast medium in T1 and expressed in msec (CMR 42 SW). The calculation of the ECV has been performed using the mathematical formula using the hematocrit value [DR1 myocardium: (1/T1 myocardial-post) − (1/T1 myocardial-pre); DR1 blood: (1/T1 blood-post) − (1/T1 blood-pre); Myocardial partition coefficient (λ) = (DR1 myocardial/DR1 blood); ECV = (1 − hematocrit) × (λ)]. A cut-off of ECV > 30% was used to identify increased interstitial fibrosis [35].

CMR findings have been compared between patient groups (CS vs NFAI). Moreover, the comparison of cardiac parameters has also been performed in CS patients according to cardiometabolic comorbidities, disease status, and sex.

The main steps of CMR image acquisition are shown in Fig. 1.

Fig. 1

figure 1

Cardiac magnetic resonance image acquisition protocol. T1-weighted, late gadolinium enhancement cardiac MR images of a 71-year-old female patient with Cushing’s disease, cured after successful neurosurgery. A Vertical long axis slice, coronal plane, two-chamber view. B Horizontal long axis slice, axial plane, four-chamber view. C Short-axis slice at the end of the diastole, sagittal plane. Red circle: endocardium; Blue circle: epicardium. LA left atrium, LV left ventricle, RA right atrium, RV right ventricle

Statistical analysis

Continuous variables are expressed as standard deviation (SD), median and 95% confidence interval (95%CI) as per data distribution, assessed through the Shapiro–Wilk test. Dichotomous variables are expressed as frequencies and percentages when relevant. According to variable distribution, the Student’s t-test or the non-parametric Mann–Whitney U test was performed to compare continuous variables between CS and NFAI and between cured and drug-controlled patients. Differences between groups regarding qualitative variables were evaluated by χ2 statistics. Bivariate correlations between numerical variables were analyzed using Pearson’s or Spearman’s correlation test, as appropriate. The statistical significance was set at p < 0.05. Statistical analyses were performed using SPSS 20.0 for MacOS (SPSS Inc.).

Results

Patient characteristics

The cohort characteristics are summarized in Table 1. Sixteen patients with CS (12 females, mean age 47 ± 12 years) and 15 with NFAI (7 females, mean age 55 ± 10 years) were enrolled during the study period. Twelve patients (75%) had been diagnosed with Cushing’s disease (CD), while four (25%) had ACTH-independent CS due to a cortisol-secreting adrenal adenoma.

Table 1 Baseline characteristics of patients with CS

At enrollment, eleven (69%) patients were cured and five (31%) had drug-treated CD. Among patients with CD, nine had previously undergone pituitary surgery, seven (58%) were cured, and five (42%) presented with a biochemically persistent disease. In the latter group, 3 patients had adequate biochemical control under medical therapy, whereas 2 patients were not entirely on target, because of low compliance and intolerance to medical treatments.

All patients with a cortisol-secreting adrenal adenoma had undergone unilateral adrenalectomy and were cured at the time of enrollment.

Table 2 details comorbidities and their therapies for CS and NFAI patients.

Table 2 Biochemical and clinical parameters in CS patients and NFAI

Biochemical and clinical evaluation

The main clinical and biochemical parameters are reported in Table 2. Sex, age, and BMI did not differ between the CS patients and NFAI. The two groups were similar concerning HbA1c, fasting insulin or homeostatic model assessment for insulin resistance, and lipid levels; fasting glucose levels were marginally lower in CS than in NFAI (p < 0.001). No differences were found in systolic and diastolic blood pressure, the prevalence of cardiometabolic complications or drugs (i.e., diagnosis of hypertension, dyslipidemia, obesity, and diabetes or prescriptions needed to control such comorbidities), suggesting that GC excess was resolved (or adequately controlled) at the time of enrollment for the great majority of patients.

Subgroup analysis of cardiac parameters in patients with Cushing’s syndrome

A subgroup analysis was performed to assess possible differences in cardiac parameters when the CS cohort was stratified according to disease status and cardiometabolic comorbidities (i.e., between patients with or without hypertension, glucose metabolism impairment, dyslipidemia, obesity), smoking, sex, and disease status.

Firstly, pharmacologically treated CS exhibited higher systolic and diastolic blood pressure levels than cured CS (p = 0.027), but no other differences were found regarding CMR parameters. Subgroup analysis according to the presence/absence of comorbidities revealed no significant effect on cardiac parameters, except for CS patients with impaired glucose tolerance, who showed a lower RV-EF compared with the remaining CS patients (p = 0.017).

Analyzing sex differences, male CS patients displayed higher RV-EDVi (p = 0.035) and RV-ESVi (p = 0.044), as well as a trend toward higher LV-EDVi (p = 0.067), LV-ESVi (p = 0.053) and LVMi (p = 0.066) compared to females. However, male CS patients only exhibited higher interventricular septum (IVS) thickness (p = 0.001) when compared to male and female reference ranges for the general population, age and sex-matched [36].

Comparison of cardiac parameters between patients and controls

A comparison of the main morphostructural and functional cardiac parameters between CS and NFAI in the left and the right ventricle is reported in Fig. 2 and Fig. 3, respectively. CMR cardiac morphology revealed an increased left ventricle-end systolic volume index (LV-ESVi) (31.0 ± 8.7 vs 24.1 ± 7.4, p = 0.027) in CS compared to NFAI (Fig. 2). Left ventricle mass index (LVMi) was also higher in CS (51.0 ± 11.8 vs 41.8 ± 6.9, p = 0.013) (Fig. 2), albeit none matched the criteria for left ventricular hypertrophy [37]. Regarding cardiac function, a trend toward lower left ventricle-ejection fraction (LV-EF) was measured in CS (57.1 ± 6.3 vs 61.9 ± 7.0, p = 0.056). Mirroring the alterations found in the left ventricle, higher indexed right ventricle-end systolic volume (RV-ESVi) (34.0 ± 7.7 vs 26.3 ± 6.0, p = 0.006) and right ventricle-end diastolic volume (RV-EDVi) (74.8 ± 14.2 vs 64.9 ± 9.3, p = 0.035), as well as lower right ventricle-ejection fraction (RV-EF) (54.6 ± 5.5 vs 59.5 ± 7.1, p = 0.044) were measured in patients with CS (Fig. 3). Dedicated T1 mapping technique did not reveal any difference between CS and NFAI, either before or after contrast administration. No patient had ECV greater than 30%, and no difference in ECV values was observed between groups.

Fig. 2
figure 2

Comparative analysis of left ventricle parameters in Cushing’s syndrome and NFAI patients. Left ventricle morphological and functional cardiac parameters in patients with Cushing’s syndrome (gray bars) and patients with NFAI (black bars). Data are expressed as mean ± SD. *p < 0.05. CS Cushing’s syndrome, CNT NFAI, LV-EDVi Left Ventricle End-Diastolic Volume index, LV-ESVi Left Ventricle End-Systolic Volume index, LV-SVi Left Ventricle Stroke Volume index, LVMi Left Ventricular Mass index, LV-EF Left Ventricle Ejection Fraction

Fig. 3
figure 3

Comparative analysis of right ventricle parameters in Cushing’s syndrome and NFAI patients. Right ventricle morphological and functional cardiac parameters in patients with Cushing’s syndrome (gray bars) and patients with NFAI (black bars). Data are expressed as mean ± SD. *p < 0.05; **p < 0.01; CS Cushing’s syndrome, CNT NFAI, RV-EDVi Right Ventricle End-Diastolic Volume index, RV-ESVi Right Ventricle End-Systolic Volume index, RV-SVi Right Ventricle Stroke Volume index, RV-EF Right Ventricle Ejection Fraction

No significant correlations were found between CMR parameters and UFC x ULN (assessed at diagnosis or date of CMR evaluation), serum cortisol after dexamethasone suppression test (at diagnosis) or disease duration from diagnosis. An explicative summary of cardiac parameters is shown in Table 3.

Table 3 Cardiac parameters in CS patients and NFAI

Discussion

The current study reveals that exposure to endogenous GC excess induces a peculiar early remodeling of affected patients’ left and right ventricles, which can persist after CS remission and is independent of traditional cardiometabolic risk factors. Namely, the higher LV and RV ESVi and EDVi observed in patients exposed to GC excess is accompanied by higher LVMi. However, LV and RV ejection fractions are only mildly reduced, suggesting that a morphological impairment anticipates a performance dysfunction. The fact that such alterations occur rapidly in CS and are partially irreversible after remission advocates the use of CMR to improve the management of fatal cardiac complications in this rare endocrine disease.

Several echocardiographic studies have evaluated cardiac structure and function in patients with CS and found LV systolic and diastolic dysfunction [19, 21, 38,39,40,41]. Albeit cardiac echocardiography is more practical in everyday clinical practice, CMR allows an evaluation of ventricular mass and volumes free of cardiac geometric assumption, ensuring a higher accuracy and reproducibility [29, 42].

Few controlled studies evaluating small cohorts have analyzed patients with CS using CMR [18, 26,27,28]. Kamenicky and coworkers compared 18 patients with active CS with 18 controls matched for age, sex, and BMI and found that patients had lower LV, RV, and left atrium ejection fractions, along with increased left and right ESVi and end-diastolic LV segmental thickness. Of note, successful treatment of CS was associated with an improvement in ventricular and atrial systolic performance [18]. A later study from the same group evaluated 23 patients with active CS and compared them with 27 controls matched for age, sex, and BMI, reporting increased left ventricular wall thickness, and reduced ventricular stroke volumes in patients [28]. A CMR study comparing CS patients with age and sex-matched controls showed that patients with active disease had higher LVMi than controls, as opposed to those in disease remission [27]. In all the studies mentioned above, patients and controls significantly differed in cardiovascular risk factors, with a worse cardiovascular profile in patients than controls. Conversely, our cohorts were largely homogeneous, without any significant difference between patients with CS and NFAI in glycometabolic profile, except for a surprisingly marginally lower fasting glucose levels in CS than in NFAI. This is likely because CS patients were either cured or drug-treated, and NFAI were comparable in terms of BMI and known CV risk factors.

As a result, the two groups did not significantly differ either in systolic and diastolic blood pressure levels or in the overall prevalence of cardiometabolic complications or the drugs prescribed to treat them. Nevertheless, our results confirmed the CMR findings of previous studies regarding higher cardiac volumes and mass and lower ejection fractions in patients with CS than in NFAI, advocating a direct effect of GC excess exposure in cardiac impairment beyond the known cardiovascular risk factors. Moreover, the results of the current study highlight the importance of a biventricular evaluation in this context, as opposed to most 2D-echocardiographic studies. Ultrasound measurement of RV volumes is challenging; therefore, most CS echocardiographic studies have mainly focused on the LV [19, 21, 38,39,40,41], whereas CMR studies suggest an impairment in both left and right ventricles. The RV is anatomically and functionally different from the LV. In the absence of clear alterations in pulmonary resistance, our findings suggest RV involvement is a direct effect of GC excess on cardiomyocytes, whose receptors are equally expressed in left and right ventricles in donor hearts and dilated cardiomyopathy [43].

Cardiac morphological alterations in our cohort were not related to increased myocardial fibrosis, as we did not find any difference between patients and controls in T1 mapping evaluation, probably also due to the superimposable cardiometabolic profile of the two study groups. Albeit patients had non-significantly higher postcontrast T1 values, none had ECV values compatible with fibrosis. Similarly, Roux and coworkers evaluated 10 patients with active CD matched with 10 hypertensive and 10 healthy controls and performed a CMR study using the T1 mapping technique and found increased native myocardial T1 in CD, independently from hypertension, without differences in myocardial partition coefficient (λ) between groups. These results support the hypothesis of a potential role of T1 mapping in identifying early biomarkers of subclinical myocardial fibrosis in this disease [26].

Even though we didn’t find any significant correlation between indicators of hypercortisolism severity (UFC x ULN, disease duration) and CMR parameters, the independency of cardiac alterations from traditional cardiometabolic risk factors, claims a direct role of hypercortisolism on cardiac impairment, acting as a fingerprint of GC excess exposure. Our data point toward a persistent toxic effect on the heart, mediated directly through GC and/or mineralocorticoid receptors [2, 11, 44], that produces changes in cardiac structure that are clinically silent but long-lasting, as if the heart retained a memory of GC excess exposure. The mineralocorticoid pathway increases collagen secretion by activating fibroblasts [45]. In addition, stimulating mineralocorticoid receptors decreases myocyte contractility and stimulates mitosis, resulting in myocardial hypertrophy and dysfunction [46]. However, previous data on mineralocorticoid antagonism in GC-induced hypertension did not prove convincing [47], disclosing the need for direct control of GC receptors (for example, via selective GC receptor antagonists such as relacorilant). Indeed, there is evidence supporting the role of GCs in driving alterations in vasoactive substances, thus impacting the balance between vasoconstriction and vasodilation (including catecholamines, nitric oxide, and atrial natriuretic peptide), as well as the activation of the renin-angiotensin system, leading to cardiac hypercontractility [11, 48].

The present study has shown more structural rather than functional changes at CMR in CS patients without evidence of fibrosis, thus suggesting the latter probably as a late phenomenon.

Additive to the direct role of cortisol, almost 60% of our patients presented hypertension, which could have contributed to the development of cardiac impairment. Similarly, the impact of other CS-related cardiovascular risk factors, such as visceral obesity, glucose intolerance and dyslipidemia, cannot be entirely ruled out.

Finally, our study showed for the first time that sex might affect cardiac morphological changes induced by GC excess. Male CS patients exhibited higher IVS thickness compared to females after adjusting for population age and sex reference ranges, independently from the prevalence of hypertension, supporting sex-related differences as observed in other cardiovascular diseases [49, 50]. Recently, a study by Wolf et al. showed that male sex was an independent predictor of increased epicardial and pericardial fat [28], which may play a role in the pathogenesis of CS cardiomyopathy. However, among CS patients, we did not find any differences in the prevalence of male and female hypogonadism (50% vs 42%, p = 1.000). Still, we can not exclude that estrogen exposure could have protected GC-related cardiomyopathy [51].

Very few studies have evaluated cardiac structure and function in CS using CMR, and this is a strength of the current study. However, it does have some limitations. The cross-sectional design and the lack of sample size in such a small and heterogeneous study population with different etiologies of endogenous CS, including both cured and well-controlled patients, might have underestimated the cardiac impairment. Anyway, considering that CS is a rare disease, we opted for a study design closer to a CS clinic’s real-life setting; this aspect represents a strength of this study. Nevertheless, according to the published evidence, as well as to our results, it is likely that cardiac dysfunction might persist in CS even after disease remission. Indeed, although our CS patients had higher biventricular volumes, the subgroup comparison between surgically cured and drug-treated patients revealed no differences in cardiac morphology or biochemical or cardiometabolic complications prevalence, althoghut the lack of standardization of the evaluation period. A previous paper found a significantly higher LVMi in active patients than in remission [27]. Anyway, longitudinal studies (baseline versus post-treatment) with larger population are needed to better clarify the reversibility of cardiac changes after treatment.

We propose a novel approach to cardiac disease in CS, going beyond the traditional cardiometabolic risk factors and evaluating both ventricles, preferably with CMR. Moreover, the present study highlights the importance of a sex-oriented approach in the management of CS complications, taking into account the sex-related differences in cardiac damage of these patients, for whom cardiac complications still represent the major cause of death, very often occurring during remission [2].

Conclusions

In CS biventricular cardiac remodeling associated with functional impairment, has been ascribed to a multifactorial pathogenesis. Our findings highlight the greater contribution of direct effect of GC excess exposure on myocardium than on cardiovascular risk factors, suggesting a sex-related differences in cardiac impairment. More importantly, the maladaptive change triggered by chronic exposure to GC excess, even if the latter is resolved, is persistent and clinically silent and could be detected though a more sensitive and precise approach with CMR.

Data availability

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

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Funding

This work was supported by the PRecisiOn Medicine to Target Frailty of Endocrine-metabolic Origin (PROMETEO) project (NET-2018-12365454) by the Ministry of Health and the European Union – NextGenerationEU through the Italian Ministry of University and Research under PNRR – M4C2-I1.3 Project PE_00000019 “HEAL ITALIA” to Andrea Isidori CUP B53C22004000006. Open access funding provided by Università degli Studi di Roma La Sapienza within the CRUI-CARE Agreement.

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Author notes

  1. These authors contributed equally: Tiziana Feola, Alessia Cozzolino
  2. These authors jointly supervised this work: Andrea M. Isidori, Elisa Giannetta

Authors and Affiliations

  1. Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy

    Tiziana Feola, Alessia Cozzolino, Dario De Alcubierre, Federica Campolo, Andrea M. Isidori & Elisa Giannetta

  2. Neuroendocrinology, Neuromed Institute, IRCCS, Pozzilli, Italy

    Tiziana Feola & Dario De Alcubierre

  3. Oxford Centre for Diabetes, Endocrinology, and Metabolism, Churchill Hospital, Oxford University Hospitals, NHS Trust, Oxford, UK

    Riccardo Pofi

  4. Department of Radiological Sciences, Oncology and Pathology, Sapienza University of Rome, Rome, Italy

    Nicola Galea & Carlo Catalano

  5. Dipartimento di Medicina Clinica e Chirurgia, Università Federico II di Napoli, Naples, Italy

    Chiara Simeoli, Nicola Di Paola & Rosario Pivonello

  6. Centre for Rare Diseases (ENDO-ERN accredited), Policlinico Umberto I, Rome, Italy

    Andrea M. Isidori

Contributions

A.M.I., E.G., T.F., A.C. contributed to the idea and design of the study, analysis of the data, and writing of the manuscript. D.D.A., R.P., C.S., N.D.P., F.C. and R.P.i. contributed to the design of the study, analysis of the data, and revision of the report. T.F., A.C., D.D.A., N.G. and C.C. analyzed the data. All authors contributed to the interpretation of the data and the writing of the paper. All authors read and approved the final manuscript.

Corresponding authors

Correspondence to Andrea M. Isidori or Elisa Giannetta.

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Conflict of interest

RPi has received research support to Università Federico II di Napoli as a principal investigator for clinical trials from Novartis Pharma, Recordati, Strongbridge Biopharma, Corcept Therapeutics, HRA Pharma, Shire, Takeda, Neurocrine Biosciences, Camurus AB, and Pfizer, has received research support to Università Federico II di Napoli from Pfizer, Ipsen, Novartis Pharma, Strongbridge Biopharma, Merk Serono, and Ibsa, and received occasional consulting honoraria from Novartis Pharma, Recordati, Strongbridge Biopharma, HRA Pharma, Crinetics Pharmaceuticals, Corcept Therapeutics, Pfizer, and Bresmed Health Solutions. AMI has been a consultant for Novartis, Takeda, Recordati, and Sandoz companies and has received unconditional research grants from Shire, IPSEN, and Pfizer. All the other authors have nothing to disclose.

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The authors affirm that human research participants provided informed consent for publication of the images in Fig. 1.

Ethics approval and conset to participate

All patients provided written informed consent after fully explaining the purpose and nature of all procedures used. The study was approved by the Ethical Committee of Policlinico Umberto I (ref. number 4245). The study has been performed according to the ethical standards of the 1964 Declaration of Helsinki and its later amendments.

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Feola, T., Cozzolino, A., De Alcubierre, D. et al. Cardiac magnetic resonance reveals biventricular impairment in Cushing’s syndrome: a multicentre case-control study. Endocrine (2024). https://doi.org/10.1007/s12020-024-03856-7

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A More Accurate Diagnosis of Cushing’s Syndrome

Posted on May 29, 2024 by MaryO

Cushing’s syndrome is associated with excessive cortisol production and, if left untreated, can result in severe complications, such as heart attacks, strokes, and type 2 diabetes. To diagnose this condition, a dexamethasone suppression test is commonly performed.

Various factors, such as metabolic rate and interactions with other medications, can affect test efficacy. Therefore, it is crucial to measure the concentration of dexamethasone concurrently with cortisol to avoid false-positive results.

To address this issue, a team of researchers at the University of Turin, led by Professor Giulio Mengozzi in the Department of Medical Sciences, has developed a liquid chromatography-tandem mass spectrometry method.

This new method enables the simultaneous quantification of cortisol, cortisone, dexamethasone, and six additional exogenous corticosteroids, leading to a more accurate diagnosis of Cushing’s syndrome.

The symptoms of Cushing’s syndrome

Cushing’s syndrome is a medical condition characterized by an abnormal and prolonged increase in cortisol production, typically affecting females between the ages of 30 and 50.1

While the issue may originate from within the body (endogenous), it is more commonly caused by external factors, such as the use of glucocorticoid medications.

Visible symptoms of Cushing’s syndrome include weight gain, an accumulation of fat around the base of the neck, a fatty hump between the shoulders, the appearance of a “moon face”, and easy bruising. However, not all individuals with the syndrome exhibit these symptoms, rendering diagnosis challenging. Without timely treatment, Cushing’s syndrome can lead to severe complications, including heart attack, stroke, blood clots in the legs and lungs, increased susceptibility to infections, memory loss, and type 2 diabetes.

Dexamethasone testing

A commonly used method for diagnosing Cushing’s syndrome is the dexamethasone suppression test (DST), which measures the adrenal gland’s response to adrenocorticotropic hormone (ACTH).

ACTH regulates cortisol levels in the blood plasma and stimulates the adrenal cortex to produce cortisol. When cortisol levels increase, ACTH secretion is suppressed. Dexamethasone, a synthetic steroid similar to cortisol, is administered during the DST to lower ACTH levels.

DSTs are available in low-dose (LDDST) and high-dose (HDDST). They can be performed overnight or over two days.

LDDSTs are used initially to diagnose Cushing’s syndrome. If the result is positive, HDDSTs help classify the disease as ACTH-dependent or independent. These tests are typically conducted in the following manner.2

A more accurate diagnosis of Cushing’s syndrome

Cortisol is a steroid hormone of the glucocorticoid class made by the adrenal glands.

Image Credit: Shutterstock/Kateryna Kon

LDDST

  • Overnight protocol: 1 mg of dexamethasone is administered at 11:00 pm, and the serum cortisol levels are measured at 8:00 am the following morning.
  • Two-day protocol: serum cortisol levels are measured at 8:00 am and 0.5 mg of dexamethasone is administered every six hours (9:00 am, 3:00 pm, 9:00 pm, 3:00 am) for two days, totalling 4 mg. Serum cortisol levels are then measured at 9:00 am, six hours after the last dose has been delivered.

HDDST

  • Overnight protocol: baseline serum cortisol or 24-hour urinary free cortisol (UFC) is measured in the morning, and 8 mg of dexamethasone is given at 11.00 pm. Cortisol level in blood is then measured at 8.00 am the following morning.
  • Two-day protocol: Baseline serum cortisol or 24-hour UFC is measured at 8:00 am; 2 mg of dexamethasone is administered every six hours (9:00 am, 3:00 pm, 9:00 pm, 3:00 am) for two days, totaling 16 mg, in tandem with the collection of urine for UFC measurements. Serum cortisol levels are measured at 9:00 am, six hours after the last dose.

Patients whose pituitary glands produce excessive amounts of ACTH will exhibit an abnormal response to the low-dose test but a normal reaction to the high-dose test.

During the LDDST, cortisol levels should decrease following the administration of dexamethasone, and a cut-off value of below 18 ng/mL is recommended to distinguish a healthy response from an unhealthy one.

For the HDDST, a decrease in urine-free cortisol (UFC) or serum cortisol greater than 50% indicates the presence of ACTH-dependent Cushing’s syndrome. This rule applies to both the overnight LDDST and the two-day HDDST methods.

Measuring cortisol levels

Chemiluminescence immunoassay (CLIA) is a widely used method for measuring cortisol and other steroids due to its simplicity, automation, and good sensitivity.

However, it has some drawbacks, including cross-reactivity leading to overestimation of target analyte levels, non-standardization of kits, and the inability to measure more than one analyte per analysis. This is particularly problematic since studies indicate that measuring dexamethasone in combination with cortisol can reduce the number of false-positive DST results and improve interpretability. 3,4,5

Liquid chromatography-tandem mass spectrometry (LC-MS/MS) has emerged as a popular alternative to CLIA for DSTs due to its ability to measure multiple analytes simultaneously and its superior specificity.

Analytes are separated via LC, and their concentrations are measured by MS, with triple quadrupole MS configurations commonly used for this purpose. This technique provides the ability to measure multiple analytes simultaneously, along with higher accuracy and sensitivity than CLIA.

Increased ease of use and accuracy

In the Division of Endocrinology, Diabetes, and Metabolism at the University of Turin, a team has developed an LC-MS/MS technique for simultaneous quantifying cortisol, cortisone, dexamethasone, and six other exogenous corticosteroids in serum/plasma samples.6

This method can be readily applied in any clinical laboratory equipped with a mass spectrometer and is effective in DSTs, enabling precise measurements of the target analytes in a single chromatographic run (Figure 1).

Sample preparation (1 Hour)

  1. Dilute 200 μL of the serum/plasma sample with 200 μL of water.
  2. Perform supported liquid extraction, manually transferring 400 μL of sample to a microplate.
  3. Apply positive pressure using Tecan Resolvex® A200 automated positive pressure processor.
  4. Elute with 700 μL of methyl tert-butyl ether.
  5. Evaporate and reconstitute in H2 O/MeOH (1:1, v/v).
  6. Agitate.

LC-MS/MS analysis (10 Minutes)

  • LC column: C18 (100 × 2.1 mm, 1.7 μm)
  • Flow rate: 400 μL/min
  • Temperature: 30 °C
  • Injection volume: 20 μL
  • Mobile phase A: H2O + 0.2 mM ammonium fluoride
  • Mobile phase B: acetonitrile
  • Elution programme: Table 1.

The study demonstrated a strong correlation between the results obtained from the newly developed LC-MS/MS method and those obtained using a commercially available CE IVD-marked Steroid Panel LC-MS* kit (Tecan).

The Tecan kit enables simultaneous dexamethasone, cortisol, and cortisone measurement and includes all the necessary components for easy implementation, such as calibrators and controls. The samples are prepared using solid-phase extraction (SPE), which can be semi-automatically performed on a Resolvex® A200 positive pressure processor (Tecan). The kit can measure 15 other steroids in the core steroid metabolism pathway due to the effectiveness of the SPE process.

Table 1. LC gradient elution programme. Source: Tecan

Time (min) Mobile phase A (%) Mobile phase B (%)
0 90 10
0.5 65 35
4.5 65 35
4.51 35 65
6.0 2 98
8.0 2 98
8.01 90 10
10.0 90 10

* In USA: for research use only. Not for use in diagnostic procedures. Product availability and regulatory status may vary from country to country. Consult with your Tecan associate for further information.

A more accurate diagnosis of Cushing’s syndrome

Figure 1. Example chromatogram of the Steroid Panel LC-MS internal standard – run 1. ESI, electrospray ionization; 1, aldosterone; 2, cortisone; 3, dehydro-epiandrosterone sulfate; 4, cortisol; 5, 21-deoxycortisol; 6, corticosterone; 7, dexamethasone; 8, 11-deoxycortisol; 9, androstenedione; 10, 11-deoxycorticosterone; 11, testosterone; 12, dehydroepiandrosterone; 13, 17-hydroxyprogesterone; 14, dihydrotestosterone; 15, progesterone.

Image Credit: Tecan

Summary

Early diagnosis of Cushing’s syndrome is critical to prevent potentially fatal complications. A reliable method for reducing the number of false positives in DSTs involves the simultaneous measurement of cortisol and dexamethasone levels, which can be accurately achieved using LC-MS/MS.

The LC-MS/MS method described in this article enables the simultaneous measurement of multiple analytes, such as cortisol, cortisone, and dexamethasone, in serum or plasma.

This analytical approach can provide clinical laboratories with a straightforward method for performing DSTs, and the commercially available kit can ensure consistent and dependable results.

References and further reading

  1. Cushing’s syndrome [website]. National Institute of Diabetes and Digestive and Kidney Diseases 2018 (https://www.niddk.nih.gov/health-information/endocrine-diseases/cushings-syndrome).
  2. Dogra P, Vijayashankar NP. Dexamethasone suppression test. StatPearls 2022, 8 August (https://www.ncbi.nlm.nih.gov/books/NBK542317 ).
  3. Ceccato F, Artusi C, Barbot M, et al. Dexamethasone measurement during low-dose suppression test for suspected hypercortisolism: threshold development with and validation. J Endocrinol Invest 2020;43(8):1105–1113. doi: 10.1007/s40618-020-01197-6.
  4. Roper SM. Yield of serum dexamethasone measurement for reducing false-positive results of low-dose dexamethasone suppression testing. J Appl Lab Med 2021;6(2):480–485. doi: 10.1093/jalm/jfaa193.
  5. Fleseriu M, Auchus R, Bancos I, et al. Consensus on diagnosis and management of Cushing’s disease: a guideline update. Lancet Diabetes Endocrinol 2021;9(12):847–875. doi: 10.1016/S2213- 8587(21)00235-7.
  6. Ponzetto F, Parasiliti-Caprino M, Settanni F, et al. Simultaneous measurement of cortisol, cortisone, dexamethasone and additional exogenous corticosteroids by rapid and sensitive LC-MS/MS analysis. Molecules 2022;28(1):248. doi: 10.3390/molecules28010248.

From https://www.news-medical.net/whitepaper/20240524/A-more-accurate-diagnosis-of-Cushinge28099s-syndrome.aspx

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Repeat Endoscopic Endonasal Transsphenoidal Surgery for Residual or Recurrent Cushing’s Disease: Safety, Feasibility, And Success

Posted on May 27, 2024 by MaryO

Abstract

Purpose

The success and outcomes of repeat endoscopic transsphenoidal surgery (ETS) for residual or recurrent Cushing’s disease (CD) are underreported in the literature. This study aims to address this gap by assessing the safety, feasibility, and efficacy of repeat ETS in these patients.

Methods

A retrospective analysis was conducted on 56 patients who underwent a total of 65 repeat ETS performed by a single neurosurgeon between January 2006 and December 2020. Data including demographic, clinical, laboratory, radiological, and operative details were collected from electronic medical records. Logistic regression was utilized to identify potential predictors associated with sustained remission.

Results

Among the cases, 40 (61.5%) had previously undergone microscopic surgery, while 25 (38.5%) had prior endoscopic procedures. Remission was achieved in 47 (83.9%) patients after the first repeat ETS, with an additional 9 (16.1%) achieving remission after the second repeat procedure. During an average follow-up period of 97.25 months, the recurrence rate post repeat surgery was 6.38%. Sustained remission was achieved in 48 patients (85.7%), with 44 after the first repeat ETS and 4 following the second repeat ETS. Complications included transient diabetes insipidus (DI) in 5 (7.6%) patients, permanent (DI) in 2 (3%) patients, and one case (1.5%) of panhypopituitarism. Three patients (4.6%) experienced rhinorrhea necessitating reoperation. A serum cortisol level > 5 µg/dL on postoperative day 1 was associated with a reduced likelihood of sustained remission.

Conclusion

Repeat ETS is a safe and effective treatment option for residual or recurrent CD with satisfactory remission rates and low rates of complications.

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Introduction

Cushing’s disease (CD) arises from an adrenocorticotropic hormone (ACTH)-secreting pituitary adenoma, leading to excessive endogenous glucocorticoid production [1]. The reported incidence of CD varies from 0.7 to 2.4 cases per million individuals annually [2,3,4,5,6]. Hypercortisolism impacts every bodily system and is linked to elevated morbidity and mortality risks [7, 8]. Therefore, prompt CD diagnosis and management are crucial to enhance patient outcomes.

Transsphenoidal surgery remains the primary treatment for CD, and have been associated with satisfactory remission rates ranging from 65 to 94% [2, 3, 5, 9,10,11]. Two surgical techniques are utilized: microscopic and endoscopic approaches. While both methods are effective, studies indicate that endoscopic transsphenoidal surgery (ETS) offers higher rates of complete tumor removal and lower complication rates [12,13,14]. ETS holds advantages over microscopic transsphenoidal surgery (MTS) due to superior tumor visualization, especially for laterally invasive tumors and macroadenomas [15]. Since its introduction in 1997, ETS has gained popularity and is now the standard surgical approach for managing CD [16].

Remission rates post-ETS for CD treatment range from 77 to 90% [17,18,19,20,21,22]. Despite ETS’s technical benefits and favorable outcomes, recurrence rates for Cushing’s disease after successful ETS range between 5.6% and 22.8% [17, 18, 22, 23]. Reoperating for residual or recurrent CD presents challenges due to altered surgical landmarks and scar tissue formation from previous surgeries, potentially elevating morbidity, and mortality risks [24, 25]. Limited literature exists on the success and outcomes of repeat endoscopic transsphenoidal surgery for residual or recurrent CD. This study aims to address this gap by assessing the safety, feasibility, and efficacy of repeat ETS in patients with residual or recurrent Cushing’s disease.

Methods

Study design

This is a retrospective cohort study of repeat endoscopic transsphenoidal surgery for residual or recurrent Cushing’s disease. All patients underwent endoscopic endonasal transsphenoidal surgery by the senior author between 2006 and 2020. The study protocol was approved by the local ethics committee for clinical studies.

Patient selection

The study participants were selected based on specific inclusion and exclusion criteria. Inclusion criteria were as follows: (i) a confirmed diagnosis of Cushing’s disease, (ii) prior transsphenoidal surgery, and (iii) confirmation of residual or recurrent CD through clinical, laboratory, and/or imaging assessments. Exclusion criteria included: (i) prior craniotomy without transsphenoidal surgery, (ii) previous radiotherapy before reoperation, (iii) inaccessible clinical, laboratory, or radiological data, and (iv) follow-up duration of less than 6 months.

Diagnostic criteria

Each patient underwent thorough screening for active Cushing’s disease. An increased 24-hour urine cortisol level > 45 µg/day or a serum fasting cortisol level exceeding 1.8 µg/dl following a low-dose (2 mg) dexamethasone suppression test was deemed abnormal. Subsequently, a high-dose (8 mg) dexamethasone test was administered, and a reduction of 50% or more from the baseline value was indicative of active Cushing’s disease. Due to the technical limitations of the institution that the research has been done, late-night salivary cortisol tests were not performed. Early remission was characterized by a fasting serum cortisol level below 5 µg/dl on the 1st and 7th postoperative days. Patients displaying a serum cortisol level below 1.8 µg/dl after the low-dose dexamethasone suppression test or those requiring continued corticosteroid replacement post-surgery were considered to maintain remission. The presence of a residual adenoma on postoperative magnetic resonance imaging (MRI) confirmed residual disease.

Routine follow-up protocol

Patients were evaluated for Cushing’s disease symptoms before surgery and monitored at 6 months after surgery, as well as during yearly check-ups for any changes in their condition. Fasting serum ACTH and cortisol levels were measured in the morning before surgery, on the 1st and 7th days after surgery, at the 1st, 3rd, and 6th months, and during yearly follow-up appointments. Prior to surgery, all patients underwent contrast-enhanced pituitary MRI and paranasal sinus CT scans. Follow-up pituitary MRI scans were conducted on the 1st day, at 3 and 12 months after surgery, and then annually thereafter.

Data collection

Data from electronic medical records were gathered, encompassing demographic, clinical, laboratory, radiological, and operative details. Laboratory assessments comprised an anterior pituitary hormone panel (Follicle-stimulating hormone [FSH], Luteinizing hormone [LH], Thyroid-stimulating hormone [TSH], Prolactin [PRL], Growth hormone [GH]), serum electrolytes, preoperative and postoperative serum ACTH, and cortisol levels. Patient records, along with CT and MRI scans, were scrutinized to document preoperative tumor characteristics such as size, multifocality, relationship with the cavernous sinus, Hardy-Wilson classification of sellar destruction, and suprasellar extension. Tumors larger than 10 mm were classified as macroadenomas. The operative database was examined to collect data on previous surgeries, including the number and dates of prior procedures, as well as the surgical techniques utilized. Outcome measures comprised remission rates and surgical complications.

Statistical analysis

Statistical analysis was conducted utilizing SPSS 23.0 software (IBM, New York). Two-group comparisons were performed using Chi-square and Fisher’s exact tests for categorical variables and Student’s t-test for continuous variables. Categorical variables were presented as numbers and percentages, while continuous variables were presented as means ± SD or median [IQR]. Logistic regression was performed to investigate potential predictors linked to sustained remission. A p-value of < 0.05 was deemed statistically significant.

Results

Baseline characteristics

Supplementary File 1 displays the demographic characteristics of the patient cohort.

A retrospective analysis was conducted on 190 patients who underwent a total of 212 operations for CD at our department between January 2006 and December 2020. Among them, 56 patients, comprising 65 repeat endonasal transsphenoidal surgeries due to either recurrence (n = 18, 27.7%) or residual disease (n = 47, 72.3%), were identified. The majority of patients were female (n = 48, 85.7%), with a mean age of 37.6 ± 12.4 years. Of the 56 patients, 43 (76.8%) were referred from another institution. Most patients (n = 42, 75%) had undergone only one prior surgery, while 12 patients (21.4%) had a history of two previous surgeries, and 2 patients (3.6%) had undergone three prior surgeries before referral to our center. The average follow-up duration since the first repeat ETS was 97.2 ± 36.8 months. The mean time to recurrence was 80.2 ± 61.1 months (median 75 months, range 23.2 to 103.5 months).

Hormonal data

Table 1 depicts the preoperative and postoperative serum ACTH and cortisol levels. The average preoperative serum cortisol levels for the entire patient cohort stood at 18.7 ± 11.1 µg/dL (median 17, range 12-24.6). The median preoperative 24-hour urine free cortisol level was 237 µg /day [188.5–425.5]. On the initial postoperative day, the mean serum cortisol levels for all patients were 13.4 ± 13.8 µg/dL (median 6.4, range 1.7–21). In 46.2% of cases (n = 30), cortisol levels on the first postoperative day were below 5 µg/dL (< 2 µg/dL in 33.8%). A comparison of the mean preoperative and postoperative serum ACTH and cortisol levels between the groups with residual disease and recurrence is detailed in Table 1.

Table 1 Cohort overview and comparison of recurrence and residual disease groups

Radiological findings

In the entire case cohort, there were 41 microadenomas (63.1%) and 24 macroadenomas (36.9%). Fifteen cases (23.1%) exhibited bifocal adenomas. Adenoma extension into the cavernous sinuses, indicated by cavernous sinus wall displacement, was present in 21 cases (32.3%), while invasion into the cavernous sinuses was observed in 10 cases (15.4%). Based on the Hardy-Wilson Classification, there were 38 Grade I adenomas (58.5%), 16 Grade II adenomas (24.6%), 6 Grade III adenomas (9.2%), and 5 Grade IV adenomas (7.7%). Thirty patients (46.2%) presented with Stage A adenoma, 7 (10.8%) with Stage B adenoma, 2 (3.1%) with Stage C adenoma, 1 (1.5%) with Stage D adenoma, and 25 (38.5%) with Stage E adenoma. As indicated in Table 1, there were no statistically significant differences between patients with residual disease and recurrence concerning radiological findings.

Surgical characteristics

A single surgeon conducted all 65 reoperations. Among these, 47 patients (72.3%) underwent repeat ETS due to residual disease, while 18 (27.7%) did so due to recurrence. The previous surgical technique was microscopic in 40 cases (61.5%) and endoscopic in 25 cases (38.5%). Microscopic transsphenoidal surgeries were exclusively performed at other institutions. There was a notable disparity between patients with residual disease and recurrence regarding the technique of the previous surgery. Residual disease occurrence following endoscopic transsphenoidal surgery was less frequent (n = 11/25, 44%) compared to after microscopic transsphenoidal surgery (n = 36/40, 90%; p < 0.001) (Table 1). Immunohistochemical staining of the specimens indicated that 55 cases (85%) exhibited ACTH-positive adenoma. Nevertheless, all patients with a negative pathology at the repeat surgery had a confirmed ACTH-adenoma at the first surgery. Of the 10 patients (15%) with a negative ACTH-positive adenoma pathology, two patients underwent inferior petrosal sinus sampling (IPSS) previously and were confirmed to have CD. Remaining patients did not undergo an additional inferior petrosal sinus sampling (IPSS) because all functional test results indicated a central source and MRI confirmed pituitary microadenoma in all cases. Notably, there are studies reporting that IPSS may not be required in patients with a sellar mass and a biochemical testing suggestive of CD [26, 27]. Additionally, we also explored both sides of the pituitary and confirmed the adenoma intraoperatively. Therefore, negative pathology in the repeat surgery is most likely due to sampling error.

Outcomes

As depicted in Fig. 1, among the 56 patients, 47 (83.9%) experienced initial remission following the first repeat ETS, while 9 (16.1%) still had residual adenoma. Within the group achieving initial remission, 44 patients (93.6%) maintained remission without the need for further surgeries, while 3 (6.4%) experienced recurrence during follow-up and required a second repeat ETS.

Fig. 1
figure 1

Outcomes of repeat endoscopic transsphenoidal surgery for residual or recurrent Cushing’s disease

Among the 9 patients with residual disease after the first repeat ETS, 1 (11.1%) opted to defer further treatment, 1 (11.1%) received radiotherapy, 1 (11.1%) chose adrenalectomy, and 6 (66.7%) underwent a second repeat ETS. Of the 9 patients who underwent a second repeat ETS due to residual disease or recurrence, 4 (44.4%) sustained remission, 5 (55.6%) still had residual disease, but 3 of them deferred further treatment, 1 received radiotherapy, while 1 achieved remission after adrenalectomy. Overall, 78.5% (n = 51) of the entire case cohort achieved remission following repeat ETS. Representative cases are presented in Fig. 2.

Fig. 2
figure 2

Case 1: Preoperative and postoperative magnetic resonance imaging (MRI) scans of a 49-year-old female who underwent repeat endoscopic transsphenoidal surgery (ETS) due to recurrent Cushing’s disease and achieved remission. The patient underwent initial surgery 14 years ago at an outside institution. Preoperative T2 (A), and T1 contrast-enhanced (B) MRI scans demonstrate a right-sided pituitary adenoma. Postoperative T2 (C), and T1 contrast-enhanced (D) MRI scans demonstrate total resection of the adenoma. Case 2: Preoperative and postoperative magnetic resonance imaging (MRI) scans of a 53-year-old female who underwent repeat endoscopic transsphenoidal surgery (ETS) due to recurrent Cushing’s disease and achieved remission. The patient underwent initial surgery 3 years ago at an outside institution. Preoperative T2 (E), and T1 contrast-enhanced (F) MRI scans demonstrate a left-sided pituitary adenoma, in close relation to ICA. Postoperative T2 (G), and T1 contrast-enhanced (H) MRI scans demonstrate total resection of the adenoma

Transient diabetes insipidus (DI) developed in 5 patients (7.6%), while 2 (3%) experienced permanent DI following repeat ETS. Intraoperative cerebrospinal fluid (CSF) leak occurred in 20 operations (30.7%). Three patients (4.6%) developed rhinorrhea and required reoperation. Five patients (7.6%) developed prolactin deficiency, 3 patients (4.6%) had GH deficiency, and another 3 patients (4.6%) had TSH deficiency requiring thyroxine replacement. Four patients (6.2%) had combined deficiencies in TSH, FSH, LH and prolactin, while one patient (1.5%) developed panhypopituitarism following the second repeat ETS.

Factors predisposing to unsuccessful repeat endoscopic transsphenoidal surgery

Among the 42 patients who underwent repeat ETS for residual disease, 9 (21.4%) still had residual disease after the first repeat ETS. We conducted a multivariable logistic regression analysis to explore potential risk factors for unsuccessful repeat ETS. However, the analysis did not reveal any significant association between the success of repeat ETS and factors such as extension or invasion into cavernous sinuses, sellar or parasellar extension, or tumor size (Supplementary File 1).

Potential predictors of sustained remission

We conducted a multivariable logistic regression analysis to investigate possible predictors of sustained remission. The variables included in the analysis are detailed in Table 5. The results indicated that having a serum cortisol level exceeding 5 µg/dL on postoperative day 1 was linked to a decreased likelihood of achieving sustained remission (Odds ratio [OR] 0.09, 95% confidence interval [CI] 0.01–0.52, p = 0.006) (Table 2).

Table 2 Logistic regression analysis of potential predictors for continued remission

Discussion

Transsphenoidal surgery remains the established standard for treating Cushing’s disease, with demonstrated remission rates ranging from 65 to 94%, contingent upon the surgeon’s expertise and remission criteria [2, 3, 5, 9,10,11]. The advent of endoscopic techniques has notably augmented this approach, offering wider visibility, reduced nasal trauma, and shorter hospital stays [16, 25, 28, 29]. While the effectiveness of ETS in managing CD is well-documented, literature on its efficacy in treating residual or recurrent cases is limited. Our study addresses this gap by assessing the safety, feasibility, and outcomes of repeat ETS for patients with persistent or recurrent Cushing’s disease.

In our study, 56 patients underwent 65 repeat ETS procedures for residual or recurrent Cushing’s disease. Mean follow-up duration was 97.2 ± 36.8 months, which is one of the longest follow-up durations that has been reported following repeat endoscopic transsphenoidal surgery [5, 30,31,32]. Of these patients, 40 (61.5%) had previously undergone microscopic surgery, while 25 (38.5%) had undergone prior endoscopic procedures. Importantly, a notable difference emerged between patients with residual disease and those experiencing recurrence regarding the prior surgical approach, with residual disease being less frequent after endoscopic surgery compared to microscopic surgery (p < 0.001). This variance was expected, as numerous studies have indicated that ETS yields a higher rate of complete resection compared to MTS [12,13,14].

After the first repeat ETS, 47 patients (83.9%) achieved remission, and 78.5% (n = 44) of them maintained remission at a mean follow-up of 97.2 months without requiring additional surgery. Limited data exists regarding the remission rates of CD following repeat transsphenoidal surgery, with reported rates ranging from 28.9 to 73% [33, 34, 35]. Burke et al. reported an immediate remission rate of 86.7% and a continued remission rate of 73.3% at follow-up after repeat ETS [36]. Among our patients who achieved remission after successful repeat ETS, 3 individuals (6.38%, n = 3/47) experienced recurrence after the first repeat ETS, with a mean time to recurrence of 45.6 months. The rates of CD recurrence following reoperation vary, with documented rates ranging between 22% and 63.2% [37, 38]. In our study, 9 patients required a second repeat ETS due to residual disease or recurrence. Of these, 4 (44.4%) achieved continued remission following the second repeat ETS, while 5 (55.6%) had residual disease; however, 4 of them deferred further treatment, and 1 achieved remission after adrenalectomy. In total, 47 patients (83.9%) in the entire patient cohort achieved remission following endoscopic transsphenoidal surgery and did not require further intervention.

Within our case cohort, among the 42 patients who underwent repeat ETS for residual disease, 9 individuals (21.4%) continued to exhibit residual disease following the first repeat ETS. We did not establish a significant association between the success of repeat ETS and factors such as extension or invasion into cavernous sinuses, sellar or parasellar extension, or tumor size.

The degree of hypocortisolism following transsphenoidal surgery is considered a potential indicator of remission in the postoperative period [3]. Numerous studies have indicated that patients with subnormal postoperative cortisol levels tend to experience a lower recurrence rate compared to those with normal or supranormal levels, although consensus on the precise cutoff level remains elusive [30,31,32, 39]. In a retrospective study involving 52 patients with CD, researchers reported a 100% positive predictive value of a postoperative nadir cortisol level < 2 µg/dL for achieving remission [5]. Additionally, Esposito et al. observed that a morning serum cortisol level ≤ 5 µg/dL on postoperative day 1 or 2 appears to serve as a reliable predictor of remission [11]. In our investigation, logistic regression analysis revealed that patients with a serum cortisol level > 5 µg/dL on postoperative day 1 were less inclined to achieve continued remission compared to those with a serum cortisol level < 5 µg/dL on postoperative day 1.

Repeat transsphenoidal surgery presents unique challenges due to distorted surgical landmarks and the presence of scar tissue from prior procedures, often resulting in lower cure rates and increased morbidity risk [24, 25, 28]. Non-surgical options such as radiotherapy and radiosurgery have been considered as an effective treatment option for recurrent or residual CD due to low rates of morbidity and acceptable remission rates [28, 40]. However, our findings suggest that the outcomes and complication rates associated with repeat ETS are comparable to primary ETS for CD and superior to other non-surgical options for residual or recurrent CD. Within our patient cohort, 5 (7.6%) individuals experienced transient diabetes insipidus (DI), while 2 (3%) developed permanent DI. Additionally, one patient (1.5%) experienced panhypopituitarism following the second repeat ETS. Similarly, various studies have reported DI rates ranging from 2 to 13% and panhypopituitarism rates between 2% and 9.7% [25, 28, 41,42,43]. In our series, 3 (5.3%) patients developed rhinorrhea and required reoperation, consistent with reported rates of postoperative CSF leak ranging from 1 to 5% following repeat endoscopic transsphenoidal surgery for residual or recurrent pituitary tumors [25, 28, 44]. While radiotherapy and radiosurgery are options for patients who have failed transsphenoidal surgery or experienced recurrence, the literature suggests remission rates ranging from 46 to 84%, with several studies indicating high recurrence rates (25-50%) following radiotherapy [40, 45,46,47]. In our study, among 56 patients, 47 (83.9%) achieved remission following the first repeat ETS, while 4 (17.8%) achieved remission after the second repeat ETS. Over a mean follow-up duration of 97.25 months, our recurrence rate following repeat ETS was 27.7%, with a mean time to recurrence of 45.62 months.

At our institution, we adhere to a specific algorithm (Fig. 3) for managing Cushing’s disease patients and implement a meticulous protocol for individuals undergoing repeat ETS for residual or recurrent CD. A thorough clinical and radiological assessment is conducted for all patients before surgery. Detailed radiological evaluation is particularly essential to identify any distortions in surgical landmarks from prior procedures, such as the course of sphenoidal septa and the location of the sellar floor opening, as well as other potential aberrations like internal carotid artery and optic nerve dehiscence. Imaging techniques should encompass dynamic pituitary MRI with and without contrast and paranasal CT scans. Our objective is to achieve extensive exposure during surgery, which is especially critical for managing bifocal adenomas or adenomas with cavernous sinus invasion or extension. The expanded visual field also facilitates the visualization of concealed parts of the adenoma, allowing the surgeon to achieve complete resection, which may be challenging or even impossible with limited exposure. We employ a multilayer closure technique to prevent CSF leaks, and if necessary, utilize a vascularized pedicled nasoseptal flap (Hadad-Bassagasteguy flap).

Fig. 3
figure 3

Specific algorithm for the management of Cushing’s disease patients

In summary, our findings suggest that in the hands of experienced surgeons, repeat ETS represents a safe and effective treatment option for managing residual or recurrent Cushing’s disease.

Strengths and limitations

Our study represents one of the largest case series in the literature examining the safety, feasibility, and efficacy of repeat ETS for managing recurrent or residual CD. Our findings underscore the safety and efficacy of repeat ETS in experienced centers, showcasing satisfactory remission rates and minimal complications. However, it is important to acknowledge the retrospective nature of our study, which inherently introduces potential biases such as selection bias. Lastly, our study exclusively focuses on patients undergoing surgical intervention for recurrent or residual CD, limiting our ability to compare the effectiveness of surgical treatment with alternative modalities like radiotherapy or radiosurgery.

Conclusion

Our study underscores the efficacy and safety of repeat endoscopic transsphenoidal surgery in managing residual or recurrent Cushing’s disease. Remarkably, 82.1% of patients achieved remission after their first reoperation, aligning closely with reported remission rates following primary endoscopic transsphenoidal surgery. Furthermore, the complication rates observed in our cohort were consistent with documented rates for both primary and repeat transsphenoidal surgeries. Notably, patients with serum cortisol levels < 5 µg/dL are more likely to maintain remission. Overall, our findings emphasize that in the hands of experienced surgeons, repeat endoscopic transsphenoidal surgery emerges as a reliable and safe treatment modality for residual or recurrent Cushing’s disease, offering satisfactory remission rates and minimal complications.

Data availability

No datasets were generated or analysed during the current study.

Abbreviations

ACTH:
adrenocorticotropic hormone
CD:
Cushing’s disease
CT:
computed tomography
DI:
diabetes insipidus
ETS:
endoscopic endonasal transsphenoidal surgery
MRI:
magnetic resonance imaging
MTS:
microscopic transsphenoidal surgery

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Acknowledgements

Not applicable.

Funding

The authors declare that no funds, grants, or other support were received during the preparation of this manuscript.

Open access funding provided by the Scientific and Technological Research Council of Türkiye (TÜBİTAK).

Author information

Authors and Affiliations

  1. Department of Neurosurgery, Faculty of Medicine, Hacettepe University, Ankara, Turkey

    Sahin Hanalioglu, Muhammet Enes Gurses, Neslihan Nisa Gecici, Baylar Baylarov & Ilkay Isikay

  2. Department of Neurosurgery, Miller School of Medicine, University of Miami, Miami, FL, USA

    Muhammet Enes Gurses

  3. Department of Endocrinology and Metabolism, Faculty of Medicine, Hacettepe University, Ankara, Turkey

    Alper Gürlek

  4. Department of Neurosurgery, Hacettepe University School of Medicine, Sihhiye, Ankara, 06230, Turkey

    Mustafa Berker

Contributions

Conceptualization: S.H, M.B; Methodology: S.H, M.E.G, N.N.G; Formal analysis and investigation: M.E.G, N.N.G, B.B; Writing – original draft preparation: N.N.G; Writing – review and editing: S.H, M.E.G, B.B, I.I, A.G, M.B; Supervision: S.H, I.I, A.G, M.B.

Corresponding author

Correspondence to Mustafa Berker.

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Hanalioglu, S., Gurses, M.E., Gecici, N.N. et al. Repeat endoscopic endonasal transsphenoidal surgery for residual or recurrent cushing’s disease: safety, feasibility, and success. Pituitary (2024). https://doi.org/10.1007/s11102-024-01396-x

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Venous Thromboembolism in Cushing Syndrome

Posted on May 22, 2024 by MaryO

Abstract

Background

Patients with Cushing syndrome (CS) are at increased risk of venous thromboembolism (VTE).

Objective

The aim was to evaluate the current management of new cases of CS with a focus on VTE and thromboprophylaxis.

Design and methods

A survey was conducted within those that report in the electronic reporting tool (e-REC) of the European Registries for Rare Endocrine Conditions (EuRRECa) and the involved main thematic groups (MTG’s) of the European Reference Networks for Rare Endocrine Disorders (Endo-ERN) on new patients with CS from January 2021 to July 2022.

Results

Of 222 patients (mean age 44 years, 165 females), 141 patients had Cushing disease (64%), 69 adrenal CS (31%), and 12 patients with ectopic CS (5.4%). The mean follow-up period post-CS diagnosis was 15 months (range 3–30). Cortisol-lowering medications were initiated in 38% of patients. One hundred fifty-four patients (69%) received thromboprophylaxis (including patients on chronic anticoagulant treatment), of which low-molecular-weight heparins were used in 96% of cases. VTE was reported in six patients (2.7%), of which one was fatal: two long before CS diagnosis, two between diagnosis and surgery, and two postoperatively. Three patients were using thromboprophylaxis at time of the VTE diagnosis. The incidence rate of VTE in patients after Cushing syndrome diagnosis in our study cohort was 14.6 (95% CI 5.5; 38.6) per 1000 person-years.

Conclusion

Thirty percent of patients with CS did not receive preoperative thromboprophylaxis during their active disease stage, and half of the VTE cases even occurred during this stage despite thromboprophylaxis. Prospective trials to establish the optimal thromboprophylaxis strategy in CS patients are highly needed.

Significance statement

The incidence rate of venous thromboembolism in our study cohort was 14.6 (95% CI 5.5; 38.6) per 1000 person-years. Notably, this survey showed that there is great heterogeneity regarding time of initiation and duration of thromboprophylaxis in expert centers throughout Europe.

Keywords: endogenous hypercortisolism; Cushing disease; Cushing syndrome; thromboprophylaxis; venous thromboembolism

Introduction

Endogenous hypercortisolism (Cushing syndrome, CS) is a rare disorder with an estimated incidence of 0.2–5.0 cases per million inhabitants per year in various populations, whereas its prevalence is close to 39–79 cases per million (1, 2). The majority of cases are adrenocorticotropic hormone (ACTH) dependent, of which a pituitary corticotrope adenoma (Cushing disease, CD) is the most prevalent cause, whereas ACTH-secreting non-pituitary tumors (ectopic ACTH and corticotropin-releasing hormone syndrome secretion) are responsible for about 5–10% of cases. ACTH-independent cases of CS (adrenal adenomas or uni- or bilateral adrenal hyperplasia) account for the remaining 20% of cases (1, 3).

It is well-known that endogenous hypercortisolism is associated with increased morbidity and mortality (4, 5, 6). This increased risk is mainly driven by cardiovascular events, including venous thromboembolic events (VTEs) such as pulmonary embolism (PE) and deep vein thrombosis (DVT). It has been demonstrated that the primary risk factors associated with VTE include older age (>69 years), reduced mobility, acute severe infections, previous cardiovascular events, higher midnight plasma cortisol levels, and shorter activated partial thromboplastin time (7). Additionally, a recent analysis of the ERCUSYN database found a higher prevalence of VTE among male patients, patients with a history of multiple surgeries, and those with high urinary cortisol levels (8). Several studies have observed an increased risk of VTE in patients with endogenous hypercortisolism even long after successful treatment. A study showed that the VTE incidence is almost seven times higher in the years before diagnosing endogenous hypercortisolism and almost 17 times higher in the first year after diagnosis; this incidence remains increased in the initial months following successful treatment (9). This results in an increased incidence rate of 14.6 per 1000 person-years for VTE in patients with endogenous hypercortisolism compared to the general population (10). The cortisol-induced hypercoagulability is thought to be partially caused by activation of the coagulation cascade with an increase in, e.g. von Willebrand factor, fibrinogen, and factor VIII concentrations (11, 12), impaired fibrinolysis (4) and endothelial dysfunction (13). Changes in pro- and anticoagulant factors may persist after successful surgery or medical therapy for at least several months (14, 15).

Given the lack of evidence from clinical trials, there is a large practice variation regarding thromboprophylaxis management and perioperative medical treatment in patients with endogenous hypercortisolism, even among reference centers that have obtained specific national and international accreditation for the diagnosis and treatment of CS (16). To further map local practice patterns and associated VTE complications in CS, we performed a study across the European Reference Network on Rare Endocrine Conditions (Endo-ERN) expert centers using the European Registries for Rare Endocrine Conditions (EuRRECa), and the contributors to the relevant main thematic groups (MTGs), i.e. Adrenal (one) and Pituitary (six) of the Endo-ERN.

Methods

The main objective of this study was to collect epidemiological and routine clinical data on new CS cases reported on the EuRRECa electronic reporting tool (e-REC) and Endo-ERN with a focus on VTE and thromboprophylaxis.

EuRRECa was constructed to support the needs of Endo-ERN, maximizing the opportunity for all patients, healthcare professionals, and researchers to participate and use high-quality, patient-centered registries for these rare conditions. The two platforms of the EuRRECa project encompass the Core registry, which collects a common dataset and clinician- and patient-reported outcomes, and an electronic surveillance system, the e-Reporting on Rare Endocrine Conditions (e-REC) program (17).

e-REC is a program that monthly captures the number of new cases of rare endocrine conditions seen at the participating centers.

e-REC is used for continuous monitoring of the expert centers of ERNs (Endo-ERN, ERN BOND), for mapping expert centers not only within European Union, for understanding the occurrence of the rare endocrine and bone conditions, and for conducting secondary surveys.

Because e-REC only provides a number of cases with a specific diagnosis without any personal data, there is no informed consent needed. e-REC is open to Endo-ERN and other centers involved in the care of patients with rare endocrine conditions.

Secondary survey

Secondary surveys (https://eurreb.eu/registries/e-rec/secondary-survey/) on e-REC-reported cases allow for the collection of well-defined routine clinical data for quality assurance and for understanding the clinical presentation of the reported condition. No personally identifiable data, such as date of birth, date of surgery, date of VTE, or exact laboratory tests, were collected.

First, the e-REC team sorted e-REC IDs of patients with endogenous hypercortisolism (ORPHA443287, ORPHA1501, ORPHA99408, ORPHA96253) reported between January 2021 and July 2022. Then the centers were provided with the list of IDs and queried to revisit these cases and to add clinical data to the online questionnaire. The survey questionnaire utilized Webropol survey, a secure online tool endorsed and supported by NHS Greater Glasgow & Clyde and NHS Scotland. The use of e-REC and secondary surveys was approved by the institutional board of the Leiden University Medical Center, and participating centers were advised to seek local approval if needed.

In addition, healthcare providers (not reporting in e-REC) of the relevant main thematic groups (‘Adrenal’ and ‘Pituitary’) of Endo-ERN were queried regarding any of their reported new encounters with a confirmed diagnosis of CS from January 2021 to July 2022. Patients with suspected but not confirmed CS were excluded (according to the current guideline) (18).

VTE in CS survey

The survey was open for entry from October 2022 to June 2023. Follow-up started on the date of initial CS diagnosis (within the period of interest – January 2021 till July 2022) and ended when an endpoint of interest occurred (VTE, bleeding, death) or on the date of filling in the questionnaire, whichever came first.

A survey was designed consisting of questions on the occurrence of VTE, and if so, additional questions assessed risk factors of VTE, treatment regimens, and VTE complications. Questions included data about relevant co-morbidities and the different items of the Cushing severity index (CSI) – a validated score for reliable clinometric evaluation of severity in endogenous hypercortisolism (19) using eight different parameters (fat distribution, skin lesions, muscle weakness, mood disorders, hypertension, diabetes mellitus, hypokalemia, and sex-related disturbances), each one graded from 0 to 2 with a maximum score of 16. These components enabled the calculation of the CSI score of all subjects. For the full questionnaire, see Annex 1 (see section on supplementary materials given at the end of this article).

Statistical analyses

Continuous data are presented as mean ± s.d. (range) and were compared using ANOVA. All the other values, if not normally distributed, are expressed as median with interquartile range (IQR) and compared using ANCOVA. Statistical analysis was performed using SPSS version 25.0.

The individual person-time was calculated based on the dates of reporting in e-Rec and filling in the survey and on the date of VTE. Incidence rates for VTE were calculated by dividing the observed number of VTE cases within the study period by the sum of individual person-years and were presented with accompanying 95% CI. Any VTE occurring before diagnosis was ignored in the estimation of the incidence rate.

Results

Patient characteristics

The survey was completed by 35 clinicians in 20 centers from six countries (Fig. 1). Within the 18-month study period, a total of 222 new patients were reported with endogenous hypercortisolism. The mean follow-up period was 15 ± 8 months (range 3–30). The total number of person-years was 274. Table 1 shows the clinical and demographic characteristics of patients with CS.

Figure 1View Full Size
Figure 1

Overview of countries responding to the survey.

Citation: Endocrine Connections 13, 6; 10.1530/EC-24-0046

Table 1Clinical and demographic characteristics of patients with Cushing syndrome of different origin.

Demographic/clinical variable Cushing disease Adrenal Cushing syndrome Ectopic Cushing syndrome Total
Number of patients: n (%) 141 (63.5%) 69 (31.1%) 12 (5.4%) 222 (100%)
Age (years): median (IQR) (range) 43 (22.5) (7–79) 46 (25.5) (3–80) 48 (37) (22–77) 43 (25) (3–80)
Female: n (%) 105 (74.4%) 54 (78.2%) 6 (50%) 165 (74.3%)
СSI: mean ± s.d. 5.77 ± 2.88 4.81 ± 2.72 8.5 ± 2.87 5.6 ± 2.9
Number of comorbidities: mean ± s.d. 1.9 ± 1.58 1.97 ± 1.39 2.17 ± 1.7 1.93 ± 1.53
Obesity: n (%) 49 (34.8%) 23 (33.3%) 4 (33.3%) 76 (34.2%)
Hypertension: n (%) 90 (63.8%) 49 (71%) 9 (75%) 148 (66.7%)
Diabetes: n (%) 30 (21.3%) 17 (24.6%) 5 (41.7%) 52 (23.4%)
Previous VTE: n (%) 9 (6.4%) 2 (2.9%) 0 11 (4.9%)
VTE: n (%) 4 (2.8%) 1 (1.4%) 1 (8.3%) 6 (2.7%)
Cortisol-lowering treatment: n (%) 60 (42.6%) 14 (20.2%) 10 (83.3%) 84 (37.8%)
Thromboprophylaxis: n (%) 103 (73%) 41 (59.4%) 10 (83.3%) 154 (69.3%)
Surgery: n (%) 133 (94.3%) 64 (92.8%) 7 (58.3%) 204 (91.9%)

CSI, Cushing severity index; VTE, venous thromboembolism.

 

One hundred forty-one patients had Cushing’s disease (64%), 69 had ACTH-independent CS (31%), and 12 patients had ectopic CS (5.4%). One hundred sixty-five (74%) were female with a mean age of 44 ± 16 years (range 3–80). Ninety-one patients (41%) were overweight (BMI 25–30 kg/m2), and 76 (34%) were obese (BMI ≥ 30 kg/m2). A previous VTE (not related to CS based on the clinical judgment of the reporters, information on the time of occurrence was unavailable) was reported in 11 (4.9%) patients, and other cardiovascular events (e.g. myocardial infarction, myocarditis, cerebrovascular disease, and stroke) in 11 patients (4.9%). Most patients underwent surgery (n = 204, 92%), pituitary (n = 130, 64%), adrenal surgery (n = 68, 33%), and other surgery (n = 6, 3%); 47 (23%) of them had repeated surgery.

The mean number of comorbidities was 2 ± 1.5 (range 0–10). In 36 (16.2%) patients, no relevant comorbidities were reported, and 25 had more than 4 (11%). Mean CSI was 5.6 ± 2.9 (0–13), patients with CD had higher scores compared to patients with adrenal CS 5.8 ± 2.9 vs 4.8 ± 2.7 (MD 1.0; 95% CI 0.2; 1.8). Patients with ectopic CS had the highest scores (8.5 ± 2.9), with a mean difference of 3.7 (95% CI 2.0; 5.4) compared to adrenal CS, and a mean difference of 2.7 (95% CI 1.0; 4.4) when compared to CD.

Cortisol-lowering medical treatment

Eighty-four patients (38%) received pre-surgical cortisol-lowering medical treatment, the majority receiving metyrapone (68%) or ketoconazole (30%). Other used agents were osilodrostat (8%), mitotane (1%), and levoketoconazole (1%). Of the pre-treated patients, 60 had CD (43% of the total CD group), 14 had adrenal CS (20% of the total adrenal CS group), and 10 had ectopic CS (83% of the total ectopic CS group). Patients with CD and ectopic CS were treated more often in comparison with patients with adrenal CS, with OR 2.9 (1.5; 5.7), P = 0.0019 and OR 19.6 (3.9; 100), P = 0.0003, respectively.

There were no major differences in patient characteristics between pre-treated and non-pre-treated patients in terms of age (44 ± 17 vs 43 ± 15 years; MD 1.0; 95% CI −3.4; 5.4), sex distribution (65/83 vs 101/138, OR 1.3; 95% CI 0.7; 2.5), number of comorbidities (1.8 ± 1.2 vs 2.0 ± 1.8; MD 0.2; 95% CI −0.2; 0.6), and CSI (6.2 ± 3.0 vs 5.4 ± 2.8; MD 0.8; 95% CI 0.01; 1.6).

Medical cortisol-lowering treatment was initiated at the time of diagnosis in 59 cases (70%) and usually discontinued 1 day before or after surgery (91%). Hypercortisolism was completely controlled in 43 patients (21%) and partially controlled in 40 (20%) before surgery, irrespective of disease origin (based on the cortisol levels).

VTE prophylaxis

Protocolled and unprotocolled initiation of thromboprophylaxis

A thromboprophylaxis protocol specific for patients with CS was present in 6 out of 20 centers (30%), while three centers (15%) had no thromboprophylaxis protocol, and 11 out of 20 (55%) had a protocol not specific for CS. Thromboprophylaxis was given to 154 out of 222 patients (69%); in 15 cases (9.7%), this was a therapeutic treatment due to a previous event/condition. Thromboprophylaxis was initiated from CS diagnosis onward in 43 cases (28%): thirty-one patients (31/43, 72%) were from centers (n = 3) with specific thromboprophylaxis protocols for patients with CS, and consequently, the treatment was initiated at the time of diagnosis. The remaining 12 patients (28%) started thromboprophylaxis due to the presence of risk factors such as severe CS, older age, limited mobility, active malignancy, or additional cardiovascular comorbidities. Thromboprophylaxis was initiated 2−6 weeks before surgery – in nine cases (5.8%), 1 week before surgery – in eight cases (5.2%), the day before/of surgery in 50 cases (33%), and after surgery – in 26 cases (19%). The remaining 30% of patients did not receive any thromboprophylaxis. In three cases (1.9%), data about the initiation of thromboprophylaxis were missing. In patients with CD, therapy was started more often on the day before/of surgery (40%) compared to adrenal CS patients (20%), OR 2.7 (95% CI 1.1; 6.5). At the same time, thromboprophylaxis was more often prescribed after surgery in patients with adrenal CS (12/41 vs 13/103; OR 2.86 (95% CI 1.1; 7.0)). The use of elastic compressive stockings was reported in 83 (37%) of patients.

Thromboprophylactic agents and duration of treatment

Low-molecular-weight heparins (LMWHs) were prescribed in the vast majority of cases, with n = 147 (96%). Nadroparine was used in 57 patients (39%), with a dose ranging from 2850 to 5700 IU per day depending on BMI. Enoxaparin, ranging from 4000 to 6000 IU per day, was prescribed in 52 patients (35%), while dalteparin, ranging from 2500 to 5000 IU per day, was used in 32 patients (22%). Other drugs included tinzaparin and fondaparinux. Direct oral anticoagulants (DOACs) were used in only six patients (3.9%) (with dosages ranging from 10 to 20 mg/day for rivaroxaban and 2.5–10 mg/day for apixaban), and warfarin was prescribed in one patient (0.6%).

Thromboprophylaxis was discontinued during the first week after surgery in 55 patients (36%), during 2–4 weeks in 28 patients (18%), 6–12 weeks in 26 patients (17%), and was continued longer in 17 patients (11%). The median pre- and postoperative duration of thromboprophylaxis was 14 days (IQR = Q3–Q1 = 28–7 = 21).

Differences between patients that received and those that did not receive thromboprophylaxis

The 68 patients not receiving any thromboprophylaxis had lower CSI scores 4.3 ± 2.5 vs 6.2 ± 2.9 (MD 1.9; 95% CI 1.1; 2.8), and more often did not undergo surgery, 12/68 vs 6/154 (OR 5.3 (95% CI 1.9; 14.8)). Within the cohort of patients with CD, thromboprophylaxis was prescribed more often to older patients (45 ± 15 vs 37 ± 15 years) and to patients with higher CSI (6.1 ± 2.8 vs 4.7 ± 2.7, MD 1.4, 95% CI 0.4; 2.4). Among the patients with adrenal CS, thromboprophylaxis was initiated more often with higher CSI (5.8 ± 2.9 vs 3.6 ± 1.9, MD 2.2, 95% CI 0.9; 3.5), but no differences were observed in age and number of comorbidities (MD 4.6, 95% CI (−4.0; 13.2) and MD 0.1 (−0.5; 0.8), respectively).

Bleeding complications

No major bleeding was reported; two patients reported epistaxis, not related to pituitary surgery.

Venous thromboembolic event

Six cases of VTE were reported (2.7%, 95% CI 1; 6), (Table 2): four patients with CD, one patient with adrenal CS, and one patient with ectopic CS. At the time of VTE, 5 out of 6 had uncontrolled hypercortisolemia.

Table 2Clinical and demographic characteristics of patients with Cushing syndrome of different origin and VTE.

Demographic/clinical variable Case 1 Case 2 Case 3 Case 4 Case 5 Case 6
Type of CS CD CD CD CD Benign adrenal CS Ectopic CS
Sex F F F M M F
Age 48 55 33 54 35 39
Risk factors Overweight

Hypertension

Osteoporosis with fractures

 Obesity

Hypertension

Previous VTE

 Obesity

Hypertension

Repeated pituitary surgery

 Obesity

Hypertension

Previous VTE

Diabetes

 Overweight

Hypertension

Osteoporosis with fractures

Previous VTE

 Hypertension
CSI 7 5 7 5 1 11
Medical treatment No No Yes (controlled CS) No No Yes (uncontrolled CS)
TPX start 1 week pre-op The day of surgery 1 week pre-op Before Dz of CS Before Dz of CS From diagnosis
TPX stop 2 weeks post-op 1 week post-op 6 weeks post-op Ongoing DOAC Ongoing LMWH Ongoing LMWH
TPX type Nadroparine Nadroparine Nadroparine Rivaroxaban Fondaparinux Tinzaparin
VTE type Central retinal vein occlusion PE Thrombophlebitis with thrombus v. cephalica PE + DVT PE Inferior vena cava thrombosis resulting to death
VTE timing 12 weeks pre-op 6 weeks post-op 9 days post-op 24 months before diagnosis 4 weeks before diagnosis Was not operated

CSI, Cushing severity index; CS, Cushing syndrome; CD, Cushing disease; DVT, deep vein thrombosis; DOAC, direct oral anticoagulants; LMWH, low-molecular-weight heparin; PE, pulmonary embolism; TPX, thromboprophylaxis; VTE, venous thromboembolism.

 

Three patients (3/6) had a previous VTE, and most of them had several additional risk factors for thrombosis. There were three cases of PE (one combined with DVT), one case of central retinal vein thrombosis, and one case of thrombophlebitis with thrombus of the vena cephalica. The patient with ectopic CS died because of thrombosis of the vena cava inferior despite cortisol-lowering treatment with four different agents and thromboprophylaxis with LWMH treatment. VTE episodes were registered during a very wide time frame: from 2 years before the diagnosis of CS to 6 weeks after surgery. One VTE episode was reported in the group of patients with elastic stockings usage (1/83), three in group without stockings (3/121), and two in the group with unknown status (OR 0.7 (95% CI 0.1; 8.1)).

The incidence rate of VTE after CS diagnosis in this survey was 14.6 (95% CI 5.5; 38.6) per 1000 person-years (four events for 274 person-years).

The incidence rate of VTE in CS of different origins in patients receiving thromboprophylaxis was 10.2 (95% CI 2.6; 40.5) vs 25.6 (95% CI 6.5; 100.7) cases per 1000 person-years without thromboprophylaxis (two events for 196 person-years vs two events for 78 person-years), which was an incidence rate ratio between the two groups of 2.5 (95% CI 0.18; 34.7), P > 0.05.

Discussion

The results of this study, which represent real-world clinical data of patients treated for CS in European reference centers, are consistent with previous cohort studies and demonstrate similar rates. In the presence of heterogeneous policies on thromboprophylaxis in expert centers throughout Europe, our study also provides better insight into the various policies on pre-surgery cortisol-lowering treatment. We found that the incidence rate of VTE in patients with CS was 14.6 (95% CI 5.5; 38.6) per 1000 person-years, and VTE occurred even in patients on cortisol-lowering medication and anticoagulants.

A specific thromboprophylaxis protocol for patients with CS was not available in the vast majority of centers, despite the fact that retrospective cohort studies have shown a decrease in VTE-associated mortality and morbidity in patients with endogenous hypercortisolism on anticoagulant treatment (20, 21). Thromboprophylaxis in CS patients has been reported to be associated with low bleeding rates (22, 23), which is confirmed in the present study.

The optimal timing for initiation of thromboprophylaxis probably depends on the risk profile of individual patients (especially patient’s mobility) and remains unclear, which is reflected by the diverse start dates in our study: 28% of patients started at the time of CS diagnosis, 33% the day before/of surgery, and 19% directly after surgery. The duration of thromboprophylaxis is also unclear and differed greatly among the study population. At present, different studies have confirmed that the risk of VTE remains increased at least until 3 months after successful surgery and may normalize after 6 months (9, 24). Prolonging thromboprophylaxis with LMWH until 30 days after surgery appears to reduce the VTE incidence in patients with CD without any significant side effects (9, 14, 20). Of note, in our study, half of the VTE events (n = 3) occurred despite active thromboprophylaxis, highlighting the fact that thromboprophylaxis (or dosages which were used) may be insufficient in the highest risk categories, such as previous VTE and ectopic CS. Unfortunately, the design of the secondary survey does not allow us to answer the question of whether the doses were adapted accordingly to glomerular filtration rate and weight. Nowadays, it is generally accepted that hypercortisolism per se is an important risk factor for VTE, although a relation between the severity of hypercortisolism and changes in coagulation factors has not been demonstrated (11). Consequently, it seems beneficial to start cortisol-lowering treatment in patients with CS while awaiting curative surgery regardless of thromboprophylaxis, to decrease the risk of postoperative withdrawal syndrome. This might be beneficial for the postoperative VTE risk as the corticosteroid withdrawal syndrome is a pro-inflammatory, and thus a pro-thrombotic, state in itself, thereby theoretically reducing the risk of VTE (11). Unfortunately, no clinical guidance exists on this topic, which is reflected by the real-world outcome data of this study. Initiation of cortisol-lowering medication varies from center to center and between countries and also depends on the origin of the underlying disease. As observed in this study, only 20% of patients with adrenal CS were treated with cortisol-lowering medication vs 83% of patients with ectopic CS and 43% of patients with Cushing’s disease. It is plausible to assume that this reflects both differences in disease severity and differences in the pre- and peri-operative management of adrenal and neurosurgical surgeries and the availability or lack of surgical procedures. In agreement with this, it has been suggested that in patients pretreated with cortisol-lowering medication before surgery, VTE risk was lower than patients not receiving cortisol-lowering medication before surgery (10). However, a recent larger study of the European Registry on Cushing syndrome (ERCUSYN) did not observe differences in post-surgical morbidities including thromboembolism within 180 days of surgery (6), although the proportion of patients receiving thromboprophylaxis in their study was lower, which may have influenced the results. Similar data were published in a more recent analysis of the ERCUSYN database (8). However, it has been reported that patients with higher cortisol levels (blood samples measured at midnight and free cortisol measured in urine) also had a higher VTE risk (7, 8, 25). The present study did not detect a difference in VTE risk between the different types of endogenous hypercortisolism, as in other studies, probably due to the small number of events. Also, other preventive measures, such as early mobilization after surgery and the use of elastic compressive stocking until mobilization, may have a role in the management of thromboprophylaxis, but we have not found difference within the groups in our survey (20).

Our study has some limitations as it was a retrospective survey, which may have introduced selection and detection bias. The secondary survey design limits the access to exact data (as precise date of VTE, surgery, details on previous VTE, adjustment of LMWH dosage for weight and others), so the dataset is rather different from a single-center chart review. Even with the use of e-REC, we cannot be sure that all new cases of CS have been included in the registry and in the survey. Also, several centers have reported less than five cases. Additionally, the date of e-REC registration is probably not the exact date of diagnosis, since there could be referral delay before patients are seen in a tertiary center. This might affect the VTE incidence rate.

Moreover, the total number of patients and events related to VTE is comparatively smaller than in previous studies. This limited dataset poses challenges in drawing robust conclusions regarding predisposing factors, subgroupings, optimal dosages, and clinical strategies for preventing VTEs. All these factors should be taken into account when designing a prospective observational study on the incidence of VTEs in patients with Cushing syndrome. However, we do feel that considering the similarities of our data with previously reported studies, the findings of the survey are consistent with current daily clinical practice throughout different expert centers in Europe. Additionally, the unique setup of this real-world multiple tertiary expert center collaborative study can be a starting point for the prospective registry on the EuRRECa platform aimed at improving best practice.

Conclusion

The incidence rate of VTE in patients after CS diagnosis in our study cohort was 14.6 (95% CI 5.5; 38.6) per 1000 person-years.

Of patients with CS, 30% did not receive preoperative thromboprophylaxis, and at the same time, half of the VTE cases occurred despite active thromboprophylaxis. Prospective clinical trials are needed to develop evidence-based guidelines on thromboprophylaxis and harmonized local protocols throughout the Endo-ERN.

Supplementary materials

This is linked to the online version of the paper at https://doi.org/10.1530/EC-24-0046.

Declaration of interest

NMA-D the LUMC funding (EuRRECa is funded through ENDO ERN within the European Union within the framework of the EU4H Programme, grant agreement no. 101084921). FAK has received research funding from Bayer, BMS, BSCI, AstraZeneca, MSD, Leo Pharma, Actelion, Farm-X, The Netherlands Organisation for Health Research and Development, the Dutch Thrombosis Foundation, the Dutch Heart Foundation and the Horizon Europe Program, all outside this work and paid to his institution. FG has received funding from research purposes from Pfizer, Ipsen, and Camurus. EN is supported by the Clinician Scientist Program RISE (Rare Important Syndromes in Endocrinology), supported by the Else-Kröner-Fresenius Stiftung and Eva Luise und Horst Köhler Stiftung. RP has received research funding from Recordati AG., Corcept Therapeutics, Strongbridge Biopharma, Neurocrine Biosciences; and served as a consultant for Corcept Therapeutics, Recordati AG., Crinetics Pharmaceuticals, H. Lundbeck A/S. SFA (EuRRECa is funded through ENDO ERN within the European Union within the framework of the EU4H Programme, grant agreement no. 101084921). AMP (Endo-ERN is funded by the European Union within the framework of the EU4H Programme, grant agreement no. 101084921). Other co-authors – none. SFA is Editor-in-Chief of Endocrine Connections. SFA was not involved in the review or editorial process for this paper, on which he is listed as an author.

Funding

This publication is supported by Endo-ERN. Endo-ERN is funded by the European Union within the framework of the EU4H Programme, grant agreement no. 101084921.

Acknowledgements

L Bakker (Department of Medicine, Division of Endocrinology, Leiden University Medical Centre, Leiden, Netherlands); S Bensing, K Berinder, M Petersson (Department of Endocrinology, Karolinska University Hospital, Stockholm, Sweden); and C Brachet, P Chausseur, B Corvilain, N Driessens, R Fishler (Department of Endocrinology, Hôpital Universitaire de Bruxelles, Hôpital Erasme, Brussels, Belgium).

References

From https://ec.bioscientifica.com/view/journals/ec/13/6/EC-24-0046.xml

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