27 research outputs found
Levoketoconazole improves clinical signs and symptoms and patient-reported outcomes in patients with Cushingâs syndrome
Purpose: The efficacy of levoketoconazole in treating hypercortisolism was demonstrated in an open-label phase 3 study (SONICS) of adults with endogenous Cushingâs syndrome (CS) and baseline mean urinary free cortisol (mUFC) â„ 1.5Ă ULN. Clinical signs and symptoms and patient-reported outcomes from the SONICS trial were evaluated in the current manuscript. Methods: Patients titrated to an individualized therapeutic dose entered a 6-month maintenance phase. Secondary endpoints included investigator-graded clinical signs and symptoms of CS during the maintenance phase, and patient-reported quality of life (CushingQoL questionnaire) and depression symptoms (Beck Depression Inventory II [BDI-II]). Results: Of 94 enrolled patients, 77 entered the maintenance phase following individualized dose titration. Significant mean improvements from baseline were noted at end of maintenance (Month 6) for acne, hirsutism (females only), and peripheral edema. These improvements were observed as early as Day 1 of maintenance for hirsutism (mean baseline score, 7.8; â â 1.9; P < 0.0001), end of Month 1 for acne (mean baseline score, 2.8; â â 1.2; P = 0.0481), and Month 4 for peripheral edema (mean baseline score, 1.0; â â 0.5; P = 0.0052). Significant mean improvements from baseline were observed by Month 3 of maintenance for CushingQoL (mean baseline score, 44.3; â + 6.9; P = 0.0018) and at Month 6 for BDI-II (mean baseline score, 17.1; â â 4.3; P = 0.0043) scores. No significant mean improvement was identified in a composite score of 7 other clinical signs and symptoms. Conclusions: Treatment with levoketoconazole was associated with sustained, meaningful improvements in QoL, depression, and certain clinical signs and symptoms characteristic of CS. ClinialTrials.gov identifier: NCT01838551
Assay-specific spurious ACTH results lead to misdiagnosis, unnecessary testing, and surgical misadventure-a case series
The proper clinical evaluation of pituitary and adrenal disorders depends on the accurate measurement of plasma ACTH. The modern two-site sandwich ACTH immunoassay is a great improvement compared with older methods but still has the potential for interferences such as heterophile antibodies and pro-opiomelanocortin (POMC) and ACTH fragments. We report the cases of five patients in whom the diagnosis or differential diagnosis of Cushing syndrome was confounded by erroneously elevated results from the Siemens ACTH Immulite assay [ACTH(Immulite)] that were resolved using the Roche Cobas or Tosoh AIA [ACTH(Cobas) and ACTH(AIA), respectively]. In one case, falsely elevated ACTH(Immulite) results owing to interfering antibodies resulted in several invasive differential diagnostic procedures (including inferior petrosal sinus sampling), MRI, and unnecessary pituitary surgery. ACTH(Cobas) measurements were normal, and further studies excluded the diagnosis of Cushing syndrome. In three cases, either Cushing disease or occult ectopic ACTH were suspected owing to elevated ACTH(Immulite) results. However, adrenal (ACTH-independent) Cushing syndrome was established using ACTH(AIA) or ACTH(Cobas) and proved surgically. In one case, ectopic ACTH was suspected owing to elevated ACTH(Immulite) results; however, the ACTH(Cobas) findings led to the diagnosis of alcohol-induced hypercortisolism that resolved with abstinence. We have concluded that ACTH(Immulite) results can be falsely increased and alternate ACTH assays should be used in the diagnosis or differential diagnosis of clinical disorders of the hypothalamic-pituitary-adrenal axis
Response to letter to the editor: Assay-specific spurious ACTH results lead to misdiagnosis, unnecessary testing, and surgical misadventure-a case series
Body Composition and Cardiovascular Risk Markers after Remission of Cushing's Disease: A Prospective Study Using Whole-Body MRI
MRI assessment of lean and adipose tissue distribution in female patients with Cushing's disease
OBJECTIVE: Chronic hypercortisolemia due to Cushingâs Disease (CD) results in abnormal adipose tissue (AT) distribution. Whole-body magnetic resonance imaging (MRI) was used to examine lean and AT distribution in female patients with CD to further understand the role of glucocorticoid excess in the development of abnormal AT distribution and obesity. DESIGN: Cross-sectional and case control study. PATIENTS: 15 females with CD and 12 healthy controls. MEASUREMENTS: Mass of skeletal muscle (SM) and AT in the visceral (VAT), subcutaneous (SAT), and inter-muscular (IMAT) compartments from whole-body MRI and serum levels of insulin, glucose, and leptin were measured. RESULTS: CD patients had leptin values that correlated to total AT (TAT) and SAT (p < 0.05) but not to VAT. CD patients had higher VAT/TAT ratios (p < 0.01) and lower SAT/TAT ratios (p < 0.05) compared to controls. TAT, VAT, and trunk SAT (TrSAT) were greater in CD patients (p < 0.01). SM was less in CD (p < 0.001) but IMAT was not different. CONCLUSIONS: TAT, VAT, trSAT, and the proportion of AT in the visceral depot were greater in CD, though the proportion in the subcutaneous depot was less. SM was less but IMAT was not different. These findings have implications for understanding the role of cortisol in the abnormal AT distribution and metabolic risk seen in patients exposed to chronic excess glucocorticoids
Lower Visceral and Subcutaneous but Higher Intermuscular Adipose Tissue Depots in Patients with Growth Hormone and Insulin-Like Growth Factor I Excess Due to Acromegaly
Context: GH and IGF-I are important regulators of metabolism and body composition. In acromegaly, a state of GH and IGF-I excess, the lipolytic and insulin antagonistic effects of GH may alter adipose tissue (AT) distribution
Glucocorticoid regulation of food-choice behavior in humans: Evidence from Cushingâs syndrome
The mechanisms by which glucocorticoids regulate food intake and resulting body mass in humans are not well-understood. One potential mechanism could involve modulation of reward processing, but human stress models examining effects of glucocorticoids on behavior contain important confounds. Here, we studied individuals with Cushingâs syndrome, a rare endocrine disorder characterized by chronic excess endogenous glucocorticoids. Twenty-three patients with Cushingâs syndrome (13 with active disease; 10 with disease in remission) and 15 controls with a comparably high body mass index completed two simulated food-choice tasks (one with âexplicitâ task contingencies and one with âprobabilisticâ task contingencies), during which they indicated their objective preference for viewing high calorie food images versus standardized pleasant, unpleasant, and neutral images. All participants also completed measures of food craving, and approximately half of the participants provided 24-hour urine samples for assessment of cortisol and cortisone concentrations. Results showed that on the explicit task (but not the probabilistic task), participants with active Cushingâs syndrome made fewer food-related choices than participants with Cushingâs syndrome in remission, who in turn made fewer food-related choices than overweight controls. Corroborating this group effect, higher urine cortisone was negatively correlated with food-related choice in the subsample of all participants for whom these data were available. On the probabilistic task, despite a lack of group differences, higher food-related choice correlated with higher state and trait food craving in active Cushingâs patients. Taken together, relative to overweight controls, Cushingâs patients, particularly those with active disease, displayed a reduced vigor of responding for food rewards that was presumably attributable to glucocorticoid abnormalities. Beyond Cushingâs, these results may have relevance for elucidating glucocorticoid contributions to food-seeking behavior, enhancing mechanistic understanding of weight fluctuations associated with oral glucocorticoid therapy and/or chronic stress, and informing the neurobiology of neuropsychiatric conditions marked by abnormal cortisol dynamics (e.g., major depression, Alzheimerâs disease)
Levoketoconazole in the Treatment of Patients With Cushing's Syndrome and Diabetes Mellitus: Results From the SONICS Phase 3 Study
BackgroundCushing's syndrome (CS) is associated with numerous comorbidities, including diabetes mellitus (DM). Levoketoconazole, an orally administered ketoconazole stereoisomer, is in clinical trials for the treatment of CS.MethodsSONICS, a prospective, open-label, phase 3 study in adults with confirmed CS and mean 24-h urinary free cortisol (mUFC) >= 1.5x ULN, included dose-titration, 6-month maintenance, and 6-month extension phases. This subanalysis evaluated the efficacy of levoketoconazole in patients with DM (n = 28) or without DM (n = 49) who entered the maintenance phase. Safety was evaluated in the overall population (N = 94) during the dose-titration and maintenance phases.ResultsNormalization of mUFC at the end of maintenance phase (EoM), without a dose increase during maintenance (SONICS primary endpoint) was observed in 46% of patients with DM (95% CI, 28 to 66%; P = 0.0006 vs null hypothesis of <= 20%) and 33% of patients without DM (95% CI, 20 to 48%; P = 0.0209). At EoM, mean HbA1c decreased from 6.9% at baseline to 6.2% in patients with DM and from 5.5 to 5.3% in patients without DM. Mean fasting blood glucose decreased from 6.85 mmol/L (123.4 mg/dl) to 5.82 mmol/L (104.9 mg/dl) and from 5.11 mmol/L (92.1 mg/dl) to 4.66 mmol/L (84.0 mg/dl) in patients with and without DM, respectively. Adverse events that were more common in patients with DM included nausea (58.3%), vomiting (19.4%), and urinary tract infection (16.7%); none prompted study drug withdrawal.ConclusionsTreatment with levoketoconazole led to sustained normalization of mUFC and improvement in glycemic control that was more pronounced in patients with DM
A novel mutation of the hGR gene causing Chrousos syndrome
Background Natural mutations in the human glucocorticoid receptor (hGR,
NR3C1) gene cause Chrousos syndrome, a rare condition characterized by
generalized, partial, target-tissue insensitivity to glucocorticoids.
Objective To present a new case of Chrousos syndrome caused by a novel
mutation in the hGR gene, and to elucidate the molecular mechanisms
through which the natural mutant receptor affects glucocorticoid signal
transduction.
Design and Results The index case presented with hirsutism, acne,
alopecia, anxiety, fatigue and irregular menstrual cycles, but no
clinical manifestations suggestive of Cushingâs syndrome. Endocrinologic
evaluation revealed elevated 08:00h plasma adrenocorticotropic hormone,
serum cortisol and androstenedione concentrations and increased urinary
free cortisol excretion. The patient harbored a novel A>G transition at
nucleotide position 2177, which resulted in histidine (H) to arginine
(R) substitution at amino acid position 726 of the receptor (c.2177A>G,
p.H726R). Compared with the wild-type receptor, the mutant receptor
hGRH726R demonstrated decreased ability to transactivate
glucocorticoid-responsive genes and to transrepress the nuclear factor-B
signalling pathway, displayed 55% lower affinity for the ligand and a
four-fold delay in nuclear translocation, and interacted with the
glucocorticoid receptor-interacting protein 1 coactivator mostly through
its activation function-1 domain. Finally, a 3-dimensional molecular
modelling study of the H726R mutation revealed a significant structural
shift in the rigidity of helix 10 of the receptor, which resulted in
reduced flexibility and decreased affinity of the mutant receptor for
binding to the ligand.
Conclusions The natural mutant receptor hGRH726R impairs multiple steps
of glucocorticoid signal transduction, thereby decreasing tissue
sensitivity to glucocorticoids