A Single Midnight Serum Cortisol Measurement Distinguishes Cushing’s Syndrome from Pseudo-Cushing States

Address all correspondence and requests for reprints to: Dimitris A. Papanicolaou, M.D., Developmental Endocrinology Branch, National Institute of Child Health and Human Development, National Institutes of Health, Building 10, Room 10N262, 10 Center Drive, MSC 1862, Bethesda, Maryland 20892-1862. E-mail: papanicd@cc1.nichd.nih.gov.
Received: October 22, 1997
Accepted: January 05, 1998
First Published Online: July 01, 2013

Cushing’s syndrome (CS) may be difficult to distinguish from pseudo-Cushing states (PCS) based on physical findings or urinary glucocorticoid excretion. As the lack of diurnal variation in serum cortisol is characteristic of CS, we studied whether diurnal cortisol determinations could discriminate CS from PCS. Two hundred and sixty-three patients were evaluated: 240 had CS, and 23 had PCS. Urine was collected for 24 h for measurement of cortisol and 17-hydroxycorticosteroids (17OHCS). Blood was drawn at 2300, 2330, 0000, 0030, and 0100 h and at 0600, 0630, 0700, 0730, and 0800 h the next morning for serum cortisol determination. The main outcome measure was the sensitivity of these parameters for the diagnosis of CS at 100% specificity. A midnight cortisol value greater than 7.5 μg/dL correctly identified 225 of 234 patients with CS and all PCS patients. This sensitivity (96%) was superior to that obtained for any other measure, including urinary cortisol (45%), 17OHCS (22%), any other individual cortisol time point (10–92%), the morning (23%) or the evening (93%) cortisol mean, and the ratio (11%) of morning to evening values. We conclude that at 100% specificity, a single serum cortisol value above 7.5 μg/dL at midnight discriminates CS from PCS with higher sensitivity than 24-h urinary cortisol or 17OHCS, or other individual or combined measures of serum cortisol.

OVERPRODUCTION of cortisol is the biochemical hallmark of Cushing’s syndrome (CS) regardless of its etiology and is evidenced by increased urinary cortisol excretion, and a decrease in the circadian variation of serum cortisol (1).

Pseudo-Cushing states (PCS), as the name implies, share many of the features of Cushing’s syndrome, including cortisol overproduction. The hypercortisolism of PCS is hypothesized to be caused by increased activity of the CRH neuron, which, in turn, stimulates ACTH production and release (2). PCS are a heterogeneous group of disorders, including chronic alcoholism and alcohol withdrawal syndrome (3, 4), major depression (5), poorly controlled diabetes mellitus (6, 7), and obesity (8). Additionally, transient hypercortisolism may be associated with less obvious psychiatric conditions (e.g. anxiety) in patients with clinical features reminiscent of CS, such as obesity and hypertension, which are common in the general population. The substantial overlap in urinary free cortisol (UFC) excretion and clinical features between some patients with CS and those with PCS can make it difficult to distinguish between the two conditions (9). Thus, although persistent elevation of 24-h UFC in the presence of unequivocal signs of CS (particularly classic moon facies, prominent centripetal obesity, severe proximal muscle weakness, and violaceous striae) suggest the diagnosis of CS, patients with less obvious signs pose a diagnostic dilemma.

Several tests have been proposed to diagnose CS, including 24-h UFC measurements, the 1-mg overnight dexamethasone suppression test (DST) (10), the 2-day DST (1), and the dexamethasone-CRH (Dex-CRH) stimulation test (8). Each has drawbacks. Twenty-four-hour urinary collections are inconvenient and often incomplete. The 1-mg overnight DST is commonly used as a screening test to exclude the diagnosis of CS. This test has two caveats. First, a criterion for the level of serum cortisol suppression to exclude CS has not been developed using modern RIAs. Second, although the test has a false negative rate of only 2%, it has a significant false positive rate, especially in chronically ill (23%) or obese patients (13%) (11) and in patients with major depression (43%) or other psychiatric disorders (8–41%) (12). Even in normal individuals, the test may be consistent with CS in up to 30% (9).

Similarly, the 2-mg 2-day DST, often used as a confirmatory diagnostic test, has a diagnostic accuracy of only 71% (8). An additional problem is the variable metabolic clearance of dexamethasone (13), which is especially problematic in patients receiving medications that induce the cytochrome P450-related enzymes (e.g.phenytoin, rifampin, and phenobarbital) (14) or in patients with renal or hepatic failure. In such cases, neither DST gives reliable results. Finally, the drawbacks of 24-h urine collections apply to the DST as well.

We previously determined that the dexamethasone-CRH test has a diagnostic accuracy of 98% in the distinction of CS from PCS (8, 15). However, although accurate, this test has the drawbacks related to dexamethasone clearance, as discussed above.

Physiological cortisol secretion is characterized by circadian rhythmicity. Serum cortisol concentration reaches its zenith in the morning (0600–0800 h) and its nadir in the night during the first half of normal sleep. Krieger et al. defined the normal circadian rhythm of plasma corticosteroid levels as the pattern where all plasma glucocorticoid levels from 1600–2400 h were 75% or less of the 0800 h value (16). As previous studies have found that obese individuals retain a normal circadian cortisol rhythm (17), we hypothesized that differences in circadian plasma cortisol values would distinguish CS from PCS. To test this hypothesis, we prospectively measured serum cortisol values during the normal nadir and zenith periods in patients being evaluated for CS.

Read the entire study at http://press.endocrine.org/doi/10.1210/jcem.83.4.4733?url_ver=Z39.88-2003&rfr_id=ori%3Arid%3Acrossref.org&rfr_dat=cr_pub%3Dpubmed

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