Outcome of Petrosal Venous Sampling in Consecutive 68 Patients From a Major Neurosurgical Center in the United Kingdom

Abstract Background: Cushing’s disease is a challenging endocrine disorder caused by non-physiological cortisol excess from adrenocorticotropic hormone (ACTH) secreting pituitary adenoma. Inferior petrosal venous sampling (IPSS) is considered the gold standard investigation to differentiate Cushing’s disease from ectopic ACTH syndrome. Methods: This retrospective study included all patients who underwent IPSS between January 2011 and October 2020 at The National Hospital for Neurology and Neurosurgery in London. Patients demographics, radiological, surgical, endocrinological and, histological data were retrieved. We assessed the accuracy of IPSS in localizing ACTH secreting pituitary adenoma and its concordance with neuroimaging and surgical findings at the time of tumor resection. Results: In total 68 patients underwent IPSS, 22 males and 46 females. The median age was 42 years. IPSS was performed prior to primary surgery in 61 patients (90%) and before secondary surgery in 4 patients (6%). Three patients (4%) are awaiting surgery at the time of our study. Fifty-two patients (80%) had positive histology of ACTH expressing adenoma. Four patients (8%) had ectopic ACTH syndrome. The sensitivity of IPSS in predicting Cushing’s disease prior to corticotropin-releasing hormone (CRH) stimulation was 91% (95% CI [83% to 97%]) and accuracy of 88% (95% CI [77% to 95%]). The sensitivity of IPSS post CRH administration was 96% (95% CI [87% to 100%]) with accuracy of 86% (95% CI [75% to 93%]). Data on lateralization of pituitary adenoma were available for 63 patients. Prior to CRH stimulation, lateralization was right sided in 35 patients (56%), left sided in 15 (24%), and 13 patients (20%) did not have adequate interpetrosal sinus ACTH ratio. Lateralization post CRH stimulation was right sided in 40 patients (64%), left sided in 20 (32%), and 3 patients (4%) did not achieve adequate ACTH gradient ratio between two sides. Eighteen patients (30%) switched adenoma lateralization between pre and post CRH stimulation. Post CRH IPSS was consistent with neuroradiology in localizing pituitary adenomas in 59% (29 out of 49 patients) and concordant with surgical findings in 41% (25 out of 61 patients). Patients with ectopic ACTH syndrome had negative IPSS at all stages. IPSS procedure failed in 2 patients (3%). No post procedure complications were reported. Conclusion: IPSS has high sensitivity in diagnosing pituitary driven Cushing’s disease with good safety profile. However, the reliability in lateralizing pituitary adenoma is debated. One third of patients in this cohort switched lateralization before and after CRH administration. Studies on monkeys and rats showed that CRH induces coronary vasodilation and reduction in systemic vascular resistance. This suggest that CRH might have vasoactive effect on pituitary blood vessels with subsequent influence on IPS:P ACTH gradient ratio between the two sides.

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Selective Venous Sampling for ACTH in Cushing’s Syndrome: Differentiation Between Cushing’s Disease and the Ectopic ACTH Syndrome

The Journal of Urology ◽

10.1016/s0022-5347(17)53960-9 ◽

1982 ◽

Vol 127 (3) ◽

pp. 618-619

Author(s):

J.W. Findling ◽

D.C. Aron ◽

J.B. Tyrrell ◽

J.H. Shinsako ◽

P.A. Fitzgerald ◽

...

Keyword(s):

Cushing’S Syndrome ◽

Cushing’S Disease ◽

Cushing's Syndrome ◽

Cushing's Disease ◽

Ectopic Acth Syndrome ◽

Syndrome Differentiation ◽

Venous Sampling ◽

Ectopic Acth ◽

Selective Venous Sampling

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Intraoperative Adrenocorticotropin Levels During Transsphenoidal Surgery for Cushing’s Disease Do Not Predict Cure

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jcem.82.6.4005 ◽

1997 ◽

Vol 82 (6) ◽

pp. 1776-1779

Author(s):

Kathryn E. Graham ◽

Mary H. Samuels ◽

Hershel Raff ◽

Stanley L. Barnwell ◽

David M. Cook

Keyword(s):

Cushing’S Disease ◽

Pituitary Tumor ◽

Transsphenoidal Surgery ◽

Tumor Resection ◽

Cushing's Disease ◽

Ectopic Acth Syndrome ◽

Plasma Acth ◽

Tumor Removal ◽

Ectopic Acth ◽

Percentage Decrease

Abstract Recently, intraoperative rapid immunochemiluminometric assay (ICMA) ACTH measurements have been used to evaluate the completeness of resection of ectopic ACTH-secreting tumors. This study evaluates whether this method can be applied to patients undergoing transsphenoidal surgery (TSS) for Cushing’s disease to predict complete pituitary tumor resection. Eighteen patients with Cushing’s disease undergoing TSS had plasma ACTH concentrations measured by a standard ICMA every 10 min for 1 h immediately after pituitary tumor removal. Patients were evaluated postoperatively for cure by standard criteria. ACTH levels were evaluated for percentage decrease from baseline at each time point. Patients who were cured (n = 11) had statistically greater decreases in ACTH levels (mean decrease 54%) than patients who were not (n = 7; 26% mean decrease, P < 0.04). By Receiver-Operator Characteristic (ROC) analysis, a reduction of at least 40% best predicted which patients were cured and which were not cured. This level of reduction was observed in 82% of cured patients, and a reduction of less than 40% was observed in 71% of those not cured. The analysis misclassified 4 of the 18 patients, resulting in a diagnostic accuracy of 78%. Although the mean maximal decrease in ACTH concentrations after tumor removal was significantly different between cured and not cured patients with Cushing’s disease, it was less dramatic than results in the previous ectopic ACTH study. This may relate to incomplete suppression and/or surgical manipulation of normal pituitary corticotrophs in patients with pituitary disease. In summary, in contrast to the ectopic ACTH syndrome, decline of plasma ACTH during TSS does not accurately predict complete tumor resection.

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Usefulness of inferior petrosal sinus venous endocrine markers in Cushing's disease

Journal of Neurosurgery ◽

10.3171/jns.1988.68.2.0205 ◽

1988 ◽

Vol 68 (2) ◽

pp. 205-210 ◽

Cited By ~ 30

Author(s):

John Zovickian ◽

Edward H. Oldfield ◽

John L. Doppman ◽

Gordon B. Cutler ◽

D. Lynn Loriaux

Keyword(s):

Cushing’S Disease ◽

Venous Blood ◽

Pituitary Hormones ◽

Cushing's Disease ◽

Ectopic Acth Syndrome ◽

Inferior Petrosal Sinus ◽

Ectopic Acth ◽

Content Type ◽

Acth Secreting ◽

Fine Print

✓ Bilateral and simultaneous sampling of the inferior petrosal sinuses in patients with Cushing's disease has been used to establish the presence and laterality of adrenocorticotropic hormone (ACTH)-producing microad-enomas prior to transsphenoidal surgery. Successful preoperative lateralization depends upon equivalent dilution of pituitary venous blood on the two sides since samples which are diluted by unequal amounts of non-pituitary blood may lead to erroneous results. To assure valid sampling results, the use of other pituitary hormones, measured simultaneously, has been proposed to correct the ACTH concentrations from the inferior petrosal sinuses against unequal dilution by non-pituitary venous blood. This proposal presumes that ACTH-secreting microadenomas will not cause unequal delivery of the other pituitary hormones into the two inferior petrosal sinuses. The inferior petrosal sinus concentrations of prolactin (PRL), thyrotropin (TSH), and the alpha subunit of human chorionic gonadotropin (α-HCG) were evaluated as indicators of pituitary venous blood dilution in 11 patients with Cushing's disease. Four patients with ectopic ACTH syndrome served as controls. Blood was withdrawn simultaneously from catheters in both inferior petrosal sinuses and from a peripheral vein for measurement of ACTH, PRL, TSH, and α-HCG. The ACTH concentrations were then corrected for dilution by non-pituitary blood by dividing the ACTH concentration from each side by the ratio of the inferior petrosal sinus to peripheral blood concentrations of PRL, TSH, and α-HCG for that side. At surgery, all 11 patients had ACTH-secreting microadenomas on the side predicted by the uncorrected ACTH concentrations. However, in three patients the corrected ACTH values would have led to erroneous results. Among the 18 sets of corrected inferior petrosal sinus measurements in these three patients, the corrected ACTH values failed to show an inferior petrosal sinus gradient in six and localized the tumor to the side opposite the adenoma in four. Incorrect lateralization was obtained with each of the hormones (PRL, TSH, and α-HCG) used for correction. Furthermore, the ipsilateral (side of tumor)-to-contralateral inferior petrosal sinus gradient of ACTH in patients with Cushing's disease was generally paralleled by a significant inferior petrosal sinus gradient of PRL, TSH, and α-HCG to the side of the tumor, whereas patients with the ectopic ACTH syndrome tended not to exhibit lateralizing (side-to-side) gradients. These findings indicate that the simultaneous measurement of inferior petrosal sinus concentrations of PRL or TSH or of the glycoprotein hormone α subunit does not improve preoperative localization of ACTH-secreting microadenomas and may lead to incorrect lateralization of the tumor. The results also suggest that ACTH-secreting microadenomas cause enhanced delivery of PRL, TSH, and α subunit into the inferior petrosal sinus ipsilateral to the tumor which, in turn, may reflect paracrine stimulation of hormone secretion in the anterior pituitary gland surrounding ACTH-secreting microadenomas.

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Treatment of Adrenocorticotropin-Dependent Cushing’s Syndrome: A Consensus Statement

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2007-2734 ◽

2008 ◽

Vol 93 (7) ◽

pp. 2454-2462 ◽

Cited By ~ 540

Author(s):

B. M. K. Biller ◽

A. B. Grossman ◽

P. M. Stewart ◽

S. Melmed ◽

X. Bertagna ◽

...

Keyword(s):

Medical Therapy ◽

Cushing’S Syndrome ◽

Cushing’S Disease ◽

Consensus Statement ◽

Tumor Resection ◽

Cushing's Syndrome ◽

Scientific Data ◽

Cushing's Disease ◽

Ectopic Acth Syndrome ◽

Ectopic Acth

Abstract Objective: Our objective was to evaluate the published literature and reach a consensus on the treatment of patients with ACTH-dependent Cushing’s syndrome, because there is no recent consensus on the management of this rare disorder. Participants: Thirty-two leading endocrinologists, clinicians, and neurosurgeons with specific expertise in the management of ACTH-dependent Cushing’s syndrome representing nine countries were chosen to address 1) criteria for cure and remission of this disorder, 2) surgical treatment of Cushing’s disease, 3) therapeutic options in the event of persistent disease after transsphenoidal surgery, 4) medical therapy of Cushing’s disease, and 5) management of ectopic ACTH syndrome, Nelson’s syndrome, and special patient populations. Evidence: Participants presented published scientific data, which formed the basis of the recommendations. Opinion shared by a majority of experts was used where strong evidence was lacking. Consensus Process: Participants met for 2 d, during which there were four chaired sessions of presentations, followed by general discussion where a consensus was reached. The consensus statement was prepared by a steering committee and was then reviewed by all authors, with suggestions incorporated if agreed upon by the majority. Conclusions: ACTH-dependent Cushing’s syndrome is a heterogeneous disorder requiring a multidisciplinary and individualized approach to patient management. Generally, the treatment of choice for ACTH-dependent Cushing’s syndrome is curative surgery with selective pituitary or ectopic corticotroph tumor resection. Second-line treatments include more radical surgery, radiation therapy (for Cushing’s disease), medical therapy, and bilateral adrenalectomy. Because of the significant morbidity of Cushing’s syndrome, early diagnosis and prompt therapy are warranted.

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Immunochistochemical characteristics of blood vessels in non-visualized and visualized on MRI pituitary adenoma in patients with Cushing’s disease

Problems of Endocrinology ◽

10.14341/probl201662565-66 ◽

2016 ◽

Vol 62 (5) ◽

pp. 65-66

Author(s):

Patimat M. Khandaeva ◽

Iya A. Voronkova ◽

Zhanna E. Belaya ◽

Lyudmila Y. Rozhinskaya ◽

Aleksandr V. Vorontsov ◽

...

Keyword(s):

Pituitary Adenoma ◽

Blood Vessels ◽

Cushing’S Disease ◽

Pituitary Tumor ◽

Pituitary Tumors ◽

Average Diameter ◽

Cushing's Disease ◽

Retrospective Evaluation ◽

Acth Secreting ◽

Microvessels Density

Backgraund. Regardless of improvements in MRI, up to 20% of ACTH-secreting pituitary tumors are only identified at surgical exploration.Aim: to estimate whether there is any difference in blood vessels and the subsequent ability to uptake contrast agent in visualized microadenoma as compared to non-visualized on MRI ACTH-secreting pituitary tumors.Materials and methods. retrospective evaluation of ACTH-positive pituitary tumors from patients with Cushing’s disease (n=39) with either non-visualized pituitary tumor on MRI (n=17) or pituitary tumor less then 25 mm (n=22). MRI was performed using Siemens Magnetom Harmony 1.0T with gadolinium. Selected tumors were stained with anty-СD34 antibody (clone QBEnd/10, RTU, Leica) and anty-D2-40 antibody (clone D2-40, RTU, Dako). We evaluated the microvessels density and measured the diameter of larger and smaller vessel.Results. The microvessels density were not different in subject with visualized (123 [77;136]) and non-visualized (112 [110,0;126,5]) pituitary adenomas as well as number of slit-shaped vessels (32 [5;50] in visualized vs 25 [5;50] in non-visualized pituitary adenoma). The diameter of these vessels also did not differ: the diameter of the largest vessels in patients without visualization 53 µm [32,5;63,5] vs 33 µm [30,0;51,5], the average diameter of the blood vessels 15 µm [14,5-26,0] against 13 µm [12;14].Conclusions. The diameter and microvessels density in ACTH-producing pituitary adenoma does not affect the visualization of adenoma on MRI in patients with Cushing 's disease.

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Ectopic ACTH syndrome caused by bronchial carcinoid tumor indistinguishable from Cushing’s disease

Endocrine Journal ◽

10.1507/endocrj.k10e-129 ◽

2010 ◽

Vol 57 (8) ◽

pp. 679-686 ◽

Cited By ~ 10

Author(s):

Yuji Tani ◽

Toru Sugiyama ◽

Shinichi Hirooka ◽

Hajime Izumiyama ◽

Yukio Hirata

Keyword(s):

Carcinoid Tumor ◽

Cushing’S Disease ◽

Cushing's Disease ◽

Ectopic Acth Syndrome ◽

Bronchial Carcinoid ◽

Ectopic Acth

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Cushing’s Syndrome: Important Issues in Diagnosis and Management

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2006-0997 ◽

2006 ◽

Vol 91 (10) ◽

pp. 3746-3753 ◽

Cited By ~ 196

Author(s):

James W. Findling ◽

Hershel Raff

Keyword(s):

Cushing’S Syndrome ◽

Cushing’S Disease ◽

Evidence Synthesis ◽

Somatostatin Receptor ◽

Cushing's Syndrome ◽

Cushing's Disease ◽

Ectopic Acth Syndrome ◽

Ectopic Acth ◽

Late Night ◽

Recent Monograph

Abstract Context: The diagnosis, differential diagnosis, and treatment of Cushing’s syndrome are challenging problems in clinical endocrinology. We focus on critical questions addressing screening for Cushing’s syndrome, differentiation of Cushing’s subtypes, and treatment options. Evidence Acquisition: Ovid’s MEDLINE (1996 through April 2006) was used to search the general literature. We also relied on previously published reviews and a recent monograph and cite a mix of primary articles and recent reviews. Evidence Synthesis: Although this article represents our opinion, it draws heavily on a recent consensus statement from experts in the field and a recent monograph on Cushing’s syndrome. Conclusions: We concluded that: 1) measurement of late-night or bedtime salivary cortisol is a useful approach to screen for Cushing’s syndrome; 2) measurement of suppressed plasma ACTH by immunometric assay is useful to differentiate ACTH-dependent and -independent Cushing’s syndrome; 3) inferior petrosal sinus sampling for ACTH should be performed in patients with ACTH-dependent hypercortisolism in whom a pituitary magnetic resonance imaging is normal or equivocal (in the absence of a pituitary ACTH gradient, prolactin levels should be measured to confirm the integrity of venous sampling); 4) computed tomography of the chest and abdomen and somatostatin receptor scintigraphy should be performed in patients with the occult ectopic ACTH syndrome; and 5) patients with Cushing’s disease should be referred to a neurosurgeon with extensive experience operating on corticotroph microadenomas. Bilateral laparoscopic adrenalectomy should be considered in patients with Cushing’s disease who fail therapies directed at the pituitary.

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Cavernous Sinus Sampling Is Highly Accurate in Distinguishing Cushing’s Disease from the Ectopic Adrenocorticotropin Syndrome and in Predicting Intrapituitary Tumor Location1

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jcem.84.5.5654 ◽

1999 ◽

Vol 84 (5) ◽

pp. 1602-1610 ◽

Cited By ~ 1

Author(s):

Kathryn E. Graham ◽

Mary H. Samuels ◽

Gary M. Nesbit ◽

David M. Cook ◽

Oisin R. O’Neill ◽

...

Keyword(s):

Cavernous Sinus ◽

Cushing’S Disease ◽

Tumor Location ◽

Cushing's Disease ◽

Ectopic Acth Syndrome ◽

Plasma Acth ◽

Catheter Position ◽

Venous Flow ◽

Ectopic Acth ◽

Before And After

Inferior petrosal sinus sampling (IPSS) is used to distinguish pituitary Cushing’s disease from occult cases of the ectopic ACTH syndrome, but is limited in that it requires the use of ovine CRH (oCRH) and is not highly accurate at predicting the intrapituitary location of tumors. This study was designed to determine whether cavernous sinus sampling (CSS) is as safe and accurate as IPSS, whether CSS can eliminate the need for oCRH stimulation, and whether CSS can accurately predict the intrapituitary location of tumors. Ninety-three consecutive patients with ACTH-dependent Cushing’s syndrome were prospectively studied with bilateral, simultaneous CSS before and after oCRH stimulation. Prediction of a pituitary or ectopic ACTH source was based on cavernous/peripheral plasma ACTH ratios. Intrapituitary tumor location was predicted based on lateralization (side to side) ACTH ratios. These predictions were compared to surgical outcome in the 70 patients who had surgically proven pituitary (n= 65) or ectopic (n = 5) disease. CSS distinguished pituitary Cushing’s disease from the ectopic ACTH syndrome in 93% of patients with proven tumors before oCRH administration and in 100% of patients with proven tumors after oCRH. It was as safe and efficacious as published IPSS results. CSS accurately predicted the intrapituitary lateralization of the tumor in 83% of all patients and 89% of those patients with good catheter position and symmetric venous flow. CSS is as safe and accurate as IPSS for distinguishing patients with pituitary Cushing’s disease from those with the ectopic ACTH syndrome. In addition, CSS appears to be superior to IPSS for predicting intrapituitary tumor lateralization.

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Two Distinctive POMC Promoters Modify Gene Expression in Cushing’s Disease

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/clinem/dgab387 ◽

2021 ◽

Author(s):

Takako Araki ◽

Yukiko Tone ◽

Masaaki Yamamoto ◽

Hiraku Kameda ◽

Anat Ben-Shlomo ◽

...

Keyword(s):

Cushing’S Disease ◽

Methylation Status ◽

Regulatory Region ◽

Pituitary Tumors ◽

Cushing's Disease ◽

Human Pituitary ◽

Ectopic Acth ◽

Pomc Gene ◽

Acth Secreting

Abstract Context Mechanisms underlying pituitary corticotroph adenoma ACTH production are poorly understood, yet circulating ACTH levels closely correlate with adenoma phenotype and clinical outcomes. Objective We characterized the 5’ ends of proopiomelanocortin (POMC) gene transcripts, which encode the precursor polypeptide for ACTH, in order to investigate additional regulatory mechanisms of POMC gene transcription and ACTH production. Methods We examined 11 normal human pituitary tissues, 32 ACTH-secreting tumors, as well as 6 silent pituitary corticotroph adenomas (SCA) that immunostain for but do not secrete ACTH. Results We identified a novel regulatory region located near the intron2/exon3 junction in the human POMC gene, which functions as a second promoter and an enhancer. In vitro experiments demonstrated that CREB binds the second promoter and regulates its transcriptional activity. The second promoter is highly methylated in SCA, partially demethylated in normal pituitary tissue, and highly demethylated in pituitary and ectopic ACTH-secreting tumors. In contrast, the first promoter is demethylated in all POMC-expressing cells and is highly demethylated only in pituitary ACTH-secreting tumors harboring the USP8 mutation. Demethylation patterns of the second promoter correlate with clinical phenotypes of Cushing’s disease. Conclusion We identified a second POMC promoter regulated by methylation status in ACTH-secreting pituitary tumors. Our findings open new avenues for elucidating subcellular regulation of the hypothalamic-pituitary-adrenal axis and suggest the second POMC promoter may be a target for therapeutic intervention to suppress excess ACTH production.

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