Simultaneous Inferior Petrosal Sinus Research Articles

Investigation of Cushing's syndrome by inferior petrosal sinus sampling

Bilateral simultaneous inferior petrosal sinus sampling, in combination with CRH stimulation, is now able to confirm the diagnosis of pituitary-dependent Cushing's disease with near certainty. In expert hands, the procedure is straightforward and safe. As well as confirming the differential diagnosis, the test may aid surgical success, especially if no adenoma is apparent at transsphenoidal exploration. In this article, we review the technique and its interpretation and consider which patients should undergo the procedure.

Alpha-melanocyte-stimulating hormone is present in the inferior petrosal sinuses in patients with Cushing's disease.

Plasma ACTH, beta-endorphin and alpha-melanocyte-stimulating hormone levels were evaluated in the inferior petrosal sinuses and in the periphery of 22 patients affected by Cushing's disease, 11 patients with other pituitary diseases subjected to simultaneous and bilateral inferior petrosal sinus sampling and in the peripheral blood of 15 normal subjects. In patients with Cushing's disease ACTH, beta-endorphin and alpha-melanocyte-stimulating hormone levels in the inferior petrosal sinus ipsilateral to the adenoma were significantly higher than in the periphery and in the contralateral inferior petrosal sinus (p < 0.01, p < 0.01 and p < 0.05, respectively). In patients with other pituitary diseases only ACTH and beta-endorphin, but not alpha-melanocyte-stimulating hormone levels in both inferior petrosal sinuses were significantly higher than in the periphery (p < 0.01). Furthermore, no difference was found in the peripheral blood among patients with Cushing's disease, patients with other pituitary diseases and normal subjects for ACTH and beta-endorphin level. By contrast, in patients with Cushing's disease peripheral alpha-melanocyte-stimulating hormone levels were significantly higher than in patients with other pituitary diseases and in normal subjects (p < 0.05). In conclusion, the results of the present study suggest that only in patients with Cushing's disease, but not in patients with other pituitary diseases, alpha-melanocyte-stimulating hormone is released by adenomatous pituitary corticotrophs together with ACTH and beta-endorphin.

Selective venous sampling in the differential diagnosis of ACTH-dependent Cushing's syndrome.

Bilateral simultaneous inferior petrosal sinus sampling, associated with the oCRH stimulation test (100 micrograms i.v. as a bolus) was performed in 22 patients with Cushing's syndrome and no signs of pituitary abnormalities. Catheters were inserted into both femoral veins. More than one site in the superior and inferior vena cava was sampled before reaching the inferior petrosal sinuses. Blood samples for ACTH and beta-endorphin were gently aspirated from both petrosal sinuses and from a peripheral vein simultaneously. Blood was drawn at 0, 5, 10 and 15 min after oCRH injection. Seventeen of 22 patients showed an ipsilateral to peripheral vein ratio higher than 1.5, and 12 patients showed a lateralization of ACTH levels after oCRH stimulation. Seventeen patients underwent transsphenoidal pituitary surgery. Nine patients had a pituitary adenoma at the expected side; 1 at the contralateral side, while in 2 it was central. Three of 4 patients in whom the ipsilateral/peripheral ratio was less than 1.5 had the highest ACTH levels at the superior or inferior vena cava, not responsive to oCRH stimulation. One of these had a mediastinal and one a pulmonary mass. The third one, with an occult ectopic source, is still under investigation. At immunohistochemical and biological in vitro studies, both tumors were shown to secrete ACTH. In 13 patients in whom both beta-endorphin and ACTH measurements were performed, these hormones showed similar patterns of response. In conclusion, simultaneous bilateral petrosal sinus catheterization is a useful tool in the differential diagnosis of Cushing's syndrome as concerning pituitary and ectopic forms.(ABSTRACT TRUNCATED AT 250 WORDS)

Corticotrophin releasing hormone (CRH1–41) stimulates the secretion of adrenocorticotrophin, vasopressin and oxytocin but not adrenocorticotrophin precursors: evidence from petrosal sinus sampling in man

To examine the relationship between corticotrophin releasing hormone (CRH), arginine vasopressin (AVP) and oxytocin (OXT) we have studied the responses of adenohypophyseal and neurohypophyseal hormones to CRH in eight patients (age 26-64 years, six female) with suspected pituitary-dependent Cushing's syndrome during bilateral, simultaneous inferior petrosal sinus catheterization. Blood samples were taken from both petrosal sinuses and a peripheral vein before, and at 5-min intervals for 15 min after, an intravenous injection of 100 micrograms human CRH1-41. CRH increased sinus AVP concentrations in all eight patients and OXT concentrations in four of five patients studied. Although AVP concentrations often increased in both sinuses, the side of maximal AVP rise was termed side(max-AVP). CRH did not affect peripheral or petrosal sinus mean concentrations of LH, FSH, GH or TSH. While there was no change in mean peripheral concentrations of AVP, OXT, ACTH, ACTH precursors or prolactin after CRH, sinus concentrations of OXT, ACTH and prolactin on side(max-AVP) were markedly elevated over contralateral values. CRH did not increase mean sinus concentrations of ACTH precursors. In seven patients with either no radiological abnormality or the pituitary fossa or a small adenoma the mean ACTH precursor/ACTH ratio in blood sampled from all sites was 2.1 +/- 0.16 (mean +/- SEM, n = 50). In a patient with a large, locally invasive tumour the mean ACTH precursor/ACTH molar ratio was 32.1 +/- 1.3 (n = 12; P less than 0.001), suggesting that alterations in this molar ratio may reflect the biological properties of the tumour. The source of CRH-stimulatable AVP and OXT remains uncertain.(ABSTRACT TRUNCATED AT 250 WORDS)

Inferior petrosal sinus sampling in acromegaly.

In view of the diagnostic value of bilateral simultaneous inferior petrosal sinus sampling (BSIPSS) in localising preoperatively the site of the microadenoma in pituitary dependent Cushing's disease, the clinical value of BSIPSS was evaluated in five acromegalic patients with equivocal or negative pituitary CT scans. Intersinus GH gradients were obtained for all patients (range 1.6-4.2) but in only one case was the gradient correctly localised to the side of the tumour. Gradients of several other pituitary hormones, particularly prolactin (range 1.6-4.0), also demonstrated gradients parallel to the GH intersinus gradients. Despite the paradoxical intersinus GH gradients, the surgeon was able to readily identify the tumour at the time of surgery. Thus BSIPSS is of little assistance to the surgeon for the preoperative radiological evaluation in acromegaly and these results caution against the universal adoption of the BSIPSS technique in the radiological assessment of all secretory pituitary microadenomas.

Multiple pituitary hormone gradients from inferior petrosal sinus sampling in Cushing's disease.

Pre-operative bilateral simultaneous inferior petrosal sinus sampling with assessment of ACTH levels in the left and right sinuses and the periphery was performed in 9 patients with pituitary dependent Cushing's disease who were subsequently found at surgery to have basophil microadenomata. The novel observation of this study was the pattern of secretion of other pituitary hormones so that significant inter-sinus gradients greater than or equal to 1.4:1 were seen for beta-endorphin (2.8 +/- 1.3, mean +/- SEM), PRL (4.2 +/- 1.3) and GH (6.9 +/- 2.4) as well as for ACTH (5.1 +/- 1.1). There was no inter-sinus gradient for LH, FSH and TSH. In these 9 patients with adenomata, the correlations between the inter-sinus gradients for ACTH and beta-endorphin were r = 0.95 (P less than 0.01), ACTH and PRL r = 0.90 (P less than 0.01) and for ACTH and GH r = 0.89 (P less than 0.05). This close association between the gradients for ACTH and other anterior pituitary hormones could be due either to co-secretion of beta-endorphin, PRL and GH by the ACTH-producing pituitary adenomata or to a paracrine effect of beta-endorphin from the tumours on adjacent pituitary tissue. By reflecting the central pituitary hormone milieu, petrosal sinus sampling can give information about pituitary function unobtainable from peripheral hormone levels.

Localization of an ACTH-producing pituitary microadenoma using bilateral and simultaneous catheterization of the inferior petrosal sinus

The experience with bilateral simultaneous inferior petrosal sinus catheterization and determination of the ACTH-concentration in 21 patients is reported. Venous blood sampling in the right and left inferior petrosal sinus was obtained before and after stimulation with Corticotropin-Releasing-Hormone (CRH). In 13 patients with Cushing's Syndrome a ACTH gradient (central versus peripheral) was measured. In all patients who were operated (11/13) a microadenoma was confirmed. In all patients with a central/peripheral gradient of the ACTH-levels at the same time an ipsi versus contralateral gradient between the two sides could be established after administration of CRH, which allowed a correct localization of the microadenoma. In 11 of 13 patients the site of the microadenoma was confirmed intraoperatively.

Corticotrophin-releasing factor-test used with bilateral, simultaneous inferior petrosal sinus blood-sampling for the diagnosis of pituitary-dependent Cushing's disease.

Bilateral, simultaneous inferior petrosal sinus blood-sampling for determinations of ACTH levels has improved the ability to establish a differential diagnosis of Cushing's disease, particularly in patients whose endocrinological studies show equivocal results and whose computed tomography scans yield negative or inconclusive findings. Individual anatomical variations in the configuration of the sinus and insignificant differences between the ACTH levels obtained from its two sides may be a problem. Seven patients with clinically and biochemically typical Cushing's disease and one with atypical Cushing's disease were examined. An alternative approach for catheterization of the inferior petrosal sinus through the deep vertebral venous plexus was used in those patients who did not have direct connections between the sinus and the internal jugular vein. In two of the eight patients, only ACTH secretion stimulated with corticotrophin-releasing factor could unmask a significant difference between the ACTH levels on the two sides which was not obvious from the basal ACTH levels. Beta-lipotrophin values showed a behaviour similar to that of ACTH values, but because of a slower turn-over rate, the CRF-induced peaks were better visible. The aetiology of Cushing's disease was established from the results of this examination and corresponded with the surgical findings in this series, with the exception of one in which the patient had a highly atypical form of the disease. The abnormal ACTH source was found later to be a thymus carcinoid.

Absence of intercavernous venous mixing: evidence supporting lateralization of pituitary microadenomas by venous sampling.

Preoperative lateralization of endocrine-active pituitary tumors may be possible by bilateral inferior petrosal sinus (IPS) sampling for hormone measurement. The reliability of this technique depends on unilateral drainage of blood from the adenoma within the pituitary gland, in its course from the gland to the ipsilateral cavernous sinus, and from the cavernous sinus to the junction of the IPS and the internal jugular vein. Anatomical studies demonstrate unilateral drainage of each hemihypophysis into the ipsilateral cavernous sinus. The degree of mixing of blood between the cavernous sinuses, via the intercavernous sinus, and between the IPSs, via the basilar plexus, is unknown. We determined the extent of mixing of blood flowing from the superior orbital vein to the junction of the IPS and the internal jugular vein in four rhesus monkeys. After catheterization of a superior orbital vein and both IPSs, 99Tc-colloidal sulfur was infused into the superior orbital vein while blood samples were taken simultaneously from both IPSs and a peripheral vein at 3-min intervals. Mean relative radioactivity was 100 +/- 14% (+/- SEM) in the ipsilateral IPS, 8 +/- 2% in the contralateral IPS, and 3 +/- 1% in a peripheral vein. Isotope reaching the ipsilateral IPS before recirculation from the periphery was 10- to 313-fold more concentrated than in the contralateral IPS. These findings suggest that mixture of blood between the cavernous sinuses and between the IPSs is insignificant and support the capability of preoperative lateralization of pituitary microadenomas by bilateral and simultaneous IPS sampling.

Simultaneous bilateral venous sampling for adrenocorticotropin in pituitary-dependent cushing's disease: evidence for lateralization of pituitary venous drainage.

At present it is not established whether lateralization of pituitary venous drainage occurs in humans. To explore this possibility, we performed bilateral simultaneous inferior petrosal sinus sampling for ACTH in three patients with surgically proven ACTH-secreting pituitary microadenomas laterally located in the pituitary gland. In each patient, a gradient for ACTH correctly identified the location of the tumor. This finding suggests that pituitary venous drainage in humans is lateralized. These data also demonstrate that inferior petrosal sinus sampling needs to be bilateral before the pituitary origin of ACTH hypersecretion can be safely excluded in patients with Cushing's syndrome. In at least one and possibly two patients, the pituitary origin of ACTH excess would have been missed had we only sampled one inferior petrosal sinus. Finally, the demonstration of a left to right central gradient for PRL in addition to ACTH in one patient suggests that this technique may be useful in lateralizing functioning pituitary tumors other than ACTH-secreting tumors.