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Original Studies |
Departments of Endocrinology (G.A.K., M.G.G., J.D.C.N.-P., J.P.M., A.B.G., G.M.B., P.J.T.) and Radiology (J.E.D.), St. Bartholomew’s Hospital EC1A 7BE; and Departments of Radiology (C.T.) and Neurosurgery (F.A.), Royal London Hospital E11BB, London, United Kingdom
Address all correspondence and requests for reprints to: Prof. A. B. Grossman, Department of Endocrinology, St. Bartholomew’s Hospital EC1A 7BE, London, United Kingdom. E-mail: a.b.grossman{at}mds.qmw.ac.uk
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Abstract |
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Since 1985, we have been using this technique in all patients presenting with ACTH-dependent CS. We have previously presented our preliminary experience of performing IPSCS and established our diagnostic criteria in 32 patients (11). We have now applied the same criteria to a further 96 patients, and we include these in our current series of 128 consecutive IPSCS catheterizations. The catheterization success rate, the diagnostic sensitivity and specificity of the procedure in distinguishing CD from oEAS, and its ability to localize the pituitary adenoma in patients with CD, in comparison with radiological and transsphenoidal findings, have been analyzed. Furthermore, 10 patients underwent stimulation with desmopressin, which may have ACTH secretory activity in CD (5, 6), with or without CRH, to assess the ability of this peptide to help distinguish between CD and oEAS and/or to improve the diagnostic sensitivity of CRH in IPSCS.
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Between 1985 and 1997, we attempted bilateral IPSCS in 128 patients with ACTH-dependent CS (106 women; mean ± SE age, 39.8 ± 1.5; range, 12–77 yr). All patients were clinically and biochemically hypercortisolemic at the time of the procedure. The diagnosis of CS was based on clinical findings and the demonstration of persistently and inappropriately elevated circulating cortisol levels. The biochemical investigations included: circadian rhythm studies of circulating cortisol, a low- and high-dose dexamethasone suppression test, CRH stimulation tests, and appropriate imaging (1, 2, 3). The diagnosis of ACTH-dependent CS was based on the presence of detectable ACTH in patients with pathological hypercortisolism, principally a failure to suppress serum cortisol during the low-dose dexamethasone suppression test and an elevated midnight sleeping cortisol (2, 3). One hundred seven patients had CD, proven by the presence of positive immunostaining for ACTH in the pituitary tumor obtained at surgery (92 patients), and/or clinical and biochemical resolution of the hypercortisolism after successful transsphenoidal exploration of the pituitary fossa (15 patients). Six of the 15 patients with biochemical remission and negative histology achieved a substantial reduction of their hypercortisolism, but the postoperative serum cortisol level became undetectable (<50 nmol/L) in only 9 patients; these 9 patients have been followed up for 7 yr (range, 1–9 yr) and remain in remission. Six patients had histologically-confirmed oEAS: 5 had bronchial carcinoid tumors, and 1 had a pancreatic tumor. Histological confirmation was also obtained in a patient with an adrenal adenoma (IPSCS was performed because of a just-measurable peripheral ACTH level), a patient with Nelson’s syndrome, and a patient with a pituitary gangliocytoma. In the remaining 12 of the 128 patients, the source of ACTH secretion remains unknown.
Catheterization protocol
The catheterization protocol has evolved over the 12 yr of the study with two radiologists (J. E. Dacie and C. Thakkar), but the timing of the samples has remained constant. Informed written consent was obtained from all the patients before the procedure. Under local anesthesia, two 7F angiographic sheaths were introduced into the femoral vein by the Seldinger technique, and then two 6F multipurpose-shaped catheters were inserted through these sheaths; one of the sheaths was also used for peripheral vein sampling. Systemic anticoagulation was induced with an iv bolus injection of 3500 IU heparin after vascular access had been obtained. Under fluoroscopic control, the catheters were advanced over a guide wire through the right heart and were manipulated into both low internal jugular veins. Blood was then aspirated over 2 min simultaneously from both catheters and one of the femoral sheaths. The same procedure was repeated after the catheters were advanced into the high internal jugular veins (HIJV). When the sampling at this level was completed, the catheters were advanced further into the IPS. The position of the catheters in the IPS was checked in both posteroanterior and lateral projections, after injecting 1–2 mL of nonionic contrast medium before, and again after, sampling. After optimal catheter placement, blood samples were collected over 2 min before and 3–5, 8–10, and 13–15 min after the bolus administration of 100 µg CRH iv into a vein in the arm. Hemostasis was achieved by manual compression after removal of the sheaths. The duration of the whole procedure was 60–90 min.
The initial 11 patients (1986–1988) underwent IPSCS with ovine-sequence CRH (oCRH; courtesy of Dr. D. H. Coy, New Orleans, LA); thereafter, human-sequence CRH (hCRH; Ferring, Pharmaceuticals Ltd., Malmo, Sweden) has been used. Four patients had stimulation with desmopressin (DDAVP, Ferring, 10 µg iv alone), and another six with both hCRH 100 µg iv and desmopressin (10 µg iv). Samples for ACTH measurement were immediately spun at 4 C; the plasma was separated, flash-frozen, and stored at -20 C until assay. All samples from each procedure were analyzed in the same assay, using an RIA for ACTH. The assay uses an initial extraction procedure, followed by a late addition of tracer RIA. ACTH is extracted from plasma onto powdered glass (Vycor Sociéte-ATA, Geneva, Switzerland), then washed, and eluted into acetone. The acetone extract is evaporated and the residue reconstituted in assay buffer. Assay standards (in triplicate) are also subject to the extraction procedure. Extracted standards, quality controls, and patient samples (at a minimum of four doubling dilutions) are incubated with antiserum for 24 h, then further incubated for 48 or 72 h after the addition of 125I-ACTH. Dextran-coated charcoal suspension is used for the separation of antibody-bound and -free hormone. The radioactive counts recorded in the pellet are inversely proportional to the concentration of ACTH in the tube. Assay reporting range is 10–2000 ng/L, whereas the mean intrassay and interassay coefficients of variation are both less than 10%.
Diagnostic criteria
The ratio of the ACTH values, in the right or left IPS, to the level simultaneously measured from the peripheral vein sample (P), either at baseline or after CRH stimulation, was used as an indicator of the diagnosis of CD (IPS/P ratio): an IPS/P ratio of more than 2, either pre- or post CRH stimulation, was taken as suggestive of CD (8, 9, 10). This critical value for the IPS/P ratio was established after analysis of the first 32 patients (11) and then applied prospectively to subsequent studies. The value of simultaneously obtained IPSCS in determining the site of the pituitary adenoma within the fossa before and after CRH stimulation was assessed and was compared with the findings of pituitary imaging with either CT or magnetic resonance imaging (MRI) scanning. An IPS ACTH gradient (IPSG) more than 1.4, between the ACTH values in the two IPSCS, was taken as indicative of lateralization of the pituitary adenoma (7). The surgeon’s findings at transsphenoidal exploration were taken as the reference for localization. All patients with CD were operated on using the transnasal-transsphenoidal microsurgical approach. Histopathological analysis from patients with surgically-identified adenomas included both histological and immunocytochemical examination.
Radiology
Pituitary imaging with CT scanning was performed from 1985 to 1993 using a GE 9800 Scanner, and from 1993 onwards using a GE High-Speed Advantage Scanner. After injecting 100 mL Omnipaque 300, a 1-mm thick slice and 1-mm increment cuts were taken through the pituitary in the axial plain, with coronal and sagittal reformatting. Pituitary imaging with MRI was performed from 1993 with a GE Sigma Chemical Co. (St. Louis, MO) LST Scanner of 1.5 T. After sagittal localization, coronal scans through the pituitary were taken, followed by dynamic scan postgadolinium injection at 10 and 40 sec, and then 3D volume reconstruction. All scans were reviewed by one radiologist, who had no knowledge of the results of the IPSCS or surgical findings. Seventy-nine patients had pituitary imaging with CT scanning, and 47 with MRI scanning (25 of these latter patients had both imaging modalities).
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Results |
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Simultaneous bilateral IPSCS was obtained in 86 of 128 patients
(an overall catheterization success rate of 67.2%). Simultaneous
bilateral IPS catheterization was obtained in 69 of the 107 patients
(64.5%) with proven CD; in a further 19 patients (17.7%), 1 catheter
was placed in 1 IPS, but the other could not be advanced that far, and
sampling occurred from the contralateral HIJV; in the remaining 19
patients (17.7%), bilateral sampling was obtained from the HIJV alone.
Bilateral successful IPSCS was achieved in all 6 patients with proven
oEAS and in the patients with an adrenal adenoma, a pituitary
gangliocytoma, and Nelson’s syndrome. We divided the success rate into
successive 3-yr periods; as shown in Fig. 1
, the relative success rate for
bilateral IPSCS has gradually improved from 65.2 to 87.5%.
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In the first 11 patients of this series, oCRH was used; all patients had CD. There was no significant difference between the results in these patients and those subsequently given hCRH, and the results using both sequence peptides have therefore been amalgamated.
Differential diagnosis of ACTH-dependent CS
Patients with CD. Basal ACTH values in the IPS were
significantly higher in patients with CD, compared with patients with
oEAS [269 ± 43 (range, 13–1340 ng/L) vs. 75 ±
15 (range, 28–129 ng/L), P < 0.05]. Sixty-nine of
the 107 patients with CD had successful bilateral IPSCS; 50 of these
obtained an IPS/P ratio more than 2 (diagnostic sensitivity of 72.5%).
However, 19 patients with definite CD had a maximal basal IPS/P ratio
less than 2, i.e. within the range found in the patients
with ectopic ACTH production. After CRH stimulation, both peripheral
and central ACTH levels increased in all patients with CD, and 67 of
the 69 patients obtained a maximal IPS/P ratio of more than 2
(diagnostic sensitivity 97%) (Fig. 2).
The individual maximal IPS/P ratio after CRH stimulation was
significantly higher than the basal ratio (maximal basal vs.
post-CRH ratio, 55.8 ± 7.5 vs. 9.5 ± 1.4;
P < 0.05). This was achieved at 5 min in 60 patients,
and at 10 min and 15 min in 6 patients and 1 patient, respectively;
however, all of the 67 patients obtained an IPS/P ratio of more than 2,
at 5 min post-CRH. The 2 patients who had an IPS/P ratio of less than 2
even after CRH administration (false negative results) underwent
transsphenoidal hypophysectomy based on high biochemical and
radiological suspicion. A pituitary adenoma was present in both
patients, and they were both cured after successful surgical
excision.
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Patients with oEAS. ACTH levels in both the IPS and the periphery did not rise after the administration of a stimulus in any patient with oEAS [five patients had stimulation with CRH and one with desmopressin (mean 75 ± 15, range 28–129 ng/L vs. 81 ± 20, range 22–155 ng/L)], but there was significant overlap of individual values with those obtained from patients with CD. The IPS/P ratio from either the dominant (maximal IPS/P ratio) or nondominant IPS site was less than 2 in all patients, both before and after stimulation (before stimulation: 1.3 ± 0.1, range 1.1–1.8 vs. after stimulation: 1.3 ± 0.15, range 0.8–1.8). Thus, the specificity of an IPS/P ratio of more than 2, in distinguishing patients with CD from those with EAS, was 100% (either before or after CRH stimulation).
Lateralization of the pituitary adenoma in patients with CD. The operative findings of the surgeon were used as the reference standard for lateralization of the pituitary tumor. The value of IPSCS in lateralizing tumors within the pituitary was analyzed in 60 patients with CD, i.e. an IPS/P ratio more than 2, who were operated on by a single surgeon (F. Afshar). Analysis of these results indicated that an ACTH gradient of more than 1.4, between the IPS before or after CRH stimulation, correlated best with the lateralization of the adenoma, in keeping with the data of Oldfield et al. (7). Forty-three of the 60 patients obtained a basal IPSG of more than 1.4 pre-CRH administration and in 32 out of 43, a pituitary adenoma was found on surgical exploration on the side indicated by the IPSG (positive predictive value of 74%). In the other 11 patients who obtained an IPSG more than 1.4, lateralization was incorrect in 6; 5 had a midline adenoma, whereas 1 showed pituitary hyperplasia but no true tumor. After CRH stimulation, an IPSG more than 1.4 was obtained in 48 out of 60 patients, the highest positive predictive value being achieved 5 min after CRH stimulation. In 40 of these 48 patients, the surgical findings were consistent with the side indicated by the IPSG (positive predictive value of 83%). In 6 patients with IPSG suggesting lateralization of an adenoma, a microadenoma was found on the contralateral side; whereas in 2, pituitary hyperplasia was shown on histology. Six patients with an IPSG less than 1.4 were all found to have a midline microadenoma.
A lesion was seen in 31 of the 79 patients in whom a pituitary CT scan was performed but was confirmed in only 26 of these at surgery (diagnostic accuracy 33%). Forty-seven patients had an MRI scan performed; a lesion consistent with a tumor was seen in 37 and subsequently confirmed at surgery in 27 (diagnostic accuracy 60%). Twenty-five patients who had MRI imaging also underwent successful IPSCS. Of these, an IPSG more than 1.4 suggested lateralization of an adenoma in 20 patients, which was confirmed at surgery in 18 (diagnostic accuracy 72%), whereas 19 patients had an abnormality consistent with an adenoma seen on MRI, confirmed at surgery in 14 (diagnostic accuracy 56%). Thus, if the IPSG was greater than 1.4, there was correct lateralization in 18 of 20 (90%) of patients; whereas, if the MRI was abnormal, this demonstrated the tumor in 14 of 19 (74%). Imaging with MRI and IPSG agreed on the localization of the pituitary tumor in 9 (50%) of the 18 patients in whom an adenoma was subsequently confirmed at surgery. In patients in whom the 2 procedures showed contradictory results, IPS was correct in 6 when MRI was wrong, whereas MRI was correct in 2 patients where IPSG falsely lateralized a tumor.
Patients who received desmopressin ± CRH. Six patients
had stimulation with the combination of hCRH and desmopressin (10 µg
iv), and four with desmopressin only. The catheterization results,
using the IPS/P ratio of more than 2, were correct in all nine patients
with CD and in the one with oEAS (Table 1). Although desmopressin alone
successfully distinguished patients with CD from those with oEAS, the
combination of CRH and desmopressin achieved greater ACTH IPS values
which were significantly higher than those obtained with CRH alone
(4360 ± 508.5, range 4,001–21,600 ng/L vs. 2847
± 438, range 48–14,400 ng/L, P < 0.05).
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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The usefulness of performing IPSCS to distinguish the rare cases of oEAS from patients with CD has been questioned, especially because IPSCS is an invasive procedure requiring a high technical success rate in catheterizing both IPS (4, 8), and it has been reported (albeit rarely) to be associated with serious adverse effects (16, 17, 18). It has been suggested that it should be reserved for patients with classic clinical and biochemical CD and negative or equivocal MRI findings, and for patients with equivocal suppression and stimulation tests (19). Most patients with CD have microadenomas (14), and a modern MRI scan previously has been reported to have a diagnostic sensitivity of only 70%–80% (4, 10, 20), so some pituitary microadenomas will still be missed (21, 22). Furthermore, 10–20% of endocrinologically normal people have pituitary lesions of no clinical significance on pituitary imaging (8). Thus, the demonstration of a pituitary lesion can be coincidental and occasionally misleading (19). In addition, a significant number of small EAS tumors may elude conventional imaging detection (1). Thus, a considerable number of patients who fall into one of the above groups will need further investigation, such as IPSCS, to establish the correct diagnosis. This is particularly important because pituitary microsurgery can cure 50%, and normalize cortisol levels in a further 30–40%, of patients with CD (14).
Our results support the view that the high technical success rate in
catheterizing both IPS and improved sensitivity of the procedure are
operator dependent, because, in our series, the sensitivity improved
with the increase in the number of the procedures performed (Fig. 1
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Variations in the success rate and morbidity are found mainly in the
series including the smallest number of patients (8), whereas the
highest sensitivity of the procedure was obtained from a center where
additional expertise and skills were obtained after a very large number
of procedures were performed. This latter center performed additional
sampling 3 min after CRH administration (7); however, it is unlikely
that an additional sample at this time would materially alter, to any
extent, the central-to-peripheral ratio. Overall, in our series,
bilateral IPS sampling was successful in 67.2% of the patients, rising
in the most recent 3 yr to 87.5%, and without significant
complications. This reinforces the evidence that, in trained hands,
IPSCS is a safe procedure, that it can be properly performed on most
patients, and that such a level of expertise improves with experience:
thus, IPSCS represents the method with the highest diagnostic
sensitivity in confirming pituitary ACTH hypersecretion. However,
studies of a greater number of patients with oEAS are still needed to
assure the high specificity of the procedure, because patients with
oEAS and false positive results have recently been described (23).
The main reason for using IPSCS to demonstrate a pituitary hypersecretory state, such as CD, is that ACTH is expected to be found at higher levels close to the pituitary than the peripheral veins, where significant admixture has already occurred (10). However, because ACTH secretion may be intermittent (10, 22), there is a risk of sampling in the interval between two secretory phases and thus obtaining a false negative IPS/P ratio (9, 10). CRH stimulation has been successfully used by many authors to increase the diagnostic sensitivity of the IPSCS (9, 22). Our findings fully support the use of CRH stimulation during IPSCS; a diagnostic IPS/P ratio more than 2, at 5 min after CRH administration was obtained, in 67 of the 69 patients with CD, and the diagnostic sensitivity of the procedure increased from 72.5% to 97%. The administration of CRH amplified ACTH differences between the IPS and the periphery in most patients with CD, and the 19 false negative basal results were reduced to just 2. Both these patients were hypercortisolemic at the time of the procedure; had normal petrosal sinus anatomy; and, after pituitary surgery, the hypercortisolism was corrected. The reason for the lack of response to CRH stimulation and the false negative result is still unclear, although it has also been reported by others using oCRH (24). This is in contrast to the 100% sensitivity reported by Oldfield et al. (7). It implies that either the current criteria used to diagnose CD should be altered to increase sensitivity (with the danger of a loss in specificity), or other factors that could increase diagnostic accuracy and overall sensitivity should be employed. Furthermore, we found no difference when using either hCRH or oCRH (25), as might be expected because the principal difference between the two peptide sequences is pharmacokinetic, in that only the human-sequence peptide binds to an endogenous binding-peptide (CRH-BP), which shortens its half-life (26).
We and others have shown that patients with CD have an exaggerated
response to vasopressin analogues, probably because of abnormal
expression of V3 or V2 receptors in the adenomas (27); this property
can be used to amplify the diagnostic sensitivity of CRH stimulation,
in distinguishing patients with CD from those with oEAS (5). In
patients in whom both compounds were used, ACTH responses were
significantly higher than those in whom CRH was used alone;
furthermore, in nine patients with CD, either desmopressin alone or the
combination of CRH and desmopressin obtained IPS/P ratios more than 2,
whereas in a patient with oEAS, the IPS/P ratio was less than 2 (Table 1). It is possible that the combination of CRH and desmopressin may be
necessary to obtain 100% sensitivity in diagnosing CD, because there
have been reports of false negative results with CRH stimulation alone
(21). However, false positive results have been reported in patients
with oEAS using desmopressin (28), and its use on its own cannot be
recommended until data from a larger number of patients with oEAS are
obtained.
Patients with oEAS obtained IPS/P ratios of less than 2, either before or after CRH stimulation (100% specificity in diagnosing CD), indicating that CRH administration is necessary mainly to improve the sensitivity of the procedure for the diagnosis of CD. Furthermore, even in the 19 patients who had only one IPS successfully catheterized, the specificity of an IPS/P ratio of more than 2, in excluding patients with oEAS, was still 100%, either before or after CRH stimulation. It has been suggested that, after CRH, an IPS/P ratio of more than 3 is necessary to achieve 100% sensitivity and specificity (7). None of our 6 patients with definite oEAS has achieved a ratio more than 2; and thus, we consider that an IPS/P ratio more than 2 provides 100% specificity for excluding oEAS, either before or after CRH stimulation (9). Our findings clearly demonstrate that, even when only 1 IPS is successfully catheterized, the IPS/P ratio obtained may still be of diagnostic significance, distinguishing 89.5% of the patients with CD (22).
Most pituitary ACTH-secreting microadenomas are confined to one side of the pituitary gland (14). Previous studies have demonstrated the ipsilateral drainage of left and right pituitary halves into the collateral IPS (29), and thus, IPSG have been applied for the preoperative localization of the pituitary microadenomas in patients with CD (7, 29). Earlier studies have revealed an excellent correlation between the IPSG-predicted localization of a microadenoma and the operative findings, leading several authors to recommend hemihypophysectomy directed at the pituitary half where the ACTH secretion is prominent, when an adenoma is not identified on surgical exploration (29). However, others have failed to reproduce the initial results, and the predictive value of the IPSG in microadenoma localization is reported to be between 47% and 68% (22); the incorrect localization has been attributed to shunting of blood between the IPS (15). The combination of IPSCS and CRH stimulation has not been shown to enhance the sensitivity of the procedure (7, 21, 22), and it has been suggested that MRI imaging is at least as sensitive (21), if not more so (20), in achieving microadenoma lateralization, compared with the IPSG. After assessing a variety of criteria, in our patients the ratio of central-to-peripheral ACTH values more than 1.4, obtained 5 min after CRH administration, correlated best with the intraoperative identification of an adenoma. After CRH stimulation, several misleading basal IPSG lateralizations were corrected, and the overall predictive value was 83%, compared with 72% obtained with MRI scanning. When both of these techniques were applied, 76% of the cases were accurately lateralized, compared with 56% for the MRI scan alone. Furthermore, when the results were contradictory, the MRI was more often erroneous than the IPSG. Pituitary imaging with CT scanning was even less accurate than MRI (4). Thus, the overall sensitivity of IPSG is 78%, with a positive predictive value of 83%. We would suggest that, in cases where the findings of the MRI scan are contradictory or when there is no visible tumor, the surgeon should still perform a hemihypophysectomy on the side indicated by the IPSG if a 5-min post-CRH gradient of more than 1.4 is obtained, accepting that occasional patients may still not be cured. If, however, a reversal of the lateralizating gradient is seen from the pre- to the post-CRH values, the test cannot be relied upon for lateralization (10).
In conclusion, our analysis of 128 consecutive patients with ACTH-dependent CS indicates that IPSCS has a very high sensitivity and specificity in diagnosing pituitary CD. High success rates of bilateral catheterization and minimal complications are obtained only after sufficient experience with the technique has been obtained. The ratio of IPS/P, 5 min after CRH stimulation, has the highest diagnostic sensitivity for CD; sampling after 5 min does not contribute any further diagnostic information. A lateralizing IPSG ratio more than 1.4 has a positive predictive value, of lateralizing a pituitary microadenoma, of 83%. Even when only one IPS is successfully catheterized, there remains a 89.5% sensitivity and 100% specificity in diagnosing pituitary-dependent CD. hCRH is as effective a stimulus as oCRH, whereas the combination of CRH and desmopressin stimulation, as a means of increasing the sensitivity of the test, needs further evaluation.
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Footnotes |
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A. Lienhardt, A. B. Grossman, J. E. Dacie, J. Evanson, A. Huebner, F. Afshar, P. N. Plowman, G. M. Besser, and M. O. Savage Relative Contributions of Inferior Petrosal Sinus Sampling and Pituitary Imaging in the Investigation of Children and Adolescents with ACTH-Dependent Cushing's Syndrome J. Clin. Endocrinol. Metab., December 1, 2001; 86(12): 5711 - 5714. [Abstract] [Full Text] [PDF]
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 M. Boscaro, L. Barzon, and N. Sonino The Diagnosis of Cushing's Syndrome: Atypical Presentations and Laboratory Shortcomings Arch Intern Med, November 13, 2000; 160(20): 3045 - 3053. [Abstract] [Full Text] [PDF]
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P. Putignano, G. A. Kaltsas, M. Korbonits, P. J. Jenkins, J. P. Monson, G. M. Besser, and A. B. Grossman Alterations in Serum Protein Levels in Patients with Cushing's Syndrome before and after Successful Treatment J. Clin. Endocrinol. Metab., September 1, 2000; 85(9): 3309 - 3312. [Abstract] [Full Text]
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G. A. Kaltsas, J. D. C. Newell-Price, P. J. Trainer, G. M. Besser, and A. B. Grossman Complications of Inferior Petrosel Sinus Sampling J. Clin. Endocrinol. Metab., April 1, 2000; 85(4): 1741 - 1741. [Full Text]
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P. U. Freda and S. L. Wardlaw Diagnosis and Treatment of Pituitary Tumors J. Clin. Endocrinol. Metab., November 1, 1999; 84(11): 3859 - 3866. [Full Text]
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V. Lefournier, B. Gatta, M. Martinie, A. Vasdev, A. Tabarin, P. Bessou, J. Berge, I. Bachelot, and O. Chabre One Transient Neurological Complication (Sixth Nerve Palsy) in 166 Consecutive Inferior Petrosal Sinus Samplings for the Etiological Diagnosis of Cushing's Syndrome J. Clin. Endocrinol. Metab., September 1, 1999; 84(9): 3401 - 3402. [Full Text]
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