scholarly journals Identification of glucocorticoid-related molecular signature by whole blood methylome analysis

2021 ◽  
Author(s):  
Roberta Armignacco ◽  
Anne Jouinot ◽  
Lucas Bouys ◽  
Amandine Septier ◽  
Thomas Lartigue ◽  
...  
Keyword(s):  
Adrenal Insufficiency ◽  
Cushing’S Syndrome ◽  
Whole Blood ◽  
Penalized Regression ◽  
Cushing's Syndrome ◽  
High Morbidity ◽  
Dna Hypomethylation ◽  
Dna Methylome ◽  
Cpg Sites ◽  
Glucocorticoid Action

Objective: Cushing’s syndrome represents a state of excessive glucocorticoids related to glucocorticoid treatments or to endogenous hypercortisolism. Cushing’s syndrome is associated with high morbidity, with significant inter-individual variability. Likewise, adrenal insufficiency is a life-threatening condition of cortisol deprivation. Currently, hormone assays contribute to identify Cushing’s syndrome or adrenal insufficiency. However, no biomarker directly quantifies the biological glucocorticoid action. The aim of this study was to identify such markers. Design: We evaluated whole blood DNA methylome in 94 samples obtained from patients with different glucocorticoid states (Cushing’s syndrome, eucortisolism, adrenal insufficiency). We used an independent cohort of 91 samples for validation. Methods: Leukocyte DNA was obtained from whole blood samples. Methylome was determined using the Illumina methylation chip array (~850000 CpG sites). Both unsupervised (Principal Component Analysis) and supervised (Limma) methods were used to explore methylome profiles. A Lasso-penalized regression was used to select optimal discriminating features. Results: Whole blood methylation profile was able to discriminate samples by their glucocorticoid status: glucocorticoid excess was associated with DNA hypomethylation, recovering within months after Cushing’s syndrome correction. In Cushing’s syndrome, an enrichment in hypomethylated CpG sites was observed in the region of FKBP5 gene locus. A methylation predictor of glucocorticoid excess was built on a training cohort and validated on two independent cohorts. Potential CpG sites associated with the risk for specific complications, such as glucocorticoid-related hypertension or osteoporosis, were identified, needing now to be confirmed on independent cohorts. Conclusions: Whole blood DNA methylome is dynamically impacted by glucocorticoids. This biomarker could contribute to better assess glucocorticoid action beyond hormone assays.

scholarly journals Circulating microRNA Expression in Cushing’s Syndrome

2021 ◽  
Vol 12 ◽  
Author(s):  
Sharmilee Vetrivel ◽  
Ru Zhang ◽  
Mareen Engel ◽  
Barbara Altieri ◽  
Leah Braun ◽  
...  
Keyword(s):  
Cushing’S Syndrome ◽  
Validation Cohort ◽  
Cushing's Syndrome ◽  
Circulating Microrna ◽  
High Morbidity ◽  
Discovery Cohort ◽  
Serum Samples ◽  
Curative Surgery ◽  
Before And After ◽  
Diagnosis And Classification

ContextCushing’s syndrome (CS) is a rare disease of endogenous hypercortisolism associated with high morbidity and mortality. Diagnosis and classification of CS is still challenging.ObjectiveCirculating microRNAs (miRNAs) are minimally invasive diagnostic markers. Our aim was to characterize the circulating miRNA profiles of CS patients and to identify distinct profiles between the two major CS subtypes.MethodsWe included three groups of patients from the German Cushing’s registry: ACTH-independent CS (Cortisol-Producing-Adenoma; CPA), ACTH-dependent pituitary CS (Cushing’s Disease; CD), and patients in whom CS had been ruled out (controls). Profiling of miRNAs was performed by next-generation-sequencing (NGS) in serum samples of 15 CS patients (each before and after curative surgery) and 10 controls. Significant miRNAs were first validated by qPCR in the discovery cohort and then in an independent validation cohort of 20 CS patients and 11 controls.ResultsNGS identified 411 circulating miRNAs. Differential expression of 14 miRNAs were found in the pre- and postoperative groups. qPCR in the discovery cohort validated 5 of the significant miRNAs from the preoperative group analyses. Only, miR-182-5p was found to be significantly upregulated in the CD group of the validation cohort. Comparing all CS samples as a group with the controls did not reveal any significant differences in expression.OutcomeIn conclusion, our study identified miR-182-5p as a possible biomarker for CD, which has to be validated in a prospective cohort. Furthermore, our results suggest that presence or absence of ACTH might be at least as relevant for miRNA expression as hypercortisolism itself.

scholarly journals Steroid withdrawal syndrome after successful treatment of Cushing’s syndrome: a reminder

2005 ◽  
Vol 153 (2) ◽  
pp. 207-210 ◽  
Author(s):  
A Bhattacharyya ◽  
K Kaushal ◽  
D J Tymms ◽  
J R E Davis
Keyword(s):  
Adrenal Insufficiency ◽  
Replacement Therapy ◽  
Cushing’S Syndrome ◽  
Withdrawal Syndrome ◽  
Pituitary Surgery ◽  
Cushing's Syndrome ◽  
Temporary Increase ◽  
Steroid Withdrawal ◽  
Glucocorticoid Replacement Therapy ◽  
Cortisol Levels

Steroid withdrawal syndrome (SWS) usually refers to relapse of the disease being treated after withdrawal of glucocorticoid therapy, or the symptoms of adrenal insufficiency which occur when glucocorticoids are rapidly reduced or stopped. A less well-recognised form of SWS is that which develops when patients experience a symptom complex similar to that of adrenal insufficiency despite acceptable cortisol levels. We describe three patients who presented with this form of SWS following surgical treatment for endogenous Cushing’s syndrome. All responded well to a short-term increase in the dose of glucocorticoid replacement therapy, with the median duration of the syndrome being 10 months (range 6–10 months). Trough serum cortisol levels above 100 nmol/l, with peaks between 460 and 750 nmol/l were documented in the first two patients at presentation with SWS. It is thought that the syndrome may result from development of tolerance to glucocorticoids, and mediators considered to be important in its development include interleukin-6, corticotrophin-releasing hormone, vasopressin, and central noradrenergic and dopaminergic systems. The exact underlying mechanism for SWS remains unclear. However, with increasing recommendations for use of lower doses of replacement glucocorticoids, its incidence may increase. Physicians need to be aware of this condition, which is self-limiting and easily treated by a temporary increase in the dose of glucocorticoid replacement therapy. It is possible that a slower glucocorticoid tapering regimen than that used in the standard postoperative management of patients undergoing pituitary surgery may reduce the risk of development of SWS.

scholarly journals Mifepristone (RU 486) in Cushing's syndrome

2007 ◽  
Vol 157 (5) ◽  
pp. 561-569 ◽  
Author(s):  
Sarah Johanssen ◽  
Bruno Allolio
Keyword(s):  
Adrenal Insufficiency ◽  
Cushing’S Syndrome ◽  
Case Reports ◽  
Evidence Synthesis ◽  
Cushing's Syndrome ◽  
Therapeutic Effects ◽  
Receptor Blockade ◽  
Onset Of Action ◽  
Ru 486 ◽  
Long Term Treatment

AbstractContextMifepristone (RU 486) blocks the action of cortisol by binding to the glucocorticoid receptor and, therefore, is of potential therapeutic value in Cushing's syndrome. However, research in endogenous hypercortisolism has been hampered by the controversy related to the use of mifepristone for inducing abortion. Currently, new studies are planned to better define the role of RU 486 in Cushing's syndrome. This paper reviews the available evidence concerning the therapeutic effects and adverse events of RU 486 in Cushing's syndrome.Evidence acquisitionOriginal articles and reviews were identified using a PubMed search strategy covering the time period until February 2007.Evidence synthesisTreatment of Cushing's syndrome with mifepristone has been reported in a total of 18 patients, with daily doses ranging from 5 to 30 mg/kg. Case reports indicate that the mifepristone-induced receptor blockade may lead to significant clinical improvement in patients with Cushing's syndrome in whom surgery and inhibitors of adrenal steroidogenesis fail to control hypercortisolism. Due to its rapid onset of action, mifepristone may be particularly useful in acute crises, e.g. in cortisol-induced psychosis. Side effects include adrenal insufficiency and, as a result of its antiprogestin action, endometrial hyperplasia in long-term treatment. Adrenal insufficiency can be assessed only by careful clinical evaluation, as the hormonal parameters are not reliable during receptor blockade, and is rapidly reversed by exogenous dexamethasone. Well-designed larger clinical trials are needed to better assess the value of this interesting drug in the treatment of Cushing's syndrome.

scholarly journals The incidence of adrenal crisis in the postoperative period of HPA axis insufficiency after surgical treatment for Cushing’s syndrome

2019 ◽  
Vol 181 (2) ◽  
pp. 201-210 ◽  
Author(s):  
Leonie H A Broersen ◽  
Femke M van Haalen ◽  
Tina Kienitz ◽  
Olaf M Dekkers ◽  
Christian J Strasburger ◽  
...  
Keyword(s):  
Adrenal Insufficiency ◽  
Hpa Axis ◽  
Cushing’S Syndrome ◽  
Cushing's Syndrome ◽  
Adrenal Crisis ◽  
Pituitary Hormone ◽  
Increased Risk ◽  
Potential Risk Factors ◽  
Life Threatening ◽  
Glucocorticoid Deficiency

Background Adrenal crisis, the most feared complication of adrenal insufficiency, is a potentially life-threatening state of acute glucocorticoid deficiency. After successful surgery for Cushing’s syndrome, many patients develop (transient) adrenal insufficiency. The incidence of adrenal crisis in patients treated for hypercortisolism is unknown. Methods Cohort study included consecutive patients with Cushing’s syndrome with adrenal insufficiency after surgery from Leiden and Berlin from 2000 to 2015. We summarized the incidence of adrenal crisis, compared patients with and without adrenal crisis regarding potential risk factors for its occurrence and assessed the effect of better education in time on incidence of adrenal crisis. Results We included 106 patients, of whom 19 patients had a total of 41 adrenal crises. There were 9.0 crises per 100 patient-years at risk (95% confidence interval (CI): 6.7–12.0). All crises occurred while on hydrocortisone replacement. The risk ratio for a recurrent crisis was 2.3 (95% CI: 1.2–4.6). No clear change in incidence of adrenal crisis due to better education in time was observed. There was no difference in recurrence rate between patients with, and without any crisis, but patients with adrenal crisis had more often pituitary deficiencies. Conclusions The incidence of adrenal crises after treatment for Cushing’s syndrome is substantial, and patients who suffered from an adrenal crisis have higher risk for recurrent crisis. Adrenal crisis tends to present early after remission of Cushing’s syndrome, which is probably the period of severest HPA axis suppression, despite in general higher hydrocortisone replacement doses for withdrawal complaints in this period. Additional pituitary hormone deficiencies may be a risk marker for increased risk of adrenal crisis. However, further risk factor analysis is needed to identify risks for a first crisis. Effective education methods to prevent adrenal crises should be identified and implemented, including stress instructions by trained nursing staff before hospital discharge.

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