Distinct Late-Night Salivary Cortisol Cut-Off Values for the Diagnosis of Hypercortisolism

AbstractDue to high morbidity and mortality of untreated hypercortisolism, a prompt diagnosis is essential. Measurement of late-night salivary cortisol provides a simple and non-invasive method. However, thresholds and reference ranges differ among studies. The goal of this study was to define a threshold of late-night salivary cortisol for the diagnosis of hypercortisolism based on the used assay. Moreover, the influence of different aetiologies of hypercortisolism and individual comorbidities were investigated. Prospective analyses of 217 patients, including 36 patients with proven hypercortisolism were carried out. A sum of 149 patients with suspicion of hypercortisolism but negative endocrine testing and 32 patients with hypercortisolism in remission served as control group. Late-night salivary cortisol was measured using an automated chemiluminescence immunoassay. Cut-off values were calculated by ROC analysis. The calculated cut-off value for the diagnosis of hypercortisolism was 10.1 nmol/l (sensitivity 94%; specificity 84%). Only slightly lower thresholds were obtained in patients with suspected hypercortisolism due to weight gain/obesity (9.1 nmol/l), hypertension or adrenal tumours (both 9.8 nmol/l) or pituitary adenomas (9.5 nmol/l). The late-night salivary cortisol threshold to distinguish between Cushing’s disease and Cushing’s disease in remission was 9.2 nmol/l. The cut-off value for the diagnosis of ectopic ACTH-production was 109.0 nmol/l (sensitivity 50%, specificity 92%). Late-night salivary cortisol is a convenient and reliable parameter for the diagnosis of hypercortisolism. Except for ectopic ACTH-production, thresholds considering different indications for evaluation of hypercortisolism were only slightly different. Therefore, they might only be useful if late-night salivary cortisol results near the established cut-off value are present.

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Pitfalls in the diagnosis and management of Cushing's syndrome

Neurosurgical FOCUS ◽

10.3171/2014.11.focus14704 ◽

2015 ◽

Vol 38 (2) ◽

pp. E4 ◽

Cited By ~ 34

Author(s):

Vivek Bansal ◽

Nadine El Asmar ◽

Warren R. Selman ◽

Baha M. Arafah

Keyword(s):

Cushing’S Syndrome ◽

Cushing’S Disease ◽

Salivary Cortisol ◽

Clinical Symptoms ◽

Cushing's Syndrome ◽

Cushing's Disease ◽

Biochemical Tests ◽

Late Night ◽

Late Night Salivary Cortisol ◽

Free Cortisol

Despite many recent advances, the management of patients with Cushing's disease continues to be challenging. Cushing's syndrome is a complex metabolic disorder that is a result of excess glucocorticoids. Excluding the exogenous causes, adrenocorticotropic hormone–secreting pituitary adenomas account for nearly 70% of all cases of Cushing's syndrome. The suspicion, diagnosis, and differential diagnosis require a logical systematic approach with attention paid to key details at each investigational step. A diagnosis of endogenous Cushing's syndrome is usually suspected in patients with clinical symptoms and confirmed by using multiple biochemical tests. Each of the biochemical tests used to establish the diagnosis has limitations that need to be considered for proper interpretation. Although some tests determine the total daily urinary excretion of cortisol, many others rely on measurements of serum cortisol at baseline and after stimulation (e.g., after corticotropin-releasing hormone) or suppression (e.g., dexamethasone) with agents that influence the hypothalamic-pituitary-adrenal axis. Other tests (e.g., measurements of late-night salivary cortisol concentration) rely on alterations in the diurnal rhythm of cortisol secretion. Because more than 90% of the cortisol in the circulation is protein bound, any alteration in the binding proteins (transcortin and albumin) will automatically influence the measured level and confound the interpretation of stimulation and suppression data, which are the basis for establishing the diagnosis of Cushing's syndrome. Although measuring late-night salivary cortisol seems to be an excellent initial test for hypercortisolism, it may be confounded by poor sampling methods and contamination. Measurements of 24-hour urinary free-cortisol excretion could be misleading in the presence of some pathological and physiological conditions. Dexamethasone suppression tests can be affected by illnesses that alter the absorption of the drug (e.g., malabsorption, celiac disease) and by the concurrent use of medications that interfere with its metabolism (e.g., inducers and inhibitors of the P450 enzyme system). In this review, the authors aim to review the pitfalls commonly encountered in the workup of patients suspected to have hypercortisolism. The optimal diagnosis and therapy for patients with Cushing's disease require the thorough and close coordination and involvement of all members of the management team.

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Accuracy of repeated measurements of late-night salivary cortisol to screen for early-stage recurrence of Cushing's disease following pituitary surgery

Clinical Endocrinology ◽

10.1111/cen.12534 ◽

2014 ◽

Vol 82 (2) ◽

pp. 260-266 ◽

Cited By ~ 14

Author(s):

Marie Danet-Lamasou ◽

Julien Asselineau ◽

Paul Perez ◽

Alexandre Vivot ◽

Marie-Laure Nunes ◽

...

Keyword(s):

Cushing’S Disease ◽

Salivary Cortisol ◽

Early Stage ◽

Pituitary Surgery ◽

Repeated Measurements ◽

Cushing's Disease ◽

Late Night ◽

Late Night Salivary Cortisol

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Specificity of late-night salivary cortisol measured by automated electrochemiluminescence immunoassay for Cushing’s disease in an obese population

Journal of Endocrinological Investigation ◽

10.1007/s40618-018-0870-8 ◽

2018 ◽

Vol 41 (11) ◽

pp. 1325-1331 ◽

Cited By ~ 5

Author(s):

J. Aberle ◽

C. Schulze zur Wiesch ◽

J. Flitsch ◽

J. Veigel ◽

G. Schön ◽

...

Keyword(s):

Cushing’S Disease ◽

Salivary Cortisol ◽

Cushing's Disease ◽

Late Night ◽

Late Night Salivary Cortisol ◽

Obese Population ◽

Electrochemiluminescence Immunoassay

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Use of late-night salivary cortisol to monitor response to medical treatment in Cushing’s disease

Acta Endocrinologica ◽

10.1530/eje-19-0695 ◽

2020 ◽

Vol 182 (2) ◽

pp. 207-217 ◽

Cited By ~ 1

Author(s):

John Newell-Price ◽

Rosario Pivonello ◽

Antoine Tabarin ◽

Maria Fleseriu ◽

Przemysław Witek ◽

...

Keyword(s):

Cushing’S Disease ◽

Salivary Cortisol ◽

Clinical Signs ◽

Urinary Free Cortisol ◽

Phase Iii ◽

Cushing's Disease ◽

Late Night ◽

Late Night Salivary Cortisol ◽

Free Cortisol ◽

Two Samples

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 the 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. Conclusion 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.

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