Osilodrostat Treatment for Adrenal and Ectopic Cushing Syndrome

Posted on May 9, 2025 by MaryO

Integration of Clinical Studies With Case Presentations

Maria Fleseriu, Richard J Auchus, Irina Bancos, Beverly MK Biller
Journal of the Endocrine Society, Volume 9, Issue 4, April 2025, bvaf027
https://doi.org/10.1210/jendso/bvaf027

Abstract

Although most cases of endogenous Cushing syndrome are caused by a pituitary adenoma (Cushing disease), approximately one-third of patients present with ectopic or adrenal causes.

Surgery is the first-line treatment for most patients with Cushing syndrome; however, medical therapy is an important management option for those who are not eligible for, refuse, or do not respond to surgery.

Clinical experience demonstrating that osilodrostat, an oral 11β-hydroxylase inhibitor, is effective and well tolerated comes predominantly from phase III trials in patients with Cushing disease. Nonetheless, reports of its use in patients with ectopic or adrenal Cushing syndrome are increasing. These data highlight the importance of selecting the most appropriate starting dose and titration frequency while monitoring for adverse events, including those related to hypocortisolism and prolongation of the QT interval, to optimize treatment outcomes. Here we use illustrative case studies to discuss practical considerations for the management of patients with ectopic or adrenal Cushing syndrome and review published data on the use of osilodrostat in these patients.

The case studies show that to achieve the goal of reducing cortisol levels in all etiologies of Cushing syndrome, management should be individualized according to each patient’s disease severity, comorbidities, performance status, and response to treatment. This approach to osilodrostat treatment maximizes the benefits of effective cortisol control, leads to improvements in comorbid conditions, and may ameliorate quality of life for patients across all types and severities of Cushing syndrome.

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From https://www.endocrine.org/journals/journal-of-the-endocrine-society/osilodrostat-treatment-for-adrenal-and-ectopic-cushing-syndrome

Filed under: adrenal, Cushing's, pituitary, Treatments | Tagged: , , , , , , , | Leave a comment »

The Impact of Prolonged High-Concentration Cortisol Exposure on Cognitive Function and Risk Factors: Evidence From Cushing’s Disease Patients

Posted on May 7, 2025 by MaryO

Abstract

Background

Prolonged high-concentration cortisol exposure may impair cognitive function, but its mechanisms and risk factors remain unclear in humans.

Objective

Using Cushing’s disease patients as a model, this study explores these effects and develops a predictive model to aid in managing high-risk patients.

Methods

This single-center retrospective study included 107 Cushing’s disease patients (January 2020–January 2024) at the First Medical Center of the PLA General Hospital. Cognitive function, assessed using the Montreal Cognitive Assessment, revealed 58 patients with cognitive impairment and 49 with normal cognitive function. Patients were divided into training (n = 53) and validation cohorts (n = 54) for constructing and validating the predictive model. Risk factors were identified via univariate analysis and least absolute shrinkage and selection operator regression, and a nomogram prediction model was developed. Performance was evaluated using receiver operating characteristic (ROC) curves, calibration curves, and decision curve analysis (DCA).

Results

Cortisol AM/PM ratio, 8 a.m. cortisol concentration, body mass index, and fasting plasma glucose were significant risk factors for cognitive impairment. The nomogram demonstrated strong predictive ability, with ROC values of 0.80 (training) and 0.91 (validation). DCA indicated superior clinical utility compared to treating all or no patients.

Conclusions

This study confirms the significant impact of prolonged high cortisol exposure on cognitive function and identifies key risk factors. The nomogram model offers robust performance, providing a valuable tool for managing Cushing’s disease patients’ cognitive health and informing strategies for other cortisol-related disorders.

Introduction

Chronic stress and prolonged pressure increasingly pose significant burdens on individual health and social systems, particularly on a global scale. Their impact on cognitive function, mental health, and physical well-being cannot be ignored.1 Long-term stress responses and sustained exposure to pressure not only elevate the risk of multiple diseases but also result in considerable socioeconomic burdens. According to the World Health Organization (WHO), approximately 300 million people worldwide suffer from depression, with stress and emotional disorders being critical contributing factors.2 This phenomenon may be associated with prolonged exposure to high concentrations of cortisol induced by chronic stress.3 Such long-term elevated cortisol exposure is thought to exert adverse effects on multiple systems, including the nervous system, leading to anxiety, depression, and cognitive impairment. While the roles of anxiety and depression have been well established,4 the specific impact on cognitive function remains unclear.
Research suggests that abnormally elevated cortisol levels significantly affect brain structure and function. The hippocampus, a key target highly sensitive to cortisol and central to learning and memory, is particularly affected. High cortisol exerts its effects through glucocorticoid receptors and mineralocorticoid receptors in the hippocampus, mediating neurophysiological responses. Prolonged activation may lead to neuronal damage, reduced neuroplasticity, and cognitive impairment.5,6 Additionally, brain regions such as the prefrontal cortex and amygdala are also impacted, potentially causing attentional deficits, impaired executive function, and emotional regulation disturbances.7 Furthermore, abnormal diurnal cortisol rhythms are closely linked to neuroinflammation, oxidative stress, and cerebrovascular lesions.8,9 These mechanisms may interact synergistically to exacerbate cognitive impairment. While animal studies provide substantial evidence for cortisol’s effects on cognitive function, human studies face ethical constraints and experimental limitations. The lack of models for long-term stress and pressure in humans, coupled with challenges in conducting long-term follow-ups, highlights the need for suitable research subjects.
Cushing’s disease is an endocrine disorder caused by excess adrenocorticotropic hormone (ACTH) secretion by anterior pituitary adenomas, leading to abnormally elevated cortisol levels.10 The unique pathological features of Cushing’s disease offer a natural model for studying the effects of prolonged high cortisol exposure on human cognitive function. Patients with Cushing’s disease often experience cognitive impairments, with clinical manifestations including memory decline, attention deficits, and impaired executive function.11–13 However, the specific mechanisms and risk factors underlying these impairments remain unclear.
Against this backdrop, this study uses Cushing’s disease patients as subjects to systematically evaluate the impact of prolonged high cortisol exposure on cognitive function and analyze associated risk factors. Additionally, we develop a nomogram prediction model aimed at improving the identification of high-risk patients, providing a reference for clinical interventions, and offering new perspectives and evidence for the cognitive management and research of cortisol-related disorders.

Methods

Study subjects

This study is a single-center retrospective study that included 107 patients diagnosed with Cushing’s disease at the First Medical Center of the PLA General Hospital between January 2017 and January 2024. Inclusion criteria were as follows: (i) meeting the WHO diagnostic criteria for Cushing’s disease; (ii) disease duration >3 months; (iii) no prior surgical treatment; (iv) complete laboratory and imaging data; (v) no other neurological or psychiatric disorders that could cause cognitive impairment (e.g., dementia, depression, stroke). Exclusion criteria included: (i) disease duration ❤ months; (ii) prior surgical treatment; (iii) missing critical baseline or laboratory data; (iv) severe visual or hearing impairments that could affect cognitive testing results. A total of 107 patients were included in the study, among whom 58 had cognitive impairment and 49 exhibited mild cognitive decline. Cognitive function was classified as follows: Montreal Cognitive Assessment (MoCA) score ≤26 was defined as cognitive impairment, 27–29 as mild cognitive decline, and 30 as normal cognitive function.

Study design

A random allocation method was used to divide all patients into a training cohort (n = 53) and a validation cohort (n = 54) at a 5:5 ratio. The training cohort was used for variable selection and predictive model development, while the validation cohort was used for performance evaluation of the model. The study was approved by the hospital ethics committee (approval number: [S2021-677-01]).

Clinical data collection

Clinical characteristics and laboratory data of patients were obtained from the hospital’s electronic medical record system and included the following: (i) Demographic and clinical characteristics: age, sex, disease duration, years of education, body mass index (BMI), systolic blood pressure, and diastolic blood pressure; (ii) Laboratory indicators: fasting plasma glucose (FPG), 24-h urinary free cortisol, serum cortisol concentrations (0 a.m., 8 a.m., 4 p.m.), ACTH concentrations (0 a.m., 8 a.m., 4 p.m.), total cholesterol, triglycerides, alanine aminotransferase, aspartate aminotransferase, gamma-glutamyl transferase, cortisol AM/PM ratio (CORT AM/PM), and results of low-dose dexamethasone suppression tests and high-dose dexamethasone suppression tests; (iii) Cognitive function assessment: conducted using the MoCA scale.

Statistical analysis and model development

Categorical variables were expressed as numbers (%), and continuous variables as mean ± standard deviation (SD) or median (interquartile range, IQR). Intergroup comparisons were performed using the chi-square test or Fisher’s exact test for categorical variables. A nomogram was constructed to predict the risk factors for cognitive impairment in patients exposed to prolonged high cortisol levels. Significant clinical features associated with cognitive function were identified through univariate analysis and least absolute shrinkage and selection operator (LASSO) regression analysis.
Based on the final results, a novel nomogram was developed, incorporating all independent prognostic factors to predict the presence or absence of cognitive impairment in individuals exposed to prolonged high cortisol levels. The performance of the nomogram was evaluated using the concordance index (C-index), area under the receiver operating characteristic (ROC) curve (AUC), calibration curves, and decision curve analysis (DCA). The C-index was calculated using 1,000 bootstrap samples to assess the internal validity of the model. Each patient’s total score was calculated using the nomogram approach.
Statistical analysis was performed using R programming language and version 4.2.3 of the R environment (http://cran.r-project.org). The main R packages used in this study included gtsummary (version 1.7.0), survival (version 3.5-3), RMS (version 6.3-0), time ROC (version 0.4), and ggplot2 (version 3.4.0).

Results

Patient characteristics

A total of 107 patients with Cushing’s disease were included in this study. MoCA scores revealed that all patients exhibited either cognitive decline or impairment. Among them, 58 patients (54.2%) were classified into the cognitive impairment group, and 49 patients (45.8%) were categorized into the cognitive decline group. Significant differences were observed in demographic characteristics and clinical indicators between the two groups. Detailed information is presented in Table 1.
Table 1. General characteristics of patients.
Variables Total (n = 107) 0 (n = 49) 1 (n = 58) p
sex, n (%) 1
1 10 (9) 5 (10) 5 (9)
2 97 (91) 44 (90) 53 (91)
age, Mean ± SD 41.22 ± 11.19 39.16 ± 11.21 42.97 ± 10.96 0.08
Education y, Median (Q1,Q3) 12 (8, 16) 12 (8, 16) 12 (8.25, 15) 0.835
BMI, Mean ± SD 27.01 ± 3.46 25.49 ± 2.25 28.29 ± 3.79 <0.001
Illness duration, Median (Q1,Q3) 26 (12, 48) 24 (12, 48) 33 (12, 48) 0.6
COR-0am, Mean ± SD 565.86 ± 207.53 513.69 ± 185.87 609.94 ± 216.06 0.015
COR-8am, Mean ± SD 725.63 ± 259.03 612.26 ± 197.79 821.41 ± 267.29 <0.001
COR-4pm, Median (Q1,Q3) 619.19 (491.14, 744.17) 598.3 (472.49, 678.18) 650.43 (503.34, 803.88) 0.109
ACTH0am, Median (Q1,Q3) 12.4 (9.02, 18.4) 11 (8.46, 17.2) 13.95 (9.57, 19.51) 0.114
ACTH8am, Median (Q1,Q3) 15.2 (11.1, 23.5) 13.3 (10.6, 19.4) 17.4 (13.33, 26.27) 0.027
ACTH4pm, Median (Q1,Q3) 15.9 (10.45, 22.75) 13.6 (10.4, 22.6) 16.6 (10.95, 25.15) 0.275
UFC, Median (Q1,Q3) 1644.9 (1146.2, 2501.75) 1483 (1092.3, 2020.6) 1931 (1168.85, 2793.02) 0.131
LDDST-ACTH, Median (Q1,Q3) 16.9 (9.31, 21.15) 16.1 (8.35, 20.6) 17.25 (10.12, 21.17) 0.555
LDDST-CORT, Median (Q1,Q3) 532.95 (390.46, 787.61) 501.63 (360.4, 792.18) 568.37 (398.76, 781.7) 0.606
LDDST-UFC, Median (Q1,Q3) 1050.8 (531.9, 2077.2) 880.6 (454.4, 2419.9) 1200 (580.62, 2010.23) 0.589
HDDST-ACTH, Median (Q1,Q3) 8.81 (5.2, 15.7) 8.48 (4.91, 16.6) 9.12 (5.42, 14.45) 0.837
HDDST-CORT, Median (Q1,Q3) 222.3 (62.41, 354.31) 222.3 (61.7, 348.84) 217.56 (76.25, 356.78) 0.662
HDDST-UFC, Median (Q1,Q3) 336.9 (130.9, 870.86) 281.2 (128.4, 791.7) 391.4 (140.25, 923.43) 0.488
SBP, Mean ± SD 159.09 ± 26.08 157.76 ± 26.67 160.22 ± 25.75 0.629
DBP, Median (Q1,Q3) 105 (92, 116.5) 105 (90, 119) 102.5 (94.5, 114) 0.927
TC, Median (Q1,Q3) 5.13 (4.46, 6.17) 4.92 (4.47, 5.72) 5.24 (4.44, 6.31) 0.386
TG, Median (Q1,Q3) 1.42 (0.99, 2.04) 1.39 (0.99, 2.41) 1.42 (0.99, 1.97) 0.861
ALT, Median (Q1,Q3) 23 (17.55, 33.7) 20.7 (15.8, 33) 23.85 (18.45, 34.3) 0.35
AST, Median (Q1,Q3) 15.2 (13, 18.5) 14.1 (12.7, 18.5) 16.35 (13.62, 18.45) 0.184
GGT, Median (Q1,Q3) 27.6 (21.75, 44.25) 26.7 (22.6, 45.9) 28.95 (21.32, 41.9) 0.913
FPG, Median (Q1,Q3) 7.62 (5.43, 9.66) 5.7 (4.83, 7.49) 8.95 (7.05, 10) <0.001
CORT AM/PM, Median (Q1,Q3) 1.19 (0.99, 1.34) 1.05 (0.88, 1.2) 1.25 (1.15, 1.4) <0.001
ACTH: adrenocorticotropic hormone; ALT: alanine aminotransferase; AST: aspartate aminotransferase; BMI, body mass index; COR/CORT: cortisol; DBP: diastolic blood pressure; FPG: fasting plasma glucose; GGT: gamma-glutamyl transferase; HDDST: high-dose dexamethasone suppression tests; LDDST: low-dose dexamethasone suppression tests; SBP: systolic blood pressure; TC: total cholesterol; TG: triglycerides; UFC: urinary free cortisol.

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Model development

In the modeling cohort, LASSO regression analysis was used for variable selection. The regression coefficient path diagram and cross-validation curve are shown in Figure 1A and 1B. To ensure a good model fit, the λ corresponding to the minimum mean squared error was chosen through cross-validation. Four variables were identified through LASSO regression analysis: CORT AM/PM, COR-8am, FPG, and BMI. These variables were ultimately deemed risk factors for cognitive impairment associated with prolonged high cortisol exposure. Based on these four significant variables, a nomogram was developed to predict cognitive impairment under prolonged high cortisol exposure, and the model was visualized using a nomogram (Figure 2).
Figure 1. LASSO Cox regression model construction. (A) LASSO coefficient of 27 features. (B) Selection of tuning parameter (k) for the LASSO model.

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Figure 2. Nomogram predicting cognitive impairment in patients with prolonged high cortisol exposure.

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Model performance and validation

To comprehensively evaluate the model’s performance, multiple metrics were employed to verify its accuracy, stability, and clinical utility, including the concordance index (C-index), AUC, calibration curves, and DCA. The AUC values for the training cohort (Figure 3A) and the internal validation cohort (Figure 3B) were 0.80 and 0.91, respectively. These results indicate that the nomogram model effectively distinguishes patients with cognitive impairment in different sample datasets and demonstrates strong predictive accuracy. Calibration curves showed a high level of agreement between the predicted and actual probabilities of cognitive impairment in both the training cohort (Figure 4A) and the validation cohort (Figure 4B), further confirming the model’s stability and utility.
Figure 3. The ROC curve of the predictive model for cognitive impairment in patients with prolonged high cortisol exposure. (A) Derivation cohort. (B) Validation cohort.

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Figure 4. Calibration curves of the nomogram. (A) Derivation cohort. (B) Validation cohort.

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To assess the clinical utility of the model, DCA was performed (Figure 5). The results demonstrated that the clinical benefit of using the model to predict cognitive impairment was significantly higher than strategies of treating all patients or treating none (Figure 5). This finding suggests that the nomogram model provides substantial net benefit in clinical decision-making, effectively aiding clinicians in identifying high-risk patients and implementing appropriate interventions.
Figure 5. DCA curves of the nomogram in the training cohort and test cohort.

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Discussion

This study used patients with Cushing’s disease as a model to investigate the effects of prolonged high-concentration cortisol exposure on human cognitive function. The findings revealed that individuals exposed to long-term high cortisol levels generally experienced cognitive decline, with the CORT AM/PM, COR-8am, BMI, and FPG identified as major risk factors for cognitive impairment. Additionally, the developed nomogram model demonstrated excellent predictive performance in both the training (AUC = 0.80) and validation (AUC = 0.91) cohorts, highlighting its strong discriminative ability and clinical utility. These findings provide a foundation for mechanistic research and clinical management of prolonged high cortisol exposure.
BMI, FPG, CORT AM/PM, and COR-8am, as risk factors, are closely related to cortisol levels and its effects on the nervous system. Increased BMI was identified as an independent risk factor for cognitive impairment, likely due to chronic inflammation and oxidative stress caused by metabolic disorders.14–16 Obesity and elevated cortisol levels may form a vicious cycle, further exacerbating damage to the nervous system. Studies have shown that reduced cerebral blood flow and neuronal damage in obese individuals are directly linked to cognitive impairment,17 underscoring the importance of monitoring metabolic status in Cushing’s disease patients. High blood glucose was another critical risk factor, potentially affecting cognitive function through various mechanisms: prolonged hyperglycemia can lead to cerebrovascular damage and impaired blood supply to the brain;18 it may also directly harm neurons through oxidative stress and inflammatory responses.19 Moreover, chronic hyperglycemia alters insulin signaling pathways, disrupting glucose metabolism in the brain and further aggravating cognitive decline.20 Additionally, the study showed that disrupted cortisol circadian rhythms (elevated CORT AM/PM) and increased morning cortisol peaks (COR-8am) were closely associated with cognitive impairment. Circadian rhythm disruption may accelerate hippocampal atrophy and prefrontal cortex dysfunction by affecting the regulation of the hypothalamic-pituitary-adrenal (HPA) axis.21 Excessive morning cortisol peaks may exacerbate neuroinflammation and synaptic dysfunction,22 a finding also supported by previous animal studies.
Cushing’s disease serves as an effective model for studying high cortisol states induced by chronic stress, given the high similarity in pathophysiological mechanisms between the two. Cushing’s disease results from tumor-induced HPA axis hyperactivation, causing sustained cortisol overproduction,23 while chronic stress similarly activates the HPA axis, maintaining cortisol at persistently high levels. Although the etiology of Cushing’s disease is endogenous and pathological, whereas high cortisol in chronic stress is environmentally induced, both share similar features such as metabolic disturbances (e.g., insulin resistance, central obesity), immunosuppression (e.g., increased infection susceptibility), osteoporosis, and psychological disorders (e.g., anxiety and depression).24 Therefore, Cushing’s disease provides an effective model for studying metabolic, immune, and neurological changes in high cortisol states, offering experimental evidence for understanding chronic stress-related disorders and developing intervention strategies.
The results of this study align with previous animal experiments. For instance, animal studies have shown that prolonged cortisol exposure leads to hippocampal atrophy and neuronal damage, impairing cognitive function.25 This study provides supportive evidence in human samples. Furthermore, prior research has found that disrupted cortisol circadian rhythms are often associated with executive function decline in patients with depression,26 consistent with our findings that CORT AM/PM is significantly associated with cognitive impairment in Cushing’s disease patients. Unlike earlier studies focusing primarily on cortisol’s direct neurotoxic effects, this study integrated metabolic indicators (e.g., BMI, FPG) to comprehensively analyze the interaction between cortisol and metabolic disturbances, expanding the understanding of mechanisms underlying cortisol-induced cognitive impairment.
Moreover, unlike previous research that was predominantly based on animal models, this study systematically analyzed data from 107 Cushing’s disease patients, further validating these mechanisms in humans. The construction of the nomogram model significantly enhanced predictive accuracy, providing a practical tool for clinical application.
Despite providing important evidence for the impact of prolonged high cortisol exposure on cognitive function, this study has limitations. First, as a single-center retrospective study with a limited sample size, the results may lack generalizability and require prospective validation. Although Cushing’s disease serves as a model for high cortisol exposure, further validation in populations experiencing chronic stress or prolonged pressure is needed. Second, the lack of long-term follow-up data prevents evaluation of the effects of surgical treatment or other interventions on cognitive function. Third, this study did not consider the impact of sex hormones on cortisol levels and cognitive function. Sex hormones (such as estrogen and testosterone) may regulate cortisol and influence the central nervous system.

Conclusion

This study, using patients with Cushing’s disease as a model, explored the impact of prolonged high-concentration cortisol exposure on human cognitive function. The findings revealed that individuals with prolonged high cortisol exposure commonly experience cognitive decline, with CORT AM/PM, COR-8am, BMI, and FPG identified as major risk factors for cognitive impairment. The nomogram model developed based on these risk factors demonstrated excellent predictive performance and clinical applicability in both the training and validation cohorts, providing an effective tool for the early identification of high-risk patients. These results not only confirmed the significant impact of prolonged high cortisol exposure on the central nervous system but also highlighted the critical role of metabolic factors in this process, emphasizing the multifactorial mechanisms of cognitive impairment. These findings offer a scientific basis for managing the cognitive health of Cushing’s disease patients and provide important insights for prevention and treatment strategies for other cortisol-related conditions, such as chronic stress and metabolic syndrome.

Acknowledgments

We thank the patient for granting permission to publish this information. We appreciate all the team members who have shown concern and provided treatment advice for this patient the Chinese People’s Liberation Army (PLA) General Hospital.

Ethical considerations

This study was approved by the Ethics Committee of the Chinese PLA General Hospital (Approval No. [S2021-67701]).

Consent to participate

All participants provided written informed consent prior to inclusion in the study.

Declaration of conflicting interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by the National Natural Science Foundation of China (Grant Nos. 82001798 to Xinguang Yu; Grant Nos. 81871087 to Yanyang Zhang) and the Young Talent Project of Chinese PLA General Hospital (Grant Nos. 20230403 to Yanyang Zhang).

ORCID iDs

Data availability statement

Data are available from the corresponding authors on reasonable request.

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Connecting Canine and Human Health to Fight Cushing’s Disease

Posted on May 5, 2025 by MaryO

Cushing’s Disease is common in dogs but rare and hard to diagnose in people. That’s why University of Georgia researchers are leveraging canine treatments to find new solutions to battle the condition in humans. This collaboration between veterinary medicine and human health care is just one example of how UGA uses a Precision One Health approach to find and tailor new medical treatments for people and animals.

~~~

Imagine your body as a well-run newsroom. Each day, the editor-in-chief—in this case, the pituitary gland—provides assignments, keeping everything running smoothly. One day, however, the editor’s role is usurped by a rogue reporter who declares breaking news nonstop, flooding the newsroom with bulletins and sending everyone into overdrive.

This is a bit like Cushing’s Disease. The rogue reporter is a tiny, usually benign tumor, the stress bulletins cortisol. The newsroom—your body—responds with metabolic fluctuations, burnt out muscles, emotional distress, and more. Over the long haul, Cushing’s Disease can cause lasting deterioration of the body: osteoporosis, muscle weakness, high blood pressure and heart disease, diabetes, memory and mood issues, fatigue, and more.

It’s a common disease and easier to detect in canines. In people, however, it is rare and difficult to diagnose. University of Georgia researchers are leveraging canine treatments to find new solutions to battle the condition in humans.

This collaboration between veterinary medicine and human health is just one example of how UGA uses a Precision One Health approach to find and tailor new medical treatments for people and animals.

From https://research.uga.edu/news/connecting-canine-human-health-to-fight-cushings-disease/

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Ectopic ACTH-secreting Pheochromocytoma Without Typical Signs of Cushing Syndrome

Posted on May 3, 2025 by MaryO

Abstract

This case report describes a 42-year-old female with a rare pheochromocytoma presenting without classic Cushingoid features but with uncontrolled hypertension, type 2 diabetes, and recurrent headaches. Despite the absence of typical signs, biochemical analysis revealed elevated cortisol and ACTH levels, and imaging showed a 6 cm adrenal mass. The patient was stabilized preoperatively with alpha-blockers and metyrapone before undergoing a successful laparoscopic adrenalectomy. Histopathology confirmed pheochromocytoma with aggressive features. Postoperatively, her blood pressure and symptoms improved, and her cortisol levels normalized. This case underscores the diagnostic challenges of ACTH-secreting pheochromocytomas without classic hypercortisolism signs and emphasizes the need for thorough endocrine and imaging assessments. Surgical resection remains the definitive treatment, with long-term follow-up essential to monitor for recurrence. This case contributes to the limited literature on the coexistence of pheochromocytoma and ectopic ACTH secretion.

Introduction

Ectopic ACTH-dependent tumors are rare, comprising approximately 5%–10% of Cushing syndrome cases, and are infrequently associated with pheochromocytomas, making this a unique presentation [1, 2]. Pheochromocytomas, though rare, can present as adrenal incidentalomas, often discovered during imaging for unrelated conditions. They represent 7% of adrenal incidentalomas and pose clinical challenges due to the risk of hormonal hypersecretion, including excess catecholamines and cortisol [1]. This case highlights the coexistence of an ectopic ACTH-producing tumor and pheochromocytoma, a combination rarely reported in the literature [3, 4]. While Cushing syndrome typically arises from adrenal or pituitary sources, ectopic ACTH secretion from pheochromocytomas presents a diagnostic and therapeutic challenge due to its rarity and aggressive potential [4–6]. Early diagnosis is crucial, particularly in cases with comorbidities like hypertension and diabetes, which are common in pheochromocytomas [1, 2]. This case underscores the need for a multidisciplinary approach to managing rare endocrine tumors.

Case report

A 42-year-old female from Mexico City presented with a history of treatment-resistant hypertension and a newly identified adrenal mass. She had no history of alcohol or tobacco use and led a generally healthy lifestyle. She was diagnosed with type 2 diabetes five years before symptoms appeared and developed hypertension five years before hospitalization, managed with valsartan and amlodipine verapamil.

The patient’s hypertension worsened, with blood pressure readings reaching 200/160 mmHg. She presented with asthenia and adynamia, and a CT scan revealed a 4 cm right adrenal mass, confirmed as 4.7 cm on a subsequent scan (Fig. 1). No signs of metastasis were observed. Upon hospital admission, her physical examination revealed a blood pressure of 95/84 mmHg, a heart rate of 95 beats per minute, a respiratory rate of 28 breaths per minute, and a systolic murmur. She exhibited no Cushingoid features.

 

The imaging identified a hyperdense area at the lower pole of the left kidney. A heterogeneous image was visualized in the right adrenal gland, characterized by a hypodense lesion measuring 40 × 47 × 43 mm, with a density of 36 Hounsfield units (HU) in the simple phase, 107 HU in the venous phase and 61 HU in the delayed phase (15 min), with an absolute washout of 64%.

Figure 1

The imaging identified a hyperdense area at the lower pole of the left kidney. A heterogeneous image was visualized in the right adrenal gland, characterized by a hypodense lesion measuring 40 × 47 × 43 mm, with a density of 36 Hounsfield units (HU) in the simple phase, 107 HU in the venous phase and 61 HU in the delayed phase (15 min), with an absolute washout of 64%.

Initial laboratory tests showed elevated white blood cells (11 000/mm3), hemoglobin of 12.5 g/dl, and platelet count of 305 000/mm3. Blood chemistry indicated hyperglycemia (132 mg/dl), hyponatremia (129 mEq/l), and hypokalemia (3.4 mEq/l). Cortisol levels were elevated at 31.53 μg/dl, and a 1 mg low-dose dexamethasone suppression test showed cortisol levels of 16.65 μg/dl and 14.63 μg/dl, suggesting ACTH-dependent Cushing syndrome.

ACTH levels were 24 pg/ml, which, while elevated, were not suppressed. However, elevated 24-h urinary metanephrines (9881 μg/24 h) confirmed the presence of pheochromocytoma. The patient’s aldosterone-to-renin ratio was measured, revealing a ratio of 4. The serum aldosterone level was 5 ng/dl (138 pmol/l), while plasma renin activity was recorded at 1.1 ng/ml/h.

Imaging revealed a 4.7 cm right adrenal mass with a density of 36 Hounsfield Units and an absolute washout of 64%, with no signs of malignancy (Fig. 1).

The patient’s hypertension was initially managed with prazosin and metoprolol, but her blood pressure spiked to 200/160 mmHg during a hypertensive crisis, requiring nitroprusside. Surgical intervention was planned after diagnosis was confirmed.

The patient underwent a successful laparoscopic right adrenalectomy. The tumor measured 6 cm, and histopathology confirmed a pheochromocytoma with a PASS score of 4, indicating potential for aggressive behavior (Table 1). Histological and immunohistochemical analysis revealed the tumor’s characteristic organoid pattern (Zellballen) with chromogranin and synaptophysin positivity in principal cells and S100 protein staining in sustentacular cells, consistent with pheochromocytoma (Fig. 2). Postoperatively, her blood pressure stabilized, and symptoms of palpitations and sweating resolved. She has weaned off antihypertensives, and a follow-up dexamethasone suppression test showed a significant reduction in cortisol levels (1.2 μg/dl), indicating successful tumor removal.

 

Table 1

Histopathological report.

HISTOPATHOLOGICAL DIAGNOSIS
Specimen from right adrenalectomy:
Pheochromocytoma measuring 6×6 cm (positive for chromogranin 7, synaptophysin +S100, with sustentacular cells staining positive)

  • Marked nuclear pleomorphism: 1 point
  • Diffuse growth pattern: 2 points
  • Capsular invasion: 1 point
Total: 4 points.
Tumors with a score greater than 4 may exhibit aggressive biological behavior.

 

Histological and microscopic findings of adrenal Pheochromocytoma. (A) Macroscopic appearance. The ovoid tissue specimen has a light, smooth, soft external surface. The cut surface reveals a dark inner surface with light and hemorrhagic areas. Two cystic lesions with smooth walls are observed in the center (gross view). (B) A well-demarcated hypercellular lesion with an organoid pattern (Zellballen), separated by thin fibrovascular septa (Hematoxylin and eosin stain, 40×). (C) Nest of polygonal principal cells with ample eosinophilic granular cytoplasm, well-defined plasma membranes, hyperchromatic nuclei, and mild nuclear pleomorphism. Adjacent to the principal cells are spindle-shaped sustentacular cells with eosinophilic cytoplasm (Hematoxylin and eosin stain, 400×). (D) Positive immunoreactivity for chromogranin in principal cells. (E) Intense cytoplasmic reaction for synaptophysin in principal cells (immunohistochemistry, 400×). (F) Positive immunoreactivity for S100 protein, showing nuclear and cytoplasmic staining in sustentacular cells (immunohistochemistry, 400×).

Figure 2

Histological and microscopic findings of adrenal Pheochromocytoma. (A) Macroscopic appearance. The ovoid tissue specimen has a light, smooth, soft external surface. The cut surface reveals a dark inner surface with light and hemorrhagic areas. Two cystic lesions with smooth walls are observed in the center (gross view). (B) A well-demarcated hypercellular lesion with an organoid pattern (Zellballen), separated by thin fibrovascular septa (Hematoxylin and eosin stain, 40×). (C) Nest of polygonal principal cells with ample eosinophilic granular cytoplasm, well-defined plasma membranes, hyperchromatic nuclei, and mild nuclear pleomorphism. Adjacent to the principal cells are spindle-shaped sustentacular cells with eosinophilic cytoplasm (Hematoxylin and eosin stain, 400×). (D) Positive immunoreactivity for chromogranin in principal cells. (E) Intense cytoplasmic reaction for synaptophysin in principal cells (immunohistochemistry, 400×). (F) Positive immunoreactivity for S100 protein, showing nuclear and cytoplasmic staining in sustentacular cells (immunohistochemistry, 400×).

Postoperatively, her course was uneventful, with stable blood pressure without antihypertensives. A follow-up evaluation revealed normal cortisol levels, and 24-h urinary metanephrines returned to normal (312 μg/24 h for metanephrines; 225 μg/24 h for normetanephrines). Repeat imaging showed no residual adrenal mass. At her most recent follow-up, the patient remained asymptomatic with normal laboratory values, and no recurrence has been detected.

Discussion

Ectopic ACTH-secreting pheochromocytomas are rare, accounting for a small percentage of ACTH-dependent Cushing syndrome cases [1, 4–6]. These tumors present diagnostic challenges, mainly when typical signs of Cushing syndrome, such as moon face, abdominal striae, or muscle weakness, are absent [3]. In this case, the patient exhibited only diabetes, uncontrolled hypertension, and recurrent headaches, symptoms that can also be attributed to pheochromocytoma itself [1]. The absence of Cushingoid features delayed the identification of ectopic ACTH secretion, making this case particularly difficult and unusual.

According to Gabi JN et al., most patients with ACTH-secreting pheochromocytomas present with severe hypercortisolism, including rapid weight gain and characteristic facial changes [3]. The absence of such features in this patient highlights the need to consider ectopic ACTH secretion in cases of adrenal masses, even without typical Cushing syndrome symptoms. This case illustrates how subtle presentations can lead to delayed diagnoses, emphasizing the importance of thorough evaluation in patients with adrenal tumors and metabolic abnormalities [1, 3].

The diagnostic approach for pheochromocytomas includes hormonal assays and imaging [7, 8]. Preoperative management for pheochromocytomas typically includes alpha-blockers to manage catecholamine excess [4, 7, 8]. This patient was managed with prazosin for blood pressure control and metyrapone to suppress cortisol production, consistent with clinical guidelines for managing ACTH-secreting tumors [5, 7, 8]. Despite the absence of Cushingoid features, careful preoperative preparation was essential to prevent complications during surgery.

Surgical resection is the definitive treatment for pheochromocytomas, particularly those secreting ACTH [8]. In this case, the patient underwent a successful laparoscopic adrenalectomy with no intraoperative complications. Histopathology confirmed a pheochromocytoma with marked nuclear pleomorphism and capsular invasion, suggesting potential aggressive behavior. Postoperatively, the patient’s blood pressure normalized, and her diabetes improved, aligning with outcomes reported in similar cases [4, 6]. Cortisol levels also returned to normal, demonstrating the effectiveness of adrenalectomy in resolving hypercortisolism.

A limitation in this case was the delayed recognition of ectopic ACTH secretion due to the absence of typical Cushingoid signs. The literature underscores the importance of considering this diagnosis, even in nonspecific cases [5].

Long-term management of pheochromocytomas, particularly those with aggressive features like capsular invasion, requires close follow-up [5, 7, 8]. Genetic testing should be considered, especially in patients with unusual presentations or family histories of endocrine disorders [1, 5]. Although not performed in this case, genetic testing could have provided further insight into the tumor’s etiology.

Acknowledgements

We thank the radiology department for interpreting the CT.

Conflict of interest

The authors declare no conflicts of interest related to this case report.

Funding

No external funding was received for this study.

Ethical approval

No approval was required.

Consent

Written informed consent was obtained from the patient and her parents to publish this case report and any accompanying images.

Guarantor

Froylan D. Martinez-Sanchez is the guarantor for this publication and accepts full responsibility for the work.

© The Author(s) 2025. Published by Oxford University Press.
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.

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Cardiometabolic Complications After Cushing’s Disease Remission

Posted on April 30, 2025 by MaryO

Abstract

Background and aim

Cushing’s disease (CD) is associated with phenotypic traits and comorbidities that may persist after the normalization of cortisol levels. Medical therapy is usually given in recurrent or persistent CD after transsphenoidal surgery. We aimed to investigate the impact of long-term normalization of daily cortisol secretion on clinical picture and cardiometabolic comorbidities, comparing surgical remission to medical treatment.

Methods

Monocentric retrospective study, two- and five-years observation. Sixty CD patients, with sustained normal 24-h urinary free cortisol (UFC) levels, divided group 1 (surgical remission, n = 36) and group 2 (medical remission, n = 24).

Results

Patients were different after achieving eucortisolism with surgery or medical treatment. Phenotypic traits: round face, dorsocervical fat pad, and bruisability persisted more prominently in the group 2, however abdominal obesity and muscle weakness persisted in both groups, especially in those patients with increased late-night salivary cortisol (LNSC). Hypertension: greater improvement was observed in group 1 (-31% vs. -5%, p = 0.04). Diabetes: less prevalent in group 1 after 2 years (2/36 vs. 9/24, p = 0.002), with a corresponding reduction in glucose-lowering treatments and persistence of impaired LNSC in diabetic patients (p < 0.001). Dyslipidemia: remained widespread in both groups, with minimal improvement over time (-22% in surgical and − 6% in medical cohort).

Conclusions

Surgical remission leads to faster and sustained improvements in clinical phenotype. However, obesity, arterial hypertension, and dyslipidemia do not completely revert in five years, especially during medical treatment. Most comorbidities persist despite UFC normalization, due to impaired LNSC: the recovery of cortisol rhythms confirms the remission of hypercortisolism.

Introduction

Cushing’s disease (CD) is caused by an adrenocorticotropic hormone (ACTH)-secreting pituitary tumor, resulting in persistent endogenous hypercortisolism. The cortisol excess leads to a typical clinical picture: round face, facial plethora, buffalo hump, cutaneous striae rubrae, easy bruising, proximal myopathy, weight gain with visceral obesity, hirsutism and acne [1,2,3]. Moreover, several comorbidities are cortisol-related: metabolic syndrome (visceral obesity, arterial hypertension, glucose intolerance or diabetes, and dyslipidemia), acquired thrombophilia, osteoporosis or vertebral fractures, immunological impairments with increased infection susceptibility, and psychiatric disorders [4]. The sum of physical changes and comorbidities leads to a reduced life expectancy and a worsening of the quality of life [5]. Pituitary trans-sphenoidal surgery (TSS) is the first-choice CD treatment [1]. Despite high remission rates (up to 90% in referral centers) [6], the risk of recurrence varies from 10 to 47% [7], especially in series with long-term follow-up. If surgery fails or is not feasible, cortisol excess can be managed with medical therapy. Not rarely, patients on cortisol-lowering therapy experience fluctuations of their cortisol levels, making outcome evaluations difficult and hardly standardized. The goals of CD treatment are to normalize cortisol levels, and to reduce the burden of comorbidities. The most used biochemical marker in clinical practice is urinary free cortisol (UFC), which estimates the cumulative daily secretion of cortisol, but does not offer information about cortisol rhythm [8].

In this study we compared two groups of CD patients with sustained normalization of 24-h UFC due either to post-surgical or medical cortisol-lowering therapy remission. The aim of the study was to analyze the impact of long-term normalization of hypercortisolism in terms of UFC, achieved with surgical or medical treatment, on endocrine parameters, cortisol-related clinical picture and comorbidities, in a five-years observation period of patients with CD.

Materials and methods

Subjects

Sixty CD patients were enrolled (75% female); the median age at diagnosis was 41 years (interquartile range [IQR] 32–52), followed at the Endocrinology Unit of Padua University Hospital from 2000 to 2021. This observational study was conducted in accordance with the STROBE (STrengthening the Reporting of OBservational studies in Epidemiology) guidelines [9]. The study, following the guidelines in the Declaration of Helsinki, was approved by the ethics committee of Padova University Hospital (PITACORA, protocol No. AOP3318, ethics committee registration 5938-AO-24), and all patients gave informed consent. All data are included in the Repository of the University of Padova [10].

The first normalized UFC is considered as the starting point of observation at follow-up (two or five years). The cohort was divided into two cohorts: group 1 achieved CD remission after surgery, and group 2 achieved long-term eucortisolism during medical therapy. The inclusion criterion was 24-h UFC levels (mean of two collections) below the upper limit of normality during the observational period. Postoperative long-term adrenal insufficiency requiring substitutive glucocorticoid treatment (with hydrocortisone or cortisone acetate tablets) 12 months after surgery or new-onset hypopituitarism were considered exclusion criteria. The group 1 was made of 36 patients (69% female) in remission after successful TSS. The second group consisted of 24 patients (83% female) on long-term medical treatment for CD persistence (n = 17) or relapse (n = 4) after surgery and three patients in primary medical therapy for poor surgical eligibility, as shown in Fig. 1. Within group 2, nine patients underwent previous radiotherapy without efficacy, at least 5 years before reaching adequate biochemical control with medical treatment; none developed hypopituitarism. 14/24 patients (58%) were treated with a monotherapy and 11/24 (46%) with combined therapies during the observation period. Details on medical therapies are shown in Table 1. In particular, 3 patients were treated with metyrapone + pasireotide s.c., 1 with metyrapone + ketoconazole, 2 with ketoconazole and cabergoline, 1 with metyrapone + cabergoline, 1 with metyrapone + ketoconazole + cabergoline, 1 with metyrapone + ketoconazole + pasireotide s.c., 1 with metyrapone + ketoconazole + pasireotide s.c. + cabergoline. Metyrapone and ketoconazole were administered two/three times a day, pasireotide s.c. twice daily and cabergoline once daily in the evening.

Fig. 1
figure 1

Treatment and outcome of the described cohort. Light gray box indicates those patients in group 1 (surgical remission, n = 36), dark gray box indicates the patients in group 2 that achieved normalization of UFC with medical therapy (n = 24, either primary or after surgical failure)

Table 1 Cortisol-lowering drugs, dose, and time in treatment of subjects treated with a single and combined lines of therapy

All 60 patients completed at least 2 years of follow-up; a long-term 5-years evaluation was available in 43 patients of the original cohort (32 after surgery and 11 with medical therapy). Baseline characteristics of the two cohorts are reported in Table 2.

Table 2 Baseline characteristics of the two groups and previous treatment modalities

Data collection and study design

Two researchers retrieved clinical and biochemical data independently from the local digital medical records. We considered as baseline visit the clinical and endocrine evaluation performed with active hypercortisolism. Therefore, the baseline visit consists in the pre-surgical evaluation in group 1, and in the post-surgical confirmation of active hypercortisolism in those in medical treatment (or diagnosis in case of primary treatment, group 2).

We considered clinical and biochemical outcomes during routine follow-up at two- and five-years in each group, starting from surgical remission or the beginning of a stable normalization of UFC under medical therapy. CD diagnosis was based on at least two parameters among 24-h UFC above the upper normal limit (ULN, at least two collections), unsuppressed cortisol levels (> 50 nmol/L) after 1 mg overnight dexamethasone test (1 mg-DST) or late-night salivary cortisol (LNSC) > ULN (at least two samples). In all subjects, CD diagnosis was considered in case of normal-high ACTH levels, positive response to dynamic tests (corticotropin-releasing hormone or desmopressin test, high-dose dexamethasone test), and, two cases, with petrosal sinus sampling (BIPSS) [11]. Long-term remission after TSS was defined through normal UFC, combined with serum cortisol levels < 50 nmol/L in the first month after surgery and need of glucocorticoid replacement therapy. A relapse of CD was defined as the reappearance of the typical signs and symptoms of CD associated with the alteration of at least two first-line screening tests. Presence/absence of clinical signs of CD (round face, facial rubor, buffalo hump, bruising, cutaneous red striae, acne, hirsutism and oligo/amenorrhea in females) were evaluated during outpatient visits by expert endocrinologists. The presence of hirsutism in females was measured according to the Ferriman–Gallwey score > 8 (extent of hair growth in 9 locations was rated 0–4). Proximal muscle strength was diagnosed if patients were not able to stand up from a low seated position with anteriorly extended arms. Bodyweight, body mass index (BMI), waist and hip circumference, systolic (SBP), and diastolic blood pressure (DBP) were assessed with calibrated tools. Overweight was diagnosed in patients with BMI 25–30 kg/m2, obesity with BMI > 30 kg/m2. Visceral obesity was diagnosed as waist circumference ≥ 94 cm in men and ≥ 80 cm in women, or with a waist/hip ratio (WHR) ≥ 1 according to International Diabetes Federation criteria. Arterial hypertension was diagnosed for SBP above 140 mm Hg and/or DBP above 90 mm Hg and/or in patients on antihypertensive drugs. Diabetes mellitus (DM) was diagnosed according to American Diabetes Association criteria or when patients were taking antidiabetic medication. Dyslipidemia was diagnosed when low-density lipoprotein (LDL) calculated cholesterol was ≥ 100 mg/dL and hypertriglyceridemia when triglycerides were ≥ 150 mg/dL or when patients were on lipid-lowering medication. The presence of carotid vascular disease (CVD) has been assessed by supra-aortic vessels duplex ultrasound. Cushing’s cardiomyopathy (CCM) was diagnosed by doppler echocardiography with evidence of impaired relaxation and left ventricular filling pattern. The medical history was checked for cardiovascular disease (acute coronary syndrome, ACS) in all cases. A shortened activated partial thromboplastin time (aPTT < 29 s) defined pro-thrombotic status.

Assays

All biochemical analyses were carried out in an ISO15189:2012-accredited clinical laboratory [12], cortisol levels have been measured in urine or saliva with a mass-spectrometry home-made validated method. UFC was determined by a home-brew liquid chromatography-mass spectrometry (LC-MS/MS) method (intra-assay/interassay coefficient of variation [CV] < 6%/< 8%) since 2011 [13], previously by a radio-immunometric assay (Radim, intra-assay/interassay CV < 3%/< 9%). The patients were instructed to discard the first morning urine void and to collect all urine for the next 24 h, so that the morning urine void on the second day was the final collection. The sample was kept refrigerated from collection time until it was analyzed: normal range for UFC is 16–168 nmol/24 h.

Salivary cortisol was measured by a radio-immunometric assay (Radim, intra-assay/interassay CV < 3%/< 9%) until 2014 [14], after then by LC-MS/MS method (intra-assay/interassay CV < 6%/< 8% [15]). In order to prevent food or blood contamination, samples were collected at least 30 min after subjects had eaten, brushed their teeth, smoked or assumed liquorice; undertaken using Salivette® devices containing a cotton swab with or without citric acid (Sarstedt, Nümbrecht, Germany). The sample was stored at − 80 °C, before analyses [15].

The 1-mg DST test was performed orally assuming 1 mg of dexamethasone between 11 P.M. and midnight, sampling serum cortisol the next morning at 8 A.M. Serum dexamethasone levels, routinely evaluated since 2017, were adequate in all cases [16]. Serum cortisol (RRID: AB_2810257) and ACTH (RRID: AB_2783635) were determined by immune-chemiluminescence assay (Immulite 2000, Siemens Healthcare). Dynamic second-line tests and BIPSS were performed according to international standards.

Statistical analysis

Data were analyzed using SPSS Software for Windows, version 24.0 (SPSS Inc). Data are reported as medians and interquartile range or as percentages. The comparison between continuous variables was performed by non-parametric Wilcoxon test or Mann–Whitney test, as appropriate. The comparison between categorical variables was performed by the χ2 test. The correlation between continuous variables was performed by linear regression analysis. The level of significance for the overall difference between the groups was tested with one-way ANOVA. A p value < 0.05 was considered statistically significant.

Results

Endocrine evaluation

At baseline the two groups were similar for morning serum/salivary cortisol, LNSC, cortisol after 1 mg DST and morning ACTH levels (Table 3); UFC levels were higher in the surgical cohort (p < 0.001). Endocrine parameters were not influenced by sex and BMI. At baseline, all patients had impaired salivary cortisol rhythm with increased LNSC and inadequate cortisol suppression after 1-mg DST. At two years the recovery of salivary cortisol rhythm was observed in 97% of patients after surgery and 50% of patients during medical therapy. The only patient who did not show recovery of cortisol rhythm in the surgical cohort had LNSC of 5.4 nmol/L (range 0.5–2.6 nmol/L), with adequate cortisol suppression after 1-mg DST and sustained normal UFC: it was considered a false-positive due to residual minor depression state.

Table 3 Biochemical pattern at baseline and during the follow-up

Adequate cortisol suppression after 1-mg DST (both with normal UFC and LNSC) was observed in 34 out of 36 patients (94%) in the surgical cohort; the two patients who did not show complete cortisol suppression after 1-mg DST had cortisol levels of 60 and 119 nmol/l, respectively. On the contrary, as per selection criteria, none of the patients in group 2 presented suppressed cortisol after 1-mg DST.

At 5 years follow-up, all cases in the surgical cohort had suppressed cortisol after 1-mg DST and normal salivary cortisol rhythm, whereas in group 2 9% had suppressed cortisol after 1-mg DST and 36% recovered salivary cortisol rhythm. At 5 years, UFC and salivary cortisol levels (either morning or late night) were similar in the two groups, while the median value of serum cortisol after 1-mg DST remained not adequately suppressed (median 75 nmol/L, from 18 to 257 nmol/L) during medical therapy (See Table 3). In group 2, patients on combined therapy had higher UFC (102 vs. 76 nmol/24h p = 0.03) and LNSC (2.4 vs. 1.9 p = 0.05) at 5 years, compared to patients on monotherapy.

Hirsutism, abdominal obesity, round face and facial rubor were prevalent in group 1 at baseline. On the contrary, the abdominal obesity, facial rubor and easy bruising were most commonly found in the medical cohort. The prevalence of facial rubor, buffalo hump and bruisability was higher after medical than surgical remission after 2 years of eucortisolism; at 5 years the prevalence of buffalo hump and bruisability was higher in patients under drug therapy as well (Table 4; Fig. 2). Higher levels of UFC at baseline were observed in all patients with proximal myopathy (p < 0.001).

Table 4 Two- and five-years changes in clinical phenotype from baseline in group 1 and group 2
Fig. 2

figure 2

Signs and symptoms of hypercortisolism at baseline (grey bars), two-years (orange bars) and five-years (blue bars) follow up after surgical (TSS) or medical remission (MED)

Arterial hypertension

Arterial hypertension (AH) was the most frequent comorbidity in both groups at baseline, with similar distribution in the two groups (Table 5). The prevalence of AH decreased after two years in both groups, especially in the surgical cohort (64% vs. 44% in group 2, p < 0.001; 75% vs. 71% p = 0.003), with no further improvement after five years. Overall, hypertensive patients were older at diagnosis (45yrs vs. 31y; p < 0.001) and with larger BMI (29 vs. 25 kg/m2; p = 0.03). Median UFC, morning salivary cortisol and LNSC, and 1-mg DST were not different in patients with/without AH at baseline and at 2 years. SBP and DBP values were similar in the two cohorts and were not correlated to UFC, LNSC or 1-mg DST throughout the follow-up. At 2 years, hypertensive patients had higher levels of morning salivary cortisol and LNSC with impaired rhythm (respectively 10.4 vs. 6 nmol/L, p = 0.01 and 3.2 vs. 1 nmol/l, p = 0.007). SBP and DBP values did not change during the five-years observation time in both groups; however, the number of anti-hypertensive drugs was higher in group 2 than in group 1 (p = 0.007). Overall patients treated with metyrapone showed higher values of DBP at 2 years (mean 89.4 vs. 81.7 mmHg, p = 0.01), the prevalence of AH did not differ from patients with other medical treatments.

Table 5 Two- and five-years changes in cardio-metabolic cortisol-related comorbidities of CD from baseline in group 1 and group 2

Glucose metabolism

DM prevalence at baseline did not show a correlation with BMI and age at CD diagnosis. DM prevalence was similar in group 1 and 2 after two and five years of follow-up. The follow-up analysis of DM was performed excluding patients in pasireotide, since its known impact in glucose metabolism. In both groups, median UFC, morning salivary and LNSC, and 1-mg DST were similar in patients with/without DM at baseline. At 5 years, patients with diabetes had higher levels of morning salivary cortisol and LNSC with impaired cortisol rhythm (respectively 15 vs. 7 nmol/L, p < 0.001 and 5.4 vs. 1.5 nmol/l, p < 0.001). None of the explored hormonal parameters was correlated with HbA1c levels in both groups at any time point considered. The number of antidiabetic drugs was higher after medical than surgical remission (Table 5).

As expected, patients treated with pasireotide had higher incidence of newly onset DM at 2- and 5 years (p = 0.02 and p = 0.05 respectively) and required more antidiabetic drugs at 2- and 5 years (p = 0.002, p = 0.05) or insulin units at 5 years (p = 0.03). HbA1c levels during pasireotide were higher than patients treated with other drugs (55.6 vs. 38 nmol/l, p = 0.002), requiring a higher number of antidiabetic drugs (p = 0.008). Patients on combined therapy with pasireotide had higher rates of DM at 2- and 5 years (p < 0.001 and p = 0.01) and used more antidiabetic drugs at 2- and 5 years (p = 0.004, p = 0.01) than those on monotherapy.

Lipid metabolism

The prevalence of dyslipidemia was similar in the two groups at baseline and after two years, and higher in the medical remission cohort after five years (p = 0.01). Overall, dyslipidemic patients were older at diagnosis (46y vs. 36y; p = 0.006) and had higher BMI (30 vs. 25 kg/m2; p < 0.001). There was no correlation between hormone parameters and LDL or triglycerides levels. Lipid profile was similar between patients treated with different drugs.

Vascular disease and coagulative profile

There was no difference between the two groups, at baseline, in the prevalence of carotid vascular disease, history of ACS, and CCM; at 5 years, in both groups, no patient had a worsening of a previously diagnosed stenosis, or novel diagnosis of CVD, ACS and CCM.

The median aPTT value at baseline was in the pro-thrombotic range in both groups (25s), without sex and BMI differences. No correlation was observed between aPTT and UFC, LNSC and 1-mg DST levels. Patients who manifested easy bruising, had shorter aPTT at 2- and 5 years (median 24 vs. 27s, p = 0.03). aPTT does not increase within both groups at 2- and 5-years and aPTT was shorter during medical therapy compared to surgical remission both after 2 and 5 years (22.5s vs. 27s, p = 0.02 at 2y and 23.5s vs. 27.9s, p = 0.02 at 5y).

Discussion

The impact of CD remission on clinical picture and hypercortisolism-related comorbidities is still controversial. The current knowledge suggests that long-term CD surgical remission is associated with increased metabolic and vascular damage, not only if compared to active disease, but also even after long-term normalization of cortisol secretion [17]. If CD recurs after successful TSS, or if surgery fails/is not feasible, cortisol excess can be treated with medical therapy. Likewise, long-term studies (> 2 years) on the clinical effects of medical therapy on CD are lacking. Some prospective registry studies have been published [1], only one retrospective study on long-term use of ketoconazole described a multicentric cohort of CD patients without a control group [18].

In our study, we enrolled 60 patients with CD diagnosed and treated in a single tertiary care center, with sustained and long-term (2 and 5 years) UFC normalization after surgery or during medical therapy. As expected, UFC levels at baseline were different in the two groups, due to the distinct starting point of medical history: a patient with persistent-recurrent CD after pituitary surgery presents with lower UFC than the new diagnosis. After surgical remission, patients achieved the recovery of salivary cortisol rhythm and the complete suppression of cortisol after 1-mg DST (investigated after substitutive glucocorticoid treatment discontinuation) in almost all cases. On the contrary, if eucortisolism is achieved with long-term medical therapy the recovery of salivary cortisol rhythm was observed only in half of patients and only few of them showed cortisol suppression after 1-mg DST within the 5 years observation time. Patients who were more resistant to the recovery of cortisol rhythm were more likely to receive combined treatment, even if no treatment is superior to others in normalizing salivary cortisol rhythm, in line with previous reports [1, 18, 19].

Within 2 years, patients in the surgical remission group showed a marked improvement of all phenotypic traits common at CD diagnosis compared to those in medical therapy. As observed also in other series of CD patients in remission [20], abdominal obesity persisted more than other clinical features over time, leading to an impaired body composition especially in the medically treated group [21]. Considering hyperandrogenism, acne improvement was more relevant at 2 and 5-years of follow up, probably due to a differential effect of ACTH-dependent adrenal androgens compared to hirsutism.

The impaired cortisol rhythm was a predictor of the long-lasting of most CD phenotypic features, as round face, buffalo hump, facial rubor, abdominal obesity, proximal myopathy and bruisability. A more severe clinical phenotype at baseline can explain a reduced control of hypercortisolism in monotherapy, requiring drug combination, and signs or symptoms are likely to persist despite the normalization of UFC [22]. In this study, no medication outperformed the others in terms of recovery from the CD phenotype.

The aetiology of hypertension and dyslipidemia is known to be heterogeneous, since both are influenced also by age at diagnosis and BMI, causing low rates of remission after UFC normalization [23, 24]. Arterial hypertension showed a decreasing trend with the best response within 2 years after UFC normalization only after surgical remission. Patients with disrupted salivary cortisol rhythm were more likely to remain hypertensive during the 5 years follow-up. Likewise, DM persistence during follow up correlates to impaired salivary cortisol rhythm and not with UFC. This finding is in contrast with the observations of Schernthaner-Reiter et al. [25]. on CD remission, and, on the contrary, supports data described by Guarnotta et al. [22]. Newell-Price et al.. recently found that when UFC and LSNC are both normal in patients treated with pasireotide, the rise in HbA1c levels is less evident than in patients with normal UFC but uncontrolled LNSC [26]. This observation underlines the importance of the impaired cortisol rhythm in the glucose impairment pathogenesis in CD. During the 5 years observation time, a worsening of previously diagnosed cardiovascular conditions, or novel acute vascular events, was not observed in both groups. This finding suggested that normalized UFC and intensive treatment of cardio-metabolic CD comorbidities play a fundamental role in reducing cardiovascular mortality [27]. A minor impact of CD therapy was observed in dyslipidemia, which persisted in both groups, with minimal improvement over time (−22% in surgical and − 6% in medical cohort). The criterion of 100 mg/dL LDL cut-off identifies a moderate CV risk reflecting the main focus of the study: the assessment of cardiometabolic complication after CD remission, assuming that they present a lower cardiovascular risk compared to patients with overt hypercortisolism.

Plasma hypercoagulability, with shortened aPTT, was found in all patients with active hypercortisolism. In the 5 years observation time, this parameter showed latency in increasing in both groups and in none achieved normality (> 28s). As previously observed in other studies, no correlation is observed between aPTT and any of the explored hormonal parameters [22, 28]. At 2- and 5 years, instead, shorter aPTT was observed during medical treatment than after surgical remission cohort. In both groups a shorter aPTT was associated with bruisability, which is related to impaired LNSC, strengthening the role of the impaired cortisol rhythm as a major driver of hypercoagulability. Also, Ferrante et al.. observed the long latency of plasma hypercoagulability, persisting for years after biochemical remission of CD: in that series thrombophilia appeared to be reversible within 5 years [29], while in our cohort the recovery takes longer.

Additionally, sexual differences characterize patients with patients with Cushing’s syndrome and hypogonadism in hypercortisolism is known to further increase the cardiovascular risk [30, 31]. However, it was not an interfering factor in our study population since hypopituitarism was considered an exclusion criterion, no case of new-onset hypogonadism was reported (even in male patients treated with ketoconazole), and the menopause transition in six women during the observation was not considered relevant.

The limits of the present study are its retrospective design, the variability of concomitant treatments, the heterogenous combinations of medical therapy used in clinical practice, the presence of treatment-specific adverse events that mimic the effects of hypercortisolism (such as pasireotide-induced DM and hypertension with metyrapone), the unpredictable effect of previous treatments, including radiotherapy. We considered UFC and LNSC as markers of hypercortisolism remission; nonetheless we acknowledge that both of them present some limitations, especially during medical treatment. The former considers the whole cortisol secretion during the day, and albeit UFC normalization is the main outcome of all trials for medical treatment [32, 33] it does not detect mild hypercortisolism. On the other hand, a normal LNSC does not fully reflect a normal circadian rhythm: only high cortisol levels in the morning with a decline in the night are able to restore clock-related activities [34].

Its strengths are the complete patient characterization in a single tertiary care center, the comparative study design, and the standardized protocols for diagnosis and long-term follow-up. In particular, samples have been processed within a single laboratory with accurate methods (LC-MS for urinary and salivary steroids), and all endocrine aspects of hypercortisolism were considered (overall daily cortisol production by UFC, circadian cortisol rhythm, and the recovery of the hypothalamic-pituitary axis by 1-mg DST overnight test).

To conclude, despite UFC normalization in both groups during follow-up, surgical remission results in more rapid and relevant improvements in CD phenotype and comorbidities. During medical therapy the UFC levels can be higher than after surgery, although in the normal range, and the normalization of LNSC is not always achieved: both conditions suggests that stricter criteria should be considered to define eucortisolism in patients with CD under medical treatment. Conditions such as obesity, hypertension, dyslipidemia, and hypercoagulability are not completely reversible in a 5-year observation time even in the surgical remission group. This observation underlines that all the comorbidities, independently of the normalization of UFC, must be intensively treated. Moreover, UFC normalization should not be considered the only biochemical goal to be reached, since the persistence of comorbidities seems to be more related to an impaired cortisol rhythm rather than to the cortisol secretory burden.

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All authors certify that they have no affiliations with or involvement in any organization or entity with any financial interest or non-financial interest in the subject matter or materials discussed in this manuscript.

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  1. Department of Medicine-DIMED, University of Padova, Padova, Italy

    Irene Tizianel, Laura Lizzul, Alessandro Mondin, Giacomo Voltan, Pierluigi Mazzeo, Carla Scaroni, Mattia Barbot & Filippo Ceccato

  2. Endocrinology Unit, Department of Medicine DIMED, University Hospital of Padova, Via Ospedale Civile, 105, Padova, 35128, Italy

    Irene Tizianel, Laura Lizzul, Alessandro Mondin, Giacomo Voltan, Pierluigi Mazzeo, Carla Scaroni, Mattia Barbot & Filippo Ceccato

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Correspondence to Filippo Ceccato.

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Tizianel, I., Lizzul, L., Mondin, A. et al. Cardiometabolic complications after Cushing’s disease remission. J Endocrinol Invest (2025). https://doi.org/10.1007/s40618-025-02572-x

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