Simultaneous Inferior Petrosal Sinus Research Articles

Comparisons in the epidemiology, diagnostic features and cure rate by transsphenoidal surgery between paediatric and adult-onset Cushing's disease

There are few published comparisons between paediatric and adult-onset Cushing's disease (CD). We compare the epidemiology, diagnostic features and cure rate by transsphenoidal surgery (TSS) in these groups. Retrospective review of patient databases in a single university hospital centre. Totally, 41 paediatric (mean age 12.3 ± 3.5 years; range 5.7-17.8) and 183 adult (mean age 40 ± 13 years; range 18.0-95.0) patients with CD were investigated. Paediatric CD was characterised by male (63%) and adult CD by a female predominance (79%, P<0.0001). There were small but significant differences in clinical presentation. Biochemical features of CD were comparable except the serum cortisol increase during a CRH test: mean change (105%, n=39) in paediatric and (54%, n=123) in adult subjects (P<0.0001). Macroadenomas were more common in adult (15%, 28/183) than in paediatric (2%, 1/41, P=0.04) CD. Corticotroph microadenomas were more easily visualised by pituitary magnetic resonance imaging (MRI) in adult (76%, 50/66) compared with paediatric (55%, 21/38, P=0.045) CD with poorer concordance of imaging with surgical findings in children (P=0.058). The incidence of ACTH lateralisation by bilateral simultaneous inferior petrosal sinus sampling was comparable in paediatric (76%, 25/33) and adult (79%, 46/58; P=0.95) patients with good surgical concordance in both (82% paediatric and 79% adult). Cure rates by TSS were comparable, with a paediatric cure rate of 69%. Several features of paediatric CD are distinct: increased frequency of prepubertal CD in males, the different clinical presentation, the decreased presence of macroadenomas and the frequent absence of radiological evidence of an adenoma on MRI.

Diagnosis, management and therapeutic outcome in prepubertal Cushing's disease

Cushing's disease (CD) in prepubertal children is very rare and presents important diagnostic and therapeutic challenges. We report experience of the management of this subpopulation of CD patients. Retrospective patient case note review. Between 1985 and 2008, 17 prepubertal children (13M, 4F), aged 5.7-14.1 years presented to our centre for diagnosis and management of CD. All children had subnormal linear growth and excessive weight gain at presentation. A high proportion (85% of males, 75% of females) had evidence of excessive virilisation. Striae and hypertension were seen in 41% of patients. The investigation with highest sensitivity (100%) for CD was excessive increase of serum cortisol to i.v. CRH (mean increase 113%). Pituitary imaging performed in all the patients showed poor concordance with findings at surgery (31%). In contrast bilateral simultaneous inferior petrosal sinus sampling (BSIPSS), performed in 11/16 subjects showed a high correlation with surgical findings (91%). In 16 patients, transsphenoidal selective adenomectomy (TSS) achieved a cure rate of 44%. However, in the 11 patients who had pre-operative BSIPSS, the cure rate was 64%. Of the 16 patients, 9 patients who were not cured by TSS received external pituitary radiotherapy. Prepubertal CD had distinctive features with increased frequency in males, abnormal auxology and excessive virilisation. The cortisol response to i.v. CRH administration was particularly exuberant and contributed to diagnosis. BSIPSS was much more helpful than pituitary imaging in localisation of the microadenoma and was associated with improved cure rate by TSS.

The role of desmopressin in bilateral and simultaneous inferior petrosal sinus sampling for differential diagnosis of ACTH‐dependent Cushing's syndrome

Bilateral inferior petrosal sinus sampling (BIPSS) with corticotrophin-releasing hormone (CRH) stimulation is currently the gold standard test for the differential diagnosis of ACTH-dependent Cushing's syndrome. Reports on the use of desmopressin in this approach are limited. The aim of this study was to evaluate the use of desmopressin during BIPSS in a cohort of patients with ACTH-dependent Cushing's syndrome. A retrospective case-record study. Fifty-six patients with confirmed ACTH-dependent Cushing's syndrome underwent BIPSS with desmopressin stimulation when presenting negative pituitary tumour imaging. Central to peripheral (CEN:PER) ACTH gradient, lateralization of the ACTH source and surgical tumour confirmation were evaluated. A CEN:PER ACTH gradient was found in 40 patients under basal conditions (CEN:PER >or= 2) and in 47 patients after desmopressin stimulation (CEN:PER >or= 3). Ectopic ACTH-producing tumours (three lung carcinoid tumour, one thymus carcinoid tumour and one thymus hyperplasia) were confirmed in five out of nine patients without the CEN:PER ACTH gradient, and four cases were false negative for Cushing's disease. Lateralization (IPS:IPS >or= 1.4) was observed in 80.8% of patients under basal conditions (38/47) and in 97.8% after desmopressin (46/47), and it was surgically confirmed in 78.7%. There were no false-positive cases. Sensitivity and specificity were 92.1% and 100%, respectively. Desmopressin improves the differential diagnosis of ACTH-dependent Cushing's syndrome by amplifying the CEN:PER and IPS:IPS ACTH gradients, and is therefore a useful ACTH secretagogue in BIPSS.

Factors influencing cure by transsphenoidal selective adenomectomy in paediatric Cushing’s disease

Early diagnosis and effective treatment of paediatric Cushing's disease (CD) is necessary to minimise associated morbidity. Accepted first-line treatment is selective transsphenoidal microadenomectomy (TSS), which can be technically difficult, and cure rates vary considerably between centres. In our paediatric CD patient group we have assessed the possible factors which may influence cure by TSS. From 1983-2004, 27 paediatric patients (16 males, 11 females; mean age+/-s.d., 13.1+/-3.2 yr; range, 6.4-17.8 yr) with CD were managed in our centre and underwent TSS. Sixteen patients (59%), seven males and nine females (mean age+/-s.d., 14.2+/-2.5 yr; range, 8.2-17.8 yr), were cured (post-operative serum cortisol < 50 nM). Eleven patients, nine males and two females (mean age+/-s.d., 11.5+/-3.6 yr; range, 6.4-17.8 yr) had post-operative cortisol levels above 50 nM (2-20 days), with mean serum cortisol levels at 09:00 h of 537 nM (range 269-900 nM) indicating a lack of cure. These 11 patients received external beam pituitary radiotherapy (RT). One patient with a pituitary macroadenoma had a post-operative cortisol level of < 50 nM but 0.8 yr later showed an elevated cortisol and residual disease. The patients cured by TSS alone were significantly older than those not cured (P = 0.038; Student's t test). All patients had CT/MRI pituitary imaging: 14 were reported to have microadenomas and one macroadenoma, while 12 were reported as normal. Bilateral simultaneous inferior petrosal sinus sampling (BSIPSS) with i.v. corticotropin-releasing hormone (CRH) administration was introduced as a pre-operative investigation in 1986 and was performed in 21 patients (78%), on BSIPSS, 16 (76%) had evidence suggesting pituitary adrenocorticotropic hormone (ACTH) secretion (central to peripheral (IPS:P) ACTH ratio after CRH of > or = 3.0) and 16 (76%) showed lateralisation of ACTH secretion (IPSG of > or = 1.4). There was concordance between the BSIPSS finding and the position of the microadenoma at surgery in 17/21 (81%) patients. Of the 16 patients showing lateralisation of ACTH secretion, 12 (75%) were cured by TSS. Of the four without lateralisation of ACTH, suggesting a midline lesion, 3 (75%) were cured by TSS. Post-operative pituitary hormone deficiencies in the patients cured by TSS were: pan-hypopituitarism 1/16, isolated growth hormone deficiency (GHD) (peak GH on glucagon/ITT < 1-17.9 mU/l) 9/16 and diabetes insipidus 3/16. Over a 21-year period selective adenomectomy by TSS cured 59% of all paediatric CD patients, with higher age favouring cure. Introduction of BSIPSS resulted in the demonstration of a high rate of lateralisation of ACTH secretion consistent with the surgical identification of the adenoma, and therefore appears likely to have contributed to the higher surgical cure rate.

Acromegaly – successful preoperative lateralization of a growth hormone-producing pituitary microadenoma by simultaneous bilateral inferior petrosal venous sinus sampling with GHRH stimulation

Acromegaly – successful preoperative lateralization of a growth hormone-producing pituitary microadenoma by simultaneous bilateral inferior petrosal venous sinus sampling with GHRH stimulation

Inferior petrosal sinus sampling: pros and cons; when and where.

193 The differential diagnosis of Cushing’s syndrome has generated more diagnostic tests, more controversy, and more passionate debate than nearly any subject in clinical endocrinology. The introduction of pituitary surgery as the treatment of choice for Cushing’s disease, the absence of abnormalities on pituitary imaging studies in many patients with the disorder, and the recognition that some patients with non-pituitary (ectopic) ACTH-secreting neoplasms have endogenous hypercortisolism many years before their tumor becomes clinically apparent, has created a need for a precise differential diagnosis. Before considering whether any diagnostic study should be done, endocrinologists must remember that the pre-test probability of Cushing’s disease is at least 90%. In addition, it has been shown that a simple logistic model of clinical variables including the patient’s gender, age, approximate duration of symptoms, urine free cortisol, plasma potassium, and plasma ACTH will yield a diagnostic sensitivity of 95-98% for Cushing’s disease (1). Therefore, the clinician must compare the diagnostic sensitivity, specificity, and accuracy of any test used in the differential diagnosis of Cushing’s syndrome with the use of common sense and the recognition that the majority of patients with ACTH-dependent Cushing’s syndrome will have a corticotroph adenoma. In many medical centers around the world, bilateral simultaneous inferior petrosal sinus ACTH sampling (IPSS) has emerged as the most accurate and reliable means of distinguishing pituitary from non-pituitary ACTH-dependent Cushing’s syndrome (25). The major advantage of this procedure is that it is the only diagnostic study that has been reported to yield a diagnostic sensitivity, specificity, and accuracy that is substantially better than the pre-test probability of Cushing’s disease. IPSS has been used to help with pre-operative localization of pituitary microadenoma and has been reported to provide accurate localization in 75-90% of patients (3-5). Recently, it has been shown that accurate localization of a pituitary lesion occurred more frequently when based on IPSS results than on imaging results (70% vs 49%, respectively). In fact, in patients with discrepant results, IPSS was more likely than pituitary imaging to agree with the final pathological findings (62% vs 13%, respectively) (5). Investigators have suggested that sampling directly from the cavernous si

The continuous 7-hour intravenous dexamethasone suppression test in the differential diagnosis of ACTH-dependent Cushing's syndrome.

A recent report showing disappointingly low sensitivity and specificity for the oral high dose dexamethasone test in the differential diagnosis of Cushing's syndrome prompted us to re-evaluate the results obtained in our centre using the continuous 7-hour intravenous dexamethasone suppression test for this purpose. 105 patients with ACTH-dependent Cushing's syndrome were included in this study; 78 with Cushing's disease, 8 with ectopic ACTH-secreting tumours and 19 were classified as 'of unknown aetiology'. In 74/78 (94.9%) of patients with Cushing's disease and in 3/8 (37.5%) patients with the ectopic ACTH syndrome, a plasma cortisol decrease > 190 nmol/l at 7 h as compared to baseline values was achieved in the continuous 7-hour intravenous dexamethasone suppression test. Using a plasma cortisol decrease > 190 nmol/l at 7 h as compared to baseline values as the cut-off value, the sensitivity and specificity of the continuous 7-hour intravenous dexamethasone suppression test for the diagnosis of Cushing's disease in patients with ACTH-dependent Cushing's syndrome were 94.9% and 62.5%, respectively. In patients with ACTH-dependent Cushing's syndrome with a plasma cortisol decrease > 190 nmol/l at 7 h in the continuous 7-hour intravenous dexamethasone suppression test, additional localizing investigations such as bilateral simultaneous inferior petrosal sinus sampling and/or pentetreotide scintigraphy should be performed when no clearly discernible pituitary adenoma is observed on MRI studies. Patients with ACTH-dependent Cushing's syndrome with a plasma cortisol decrease < 190 nmol/l at 7 h in the continuous 7-hour intravenous dexamethasone suppression test should also undergo bilateral simultaneous inferior petrosal sinus sampling and/or pentetreotide scintigraphy to demonstrate the presence of a nonpituitary source of ACTH overproduction.

A critical analysis of the value of simultaneous inferior petrosal sinus sampling in Cushing's disease and the occult ectopic adrenocorticotropin syndrome.

The clinical, biochemical, and radiological features of pituitary ACTH-dependent Cushing's syndrome (CS) [Cushing's disease (CD)] are often indistinguishable from those of occult ectopic ACTH-dependent CS (oEAS). We have evaluated, retrospectively, the results of simultaneous bilateral inferior petrosal sinus (IPS) ACTH sampling before and after CRH stimulation in 128 patients with ACTH-dependent CS: 107 patients with CD, 6 with oEAS, 1 with an adrenal adenoma, 1 with a pituitary gangliocytoma, and 1 with Nelson's syndrome; while, in the remaining 12, the source remains unclear. One hundred seven patients received human-sequence CRH (hCRH), and 11 received ovine CRH; another 6 patients underwent stimulation with desmopressin and hCRH, and 4 with desmopressin alone. A successful bilateral IPS catheterization and sampling (IPSCS) rate of 87.5% was obtained only after considerable experience had been gained. Sixty-nine patients with CD underwent successful bilateral IPSCS: the IPS-to-peripheral ratio of plasma ACTH value (IPS/P) rose from 9.5 +/- 1.4 to a maximum ratio of 55.8 +/- 7.5 in 67 patients, after CRH stimulation. The maximum ratio was obtained at 5 min in 60 of the 69 patients with CD; however, all 69 patients obtained a ratio of more than 2, at that time. In contrast, the 6 patients with occult ACTH-secreting neoplasms had a maximal IPS/P ratio of 1.3 +/- 0.16, and this did not change after CRH stimulation. A bilateral IPS/P ratio more than 2, obtained 5 min after CRH stimulation, had a sensitivity of 97% and a specificity of 100% in diagnosing CD. Two patients with proven active CD had an IPS/P ratio of less than 2. After successful bilateral IPSCS, the gradients between the IPS ACTH concentrations [IPS ACTH gradient (IPSG)] of more than 1.4, at 5 min after CRH stimulation, had a sensitivity of 83% in correctly lateralizing the pituitary microadenoma, compared with 72% sensitivity for magnetic resonance imaging (MRI) scanning. Furthermore, when IPSG and MRI findings were contradictory, IPSG was more often correct than MRI scanning. Although oEAS is a relatively uncommon cause of ACTH-dependent hypercortisolism (5.5% in our series), the accurate diagnosis of ACTH-dependent CS and localization of an intrapituitary microadenoma requires bilateral IPSCS with CRH stimulation, provided that the appropriate technical experience is available. hCRH is as effective a secretagogue as ovine CRH, and either may be used. The value of the combination of CRH and desmopressin stimulation requires more detailed investigation.

Bilateral sequential inferior petrosal sinus sampling with corticotrophin-releasing hormone stimulation in the diagnosis of Cushing's disease.

The demonstration of a central to peripheral ACTH gradient in a hypercortisolaemic patient is diagnostic of Cushing's disease. We tried to determine whether single blood samples for ACTH obtained sequentially from each of the inferior petrosal sinuses following human corticotrophin-releasing hormone (hCRH) stimulation can reliably establish such a gradient. Prospective study. Seventeen patients with clinical and biochemical features of Cushing's syndrome. After the administration of hCRH, the patients underwent bilateral sequential inferior petrosal sinus sampling, with a single blood sample obtained from each of the inferior petrosal sinuses sequentially, along with a peripheral venous sample. The petrosal sinus catheter was withdrawn immediately after obtaining a blood sample. Patients did not require indwelling catheters in the petrosal sinuses, nor heparinisation. Bilateral sequential inferior petrosal sinus sampling correctly identified a pituitary source of ACTH, as shown by a central to peripheral ACTH ratio >2, in all patients in whom the procedure was successfully carried out. All patients underwent transsphenoidal pituitary surgery resulting in remission. The simplified method of inferior petrosal sinus sampling, using a single sequential sample from each of the inferior petrosal sinuses, following initial hCRH stimulation, is as accurate as the more complex test using multiple bilateral simultaneous inferior petrosal sinus samples. It avoids the use of indwelling cerebral venous catheters and is therefore unlikely to cause brain stem damage.

A neurological complication of inferior petrosal sinus sampling during investigation for Cushing's disease: a case report.

A 45 year old woman with hirsutism was found to have classic biochemical features of ACTH dependent Cushing's disease, with partial cortisol suppression in response to dexamethasone. As no pituitary...

Adrenocorticotrophic hormone-dependent Cushing's syndrome.

Excess endogenous glucocorticoid production, whether ACTH dependent or ACTH independent, results in the classic clinical and biochemical picture of Cushing's syndrome. The diagnosis requires the demonstration of an increased cortisol secretion rate, best achieved by using the 24-hour UFC corrected for body surface area as an index. In mild cases, distinction from the hypercortisolism of pseudo-Cushing states may be difficult. A dexamethasone/o CRH test or close monitoring of the patient for a few months may be helpful. A discrete pituitary lesion on imaging and a standard oCRH test with results consistent with such a lesion are sufficient to proceed to trans-sphenoidal surgery. If no visible pituitary adenoma is present or if the oCRH test is equivocal, bilateral simultaneous inferior petrosal sinus sampling with oCRH administration is necessary to distinguish between a pituitary and an ectopic source. Surgical ablation is the treatment of choice for all types of Cushing's syndrome. In the 5% of cases with Cushing's disease in whom trans-sphenoidal surgery fails and in the 5% of cases in whom the disease recurs, repeat trans-sphenoidal surgery or radiation therapy in association with mitotane treatment may be pursued. Bilateral adrenalectomy effectively cures hypercortisolism if resection of the ACTH-secreting tumor is unsuccessful and radiation/medical therapy fails.

Use of Desmopressin in Bilateral and Simultaneous Inferior Petrosal Sinus Sampling for Differential Diagnosis of ACTH-Dependent Cushingʼs Syndrome

Use of Desmopressin in Bilateral and Simultaneous Inferior Petrosal Sinus Sampling for Differential Diagnosis of ACTH-Dependent Cushingʼs Syndrome

Inferior petrosal sinus sampling in healthy subjects reveals a unilateral corticotropin-releasing hormone-induced arginine vasopressin release associated with ipsilateral adrenocorticotropin secretion.

Arginine vasopressin (AVP) acts synergistically with corticotropin-releasing hormone (CRH) to stimulate ACTH release from the anterior pituitary. In a previous study of bilateral simultaneous inferior petrosal sinus (IPS) sampling in healthy human subjects, we observed lateralized ACTH secretion, suggesting lateralized secretion of an ACTH-regulating hypothalamic factor. To investigate this possibility, we measured ACTH, CRH, AVP, and oxytocin (OT) levels in the IPS and the peripheral circulation in nine normal volunteers, before and after 1 microgram/kg i.v. bolus ovine CRH (oCRH). At baseline, ACTH, AVP, and OT exhibited a significant (P < 0.05) two to threefold intersinus gradient (ISG), indicating the existence of a dominant petrosal sinus. Endogenous CRH was undetectable in all samples. Despite similar exogenous oCRH levels in both petrosal sinuses, oCRH caused a significant increase (P < 0.001) in the ACTH ISG (15.8 +/- 5.6, mean +/- SEM), suggesting increased responsiveness of one dominant side of the anterior pituitary. This was associated with an ipsilateral CRH-induced AVP release and a significant increase (P < 0.01) in the AVP ISG (8.6 +/- 2.3), suggesting lateralized AVP secretion by the hypothalamus. Furthermore, the increased AVP ISG after oCRH correlated strongly with the ACTH ISG (r = 0.92, P < 0.01). oCRH administration did not affect OT. These findings suggest that there is a dominant petrosal sinus in healthy volunteers that appears to reflect a dominant side of the adenohypophysis, characterized by increased functional activity and/or responsiveness of the pituitary corticotrophs. This may reflect lateralized hypothalamic and/or suprahypothalamic function resulting in CRH-responsive lateralized secretion of AVP from parvocellular and/or magnocellular axons in the median eminence and the posterior pituitary. Although the functional and teleologic significance of these findings remains to be investigated, our data suggest a novel mechanism for CRH-mediated ACTH release, namely CRH-induced release of AVP which then enhances CRH action on the corticotrophs. Furthermore, our data represent the first direct evidence for the concept of brain lateralization with respect to neuroendocrine secretion.

Differential diagnosis and management of Cushing's syndrome.

The diagnosis of endogenous Cushing's syndrome requires demonstration of an increased cortisol secretion rate, best achieved by urinary free cortisol excretion determinations. In borderline or confusing cases, loss of diurnal cortisol rhythmicity, a combined dexamethasone/corticotropin releasing hormone (CRH) test, or close monitoring of the patient for a few months will be helpful in ruling out pseudo-Cushing's. Primary adrenal Cushing's syndrome can be ruled out on the basis of a normal or elevated basal and/or CRH-stimulated plasma adrenocorticotropin (ACTH) and a negative adrenal computed tomography. ACTH-dependent Cushing's syndrome can then be differentiated on the basis of a CRH test and imaging procedures. A discrete pituitary lesion on magnetic resonance imaging and a standard CRH test with results consistent with such a lesion are sufficient to proceed to transsphenoidal surgery. If no discrete pituitary lesion is present, or if the CRH test is equivocal, bilateral simultaneous inferior petrosal sinus sampling with CRH administration is necessary to distinguish between a pituitary and an ectopic source. Surgery is the treatment of choice for all types of Cushing's syndrome. In the few cases in which transsphenoidal surgery fails or the disease recurs, repeat transsphenoidal surgery, or radiation therapy in association with mitotane treatment, is a reasonable alternative. Bilateral adrenalectomy effectively cures hypercortisolism if resection of the ACTH-secreting tumor is unsuccessful and radiation/medical therapy fails.

Clinical presentation, diagnosis, and treatment of Cushingʼs syndrome

Excess endogenous glucocorticoid production, whether corticotropin-dependent or -independent, results in the classic clinical and biochemical picture of Cushing's syndrome. The diagnosis requires demonstration of an increased cortisol secretion rate, but in mild cases, distinction from the hypercortisolism of pseudo-Cushing states may prove difficult. A dexamethasone or ovine corticotropin-releasing hormone test or close monitoring of the patient for a few months may be helpful. Most cases are diagnosed using: corticotropin-releasing hormone—stimulated plasma corticotropin level measurements and adrenal imaging procedures, A discrete pituitary lesion on imaging and a standard ovine corticotropin-releasing hormone test with results consistent with such a lesion are sufficient to proceed to transsphenoidal surgery. If no visible pituitary lesion is present, or if the ovine corticotropin-releasing hormone test is equivocal, bilateral simultaneous inferior petrosal sinus sampling with ovine corticotropin-releasing hormone administration is necessary to distinguish between a pituitary and an ectopic source. Surgical ablation is the treatment of choice for all types of Cushing's syndrome. In cases in which transsphenoidal surgery fails or in which the disease recurs, repeat transsphenoidal surgery and radiation therapy in association with mitotane treatment are reasonable alternatives. Bilateral adrenalectomy effectively cures hypercortisolism if resection of the corticotropin-secreting tumor is unsuccessful and radiation or medical therapy fails.

Value of bilateral, simultaneous inferior petrosal sinus sampling for ACTH in the differential diagnosis of cushing's syndrome

Value of bilateral, simultaneous inferior petrosal sinus sampling for ACTH in the differential diagnosis of cushing's syndrome

Bilateral inferior petrosal sinus corticotropin sampling with corticotropin-releasing hormone stimulation in a pregnant patient with Cushing's syndrome

A patient was diagnosed with Cushing's syndrome during her first pregnancy. Bilateral simultaneous inferior petrosal sinus corticotropin sampling with corticotropin-releasing hormone stimulation was performed before transphenoidal pituitary adenomectomy, with successful localization of the pituitary adenoma. Her Cushing's syndrome was controlled postoperatively with resolution of hypertension. This case report demonstrates that the procedure of bilateral simultaneous inferior petrosal venous corticotropin sampling can be safely performed during pregnancy.

Preoperative diagnostic evaluation of children with Cushing's syndrome

Recent advances in biochemical and imaging studies have improved the diagnostic accuracy of Cushing's syndrome. To better define roles for these studies in children, the authors reviewed their experience with this rare group of patients. Fifteen children, aged 11 weeks to 17 years, were treated for noniatrogenic Cushing's syndrome over a 33-year period. All children presented with signs of hypercortisolism. Nineteen different diagnostic tests were used, reflecting changes in how these patients are evaluated. Pathological diagnoses were adrenal cortical carcinoma (3), primary adrenocortical nodular dysplasia (PAND) (2), and pituitary adenoma (10). Children with adrenal cortical carcinoma presented with an adrenal mass and at a younger age (mean, 22.3 months). Key diagnostic features of patients with PAND were a low plasma adrenocorticotrophin hormone (ACTH) and no suppression with high-dose dexamethasone. Children with a pituitary cause of Cushing's syndrome presented at an older age (mean, 15.7 years) and were diagnosed using a combination of high-dose dexamethasone testing, simultaneous inferior petrosal sinus sampling, and/or ovine corticotrophin-releasing hormone stimulation test. A strategy for the diagnosis of Cushing's syndrome in children is presented.

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?

We determined whether the measurement of hormones in pituitary blood permits correction for dilution by non-pituitary blood during bilateral simultaneous inferior petrosal sinus blood sampling in Cushing's syndrome. Bilateral simultaneous inferior petrosal sinus blood sampling was performed after combined hCRF and TRH stimulation. Peak ACTH concentrations were corrected for the TSH and PRL inter-sinus ratio, assuming uniform secretion of both hormones into each inferior petrosal sinus. Eight patients with clinical and biochemical features of Cushing's syndrome. Basal and stimulated ACTH, TSH and PRL concentrations were measured after bilateral simultaneous inferior petrosal sinus blood sampling and simultaneously from a peripheral forearm vein. Basal central:peripheral ACTH ratio misdiagnosed four of eight patients as having non-pituitary disease. Peak uncorrected ACTH central:peripheral ratio erroneously suggested two of eight patients had non-pituitary disease. ACTH central:peripheral ratio corrected by TSH and PRL correctly predicted pituitary-dependent disease in all eight cases and provided correct lateralization data in four of five patients with a unilateral pituitary microadenoma. This study suggests that measuring other hormones in pituitary blood after TRH stimulation can offer a simple and reliable method for correcting for dilution by non-pituitary blood during bilateral simultaneous inferior petrosal sinus blood sampling in Cushing's syndrome.

NALOXONE STIMULATION OF ACTH SECRETION DURING PETROSAL SINUS SAMPLING IN CUSHING'S SYNDROME

1. Petrosal sinus sampling has been used to establish the source of adrenocorticotropin (ACTH) in ACTH-dependent Cushing's syndrome. Naloxone, an opioid antagonist, stimulates ACTH secretion, probably via release of endogenous hypothalamic corticotropin releasing hormone (CRH). 2. Three patients with hypercortisolism were studied. Two showed suppressed (> 50%) urinary-free cortisol excretion with high-dose dexamethasone treatment (2 mg every 6 h for 2 days), one did not suppress. The patients were subjected to bilateral simultaneous inferior petrosal sinus sampling (BSIPSS) with simultaneous peripheral venous (forearm) samples. Basal (unstimulated) samples were taken and naloxone (125 micrograms/kg bodyweight) was given intravenously with subsequent simultaneous sampling. Plasma ACTH was measured by radio-immunoassay (RIA). 3. All cases exhibited a marked rise in immunoreactive (IR)-ACTH levels (pmol/L) after naloxone injection, basal to peak: case 1, left 11.5-22.1, right 9.8 with no rise, peripheral 9.1-9.5; case 2, left 456-863, right 125-501, peripheral 59-82; case 3, left 12.7-13.0, right 277-431, peripheral 12.1-11.7. All results indicate pituitary Cushing's syndrome, with a central to peripheral ratio > 2.3:1. Pituitary Cushing's syndrome was confirmed on the results of trans-sphenoidal pituitary surgery in cases 1 and 3. 4. It is suggested that naloxone injection during petrosal sinus sampling in Cushing's syndrome may assist in the diagnosis of ACTH source, by enhancing ACTH release from a pituitary micro-adenoma.