检索问题
皮质醇过高的危害，以及降低皮质醇的方法
皮质醇过高，即高皮质醇血症，是一种严重的内分泌失调，其主要形式包括库欣症（Cushing's syndrome）。这种状态的临床表现多种多样，且会对患者的整体健康产生深远的影响。
皮质醇过高的危害
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代谢综合症
高皮质醇水平会导致代谢综合症的发生，具体表现为高血压、腹部肥胖、糖尿病和血脂异常。这些病症共同增加了心血管疾病的风险，进而影响寿命和生活质量。 -
心血管疾病风险
皮质醇过高会导致高血压、促进动脉粥样硬化，并提高心脏病和中风的风险。研究表明，活跃的库欣症患者与普通人群相比，死亡率显著升高，而主要的死亡原因是心血管疾病。 -
骨骼健康风险
库欣症患者常常出现骨质疏松和骨折，特别是在长期高皮质醇状态下，骨骼的矿物质密度明显下降，这增加了骨折的风险。 -
内分泌系统与代谢
高皮质醇水平还会导致糖代谢紊乱，增加2型糖尿病的风险。此外，皮质醇对脂肪、糖和蛋白质的代谢都有显著影响，导致脂肪分布异常和体重增加。 -
精神健康问题
高皮质醇水平与多种神经精神疾病相关，包括抑郁症、焦虑和认知功能障碍。研究发现，长期的高皮质醇状态可能导致大脑结构和功能的持久改变。 -
感染风险增加
皮质醇具有免疫抑制的作用，因此高水平的皮质醇会增加感染的易感性，尤其是在库欣症患者中，其感染率显著高于正常人群。 -
生殖和性功能影响
库欣症还可能导致生殖功能障碍，包括月经不规律和性欲减退等问题。
降低皮质醇的方法
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外科手术
对于因肿瘤引起的库欣症，如垂体腺瘤或肾上腺肿瘤，手术切除是初步的治疗选择。外科手术能够有效降低皮质醇的分泌。 -
药物治疗
在一些情况下，如手术不可行、患者不适合手术，或手术后仍存在过高皮质醇的情况，可以使用药物治疗。常用的药物包括：- 酮康唑（Ketoconazole）和米非司酮（Mifepristone）：用于减少皮质醇的合成。
- 加压素拮抗剂：用于降低肺癌等疾病引起的外源性ACTH过度分泌。
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放射疗法
对于不能通过手术切除肿瘤的患者，可能需要放射疗法来控制肿瘤的生长和皮质醇的分泌，特别是在垂体腺瘤的情况下。 -
生活方式的改变
通过健康的饮食、规律的锻炼和良好的睡眠习惯，帮助调节身体的激素水平。减少压力和焦虑也是降低皮质醇水平的重要方法，常见的减压方法包括冥想、瑜伽和深度呼吸等。 -
监测与随访
对于患有库欣症的患者，必须进行定期随访和监测，包括生化指标（如尿游离皮质醇）和临床症状的评估，以确保治疗效果和及时调整治疗方案。
结论
高皮质醇水平对人体健康造成严重危害，加速代谢综合症的发展，增加心血管疾病、骨骼健康风险等。通过外科手术、药物治疗、放射疗法及生活方式调整等方法，可以有效降低皮质醇水平，从而改善患者的健康状况及生活质量。早期识别和治疗是关键，确保患者获得最佳的管理和支持。
References
1Pharmacological Treatment of Cushing's Syndrome.PubMed
Frederic Castinetti
Arch Med Res. 2023 Dec;54(8):102908. doi: 10.1016/j.arcmed.2023.102908. Epub 2023 Nov 15.
The 1 line treatment of Cushing's syndrome is surgery, whatever the aetiology. The role of pharmacological treatment is clear in cases where surgery fails or is impossible, in cases of metastases, or while awaiting the delayed effects of radiotherapy. However, certain situations remain controversial, in particular the possible role of pharmacological treatment as a preparation for surgery. This situation must be divided into 2 parts, severe hypercortisolism with immediate vital risk and non-severe hypercortisolism with diagnostic delay. The initiation and adjustment of treatment doses is also controversial, with the possibility of titration by gradual dose increase based on biological markers, or a more radical "block and replace" approach in which the ultimate goal is to achieve hypocortisolism, which can then be supplemented. Each of these approaches has its advantages and drawbacks and should probably be reserved for different patient profiles depending on the severity of hypercortisolism. In this review, we will focus specifically on these 2 points, namely the potential role of preoperative pharmacological treatment and, more generally, the optimal way to initiate and monitor drug treatment to ensure that eucortisolism or hypocortisolism is achieved. We will define for each part which profiles of patients should be the most adapted to try to give advice on the optimal management of patients with hypercortisolism.
2Epidemiology and mortality of Cushing's syndrome.PubMed
Osamah A Hakami, Shahzada Ahmed, Niki Karavitaki
Best Pract Res Clin Endocrinol Metab. 2021 Jan;35(1):101521. doi: 10.1016/j.beem.2021.101521. Epub 2021 Mar 15.
Endogenous Cushing's syndrome (CS) is a rare endocrine disorder characterised by excess cortisol secretion due to either ACTH-dependent conditions [commonly an ACTH-producing pituitary adenoma (Cushing's disease)] or ACTH-independent causes (with most common aetiology being a benign adrenal adenoma). Overall, the annual incidence of CS ranges between 1.8 and 3.2 cases per million population. Mortality in active CS is elevated compared to the general population, and a number of studies support the view that survival is also compromised even after apparent successful treatment. The main cause of death is cardiovascular disease highlighting the negative impact of cortisol excess on cardiovascular risk factors. Early diagnosis and prompt treatment of the cortisol excess, as well as vigilant monitoring and stringent control of cardiovascular risk factors are key elements for the long-term prognosis of these patients.
3Cushing's Syndrome: Screening and Diagnosis.PubMed
Filippo Ceccato, Marco Boscaro
High Blood Press Cardiovasc Prev. 2016 Sep;23(3):209-15. doi: 10.1007/s40292-016-0153-4. Epub 2016 May 9.
Endogenous Cushing's syndrome (CS) is a rare disease, and usually characterized by hypertension, diabetes, obesity, osteoporosis, facial rounding, dorsocervical fat pad, thin skin, purple striae, hirsutism, and mood disorders. Efficient diagnostic and screening strategies lead to the diagnosis of a significantly higher number of cases of CS. As a screening test for CS, the Endocrine Society's Clinical Practice Guidelines recommend a single test with a high diagnostic accuracy, among the 1-mg dexamethasone suppression test (1-mg DST), late night salivary cortisol (LNSC), and 24 h urinary free cortisol (UFC). In normal subjects, administering a higher than physiological dose of glucocorticoids prompts the suppression of cortisol secretion. The 1-mg DST explores this normal feedback reaction from the hypothalamic-pituitary-adrenal axis (HPA). It is a simple dynamic test, usually performed in outpatients. A morning serum cortisol level <50 nmol/L suffices to exclude CS, unless there is a strong clinical suspicion to suggest otherwise. The HPA axis reaches a nadir just after a person has fallen asleep, but its circadian rhythm is impaired in CS patients, who feature higher cortisol values at night, which are easy to measure in saliva (the LNSC assay). Saliva collection is also suitable for outpatients since cortisol is stable at room temperature and the collection device can be mailed to the laboratory for analysis. UFC levels reflect the integrated tissue exposure to free cortisol over 24 h, and thus provide a particular picture of endogenous hypercortisolism. In most cases, high UFC levels coincide with severe hypercortisolism. UFC is used not only to diagnose CS, but also to monitor its response to medical treatment. All screening tests have procedural snares: some drugs can interfere with the DST; false-positive or false-negative LNSC results may be due to an inadequate soaking of the device or to cyclic CS; and in the case of UFC it is important to ensure that patients provide complete urine collections with appropriate total volumes. Measuring cortisol with antibody-based immunoassays can also generate false-positive results due to cross-reactivity between cortisol, cortisone and other metabolites. Structurally-based assays, such as liquid chromatography with tandem mass spectrometry, only measure cortisol and have only recently become available for use in routine clinical practice. This review summarizes the recent literature on the clinical and biochemical aspects of CS diagnostics with a view to helping physicians choose the best screening test for diagnosing endogenous hypercortisolism.
4Complications of Cushing's syndrome: state of the art.PubMed
Rosario Pivonello, Andrea M Isidori, Maria Cristina De Martino, et al.
Lancet Diabetes Endocrinol. 2016 Jul;4(7):611-29. doi: 10.1016/S2213-8587(16)00086-3. Epub 2016 May 10.
Cushing's syndrome is a serious endocrine disease caused by chronic, autonomous, and excessive secretion of cortisol. The syndrome is associated with increased mortality and impaired quality of life because of the occurrence of comorbidities. These clinical complications include metabolic syndrome, consisting of systemic arterial hypertension, visceral obesity, impairment of glucose metabolism, and dyslipidaemia; musculoskeletal disorders, such as myopathy, osteoporosis, and skeletal fractures; neuropsychiatric disorders, such as impairment of cognitive function, depression, or mania; impairment of reproductive and sexual function; and dermatological manifestations, mainly represented by acne, hirsutism, and alopecia. Hypertension in patients with Cushing's syndrome has a multifactorial pathogenesis and contributes to the increased risk for myocardial infarction, cardiac failure, or stroke, which are the most common causes of death; risks of these outcomes are exacerbated by a prothrombotic diathesis and hypokalaemia. Neuropsychiatric disorders can be responsible for suicide. Immune disorders are common; immunosuppression during active disease causes susceptibility to infections, possibly complicated by sepsis, an important cause of death, whereas immune rebound after disease remission can exacerbate underlying autoimmune diseases. Prompt treatment of cortisol excess and specific treatments of comorbidities are crucial to prevent serious clinical complications and reduce the mortality associated with Cushing's syndrome.
5A clinical perspective on ectopic Cushing's syndrome.PubMed
Oskar Ragnarsson, C Christofer Juhlin, David J Torpy, et al.
Trends Endocrinol Metab. 2024 Apr;35(4):347-360. doi: 10.1016/j.tem.2023.12.003. Epub 2023 Dec 23.
Cushing's syndrome (CS) refers to the clinical features of prolonged pathological glucocorticoid excess. About 10-20% of individuals with CS have ectopic CS (ECS), that is, an adrenocorticotropin (ACTH)-producing tumour outside the pituitary gland. ACTH-secreting neuroendocrine neoplasia (NENs) can arise from many organs, although bronchial NEN, small cell lung cancer (SCLC), pancreatic NEN, thymic NEN, medullary thyroid cancer (MTC), and pheochromocytoma are the most common. Patients with ECS frequently present with severe hypercortisolism. The risk of life-threatening complications is high in severe cases, unless the hypercortisolism is effectively treated. A good outcome in ECS requires a methodical approach, incorporating prompt diagnosis, tumour localization, control of cortisol excess, and resection of the primary tumour when possible.
6Study protocol for a prospective, multicentre study of hypercortisolism in patients with difficult-to-control type 2 diabetes (CATALYST): prevalence and treatment with mifepristone.PubMed
Ralph A DeFronzo, Richard J Auchus, Irina Bancos, et al.
BMJ Open. 2024 Jul 16;14(7):e081121. doi: 10.1136/bmjopen-2023-081121.
INTRODUCTION: Even with recent treatment advances, type 2 diabetes (T2D) remains poorly controlled for many patients, despite the best efforts to adhere to therapies and lifestyle modifications. Although estimates vary, studies indicate that in >10% of individuals with difficult-to-control T2D, hypercortisolism may be an underlying contributing cause. To better understand the prevalence of hypercortisolism and the impact of its treatment on T2D and associated comorbidities, we describe the two-part Hyper ortisolism in P ients with Difficult to Control Type 2 Di betes Despite Receiving Standard-of-Care Therapies: Preva ence and Treatment with Korl m (Mifepri one) (CATALYST) trial. METHODS AND ANALYSIS: In part 1, approximately 1000 participants with difficult-to-control T2D (haemoglobin A1c (HbA1c) 7.5%-11.5% despite multiple therapies) are screened with a 1 mg dexamethasone suppression test (DST). Those with post-DST cortisol >1.8 µg/dL and dexamethasone level ≥140 ng/dL are identified to have hypercortisolism (part 1 primary endpoint), have morning adrenocorticotropic hormone (ACTH) and dehydroepiandrosterone sulfate (DHEAS) measured and undergo a non-contrast adrenal CT scan. Those requiring evaluation for elevated ACTH are referred for care outside the study; those with ACTH and DHEAS in the range may advance to part 2, a randomised, double-blind, placebo-controlled trial to evaluate the impact of treating hypercortisolism with the competitive glucocorticoid receptor antagonist mifepristone (Korlym). Participants are randomised 2:1 to mifepristone or placebo for 24 weeks, stratified by the presence/absence of an abnormal adrenal CT scan. Mifepristone is dosed at 300 mg once daily for 4 weeks, then 600 mg daily based on tolerability and clinical improvement, with an option to increase to 900 mg. The primary endpoint of part 2 assesses changes in HbA1c in participants with hypercortisolism with or without abnormal adrenal CT scan. Secondary endpoints include changes in antidiabetes medications, cortisol-related comorbidities and quality of life. ETHICS AND DISSEMINATION: The study has been approved by Cleveland Clinic IRB (Cleveland, Ohio, USA) and Advarra IRB (Columbia, Maryland, USA). Findings will be presented at scientific meetings and published in peer-reviewed journals. TRIAL REGISTRATION NUMBER: NCT05772169.
7Whom Should We Screen for Cushing Syndrome? The Endocrine Society Practice Guideline Recommendations 2008 Revisited.PubMed
Leah T Braun, Frederick Vogel, Stephanie Zopp, et al.
J Clin Endocrinol Metab. 2022 Aug 18;107(9):e3723-e3730. doi: 10.1210/clinem/dgac379.
CONTEXT: Cushing syndrome (CS) is a rare and serious disease with high mortality. Patients are often diagnosed late in the course of the disease. OBJECTIVE: This work investigated whether defined patient populations should be screened outside the at-risk populations defined in current guidelines. METHODS: As part of the prospective German Cushing registry, we studied 377 patients with suspected CS. The chief complaint for CS referral was documented. Using urinary free cortisol, late-night salivary cortisol, and the 1-mg dexamethasone suppression test as well as long-term clinical observation, CS was confirmed in 93 patients and ruled out for the remaining 284. RESULTS: Patients were referred for 18 key symptoms, of which 5 were more common in patients with CS than in those in whom CS was ruled out: osteoporosis (8% vs 2%; P = .02), adrenal incidentaloma (17% vs 8%, P = 0.01), metabolic syndrome (11% vs 4%; P = .02), myopathy (10% vs 2%; P < .001), and presence of multiple symptoms (16% vs 1%; P < .001). Obesity was more common in patients in whom CS was ruled out (30% vs 4%, P < .001), but recent weight gain was prominent in those with CS. A total of 68 of 93 patients with CS (73%) had typical chief complaints, as did 106 of 284 of patients with ruled-out CS status (37%) according to the Endocrine Society practice guideline 2008. CONCLUSION: The 2008 Endocrine Society Practice guideline for screening and diagnosis of CS defined at-risk populations that should undergo testing. These recommendations are still valid in 2022.
8Overlooked complication of Cushing's syndrome: Reactivation of hepatitis B.PubMed
Tugba Barlas, Mehmet Muhittin Yalcin, Hasan Selcuk Ozger, et al.
Clin Endocrinol (Oxf). 2023 Apr;98(4):481-486. doi: 10.1111/cen.14855. Epub 2022 Dec 7.
OBJECTIVE: Individuals infected with hepatitis B virus (HBV) are at increased risk of reactivation when they receive immunosuppressive therapies. Although exogenous corticosteroid use as immunosuppressive therapy is elaborated in current guidelines on HBV reactivation, Cushing's syndrome (CS) with endogenous hypercortisolemia is not addressed. We aimed to investigate the prevalence of HBV infection and discuss the necessity of antiviral prophylaxis in patients with CS as in other immunosuppressed patients. DESIGN AND PATIENTS: We included 72 patients with CS (Adrenocorticotropic hormone (ACTH) dependent or independent) who were screened for HBV between 2016 and 2021. Patients were categorized into three groups: overt, mild autonomous cortisol secretion (MACS), and remission according to the cortisol burden. Changes in patients' HBV serology and clinical findings over time were analyzed retrospectively. RESULTS: Twenty-six patients had overt hypercortisolism, 18 had mild autonomous cortisol secretion and 28 patients were in remission. Nineteen (26.3%) patients were anti-HBc IgG positive, 4 of them were chronic HBV and 15 were isolated anti-HBc IgG positive. HBsAg was positive in four (5.5%) of the patients, who were all compatible with inactive chronic HBV. While two patients developed HBV reactivation, HBV flare was observed in one patient. CONCLUSION: Since it is not always possible to achieve rapid remission in CS and these patients have long-term hypercortisolemia, we suggest that consensus should be reached on HBV serological assessment, standardization of follow-up, and planning of HBV prophylaxis in required instances in patients with CS especially in regions with a high prevalence of HBV infection.
9Cardiovascular risk assessments in patients with cortisol-producing adenoma: impact of clinical features and genetic characteristics.PubMed
Daisuke Watanabe, Satoshi Morimoto, Noriko Morishima, et al.
Heart Vessels. 2024 Jan;39(1):65-74. doi: 10.1007/s00380-023-02309-x. Epub 2023 Sep 11.
The causes of adrenal Cushing's syndrome (CS) encompass a wide spectrum of adrenal cortisol proliferations that exhibit clinical and molecular heterogeneity. The aims of our study were to investigate whether clinical and molecular heterogeneity influences endothelial function and metabolic abnormalities in patients with cortisol-producing adenoma (CPA). We retrospectively enrolled 25 patients with CPA and 45 patients with essential hypertension (EH). All CPAs were studied by direct sequencing of PRKACA. Flow-mediated vasodilation (FMD), an index of vascular endothelial function, was significantly lower in CS and subclinical CS (SCS) groups than in the EH group. FMD impairment did not differ significantly between CS and SCS groups. No differences in FMD were seen between PRKACA mutant and wild-type groups. FMD correlated negatively with hemoglobin A1c (HbA1c) in both PRKACA mutant and wild-type groups, as well as in CS and SCS groups. After adrenalectomy, systolic blood pressure (SBP) and HbA1c decreased significantly from baseline in the CS group, and SBP and low-density lipoprotein cholesterol (LDL-C) decreased significantly from baseline in the SCS group. While SBP and LDL-C decreased significantly from baseline in patients with wild-type PRKACA, only HbA1c decreased from baseline in patients harboring PRKACA mutations. Our data showed that patients with CPA have impaired endothelial function compared with EH patients and suggest the need for strict monitoring of atherosclerosis, even in patients with SCS or without PRKACA mutation.
10High prevalence of venous thrombotic events in Cushing's syndrome: data from ERCUSYN and details in relation to surgery.PubMed
Kristina Isand, Richard Feelders, Thierry Brue, et al.
Eur J Endocrinol. 2024 Jan 3;190(1):75-85. doi: 10.1093/ejendo/lvad176.
OBJECTIVE: The aim of this study was to evaluate the prevalence of venous thromboembolism (VTE) in patients included in the European Registry on Cushing's syndrome (ERCUSYN), compare their clinical characteristics with those who did not develop VTE and identify risk factors for VTE. DESIGN: A retrospective observational cohort study. METHODS: Data extraction from the registry was taken on February, 7, 2022. At the time there were 2174 patients diagnosed with Cushing's syndrome (CS) and 95 VTEs were reported in the database. RESULTS: Of 95 VTE events 70 (74%) were in pituitary-dependent CS patients, 12 (12.5%) in adrenal-dependant CS, 10 (10.5%) in ectopic CS, and 3 (3%) in CS due to other causes. Sex, 24-hour urinary free cortisol (UFC) value at diagnosis, as well as the number of operations remained statistically significant predictors of VTE. Of patients who were treated with at least one surgery, 12 (13%) VTE occurred before and 80 (87%) after the surgery. Nearly half of these VTEs occurred within six months since the operation (36; 45%). Over half of the centers that reported VTE did not routinely anticoagulate CS patients. Anticoagulation schemes varied widely. CONCLUSION: Patients with CS have an elevated risk of developing VTE for an extended period of time. From ERCUSYN cohort patients have higher risk for VTE if they need multiple surgeries to treat CS, are males and have high UFC values at the diagnosis of CS. Since there is no agreement on thromboprohpylaxis, a protocol for VTE prevention that is widely adopted appears to be necessary for patients with CS.
11Cushing Disease Clinical Phenotype and Tumor Behavior Vary With Age: Diagnostic and Perioperative Implications.PubMed
Jorge Eduardo Salcedo-Sifuentes, Ryan Shih, Anthony P Heaney, et al.
J Clin Endocrinol Metab. 2025 Aug 7;110(9):2595-2604. doi: 10.1210/clinem/dgae904.
CONTEXT: Little is known about presenting clinical characteristics, tumor biology, and surgical morbidity of Cushing disease (CD) with aging. OBJECTIVE: Using a large multi-institutional data set, we assessed diagnostic and prognostic significance of age in CD through differences in presentation, laboratory results, tumor characteristics, and postoperative outcomes. METHODS: Data from the Registry of Adenomas of the Pituitary and Related Disorders (RAPID) were reviewed for patients with CD treated with transsphenoidal tumor resection at 11 centers between 2003 and 2023. Outcomes assessed included comorbidities, presenting features, preoperative endocrine evaluations, perioperative characteristics, postoperative endocrine laboratory values, and complications. RESULTS: Of the 608 patients evaluated, 496 (81.6%) were female; median age at surgery was 44 years (range, 10-78 years). Increasing age was associated with increasing comorbidities, frailty, rates of postoperative thromboembolic disease, Knosp grade, tumor size, and postoperative cortisol and adrenocorticotropin nadirs. Conversely, increasing age was associated with decreased hallmark CD features, preoperative 24-hour urinary free cortisol, Ki-67 indices, and arginine vasopressin deficiency. Younger patients presented more frequently with weight gain, facial rounding/plethora, abdominal striae, hirsutism, menstrual irregularities, dorsocervical fat pad, and acne. Obstructive sleep apnea and infections were more common with increasing age. CONCLUSION: There are age-dependent differences in clinical presentation, tumor behavior, and postoperative outcomes in patients with CD. Compared to younger patients, older patients present with a less classic phenotype characterized by fewer hallmark features, more medical comorbidities, and larger tumors. Notably, age-related differences suggest a more indolent tumor behavior in older patients, potentially contributing to delayed diagnosis and increased perioperative risk. These findings underscore the need for tailored diagnostic and therapeutic approaches across age groups, with a focus on managing long-term comorbidities and optimizing surgical outcomes.
12Etomidate in the treatment of Cushing syndrome.PubMed
N Vergara Molina, N Ruiz Andrés, N Casas Martín, et al.
Rev Esp Anestesiol Reanim (Engl Ed). 2023 Oct;70(8):473-476. doi: 10.1016/j.redare.2023.09.001. Epub 2023 Sep 6.
Cushing syndrome is a metabolic disease caused by chronic exposure to high levels of glucocorticoids. It can present as an endocrine emergency due to a rapid increase in circulating cortisol leading to increased risk of cardiovascular disease and infection. Etomidate rapidly reduces plasma cortisol levels by inhibiting the action of 11β-hidroxilase. We report the case of a patient with severe hypercortisolaemia accompanied by metabolic and psychiatric disorders in whom administration of etomidate reduced preoperative levels of cortisol.
13Emerging diagnostic methods and imaging modalities in cushing's syndrome.PubMed
Kyla Wright, Elisabeth F C van Rossum, Elcin Zan, et al.
Front Endocrinol (Lausanne). 2023 Jul 25;14:1230447. doi: 10.3389/fendo.2023.1230447. eCollection 2023.
Endogenous Cushing's syndrome (CS) is a rare disease characterized by prolonged glucocorticoid excess. Timely diagnosis is critical to allow prompt treatment and limit long-term disease morbidity and risk for mortality. Traditional biochemical diagnostic modalities each have limitations and sensitivities and specificities that vary significantly with diagnostic cutoff values. Biochemical evaluation is particularly complex in patients whose hypercortisolemia fluctuates daily, often requiring repetition of tests to confirm or exclude disease, and when delineating CS from physiologic, nonneoplastic states of hypercortisolism. Lastly, traditional pituitary MRI may be negative in up to 60% of patients with adrenocorticotropic hormone (ACTH)-secreting pituitary adenomas (termed "Cushing's disease" [CD]) whereas false positive pituitary MRI findings may exist in patients with ectopic ACTH secretion. Thus, differentiating CD from ectopic ACTH secretion may necessitate dynamic testing or even invasive procedures such as bilateral inferior petrosal sinus sampling. Newer methods may relieve some of the diagnostic uncertainty in CS, providing a more definitive diagnosis prior to subjecting patients to additional imaging or invasive procedures. For example, a novel method of cortisol measurement in patients with CS is scalp hair analysis, a non-invasive method yielding cortisol and cortisone values representing long-term glucocorticoid exposure of the past months. Hair cortisol and cortisone have both shown to differentiate between CS patients and controls with a high sensitivity and specificity. Moreover, advances in imaging techniques may enhance detection of ACTH-secreting pituitary adenomas. While conventional pituitary MRI may fail to identify microadenomas in patients with CD, high-resolution 3T-MRI with 3D-spoiled gradient-echo sequence has thinner sections and superior soft-tissue contrast that can detect adenomas as small as 2 mm. Similarly, functional imaging may improve the identification of ACTH-secreting adenomas noninvasively; Gallium-68-tagged corticotropin-releasing hormone (CRH) combined with PET-CT can be used to detect CRH receptors, which are upregulated on corticotroph adenomas. This technique can delineate functionality of adenomas in patients with CD from patients with ectopic ACTH secretion and false positive pituitary lesions on MRI. Here, we review emerging methods and imaging modalities for the diagnosis of CS, discussing their diagnostic accuracy, strengths and limitations, and applicability to clinical practice.
14Cushing's syndrome is associated with altered adipokine profile.PubMed
Daniela Dadej, Ewelina Szczepanek-Parulska, Elżbieta Wrotkowska, et al.
Front Endocrinol (Lausanne). 2022 Dec 6;13:1032329. doi: 10.3389/fendo.2022.1032329. eCollection 2022.
INTRODUCTION: Adipokines are signaling molecules involved in the integration of metabolism. Changes in their concentrations were observed in obesity, metabolic syndrome, diabetes mellitus and cardiovascular diseases, as well as endocrine disorders. Cushing's syndrome is associated with metabolic dysregulation, but the significance of adipokines in this entity and related complications is largely unknown. The aim of our study was to determine the concentrations of adipokines: fetuin A, fatty acid binding protein 4 (FABP4) and retinol binding protein 4 (RBP4) in Cushing's syndrome and to assess their relation to established cardiovascular and diabetes risk markers. METHODS: We examined 21 subjects with Cushing's syndrome and 24 healthy controls in a cross-sectional manner. Venous blood samples were analysed for adipokines, cortisol, adrenocorticotrophin, glucose, insulin, glycated haemoglobin (HbA1c), triglycerides, cholesterol fractions, thyrotropin and free thyroid hormones concentrations. Patients' body mass index (BMI) was evaluated, homeostatic model assessment-insulin resistance and Systematic Coronary Risk Evaluation (SCORE) were calculated. RESULTS: We found that the concentration of fetuin A was lower, while FABP4 and RBP4 concentrations were higher in Cushing's syndrome compared to controls [156.4 ± 60.0 µg/ml vs 260.7 ± 49.6 µg/ml; 79.8 (35.2-156.1) ng/ml vs 27.9 (17.1-36.7) ng/ml and 34 (30-37.7) mg/l vs 25.8 (23.6-27.7) mg/l, respectively]. Fetuin A correlated inversely, while FABP4 and RBP4 positively, with the concentrations of urinary free cortisol and adrenocorticotrophin. Fetuin A was positively related to LDL-cholesterol, and negatively to SCORE and HbA1c. FABP4 was associated positively with BMI, HbA1c and triglycerides, while RBP4 correlated positively with triglycerides and systolic blood pressure. CONCLUSIONS: Adipokines' concentrations change in hypercortisolism. Further research is needed to ascertain whether adipokines are involved in the development of metabolic complications accompanying Cushing's syndrome or secondarily reflect metabolic dysregulation.
15Evaluation of procoagulant imbalance in Cushing's syndrome after short- and long-term remission of disease.PubMed
E Ferrante, A L Serban, M Clerici, et al.
J Endocrinol Invest. 2022 Jan;45(1):9-16. doi: 10.1007/s40618-021-01605-5. Epub 2021 Jun 11.
OBJECTIVE: Patients with Cushing's syndrome (CS) are at high risk of venous thromboembolism related to a hypercoagulability due to procoagulant imbalance. However, whether these alterations are reversible after disease remission is still unclear. The endogenous thrombin potential (ETP) measured with and without the addition of thrombomodulin provides a global representation of coagulation and previous data confirmed hypercoagulable profile in patients with active hypercortisolism. Aim of this study was to assess the short- and long-term modification of ETP in patients with CS after disease remission. DESIGN AND METHODS: Nineteen patients with CS for whom surgical remission was achieved, were prospectively evaluated for clinical characteristics, cortisol secretion profile and ETP at different time points: (i) before surgical intervention; (ii) after 6 months and (iii) 5 years from the time of persistent remission. Nineteen healthy subjects matched for age and gender were also evaluated as control group. RESULTS: Before surgery, patients showed higher ETP-ratio (with/without thrombomodulin) than controls (0.62 ± 0.09-vs-0.56 ± 0.09, p = 0.034). No significant correlation between ETP-ratio and cortisol secretion was found. 6 months after remission, ETP-ratio was still significantly increased compared to controls (0.64 ± 0.09-vs-0.56 ± 0.09, p = 0.01), but was similar to baseline (0.64 ± 0.09-vs-0.62 ± 0.09, p = 0.87). At 5 years, ETP-ratio showed a significant decrease (0.55 ± 0.14-vs-0.62 ± 0.09, p = 0.02) and was comparable to controls (0.55 ± 0.14-vs-0.56 ± 0.09, p = 0.7). CONCLUSIONS: Plasma hypercoagulability detected in patients with active hypercortisolism persists at short-term evaluation and seems to be completely reversible after long-term remission of disease. These data, as part of a whole evaluation of thrombotic risk, can contribute to make appropriate therapeutic choice in these patients.
16High bone marrow fat in patients with Cushing's syndrome and vertebral fractures.PubMed
Francesco Ferraù, Salvatore Giovinazzo, Erika Messina, et al.
Endocrine. 2020 Jan;67(1):172-179. doi: 10.1007/s12020-019-02034-4. Epub 2019 Aug 2.
PURPOSE: The evaluation of skeletal fragility in Cushing's syndrome (CS) is a clinical challenge, since dual-energy X-ray absorptiometry (DXA) does not capture abnormalities in bone microstructure induced by glucocorticoid excess. Hypercortisolism was shown to increase bone marrow adiposity, but it is still unknown whether high bone marrow fat (BMF) as measured by vertebral magnetic resonance spectroscopy may predict fracture risk in this clinical setting. In this cross-sectional study, we evaluated the association between BMF and vertebral fractures (VFs) in patients with CS. METHODS: Twenty patients (5 M, age 44 ± 13 years) with active CS were evaluated for morphometric VFs, lumbar spine BMF, and bone mineral density (BMD). Fifteen healthy volunteers (4 M, age 43 ± 12 years) acted as control group for BMF evaluation. RESULTS: BMF was significantly higher in CS patients vs. controls (52.0% vs. 27.0%, p < 0.01), and was directly correlated with patients' age (p = 0.03), 24-hours urine-free cortisol (p = 0.03), midnight serum cortisol (p = 0.02), and serum CTX (p = 0.01). Patients with VFs (13 cases) showed significantly higher BMF vs. patients without VFs (65.0% vs. 24.0%, p = 0.03). Fractured patients with either normal BMD or osteopenia showed comparable BMF to fractured patients with either osteoporosis or low BMD for age (p = 0.71). When the analysis was restricted to patients with normal BMD or osteopenia, VFs were still significantly associated with higher BMF (p = 0.05). CONCLUSIONS: This study provides a first evidence that vertebral adiposity may be a marker of hypercortisolism-induced skeletal fragility and measurement of spine BMF could have a role in the diagnostic work-up for the assessment of fracture risk in CS.
17Susceptibility and characteristics of infections in patients with glucocorticoid excess or insufficiency: the ICARO tool.PubMed
Marianna Minnetti, Valeria Hasenmajer, Emilia Sbardella, et al.
Eur J Endocrinol. 2022 Oct 13;187(5):719-731. doi: 10.1530/EJE-22-0454. Print 2022 Nov 1.
OBJECTIVE: Registry data show that Cushing's syndrome (CS) and adrenal insufficiency (AI) increase mortality rates associated with infectious diseases. Little information is available on susceptibility to milder forms of infections, especially those not requiring hospitalization. This study aimed to investigate infectious diseases in patients with glucocorticoid disorders through the development of a specific tool. METHODS: We developed and administered the InfeCtions in pAtients with endocRinOpathies (ICARO) questionnaire, addressing infectious events over a 12-month observation period, to 1017 outpatients referred to 4 University Hospitals. The ICARO questionnaire showed good test-retest reliability. The odds of infection (OR (95% CI)) were estimated after adjustment for confounders and collated into the ICARO score, reflecting the frequency and duration of infections. RESULTS: In total, 780 patients met the inclusion criteria: 43 with CS, 32 with adrenal incidentaloma and mild autonomous cortisol secretion (MACS), and 135 with AI, plus 570 controls. Compared to controls, CS was associated with higher odds of urinary tract infections (UTIs) (5.1 (2.3-9.9)), mycoses (4.4 (2.1-8.8)), and flu (2.9 (1.4-5.8)). Patients with adrenal incidentaloma and MACS also showed an increased risk of UTIs (3.7 (1.7-8.0)) and flu (3.2 (1.5-6.9)). Post-dexamethasone cortisol levels correlated with the ICARO score in patients with CS. AI was associated with higher odds of UTIs (2.5 (1.6-3.9)), mycoses (2.3 (1.4-3.8)), and gastrointestinal infections (2.2 (1.5-3.3)), independently of any glucocorticoid replacement dose. CONCLUSIONS: The ICARO tool revealed a high prevalence of self-reported infections in patients with glucocorticoid disorders. ICARO is the first of its kind questionnaire, which could be a valuable tool for monitoring infections in various clinical settings.
18Glucocorticoid excess and COVID-19 disease.PubMed
Valentina Guarnotta, Rosario Ferrigno, Marianna Martino, et al.
Rev Endocr Metab Disord. 2021 Dec;22(4):703-714. doi: 10.1007/s11154-020-09598-x. Epub 2020 Oct 6.
The pandemic of coronavirus disease (COVID-19), a disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is causing high and rapid morbidity and mortality. Immune system response plays a crucial role in controlling and resolving the viral infection. Exogenous or endogenous glucocorticoid excess is characterized by increased susceptibility to infections, due to impairment of the innate and adaptive immune system. In addition, diabetes, hypertension, obesity and thromboembolism are conditions overrepresented in patients with hypercortisolism. Thus patients with chronic glucocorticoid (GC) excess may be at high risk of developing COVID-19 infection with a severe clinical course. Care and control of all comorbidities should be one of the primary goals in patients with hypercortisolism requiring immediate and aggressive treatment. The European Society of Endocrinology (ESE), has recently commissioned an urgent clinical guidance document on management of Cushing's syndrome in a COVID-19 period. In this review, we aim to discuss and expand some clinical points related to GC excess that may have an impact on COVID-19 infection, in terms of both contagion risk and clinical outcome. This document is addressed to all specialists who approach patients with endogenous or exogenous GC excess and COVID-19 infection.
19Hypercoagulable state and risk of venous thromboembolism in Cushing syndrome.PubMed
Yuke Liu, Yu Tang, Huiwen Tan, et al.
Zhong Nan Da Xue Xue Bao Yi Xue Ban. 2024 Jun 28;49(6):825-831. doi: 10.11817/j.issn.1672-7347.2024.230575.
Cushing syndrome (CS) is an endocrine-metabolic disorder characterized by hypercortisolism. Elevated cortisol levels can induce a hypercoagulable state, increasing the risk of venous thromboembolism (VTE). Both pituitary-origin Cushing disease (CD) and adrenal-origin non-adrenocorticotropic hormone (ACTH)-dependent CS are primarily treated with surgery. The dual impact of surgery and the underlying disease further elevates the risk of VTE, potentially leading to pulmonary embolism, which poses a severe threat to patient survival. Additionally, CS patients in a hypercoagulable state have a higher incidence of cardiovascular diseases and VTE, and even mortality compared with the general population. Untreated active CS patients have a 17.8-fold increased risk of VTE compared to the general population. In recent years, the relationship between the hypercoagulable state in CS and VTE has garnered increasing attention from clinicians. A better understanding of the clinical epidemiological characteristics, pathophysiological mechanisms, and clinical prevention and treatment of VTE and pulmonary embolism in CS can provide valuable references for the standardized use of prophylactic anticoagulant therapy in CS patients.
20Morbidity of Cushing's Syndrome and Impact of Treatment.PubMed
Susan M Webb, Elena Valassi
Endocrinol Metab Clin North Am. 2018 Jun;47(2):299-311. doi: 10.1016/j.ecl.2018.01.001. Epub 2018 Apr 9.
Cortisol excess in Cushing's syndrome is associated with metabolic, cardiovascular, and cognitive alterations, only partially reversible after resolution of hypercortisolism. Elevated cardiovascular risk may persist after eucortisolism has been achieved. Fractures and low bone mineral density are also described in Cushing's syndrome in remission. Hypercortisolism may induce irreversible structural and functional changes in the brain, leading to neuropsychiatric disorders in the active phase of the disease, which persist. Sustained deterioration of the cardiovascular system, bone remodeling, and cognitive function along with neuropsychological impairment are associated with high morbidity and poor quality of life before and after remission.
检索问题
皮质醇过高的危害，以及降低皮质醇的方法
皮质醇是由肾上腺分泌的一种重要的应激激素，在身体的代谢、免疫反应和水电解质平衡中扮演着关键角色。然而，当体内皮质醇水平过高时，将对健康产生一系列严重的影响。这种情况通常表现为库欣综合症（Cushing's syndrome），其特征是持续性高皮质醇血症，可能由各种原因引起，包括内源性（由肾上腺或垂体肿瘤引起）和外源性（如长期使用糖皮质激素药物）等因素。
皮质醇过高的危害
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心血管疾病的风险增加： 高皮质醇水平与高血压、心脏病和中风的风险显著相关。皮质醇促使血管收缩和钠滞留，这可能导致血压升高。此外，慢性高皮质醇可导致心脏肥大，这是心脏衰竭的重要风险因素。
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代谢紊乱： 多数情况下，库欣综合症患者会出现糖代谢异常，容易发展为2型糖尿病。皮质醇干扰胰岛素的功能，使血糖水平难以控制，同时也导致脂肪沉积、体重增加和肥胖，特别是在腹部的脂肪积聚。
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精神健康问题： 高水平的皮质醇与抑郁症、焦虑症和其他情绪障碍相关。患者可能经历情绪波动、失眠、认知功能受损等问题。
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免疫系统抑制： 皮质醇具有免疫抑制作用，能够削弱机体对感染的抵抗力，使高皮质醇患者更易感染。在活跃的库欣综合症患者中，免疫功能的削弱可能导致更频繁的感染和更高的死亡率。
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肌肉和骨骼健康下降： 持续的高皮质醇水平导致骨质疏松、肌肉萎缩和骨折风险增加。这是因为皮质醇会增加骨钙流失，抑制骨生成，导致骨量的减少。
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内分泌系统干扰： 高皮质醇可削弱性激素的水平，影响生育能力，导致月经不规律或完全缺失，影响男性的性功能。
降低皮质醇水平的方法
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药物治疗： 如果皮质醇水平高是由库欣综合症或其他内分泌失调引起的，药物治疗可能包括使用抑制肾上腺皮质功能的药物，例如氟氯噻噻、米非司酮（mifepristone）等。这些药物通过不同的机制降低体内皮质醇水平（如阻止皮质醇的作用或减少其合成）。
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生活方式改变：
- 饮食管理：健康的饮食应低糖、低脂肪，增加纤维素摄入，帮助控制体重和血糖，从而可能降低皮质醇水平。
- 规律锻炼：适当的运动能够帮助减轻压力，改善身体代谢，从而促进健康的皮质醇水平。
- 改善睡眠：充足和高质量的睡眠可以帮助调节皮质醇的分泌，避免因睡眠不足而导致的皮质醇升高。
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压力管理： 由于皮质醇通常被称为“压力激素”，管理压力对于减少其分泌至关重要。瑜伽、冥想、深呼吸和其他放松技术被证明能够有效降低压力，以此帮助减少身体的皮质醇分泌。
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手术治疗： 对于因肿瘤引起的库欣综合症患者，手术切除肿瘤是根治性的方法。成功手术后，患者许多情况下可以恢复正常的皮质醇水平。此外，对于某些内分泌疾病，可能需要放疗或更复杂的外科干预。
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定期监测皮质醇水平： 定期进行激素水平检测，评估治疗效果和疾病进展，对于高危人群和已有高皮质醇症状的患者尤其重要。
结论
皮质醇的重要性不容忽视，然而当其水平超出正常限度时，将对健康构成威胁。高皮质醇的危害涉及多个系统，包括心血管、代谢、免疫、精神及骨骼肌肉等。因此，全面了解其危害及实施有效的降低措施非常重要。无论是通过药物治疗、生活方式的调整，还是手术干预，持续的监测和评估都是管理皮质醇水平和维护健康的关键。
References
1Pharmacological Treatment of Cushing's Syndrome.PubMed
Frederic Castinetti
Arch Med Res. 2023 Dec;54(8):102908. doi: 10.1016/j.arcmed.2023.102908. Epub 2023 Nov 15.
The 1 line treatment of Cushing's syndrome is surgery, whatever the aetiology. The role of pharmacological treatment is clear in cases where surgery fails or is impossible, in cases of metastases, or while awaiting the delayed effects of radiotherapy. However, certain situations remain controversial, in particular the possible role of pharmacological treatment as a preparation for surgery. This situation must be divided into 2 parts, severe hypercortisolism with immediate vital risk and non-severe hypercortisolism with diagnostic delay. The initiation and adjustment of treatment doses is also controversial, with the possibility of titration by gradual dose increase based on biological markers, or a more radical "block and replace" approach in which the ultimate goal is to achieve hypocortisolism, which can then be supplemented. Each of these approaches has its advantages and drawbacks and should probably be reserved for different patient profiles depending on the severity of hypercortisolism. In this review, we will focus specifically on these 2 points, namely the potential role of preoperative pharmacological treatment and, more generally, the optimal way to initiate and monitor drug treatment to ensure that eucortisolism or hypocortisolism is achieved. We will define for each part which profiles of patients should be the most adapted to try to give advice on the optimal management of patients with hypercortisolism.
2Epidemiology and mortality of Cushing's syndrome.PubMed
Osamah A Hakami, Shahzada Ahmed, Niki Karavitaki
Best Pract Res Clin Endocrinol Metab. 2021 Jan;35(1):101521. doi: 10.1016/j.beem.2021.101521. Epub 2021 Mar 15.
Endogenous Cushing's syndrome (CS) is a rare endocrine disorder characterised by excess cortisol secretion due to either ACTH-dependent conditions [commonly an ACTH-producing pituitary adenoma (Cushing's disease)] or ACTH-independent causes (with most common aetiology being a benign adrenal adenoma). Overall, the annual incidence of CS ranges between 1.8 and 3.2 cases per million population. Mortality in active CS is elevated compared to the general population, and a number of studies support the view that survival is also compromised even after apparent successful treatment. The main cause of death is cardiovascular disease highlighting the negative impact of cortisol excess on cardiovascular risk factors. Early diagnosis and prompt treatment of the cortisol excess, as well as vigilant monitoring and stringent control of cardiovascular risk factors are key elements for the long-term prognosis of these patients.
3Cushing's Syndrome: Screening and Diagnosis.PubMed
Filippo Ceccato, Marco Boscaro
High Blood Press Cardiovasc Prev. 2016 Sep;23(3):209-15. doi: 10.1007/s40292-016-0153-4. Epub 2016 May 9.
Endogenous Cushing's syndrome (CS) is a rare disease, and usually characterized by hypertension, diabetes, obesity, osteoporosis, facial rounding, dorsocervical fat pad, thin skin, purple striae, hirsutism, and mood disorders. Efficient diagnostic and screening strategies lead to the diagnosis of a significantly higher number of cases of CS. As a screening test for CS, the Endocrine Society's Clinical Practice Guidelines recommend a single test with a high diagnostic accuracy, among the 1-mg dexamethasone suppression test (1-mg DST), late night salivary cortisol (LNSC), and 24 h urinary free cortisol (UFC). In normal subjects, administering a higher than physiological dose of glucocorticoids prompts the suppression of cortisol secretion. The 1-mg DST explores this normal feedback reaction from the hypothalamic-pituitary-adrenal axis (HPA). It is a simple dynamic test, usually performed in outpatients. A morning serum cortisol level <50 nmol/L suffices to exclude CS, unless there is a strong clinical suspicion to suggest otherwise. The HPA axis reaches a nadir just after a person has fallen asleep, but its circadian rhythm is impaired in CS patients, who feature higher cortisol values at night, which are easy to measure in saliva (the LNSC assay). Saliva collection is also suitable for outpatients since cortisol is stable at room temperature and the collection device can be mailed to the laboratory for analysis. UFC levels reflect the integrated tissue exposure to free cortisol over 24 h, and thus provide a particular picture of endogenous hypercortisolism. In most cases, high UFC levels coincide with severe hypercortisolism. UFC is used not only to diagnose CS, but also to monitor its response to medical treatment. All screening tests have procedural snares: some drugs can interfere with the DST; false-positive or false-negative LNSC results may be due to an inadequate soaking of the device or to cyclic CS; and in the case of UFC it is important to ensure that patients provide complete urine collections with appropriate total volumes. Measuring cortisol with antibody-based immunoassays can also generate false-positive results due to cross-reactivity between cortisol, cortisone and other metabolites. Structurally-based assays, such as liquid chromatography with tandem mass spectrometry, only measure cortisol and have only recently become available for use in routine clinical practice. This review summarizes the recent literature on the clinical and biochemical aspects of CS diagnostics with a view to helping physicians choose the best screening test for diagnosing endogenous hypercortisolism.
4The Treatment of Cushing's Disease.PubMed
Rosario Pivonello, Monica De Leo, Alessia Cozzolino, et al.
Endocr Rev. 2015 Aug;36(4):385-486. doi: 10.1210/er.2013-1048. Epub 2015 Jun 11.
Cushing's disease (CD), or pituitary-dependent Cushing's syndrome, is a severe endocrine disease caused by a corticotroph pituitary tumor and associated with increased morbidity and mortality. The first-line treatment for CD is pituitary surgery, which is followed by disease remission in around 78% and relapse in around 13% of patients during the 10-year period after surgery, so that nearly one third of patients experience in the long-term a failure of surgery and require an additional second-line treatment. Patients with persistent or recurrent CD require additional treatments, including pituitary radiotherapy, adrenal surgery, and/or medical therapy. Pituitary radiotherapy is effective in controlling cortisol excess in a large percentage of patients, but it is associated with a considerable risk of hypopituitarism. Adrenal surgery is followed by a rapid and definitive control of cortisol excess in nearly all patients, but it induces adrenal insufficiency. Medical therapy has recently acquired a more important role compared to the past, due to the recent employment of novel compounds able to control cortisol secretion or action. Currently, medical therapy is used as a presurgical treatment, particularly for severe disease; or as postsurgical treatment, in cases of failure or incomplete surgical tumor resection; or as bridging therapy before, during, and after radiotherapy while waiting for disease control; or, in selected cases, as primary therapy, mainly when surgery is not an option. The adrenal-directed drug ketoconazole is the most commonly used drug, mainly because of its rapid action, whereas the glucocorticoid receptor antagonist, mifepristone, is highly effective in controlling clinical comorbidities, mainly glucose intolerance, thus being a useful treatment for CD when it is associated with diabetes mellitus. Pituitary-directed drugs have the advantage of acting at the site responsible for CD, the pituitary tumor. Among this group of drugs, the dopamine agonist cabergoline and the somatostatin analog pasireotide result in disease remission in a consistent subgroup of patients with CD. Recently, pasireotide has been approved for the treatment of CD when surgery has failed or when surgery is not an option, and mifepristone has been approved for the treatment of Cushing's syndrome when associated with impairment of glucose metabolism in case of the lack of a surgical indication. Recent experience suggests that the combination of different drugs may be able to control cortisol excess in a great majority of patients with CD.
5Complications of Cushing's syndrome: state of the art.PubMed
Rosario Pivonello, Andrea M Isidori, Maria Cristina De Martino, et al.
Lancet Diabetes Endocrinol. 2016 Jul;4(7):611-29. doi: 10.1016/S2213-8587(16)00086-3. Epub 2016 May 10.
Cushing's syndrome is a serious endocrine disease caused by chronic, autonomous, and excessive secretion of cortisol. The syndrome is associated with increased mortality and impaired quality of life because of the occurrence of comorbidities. These clinical complications include metabolic syndrome, consisting of systemic arterial hypertension, visceral obesity, impairment of glucose metabolism, and dyslipidaemia; musculoskeletal disorders, such as myopathy, osteoporosis, and skeletal fractures; neuropsychiatric disorders, such as impairment of cognitive function, depression, or mania; impairment of reproductive and sexual function; and dermatological manifestations, mainly represented by acne, hirsutism, and alopecia. Hypertension in patients with Cushing's syndrome has a multifactorial pathogenesis and contributes to the increased risk for myocardial infarction, cardiac failure, or stroke, which are the most common causes of death; risks of these outcomes are exacerbated by a prothrombotic diathesis and hypokalaemia. Neuropsychiatric disorders can be responsible for suicide. Immune disorders are common; immunosuppression during active disease causes susceptibility to infections, possibly complicated by sepsis, an important cause of death, whereas immune rebound after disease remission can exacerbate underlying autoimmune diseases. Prompt treatment of cortisol excess and specific treatments of comorbidities are crucial to prevent serious clinical complications and reduce the mortality associated with Cushing's syndrome.
6A clinical perspective on ectopic Cushing's syndrome.PubMed
Oskar Ragnarsson, C Christofer Juhlin, David J Torpy, et al.
Trends Endocrinol Metab. 2024 Apr;35(4):347-360. doi: 10.1016/j.tem.2023.12.003. Epub 2023 Dec 23.
Cushing's syndrome (CS) refers to the clinical features of prolonged pathological glucocorticoid excess. About 10-20% of individuals with CS have ectopic CS (ECS), that is, an adrenocorticotropin (ACTH)-producing tumour outside the pituitary gland. ACTH-secreting neuroendocrine neoplasia (NENs) can arise from many organs, although bronchial NEN, small cell lung cancer (SCLC), pancreatic NEN, thymic NEN, medullary thyroid cancer (MTC), and pheochromocytoma are the most common. Patients with ECS frequently present with severe hypercortisolism. The risk of life-threatening complications is high in severe cases, unless the hypercortisolism is effectively treated. A good outcome in ECS requires a methodical approach, incorporating prompt diagnosis, tumour localization, control of cortisol excess, and resection of the primary tumour when possible.
7Study protocol for a prospective, multicentre study of hypercortisolism in patients with difficult-to-control type 2 diabetes (CATALYST): prevalence and treatment with mifepristone.PubMed
Ralph A DeFronzo, Richard J Auchus, Irina Bancos, et al.
BMJ Open. 2024 Jul 16;14(7):e081121. doi: 10.1136/bmjopen-2023-081121.
INTRODUCTION: Even with recent treatment advances, type 2 diabetes (T2D) remains poorly controlled for many patients, despite the best efforts to adhere to therapies and lifestyle modifications. Although estimates vary, studies indicate that in >10% of individuals with difficult-to-control T2D, hypercortisolism may be an underlying contributing cause. To better understand the prevalence of hypercortisolism and the impact of its treatment on T2D and associated comorbidities, we describe the two-part Hyper ortisolism in P ients with Difficult to Control Type 2 Di betes Despite Receiving Standard-of-Care Therapies: Preva ence and Treatment with Korl m (Mifepri one) (CATALYST) trial. METHODS AND ANALYSIS: In part 1, approximately 1000 participants with difficult-to-control T2D (haemoglobin A1c (HbA1c) 7.5%-11.5% despite multiple therapies) are screened with a 1 mg dexamethasone suppression test (DST). Those with post-DST cortisol >1.8 µg/dL and dexamethasone level ≥140 ng/dL are identified to have hypercortisolism (part 1 primary endpoint), have morning adrenocorticotropic hormone (ACTH) and dehydroepiandrosterone sulfate (DHEAS) measured and undergo a non-contrast adrenal CT scan. Those requiring evaluation for elevated ACTH are referred for care outside the study; those with ACTH and DHEAS in the range may advance to part 2, a randomised, double-blind, placebo-controlled trial to evaluate the impact of treating hypercortisolism with the competitive glucocorticoid receptor antagonist mifepristone (Korlym). Participants are randomised 2:1 to mifepristone or placebo for 24 weeks, stratified by the presence/absence of an abnormal adrenal CT scan. Mifepristone is dosed at 300 mg once daily for 4 weeks, then 600 mg daily based on tolerability and clinical improvement, with an option to increase to 900 mg. The primary endpoint of part 2 assesses changes in HbA1c in participants with hypercortisolism with or without abnormal adrenal CT scan. Secondary endpoints include changes in antidiabetes medications, cortisol-related comorbidities and quality of life. ETHICS AND DISSEMINATION: The study has been approved by Cleveland Clinic IRB (Cleveland, Ohio, USA) and Advarra IRB (Columbia, Maryland, USA). Findings will be presented at scientific meetings and published in peer-reviewed journals. TRIAL REGISTRATION NUMBER: NCT05772169.
8Association between post-ACTH cortisol and trilostane dosage in dogs with pituitary-dependent hypercortisolism.PubMed
Fernanda Nastri Gouvêa, Alessandra Martins Vargas, Ednaldo Carvalho Guimarães, et al.
Domest Anim Endocrinol. 2024 Oct;89:106871. doi: 10.1016/j.domaniend.2024.106871. Epub 2024 Jul 4.
Trilostane is the current treatment of choice for managing pituitary-dependent hypercortisolism (PDH) in dogs. While prescribing higher initial doses may elevate the risk of iatrogenic hypocortisolism, opting for more conservative approach could result in delayed disease control, since most individuals end up requiring dosage increases. The adrenocorticotrophin stimulation test (ACTHst), a widely recognized hormonal test for assessing adrenal function, is an essential tool for monitoring the pharmacological treatment of canine hypercortisolism (CH) that can also be used for diagnostic purposes. The aim of this study was to investigate the relationship between post-ACTH cortisol (cpACTH) at PDH diagnosis and the required trilostane dose for sign control and endogenous cortisol regulation in dogs, considering a hypothesis that higher serum cpACTH concentration would necessitate a higher trilostane dosage for disease management. Data for 43 dogs with PDH had their diagnostic cpACTH recorded and correlated to the trilostane dosage necessary to control clinical signs and achieve satisfactory cortisol levels (ideally 2-7 μg/dL). The odds ratio (p=0.042) suggests that dogs with cpACTH ≥ 27 μg/dL at diagnosis are 96% more likely to need a higher trilostane dosage for achieving satisfactory control of PDH. Thus, cpACTH was found to be associated with the final trilostane dose for controlling PDH in dogs.
9Major immunophenotypic abnormalities in patients with primary adrenal insufficiency of different etiology.PubMed
Hanna F Nowotny, Thomas Marchant Seiter, Jing Ju, et al.
Front Immunol. 2023 Nov 15;14:1275828. doi: 10.3389/fimmu.2023.1275828. eCollection 2023.
INTRODUCTION: Patients with primary adrenal insufficiency (PAI) suffer from increased risk of infection, adrenal crises and have a higher mortality rate. Such dismal outcomes have been inferred to immune cell dysregulation because of unphysiological cortisol replacement. As the immune landscape of patients with different types of PAI has not been systematically explored, we set out to immunophenotype PAI patients with different causes of glucocorticoid (GC) deficiency. METHODS: This cross-sectional single center study includes 28 patients with congenital adrenal hyperplasia (CAH), 27 after bilateral adrenalectomy due to Cushing's syndrome (BADx), 21 with Addison's disease (AD) and 52 healthy controls. All patients with PAI were on a stable GC replacement regimen with a median dose of 25 mg hydrocortisone per day. Peripheral blood mononuclear cells were isolated from heparinized blood samples. Immune cell subsets were analyzed using multicolor flow cytometry after four-hour stimulation with phorbol myristate acetate and ionomycin. Natural killer (NK-) cell cytotoxicity and clock gene expression were investigated. RESULTS: The percentage of T helper cell subsets was downregulated in AD patients (Th1 p = 0.0024, Th2 p = 0.0157, Th17 p < 0.0001) compared to controls. Cytotoxic T cell subsets were reduced in AD (Tc1 p = 0.0075, Tc2 p = 0.0154) and CAH patients (Tc1 p = 0.0055, Tc2 p = 0.0012) compared to controls. NKCC was reduced in all subsets of PAI patients, with smallest changes in CAH. Degranulation marker CD107a expression was upregulated in BADx and AD, not in CAH patients compared to controls (BADx p < 0.0001; AD p = 0.0002). In contrast to NK cell activating receptors, NK cell inhibiting receptor CD94 was upregulated in BADx and AD, but not in CAH patients (p < 0.0001). Although modulation in clock gene expression could be confirmed in our patient subgroups, major interindividual-intergroup dissimilarities were not detected. DISCUSSION: In patients with different etiologies of PAI, distinct differences in T and NK cell-phenotypes became apparent despite the use of same GC preparation and dose. Our results highlight unsuspected differences in immune cell composition and function in PAI patients of different causes and suggest disease-specific alterations that might necessitate disease-specific treatment.
10Whom Should We Screen for Cushing Syndrome? The Endocrine Society Practice Guideline Recommendations 2008 Revisited.PubMed
Leah T Braun, Frederick Vogel, Stephanie Zopp, et al.
J Clin Endocrinol Metab. 2022 Aug 18;107(9):e3723-e3730. doi: 10.1210/clinem/dgac379.
CONTEXT: Cushing syndrome (CS) is a rare and serious disease with high mortality. Patients are often diagnosed late in the course of the disease. OBJECTIVE: This work investigated whether defined patient populations should be screened outside the at-risk populations defined in current guidelines. METHODS: As part of the prospective German Cushing registry, we studied 377 patients with suspected CS. The chief complaint for CS referral was documented. Using urinary free cortisol, late-night salivary cortisol, and the 1-mg dexamethasone suppression test as well as long-term clinical observation, CS was confirmed in 93 patients and ruled out for the remaining 284. RESULTS: Patients were referred for 18 key symptoms, of which 5 were more common in patients with CS than in those in whom CS was ruled out: osteoporosis (8% vs 2%; P = .02), adrenal incidentaloma (17% vs 8%, P = 0.01), metabolic syndrome (11% vs 4%; P = .02), myopathy (10% vs 2%; P < .001), and presence of multiple symptoms (16% vs 1%; P < .001). Obesity was more common in patients in whom CS was ruled out (30% vs 4%, P < .001), but recent weight gain was prominent in those with CS. A total of 68 of 93 patients with CS (73%) had typical chief complaints, as did 106 of 284 of patients with ruled-out CS status (37%) according to the Endocrine Society practice guideline 2008. CONCLUSION: The 2008 Endocrine Society Practice guideline for screening and diagnosis of CS defined at-risk populations that should undergo testing. These recommendations are still valid in 2022.