Mortality in Cushing’s Syndrome: Declining Over Two Decades but Remaining Higher Than the General Population

Posted on April 18, 2025 by MaryO

Abstract

Objective

Patients with endogenous Cushing’s syndrome (CS) have elevated mortality, particularly during active disease. A recent meta-analysis reported reduced mortality rates after 2000 in adrenal CS and Cushing disease (CD), though many studies lacked population-matched controls.

Methods Nationwide retrospective study (2000–2023) in Israel using the Clalit Health Services database to assess all-cause mortality in patients with endogenous CS matched 1:5 with controls by age, sex, socioeconomic-status, and BMI. Primary outcome was all-cause mortality. Secondary outcomes included cause-specific mortality, impact of hypercortisolism remission, disease source, and mortality risk factors.

Results The cohort included 609 cases with CS (mean age 48.1±17.2 years; 65.0% women) and 3,018 matched controls (47.9±17.2 years; 65.4% women). Over a median follow-up of 16 years, 133 cases (21.8%) and 472 controls (15.6%) died (HR=1.44, 95% CI, 1.19–1.75). Both patients with CD (HR=1.73, 95% CI, 1.27–2.36) and adrenal CS (HR=1.31, 95% CI, 1.00–1.81) had increased mortality risk. Patients without remission within 2 years had a higher mortality risk than those achieving remission (HR=1.44, 95% CI, 1.00–2.17). Mortality was similar for CD and adrenal CS (HR=0.83, 95% CI, 0.56–1.24). Older age, male gender, and prior malignancy were independent risk factors for mortality.

Conclusion This is the largest national cohort study on mortality risk in CS over the past two decades, showing a significantly higher risk compared to matched controls in a homogeneous database. While etiology had no impact, remission significantly affected mortality, highlighting the importance of disease control for long-term survival.

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Myocardial Work Impairment in Patients With Cushing’s Syndrome

Posted on April 4, 2025 by MaryO

The following is a summary of “Impact Of Hypercortisolism Beyond Metabolic Syndrome On Left Ventricular Performance: A Myocardial Work Analysis,” published in the March 2025 issue of Cardiovascular Diabetology by Sahiti et al.

Endogenous Cushing’s Syndrome (CS) is associated with an increased cardiovascular (CV) and metabolic risk profile, yet the specific impact of hypercortisolism on myocardial function remains inadequately understood. Myocardial Work analysis, a novel echocardiographic technique utilizing left ventricular pressure-strain loops, allows for the assessment of cardiac performance independently of afterload, offering valuable insight into myocardial function in CS. This cross-sectional study aimed to evaluate left ventricular function across four distinct groups: patients with overt endogenous CS (n = 31; mean age 47 ± 12 years; 71% women), patients in long-term remission following successful medical treatment (CS-LTR; n = 49; mean age 53 ± 12 years; 78% women), a healthy control group (n = 439; mean age 49 ± 11 years; 57% women), and individuals with metabolic syndrome (n = 305; mean age 59 ± 10 years; 37% women).

Both CS groups exhibited a more unfavorable metabolic and CV risk profile than healthy controls, although they presented a relatively better profile compared to individuals with metabolic syndrome. Adjusted analyses accounting for sex and age demonstrated significantly increased Wasted Work in both the overt CS group (median: 105 mmHg%; interquartile range: 74–147) and CS-LTR group (97 mmHg%; 69–158) when compared to healthy individuals (75 mmHg%; 54–109; p < 0.01). Additionally, wasted work values in patients with CS were slightly elevated in comparison to those observed in patients with metabolic syndrome (95 mmHg%; 65–136; p < 0.05), indicating persistent myocardial dysfunction. This impairment in myocardial performance translated into a significant reduction in Work Efficiency (p < 0.05), even in patients with CS who had achieved biochemical remission.

The findings suggest that hypercortisolism contributes to persistent left ventricular dysfunction beyond the effects of traditional CV risk factors. Furthermore, despite the biochemical resolution of CS, patients in long-term remission continue to exhibit myocardial abnormalities, reinforcing the notion that prior exposure to excess cortisol may induce lasting structural and functional cardiac alterations. These findings underscore the utility of Myocardial Work analysis in detecting subclinical yet clinically relevant myocardial dysfunction in patients with CS, both in its active state and after remission. Given the persistence of myocardial impairment even following the resolution of hypercortisolism, long-term cardiovascular monitoring may be warranted in this patient population. This study highlights the need for further research to determine whether targeted interventions could mitigate residual myocardial dysfunction in patients with a history of CS, ultimately improving their cardiovascular outcomes.

Source: cardiab.biomedcentral.com/articles/10.1186/s12933-025-02680-1`

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First-Episode Psychosis and Cushing Syndrome

Posted on March 28, 2025 by MaryO

Cushing syndrome, a state of hypercortisolism, has multiple etiologies, including ectopic adrenocorticotropic hormone (ACTH) syndrome (EAS). EAS is a frequently severe emergency related to the degree of hypercortisolism. Neuropsychiatric symptoms of Cushing syndrome are well documented, including irritability, anxiety, depressed mood, and cognitive impairment.1 A few prior case reports have described first episode psychosis associated with Cushing syndrome,2 sometimes leading to delayed or misdiagnosis of Cushing syndrome.

Here, we report a case of a 72-year old man diagnosed with EAS caused by excessive ACTH secretion by a metastatic neuroendocrine tumor. Our report aims to add to the body of evidence indicating that Cushing associated psychosis can cause acutely severe paranoia and delusions that significantly impact management.

Case Report

Mr A, a 72-year-old retired physician with no prior psychiatric history, was diagnosed with new-onset psychosis in the setting of hypercortisolism. He initially presented with weakness secondary to hypokalemia and was found to have Cushing syndrome. On psychiatric evaluation, he demonstrated paranoia and delusions as well as illogical, concrete, and limited thought content. Laboratory workup, neurocognitive examination, and collateral history ruled out delirium or dementias. His morning cortisol levels were up to 162 μg/dL, and ACTH levels were greater than 2,000 pg/mL.

Mr A’s cortisol levels were not suppressed with a high-dose dexamethasone test, supporting ectopic ACTH production. He was found to have a metastatic ACTH secreting large cell neuroendocrine tumor, responsible for his hypercortisolism. Magnetic resonance imaging of his brain demonstrated a pituitary mass, and a bilateral adrenalectomy revealed a small focus of neuroendocrine carcinoma on his left adrenal gland.

Mr A was treated with haloperidol for hallucinations, delusional features, and paranoia; ramelteon for delirium prophylaxis; and suvorexant for sleep initiation. His endocrinology team ultimately started him on osilodrostat (decreases cortisol synthesis via 11 β-hydroxylase inhibition), which led to improvements in his cortisol levels, and his psychotic features subsequently diminished and resolved by the fourth day. All medications for psychiatric symptoms were successfully discontinued without symptom recurrence.

Discussion

Hypothalamic-pituitary-adrenal axis abnormalities, including hypercortisolism, have been well documented in first-episode psychosis cases.3 This includes increased morning cortisol levels in the blood in individuals with first-episode psychosis and increased baseline cortisol levels in the saliva for individuals at a clinical high risk of psychosis.4 There are multiple proposed mechanisms for how excess exposure to cortisol leads to psychosis. Theories include structural and chemical changes such as abnormal regulation of neurotransmitters, impaired neurogenesis, decreased brain volume in the hippocampus, abnormal loss of synapses, and dendritic atrophy. However, these changes are typically in the setting of prolonged exposure to high levels of cortisol.

There are a limited number of case reports regarding Cushing syndrome and acute psychosis.2 Past case reports that have described Cushing syndrome and acute onset of psychosis endorse severely high levels of cortisol, which may be a driving factor, and patients presented with less profound delusional and paranoid content.2 In this case, the patient presented with severe paranoia and delusions in the setting of excess cortisol and metastatic malignancy. Similar cases have been reported and focus on reducing cortisol levels to help manage the psychiatric symptoms.2,5,6 Psychotropic management can assist with symptoms; however, the ultimate treatment remains to address the endocrinologic abnormality. While most cases have reported improvement of neuropsychiatric symptoms with resolution of hypercortisolism, others have described persisting or even exacerbation of psychiatric symptoms even after resolution of the high cortisol levels.5–7 Most importantly, we must recognize Cushing syndrome and its hormonal derangements as a possible underlying etiology of psychosis to guide effective diagnostics and therapeutic management.

Article Information

Published Online: March 25, 2025. https://doi.org/10.4088/PCC.24cr03886
© 2025 Physicians Postgraduate Press, Inc.
Prim Care Companion CNS Disord 2025;27(2):24cr03886
Submitted: November 4, 2024; accepted January 3, 2025.
To Cite: Gunther M, Jiang S. First-episode psychosis and Cushing syndrome. Prim Care Companion CNS Disord 2025;27(2):24cr03886.
Author Affiliations: Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Palo Alto, California (Gunther); Department of Psychiatry, University of Florida, Gainesville, Florida (Jiang).
Corresponding Author: Matthew Gunther, MD, MA, Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, 401 Quarry Rd, Palo Alto, CA 94304 (guntherm@stanford.edu).
Relevant Financial Relationships: None.
Funding/Support: None.
Patient Consent: Consent was received from the patient to publish the case report, and information has been de-identified to protect anonymity.

References:

  1. Santos A, Resmini E, Pascual JC, et al. Psychiatric symptoms in patients with Cushing’s syndrome: prevalence, diagnosis and management. Drugs. 2017;77(8):829–842. CrossRef
  2. Okumura T, Takayama S, Nishio S, et al. ACTH producing thymic neuroendocrine tumor initially presenting as psychosis: a case report and literature review. Thorac Cancer. 2019;10(7):1648–1653. CrossRef
  3. Misiak B, Pruessner M, Samochowiec J, et al. A meta-analysis of blood and salivary cortisol levels in first-episode psychosis and high-risk individuals. Front Neuroendocrinol. 2021;62:100930. CrossRef
  4. Chaumette B, Kebir O, Mam-Lam-Fook C, et al. Salivary cortisol in early psychosis: new findings and meta-analysis. Psychoneuroendocrinology. 2016;63:262–270. CrossRef
  5. Al-Harbi SD, Mashi AH, AlJohani NJ. A case of Cushing’s disease presenting with isolated suicidal attempt. Clin Med Insights Case Rep. 2021;14:11795476211027668.
  6. Mokta J, Sharma R, Mokta K, et al. Cushing’s disease presenting as suicidal depression. J Assoc Physicians India. 2016;64(11):82–83.
  7. Pivonello R, Simeoli C, De Martino MC, et al. Neuropsychiatric disorders in Cushing’s syndrome. Front Neurosci. 2015;9:129.

From https://www.psychiatrist.com/pcc/first-episode-psychosis-cushing-syndrome/

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Thin Skin in Cushing’s Syndrome

Posted on March 23, 2025 by MaryO

Abstract

A 53-year-old woman with a history of metastatic small-cell lung cancer was evaluated during an inpatient admission for Cushing’s syndrome on the basis of new findings of hypertension, hypokalemia, hyperglycemia, and metabolic alkalosis.
A focused physical examination was performed to assess for the antianabolic effects of excess cortisol. The thickness of the skin on the back of her third finger was 1.2 mm (reference value, >1.8) when measured with skin calipers (Panels A and B). Thin skin — a clinical sign strongly suggestive of hypercortisolism — results from inhibition of collagen synthesis by glucocorticoids.
To avoid interference from subcutaneous fat, skin thickness should be measured on the backs of the fingers. The measurement can be done with skin calipers (see Video 1) or electrocardiogram calipers (see Video 2). Levels of random plasma cortisol, midnight plasma cortisol, 24-hour urine cortisol, and corticotropin were elevated.
Magnetic resonance imaging of the brain showed no pituitary abnormalities. Whole-body restaging imaging showed new metastatic lesions in the lungs, bones, liver, and meninges. A diagnosis of Cushing’s syndrome — presumed to be paraneoplastic — was made.
After discussing her prognosis with her physicians, the patient opted for palliative care and died 1 week later.

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Bone Material Strength index is low in Patients with Cushing’s Syndrome even after long-term remission

Posted on November 25, 2024 by MaryO

Abstract

Objective: Hypercortisolism in endogenous Cushing’s syndrome (CS) results in decreased bone mineral density (BMD) and increased fracture risk. Although after remission BMD improves, fracture rate remains elevated, suggesting that BMD may not adequately reflect fracture risk in this group. The aim was to evaluate bone material properties, another component of bone quality, using Impact Microindentation (IMI) in patients with CS in remission.

Methods: Cross-sectional study in 60 patients and 60 age-, sex-, and BMD-matched controls at a tertiary referral center between 2019 and 2021. Bone material strength index (BMSi) was measured by IMI using the OsteoProbe® device at the tibia. In addition, laboratory investigation, BMD, and vertebral fracture assessment were performed.

Results: By design, patients and controls were comparable for age (median age 56.5 years), sex (48 women), BMD at the lumbar spine and femoral neck. They were also comparable regarding the number of fragility fractures (21 vs. 27, p=0.22). Median time of remission in patients was 6 years (range 1 to 41). Despite comparable BMD, BMSi was significantly lower in patients compared to controls (76.2±6.7 vs 80.5±4.9, p<0.001). In patients, BMSi was negatively correlated with BMI (r= -0.354, p=0.01), but not related to the presence of fracture, physiological hydrocortisone replacement use, other pituitary insufficiencies, or time since remission.

Conclusion: Bone material properties remain altered in patients with endogenous CS, even after long-term remission. These abnormalities, known to be associated with fractures in other populations, may play a role in the persistent bone fragility of steroid excess.

Keywords: Bone Material properties; Bone fragility; Bone quality; Fractures; Impact Microindentation (IMI); Secondary osteoporosis.

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From https://pubmed.ncbi.nlm.nih.gov/39562003/

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