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Original Studies |
2nd Chair of Endocrinology, University of Milan, Istituto Scientifico Ospedale San Luca, Istituto Auxologico Italiano Istituto di Ricerca e Cura a Carattere Scientifico, 20149 Milan, Italy
Address all correspondence and requests for reprints to: Prof. Francesco Cavagnini, Istituto Scientifico San Luca, Via Spagnoletto 3, 20149 Milano, Italy. E-mail: cavagnini{at}auxologico.it
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Pituitary surgery is the standard treatment for CD, but the success rate and incidence of relapse vary in different centres (1, 2, 3, 4, 5, 6), as a consequence of the different clinical and laboratory criteria adopted to define remission. Further, which parameters predict relapse and what represents the best therapeutic strategy after failure of pituitary surgery are still a matter of debate.
We describe the results of a retrospective multicentre study on the clinical features, diagnostic investigations, and therapeutic procedures carried out in 426 patients with CS. These data enabled us to address the above-mentioned issues and provide useful information on some of the more frequently encountered quandaries. In addition, this study draws a clear picture of the clinical course of this disease in Italy.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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A detailed questionnaire requesting demographic, clinical, biochemical, and radiological data, as well as the chosen therapeutic option(s) and subsequent follow-up of patients with CS, was sent to participating centres. In particular, laboratory evaluation of hypothalamic-pituitary-adrenal function included: the highest and lowest UFC concentrations; morning plasma cortisol levels, cortisol circadian rhythm (i.e. cortisol levels below 208 nmol/L or 7.5 µg/dL at midnight), and suppression below 138 nmol/L (5 µg/dL) after administration of 1 mg dexamethasone at midnight (7), as well as suppression of UFC or urinary 17-hydroxycorticosteroids levels below 55 nmol/24 h (20 µg/24 h) (8) or 7 µmol/24 h (3.5 mg/24 h) (9), respectively, after 2 mg dexamethasone for 2 days. Also requested were morning plasma ACTH levels, together with assay characteristics, and serum concentrations of dehydroepiandrosterone sulphate. For baseline parameters, contributors had to state the normal range adopted by their laboratory. As regards dynamic testing, we requested the percent decrease of UFC or 0800 h plasma cortisol concentrations after the high-dose dexamethasone suppression test, performed with 8 mg daily for 2 days or at midnight, and basal and peak ACTH and cortisol concentrations during stimulation with CRH (sampling at -15, 0, 15, 30, 45, 60, 90, and 120 min). Centres had to specify at what time the CRH test was performed and the dosage and species of CRH used. Pituitary imaging was performed by computed tomography, with coronal slices of 1- or 2-mm thickness, during the rapid injection of iodinated contrast and/or magnetic resonance, with 3-mm contiguous slices on a 0.5 Tesla or 1.5 Tesla scanner using T1-weighted coronal and sagittal images before and after the iv administration of gadolinium (0.1 or 0.2 mmol/kg BW). A pituitary tumor was diagnosed when a focal defect was identified, either isolated or associated with swelling of the sellar diaphragm or deviation of the pituitary stalk. The presence of abnormal tissue around the internal carotid artery was considered indicative of involvement of the cavernous sinus. As regards inferior petrosal sinus sampling, only patients in whom petrosal sinuses had been successfully catheterized and who presented normal anatomy were included; centres were required to state the centre:periphery (C:P) and intersinus ACTH gradient before and after the administration of 100 µg ovine or human CRH (sampling at 0, 2, 5, 10, and 15 min). If pituitary surgery for CD was carried out, centres were asked to describe whether an adenoma was found and, if this was the case, its location, pathology, and immunohistochemistry. Centres were also required to state whether surgery had been successful and on what grounds this was established, together with postsurgical UFC and the ACTH and cortisol responses to CRH testing. Further questions regarded the length of replacement therapy and follow-up and the occurrence of relapse(s). The questionnaire also contained inquiries into any other therapy carried out.
Diagnosis of CD was confirmed by successful pituitary surgery or irradiation. In patients in whom pituitary-directed therapy was unsuccessful (approximately 10%), the diagnosis of CD was based upon the results of dynamic testing (suppression with high doses of dexamethasone, cortisol/ACTH responsiveness to CRH, and/or ACTH C:P gradient >3 after CRH at inferior petrosal sinus sampling). The diagnosis of ectopic ACTH secretion was confirmed by the removal of the tumor in 22 patients, whereas the presence of widespread metastases supported the diagnosis in patients in whom the primary tumor was not identified. Finally, the diagnosis of ACTH-independent nodular hyperplasia was established on the basis of suppressed ACTH levels associated with nodular appearance of the adrenals and, in 3 patients, on pathology of adrenal specimens exhibiting micronodular dysplasia.
Assays and statistical evaluation
Hormones were measured in-house by each centre. Plasma and urinary cortisol and serum dehydroepiandrosterone sulphate were measured by commercially available RIAs. ACTH was measured either by RIA (Byk Gulden, Dietzenbach, Germany; Medgenix, Brussels, Belgium; Sorin, Saluggia, Italy; INCSTAR Corp., Stillwater, MN; intra- and interassay coefficients of variation ranging from 5.5–9.5%, and from 5.8–12.5%, respectively; sensitivity, 8 or 10 pg/mL) or by immunoradiometric assay (IRMA) (mostly by Nichols, San Juan Capistrano, CA; in alternative, CIS-Bio International, Gif-sur-Yvette Cedex, France; intra- and interassay coefficients of variation from 2.1–5.3% and from 3.1–8.9%, respectively; sensitivity, 2 or 5 pg/mL). Urinary 17-hydroxycorticosteroids concentrations were estimated according to the procedure of Porter and Silber (10). Reference ranges for plasma cortisol spanned 5–25 µg/dL (138–690 nmol/L); in contrast, those for ACTH and UFC reported by each centre differed somewhat. Therefore, baseline ACTH and UFC values are expressed as percent of the upper limit of the normal range. In adrenal CS, however, ACTH concentrations are depicted as absolute values, given the frequent observation of measurable levels. Values referred from ACTH RIAs yielding a sensitivity greater than 10 pg/mL were excluded. Responses to dynamic testing are expressed as percent of baseline levels.
Statistical comparisons were carried out using the Mann-Whitney test
for quantitative variables and the 
-square statistic or, when
appropriate, Fisher’s exact test, for qualitative variables.
Kaplan-Meier analysis, followed by the log-rank test, and Cox
proportional’s hazard model were used to evaluate factors influencing
relapse after pituitary surgery. Linear regression analysis was
performed for the assessment of correlations between continuous
variables. Statistical analysis was performed using StatView 4.5
(Abacus Concepts, Berkeley, CA). Sensitivity, specificity, diagnostic
accuracy, and predictive values of tests were calculated according to
standard statistical methods (11). Values are given as mean ±
SEM.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Twenty-six centres from all over Italy participated in the survey
and sent a total of 469 questionnaires spanning the last 20 yr.
Forty-three cases had to be excluded because of the lack of relevant
hormonal and clinical data. Patient distribution and demographic data,
according to the etiological diagnosis of the 426 patients studied, are
given in Table 1
. Compared with other
large series (7, 12, 13), we observed a higher proportion of adrenal
adenomas and a somewhat lower prevalence of patients with ectopic
secretion. Gender distribution differed markedly amongst the different
etiologies, CD occurring 5 times more frequently in women than in men,
and adrenal adenoma presenting a surprisingly high female
preponderance. The incidence of adrenal carcinoma was nearly equal
among sexes, whereas there was a slight male preponderance among
patients with ectopic secretion. The time elapsed between the
appearance of the first symptoms of hypercortisolism and the
recognition of CS seemed shorter in patients with adrenal carcinoma or
ectopic secretion, in whom the highest UFC concentrations were
registered, than in those with CD or adrenal adenoma and was, in fact,
inversely correlated to UFC levels (expressed as percent upper limit:
r = -0.2, P < 0.001). The prevalence of clinical
features of hypercortisolism followed the pattern described by other
large series (data not shown).
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UFC levels were elevated in all 333 patients with CS in whom they
had been measured; however, the lowest UFC values among multiple
collections fell within the normal range in 9%, 15%, and 10% of
patients with CD, adrenal adenoma, or ectopic secretion, respectively
(Fig. 1). Further, in 47% of patients
with CD and 31%, 21%, and 5% of those with adrenal adenoma, ectopic
secretion, or adrenal carcinoma, respectively, the lowest UFC value was
below 690 nmol/24 h (250 µg/24 h). In patients with CS, morning
plasma cortisol levels were often within the normal range (37%; n
= 413) but mostly lacked circadian rhythmicity (90%; n = 389) and
suppressibility after 1 mg dexamethasone overnight (95%; n =
262). Ninety-three percent of patients with CS (n = 178) did not
suppress UFC or 17-hydroxycorticosteroids levels after 2 mg
dexamethasone daily for 2 days.
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ACTH was measured in 394 patients with CS. Fifty-five percent of
patients with CD and 17% of those with ectopic secretion exhibited
normal morning plasma ACTH levels, with values as low as 2 pmol/L (9
pg/mL). ACTH concentrations, measured by RIA and IRMA presented a
similar distribution in patients with CD. In patients with ectopic
secretion, by contrast, the lowest ACTH values were measured by RIA,
and concentrations determined by IRMA mostly exceeded the normal range
(Fig. 2, left panel). ACTH
levels were detectable (i.e. above the sensitivity of the
assay) in 58% and within the normal range in 28% of patients with
ACTH-independent CS (Fig. 2, right panel). IRMA resulted
with higher frequency in subnormal (i.e. assayable ACTH
concentrations below the lower limit of the normal range) ACTH values,
compared with RIA (67% vs. 17%, P = 0.003,
by Fisher’s exact test), although concentrations were well within the
normal range on some occasions.
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, left panel). There seemed
to be no difference between the ACTH responses to CRH measured by RIA
or IRMA [diagnostic accuracy 84% and 80%, respectively;
-square = 0.03, not significant (NS)]. Three patients with an
adrenal tumor presented an apparent increase in ACTH concentrations
which could not be considered a real response because of the very low
baseline levels. Conversely, if baseline ACTH levels were within the
normal range in patients with ACTH-independent CS, ACTH did not respond
to CRH. A 50% increase over baseline seemed to be the best criterion
also for the cortisol response to CRH, because all patients with
ectopic secretion or ACTH-independent CS, except one, were excluded by
this cut-off (Fig. 3, right panel). On the other hand, 41%
of patients with CD were misdiagnosed. With the previously proposed
threshold of a 20% increase in cortisol levels (14), the sensitivity
of the test improved to 78%, but the specificity fell from 92% to
58%. As can be seen in Table 2, the
evaluation of the ACTH rather than the cortisol response yielded a
better diagnostic accuracy.
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), 86%
of patients with CD and 31% of patients with ectopic secretion
suppressed their UFC (2-day test) or plasma cortisol (overnight
administration) levels by more than 50% of baseline. Using the
stricter criterion of suppression by more than 80%, all patients with
ectopic secretion were correctly classified, but this was associated
with a decrease in sensitivity from 85% to 50%. The diagnostic
accuracy was slightly better with the overnight than with the 2-day
dexamethasone test (Table 2
). Patients with ACTH-independent CS failed
to suppress by more than 80% with either test (Fig. 4).
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Imaging studies
Pituitary radiology with enhancement was carried out in 279
patients with CD, and an adenoma was visualized in 61%. When both
magnetic resonance imaging and computed tomography were performed in a
given patient (n = 110), the same evidence was obtained in 93%.
The detection rate of magnetic resonance imaging for small adenomas
(<5 mm) was only slightly superior to that of computed tomography
(53% vs. 41%, -square = 2.2, NS). The adenoma
presented a lateral location in most cases (47% in the right lobe,
35% in the left lobe). The size of the tumor was below 5 mm in 45% of
patients and greater than 10 mm only in a scant 20%. Fifteen percent
of detected adenomas presented suprasellar extension or encroachment of
the cavernous sinus. A small pituitary lesion, most likely an
incidental tumor, was detected also in 3 of 20 patients with ectopic
secretion.
Inferior petrosal sinus sampling
Inferior petrosal sinus sampling was performed in 85 patients with
CD and 10 patients with ectopic secretion (Fig. 5). The basal C:P ACTH gradient was 
2
in 69 patients with CD and in 1 patient with ectopic secretion. Upon
stimulation with CRH, 65 of 76 patients with CD showed a C:P gradient
3. The diagnosis of CD was confirmed by successful pituitary
surgery/irradiation in 7 of 11 patients with a C:P gradient <3
after CRH. The C:P gradient was <3 in all 9 patients with ectopic
secretion submitted to CRH testing. The diagnostic performance of
inferior petrosal sinus sampling is given in Table 2. The concordance
between the location of the adenoma predicted by an intersinus gradient
1.5 and that identified at pituitary radiology or at surgery was 66%
and 68%, respectively.
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Pituitary surgery was the first therapeutic approach in 236
patients with CD. An adenoma was found in 84%, mostly staining
for ACTH (94%). The adenoma was detected more frequently in patients
with positive than in those with negative pituitary imaging (90%
vs. 69%, -square = 15.1, P <
0.01), and its location at surgery agreed with the results of pituitary
imaging in 87%. No adenoma was found in 39 patients.
Remission (i.e. appearance of clinical signs of adrenal
insufficiency associated with low/normal UFC excretion and, when
available, low/normal morning plasma ACTH and cortisol levels) was
achieved in 69% of patients. In particular, 61% and 66% of clinical
remissions were associated with subnormal UFC and plasma cortisol
levels (i.e. below the lower limit of the normal range),
respectively, whereas suppressed plasma ACTH levels were recorded in
half. The remission rate was markedly higher when an adenoma was
removed (75% vs. 36%, -square = 21.7,
P < 0.01). As a whole, the outcome of surgery was not
related to the visualization of an adenoma at pituitary radiology
(remission rate 70% vs. 67% in patients with normal
imaging, -square = 0.1, NS). Sixty-one patients in remission
were submitted to antemeridian CRH testing within 60 days from
pituitary surgery: 37% exhibited a response of both ACTH and cortisol
(i.e. 50% increase in ACTH levels and 20% increase in
cortisol, with peak hormone values within the normal range), 42% a
response of ACTH only, and 2% of cortisol only. The remainder failed
to respond with either hormone. If the hormonal responsiveness to CRH
was analyzed according to postoperative UFC and plasma cortisol levels,
there seemed to be no difference in ACTH responsiveness (84%
vs. 92% responders, NS by Fisher’s exact test for
subnormal and normal UFC, respectively; 83% vs. 84%, NS by
Fisher’s exact test for subnormal and normal plasma cortisol,
respectively). In contrast, we observed a lower frequency of cortisol
responses among patients with subnormal (compared with normal) UFC and
plasma cortisol (40% vs. 77% of responders,
P < 0.05, by Fisher’s exact test for subnormal and
normal UFC, respectively; 26% vs. 89%, P
< 0.01, by Fisher’s exact test for subnormal and normal plasma
cortisol, respectively). Most patients had been treated with adrenal
blocking agents before surgery; nevertheless, an ACTH response to CRH
was registered with comparable frequency among both treated and
untreated patients (75% and 77%, respectively). No correlation was
detected between peak ACTH and cortisol responses to CRH and the days
elapsed from surgery to CRH testing.
Follow-up (6–180 months) was available in 129 patients: the overall
relapse rate was 17% after 6–120 months (mean, 115 ± 9.5
months; median, 27 months). As shown by the Kaplan-Meier curve (Fig. 6), the probability of relapse-free
survival was 95% at 12 months, 84% at 2 yr, and 80% at 3 yr, with
most relapses occurring within 2 yr of surgery. Risk of relapse was not
related to the surgical removal of an adenoma, normal or subnormal
postoperative UFC, and plasma cortisol (NS by log-rank test).
Nevertheless, among the 58 patients in whom follow-up and postsurgical
cortisol levels were available, the relapse rate seemed to be somewhat
higher in patients with normal cortisol levels than in those with
subnormal (50–138 nmol/L; 1.8–5 µg/dL) or undetectable (<50
nmol/L; <1.8 µg/dL) concentrations (15% vs. 6% or 4%,
respectively, NS by Fisher’s exact test). No relapses were recorded in
the 37 patients with an absent response to CRH of both hormones or of
only one hormone, whereas 5 recurrences were observed among the 22
patients in whom both hormones responded to CRH. Proportional hazard
analysis demonstrated that only baseline ACTH levels (ß = 1.076,
confidence interval: 1.01–1.15, P < 0.05) and
cortisol peak values after CRH (ß = 1.096, confidence interval:
1.02–1.18, P < 0.05) were significant positive
covariates towards the risk of relapse. Mean duration of glucocorticoid
replacement therapy, which is indicative of recovery time of the
hypothalamic-pituitary-adrenal axis, was 11 ± 2.1 months.
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-square =
76.1, P < 0.01). External pituitary irradiation was
carried out in 46 patients with CD: resolution of hypercortisolism was
complete in 45% after 1–64 months and partial in 32% after 2–60
months. Bilateral adrenalectomy was performed in 27 patients with CD. Eight of the 23 patients in whom follow-up was known (2–15 yr) developed Nelson’s syndrome over 6–150 months (mean, 60 ± 25.4 months; median, 23 months). Patients who developed the syndrome were slightly younger than those who did not (30 ± 3.7 vs. 40 ± 3.2 yr, NS). Prevalence of Nelson’s syndrome was comparable in patients submitted to adrenalectomy before or after pituitary surgery (30% vs. 39%, NS by Fisher’s exact test).
Medical therapy was carried out in 178 patients with CD before a
surgical procedure, after surgical failure or relapse, and in
association with pituitary irradiation. Ketoconazole, the drug mostly
used, brought about a normalization or a reduction of UFC
concentrations in 43% and 42% of patients, respectively, whereas
other compounds (e.g. bromocriptine, sodium
valproate, cyproheptadine) had only anedoctical therapeutic
efficacy. Medical therapy did not improve the outcome of pituitary
surgery (33% failures in treated vs. 31% in untreated
patients, -square = 0, NS).
The tumor responsible for ectopic secretion was resected in 15 patients. Four of these patients had previously been submitted to pituitary surgery and another three to bilateral adrenalectomy. Eight patients were treated with medical therapy alone, resulting in transient improvement of ACTH secretion in less than half. Two patients were never treated. All together, 9 patients with ectopic secretion died 2–48 months after diagnosis (mean, 13 ± 5.2 months; median, 8 months).
Seventeen patients with adrenal carcinoma underwent radical surgery, followed by medical therapy in 8. Five patients were treated with medical therapy alone, whereas 2 patients were not treated. Survival of patients with adrenal carcinoma was 21%, after a mean follow-up of 19 months (range, 6–60 months; median, 14 months). Surgical treatment of adrenal adenoma was straightforward. All patients with nodular adrenal hyperplasia were submitted to bilateral adrenalectomy.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Plasma ACTH concentrations, the mainstay of the differential diagnosis of CS, were detectable in 58% of patients with ACTH-independent CS and fell within the normal range in 28%. Assays were performed in-house by all participating centres, and ACTH values obtained from assays with a poor sensitivity (mostly RIA) were excluded. Still, we cannot exclude that technical reasons underlie this unexpected finding, which, in fact, has also been occasionally observed by others (17, 18, 19, 20). On the other hand, detectable (though rarely normal) values have been measured also with IRMA using a commercial kit that is widely employed all over the world. Inasmuch, the possibility of an incomplete suppression of pituitary secretion by circulating glucocorticoids in some of these patients cannot be completely excluded. In ACTH-dependent CS, values observed in CD and ectopic secretion overlapped considerably. On the whole, ACTH measured by IRMA followed a more distinct pattern; indeed, normal IRMA ACTH values were rare in both adrenal tumors and ectopic secretion. In patients with CD presenting ACTH concentrations in the bottom half of the normal range, as in subjects with an adrenal mass and normal ACTH values, the results of CRH testing are discriminating.
In our study, the CRH test was performed with 100 µg, and both RIA and IRMA ACTH responses were evaluated. The major surveys on this issue have measured ACTH by RIA and performed the test mostly with 1 µg/kg BW CRH (14, 21). In our series, a 50% increase in ACTH concentrations excluded all patients with ectopic secretion; on the other hand, sensitivity for CD was 85%. The 50% cut-off, previously established for ACTH measured by RIA (14), can therefore be applied also to IRMA measurements. As to the cortisol response, a threshold of 50% resulted in a near-to-absolute specificity, whereas this parameter was far lower with the more commonly used cut-off of 20% (14). No comparison could be carried out with the results obtained by Nieman et al. (21), who used the mean increase at 30 and 45 min after CRH to establish cortisol responsiveness. On the whole, a positive response to the CRH test firmly establishes the diagnosis of CD, whereas an absent response leaves an uncomfortably high margin of doubt. The low negative predictive value also reflects the differing prevalence of the two forms of ACTH-dependent CS. The CRH test was particularly useful for the exclusion of a pituitary adenoma in patients with ACTH-independent CS and normal ACTH levels, because ACTH did not respond to CRH in any of these patients.
Another widely used test for the differential diagnosis of ACTH-dependent CS is the suppression with high doses of dexamethasone. The 2-day test reportedly carries a sensitivity of 89–94% and a widely ranging specificity (from 29–60%) (22, 23, 24) using the criterion of a 50% decrease in UFC levels; whereas the same cut-off, applied to the plasma cortisol decrease after overnight administration, bears a sensitivity of 77–92% and a specificity of 57–100% (24, 25, 26). With more stringent criteria (decrease to 68–90% of baseline), specificity rises to nearly 100%, with either test, at the expense of sensitivity (22, 23, 24, 27). In our experience, an 80% decrease in UFC or plasma cortisol can be observed only in patients with CD; however, this criterion is burdened by a low sensitivity. Overall, the high-dose dexamethasone test has a lower diagnostic accuracy, compared with the ACTH response to CRH.
In agreement with other large-scale studies (28, 29), an adenoma was visualized at pituitary imaging in just more than half of our patients with CD. In our series, the detection rate of magnetic resonance imaging seemed only slightly higher than that of computed tomography. This finding is supported by the high concordance of results when both images were obtained in the same patient. The low sensitivity of pituitary radiology and the possibility of detecting incidental pituitary tumors in patients with ectopic secretion (30) uphold its limited diagnostic value (29). By comparison, inferior petrosal sinus sampling was heralded as a test with absolute sensitivity and specificity for the differential diagnosis of ACTH-dependent CS (31). However, these parameters did not stand the test of time and widespread use (32), because there have since been case reports of false-negative (33, 34, 35) and false-positive (36) results. Our series, which reflects the findings of multiple centres rather than those of a single institution, bears out the extremely high specificity of inferior petrosal sinus sampling but indicates that 15% of patients with CD are misdiagnosed. Thus, caution must be exercised before excluding the diagnosis of CD on grounds of inferior petrosal sinus sampling. The frequent shift of the intersinus gradient upon CRH administration and the arbitrary decision to take the highest gradient, whether basal or after CRH, as indicative of the dominant sinus may explain the poor value of inferior petrosal sinus sampling in predicting the location of the adenoma.
There is no agreement on which biochemical parameters connote remission after pituitary surgery. Subnormal/normal UFC concentrations (1, 37, 38) and plasma cortisol levels below 50–138 nmol/L (1.8–5 µg/dL) (37, 38, 39) have been considered indicative of remission. However, long-lasting remission has also been reported in patients with normal postoperative plasma cortisol values (40, 41, 42). For this reason, we elected to consider as cured all patients having, besides the clinical appearance of remission, either low or normal plasma and urinary cortisol levels. Interestingly, we observed a lower frequency of cortisol responses to CRH among patients with subnormal postsurgical UFC or plasma cortisol, compared with patients with normal values, whereas the ACTH responsiveness did not differ in the two groups. This cortisol patterns seem to indicate a variable degree of adrenal insufficiency, in the face of a comparable ACTH secretion.
According to these criteria, the remission rate of pituitary surgery was 69%, in line with the results reported by several centres (1, 40, 43), although lower than others (2, 3, 38). We did not observe the previously described correlation between radiological visualization of the adenoma and likelihood of remission (3, 44), because the adenoma was actually found and successfully removed at pituitary exploration in about 70% of patients with negative imaging. Quizzically, 14 patients were cured despite the removal of apparently normal or not clearly adenomatous pituitary tissue; this evidence reproposes the problem of the pathogenesis of pituitary ACTH hypersecretion in at least a subset of these patients.
Several investigators have linked postsurgical plasma cortisol levels greater than 55–165 nmol/L (1.9–6 µg/dL) to a higher recurrence rate (37, 39, 42, 45, 46). Proportional hazard analysis of our series did not detect any association between baseline plasma cortisol levels and risk of relapse. The best parameters for predicting relapse after pituitary surgery were baseline plasma ACTH levels and peak cortisol responses to CRH. Our study confirms the usefulness of postoperative CRH testing, because recurrence developed only in patients presenting a response of both hormones to CRH stimulation. The efficacy of reoperation seemed low in our series, compared with the 71% remission rate reported after late (42, 47) or early (38) repeat transsphenoidal surgery. In patients who suffered a relapse or in whom pituitary surgery was unsuccessful, radiation or medical therapy are feasible options, because reduction of hypercortisolism can be obtained in approximately two thirds of patients. By comparison, long-term prognosis for adrenal carcinoma and ectopic secretion is dismal.
Several main conclusions can be drawn from this study: 1) moderate and inconstant elevations of UFC must not be underestimated in the diagnostic work-up of CS; 2) the CRH test is recommended in patients with CS and low-normal ACTH values and for the evaluation of risk of relapse after pituitary surgery; 3) the diagnostic accuracy of the ACTH response to CRH stimulation is comparable with that of inferior petrosal sinus sampling; 4) a prolonged follow-up after pituitary surgery is necessary, given the relatively high incidence of relapse even after several years.
Future specifically designed studies may allow a better understanding of some unexpected findings, such as measurable ACTH concentrations in patients with ACTH-independent CS. In addition, the search for more potent diagnostic tools, as well as for parameters that may herald a recurrence, is still worth pursuing.
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Footnotes |
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2 The Study Group consisted of the following participants: A.
Angeli, M. Terzolo, 2nd Dept. of Internal Medicine, Univ. of Turin,
Orbassano (Turin); G. Belotti, R. Castello, Dept. of Endocrinology,
Ospedale Maggiore, Verona; F. Bertolissi, Ospedale Civile, Udine; G.
Borretta, Ospedale S. Croce e Carle, Cuneo; M. Boscaro, E. Scarpa,
Inst. of Semeiotics, Univ. of Padua; F. Camanni, E. Mazza, Dept. of
Endocrinology, Ospedale Le Molinette, Univ. of Turin; L.
Cantala-messa, 1st Dept. of Internal Medicine, Univ. of Milan; F.
Caviezel, L. Morricone, Inst. of Medical and Surgical Sciences, S.
Donato Milanese, Univ. of Milan; C. De Sanctis, Dept. of Pediatric
Endocrinology, Ospedale Infantile Regina Margherita, Turin; E. Degli
Uberti, Sect. of Endocrinology, Dept. of Biomedical Sciences and
Advanced Therapy, Univ. of Ferrara; C. Ferrari, Ospedale
Fatebenefratelli, Milan; A. Giustina, Dept. of Internal Medicine, Univ.
of Brescia;
A. Jannì, R. Lo Coco, Dept. of Endocrinology, Ospedale "V. Cervello", Palermo; C. Letizia, 2nd Inst. of Internal Medicine, Policlinico Umberto I, Rome; A. Liuzzi, M. R. Ghiggi, Ospedale Casa Sollievo della Sofferenza, Dept. of Endocrinology, S. Giovanni Rotondo (Foggia); V. Lo Cascio, G. Francia, Dept. of Internal Medicine, Univ. of Verona; G. Lombardi, A. Colao, Dept. of Endocrinology and Molecular and Clinical Oncology, Univ. of Naples; A. Mancini, L. De Marinis, Dept of Endocrinology, Univ. of Rome; M. Mannelli, Dept. of Clinical Pathophysiology, Univ. of Florence; F. Mantero, A. M. Masini, Dept. of Endocrinology, Univ. of Ancona; C. Mazzi, Dept. of Endocrinology, Ospedale S. Antonio Abate, Gallarate (Varese); M. Muggeo, P. Moghetti, Dept. of Metabolic Diseases, Univ. of Verona; A. Pinchera, E. Martino, D. Barletta, Dept. of Endocrinology, Univ. of Pisa, Tirrenia (Pisa); G. Rizzi, Inst. of Internal Medicine, Ospedale Civile, Saluzzo (Cuneo); F. Santeusanio, Dept. of Int. Medicine and Endocrinology and Metabolic Sciences, Univ. of Perugia; F. Sciarra, C. Tosti-Croce, 3rd Dept. of Endocrinology, Univ. "La Sapienza" of Rome; P. Vezzadini, R. Toni, Dept of Internal Medicine, Ospedale Bellaria, Univ. of Bologna; G. A. Zampa, A. Sforza, Dept. of Endocrinology and Metabolic Sciences, Ospedale Maggiore, Bologna.
Received January 27, 1998.
Revised May 8, 1998.
Accepted October 19, 1998.
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P. Burman, A. Lethagen, K. Ivancev, L. Johansson, and A. Sundin Dual bronchial carcinoids and Cushing's syndrome with a paradoxical response to dexamethasone and a false positive outcome of inferior petrosal sinus sampling Eur. J. Endocrinol., October 1, 2008; 159(4): 483 - 488. [Abstract] [Full Text] [PDF]
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M. C. Machado, S. Valeria de Sa, M. L. Correa-Giannella, R. R. Giorgi, M. A. A. Pereira, V. A. S Cescato, D. Giannella-Neto, and L. R. Salgado Association between tumoral GH-releasing peptide receptor type 1a mRNA expression and in vivo response to GH-releasing peptide-6 in ACTH-dependent Cushing's syndrome patients Eur. J. Endocrinol., May 1, 2008; 158(5): 605 - 613. [Abstract] [Full Text] [PDF]
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L. K. Nieman, B. M. K. Biller, J. W. Findling, J. Newell-Price, M. O. Savage, P. M. Stewart, and V. M. Montori The Diagnosis of Cushing's Syndrome: An Endocrine Society Clinical Practice Guideline J. Clin. Endocrinol. Metab., May 1, 2008; 93(5): 1526 - 1540. [Abstract] [Full Text] [PDF]
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C. G. Patil, D. M. Prevedello, S. P. Lad, M. L. Vance, M. O. Thorner, L. Katznelson, and E. R. Laws Jr. Late Recurrences of Cushing's Disease after Initial Successful Transsphenoidal Surgery J. Clin. Endocrinol. Metab., February 1, 2008; 93(2): 358 - 362. [Abstract] [Full Text] [PDF]
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F. Pecori Giraldi, A. G. Ambrogio, M. De Martin, L. M. Fatti, M. Scacchi, and F. Cavagnini Specificity of First-Line Tests for the Diagnosis of Cushing's Syndrome: Assessment in a Large Series J. Clin. Endocrinol. Metab., November 1, 2007; 92(11): 4123 - 4129. [Abstract] [Full Text] [PDF]
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F Castinetti, I Morange, H Dufour, P Jaquet, B Conte-Devolx, N Girard, and T Brue Desmopressin test during petrosal sinus sampling: a valuable tool to discriminate pituitary or ectopic ACTH-dependent Cushing's syndrome Eur. J. Endocrinol., September 1, 2007; 157(3): 271 - 277. [Abstract] [Full Text] [PDF]
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N. Pouratian, D. M. Prevedello, J. Jagannathan, M. B. Lopes, M. L. Vance, and E. R. Laws Jr. Outcomes and Management of Patients with Cushing's Disease without Pathological Confirmation of Tumor Resection after Transsphenoidal Surgery J. Clin. Endocrinol. Metab., September 1, 2007; 92(9): 3383 - 3388. [Abstract] [Full Text] [PDF]
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 D. L. Batista, J. Riar, M. Keil, and C. A. Stratakis Diagnostic Tests for Children Who Are Referred for the Investigation of Cushing Syndrome Pediatrics, September 1, 2007; 120(3): e575 - e586. [Abstract] [Full Text] [PDF]
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S. Tsagarakis, D. Vassiliadi, I. S. Kaskarelis, J. Komninos, E. Souvatzoglou, and N. Thalassinos 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 J. Clin. Endocrinol. Metab., June 1, 2007; 92(6): 2080 - 2086. [Abstract] [Full Text] [PDF]
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F. Pecori Giraldi, M. Andrioli, L. De Marinis, A. Bianchi, A. Giampietro, M. De Martin, E. Sacco, M. Scacchi, A. Pontecorvi, and F. Cavagnini Significant GH deficiency after long-term cure by surgery in adult patients with Cushing's disease Eur. J. Endocrinol., February 1, 2007; 156(2): 233 - 239. [Abstract] [Full Text] [PDF]
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R M Testa, N Albiger, G Occhi, F Sanguin, M Scanarini, S Berlucchi, M P Gardiman, C Carollo, F Mantero, and C Scaroni The usefulness of combined biochemical tests in the diagnosis of Cushing's disease with negative pituitary magnetic resonance imaging Eur. J. Endocrinol., February 1, 2007; 156(2): 241 - 248. [Abstract] [Full Text] [PDF]
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D Vezzosi, D Cartier, C Regnier, P Otal, A Bennet, F Parmentier, M Plantavid, A Lacroix, H Lefebvre, and P Caron Familial adrenocorticotropin-independent macronodular adrenal hyperplasia with aberrant serotonin and vasopressin adrenal receptors Eur. J. Endocrinol., January 1, 2007; 156(1): 21 - 31. [Abstract] [Full Text] [PDF]
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D. L. Batista, X. Zhang, R. Gejman, P. J. Ansell, Y. Zhou, S. A. Johnson, B. Swearingen, E. T. Hedley-Whyte, C. A. Stratakis, and A. Klibanski The Effects of SOM230 on Cell Proliferation and Adrenocorticotropin Secretion in Human Corticotroph Pituitary Adenomas J. Clin. Endocrinol. Metab., November 1, 2006; 91(11): 4482 - 4488. [Abstract] [Full Text] [PDF]
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J. W. Findling and H. Raff Cushing's Syndrome: Important Issues in Diagnosis and Management J. Clin. Endocrinol. Metab., October 1, 2006; 91(10): 3746 - 3753. [Abstract] [Full Text] [PDF]
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 I. S. Kaskarelis, E. G. Tsatalou, S. V. Benakis, K. Malagari, I. Komninos, D. Vasiliadou, S. Tsagarakis, and N. Thalassinos Bilateral inferior petrosal sinuses sampling in the routine investigation of Cushing's syndrome: a comparison with MRI. Am. J. Roentgenol., August 1, 2006; 187(2): 562 - 570. [Abstract] [Full Text] [PDF]
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M. Riedl, C. Maier, G. Zettinig, P. Nowotny, W. Schima, and A. Luger Long term control of hypercortisolism with fluconazole: case report and in vitro studies. Eur. J. Endocrinol., April 1, 2006; 154(4): 519 - 524. [Abstract] [Full Text] [PDF]
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A. M. Isidori, G. A. Kaltsas, C. Pozza, V. Frajese, J. Newell-Price, R. H. Reznek, P. J. Jenkins, J. P. Monson, A. B. Grossman, and G. M. Besser The Ectopic Adrenocorticotropin Syndrome: Clinical Features, Diagnosis, Management, and Long-Term Follow-Up J. Clin. Endocrinol. Metab., February 1, 2006; 91(2): 371 - 377. [Abstract] [Full Text] [PDF]
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I. Ilias, D. J. Torpy, K. Pacak, N. Mullen, R. A. Wesley, and L. K. Nieman Cushing's Syndrome Due to Ectopic Corticotropin Secretion: Twenty Years' Experience at the National Institutes of Health J. Clin. Endocrinol. Metab., August 1, 2005; 90(8): 4955 - 4962. [Abstract] [Full Text] [PDF]
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Y. S. Woo, A. M. Isidori, W. Z. Wat, G. A. Kaltsas, F. Afshar, I. Sabin, P. J. Jenkins, J. P. Monson, G. M. Besser, and A. B. Grossman Clinical and Biochemical Characteristics of Adrenocorticotropin-Secreting Macroadenomas J. Clin. Endocrinol. Metab., August 1, 2005; 90(8): 4963 - 4969. [Abstract] [Full Text] [PDF]
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 A Levy Pituitary disease: presentation, diagnosis, and management J. Neurol. Neurosurg. Psychiatry, September 1, 2004; 75(suppl_3): iii47 - iii52. [Full Text] [PDF]
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I. Ilias, R. Chang, K. Pacak, E. H. Oldfield, R. Wesley, J. Doppman, and L. K. Nieman Jugular Venous Sampling: An Alternative to Petrosal Sinus Sampling for the Diagnostic Evaluation of Adrenocorticotropic Hormone-Dependent Cushing's Syndrome J. Clin. Endocrinol. Metab., August 1, 2004; 89(8): 3795 - 3800. [Abstract] [Full Text] [PDF]
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S. Salenave, B. Gatta, S. Pecheur, F. San-Galli, A. Visot, P. Lasjaunias, P. Roger, J. Berge, J. Young, A. Tabarin, et al. Pituitary Magnetic Resonance Imaging Findings Do Not Influence Surgical Outcome in Adrenocorticotropin-Secreting Microadenomas J. Clin. Endocrinol. Metab., July 1, 2004; 89(7): 3371 - 3376. [Abstract] [Full Text] [PDF]
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R. Pivonello, D. Ferone, W. W. de Herder, J. M. Kros, M. L. Del Basso De Caro, M. Arvigo, L. Annunziato, G. Lombardi, A. Colao, L. J. Hofland, et al. Dopamine Receptor Expression and Function in Corticotroph Pituitary Tumors J. Clin. Endocrinol. Metab., May 1, 2004; 89(5): 2452 - 2462. [Abstract] [Full Text] [PDF]
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G. A. F. S. Rollin, N. P. Ferreira, M. Junges, J. L. Gross, and M. A. Czepielewski Dynamics of Serum Cortisol Levels after Transsphenoidal Surgery in a Cohort of Patients with Cushing's Disease J. Clin. Endocrinol. Metab., March 1, 2004; 89(3): 1131 - 1139. [Abstract] [Full Text] [PDF]
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J. W. Findling, H. Raff, and D. C. Aron The Low-Dose Dexamethasone Suppression Test: A Reevaluation in Patients with Cushing's Syndrome J. Clin. Endocrinol. Metab., March 1, 2004; 89(3): 1222 - 1226. [Abstract] [Full Text] [PDF]
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G. Arnaldi, A. Angeli, A. B. Atkinson, X. Bertagna, F. Cavagnini, G. P. Chrousos, G. A. Fava, J. W. Findling, R. C. Gaillard, A. B. Grossman, et al. Diagnosis and Complications of Cushing's Syndrome: A Consensus Statement J. Clin. Endocrinol. Metab., December 1, 2003; 88(12): 5593 - 5602. [Abstract] [Full Text] [PDF]
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P. Putignano, P. Toja, A. Dubini, F. P. Giraldi, S. M. Corsello, and F. Cavagnini Midnight Salivary Cortisol Versus Urinary Free and Midnight Serum Cortisol as Screening Tests for Cushing's Syndrome J. Clin. Endocrinol. Metab., September 1, 2003; 88(9): 4153 - 4157. [Abstract] [Full Text] [PDF]
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 M. Terzolo, G. Reimondo, and A. Angeli Desmopressin Test in Mild Cushing Syndrome Arch Intern Med, April 14, 2003; 163(7): 850 - 851. [Full Text] [PDF]
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F. P. Giraldi, M. Moro, and F. Cavagnini Gender-Related Differences in the Presentation and Course of Cushing's Disease J. Clin. Endocrinol. Metab., April 1, 2003; 88(4): 1554 - 1558. [Abstract] [Full Text] [PDF]
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A. Vella, G. B. Thompson, C. S. Grant, J. A. van Heerden, D. R. Farley, and W. F. Young Jr. Laparoscopic Adrenalectomy for Adrenocorticotropin-Dependent Cushing's Syndrome J. Clin. Endocrinol. Metab., April 1, 2001; 86(4): 1596 - 1599. [Abstract] [Full Text]
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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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M. Moro, P. Putignano, M. Losa, C. Invitti, C. Maraschini, and F. Cavagnini The Desmopressin Test in the Differential Diagnosis between Cushing's Disease and Pseudo-Cushing States J. Clin. Endocrinol. Metab., October 1, 2000; 85(10): 3569 - 3574. [Abstract] [Full Text]
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IRMA); right
panel, plasma ACTH levels in patients with ACTH-independent CS,
expressed as absolute concentrations and subdivided according to assay
sensitivity (
: RIA with detection limit of 8 pg/mL and lower normal
limit ranging from 9–18 pg/mL; •, RIA with detection limit of 10
pg/mL and lower normal limit ranging from 15–20 pg/mL; 
, IRMA with detection limit of 5 pg/mL and lower normal limit
ranging from 9–20 pg/mL). Values referred as undetectable are not
shown.
