Original Article
Petrosal Sinus Sampling with and without Corticotropin-Releasing Hormone for the Differential Diagnosis of Cushing's Syndrome
N Engl J Med 1991; 325:897-905September 26, 1991
- Abstract
- Abstract
Background.
Measurement of adrenocorticotropin levels in plasma from the inferior petrosal sinuses of patients with Cushing's syndrome can distinguish adrenocorticotropin-secreting pituitary tumors (Cushing's disease) from other causes of the syndrome, principally ectopic adrenocorticotropin secretion from an occult tumor. However, it is unknown whether such measurement consistently identifies patients with Cushing's disease and whether testing with corticotropin-releasing hormone (CRH) enhances the value of the procedure.
Methods.
We prospectively studied 281 patients with Cushing's syndrome to evaluate the diagnostic efficacy of the procedure. Bilateral sampling was successfully accomplished in 278 patients, with no major morbidity; 262 of these patients underwent sampling before and after administration of ovine CRH. The adrenocorticotropin levels in the samples were used to calculate the ratio of the concentration in plasma from the inferior petrosal sinuses to the concentration in peripheral-blood plasma (the IPS:P ratio).
Results.
The diagnosis of 246 patients was confirmed surgically as Cushing's disease in 215, as ectopic adrenocorticotropin syndrome in 20, and as primary adrenal disease in 11. An IPS:P ratio ≥2.0 in basal samples identified 205 of the 215 patients with Cushing's disease (sensitivity, 95 percent), with no false positive results (specificity, 100 percent). A peak IPS:P ratio ≥3.0 after CRH administration identified all 203 of the patients with Cushing's disease who received CRH (sensitivity, 100 percent), with no false positive results (specificity, 100 percent). The sensitivity was much lower when the adrenocorticotropin concentrations in the samples from one sinus were considered alone. In patients with Cushing's disease a difference of ≥1.4-fold between the concentrations in the two sinuses (the adrenocorticotropin gradient) predicted the location of the microadenoma in 68 percent of 104 patients during basal sampling and in 71 percent of 105 patients after CRH administration.
Conclusions.
Simultaneous bilateral sampling of plasma from the inferior petrosal sinuses, with the adjunctive use of CRH, distinguishes patients with Cushing's disease from those with ectopic adrenocorticotropin secretion with high diagnostic accuracy. (N Engl J Med 1991; 325:897–905.)
Article Activity
- Article
SURGERY for Cushing's syndrome can cure hyper-cortisolism and preserve pituitary—adrenal function in most patients in whom a specific diagnosis is established. Current diagnostic tests, however, do not always distinguish clearly among the causes of the syndrome, and as a consequence, patients may not receive appropriate therapy.
We1 2 3 4 and others5 6 7 8 9 10 have described preliminary experience with simultaneous bilateral sampling of the inferior petrosal sinuses, performed without1 2 3 , 5 , 6 , 8 , 10 and with4 , 7 , 9 corticotropin-releasing hormone (CRH) stimulation, to establish the cause of Cushing's syndrome3 , 4 , 7 8 9 and to predict the side of the pituitary gland containing a microadenoma in patients with Cushing's disease (Cushing's syndrome caused by an adrenocorticotropin-secreting pituitary tumor).1 2 3 , 5 , 6 , 10 Plasma adrenocorticotropin concentrations in one or both petrosal sinuses were higher than those in peripheral blood in patients with Cushing's disease, but the concentrations were similar in petrosal sinus plasma and peripheral-blood plasma in patients with other causes of Cushing's syndrome. However, these studies did not establish the efficacy of the procedure in distinguishing Cushing's disease from other causes of Cushing's syndrome, since they reported the results in only three patients with ectopic adrenocorticotropin secretion.3 , 4 , 9 To assess the efficacy of the technique in determining the cause of Cushing's syndrome, to examine the predictive value of bilateral sampling of the inferior petrosal sinuses in localizing the site of a microadenoma in the pituitary gland, and to develop criteria for interpreting the results of the test, we carried out simultaneous bilateral sampling of inferior petrosal venous blood in a large group of patients with Cushing's syndrome. Many of these patients also received ovine CRH to evaluate whether its administration would enhance the diagnostic efficacy of the technique.
Methods
Between January 13, 1982, and December 15, 1989, we attempted simultaneous bilateral sampling of venous blood from the inferior petrosal sinuses of 281 patients with Cushing's syndrome (223 female and 58 male patients 6 to 72 years old). Each had typical clinical features of the disorder and elevated urinary corticosteroid excretion at the time of the procedure. Many patients had undergone previously unsuccessful pituitary surgery. The results of basal sampling in 26 patients and the results of sampling after CRH administration in 6 patients have previously been reported.1 2 3 4 , 11 , 12 The protocol for the use of CRH was approved by the institutional review board of the National Institute of Child Health and Human Development, and informed consent was obtained from all patients or their parents before the procedure.
The diagnosis of Cushing's syndrome was considered established if histologic examination of a surgical specimen confirmed it (in all 31 patients with ectopic adrenocorticotropin syndrome or primary adrenal disease and in 187 of the 215 patients with Cushing's disease) or if no pituitary tumor was identified at the time of transsphenoidal surgery and excision of a portion of the pituitary gland produced hypocortisolism (25 patients) or normal adrenal secretion and clinical remission (3 patients). Diagnoses were established in 246 of the 278 patients with the syndrome who underwent successful sampling — i.e., 215 patients with Cushing's disease, 20 with ectopic adrenocorticotropin syndrome, and 11 with primary adrenal disease (Table 1Table 1
Diagnosis of 278 Patients Who Underwent Successful Inferior Petrosal Sinus Sampling.). The diagnoses of 32 patients remained unconfirmed; 20 were presumed to have Cushing's disease (11 were referred after previous pituitary surgery in which no tumor was identified, 5 underwent pituitary surgery after sampling but no tumor was found and hypercortisolism persisted, and 4 were awaiting treatment), and 12 probably had the ectopic adrenocorticotropin syndrome, but no adrenocorticotropin-secreting tumor was identified.The predictive value of simultaneous bilateral sampling of the inferior petrosal sinuses for determining the site of a microadenoma in the pituitary gland was assessed in the 113 patients who had no previous pituitary surgery and in whom a microadenoma was identified intraoperatively as being either on one side of or at the midline.
Catheterization of both inferior petrosal sinuses was accomplished through a percutaneous bilateral femoral-vein approach as previously described.1 2 3 Systemic anticoagulation was induced with heparin (3500 to 4000 units intravenously) after the catheters had been inserted into both femoral veins. After a catheter was advanced into a sinus, a small amount of contrast material was injected to verify the location of the catheter tip. Blood was slowly withdrawn simultaneously from both catheters and a peripheral vein for adrenocorticotropin measurement. A second set of basal samples was usually obtained immediately after the first set. Ovine CRH in a dose of 1 μg per kilogram of body weight was then infused into a peripheral vein in 1 minute, and samples were obtained simultaneously from both inferior petrosal sinuses and a peripheral vein 2 to 3, 5, and 10 minutes, and in some patients, 15 to 20 and 30 minutes, after the administration of CRH. Retrograde venography was performed through each catheter after blood sampling, to document filling of the ipsilateral cavernous sinus from each catheter. The procedure usually required 25 to 60 minutes in patients studied for 10 minutes after CRH stimulation, as became our standard practice. Patients rested in bed for two hours after the procedure.
Blood samples were processed as previously described.3 Adrenocorticotropin was measured in all plasma samples, and Cortisol in the peripheral-blood plasma samples. The radioimmunoassay for adrenocorticotropin and the preparation of CRH for injection have been described previously.13 , 14 All samples from each patient were analyzed at the same time in each assay. The limit of detection for the adrenocorticotropin assay ranged from 0.7 to 1.1 pmol per liter. The mean intraassay and interassay coefficients of variation were 3.8 percent and 7.2 percent, respectively.
For the differential diagnosis of Cushing's syndrome, the adrenocorticotropin values were used to calculate the ratio of the concentration in the right or left inferior petrosal sinus to the concentration in the peripheral-blood plasma (the IPS:P ratio) (Table 2Table 2
Results of Inferior Petrosal Sinus Sampling in a Patient with Cushing's Disease and a Patient with Ectopic Adrenocorticotropin Syndrome.*) for each set of samples, and the maximal ratio (right or left sinus) was identified. On the basis of early results, a maximal ratio of ≥2.0 during basal sampling and ≥3.0 during sampling after CRH stimulation indicated Cushing's disease.The results of petrosal venous sampling were compared with the results of the high-dose part of the standard low-dose-high-dose dexamethasone suppression test15 in the 183 patients who underwent the test during the hospitalization in which the sampling was done (169 patients with Cushing's disease and 14 with ectopic adrenocorticotropin syndrome). A positive response to dexamethasone was defined as a decrease in urinary 17-hydroxycorticosteroid excretion on the second day of high-dose administration (8 mg of dexamethasone per day) to 50 percent or less of the mean base-line level of excretion.15 16 17
To correlate the results of sampling with the site of the microadenoma in the pituitary gland, the location of the center of the adenoma as identified at surgery was assigned to the midline or to one side of the midline. The concurrent adrenocorticotropin concentrations in the inferior petrosal sinuses were used to calculate a ratio between the concentrations of the two sides (the adrenocorticotropin gradient)3 (Table 2).
Results
Success of Inferior Petrosal Sinus Sampling
Sampling was successfully performed in 278 of the 281 patients (99 percent). One of the 3 patients in whom it was unsuccessful had anomalous venous drainage in which both sinuses drained into the vertebral venous system and neither sinus communicated with the internal jugular veins; the other 2 patients were among the first 17 in whom the procedure was attempted.3
In 274 patients (214 of the 215 patients with Cushing's disease, 18 of the 20 with ectopic adrenocorticotropin syndrome, all 11 patients with primary adrenal disease, and 31 of the 32 patients in whom the diagnosis remained unknown), each inferior petrosal sinus and a peripheral vein were sampled simultaneously. In four patients, only one sinus was sampled because only one jugular vein was patent: one patient with Cushing's disease in whom one sinus emptied into a vertebral vein, into which one of the catheter tips had been placed for sampling; one patient with ectopic adrenocorticotropin secretion who had previously undergone a radical neck dissection with excision of one internal jugular vein; and one patient with ectopic adrenocorticotropin secretion and one patient in whom the diagnosis remained unproved, both of whom had thrombosis of one of the internal jugular veins as a result of recent placement of an intravenous catheter. Although catheterization led to hematomas of the groin in several patients at the site of venous puncture, there were no major complications associated with the procedure. Several patients underwent sampling on an outpatient basis.
Representative results in a patient with Cushing's disease and a patient with ectopic adrenocorticotropin secretion are shown in Table 2. In many patients with Cushing's disease, the adrenocorticotropin concentrations in plasma from one sinus during basal sampling and after CRH stimulation were higher than the concurrent concentrations in peripheral-blood plasma, but the concentrations in the other sinus were similar to those in peripheral-blood plasma. After the administration of CRH, the adrenocorticotropin concentration in one sinus promptly increased. Generally, the highest response was observed in the early samples after CRH was administered. In contrast, in patients with ectopic adrenocorticotropin syndrome, the adrenocorticotropin concentrations in plasma from both sinuses exceeded those in the peripheral-blood plasma by less than twofold before CRH administration and by less than threefold after stimulation.
Basal Sampling
Sinus Plasma Levels
The highest basal levels of adrenocorticotropin in sinus plasma ranged from 4 to 1198 pmol per liter in the patients with Cushing's disease and from 6 to 317 pmol per liter in the patients with ectopic adrenocorticotropin syndrome, whereas the highest adrenocorticotropin level in plasma from either sinus in the patients with adrenal disease was 3 pmol per liter.
IPS:P Ratio
Two hundred five of the 215 patients with Cushing's disease (diagnostic sensitivity [the percentage of patients with Cushing's disease who were found to be positive for it], 95 percent) had an adrenocorticotropin IPS:P ratio of ≥2.0 as calculated from at least one set of basal samples (Fig. 1Figure 1
Maximal Ratio of Adrenocorticotropin Concentration in Plasma from One Inferior Petrosal Sinus to the Concentration in Peripheral Blood (IPS:P) in Patients with Cushing's Syndrome. and Table 3Table 3
Diagnostic Accuracy of Inferior Petrosal Sinus Sampling before (235 Patients) and after (220 Patients) CRH Administration in Distinguishing Cushing's Disease from Ectopic Adrenocorticotropin Syndrome.).All 20 patients with ectopic adrenocorticotropin secretion had a maximal basal IPS:P ratio of less than 2.0 for a single set of plasma samples (4 patients) or two sets (16 patients) (Table 3). The 11 patients with primary adrenal disease either had no detectable adrenocorticotropin in peripheral-blood plasma (5 patients) or had a ratio below 2.0 (6 patients) for all basal samples (Fig. 1). Thus, the diagnostic specificity (the percentage of patients with ectopic adrenocorticotropin syndrome who were negative for Cushing's disease) of a basal ratio ≥2.0 in distinguishing Cushing's disease from ectopic adrenocorticotropin secretion or primary adrenal disease was 100 percent.
There was a positive correlation between the highest IPS:P ratio and the highest sinus adrenocorticotropin concentration in the patients with Cushing's disease (Spearman rank-correlation coefficient [rs] = 0.70, P = 0.0001), but not in those with ectopic adrenocorticotropin syndrome (rs = —0.025, P = 0.91) (Fig. 2Figure 2
IPS:P Adrenocorticotropin Ratio in Relation to Petrosal Sinus Plasma Adrenocorticotropin Concentration in Patients with Cushing's Syndrome.). Thus, all 171 patients with Cushing's disease who had a basal level above 28 pmol per liter had a maximal basal IPS:P ratio of at least 2.9 (sensitivity of the ratio when the sinus adrenocorticotropin level was >28 pmol per liter, 100 percent). All 10 patients with Cushing's disease and a maximal ratio of less than 2.0 were among the 44 patients with maximal sinus adrenocorticotropin levels below 28 pmol per liter (sensitivity of the ratio when the sinus adrenocorticotropin level was <28 pmol per liter, 77 percent).Many patients had different adrenocorticotropin levels in the right and left inferior petrosal sinuses (Table 2). Thus, although 205 of the 215 patients with Cushing's disease had an IPS:P ratio of ≥2.0 when the ratio was calculated from the adrenocorticotropin concentration in plasma from the sinus with the highest value, 88 patients (41 percent) had a ratio below 2.0 in the basal samples of plasma from the other sinus. The diagnostic sensitivity of a single, randomly chosen IPS:P ratio was only 80 percent, indicating the importance of bilateral sampling.
Lateralization of the Microadenoma in Cushing's Disease
Of the 113 patients with a microadenoma confirmed on surgery, 104 (92 percent) had an adrenocorticotropin gradient of ≥1.4 between the petrosal sinuses during basal sampling (Table 4Table 4
Adrenocorticotropin Gradient between the Inferior Petrosal Sinuses, in Relation to Lateralization of Microadenomas at Surgery in 113 Patients with Cushing's Disease.). Among these 104 patients, 71 had a maximal gradient that was toward the side of a lateral microadenoma (positive predictive value, 68 percent). The positive predictive value of a gradient of ≥1.4 increased significantly if the adrenocorticotropin level in one sinus was relatively low. Thus, the location of an adenoma was correctly predicted in 42 of 50 patients in whom basal adrenocorticotropin levels in plasma from one sinus were no more than triple the corresponding peripheral-blood levels (positive predictive value, 84 percent; 95 percent confidence interval, 79 to 89 percent; P<0.04 for the comparison with all patients with a microadenoma).Sampling after CRH Stimulation
Two hundred sixty-two patients — 231 with a confirmed diagnosis and 31 in whom the diagnosis remained unconfirmed —received CRH after basal sampling: 203 patients had Cushing's disease, 17 had ectopic adrenocorticotropin secretion, and 11 had primary adrenal disease (Table 1).
Sinus Plasma Levels
Peak adrenocorticotropin concentrations in petrosal sinus plasma ranged from 24 to 12,639 pmol per liter in the patients with Cushing's disease and from 4 to 346 pmol per liter in the patients with ectopic adrenocorticotropin syndrome who received CRH. The maximal adrenocorticotropin levels after CRH stimulation were ≤3 pmol per liter in 10 of the patients with primary adrenal disease and 11 pmol per liter in the 11th patient.
Response to CRH
In the patients with Cushing's disease, sinus plasma adrenocorticotropin levels increased in response to CRH (from a mean [±SE] maximal basal level of 157±13 pmol per liter to 1337±136 pmol per liter after the administration of CRH); the mean difference between the maximal concentration after CRH administration and the maximal basal concentration was 1180±131 pmol per liter (range, —156 to 11,067; P<0.0001 by paired t-test). After CRH administration, the adrenocorticotropin concentration in the sinus plasma samples increased by more than 29 pmol per liter above the maximal basal level in 191 of the 203 patients with Cushing's disease (94 percent); 193 patients (95 percent) had an increase of more than 50 percent above the maximal basal level.
Peak sinus adrenocorticotropin levels also increased after CRH administration in the 17 patients with ectopic adrenocorticotropin secretion (from a maximal basal level of 49± 18 pmol per liter to 55± 19 pmol per liter after CRH; mean difference, 6 pmol per liter; range, —13 to 29; P = 0.03), although there was no significant change in peripheral-blood adrenocorticotropin concentrations during the same interval (from a maximal basal level of 42±16 pmol per liter to 44±15 pmol per liter after CRH). After the administration of CRH, the maximal increase in the sinus plasma adrenocorticotropin level was ≤29 pmol per liter in all 17 patients, and the increase was less than 50 percent above the maximal basal level in 16. One patient with an adrenocorticotropin-secreting bronchial carcinoid had an increase of 23 pmol per liter in the sinus adrenocorticotropin concentration, an increase of 522 percent after CRH administration; however, the response of adrenocorticotropin to CRH originated from the adrenocorticotropin-producing lung tumor, since the peripheral-blood adrenocorticotropin levels increased concurrently and equally, and the adrenocorticotropin IPS:P ratios remained the same as in the basal samples — i.e., ≤1.5. Four of the other 16 patients with ectopic adrenocorticotropin syndrome had an increase of at least 9 pmol per liter in sinus plasma adrenocorticotropin levels after the administration of CRH.
Ten of the 11 patients with primary adrenal disease had no change in the petrosal sinus adrenocorticotropin levels after CRH administration; in the 11th patient, CRH stimulated the sinus plasma concentration to increase to 11 pmol per liter, although peripheral-blood adrenocorticotropin levels were still undetectable. There was no significant difference between the maximal sinus plasma adrenocorticotropin concentration before and after CRH administration in these patients (maximal basal level vs. peak level after stimulation, 1±1 vs. 2± 1 pmol per liter; mean difference, 1±1 pmol per liter; P = 0.26).
Peak IPS:P Ratio
All 203 patients with Cushing's disease who received CRH had a peak adrenocorticotropin IPS:P ratio of ≥3.0 (diagnostic sensitivity, 100 percent) (Fig. 1 and Table 3). The maximal IPS:P ratio after CRH stimulation was significantly higher than the basal value (mean [±SE] maximal basal ratio vs. post-stimulation ratio, 16.5±1.1 vs. 86.5±7.7; P<0.0001 by paired t-test).
The 17 patients with ectopic adrenocorticotropin syndrome who received CRH had a maximal IPS:P ratio of less than 3.0 (Fig. 1 and Table 3). There was no change in the maximal IPS:P ratio after CRH administration in the patients with ectopic adrenocorticotropin secretion (maximum basal ratio vs. post-stimulation ratio, 1.4−0.1 vs. 1.5±0.1; P = 0.2).
Five of the 11 patients with primary adrenal disease had peripheral-blood plasma adrenocorticotropin levels below the limit of detection of the assay for adrenocorticotropin on all determinations after the administration of CRH; therefore, the adrenocorticotropin IPS:P ratio was not useful. The other six of these patients had peak ratios that did not change after the administration of CRH (mean maximal basal ratio vs. post-stimulation ratio, 1.1±0.1 vs. 1.3±0.1) and that remained below 3.0 (Fig. 1). Thus, the diagnostic sensitivity, specificity, and accuracy (the percentage of patients studied in whom the test gave correct results) of an adrenocorticotropin IPS:P ratio of ≥3.0 were 100 percent in the 231 patients given CRH.
The maximal adrenocorticotropin IPS:P ratio occurred two to three minutes or five minutes after CRH administration in 180 of the 203 patients with Cushing's disease (89 percent). The samples taken two to three minutes after administration were more reliable than the basal samples or the samples obtained at later times, and they distinguished Cushing's disease from ectopic adrenocorticotropin syndrome in all but one patient (Table 3). However, measurement of adrenocorticotropin in the basal samples and those obtained two to three minutes and five minutes after CRH stimulation was required to obtain a diagnostic accuracy of 100 percent.
In the patients with Cushing's disease but not those with ectopic adrenocorticotropin secretion, there was a significant correlation between the peak adrenocorticotropin concentration in the sinus plasma and the maximal adrenocorticotropin IPS:P ratio during sampling (rs = 0.69, P = 0.0001) (Fig. 2). All 187 patients with Cushing's disease who had sinus plasma levels above 97 pmol per liter, whether before or after CRH administration, had peak IPS:P ratios of ≥7.4.
When the IPS:P ratio was calculated with the value from the sinus with the lower adrenocorticotropin concentration, 58 of the 203 patients with Cushing's disease (29 percent) who received CRH had a ratio below 3.0 for the side on which the adrenocorticotropin concentration was lower (sensitivity when a post-stimulation ratio for a single side was randomly selected, 86 percent).
The basal plasma cortisol levels recorded at the time of petrosal sinus sampling did not correlate with any of the measures of adrenocorticotropin secretion during sampling, including the maximal basal or post-stimulation adrenocorticotropin levels in sinus plasma or the adrenocorticotropin IPS:P ratios (data not shown).
Lateralization of the Microadenoma in Cushing's Disease
Of the 107 patients who received CRH, 105 had an adrenocorticotropin gradient of ≥1.4 (Table 4). In 75 of these 105 patients the maximal gradient was toward the side with a lateral microadenoma (positive predictive value, 71 percent; 95 percent confidence interval, 63 to 80 percent). Furthermore, the gradient was toward a lateral adenoma in 40 of the 48 patients who had limited drainage of adrenocorticotropin into one sinus — i.e., the basal adrenocorticotropin level in one sinus was no more than triple the concurrent level in peripheral blood (positive predictive value, 83 percent; 95 percent confidence interval, 73 to 94 percent). The positive predictive value of the test for lateralization of a microadenoma was not improved by sampling after CRH stimulation as compared with basal sampling in all patients with a microadenoma (post-stimulation vs. basal, P = 0.7) or in patients with limited drainage of adrenocorticotropin levels in one sinus (post-stimulation vs. basal, P = 0.9).
Dexamethasone Suppression Test
One hundred thirty-seven of the 169 patients with Cushing's disease and 3 of the 14 patients with ectopic adrenocorticotropin secretion who underwent the standard dexamethasone suppression test had a positive response (>50 percent suppression) to the high dose of dexamethasone. Thus, 19 percent of the patients with Cushing's disease had no response, and 21 percent of the patients with ectopic adrenocorticotropin secretion did respond (three of nine patients with bronchial carcinoid tumors). The diagnostic sensitivity, specificity, and accuracy of this test in distinguishing Cushing's disease from ectopic adrenocorticotropin secretion were 81 percent, 79 percent, and 81 percent, respectively.
Discussion
Although there have been concerns about the feasibility of catheterizing both inferior petrosal sinuses consistently and safely, we successfully performed the procedure in 281 of the 284 consecutive patients (99 percent) without major complications. Patients with Cushing's disease were distinguished from patients with ectopic adrenocorticotropin secretion by basal sampling of plasma from the sinuses, with a diagnostic accuracy of 96 percent. All the patients with Cushing's disease were distinguished from the patients with ectopic adrenocorticotropin secretion by the results of basal sampling and sampling two to three minutes and five minutes after CRH infusion.
The absolute concentrations of adrenocorticotropin in the inferior petrosal sinuses were also helpful in interpreting the IPS:P ratios. In the patients with Cushing's disease, the IPS:P ratio increased as the sinus plasma adrenocorticotropin concentration increased. In contrast, in patients with ectopic adrenocorticotropin syndrome the ratio remained close to 1 regardless of the sinus adrenocorticotropin concentration. Thus, the higher the sinus concentration, the greater the difference between the IPS:P ratios of the patients with Cushing's disease and those of the patients with ectopic adrenocorticotropin syndrome. Hence, even without the administration of CRH, the diagnostic accuracy of inferior petrosal sinus sampling was 100 percent when the basal adrenocorticotropin level was above 28 pmol per liter.
Although simultaneous bilateral sampling after CRH stimulation had a diagnostic accuracy of 100 percent in the 246 patients with an established diagnosis, 32 patients do not have a confirmed diagnosis at this writing. Establishing the diagnoses of these patients could influence the final calculations of the efficacy of the test if the diagnoses prove to be other than those suggested by pituitary venous sampling. To examine the potential influence of these patients with unconfirmed diagnoses, we included them in a recalculation of the results. The three patients shown to have pituitary macroadenomas on magnetic resonance imaging were considered to have Cushing's disease. Diagnoses were assigned to the remaining 29 patients on the basis of dexamethasone and peripheral-blood CRH tests. Patients in whom either test suggested the ectopic adrenocorticotropin syndrome were assumed to have this diagnosis. Under these assumptions, sampling of the inferior petrosal sinuses predicted the assigned diagnosis in 24 patients and the opposite diagnosis in 8 patients. According to this theoretical analysis, sinus sampling had a diagnostic accuracy of 97 percent in distinguishing Cushing's disease from ectopic adrenocorticotropin secretion. Since the inferential assignment of a diagnosis was based on tests that do not always predict the correct diagnosis, the diagnosis predicted by sinus sampling may prove correct in some or all of the patients who appear to be misclassified on the basis of such assignment.
In addition to its diagnostic efficacy, bilateral sampling of the inferior petrosal sinuses permitted prediction of the location of a microadenoma with an accuracy of about 70 percent. When the adrenocorticotropin level in one sinus was relatively low, the accuracy of lateralization increased to more than 80 percent. Therefore, although the presence of an adrenocorticotropin gradient between the sinuses permits the surgeon to direct the initial search to one side of the pituitary, the entire gland must be examined in patients in whom no adenoma is evident, since the accuracy of localization within the gland by sinus plasma sampling is well below 100 percent.
How should petrosal sinus sampling be used in the differential diagnosis of Cushing's syndrome? In patients in whom radiographic images of the adrenals combined with low values for peripheral-blood plasma adrenocorticotropin indicate the presence of adrenal tumors or primary nodular adrenal disease, sampling is unnecessary.12 , 17 18 19 20 21 22 However, there may be no radiographic evidence of a pituitary tumor in patients with Cushing's disease or of a tumor anywhere in patients with ectopic adrenocorticotropin secretion.3 , 11 , 16 , 17 , 21 22 23 24 25 26 27 28 Even a pituitary microadenoma visualized by CT or magnetic resonance imaging may not be the source of the abnormal adrenocorticotropin secretion, since 12 to 27 percent of the general population have incidental pituitary adenomas.29 30 31 32 Thus, imaging studies alone cannot reliably provide a definitive diagnosis.
The low-dose-high-dose dexamethasone suppression test has been the most widely used method of distinguishing ectopic adrenocorticotropin secretion from Cushing's disease since its introduction in the early 1960s, and it is the standard by which other tests are measured.15 , 22 Recently, we and others introduced the CRH stimulation test12 , 33 34 35 36 37 38 for the same purpose. However, neither test consistently distinguishes Cushing's disease from the ectopic adrenocorticotropin syndrome. A high dose of dexamethasone fails to suppress urinary 17-hydroxycorticosteroid secretion by 50 percent in about 20 percent of patients with Cushing's disease,16 , 17 , 21 , 22 , 38 whereas it does suppress excretion in nearly half of patients with adrenocorticotropin-producing bronchial carcinoid tumors.16 , 17 , 22 , 39 , 40 Among our patients who had the dexamethasone suppression test, 32 of 169 patients with Cushing's disease (19 percent) had no suppression, whereas 3 of 14 patients with ectopic adrenocorticotropin secretion (21 percent) did have suppression, and all of them had carcinoid tumors. Diagnostic errors due to the CRH stimulation test occur with a frequency of 10 to 15 percent.14 , 16 , 33 34 35 36 37 38 , 41 42 43 44 Most errors are false negative results in patients with Cushing's disease who have no increase in plasma adrenocorticotropin or cortisol after CRH administration. A more sensitive method of detecting an adrenocorticotropin response from the pituitary tumor, such as sampling directly from the venous drainage of the adenoma (the inferior petrosal sinuses), should reduce the number of false negative results. In addition, in the rare patient with an ectopic adrenocorticotropin-secreting tumor who responds to CRH with an increase in the adrenocorticotropin level in peripheral-blood plasma, petrosal sinus sampling during the CRH test should discriminate between the response by the pituitary and the response reflected in the peripheral circulation. Although the administration of CRH stimulated a small increment in petrosal sinus adrenocorticotropin levels in some patients with ectopic adrenocorticotropin syndrome and sustained hypercortisolism, the adrenocorticotropin IPS:P ratios were not altered appreciably (maximal basal ratio of 1.4±0.1, as compared with 1.5±0.1 after CRH stimulation), and adrenocorticotropin gradients remained below 3.0 in all the patients with ectopic adrenocorticotropin syndrome.
Because of the safety and consistency of simultaneous bilateral sampling of the inferior petrosal veins and its high diagnostic accuracy, we now use it to evaluate all patients with Cushing's syndrome who do not have an obvious adrenal tumor on CT or magnetic resonance imaging. Other physicians may consider the procedure unnecessary when the results of the dexamethasone suppression test or the CRH stimulation test are consistent with radiographic studies that demonstrate a pituitary or an ectopic tumor. Since the combined results of the dexamethasone and CRH tests provide high diagnostic sensitivity and accuracy,16 others may reserve petrosal sinus sampling for patients whose combined results are ambiguous.
Previously, petrosal sinus sampling was performed unilaterally, and without CRH, to establish the differential diagnosis in patients with Cushing's syndrome.45 46 47 48 49 However, among our patients with Cushing's disease, the IPS:P ratio for adrenocorticotropin in one petrosal sinus was nondiagnostic in 41 percent during basal sampling and in 29 percent during sampling after CRH stimulation. The accuracy of sinus plasma sampling is highest when both sinuses are sampled before and immediately after CRH administration.
Correct interpretation of the results of petrosal sinus sampling requires that the patient be in a hyper-cortisolemic state. Suppression of pituitary secretion of adrenocorticotropin by sustained hypercortisolism accounts for the absence of a central-to-peripheral adrenocorticotropin gradient in ectopic adrenocorticotropin syndrome and primary adrenal disease. Thus, therapy to return cortisol production to normal or the presence of intermittent Cushing's syndrome, ectopic CRH secretion,8 or pseudo—Cushing's syndrome (hypercortisolism of depression or alcoholism) may produce a central-to-peripheral gradient during petrosal sinus sampling that could be misinterpreted as indicating a pituitary adenoma. Although sinus sampling is highly effective in distinguishing patients with Cushing's disease from patients with ectopic adrenocorticotropin syndrome when they have hypercortisolemia, sampling cannot be relied on in patients without Cushing's syndrome or in patients in whom normal corticotrophs are active, such as those with ectopic CRH syndrome or those with normal cortisol secretion after medical or surgical treatment of hypercortisolemia.
We are indebted to the medical staff fellows of the Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, and the Developmental Endocrinology Branch, National Institute of Child Health and Human Development, and the nursing staffs of the National Institute of Neurological Disorders and Stroke, the National Institute of Child Health and Human Development, and the Diagnostic Radiology Department of the Clinical Center, National Institutes of Health, who provided care for the patients; and to Hetty DeVroom, R.N., Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, for her many contributions.
Source Information
From the Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke (E.H.O.); the Diagnostic Radiology Department, the Clinical Center (J.L.D., D.L.M.); the Developmental Endocrinology Branch, National Institute of Child Health and Human Development (L.K.N., G.P.C., G.B.C., D.L.L.); and the National Institute of Neurological Disorders and Stroke and the National Cancer Institute (D.A.K.); all from the National Institutes of Health, Bethesda, Md. Address reprint requests to Dr. Oldfield at Bldg. 10, Rm. 5D37, National Institutes of Health, Bethesda, MD 20892.
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- Citing Articles (152)
Citing Articles
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Jung Soo Lim, Seung Ku Lee, Se Hoon Kim, Eun Jig Lee, Sun Ho Kim. (2011) Intraoperative multiple-staged resection and tumor tissue identification using frozen sections provide the best result for the accurate localization and complete resection of tumors in Cushing’s disease. Endocrine 40:3, 452-461
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Hidenori Fukuoka, Odelia Cooper, Anat Ben-Shlomo, Adam Mamelak, Song-Guang Ren, Dave Bruyette, Shlomo Melmed. (2011) EGFR as a therapeutic target for human, canine, and mouse ACTH-secreting pituitary adenomas. Journal of Clinical Investigation
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Philip W. Smith, John B. Hanks. (2011) Surgical Approaches to Cushing's Disease. Current Problems in Surgery 48:11, 768-830
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Shozo Yamada, Noriaki Fukuhara, Hiroshi Nishioka, Akira Takeshita, Naoko Inoshita, Junko Ito, Yasuhiro Takeuchi. (2011) Surgical Management and Outcomes in Patients with Cushing Disease with Negative Pituitary Magnetic Resonance Imaging. World Neurosurgery
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Shamim Ejaz, Rena Vassilopoulou-Sellin, Naifa L. Busaidy, Mimi I. Hu, Steven G. Waguespack, Camilo Jimenez, Anita K. Ying, Maria Cabanillas, Maher Abbara, Mouhammed Amir Habra. (2011) Cushing syndrome secondary to ectopic adrenocorticotropic hormone secretion. Cancer 117:19, 4381-4389
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Russell R. Lonser, Alexander Ksendzovsky, Joshua J. Wind, Alexander O. Vortmeyer, Edward H. Oldfield. (2011) Prospective evaluation of the characteristics and incidence of adenoma-associated dural invasion in Cushing disease. Journal of Neurosurgery1-8
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Agostino Paoletta, Giorgio Arnaldi, Roberta Papa, Marco Boscaro, Giacomo Tirabassi. (2011) Intrapituitary cytokines in Cushing’s disease: do they play a role?. Pituitary 14:3, 236-241
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Edward H Oldfield. (2011) Surgical Management of Cushingʼs Disease: A Personal Perspective. Neurosurgery 69, 13-26
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Mitsuteru Koizumi, Takeshi Usui, Shozo Yamada, Ichiro Fujisawa, Tsunehisa Tsuru, Kazutaka Nanba, Hanae Hagiwara, Takashi Kimura, Tamiko Tamanaha, Tetsuya Tagami, Mitsuhide Naruse, Akira Shimatsu. (2011) Successful treatment of Cushing’s disease caused by ectopic intracavernous microadenoma. Pituitary 14:3, 295-298
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William F. Simonds, Sarah Varghese, Stephen J. Marx, Lynnette K. Nieman. (2011) Cushing’s Syndrome in Multiple Endocrine Neoplasia Type 1. Clinical Endocrinologyno-no
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Lukas Andereggen, Gerhard Schroth, Jan Gralla, Rolf Seiler, Luigi Mariani, Jürgen Beck, Hans-Rudolf Widmer, Robert H. Andres, Emanuel Christ, Christoph Ozdoba. (2011) Selective inferior petrosal sinus sampling without venous outflow diversion in the detection of a pituitary adenoma in Cushing’s syndrome. Neuroradiology
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Chirag Patel, Matthew Matson. (2011) The role of interventional venous sampling in localising neuroendocrine tumours. Current Opinion in Endocrinology, Diabetes and Obesity 18:4, 269-277
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Francesca Pecori Giraldi, Luca Pagliardini, Maria Francesca Cassarino, Marco Losa, Giovanni Lasio, Francesco Cavagnini. (2011) Responses to Crh and Dexamethasone in a Large Series of Human Acth-Secreting Pituitary Adenomas in Vitro Reveal Manifold Corticotroph Tumoural Phenotypes. Journal of Neuroendocrinologyno-no
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Sai-Ching J Yeung, Mouhammed A Habra, Sonali N Thosani. (2011) Lung cancer-induced paraneoplastic syndromes. Current Opinion in Pulmonary Medicine 17:4, 260-268
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Ivan Ciric, Jin-Cheng Zhao, Hongyan Du, James W Findling, Mark E Molitch, Roy E Weiss, Samuel Refetoff, William D Kerr, Joel Meyer. (2011) Transsphenoidal Surgery for Cushingʼs Disease: Experience with 136 Patients. Neurosurgery1
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Nicholas A. Tritos, Beverly M. K. Biller, Brooke Swearingen. (2011) Management of Cushing disease. Nature Reviews Endocrinology 7:5, 279-289
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Nalini S. Shah, Joe George, Shrikrishna V. Acharya, Anurag R. Lila, Vijaya Sarathi, Tushar R. Bandgar, Rakesh Jalali, Atul H. Goel, Padmavathy Menon. (2011) Cushing Disease in Children and Adolescents: Twenty Years' Experience in a Tertiary Care Center in India. Endocrine Practice 17:3, 369-376
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Koshi Hashimoto, Shunichi Matsumoto, Emi Ishida, Atsuko Miura, Kazuhiko Horiguchi, Atsushi Ozawa, Nobuyuki Shibusawa, Teturou Satoh, Masanobu Yamada, Shozo Yamada, Masatomo Mori. (2011) Liver X receptor-α/β expression ratio is increased in ACTH-secreting pituitary adenomas. Neuroscience Letters 494:1, 34-37
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Guy B. Mulligan, Esin Eray, Charles Faiman, Manjula Gupta, Maria M. Pineyro, Antoine Makdissi, John H. Suh, Thomas J. Masaryk, Richard Prayson, Robert J. Weil, Amir H. Hamrahian. (2011) Reduction of False-Negative Results in Inferior Petrosal Sinus Sampling with Simultaneous Prolactin and Corticotropin Measurement. Endocrine Practice 17:1, 33-40
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Xavier Bertagna, Laurence Guignat, Marie-Charles Raux-Demay, Brigitte Guilhaume, François Girard. 2011. Cushing's disease. , 533-617.
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Serhat Aytug, Edward R. Laws, Mary Lee Vance. (2011) The Utility of the High Dose Dexamethasone Suppression Test in Confirming the Diagnosis of Cushing's Disease. Endocrine Practice 1:-1, 1-18
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Krystallenia I. Alexandraki, Ashley B. Grossman. (2010) The ectopic ACTH syndrome. Reviews in Endocrine and Metabolic Disorders 11:2, 117-126
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Ali S. Alzahrani, Rafif Farhat, Abdullah Al-Arifi, Nora Al-Kahtani, Imad Kanaan, Mohei Abouzied. (2009) The diagnostic value of fused positron emission tomography/computed tomography in the localization of adrenocorticotropin-secreting pituitary adenoma in Cushing’s disease. Pituitary 12:4, 309-314
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Xavier Bertagna, Laurence Guignat, Lionel Groussin, Jérôme Bertherat. (2009) Cushing's disease. Best Practice & Research Clinical Endocrinology & Metabolism 23:5, 607-623
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Martin H. Weiss. (2009) Editorial. Journal of Neurosurgery 111:3, 527-528
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Nestor D. Tomycz, Michael B. Horowitz. (2009) Inferior Petrosal Sinus Sampling in the Diagnosis of Sellar Neuropathology. Neurosurgery Clinics of North America 20:3, 361-367
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2009. Adrenal Gland. , 277-316.
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M. A. E. M. Wagenmakers, R. T. Netea-Maier, E. J. van Lindert, H. J. L. M. Timmers, J. A. Grotenhuis, A. R. M. M. Hermus. (2009) Repeated transsphenoidal pituitary surgery (TS) via the endoscopic technique: a good therapeutic option for recurrent or persistent Cushing's disease (CD). Clinical Endocrinology 70:2, 274-280
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Mimi I. Hu, Steven I. Sherman. 2009. Endocrine Complications of Head and Neck Surgery. , 85-103.
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C. Beauvillain de Montreuil, A. Rouger. (2009) S??ndrome paraneopl??sico y otorrinolaringolog??a. EMC - Otorrinolaringolog??a 38:3, 1-9
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Enrico Carmina, Rogerio A. Lobo. 2009. Evaluation of Hormonal Status. , 801-823.
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Alice Y. Chang, Richard J Auchus. 2009. Endocrine Disturbances Affecting Reproduction. , 561-575.
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Ajith J. Thomas, Daniel M. Prevedello, Nestor D. Tomycz, Paul Gardner, Susan Challinor, Arlan Mintz, Michael B. Horowitz, Amin Kassam. (2008) Diagnosis, Perioperative Care, and Remission in Cushing Disease. Neurosurgery Quarterly 18:3, 153-158
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Nurperi Gazioglu, Mustafa Onur Ulu, Fatma Ozlen, Sait Albayram, Civan Islak, Naci Kocer, Buge Oz, Necmettin Tanriover, Demet Ozgil Yetkin, Sadi Gundogdu, Ozer Acbay, Pinar Kadioglu. (2008) Management of Cushing's disease using cavernous sinus sampling: Effectiveness in tumor lateralization. Clinical Neurology and Neurosurgery 110:4, 333-338
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Rosario Pivonello, Maria Cristina De Martino, Monica De Leo, Gaetano Lombardi, Annamaria Colao. (2008) Cushing's Syndrome. Endocrinology & Metabolism Clinics of North America 37:1, 135-149
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Giuseppe Reimondo, Anna Pia, Silvia Bovio, Barbara Allasino, Fulvia Daffara, Piero Paccotti, Giorgio Borretta, Alberto Angeli, Massimo Terzolo. (2008) Laboratory differentiation of Cushing's syndrome. Clinica Chimica Acta 388:1-2, 5-14
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Martin O. Savage, Li F. Chan, Farhad Afshar, P. Nicholas Plowman, Ashley B. Grossman, Helen L. Storr. (2008) Advances in the Management of Paediatric Cushing’s Disease. Hormone Research 69:6, 327-333
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Nelson M. Oyesiku. (2007) Stereotactic radiosurgery for Cushing disease: a review. Neurosurgical FOCUS 23:6, E13
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Martin O. Savage, Helen L. Storr, Li F. Chan, Ashley B. Grossman. (2007) Diagnosis and treatment of pediatric Cushing’s disease. Pituitary 10:4, 365-371
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Klaus von Werder, O. Albrecht Müller. 2007. The Role of Corticotropin-Releasing Factor in the Investigation of Endocrine Diseases. , 317-341.
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Bradley A. Gross, Stefan A. Mindea, Anthony J. Pick, James P. Chandler, H. Hunt Batjer. (2007) Diagnostic approach to Cushing disease. Neurosurgical FOCUS 23:3, 1-7
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James K. Liu, Maria Fleseriu, Johnny B. Delashaw, Ivan S. Ciric, William T. Couldwell, Ph.D.. (2007) Treatment options for Cushing disease after unsuccessful transsphenoidal surgery. Neurosurgical FOCUS 23:3, 1-7
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Shivanand P. Lad, Chirag G. Patil, Edward R. Laws, Laurence Katznelson. (2007) The role of inferior petrosal sinus sampling in the diagnostic localization of Cushing's disease. Neurosurgical FOCUS 23:3, 1-6
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Jeshen H. G. Lau, William Drake, Matthew Matson. (2007) The Current Role of Venous Sampling in the Localization of Endocrine Disease. CardioVascular and Interventional Radiology 30:4, 555-570
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Miklós Tóth, Zsolt Vajda, Zoltán Görömbey, Ferenc Molnár, László Major, Judit Tőke, István Szabolcs, Nikolette Szücs, László Kovács, Róbert Kiss, Sándor Czirják, László Fütő, Edit Gláz, Miklós Góth, Károly Rácz. (2007) Sinus petrosus inferior katéterezés értékelése az adrenokortikotrop hormon dependens Cushing-szindróma elkülönítő diagnosztikájában. Orvosi Hetilap 148:18, 843-847
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Helen L. Storr, Li F. Chan, Ashley B. Grossman, Martin O. Savage. (2007) Paediatric Cushing's syndrome: epidemiology, investigation and therapeutic advances. Trends in Endocrinology & Metabolism 18:4, 167-174
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Nabeel Y. Y. Brahim, Gloria Rambaldini, Shereen Ezzat, Sylvia L. Asa. (2007) Complex Endocrinopathies in MEN-1: Diagnostic Dilemmas in Endocrine Oncology. Endocrine Pathology 18:1, 37-41
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N. Kumar Das, Bernard T. Lyngdoh, B. Kiran Bhakri, Sanjay Behari, Vijaylakshmi Bhatia, Vijendra K. Jain, Deepu Banerji. (2007) Surgical management of pediatric Cushing's disease. Surgical Neurology 67:3, 251-257
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Marcio Carlos Machado, Sandra Valeria de Sa, Sorahia Domenice, Maria Candida B. Villares Fragoso, Paulo Puglia, Maria Adelaide Albergaria Pereira, Berenice Bilharinho de Mendonça, Luiz Roberto Salgado. (2006) The role of desmopressin in bilateral and simultaneous inferior petrosal sinus sampling for differential diagnosis of ACTH-dependent Cushing's syndrome. Clinical Endocrinology 0:0, 061120012318003-???
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Rebecca L Brown, Roy E Weiss. (2006) An approach to the evaluation and treatment of Cushing’s disease. Expert Review of Anticancer Therapy 6:9s, S37-S46
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J. Kumar, M Spring, P. V. Carroll, S. F. Barrington, J. K. Powrie. (2006) 18Flurodeoxyglucose positron emission tomography in the localization of ectopic ACTH-secreting neuroendocrine tumours. Clinical Endocrinology 0:0, 060227032642001
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Lynnette K Nieman. (2006) Difficulty in the diagnosis of Cushing disease. Nature Clinical Practice Endocrinology & Metabolism 2:1, 53-57
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Shabin M. Joshi, Richard Jonathan David Hewitt, Helen L. Storr, Kia Rezajooi, Habib Ellamushi, Ashley B. Grossman, Martin O. Savage, Fary Afshar. (2005) Cushing??s Disease in Children and Adolescents: 20 Years of Experience in a Single Neurosurgical Center. Neurosurgery 57:2, 281-285
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Jay Jagannathan, Aaron S. Dumont, John A. Jane, Edward R. Laws. (2005) Pediatric sellar tumors: diagnostic procedures and management. Neurosurgical FOCUS 18:6, 1-5
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Hau Liu, Lawrence Crapo. (2005) Update on the Diagnosis of Cushing Syndrome. The Endocrinologist 15:3, 165-179
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S GALAC, H KOOISTRA, G VOORHOUT, T VANDENINGH, J MOL, G VANDENBERG, B MEIJ. (2005) Hyperadrenocorticism in a dog due to ectopic secretion of adrenocorticotropic hormone. Domestic Animal Endocrinology 28:3, 338-348
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M. Minetto, G. Reimondo, G. Osella, M. Ventura, A. Angeli, M. Terzolo. (2004) Bone loss is more severe in primary adrenal than in pituitary-dependent Cushing?s syndrome. Osteoporosis International 15:11, 855-861
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Chienying Liu, Joan C. Lo, Christopher F. Dowd, Charles B. Wilson, Sandeep Kunwar, David C. Aron, J. Blake Tyrrell. (2004) Cavernous and inferior petrosal sinus sampling in the evaluation of ACTH-dependent Cushing's syndrome. Clinical Endocrinology 61:4, 478-486
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C. Villabona Artero, M. Sahún de la Vega, D. Pérez Asensio. (2004) Hiperfunción de la corteza suprarrenal: síndrome de Cushing. Medicine - Programa de Formación Médica Continuada Acreditado 9:15, 905-915
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Dana Erickson, John Huston, William F. Young, Paul C. Carpenter, Robert A. Wermers, Frank S. Bonelli, Claudia C. Powell. (2004) Internal jugular vein sampling in adrenocorticotropic hormone-dependent Cushing's syndrome: a comparison with inferior petrosal sinus sampling. Clinical Endocrinology 60:4, 413-419
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Charlotte Höybye, Eva GrenbäcK, Marja Thorén, Anna-Lena Hulting, Lars Lundblad, Hans von Holst, Anders Änggård. (2004) Transsphenoidal surgery in Cushing disease: 10 years of experience in 34 consecutive cases. Journal of Neurosurgery 100:4, 634-638
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Margaret Castro, Lucila L. K. Elias, Paula C. L. Elias, Ayrton C. Moreira. (2003) A dose-response study of salivary cortisol after dexamethasone suppression test in Cushing's disease and its potential use in the differential diagnosis of Cushing's syndrome. Clinical Endocrinology 59:6, 800-805
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Louis J. Kim, Jeffrey D. Klopfenstein, Ming Cheng, Murugasu Nagul, Stephen Coons, Christina Fredenberg, David G. Brachman, William L. White. (2003) Ectopic intracavernous sinus adrenocorticotropic hormone—secreting microadenoma: could this be a common cause of failed transsphenoidal surgery in Cushing disease?. Journal of Neurosurgery 98:6, 1312-1317
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Giuseppe Reimondo, Piero Paccotti, Marco Minetto, Angela Termine, Guido Stura, Mauro Bergui, Alberto Angeli, Massimo Terzolo. (2003) The corticotrophin-releasing hormone test is the most reliable noninvasive method to differentiate pituitary from ectopic ACTH secretion in Cushing's syndrome. Clinical Endocrinology 58:6, 718-724
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Joseph C. T. Chen, Arun P. Amar, SooHo Choi, Peter Singer, William T. Couldwell, Martin H. Weiss. (2003) Transsphenoidal microsurgical treatment of Cushing disease: postoperative assessment of surgical efficacy by application of an overnight low-dose dexamethasone suppression test. Journal of Neurosurgery 98:5, 967-973
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W. J. Inder, E. A. Espiner, M. R. MacFarlane. (2003) Outcome from surgical management of secretory pituitary adenomas in Christchurch, New Zealand. Internal Medicine Journal 33:4, 168-173
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M. Imöhl, A. Stachon, M. Krieg. (2003) Diagnose und Differentialdiagnose des Cushing-Syndroms/Diagnosis and Differential Diagnosis of Cushing’s Syndrome. LaboratoriumsMedizin 27:1-2, 43-52
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Th. Kaltsas, G. E. Krassas, N. Pontikides, E. Tsotsia, S. Tsagarakis. (2003) Cyclical Cushing Syndrome Caused by Intermittent Ectopic ACTH Homogenesis Responsive to Somatostatin Analogues. The Endocrinologist 13:1, 7-11
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Richard J. Auchus. 2003. Cushing's Disease. , 806-808.
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Rob D. Dickerman, Edward H. Oldfield. (2002) Basis of persistent and recurrent Cushing disease: an analysis of findings at repeated pituitary surgery. Journal of Neurosurgery 97:6, 1343-1349
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Ilan Shimon, Zvi Ram, Zvi R. Cohen, Moshe Hadani. (2002) Transsphenoidal Surgery for Cushing???s Disease: Endocrinological Follow-up Monitoring of 82 Patients. Neurosurgery 51:1, 57-62
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Felix Beuschlein, Gary D. Hammer. (2002) Ectopic pro-opiomelanocortin syndrome. Endocrinology & Metabolism Clinics of North America 31:1, 191-234
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Marc de Perrot, Anastase Spiliopoulos, Stefan Fischer, Martin Totsch, Shaf Keshavjee. (2002) Neuroendocrine carcinoma (carcinoid) of the thymus associated with Cushing’s syndrome. The Annals of Thoracic Surgery 73:2, 675-681
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L. B. Yap, H. E. Turner, C. B. T. Adams, J. A. H. Wass. (2002) Undetectable postoperative cortisol does not always predict long-term remission in Cushing's disease: a single centre audit*. Clinical Endocrinology 56:1, 25-31
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Catherine Beauregard, Gabriel Dickstein, Andr?? Lacroix. (2002) Classic and Recent Etiologies of Cushing??s Syndrome. Treatments in Endocrinology 1:2, 79-94
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John Newell-Price. (2002) Transsphenoidal surgery for Cushing's disease: defining cure and following outcome*. Clinical Endocrinology 56:1, 19-21
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Christopher R. McCartney, Mary Lee Vance. (2001) Inferior Petrosal Sinus Sampling in the Differential Diagnosis of ACTH-Dependent Cushing’s Syndrome. The Endocrinologist 11:5, 388-398
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Jaroslaw P. Aniszewski, William F. Young, Geoffrey B. Thompson, Clive S. Grant, Jon A. Heerden. (2001) Gushing syndrome doe to ectopic adrenocorticotropic hormone secretion. World Journal of Surgery 25:7, 934-940
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Francesca Pecori Giraldi, Pietro Putignano, Francesco Cavagnini. (2001) Cushing's syndrome. The Lancet 357:9274, 2138
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(2000) Multiple Pituitary Adenomas. Journal of Neurosurgery 93:5,
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Robert C. Smallridge, Leo F. Czervionke, Douglas W. Fellows, VICTOR J. BERNET. (2000) Corticotropin- and Thyrotropin-Secreting Pituitary Microadenomas: Detection by Dynamic Magnetic Resonance Imaging. Mayo Clinic Proceedings 75:5, 521-528
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R C Smallridge, L F Czervionke, D W Fellows, V J Bernet. (2000) Corticotropin- and thyrotropin-secreting pituitary microadenomas: detection by dynamic magnetic resonance imaging.. Mayo Clinic Proceedings 75:5, 521-528
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H. Bethge, W. Arlt, U. Zimmermann, G. Klingelhoffer, G. Wittenberg, W. Saeger, B. Allolio. (1999) Cushing's syndrome due to an ectopic ACTH-secreting pituitary tumour mimicking occult paraneoplastic ectopic ACTH production. Clinical Endocrinology 51:6, 809-814
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Naoko Sanno, Shigeyuki Tahara, Yoichi Yoshida, Hiroyuki Onose, Ichiji Wakabayashi, Akira Teramoto. (1999) Ectopic Corticotroph Adenoma in the Cavernous Sinus: Case Report. Neurosurgery 45:4, 914
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