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Changes in the diurnal salivary cortisol pattern after the optimization of timing of metyrapone administration in Patient No. 4.
Source publication
Measuring salivary cortisol is both convenient and non-invasive for patients; however, its usefulness as a marker for monitoring medical therapy has not yet been established. The aim of this study was to assess the utility of multiple salivary cortisol measurements in patients with Cushing’s syndrome (CS) during medical therapy. Six patients with C...
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Background
Cumulative epidemiological evidence suggests that shift work exerts harmful effects on human health. However, the physiological mechanisms are not well understood. This study aimed to examine the impact of shift work on the dysregulation of the hypothalamic-pituitary-adrenal axis, i.e. diurnal cortisol rhythm.
Methods
Seventy physicians...
Citations
... It is therefore vital to assess cortisol with an assay free from interference in the presence of steroidogenesis inhibition, and the method of choice would be LC-MS/MS methods validated to be free from interference [25,144]. However, protocols involving immunoassay with urine and saliva have been reported [149]. ...
Biochemical confirmation of a diagnosis of hypercortisolism (Cushing syndrome) is vital to direct further investigations, especially given the overlap with non-autonomous conditions, such as pseudo-Cushing, and the morbidity associated with missed diagnoses. A limited narrative review was performed focusing on the laboratory perspective of the pitfalls of making a biochemical diagnosis of hypercortisolism in those presenting with presumed Cushing syndrome. Although analytically less specific, immunoassays remain cheap, quick, and reliable in most situations. Understanding cortisol metabolism can help with patient preparation, specimen selection (e.g., consideration of urine or saliva for those with possible elevations of cortisol binding globulin concentration), and method selection (e.g., mass spectrometry if there is a high risk of abnormal metabolites). Although more specific methods may be less sensitive, this can be managed. The reduction in cost and increasing ease of use makes techniques such as urine steroid profiles and sali-vary cortisone of interest in future pathway development. In conclusion, the limitations of current assays, particularly if well understood, do not impede diagnosis in most cases. However, in complex or borderline cases, there are other techniques to consider to aid in the confirmation of hyper-cortisolism.
... serum cortisol within target h <the ULN for the assay used, or <600 nmol/L (21.7 µg/dL) if the ULN was higher than this value Cushing's disease indicate that better clinical outcomes are evident for patients in whom mUFC and mLNSC measurements are controlled; the use of mUFC and mLNSC can offer a comprehensive assessment of response to treatment in patients with Cushing's disease [76]. Interestingly, results of a prospective case study indicate that multiple salivary cortisol measurements may be a useful tool to visualise the diurnal cortisol rhythm and to optimise the dose and timing of metyrapone during treatment in patients with Cushing's syndrome [79]. Metyrapone contributes to restoring the circadian rhythm [5,56,67,79] and lowers the nocturnal cortisol exposure, while leaving the cortisol levels unaltered throughout the rest of the day in subclinical Cushing's syndrome. ...
... Interestingly, results of a prospective case study indicate that multiple salivary cortisol measurements may be a useful tool to visualise the diurnal cortisol rhythm and to optimise the dose and timing of metyrapone during treatment in patients with Cushing's syndrome [79]. Metyrapone contributes to restoring the circadian rhythm [5,56,67,79] and lowers the nocturnal cortisol exposure, while leaving the cortisol levels unaltered throughout the rest of the day in subclinical Cushing's syndrome. Improvement/control of elevated cortisol levels is also required during the rest of the day in patients with Cushing's syndrome; the rapid onset of action of metyrapone together with its short duration of action, allows the timing and dosage to be fine-tuned, and may enable improvement or restoration of normal circadian rhythm. ...
Metyrapone (Metopirone®), a pyridine derivative, is a useful treatment option for the management of patients with endogenous Cushing’s syndrome, based on evidence from more than six decades of its use in clinical practice, prospective and retrospective studies, as well as case reports. Metyrapone is associated with a rapid onset of action and is effective in reducing cortisol levels and improving clinical and/or biochemical features and cortisol-related comorbidities of Cushing’s syndrome. The efficacy of metyrapone was demonstrated in all aetiologies of the condition, when used in a range of clinical settings (including presurgery treatment and when used in combination with other drugs) and in the short and long term. Metyrapone is generally well tolerated when used in the treatment of patients with endogenous Cushing’s syndrome, with gastrointestinal adverse events being the most commonly reported.
... Measuring late-night salivary cortisol (LNSC) levels can help assess loss in the diurnal physiological rhythm of cortisol secretion [53,54]. Restoring the diurnal cortisol rhythm is of clinical importance in patients with CS, as the disruption of this rhythm is thought to result in comorbidities such as hypertension and impaired glucose metabolism [55,56]. In the SONICS study, a significant decrease in mean LNSC concentration was observed from baseline to the end of month 1 (p < 0.01) and remained significantly lower than baseline through month 6 (p < 0.05) [57]. ...
... However, LNSC was less commonly normalized (ranged from 4% to 19% of patients over time) than mUFC. As the cortisol rhythm is also affected by the dose and timing of therapy administration, salivary cortisol measurement at a single time point (late night for LNSC, a measure of nadir cortisol levels) during medical treatment may not adequately reveal improvements in diurnal cortisol rhythm [55,58]. Multiple measurements of salivary cortisol throughout the day, similar to the serum cortisol day curve used for metyrapone in some countries [59], may provide a better marker for visualizing the change in diurnal cortisol rhythm; however, this information was not collected in the SONICS study. ...
Introduction
Endogenous Cushing’s syndrome (CS) is a rare, life-threatening endocrine disorder that is caused by chronic exposure to cortisol overproduction. Levoketoconazole (Recorlev), a 2S,4R stereoisomer of ketoconazole, is a steroidogenesis inhibitor under investigation for the treatment of CS.
Areas covered
This review covers the pharmacology, efficacy, and safety of levoketoconazole for the treatment of patients with endogenous CS.
Expert opinion
Based on the preclinical and clinical pharmacology findings, levoketoconazole appears to be the relevant enantiomer of ketoconazole for inhibition of steroidogenesis, with more potent inhibition of both cortisol and androgen synthesis relative to ketoconazole racemate and the 2R,4S stereoisomer dextroketoconazole. Results from the phase III SONICS study showed that levoketoconazole was effective in normalizing cortisol levels and improving biomarkers of cardiovascular risk in a significant percentage of patients. In addition, treatment with levoketoconazole showed improvements in subjective clinical assessments of clinician-rated CS clinical signs and symptoms, patient-reported quality of life, and depression symptom severity. Testosterone levels decreased significantly in women. Levoketoconazole had an acceptable safety profile with no unexpected safety signals. The favorable pharmacology, efficacy, and safety profile of levoketoconazole supports its use as medical therapy for CS, if approved.
... Endoscopic or microscopic TSS can be performed according to the neurosurgeon's preference (89). Preoperative medical treatment to improve hypercortisolemia is recommended, mainly using steroidogenesis inhibitors, including metyrapone, ketoconazole, and osilodrostat with or without hydrocortisone replacement (90)(91)(92). Since a higher rate of morbidity, including poorly controlled diabetes mellitus, hypokalemia, venous thromboembolism, gastrointestinal hemorrhage, and osteoporosis, has been complicated in patients with refractory Cushing's disease, several pharmaceutical treatments such as insulin, mineral corticoid antagonists, anticoagulants, proton pump inhibitors, and anti-osteoporotic agents are required during the perioperative period (91,93). ...
Cushing’s disease is a syndromic pathological condition caused by adrenocorticotropic hormone (ACTH)-secreting pituitary adenomas (ACTHomas) mediated by hypercortisolemia. It may have a severe clinical course, including infection, psychiatric disorders, hypercoagulability, and metabolic abnormalities, despite the generally small, nonaggressive nature of the tumors. Up to 20% of ACTHomas show aggressive behavior, which is related to poor surgical outcomes, postsurgical recurrence, serious clinical course, and high mortality. Although several gene variants have been identified in both germline and somatic changes in Cushing’s disease, the pathophysiology of aggressive ACTHomas is poorly understood. In this review, we focused on the aggressiveness of ACTHomas, its pathology, the current status of medical therapy, and future prospects. Crooke’s cell adenoma (CCA), Nelson syndrome, and corticotroph pituitary carcinoma are representative refractory pituitary tumors that secrete superphysiological ACTH. Although clinically asymptomatic, silent corticotroph adenoma is an aggressive ACTH-producing pituitary adenoma. In this review, we summarize the current understanding of the pathophysiology of aggressive ACTHomas, including these tumors, from a molecular point of view based on genetic, pathological, and experimental evidence. The treatment of aggressive ACTHomas is clinically challenging and usually resistant to standard treatment, including surgery, radiotherapy, and established medical therapy (e.g., pasireotide and cabergoline). Temozolomide is the most prescribed pharmaceutical treatment for these tumors. Reports have shown that several treatments for patients with refractory ACTHomas include chemotherapy, such as cyclohexyl-chloroethyl-nitrosourea combined with 5-fluorouracil, or targeted therapies against several molecules including vascular endothelial growth factor receptor, cytotoxic T lymphocyte antigen 4, programmed cell death protein 1 (PD-1), and ligand for PD-1. Genetic and experimental evidence indicates that some possible therapeutic candidates are expected, such as epidermal growth factor receptor tyrosine kinase inhibitor, cyclin-dependent kinase inhibitor, and BRAF inhibitor. The development of novel treatment options for aggressive ACTHomas is an emerging task.
... These agents are generally titrated toward normalizing 24-hour urinary free cortisol (UFC) or serum cortisol (the latter is generally the case for patients being treated with etomidate) (9,10). Limited data suggest that salivary cortisol may also be used to monitor therapy (11). Less frequently, steroidogenesis inhibitors are used at higher starting doses to block endogenous cortisol secretion completely while exogenous glucocorticoid replacement is administered. ...
Context
Endogenous Cushing’s syndrome (CS) is characterized by excess cortisol secretion, which is driven by tumorous secretion of corticotropin in the majority of patients. Untreated, CS results in substantial morbidity and mortality. Tumor-directed surgery is generally first-line therapy for CS. However, hypercortisolism may persist or recur postoperatively; in other cases, the underlying tumor may not be resectable or its location may not be known. Yet other patients may be acutely ill and require stabilization before definitive surgery. In all these cases, additional interventions are needed, including adrenally-directed medical therapies.
Evidence acquisition
Electronic literature searches were performed to identify studies pertaining to adrenally-acting agents used for CS. Data were abstracted and used to compile this review article.
Evidence synthesis
Adrenally-directed medical therapies inhibit one or several enzymes involved in adrenal steroidogenesis. Several adrenally-acting medical therapies for CS are currently available, including ketoconazole, metyrapone, osilodrostat, mitotane and etomidate. Additional agents are under investigation. Drugs differ with regards to details of their mechanism of action, time course of pharmacologic effect, safety and tolerability, potential for drug-drug interactions and route of administration. All agents require careful dose titration and patient monitoring to assure safety and effectiveness, while avoiding hypoadrenalism.
Conclusions
These medications have an important role in the management of CS, particularly among patients with persistent or recurrent hypercortisolism postoperatively or those who cannot undergo tumor-directed surgery. Use of these drugs mandates adequate patient instruction and close monitoring to assure that treatment goals are being met while untoward adverse effects are minimized.
... Several studies were done to diagnose AI in cirrhotic patients, either by using salivary cortisol (SC), STC, or CFC alone [10][11][12][13] or with short Synacthen test, assuming that STC should not be used in the diagnosis of AI in cirrhotic patients as it is affected by alteration in CBG levels, and SC was correlated well with FC in adrenocorticotrophic hormone (ACTH) testing [14,15]. The aim of this work is to study the diagnostic role of SC level in the assessment of AI in chronic hepatitis C (CHC) cirrhotic patients. ...
Background The assessment of adrenal insufficiency (AI) in cirrhotic patients varies according to the stage of the liver disease. The authors aimed to study the diagnostic role of salivary cortisol (SC) level in the assessment of AI in chronic hepatitis C cirrhotic patients.
Patients and methods A case–controlled study of 50 patients with liver cirrhosis owing to chronic hepatitis C infection and 34 apparently healthy persons was conducted. Fasting serum total cortisol (STC), SC, and corticosteroid-binding globulin (CBG) level assessments, as well as calculation of free cortisol level (CFC) were done.
Results SC (P
... Assessment of 24-h urinary free cortisol (UFC) and late-night salivary cortisol (LNSC) levels has an established role in the initial screening for hypercortisolism and in the detection of disease recurrence after surgery (4). LNSC has also been used in combination with morning salivary cortisol levels to assess cortisol diurnal rhythm, which is frequently disrupted in patients with Cushing's disease (5,6). Despite this, there remains a lack of guidance on the most appropriate way to monitor disease activity during medical treatment. ...
... Collection of late-night salivary samples is both simple and convenient for patients to carry out in their own homes, with samples being stable at room temperature for up to 2 weeks and easy to store (12,13). Few studies have examined the role of LNSC in monitoring response to pharmacotherapy in patients with Cushing's disease (6,14). ...
... While LNSC has an established role in the diagnosis of Cushing's disease and prediction of recurrence risk after surgery, its usefulness as a biomarker of medical treatment response is not yet known (5,6,16,17). The current analysis, which included a large subset of patients enrolled in a Phase III study, provides further evidence supporting a role for LNSC in monitoring patients with active Cushing's disease who are receiving medical treatment. ...
Objective:
Monitoring of patients with Cushing's disease on cortisol-lowering drugs is usually performed with urinary free cortisol (UFC). Late-night salivary cortisol (LNSC) has an established role in screening for hypercortisolism and can help to detect loss of cortisol circadian rhythm. Less evidence exists regarding the usefulness of LNSC in monitoring pharmacological response in Cushing's disease.
Design:
Exploratory analysis evaluating LNSC during a Phase III study of long-acting pasireotide in Cushing's disease (clinicaltrials.gov: NCT01374906).
Methods:
Mean LNSC (mLNSC) was calculated from two samples, collected on the same days as the first two of three 24-h urine samples (used to calculate mean UFC [mUFC]). Clinical signs of hypercortisolism were evaluated over time.
Results:
At baseline, 137 patients had evaluable mLNSC measurements; 91.2% had mLNSC exceeding the upper limit of normal (ULN; 3.2 nmol/L). Of patients with evaluable assessments at month 12 (n=92), 17.4% had both mLNSC ≤ULN and mUFC ≤ULN; 22.8% had mLNSC ≤ULN, and 45.7% had mUFC ≤ULN. There was high variability in LNSC (intra-patient coefficient of variation [CV]: 49.4%) and UFC (intra-patient CV: 39.2%). mLNSC levels decreased over 12 months of treatment and paralleled changes in mUFC. Moderate correlation was seen between mLNSC and mUFC (Spearman's correlation: ρ=0.50 [all time points pooled]). Greater improvements in systolic/diastolic blood pressure and weight were seen in patients with both mLNSC ≤ULN and mUFC ≤ULN.
Conclusions:
mUFC and mLNSC are complementary measurements for monitoring treatment response in Cushing's disease, with better clinical outcomes seen for patients in whom both mUFC and mLNSC are controlled.
... The early morning sF can be used also in suspected adrenal insufficiency [17]. Further, multiple sF measurement in a day could be useful to optimize metyrapone treatment in patients with Cushing's syndromes treatment and to detect subclinical hypercortisolism in patients with adrenal incidentaloma [18,19]. ...
Background:
The ISO 15189:2012 describes the requirements for quality and competence, which are specific for all sectors of a medical laboratory. Laboratory-developed methods, standard methods used outside their intended scope and validated methods subsequently modified shall be validated. The main objective of validation of an examination procedure (EP) is to demonstrate its fitness-for-purpose. The aim of the present study is to illustrate a model to validate laboratory-developed methods in agreement with the ISO 15189:2012 requirement, through the example of salivary cortisol (sF) measurement by liquid chromatography tandem mass spectrometry (LC-MS/MS).
Methods:
The proposed validation model for a laboratory developed method includes 6 steps: 1) analysis of available scientific documentation pertinent to specific EP; 2) evaluation of EP intended use; 3) identification of performance characteristics to evaluate; 4) definition of experimental procedure; 5) identification of acceptability criterion for results evaluation; 6) preparation of a validation plan; 7) production of a validation certificate.
Results:
sF is an EP sampled during the accreditation audit and resulted in compliance with the Standard. A structured procedure to certify that the achieved performance specifications are appropriate for the purpose of the test is therefore necessary.
Conclusions:
A high competence is required for laboratory professionals in order to guarantee that the validated quality specifications have a positive impact on patients' management. The ISO 15189 accreditation is an important tool that allows demonstrating the value of a medical laboratory in the clinical context.
Objective:
This extended evaluation (EE) of the SONICS study assessed effects of levoketoconazole for an additional 6 months following open-label, 6-month maintenance treatment in endogenous Cushing's syndrome.
Design/methods:
SONICS included dose-titration (150-600 mg BID), 6-month maintenance, and 6-month EE phases. Exploratory efficacy assessments were performed at Months 9 and 12 (relative to start of maintenance). For pituitary MRI in patients with Cushing's disease, a threshold of ≥2 mm denoted change from baseline in largest tumor diameter.
Results:
Sixty patients entered EE at Month 6; 61% (33/54 with data) exhibited normal mean urinary free cortisol (mUFC). At Months 9 and 12, respectively, 55% (27/49) and 41% (18/44) of patients with data had normal mUFC. Mean fasting glucose, total and LDL-cholesterol, body weight, body mass index, abdominal girth, hirsutism, CushingQoL, and BDI-II scores improved from study baseline at Months 9 and 12. Forty-six patients completed Month 12; 4 (6.7%) discontinued during EE due to adverse events. The most common adverse events in EE were arthralgia, headache, hypokalemia, and QT prolongation (6.7% each). No patient experienced ALT or AST >3× ULN, QTcF interval >460 msec, or adrenal insufficiency during EE. Of 31 patients with tumor measurements at baseline and Month 12 or follow-up, largest tumor diameter was stable in 27 (87%) patients, decreased in 1, and increased in 3 (largest increase 4 mm).
Conclusion:
In the first long-term levoketoconazole study, continued treatment through 12-month maintenance period sustained the early clinical and biochemical benefits in most patients completing EE, without new adverse effects.
