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Original Studies |
Endocrine Research Laboratory and the Endocrine-Diabetes Center, St. Luke’s Medical Center, Medical College of Wisconsin, Milwaukee, Wisconsin 53215
Address all correspondence and requests for reprints to: Hershel Raff, Ph.D., St. Luke’s Health Science Center, 2901 West KK River Parkway, Suite 503, Milwaukee, Wisconsin 53215. E-mail: hraff{at}post.its.mcw.edu
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Abstract |
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 Top Abstract IntroductionSubjects and MethodsResultsDiscussionReferences |
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We studied 73 normal subjects and 78 patients referred for the diagnosis of Cushing’s syndrome. Salivary cortisol was measured at 2300 h and 0700 h using a simple, commercially-available saliva collection device and a modification of a standard cortisol RIA. In addition, 24-h UFC was measured within 1 month of saliva sampling.
Patients with proven Cushing’s syndrome (N = 39) had significantly elevated 2300-h salivary cortisol (24.0 ± 4.5 nmol/L), as compared with normal subjects (1.2 ± 0.1 nmol/L) or with patients referred with the clinical features of hypercortisolism in whom the diagnosis was excluded or not firmly established (1.6 ± 0.2 nmol/L; N = 39). Three of 39 patients with proven Cushing’s had 2300-h salivary cortisol less than the calculated upper limit of the reference range (3.6 nmol/L), yielding a sensitivity of 92%; one of these 3 patients had intermittent hypercortisolism, and one had an abnormal diurnal rhythm (salivary cortisol 0700-h to 2300-h ratio <2). An elevated 2300-h salivary cortisol and/or an elevated UFC identified all 39 patients with proven Cushing’s syndrome (100% sensitivity). Salivary cortisol measured at 0700 h demonstrated significant overlap between groups, even though it was significantly elevated in patients with proven Cushing’s syndrome (23.0 ± 4.2 nmol/L), as compared with normal subjects (14.5 ± 0.8 nmol/L) or with patients in whom Cushing’s was excluded or not firmly established (15.3 ± 1.5 nmol/L).
Late-night salivary cortisol measurement is a simple and reliable screening test for spontaneous Cushing’s syndrome. In addition, late-night salivary cortisol measurements may simplify the evaluation of suspected intermittent hypercortisolism, and they may facilitate the screening of large high-risk populations (e.g. patients with diabetes mellitus).
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Biochemical screening studies for Cushing’s syndrome have included low-dose dexamethasone suppression testing, urine free cortisol (UFC), assessment of diurnal rhythmicity, and (more recently) measurement of unstressed late-night serum cortisol level (3). These studies are often cumbersome and sometimes require hospitalization; and, because both false positive and false negative results are common, none of these studies are ideal screening tests (2, 3).
The disruption of the circadian rhythm has been considered a hallmark of Cushing’s syndrome (2, 4). Normally, cortisol is secreted episodically with a diurnal rhythm paralleling the secretion of ACTH (4). Cortisol reaches a peak around the time of awakening and a nadir after the onset of sleep. The normal range for plasma cortisol in the morning is rather broad, and concentrations overlap with those in patients with Cushing’s syndrome. Newell-Price et al. (3) have recently demonstrated that a single midnight serum cortisol concentration greater than 50 nmol/L (1.8 µg/dL) yielded a sensitivity of 100% for the diagnosis of Cushing’s syndrome. It is neither practical nor cost effective to hospitalize patients with suspected Cushing’s syndrome for 48 h or more to obtain an unstressed late-night serum cortisol level. Therefore, a method to assess adrenal function at bedtime, without disrupting a normal routine, might be a useful screening test for Cushing’s syndrome.
To explore simple and convenient means for probing late-night cortisol secretion, we evaluated the concentration of cortisol in the saliva at 2300 h and 0700 h in a large group of patients with proven spontaneous Cushing’s syndrome, a group of patients referred for possible Cushing’s syndrome in whom other diagnostic studies excluded or did not confirm hypercortisolism, and in normal subjects. The concentration of cortisol in the saliva is in an equilibrium with free plasma cortisol and is independent of the rate of saliva production (5, 6, 7). Despite previous studies demonstrating the usefulness of the measurement of salivary cortisol to assess hypothalamic-pituitary-adrenal axis secretory activity and rhythm (5, 6, 7, 8), it is surprising that this technique has not become more widely used. The current study provides evidence that measurement of a late-night salivary cortisol is a simple and sensitive method for screening patients for spontaneous Cushing’s syndrome.
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Normal subjects. Subjects (N = 73; age = 37 ± 11 SD; 35 male/38 female) were recruited from the student/staff/faculty population at the Medical College of Wisconsin, Veterans Administration Medical Center, and St. Luke’s Medical Center. Confidentiality was maintained according to the Helsinki Declaration. Subjects in whom blood was sampled (cosyntropin stimulation test) gave written informed consent approved by the St. Luke’s Medical Center Institutional Review Board. There were not sufficient numbers of women using oral contraceptives (N = 6) to accurately compare them with women not using oral contraceptives, so all data from normal female subjects were pooled. Subjects sampled their saliva at 2300 h and 0700 h (the following morning) after a routine evening in which alcohol intake was avoided. To determine whether excitement might confound this measurement, some subjects (15 Green Bay Packer fans) repeated saliva collection on the evening and morning after watching a professional football game. On another occasion, to correlate plasma and salivary cortisol, plasma and saliva were sampled (between 0800 and 1000 h) before and 30 min after administration of cosyntropin (1 µg iv) in some subjects (N = 9).
Patients. Patients evaluated for the diagnosis of Cushing’s syndrome (N = 78) were referred because of their clinical history and features (e.g. obesity, hypertension, diabetes, hirsutism) and, in some cases, because of a single elevated UFC. Of these, the diagnosis of Cushing’s syndrome was established in 39 (age = 42 ± 14 SD, 11 male/28 female) by clinical examination, repeatedly elevated UFC, and/or failure to suppress cortisol with a low-dose dexamethasone suppression test. The diagnosis of Cushing’s disease (N = 30) was established by petrosal sinus sampling and cure by transsphenoidal microadenomectomy (9, 10). The diagnosis of ectopic ACTH (N = 4) was established by petrosal sinus sampling and successful removal of bronchial carcinoid tumors (9, 11). The diagnosis of adrenal Cushing’s syndrome (N = 5) was established by the measurement of suppressed plasma ACTH and successful removal of an adrenal adenoma.
Cushing’s syndrome was excluded or not firmly established in the remaining patients (N = 39; age = 44 ± 13 SD) independently of salivary cortisol measurement by subsequent normal UFC, normal dexamethasone suppression test, or identification of other causes of hypercortisolism (e.g. alcoholic pseudo-Cushing’s). Follow-up was not routinely performed on these patients except where described in the results.
UFC was measured by high-performance liquid chromatography or RIA within one month of saliva sampling by the referring physician or by us. To consolidate these data, they were normalized by dividing by the upper limit of normal for each UFC assay used.
Methods
We used a simple device to collect and transport saliva samples (Plain Salivette, Sarstedt, Newton, NC). This device is composed of a cotton tube (similar to dental cotton), and two plastic tubes that fit one inside the other. Saliva was sampled at 2300 h and at 0700 h the following morning by chewing on the cotton tube for 2–3 min. The cotton tube was inserted inside the plastic tube, which was then capped. The Salivette can be stored at room temperature for at least 7 days and transported to the laboratory by mail or express carrier without any loss of cortisol activity (8). The saliva was separated from the cotton tube by centrifugation at 3000 RPM for 10 min and stored at -20 C or lower.
Plasma cortisol was measured by RIA (Coat-a-Count, Diagnostic Products, Los Angeles, CA). Salivary cortisol was measured using a modification of the same assay by increasing the analyte volume (from 25 to 200 µL), increasing the incubation time from 45 to 180 min, decreasing the incubation temperature from 37 C to room temperature, and diluting the provided calibrators 1:10 in distilled water (12). The minimal detectable salivary cortisol was 0.4 mmol/L. Samples diluted in parallel down to 1:5 dilution. The intraassay coefficient of variation was 3.0% (N = 15), and interassay coefficients of variation were 12.1% (low pool, N = 23) and 6.1% (high pool, N = 16).
Data were analyzed by ANOVA, followed by Student Newman-Keuls multiple-range test and linear regression using validated software (13). The ratio of 0700-h to 2300-h salivary cortisol was used as an index of diurnal rhythmicity. Reference ranges for data from normal subjects was calculated nonparametrically by the rank number method using 2.5–97.5 percentiles (14). Data are presented as mean ± SE, with P < 0.05 considered significant.
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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There was a significant correlation between plasma and salivary cortisol before and 30 min after administration of 1 µg cosyntropin (slope = 0.04, y-intercept = -4.3 nmol/L, n = 18, r = 0.86, P < 0.001). The slope of the relationship between plasma (x-axis) and salivary (y-axis) cortisol of 0.04 indicates that salivary cortisol represented about 4% of the total circulating plasma cortisol.
Average and individual data from normal subjects is shown in Table 1
and Fig. 1, respectively. Salivary cortisol was
consistently and significantly greater at 0700 h than at 2300
h. There was no significant difference in the salivary cortisol levels
between male and female normal subjects at either time point. Reference
ranges for the salivary cortisol assay were calculated
nonparametrically as <0.4–3.6 nmol/L at 2300 h and 4.7–32.0
nmol/L at 0700 h.
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Patients
Table 1
shows the mean data of normal subjects, patients with
proven Cushing’s syndrome, and patients in whom Cushing’s syndrome
was excluded or not firmly established. The patients in whom Cushing’s
syndrome was excluded or not firmly established were statistically
indistinguishable from normal subjects. Patients with proven Cushing’s
syndrome had 2300-h salivary cortisol that were, on average, almost 20
times higher than normal subjects or than patients in whom Cushing’s
syndrome was excluded or not firmly established. Salivary cortisol at
0700 h was also significantly higher in patients with Cushing’s
syndrome than in either of the two other groups. The loss of circadian
rhythmicity was highlighted by a significantly lower ratio of 0700-h to
2300-h salivary cortisol in patients with Cushing’s syndrome. In fact,
this ratio was indistinguishable from no-rhythm (ratio = 1).
Figure 1 shows the individual data. The broken line in the
left panel indicates the nonparametric estimate of the upper
limit of the reference range for normal subjects (
3.6 nmol/L).
Most (36/39) patients with Cushing’s syndrome had 2300-h
salivary cortisol greater than the reference range. However, 3 patients
with proven Cushing’s disease had 2300-h salivary cortisol levels
within the reference range. One of these 3 patients had very low 2300-h
salivary cortisol (0.6 nmol/L) and a normal 0700-h to 2300-h ratio of
salivary cortisol (17.3) and was probably not hypersecreting cortisol
at the time of sampling. Therefore, the sensitivity of salivary
cortisol measurement, using 2300-h salivary cortisol only (3.6 nmol/L
as a cutoff), was 92% (36/39). If this cutoff was arbitrarily
lowered to 2.7 nmol/L, the sensitivity of 2300-h salivary cortisol was
increased to 97% (38/39). If a lack of diurnal rhythmicity was also
included in the analysis (0700-h:2300-h <2), 1 patient was
reclassified, yielding a sensitivity of 95% (37/39) if 3.6 nmol/L was
used as a cutoff for 2300-h data. The sensitivity was not measurably
improved if the arbitrary cutoff of 2.7 nmol/L for 2300-h salivary
cortisol was combined with an 0700-h to 2300-h ratio less than 2,
because of the 1 patient with intermittent Cushing’s disease with
completely normal 2300-h and 0700-h salivary cortisol.
Two of the 39 patients in the group in whom Cushing’s syndrome was
excluded or not firmly established had 2300-h salivary cortisol levels
more than 3.6 nmol/L (4.4 and 3.8 nmol/L). These values were within the
range of normal subjects. Furthermore, both patients had 0700-h to
2300-h ratios more than 2. Therefore, using both 2300-h less than 3.6
nmol/L, and a 0700-h to 2300-h ratio more than 2, the specificity of
salivary cortisol was 100%. If the arbitrarily lower cutoff of 2.7
nmol/L was used, which improved sensitivity (see above), the
specificity in the patients in whom Cushing’s syndrome was not firmly
established decreased to 77% (30/39). Interestingly, 69 of 73 normal
subjects had 2300-h salivary cortisol less than 2.7 nmol/L, indicating
that specificity (95%) of this lower cutoff was significantly better
than in patients in whom Cushing’s syndrome was ruled out or not
firmly established (
2 = 7.67, 1 degree of freedom,
P < 0.01). There was significant overlap between
0700-h salivary cortisol for all groups.
Figure 2 shows the individual values for
the ratio of 0700-h to 2300-h salivary cortisol (an index of diurnal
rhythmicity). A ratio of 2 was calculated (nonparametrically) as the
lower limit of the reference range for normal subjects. Of the 38
evaluable patients with Cushing’s syndrome (one of 39 was missing the
0700-h measurement), 6 had 0700-h:2300-h ratios within the reference
range for normal subjects.
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). The 1 patient with Cushing’s
syndrome in whom 2300-h salivary cortisol was less than 1.0 nmol/L had
intermittent Cushing’s disease and was probably not hypersecreting
cortisol at the time of saliva sampling (same outlier as in Fig. 1),
even though UFC was elevated 1 month earlier. Of the 39 patients with
Cushing’s syndrome, 3 had normal 2300-h salivary cortisol and elevated
UFC, whereas 1 had elevated 2300-h salivary cortisol and normal UFC
(Table 2). No patients with proven
Cushing’s syndrome had both normal 2300-h salivary cortisol and normal
UFC.
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). Thirty of 37 of these patients
had normal UFC. Seven had normal 2300-h salivary cortisol but had UFC
levels that were initially elevated. Of these 7, 2 had normal
subsequent UFC measurements, 1 was found to have alcohol-induced
pseudo-Cushing’s, and 2 were obese and hirsute females with normal
suppression of cortisol after overnight 1-mg dexamethasone. The
etiology of the elevated UFC in the remaining two subjects, with normal
salivary cortisol but elevated UFC, has not been explained. |
Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Reference ranges for 2300-h and 0700-h salivary cortisol in normal subjects were similar to those previously described using different assay methods (16, 17, 18, 19). However, we did not find a significant difference between male and female normal subjects, as has been previously described (16). We also demonstrated that the concentration of cortisol in the saliva is stimulated by administration of cosyntropin, consistent with a previous study (5), and that there was excellent correlation between salivary (free) cortisol and total serum cortisol measurements (7). Finally, we also raise the possibility that a stressful event in the evening of sampling has the potential to confound the measurement.
We clearly demonstrated that patients with spontaneous Cushing’s syndrome have a markedly elevated late-night salivary cortisol, as well as disrupted circadian rhythm (decreased ratio of 0700-h to 2300-h salivary cortisol). However, 3 of 39 patients with Cushing’s syndrome had late-night salivary cortisol within the normal reference range and, of these, 2 had normal 0700-h to 2300-h ratios. Laudat et al. (16) found no overlap in 2000-h salivary cortisol between normal subjects and patients with Cushing’s syndrome. This difference from our study may be caused by the timing of the evening sample, the degree of hypercortisolism, or the fact that we studied a larger sample size. If a late-night salivary cortisol level of 2.7 nmol/L was used as the upper limit of normal, we were able to identify all patients with Cushing’s syndrome, with the exception of a single patient who had intermittent hypercortisolism and apparently normal cortisol secretory dynamics at the time of measurement. In addition, six patients with Cushing’s disease had normal 0700-h to 2300-h ratios, suggesting intact diurnal rhythmicity. This confirms other studies that suggest that some patients with spontaneous Cushing’s syndrome actually retain normal diurnal rhythm (albeit at a higher secretory rate) (20, 21).
One of the unique aspects of this study is the reporting of a significant number of patients referred for evaluation of possible Cushing’s syndrome based on their clinical signs and symptoms but in whom the diagnosis was excluded or not firmly established. The diagnosis was excluded in most of these patients by measurement of a normal UFC by high-performance liquid chromatography. In five of the seven remaining patients, either repeated urinary free cortisol measurements were normal or the patients had adequate suppression of serum cortisol after low-dose dexamethasone suppression. All of these patients had either normal 2300-h salivary cortisol (<3.6 nmol/L) or a normal 0700-h to 2300-h ratio (>2). If the 2300-h salivary cortisol cutoff was lowered to 2.7 nmol/L to improve sensitivity for diagnosing Cushing’s syndrome (see above), the specificity in these patients decreased (77%). However, specificity in normal subjects, using 2.7 nmol/L as the cutoff, was significantly higher (95%) than in the patients in whom Cushing’s syndrome was not established, suggesting that some patients in whom Cushing’s could not be firmly established by any approach might have very mild hypercortisolism.
It is well appreciated that there is a large overlap of morning serum cortisol values between patients with Cushing’s syndrome and normal subjects; and thus, this sampling time affords poor discrimination. Two studies have attempted to take advantage of the fact that cortisol secretion in the evening in Cushing’s syndrome patients is higher than in normal subjects, by means of measuring spot or timed urine cortisol levels in the late evening (22, 23). These studies showed that the ratio of urinary cortisol to creatinine was able to distinguish patients with Cushing’s syndrome from normal subjects. However, there was some overlap between patients with hypercortisolism and a group of obese control subjects. Newell-Price et al. (3) measured a single sleeping plasma cortisol level at midnight in 150 patients with proven Cushing’s syndrome and showed that a plasma (total) cortisol greater than 50 nmol/L (1.8 µg/dL) yielded a diagnostic sensitivity for Cushing’s syndrome of 100%. This corresponds well with a salivary (free) cortisol of 2.7 nmol/L (the arbitrary cutoff point that yielded more than 95% sensitivity in our patient population. However, the measurement of an unstressed late-night serum cortisol required inpatient hospitalization for a period of at least 48 h, making it impractical as a screening test (3). Another report suggested that the assessment of midnight cortisol values may allow discrimination between Cushing’s syndrome and pseudo-Cushing states (depression, alcoholism, and eating disorders) (24). The level of plasma cortisol at midnight was greater than 7.5 µg/dL (207 nmol/L) in 96% of 234 patients with Cushing’s syndrome, whereas it was less than this in all patients with pseudo-Cushing states. Because it is well known that some patients with Cushing’s syndrome may have intermittent hypercortisolism (25, 26), normal results of any test of cortisol secretory dynamics may not be adequate in excluding the diagnosis. In the present study, UFC and salivary cortisol were not measured concurrently, and therefore, intermittent hypercortisolism could have led to one or the other being normal. That UFC and salivary cortisol correlated well, except in 1 subject, suggests that significant time between samples may not be a disadvantage.
As a screening test for Cushing’s syndrome, a late-night salivary cortisol compares favorably with the traditional overnight 1-mg dexamethasone suppression test and is easier to perform. The reported cutoff values for the suppression of serum cortisol in normal subjects after 1 mg dexamethasone, administered at 2300 h, has ranged from 3.0–7.2 µg/dL (80–195 nmol/L) (27, 28, 29). However, some patients with Cushing’s syndrome demonstrate unusual sensitivity to dexamethasone suppression; and thus, even cutoffs at this level are likely to result in a significant number of false negative responses (30). To increase the sensitivity of the overnight 1-mg dexamethasone suppression test, a recent extensive review suggested that suppression of the postdexamethasone serum cortisol to 1.8 µg/dL (50 nmol/L) more or less effectively excludes Cushing’s syndrome (30). Using such a low cutoff value will undoubtedly increase the false positive rate and may very well obfuscate its use as a screening test. Some studies have combined the dexamethasone suppression test with salivary cortisol measurement, but this does not eliminate the conceptual problems with using glucocorticoid negative feedback to evaluate hypercortisolism (31, 32, 33).
The clinical diagnosis of Cushing’s syndrome does not depend on any one specific clinical feature but on a constellation of features. The appreciation of subclinical Cushing’s syndrome in some patients with incidentally discovered adrenal masses has provided evidence that mild hypercortisolism is as difficult to appreciate as subclinical hypothyroidism or hyperthyroidism (34). Although spontaneous Cushing’s syndrome is considered to be an unusual disorder, a recent study, showing that 3–4% of poorly controlled patients with type 2 diabetes may have unsuspected Cushing’s syndrome, provides evidence that this disorder is more common than currently appreciated (35). The diagnosis can only be achieved with a high index of suspicion and the use of simple biochemical screening studies.
In summary, this study describes the use of a late-night salivary cortisol measurement as a simple and reliable means of screening patients for spontaneous Cushing’s syndrome. In addition, late-night salivary cortisol measurements may also help in the evaluation of some patients with suspected intermittent hypercortisolism (25, 26) and may also be useful in facilitating the screening of large high-risk populations (e.g. patients with diabetes mellitus).
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Acknowledgments |
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Footnotes |
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Received April 7, 1998.
Accepted May 18, 1998.
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References |
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P. Putignano, P. Toja, A. Dubini, F. P. Giraldi, S. M. Corsello, and F. Cavagnini Midnight Salivary Cortisol Versus Urinary Free and Midnight Serum Cortisol as Screening Tests for Cushing's Syndrome J. Clin. Endocrinol. Metab., September 1, 2003; 88(9): 4153 - 4157. [Abstract] [Full Text] [PDF]
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 H. Raff and J. W. Findling A Physiologic Approach to Diagnosis of the Cushing Syndrome Ann Intern Med, June 17, 2003; 138(12): 980 - 991. [Full Text] [PDF]
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H. Raff, P. J. Homar, and D. P. Skoner New Enzyme Immunoassay for Salivary Cortisol Clin. Chem., January 1, 2003; 49(1): 203 - 204. [Full Text] [PDF]
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D. A. Papanicolaou, N. Mullen, I. Kyrou, and L. K. Nieman Nighttime Salivary Cortisol: A Useful Test for the Diagnosis of Cushing's Syndrome J. Clin. Endocrinol. Metab., October 1, 2002; 87(10): 4515 - 4521. [Abstract] [Full Text] [PDF]
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H. Raff, P. J. Homar, and E. A. Burns Comparison of Two Methods for Measuring Salivary Cortisol Clin. Chem., January 1, 2002; 48(1): 207 - 208. [Full Text] [PDF]
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 J. Hjertstedt, E. A. Burns, R. Fleming, H. Raff, I. Rudman, E. H. Duthie, and C. R. Wilson Mandibular and Palatal Tori, Bone Mineral Density, and Salivary Cortisol in Community-Dwelling Elderly Men and Women J. Gerontol. A Biol. Sci. Med. Sci., November 1, 2001; 56(11): M731 - 735. [Abstract] [Full Text] [PDF]
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M. Moro, P. Putignano, M. Losa, C. Invitti, C. Maraschini, and F. Cavagnini The Desmopressin Test in the Differential Diagnosis between Cushing's Disease and Pseudo-Cushing States J. Clin. Endocrinol. Metab., October 1, 2000; 85(10): 3569 - 3574. [Abstract] [Full Text]
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M. Castro, P. C. L. Elias, A. R. P. Quidute, F. P. B. Halah, and A. C. Moreira Out-Patient Screening for Cushing's Syndrome: The Sensitivity of the Combination of Circadian Rhythm and Overnight Dexamethasone Suppression Salivary Cortisol Tests J. Clin. Endocrinol. Metab., March 1, 1999; 84(3): 878 - 882. [Abstract] [Full Text]
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