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The Application of the Combined Corticotropin-Releasing Hormone plus Desmopressin Stimulation during Petrosal Sinus Sampling Is Both Sensitive and Specific in Differentiating Patients with Cushing’s Disease from Patients with the Occult Ectopic Adrenocorticotropin Syndrome

Departments of Endocrinology, Diabetes and Metabolism (S.T., D.V., J.K., E.S., N.T.) and Radiology (I.S.K.), Evangelismos Hospital, 105 052 Athens, Greece

Address all correspondence and requests for reprints to: Dr. S. Tsagarakis, M.D., Ph.D., Department of Endocrinology, Athens Polyclinic Hospital, 105 052 Athens, Greece. E-mail: stsagara{at}otenet.gr.

	Abstract

Top Abstract Introduction Patients and Methods Results Discussion References

 
Context: Although bilateral inferior petrosal sinus sampling (BIPSS) with CRH stimulation is the most accurate procedure for the differential diagnosis of ACTH-dependent Cushing’s syndrome (CS), 4–15% of patients with Cushing’s disease (CD) fail to demonstrate diagnostic gradients. Preliminary data suggest that a more potent stimulation by the combined administration of CRH plus desmopressin during BIPSS may provide some diagnostic advantage. A crucial issue, however, is whether such an amplified stimulation may affect the specificity of the procedure, and this was the main aim of the present study.

Objective: We investigated the diagnostic accuracy of BIPSS performed by CRH plus desmopressin stimulation.

Design and Setting: A retrospective analysis was conducted at a single tertiary care center.

Participants: Fifty-four patients were admitted for the investigation of ACTH-dependent CS. CD was diagnosed in 47 patients; occult ectopic ACTH syndrome (oEAS) was histologically confirmed in seven patients.

Intervention(s): All patients underwent BIPSS with CRH plus desmopressin administration. Additional noninvasive tests included CRH test, high-dose dexamethasone suppression test, desmopressin test, and pituitary magnetic resonance imaging.

Main Outcome Measures: Gradients of inferior petrosal sinus (IPS) to peripheral (IPS/P) ACTH were calculated before and after stimulation with CRH plus desmopressin.

Results: The sensitivity for a basal IPS/P gradient greater than 2 was 61.7%, with 100% specificity and a diagnostic accuracy of 66.7%. After stimulation with CRH plus desmopressin, receiver operating characteristic (ROC) curve analysis showed that a cutoff gradient of more than 2 offers the best test performance. In total, 46 of 47 patients with CD had an IPS/P gradient greater than 2, but none of the patients with oEAS, resulting in a sensitivity of 97.9%. The specificity was 100%, diagnostic accuracy was 98.2%, and the positive and negative predictive values were 100 and 87.5%, respectively. A subgroup of 18 patients (16 with CD and two with oEAS) had contradictory responses to routine tests with CRH and/or high-dose dexamethasone suppression test; sensitivity, specificity, and accuracy of BIPSS in this subgroup were 100%.

Conclusions: The application of a combined stimulation with CRH plus desmopressin during BIPSS is associated with a high sensitivity but no loss of specificity.

	Introduction

Top Abstract Introduction Patients and Methods Results Discussion References

 
BILATERAL INFERIOR PETROSAL sinus sampling (BIPSS) has been validated as a highly accurate investigative tool in the differential diagnosis of ACTH-dependent Cushing’s syndrome (CS) (1, 2, 3, 4). Administration of CRH to induce stimulation of ACTH secretion during BIPSS is being routinely used to elicit diagnostic gradients in patients with Cushing’s disease (CD) and to improve the sensitivity of the procedure. Nevertheless, with the exception of the study of Oldfield et al. (1), which quoted an accuracy approaching 100%, in subsequent series a false-negative rate of 4–15% has been reported (2, 5, 6, 7, 8, 9). This illustrates that in many centers a significant proportion of patients with CD will undergo further unnecessary tests and sustain considerable delay of curative transsphenoidal surgery, based on such false-negative results.

The possible causes for a false-negative result during BIPSS in patients with CD are currently unclear and likely multifactorial. Besides technical factors or anatomical variation (10), insufficient ACTH stimulation by CRH used as the sole stimulus and/or CRH unresponsiveness may well be a reason of a false-negative outcome of BIPSS. It is well established that 10–20% of patients with CD do not demonstrate positive ACTH and cortisol responses in peripheral blood samples during routine CRH testing (7, 11). Some of these patients may fail to demonstrate diagnostic inferior petrosal sinus (IPS) to peripheral (IPS/P) ACTH gradients, as is suggested by the worse sensitivity and diagnostic accuracy of BIPSS in patients with equivocal responses to CRH and/or high-dose dexamethasone suppression test (HDST) (8).

Simultaneous use of CRH and desmopressin has been reported to be a much more potent stimulus for ACTH in patients harboring corticotroph adenomas (12) and, as we have reported (13), this combined stimulation during BIPSS induces a higher ACTH output, which could prove to reduce substantially the rate of false-negative results. One might argue, however, that the more potent stimulus of CRH plus desmopressin could raise the number of false-positive responses in patients with the occult ectopic ACTH syndrome (oEAS), compromising the specificity of the procedure. Therefore, in this report we sought to determine whether the application of the combined stimulation with CRH plus desmopressin affects the specificity of the procedure. To this end, we present our experience using this combined stimulus during BIPSS in a large group of patients with ACTH-dependent CS, including seven consecutive patients with histologically confirmed oEAS.

	Patients and Methods

Top Abstract Introduction Patients and Methods Results Discussion References

 
Catheterization of the petrosal sinuses has been performed in Evangelismos Hospital, since 1991, in 102 patients with various forms of CS. Stimulation with a combination of CRH plus desmopressin was introduced in 1997 and was subsequently used in all our patients with CS undergoing BIPPS. All catheterization studies were performed by a single invasive radiologist (I.S.K.). In 83 of 102 BIPSS attempts, the procedure was technically successful (overall catheterization success rate, 81.3%). The reasons for the unsuccessful procedures were: in 11 procedures, only unilateral catheterization was possible; in four cases, procedural limitations resulted in a bilateral catheterization of the high internal jugular veins; in one procedure, one of the two catheters was placed in the IPS, and the other sampling was received from the corresponding high jugular vein; two procedures were not completed due to anatomical reasons; and one procedure was interrupted because of patient’s noncompliance.

In this series, only patients that have undergone stimulation with a combination of CRH plus desmopressin during successful catheterization were included for analysis. Confirmation of a pituitary or ectopic source of ACTH production was available for 54 patients, 47 with CD and seven with oEAS. The diagnosis of CD was confirmed histologically in 35 patients after transsphenoidal surgery; in 12 cases, no tumor was found but sustained clinical and laboratory remission resulted after transsphenoidal surgery. Among the patients with oEAS, six had histologically confirmed bronchial carcinoids and one medullary thyroid cancer; all these tumors had positive immunostaining for ACTH. In none of these patients was the origin of ACTH hypersecretion evident at presentation, and the possibility of an ectopic source was raised after the hormonal and BIPSS investigations.

The study was approved by the ethical committee of our institution, and informed consent was obtained from all patients.

All patients had routine testing with the CRH (human CRH 100 µg iv bolus; Ferring Pharmaceuticals Ltd., Malmo, Sweden) and all but two patients with the desmopressin test (DDAVP; 10 µg iv bolus, Ferring Pharmaceuticals Ltd.). Our testing protocol was as follows. After an overnight fast, an indwelling catheter was inserted at 0800 h with the subject remaining supine during the whole study period. At 0830 h (0 min), 100 µg CRH or 10 µg desmopressin was given as an iv bolus injection. Blood samples for ACTH and cortisol measurements were obtained at –15, 0, 15, 30, 45, 60, 90, and 120 min. Blood pressure and heart rate were recorded during the study period. After testing with desmopressin, restriction of fluids was advised for the rest of the day. No side effects were reported during the study period or for the rest of the day. All but two patients with CD underwent the HDST (2 mg dexamethasone orally every 6 h for 2 d; blood samples for cortisol determination were obtained at 0800 h on the day before and at 0800 h on the morning after dexamethasone treatment).

A decrease of more than 50% of serum cortisol after the HDST or an increment of cortisol more than 20% and/or ACTH more than 50% over the baseline values after the CRH or the DDAVP test were considered as representing a positive response (11, 14). Pituitary imaging was performed with magnetic resonance imaging (MRI) both before and after the injection of gadolinium.

Catheterization protocol

Bilateral IPS catheter insertion was performed as previously described (1). In each patient the position of the catheters was checked after injecting a small amount of nonionic contrast medium. Correct catheter placement with the tip at the junction of the vertical and horizontal segment of the IPS was confirmed by venous angiography before sampling in all patients included in the present study. After optimal catheter placement, blood samples (6 ml) were collected simultaneously from both catheters and a peripheral vein, over a 2-min period before and at 3–5, 8–10, and 13–15 min after the bolus administration of 100 µg human CRH (Ferring Pharmaceuticals Ltd.) plus 10 µg DDAVP (Ferring). Apart from facial flushing, and ear discomfort reported when the catheter reached the petrosal sinus, no other side effects have been observed during or after the procedure. Samples for ACTH measurements were kept in ice until the completion of the procedure and then were spun at 4 C, and the plasma was separated and stored at –20 C until assay. The highest ratio of ACTH values in IPS samples to the level simultaneously measured from the peripheral vein sample was used as an indicator of the diagnosis of CD. Based on previous reports and our current ROC curve analysis, an IPS/P ratio of more than 2, either before or after stimulation, was taken as suggestive of CD (2, 13, 15, 16, 17).

Hormone assays

Plasma ACTH was measured by a highly specific immunoradiometric assay (Nichols Institute Diagnostics, San Juan Capistrano, CA). Inter- and intraassay coefficients of variation were 8 and 4%, respectively. Serum cortisol was assayed using a direct RIA featuring an iodine-125 radioligand and cortisol antibody-coated tubes (Coat-A-Count, Cortisol RIA; Diagnostic Products, Los Angeles, CA) until 2000, and subsequently by an immunofluorometric assay (Chiron, East Walpole, MA).

Statistics

The results are expressed as mean ± SE. Statistical comparisons of the data between groups were performed with the t test. The level of significance was set at 0.05 in all statistical tests. ROC curves were constructed to examine the diagnostic test performance, that is the ability to discriminate between patients with CD and EAS. Sensitivity against 100% specificity of poststimulation data was plotted at each level, and the area under the curve was computed by the nonparametric Wilcoxon statistic. Area under the curve represents the probability of correctly identifying CD and oEAS patients. Regarding calculation of the diagnostic accuracy of MRI, findings that appeared negative or equivocal were classified as negative.

	Results

Top Abstract Introduction Patients and Methods Results Discussion References

 
The clinical and laboratory characteristics of the patients are shown in Table 1.

View larger version (20K): [in this window] [in a new window]   FIG. 1. ROC curve of the performance of the stimulated IPS/P ratio during BIPSS in the differential diagnosis of CD and oEAS.

View larger version (11K): [in this window] [in a new window]   FIG. 2. Maximum IPS/P ACTH ratios after CRH plus desmopressin stimulation in patients with Cushing’s disease (CD) or occult ectopic ACTH tumors (oEAS). The continuous line crosses the y-axis at an IPS/P ratio of 2; the hatched line crosses the y-axis at an IPS/P ratio of 3. Open circles show patients with equivocal results on routine biochemical testing with CRH and/or HDST.

All our seven patients with oEAS studied after a combined stimulation during BIPSS had a basal and stimulated IPS/P ratio of less than 2. They were all unresponsive to peripheral CRH test, but two had a greater than 50% suppression of cortisol during HDST, and three had a significant response to peripherally administered desmopressin.

Eighteen patients (16 with CD and two with oEAS) had contradictory responses to CRH testing and/or HDST. Among the patients with CD, eight did not show suppression of their cortisol levels during HDST, six were unresponsive to CRH, whereas in two patients both tests were negative. All these patients had a stimulated IPS/P gradient above 2 (mean, 12.7). Moreover two of the eight patients who did not display a positive response to CRH were also unresponsive to desmopressin when administered alone. However, diagnostic stimulated IPS/P gradients were obtained even in these patients. In the two patients with oEAS who had a significant suppression of cortisol during HDST, BIPSS established the correct diagnosis. Thus, the sensitivity, specificity, and accuracy of BIPSS in this subgroup were 100%.

In this series, MRI of the pituitary was positive in only 23 patients with CD, negative in 15, and equivocal in nine. In the patients with oEAS, a lesion suggestive of a microadenoma on MRI scan was observed in three of the six that had undergone pituitary imaging. Thus, the diagnostic accuracy of MRI was only 49%.

	Discussion

Top Abstract Introduction Patients and Methods Results Discussion References

 
In a previous study, we observed significantly higher peak ACTH levels from dominant IPS samples in those patients with Cushing’s disease that received a combined stimulus with CRH plus desmopressin during BIPSS, compared with those who received stimulation with CRH alone (13). As a result, the proportion of patients with false-negative BIPSS was lower in those who received the combined stimulation during the procedure, suggesting that such a combined stimulus may provide some diagnostic advantage over the traditional CRH stimulation. A crucial issue, however, was whether such an amplified stimulation may affect the specificity of the procedure, and this was the main aim of the present study. In our initial report, only one patient with oEAS underwent BIPSS with a combined CRH-desmopressin stimulation (13). In the present study, the amplified stimulation with CRH plus desmopressin was administered to all consecutive histologically confirmed cases with oEAS that were diagnosed in our department. Indeed, none of the seven patients with oEAS tested had a false-positive outcome during BIPSS after stimulation by the combination of CRH plus desmopressin. Therefore, these data demonstrate that the application of an enhanced stimulation by CRH plus desmopressin during BIPSS in a substantial number of the rare oEAS patients does not compromise the specificity of the procedure.

In general, in the era of CRH stimulation alone, false positive results have been rarely reported in patients with oEAS (18). Most of the cases are related to ectopic CRH production by the tumor (19, 20) or to intermittent secretion of ACTH leading to inadequate suppression of pituitary corticotrophs (21). Also, on the basis of the limited existing data, administration of desmopressin alone does not seem to predispose to false-positive results during BIPSS. So far, desmopressin alone has been applied in a few patients with CD (17, 22, 23) and in only eight patients with oEAS (17, 22, 24); all patients with oEAS had an IPS/P ratio of less than 2. The only study that raised some concern on the use of desmopressin was the description of two patients with EAS in whom the sequential administration of desmopressin after CRH stimulation led to IPS/P gradients of more than 2 in both patients (25). However, none of our seven patients with oEAS tested after a combined stimulation, by giving CRH and desmopressin concomitantly and not sequentially, had an IPS/P ratio of more than 2. Interestingly this lack of a greater than 2 IPS/P gradient occurred despite a significant peripheral ACTH rise during the procedure in five of seven patients (data not shown). As previously shown (26), this peripheral ACTH rise originates from the ectopic source and is due to stimulation of the ectopic ACTH-secreting tumor by desmopressin. This explains why in these five patients the stimulated peripheral ACTH rise could not be detected in the form of a positive IPS/P gradient. However, although this may well be the case for an adequately suppressed pituitary, a critical question is whether for an inadequately suppressed pituitary, as this occurs in those cases with periodic ectopic hypercortisolemia, a more potent stimulus may possibly lead to a higher rate of false-positive gradients. It is of note, however, that although intermittent ACTH secretion was documented in three of seven of our patients with oEAS, none of them displayed an IPS/P ratio of more than 2, when these patients were tested during a hypercortisolemic phase. Nevertheless, further study with a much greater number of patients with oEAS is still required to obtain more information with regard to the specificity of such an amplified stimulation during BIPSS and to give definitive recommendations regarding changes in the well-established ratios.

In addition to the high specificity of BIPSS in this series, we managed to obtain a remarkably high sensitivity in correctly diagnosing patients with a pituitary origin of ACTH hypersecretion. Thus, in our series, 46 of 47 patients (97.9%) with CD were correctly identified, leading to one of the lowest false-negative rate results reported so far. In fact with the exception of the very initial reports (1), additional experience with BIPSS revealed a substantial rate of false-negative results leading to varying degrees of incorrect diagnoses (18). This is particularly true in those patients with equivocal biochemical results to the less invasive tests employed in the differential diagnosis of CS. In these patients an inferior diagnostic accuracy of BIPSS has been reported (7, 27). Interestingly, Invitti et al. (8) analyzed a series of such patients and reported a decreased sensitivity for the CRH-stimulated gradient during BIPSS of only 76%. In contrast, in our study the use of the combined stimulation with CRH and desmopressin during BIPSS in a similar subgroup of patients with equivocal results correctly identified all the patients with CD, resulting in a sensitivity, specificity, and diagnostic accuracy of 100%. One may argue that the lower cutoff for the stimulated IPS/P gradients used in this study may of course have contributed to the higher sensitivity observed in this series. In fact by using the more stringent threshold of greater than 3, a lower sensitivity of 91.5 and 81.3% was obtained in the whole and the equivocal groups, respectively. Therefore, based on the fact that only the combination stimulus was used and there is no control with only CRH stimulation during BIPSS, we could not be sure that by using a cutoff ratio of 2 the combined procedure would outperform CRH stimulated BIPSS.

The explanation of how the combined stimulation enhances the sensitivity of the procedure is not straightforward because a number of reasons may account for false-negative results during BIPSS (28). For example, incorrect placement of catheters, anatomical abnormalities, the rare occurrence of a hypoplastic IPS (10), unusual location of the adenoma (29, 30), anomalous venous drainage or dilution of the petrosal venous blood (31, 32) have been reported as possible causes in some of the false-negative cases. It is most unlikely that such settings could be affected by the enhanced ACTH release produced by the combined regime. However, another reason of a false-negative outcome of BIPSS could be the lack of ACTH stimulation due to CRH unresponsiveness, which is encountered in 10–20% of patients with Cushing’s disease (7, 11). Although in many of these patients a significant rise of ACTH during BIPSS with CRH stimulation is still observed, in others the expected rise in ACTH secretion may not be seen resulting in a false-negative BIPSS. Invitti et al. (8) reported that only two of 10 patients with CD who had failed to respond to CRH did not show a significant IPS/P gradient during BIPSS. However, it should be taken into account that in all series reported so far, the addition of CRH stimulation significantly increased the sensitivity of obtaining diagnostic IPS/P gradients. This is due to the fact that ACTH secretion from the neoplastic corticotrophs is rather intermittent and therefore inadequate to provide enough information in an unstimulated state. This suggests that any stimulation offers a diagnostic advantage. Therefore, a more intense stimulation by means of CRH and desmopressin may well be responsible for the observed diagnostic advantage, even in some CRH responder patients.

In conclusion, based on the data presented in this study, we suggest that the application of a combined stimulation with CRH plus desmopressin is associated with a high sensitivity but no loss of specificity. It is predicted that by using a more potent stimulus the number of false-negative patients will substantially decrease and this will lead to avoiding delays of curing these patients by transsphenoidal surgery. Also, the data of this study are encouraging that such an amplified stimulus will not lead to an inappropriate number of false-positive results. Nevertheless, despite the improved diagnostic characteristics of BIPSS by using a more intense stimulation, we still think that clinical judgment should remain the "gold standard" for the safety and benefit of our Cushing’s patients.

	Footnotes

 
Disclosure Statement: The authors have nothing to disclose.

First Published Online March 13, 2007

Abbreviations: BIPSS, bilateral inferior petrosal sinus sampling; CD, Cushing’s disease; CS, Cushing’s syndrome; HDST, high-dose dexamethasone suppression test; IPS/P, inferior petrosal sinus to peripheral; MRI, magnetic resonance imaging; oEAS, occult ectopic ACTH syndrome; ROC, receiver operating characteristic.

Received December 6, 2006.

Accepted March 2, 2007.

	References

Top Abstract Introduction Patients and Methods Results Discussion References

 

1. Oldfield EH, Doppman JL, Nieman LK, Chrousos GP, Miller DL, Katz DA, Cutler Jr GP, Loriaux DL 1991 Petrosal sinus sampling with and without corticotropin-releasing hormone for the differential diagnosis of Cushing’s syndrome. N Engl J Med 325:897–905[Abstract]
2. Newell-Price J, Trainer P, Besser M, Grossman A 1998 The diagnosis and differential diagnosis of Cushing’s syndrome and pseudo-Cushing’s states. Endocr Rev 19:647–672[Abstract/Free Full Text]
3. Kaskarelis IS, Tsatalou EG, Benakis SV, Malagari K, Komninos I, Vasiliadou D, Tsagarakis S, Thalassinos N 2006 Bilateral inferior petrosal sinuses sampling in the routine investigation of Cushing’s syndrome: a comparison with MRI. AJR Am J Roentgenol 187:562–570[Abstract/Free Full Text]
4. Findling JW, Raff H 2006 Cushing’s syndrome: important issues in diagnosis and management. J Clin Endocrinol Metab 91:3746–3753[Abstract/Free Full Text]
5. Lopez J, Barcelo B, Lucas T, Salame F, Alameda C, Boronat M, Salto L, Estrada J 1996 Petrosal sinus sampling for the diagnosis of Cushing’s disease: evidence of false negative results. Clin Endocrinol (Oxf) 45:147–156[CrossRef][Medline]
6. Heppner C, Becker K, Saeger W, Gunther RW, Allolio B, Krone W, Minkelmann W 1997 Occult eutopic Cushing’s syndrome failure of simultaneous bilateral petrosal sinus sampling to diagnose pituitary-dependent Cushing’s syndrome. Eur J Endocrinol 137:74–78[Abstract]
7. Invitti C, Giraldi FP, de Martin M, Cavagnini F 1999 Diagnosis and management of Cushing’s syndrome: results of an Italian multicentre study. Study group of the Italian Society of Endocrinology on the Pathophysiology of the Hypothalamic-Pituitary-Adrenal Axis. J Clin Endocrinol Metab 84:440–448[Abstract/Free Full Text]
8. Invitti C, Giraldi FP, Cavagnini F 1999 Inferior petrosal sinus sampling in patients with Cushing’s syndrome and contradictory responses to dynamic testing. Clin Endocrinol (Oxf) 51:255–261[CrossRef][Medline]
9. Bonelli III JH, Carpenter PC, Erickson D, Young Jr WF, Meyer FB 2000 Adrenocorticotropic hormone–dependent Cushing’s syndrome: sensitivity and specificity of inferior petrosal sinus sampling. Am J Neuroradiol 21:690–696[Abstract/Free Full Text]
10. Doppman JL, Chang R, Oldfield EH, Chrousos G, Stratakis CA, Nieman LK 1999 The hypoplastic inferior petrosal sinus: a potential source of false-negative results in petrosal sampling for Cushing’s disease. J Clin Endocrinol Metab 84:533–540[Abstract/Free Full Text]
11. Trainer PJ, Grossman A 1991 The diagnosis and differential diagnosis of Cushing’s syndrome. Clin Endocrinol (Oxf) 34:317–330[Medline]
12. Newell-Price J, Perry L, Medbak S, Monson J, Savage M, Besser M, Grossman A 1997 A combined test using desmopressin and corticotropin-releasing hormone in the differential diagnosis of Cushing’s syndrome. J Clin Endocrinol Metab 82:176–181[Abstract/Free Full Text]
13. Tsagarakis S, Kaskarelis IS, Kokkoris P, Malagari C, Thalassinos N 2000 The application of a combined stimulation with CRH and desmopressin during bilateral inferior petrosal sinus sampling in patients with Cushing’s syndrome. Clin Endocrinol (Oxf) 52:355–361[CrossRef][Medline]
14. Kaye TB, Crapo L 1990 The Cushing’s syndrome: an update on diagnostic tests. Ann Intern Med 112:432–444
15. Findling JW, Aron DC, Tyrrell JB, Shinsako JH, Fitzerald PA, Norman D, Wilson CB, Forsham PH 1991 Selective venous sampling for ACTH in Cushing’s syndrome: differentiation between Cushing’s disease and the ectopic ACTH syndrome. Ann Intern Med 94:647–652
16. Landolt AM, Schubiger O, Maurer R, Girard J 1994 The value of inferior petrosal sinus sampling in diagnosis and treatment of Cushing’s disease. Clin Endocrinol (Oxf) 40:485–492[Medline]
17. Kaltsas G, Giannulis MG, Newell-Price JDC, Dacie JE, Thakkar C, Afshar F, Monson JP, Grossman AB, Besser GM, Trainer PJ 1999 A critical analysis of the value of simultaneous inferior petrosal sinus sampling in Cushing’s disease and the occult ectopic adrenocorticotropin syndrome. J Clin Endocrinol Metab 84:487–492[Abstract/Free Full Text]
18. Swearingen B, Katznelson L, Miller K, Grinspoon S, Waltman A, Dorer DJ, Klibanski A, Biller BM 2004 Diagnostic errors after inferior petrosal sinus sampling. J Clin Endocrinol Metab 89:3752–3763[Abstract/Free Full Text]
19. O’Brien T, Young Jr WF, Davila DG, Scheithauer BW, Kovacs K, Horvath E, Vale W, van Heerden JA 1992 Cushing’s syndrome associated with ectopic production of corticotrophin-releasing hormone, corticotrophin and vasopressin by a phaeochromocytoma. Clin Endocrinol (Oxf) 37:460–467[Medline]
20. Case records of the Massachusetts General Hospital 1987 Weekly clinicopathological exercises. Case 52: 1987 A 20-year-old woman with Cushing’s disease and a pulmonary nodule. N Engl J Med 317:1648–1658[Medline]
21. Yamamoto Y, Davis DH, Nippoldt TB, Young Jr WF, Huston J, Parisi JE 1995 False-positive inferior petrosal sinus sampling in the diagnosis of Cushing’s disease. Report of two cases. J Neurosurg 83:1087–1091[Medline]
22. Salgado LR, de Mendonca BB, Pereira MAA, Goic MSZ, Semer M, Moreira AC, Knoepfelmacher M, Nery M, Magalhaes ACA, Tovo R, Wajchenberg BL, Liberman B 1997 Use of desmopressin in bilateral and simultaneous inferior petrosal sinus sampling for the differential diagnosis of ACTH-dependent Cushing’s syndrome. Endocrinologist 7:135–140
23. Booth GL, Redelmeier DA, Grosman H, Kovacs K, Smyth HS, Ezzat S 1998 Improved diagnostic accuracy of inferior petrosal sinus sampling over imaging for localizing pituitary pathology in patients with Cushing’s disease. J Clin Endocrinol Metab 83:2291–2295[Abstract/Free Full Text]
24. Salgado LR, Fragoso MC, Knoepfelmacher M, Machado MC, Domenice S, Pereira MA, de Mendonca BB 2006 Ectopic ACTH syndrome: our experience with 25 cases. Eur J Endocrinol 155:725–733[Abstract/Free Full Text]
25. Findling JW, Raff H 1999 Newer diagnostic techniques and problems in Cushing’s disease. Endocrinol Metab Clin North Am 28:191–210[CrossRef][Medline]
26. Tsagarakis S, Tsigos C, Vasiliou V, Tsiotra P, Kaskarelis IS, Sotiropoulou C, Raptis SA, Thalassinos N 2002 The desmopressin and combined CRH-desmopressin tests in the differential diagnosis of ACTH-dependent Cushing’s syndrome: constraints imposed by the expression of V2 vasopressin receptors in tumors with ectopic ACTH secretion. J Clin Endocrinol Metab 87:1646–1653[Abstract/Free Full Text]
27. Jeffcoate W 1997 Probability in practice in the diagnosis of Cushing’s syndrome. Clin Endocrinol (Oxf) 47:271–272[CrossRef][Medline]
28. Pecori GF, Invitti C, Cavagnini F 2001 Inferior petrosal sinus sampling ten years down the road. J Endocrinol Invest 23:325–327
29. Bethge H, Arlt W, Zimmermann U, Klingelhoffer G, Wittenberg G, Saeger W, Allolio B 1999 Cushing’s syndrome due to an ectopic ACTH-secreting pituitary tumour mimicking occult paraneoplastic ectopic ACTH production. Clin Endocrinol (Oxf) 51:809–814[CrossRef][Medline]
30. Al-Gahtany M, Bilbao J, Kovacs K, Horvath E, Smyth HS 2003 Juxtaposition of an ectopic corticotroph adenoma of the sphenoid sinus with orthotopic intrasellar corticotroph hyperplasia in a patient with Cushing disease. Case report. J Neurosurg 98:891–896[Medline]
31. McNally PG, Bolia A, Absalom SR, Falconer-Smith J, Howlett TA 1993 Preliminary observations using endocrine markers of pituitary venous dilution during bilateral simultaneous inferior petrosal sinus catheterization in Cushing’s syndrome: is combined CRF and TRH stimulation of value? Clin Endocrinol (Oxf) 39:681–686[Medline]
32. Findling JW, Kehoe ME, Raff H 2004 Identification of patients with Cushing’s disease with negative pituitary adrenocorticotropin gradients during inferior petrosal sinus sampling: prolactin as an index of pituitary venous effluent. J Clin Endocrinol Metab 89:6005–6009[Abstract/Free Full Text]

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