Inferior Petrosal Sinus Sampling Research Articles

Personalized non-invasive diagnostic algorithms based on urinary free cortisol in ACTH-dependant Cushing's syndrome.

Current guidelines for distinguishing Cushing's disease (CD) from ectopic ACTH secretion (EAS) are questionable, as they use pituitary MRI as first-line investigation for all patients, CRH testing is no longer available and they suggest performing inferior petrosal sinus sampling (BIPPS), an invasive and rarely available investigation, in many patients. To establish non-invasive personalized diagnostic strategies based on the probability of EAS estimated from simple baseline parameters. Retrospective study. University hospitals. 247 CD and 36 EAS patients evaluated between 2001 and 2023 in 2 French hospitals. A single-center cohort of 105 Belgian patients served for external validation. 24h-urinary free cortisol (UFC) had the highest area under ROC curve for discrimination of CD from EAS (0·96 [95% CI, 0·92-0·99] in the primary study and 0·99 [95% CI, 0·98-1·00] in the validation cohort). The addition of clinical, imaging and biochemical parameters did not improve EAS prediction over UFC alone, with only BIPPS showing a modest improvement (c-statistic index 0·99 [95% CI, 0·97-1·00]). 3 groups were defined based on baseline UFC: < 3 (group one), 3-10 (group 2) and > 10 x the upper limit of normal (group 3), and were associated with 0%, 6·1% and 66·7% prevalence of EAS, respectively. Diagnostic approaches performed in our cohort support the use of pituitary MRI alone in group one, MRI first followed by neck-to-pelvis CT-scan (npCT) when negative in group 2, and npCT first followed by pituitary MRI when negative in group 3. When not combined with the CRH test, the desmopressin test has limited diagnostic value. UFC accurately predicts EAS and can serve to define personalized and non-invasive diagnostic algorithms.

Bilateral inferior petrosal sinus sampling in the differential diagnosis of ACTH-dependent Cushing's syndrome: A reappraisal.

Cushing's syndrome (CS) is a rare disorder, once exogenous causes have been excluded. However, when diagnosed, the majority of cases are adrenocorticotropic hormone (ACTH)-dependent, of which a substantial minority are due to a source outside of the pituitary, ectopic ACTH syndrome (EAS). Differentiating among pituitary-dependent CS, Cushing's disease (CD) and an ectopic source can be problematic. Because non-invasive tests in the evaluation of CS patients often lack adequate sensitivity and specificity, bilateral inferior petrosal sinus sampling (BIPSS), a minimally invasive procedure performed during the investigation of ACTH-dependent CS, can be extremely helpful. BIPSS is considered to be the gold standard for differentiating CD from the EAS. Furthermore, although such differentiation may indeed be challenging, BIPSS is itself a complex investigation, especially in recent times due to the widespread withdrawal of corticotrophin-releasing hormone and its replacement by desmopressin. We review current published data on this investigation and, in the light of this and our own experience, discuss its appropriate use in diagnostic algorithms.

The diagnostic yield of inferior petrosal sinus sampling in Cushing syndrome in the era of ovine CRH shortage

PurposeThe ovine corticotropin-releasing hormone (oCRH) stimulation test has been routinely used in the diagnostic work-up of ACTH-dependent Cushing syndrome (CS). With oCRH currently being out-of-stock in Europe, we aimed at evaluating the diagnostic performance of inferior petrosal sinus sampling (IPSS) without oCRH stimulation.MethodsWe compared the values of 40 patients with ACTH-dependent CS and negative MRI findings in whom ACTH was measured before and after oCRH stimulation.ResultsThe ratio of central-to-peripheral ACTH measurement (IPS:P) before the combined 3, 5, and 10 min of oCRH stimulation yielded diminished sensitivity (85% vs. 97%), alongside markedly decreased specificity (57% vs. 71%), as well as reduced positive and negative predictive values (90% vs. 94% and 44% vs. 83%), respectively.ConclusionsWith the current drug shortages in Europe, ACTH measurements without oCRH stimulation in IPSS cannot be recommended. Thus, we call for desmopressin or the commercially available human CRH as a potential alternative in the confirmation of ACTH excess by IPSS in equivocal MRI findings.

[18F]FET PET/MRI: An Accurate Technique for Detection of Small Functional Pituitary Tumors.

Small functional pituitary tumors can cause severely disabling symptoms and early death. The gold standard diagnostic approach includes laboratory tests and MRI, with or without inferior petrosal sinus sampling (IPSS). In up to 40% of patients, however, the source of excess hormone production remains unidentified or uncertain. This excludes patients from surgical, Gamma Knife, and CyberKnife therapy and adversely affects overall cure rates. We here assess the diagnostic yield of O-(2-[18F]fluoroethyl)-l-tyrosine ([18F]FET) PET/MRI for detection of small functional pituitary tumors in these patients. Methods: This retrospective analysis included patients with Cushing disease (CD) but prior negative or inconclusive MRI results who underwent [18F]FET PET/MRI between February 1, 2021, and December 1, 2022. PET/MR images and MR images alone were evaluated by experienced nuclear radiologists, neuroradiologists, or radiologists. Postoperative tissue analysis (when performed) was used as a reference standard to assess diagnostic metrics (i.e., sensitivity and positive predictive value). Results were also compared with previously obtained MR images, preceding IPSS, and clinical or biochemical follow-up. Results: Twenty-two patients (68% female; mean age ± SD, 48 ± 15 y; range, 24-68 y) were scanned. All patients showed a clear metabolic focus on [18F]FET PET, whereas reading of the MRI alone yielded a suspected lesion in only 50%. Fifteen patients underwent surgery directed at the [18F]FET-positive focus. Tissue analysis confirmed a pituitary adenoma/pituitary neuroendocrine tumor of the corticotroph cell type (TPIT lineage) in 10 of 15 and a pituicytoma in 1 of 15, rendering a sensitivity of 100% and a positive predictive value of 73%. Lateralization was more accurate with [18F]FET PET/MRI than with IPSS in 33%. Twelve of 16 (75%) patients who received surgical, Gamma Knife, or CyberKnife therapy after [18F]FET PET/MRI reached short-term remission. Conclusion: [18F]FET PET/MRI shows a high diagnostic yield for localizing small functional pituitary tumors. This multimodal imaging technique provides a welcome improvement for diagnosis, planning of surgery, and clinical outcome in patients with Cushing disease, particularly those with repeated negative or inconclusive MRI results with or without IPSS.

Bilateral Inferior Petrosal Sinus Sampling Without Lateralization Is Less Accurate for the Diagnosis of Cushing Disease

Abstract Context During bilateral inferior petrosal sinus sampling (BIPSS), the side-to-side adrenocorticotropic hormone (ACTH) ratio, referred to as sampling lateralization, was used to predict pituitary adenoma localization. Objective To investigate the potential different diagnostic accuracy of BIPSS for differentiating Cushing disease (CD) and ectopic ACTH secretory syndrome (EAS) patients with low lateralization (inferior petrosal sinus [IPS]:IPS ≤ 1.4) and high lateralization (IPS:IPS &amp;gt; 1.4). Methods This single-center retrospective study (2011-2021) included (all patients had BIPSS results and confirmed pathologic diagnoses) 220 consecutive CD patients (validation set), 30 EAS patients, and 40 of the CD patients who had digital subtraction angiography (DSA) videos (discovery set). Results In the discovery set, the low-lateralization CD group (n = 11) had a higher median plasma ACTH concentration (62.2, IQR 44.7-181.0 ng/L) than the high-lateralization CD group (n = 29) (33.0, IQR 18.5-59.5, P = .013). Lower IPS to peripheral ratios were observed in the low-lateralization group during BIPSS, both before and after stimulation (P = .013 and P = .028). The sensitivity of BIPSS before stimulation in differentiating CD from EAS was lower in the low-lateralization group than the high-lateralization group (54.6% vs 93.1%, P = .003), as validated in the validation set. DSA videos revealed higher vascular area difference visible in the 2 sides of the pituitary in low lateralization (median 1.2 × 105 pixels, IQR 0.5-1.8) than the high-lateralization group (0.4 × 105 pixels, IQR 0.1-0.7, P = .008). The vascular area ratio of the 2 sides was also significantly higher in low (1.55, IQR 1.31-2.20) than high lateralization (1.19, IQR 1.07-1.35, P = .010). Conclusion Our study suggested that low lateralization in CD patients may reduce the diagnostic sensitivity of BIPSS, which might be potentially associated with peripituitary vascular anatomy.

Prevalence of endocrine disorders in 304 premenopausal women referred with oligomenorrhoea.

We aimed to evaluate 304 premenopausal women admitted to our clinic for oligomenorrhoea, and to screen for Cushing's syndrome (CS) in this population. The study included 304 premenopausal women referred to our clinic for oligomenorrhoea. Anthropometric measurements and Ferriman-Gallwey score were evaluated, and thyroid hormone, follicle-stimulating hormone (FSH), luteinizing hormone (LH), total testosterone, prolactin, dehydroepiandrosterone sulphate (DHEA-S), and 17-hydroxyprogesterone (17-OHP) levels were measured in all patients. If basal 17-OHP was > 2 ng/mL, we evaluated adrenocorticotropic hormone (ACTH)-stimulated 17-OHP levels. CS was screened by 1 mg-dexamethasone suppression test, and if the cortisol value was > 1.8 μg/dL, we performed additional confirmatory tests, and if necessary, pituitary magnetic resonance imaging (MRI) and inferior petrosal sinus sampling (IPSS) were performed. The most common cause of oligomenorrhoea was polycystic ovary syndrome (PCOS) that was detected in 81.57% of cases, followed by hyperprolactinemia at 7.23% and hypothalamic anovulation at 5.26%. The prevalence of premature ovarian failure (POF) was 1.6%, and non-classical congenital adrenal hyperplasia (NCAH) was 1.97%. CS was detected in 7 (2.30%) patients. All the patients with CS were found to have Cushing's disease (CD). Although 3 patients with CD had classical signs and symptoms, 4 had none. Patients with CD had similar total testosterone values to those in the PCOS and NCAH groups, but they had significantly higher DHEA-S compared to both groups (CD vs. PCOS, p = 0.001 and CD vs. NCAH, p = 0.030). We found higher prevalence of CS in patients with oligomenorrhoea even in the absence of clinical signs. Therefore, we suggest routine screening for CS during the evaluation of patients with oligomenorrhoea and/or PCOS. The likelihood of CS is greater in patients with high androgen, especially DHEA-S levels.

Utility of Simple and Non-Invasive Strategies Alternative to Inferior Petrosal Sinus Sampling and Peripheral CRH Stimulation in Differential Diagnosis of ACTH-Dependent Cushing Syndrome.

We aimed to evaluate the utility of simple, cost-effective, and non-invasive strategies alternative to BIPSS and peripheral CRH stimulation in differential diagnosis of ACTH-dependent CS. First, we performed ROC analysis to evaluate the performance of various tests for differential diagnosis of ACTH-dependent CS in our cohort (CD, n=76 and EAS, n=23) and derived their optimal cut-offs. Subsequently, combining various demographic (gender), clinical (hypokalemia), biochemical (plasma ACTH, HDDST, peripheral CRH stimulation) and imaging (MRI pituitary) parameters, we derived non-invasive models with 100% PPV for CD. Patients with pituitary macroadenoma (n=14) were excluded from the analysis involving non-invasive models. Relative percent ACTH (AUC: 0.933) and cortisol (AUC: 0.975) increase on peripheral CRH stimulation demonstrated excellent accuracy in discriminating CD from EAS. Best cut-offs for CD were plasma ACTH<97.3 pg/ml, HDDST≥57% cortisol suppression, CRH stimulation≥77% ACTH increase and≥11% cortisol increase. We derived six models that provided 100% PPV for CD and precluded the need for BIPPS in 35/85 (41.2%) patients with ACTH-dependent CS and no macroadenoma (in whom BIPSS would have otherwise been recommended). The first three models included basic parameters and avoided both peripheral CRH stimulation and BIPSS in 19 (22.4%) patients, while the next three models included peripheral CRH stimulation and avoided BIPSS in another 16 (18.8%) patients. Using simple and non-invasive alternative strategies, BIPSS can be avoided in 41% and peripheral CRH stimulation in 22% of patients with ACTH-dependent CS and no macroadenoma; such patients can be directly referred for a pituitary surgery.

Angiographic cross-filling between inferior petrosal sinuses and alteration of adrenocorticotropic hormone sampling results for tumor localization in Cushing disease.

Inferior petrosal sinus (IPS) sampling (IPSS) is a diagnostic procedure used to guide diagnostic localization of imaging-negative adrenocorticotropic hormone (ACTH)-secreting pituitary microadenomas. However, the efficacy of IPSS has been suboptimal at accurately lateralizing the adenoma, reducing surgical cure rates and leading to unintended pituitary dysfunction due to the added exploration. One rationale for the occasional imprecision is the existence of additional petrosal sinus collateral channels that connect the IPS bilaterally, which may lead to false localization results during sampling. The aim of this study was to explore a potential connection between normal anatomical variation in the angioarchitecture of the IPSs and the ACTH results obtained in subsequent IPSS tests. A retrospective review was performed on all cases between 1998 and 2013 involving patients at a single institution who underwent IPSS for radiographically equivocal pituitary microadenomas. Cases were reviewed for tumor laterality noted on either operative or pathology reports, as well as the presence of angiographic evidence of cross-filling between the sinuses. In addition, ACTH levels from the right and left IPSs were documented at baseline and at 2, 5, and 10 minutes after corticotropin-releasing hormone (CRH) administration. A ratio of the change in ACTH levels measured at the time of maximal response (10 minutes) versus the levels measured at the initial response (2 minutes) was computed for each patient and compared between patients by their angiographic cross-filling status. There were 41 patients with a histopathologically confirmed right- or left-sided ACTH-secreting pituitary microadenoma who underwent preoperative IPSS. Among these patients, 28 (68%) showed angiographic evidence of cross-filling between the IPSs, and 13 showed no cross-filling. On average, ACTH levels increased by a factor of 3.91 ± 0.77 in the contralateral IPS in patients with angiographic cross-filling, compared with a factor increase of only 1.80 ± 0.27 in patients without cross-filling (p = 0.014). In comparison, ACTH levels increased by a factor of 2.01 ± 0.57 in the ipsilateral IPS in patients with cross-filling, and by 8.78 ± 7.30 in those without cross-filling (p = 0.373). The presence of angiographic cross-filling, suggestive of a greater degree of vascular channel networking between the right and left IPS, is a significant factor influencing the measured rates of change of ACTH in IPSS and may impact the specificity of this test to accurately determine microadenoma laterality in the preoperative setting.

Bilateral simultaneous sampling of the cavernous and inferior petrosal sinuses in the differential diagnosis of Cushing’s disease

Background. Currently, the “gold standard” of differential diagnosis of Cushing’s disease is inferior petrosal sinus sampling and measurement of the adenocorticotropic hormone (ACTH) level. The studied literature data indicate a wide variability in the sensitivity and specificity of inferior petrosal sinus sampling in the range of 85–100 and 67–100 %, respectively, which can lead to an erroneous diagnosis of the source of ACTH hyperproduction and, as a consequence, to incorrect and untimely treatment.Aim.To improve the results of differential diagnosis of Cushing»s disease by using bilateral simultaneous sampling of the cavernous and inferior petrosal sinuses.Materials and methods. Cohort single-center retro/prospective study of 70 patients with confirmed ACTH-dependent Cushing’s syndrome. For the purpose of differential diagnosis, a number of indicators were calculated: central-peripheral ratio, prolactin-normalized ACTH ratio, successful catheterization. Sampling results were evaluated in comparison with contrast-enhanced pituitary magnetic resonance imaging data and intraoperative data.Results. The study of the central-peripheral ratio showed the need to assess it simultaneously at the level of the cavernous and inferior petrosal sinuses. This approach makes it possible to significantly increase the sensitivity and specificity of the applied gradient to 93.1 and 85.7 %, respectively. Prolactin-normalized ACTH ratio is a second line predictor in the differential diagnosis of Cushing’s disease with sensitivity and specificity reaching 94.7 and 28.6 %, respectively. The gradient of successful catheterization is a reflection of possible hemodynamic features of a particular sinus, does not serve as an indicator of the correct positioning of microcatheters in the vascular bed.Conclusion. Bilateral simultaneous sampling of the cavernous and inferior petrosal sinuses is an effective method of differential diagnosis of Cushing’s disease and ectopic ACTH-dependent syndrome.

[Diagnostic value of bilateral inferior petrosal sinus sampling in various modifications and methods of radiation and radionuclide imaging in the diagnosis and differential diagnosis of ACTH-dependent endogenous hypercortisolism].

To analyze the diagnostic performance of bilateral inferior petrosal sinus sampling (BIPSS) with desmopressin as a stimulation agent and prolactin measurements to control catheter position with or without the ACTH/prolactin normalized ratio calculation in the differential diagnosis of ACTH-dependent endogenous hypercortisolism, and the diagnostics performance of ectopic ACTH-syndrome (EAS) visualization. A single-center diagnostic study with a retrospective analysis of the data was carried out. The study included patients with ACTH-dependent endogenous hypercorticism with no visualization of pituitary adenoma on MRI or adenoma sizes less than 6 mm. All patients underwent BIPSS with and without calculation of the ACTH/prolactin normalized ratio. Visualization of an EAS included pituitary MRI (to exclude EAS), whole-body CT scan with contrast, and somatostatin receptor scintigraphy with 99mTc-Tectrotide and CT (99mTc-Tectrotide SPECT). The final verification was based on immunohistochemical confirmation of the tumor or stable remission of Cushing's disease (CD) after surgical treatment. Statistical data processing was carried out by using IBM SPSS Statistics 23. Confidence intervals were calculated using the JavaStat online calculator. 230 BIPSS were performed in 228 patients (166 women, 62 men), of which 178 patients were verified as CD and 50cases were EAS of various localization. The effectiveness of catheterization of petrosal sinuses was 96.9%. The sensitivity of BIPSS without ACTH/prolactin ratio calculation (n=70) was 95.9% (95% CI 86.3-98.9), specificity was 92% (95% CI 75.0-97.8), for the BIPSS with additional determination of ACTH/prolactin-normalized ratio (n=51) - 97.3% (95% CI 86.2-99.5) and 93.8% (95% CI 71.7-98.9), respectively. The use of the MRI method for this sample of patients had a sensitivity of 60.2% (95% CI 52.6-67.5), specificity of 59.2% (95% CI 44.2-73.0), the total body CT with contrast has a sensitivity of 74% (95% CI 59.7-85.4), specificity of 100% (95% CI 97.95-100). The diagnostic accuracy for 99mTc-Tectrotide SPECT in NET visualization has a sensitivity of 73.3% (95% CI 44.9-92.2), specificity of 100% (95% CI 95.3-100). BIPSS with desmopressin stimulation and prolactin measurements to control catheter position, as well as the additional calculation of the ACTH/prolactin-normalized ratio, is an optimal method for the differential diagnosis of EAS. Patients who are identified an EAS on BIPSS may be further referred for 99mTc-Tectrotide SPECT and CT for tumor visualization.

P-61 From Cushing to Nelson Syndrome: Diagnostic challenges and Surgical Dilemma

Abstract Introduction Diagnosis of the origin of ACTH-dependent Cushing's syndrome (CS) can be difficult in some cases, especially when MRI of the pituitary gland does not reveal an adenoma. Inferior petrosal (IPSS) or cavernous sinus sampling (CSS) with CRH stimulation helps confirm the central origin in most cases. CSS also helps lateralize the tumor within the pituitary gland with a sensitivity of 80%. Because transsphenoidal pituitary surgery is successful in the majority of MRI-negative cases, bilateral adrenalectomy is performed less frequently. Even with advanced radiologic studies, the origin may not be detected. Adrenalectomy may be an option in these cases. However, loss of feedback inhibition of the hypothalamic-pituitary-adrenal axis; can lead to aggressive transformation of an existing ACTH-secreting pituitary adenoma into Nelson's syndrome within 1-5 years. Clinical Case A 46-year-old female patient complaining of hot flashes and unable to lose weight was evaluated for CS and referred to the Department of Neurosurgery for a pituitary adenoma (Table 1). Since the adenoma was &amp;lt;6mm CSS with CRH stimulation was performed. The results did not support central origin (Table 2). Ectopic ACTH secretion was considered, but without finding the origin of the tumor on radiological examination, and treatment with ketoconazole and metyrapone was started for CS. However the patient then discontinued outpatient follow-up. The patient presented to our clinic 6 years later with a new pituitary MRI showing tumor growth (Fig.1b). She complained of fatigue and obesity. She was depressed and anxious. The skin on her face, hands and hump was dark and patchy (Fig.1c). During these years, she consulted several endocrinologists. MRI was performed annually. Brain MRI had showed a fronto-basal extraaxial mass lesion. The patient underwent microsurgical resection and pathology revealed a microcystic meningioma (WHO grade I). 3 months later bilateral nodular hyperplasia of adrenal gland was detected; she underwent bilateral laparoscopic adrenalectomy (no neoplasia). ACTH gradually increased up to 418pg/ml; the diagnosis of Nelson's syndrome was established. The patient underwent endoscopic transsphenoidal adenomectomy. The ACTH level was found to be 12pg/ml on the 2nd postoperative day. Pathological examination revealed a ACTH secreting pituitary adenoma (Ki-67:7%). CS patients suffer from emotional lability due to the effects of elevated cortisol and to the physical changes of their body. Proximal muscle weakness and obesity causes fatigue symptoms. The diagnosis is often delayed until complications occur. Differential diagnosis could be difficult and challenging. Patient's emotional lability could adversely affect treatment/follow-up compliance. The presented case had meningioma resection which could be delayed until remission from CD and bilateral adrenalectomy which could be avoided by endoscopic pituitary surgery. This case is a good example of the need for pituitary centers of excellence.Figure.Fig.1.a. MRI scan of the pituitary gland at first admission shows (a) a lesion extending posteriorly inferior to the right half of the pituitary gland, hyperintense at T2-weighted, iso-hypointense at T1-w, with heterogeneous contrast enhancement consistent with pituitary microadenoma (4mm*2mm) Fig.1.b. Progression in size of the adenoma (6mm*4mm) Fig.1.c. Darkening of the skin due to hypersecretion of ACTH.  Table 1.Cavernous sinus sampling with corticotropin-releasing hormone stimulation  Table 2.Laboratory tests in different times

Subcentimeter Corticotroph Adenoma: an Evaluation of Diagnostic Elements

Cushing’s disease (CD) is an uncommon yet serious disorder, linked to increased morbidity and mortality. Diagnosis of these patients are complex, and emphasis should be placed on early detection for better management of these patients. The objective of this case report is to evaluate the diagnostic elements in the identification of a subcentimeter adrenocorticotrophic hormone (ACTH)-dependent pituitary adenoma. We report a case of a 26-year-old man who presented with extensive superficial fungal infection of the skin, unintentional weight gain, hypertension, dyslipidaemia as well as cushingoid appearance suspicious of hypercortisolism. Raised midnight plasma cortisol and 24-hour urinary cortisol levels warranted further investigation. Overnight and 48-hour low-dose dexamethasone suppression test (LDDST) were non-suppressed. Subsequent bilateral inferior petrosal sinus sampling (BIPSS) was not only efficient in differentiating pituitary from ectopic Cushing’s syndrome (CS) but was shown to be superior to magnetic resonance imaging (MRI) in lateralisation of the pituitary adenoma.

False-Negative Inferior Petrosal Sinus Sampling in Young-Onset Cushing Disease: What Happens Next

&lt;b&gt;&lt;i&gt;Introduction:&lt;/i&gt;&lt;/b&gt; False-negative results during inferior petrosal sinus sampling (IPSS) may complicate the diagnostic evaluation of patients with ACTH-dependent Cushing syndrome (CS). The management of these patients can be confusing for clinicians and lead to delayed management. &lt;b&gt;&lt;i&gt;Methods:&lt;/i&gt;&lt;/b&gt; We studied patients with young-onset (&amp;lt;21 years old) CD who underwent IPSS during their diagnostic evaluation. For all patients, diagnosis of CD was eventually confirmed based on histologic evaluation of a resected pituitary tumor or remission after transsphenoidal surgery. &lt;b&gt;&lt;i&gt;Results:&lt;/i&gt;&lt;/b&gt; We recorded a rare incidence of false-negative IPSS results in 5 out of the 142 IPSS procedures (3.5%), performed in 4 unique patients. Patients with negative IPSS did not differ in demographic (age and sex) or biochemical (diurnal ACTH/cortisol or 24-hour urinary free cortisol) data from the remaining. Additional workup was performed in three of the four patients including evaluation for ectopic sources of CS and repeat IPSS. Two of these patients also received medical treatment for suppression of cortisol production. One patient decided to proceed with pituitary exploration without additional evaluation. All patients finally underwent surgery and achieved remission. &lt;b&gt;&lt;i&gt;Discussion/Conclusion:&lt;/i&gt;&lt;/b&gt; In patients with CD, IPSS may rarely lead to false-negative results. Management of these patients usually includes screening for ectopic sources of ACTH/CRH secretion, repeating IPSS if ectopic workup is negative, and considering medical management until final diagnosis of the source of hypercortisolism is made.

Inferior Petrosal Sinus Sampling Tumor Lateralization and the Surgical Treatment of Cushing Disease: A Meta-Analysis and Systematic Review

To determine whether accurate inferior petrosal sinus sampling (IPSS) tumor lateralization is associated with improved clinical outcomes following the surgical treatment of Cushing disease. The presented study was performed in accordance with Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines. Data regarding patient demographics, IPSS tumor lateralization, and postoperative endocrinologic outcomes were abstracted and pooled with random effects meta-analysis models. Additional meta-regression models were used to examine the association between the accuracy of IPSS tumor lateralization and postoperative outcomes (recurrence/persistence or remission/cure). Statistical analyses were performed using the Comprehensive Meta-Analysis software (significance of P < 0.05). Seventeen eligible articles were identified, yielding data on 461 patients. Within average follow-up duration (∼59months), the rate of correct IPSS tumor lateralization was 69% [95% confidence interval: 61%, 76%], and the rate of postoperative remission/cure was 78% [67%, 86%]. Preoperative IPSS tumor lateralization was concordant with magnetic resonance imaging lateralization for 53% of patients [40%, 66%]. There was no significant association between the rate of correct IPSS tumor lateralization and postoperative remission/cure among study-level data (P= 0.735). Additionally, there was no association among subgroup analyses for studies using stimulatory agents during IPSS (corticotropin-releasing hormone or desmopressin, P= 0.635), nor among subgroup analyses for adult (P= 0.363) and pediatric (P= 0.931) patients. Limited data suggest that the rate of correct IPSS tumor lateralization may not be positively associated with postoperative remission or cure in patients with Cushing disease. These findings bring into question the utility of IPSS tumor lateralization in the context of preoperative planning and surgical approach rather than confirming a pituitary source.

Consecutive resections of double pituitary adenoma for resolution of Cushing disease: illustrative case.

Double pituitary adenomas are rare presentations of two distinct adenohypophyseal lesions seen in <1% of surgical cases. Increased rates of recurrence or persistence are reported in the resection of Cushing microadenomas and are attributed to the small tumor size and localization difficulties. The authors report a case of surgical treatment failure of Cushing disease because of the presence of a secondary pituitary adenoma. A 32-year-old woman with a history of prolactin excess and pituitary lesion presented with oligomenorrhea, weight gain, facial fullness, and hirsutism. Urinary and nighttime salivary cortisol elevation were elevated. Magnetic resonance imaging confirmed a 4-mm3 pituitary lesion. Inferior petrosal sinus sampling was diagnostic for Cushing disease. Primary endoscopic endonasal transsphenoidal resection was performed to remove what was determined to be a lactotroph-secreting tumor on immunohistochemistry with persistent hypercortisolism. Repeat resection yielded a corticotroph-secreting tumor and postoperative hypoadrenalism followed by long-term normalization of the hypothalamic-pituitary-adrenal axis. This case demonstrates the importance of multidisciplinary management and postoperative hormonal follow-up in patients with Cushing disease. Improved strategies for localization of the active tumor in double pituitary adenomas are essential for primary surgical success and resolution of endocrinopathies.

Letter: Toward Optimized and Cost-Efficient Protocols for Inferior Petrosal Sinus Sampling in the Diagnosis of Cushing Disease.

Letter: Toward Optimized and Cost-Efficient Protocols for Inferior Petrosal Sinus Sampling in the Diagnosis of Cushing Disease.

Interpetrosal sphingosine-1-phosphate ratio predicting Cushing's disease tumor laterality and remission after surgery.

Cushing's disease (CD) poses significant challenges in its treatment due to the lack of reliable biomarkers for predicting tumor localization or postoperative clinical outcomes. Sphingosine-1-phosphate (S1P) has been shown to increase cortisol biosynthesis and is regulated by adrenocorticotropic hormone (ACTH). We employed bilateral inferior petrosal sinus sampling (BIPSS), which is considered the gold standard for diagnosing pituitary sources of CD, to obtain blood samples and explore the clinical predictive value of the S1P concentration ratio in determining tumor laterality and postoperative remission. We evaluated 50 samples from 25 patients who underwent BIPSS to measure S1P levels in the inferior petrosal sinuses bilaterally. Serum S1P levels in patients with CD were significantly higher on the adenoma side of the inferior petrosal sinus than on the nonadenoma side (397.7 ± 15.4 vs. 261.9 ± 14.88; P < 0.05). The accuracy of diagnosing tumor laterality with the interpetrosal S1P and ACTH ratios and the combination of the two was 64%, 56% and 73%, respectively. The receiver operating characteristic curve analysis revealed that the combination of interpetrosal S1P and ACTH ratios, as a predictor of tumor laterality, exhibited a sensitivity of 81.82% and a specificity of 75%, with an area under the curve value of 84.09%. Moreover, we observed that a high interpetrosal S1P ratio was associated with nonremission after surgery. Correlation analyses demonstrated that the interpetrosal S1P ratio was associated with preoperative follicle-stimulating hormone (FSH), luteinizing hormone (LH), and postoperative ACTH 8 am levels (P < 0.05). Our study demonstrated a significant association between the interpetrosal S1P ratio and tumor laterality, as well as postoperative remission in CD, suggesting that the interpetrosal S1P ratio could serve as a valuable biomarker in clinical practice.

Bilateral inferior petrosal sinus sampling: validity, diagnostic accuracy in lateralization of pituitary microadenoma, and treatment in eleven patients with Cushing’s syndrome – a single-center retrospective cohort study

BackgroundThis single-center retrospective cohort study aimed to describe the findings and validity of Bilateral inferior petrosal sinus sampling (BIPSS) in the differential diagnosis of patients with ACTH-dependent Cushing’s syndrome (CS).MethodsEleven patients underwent BIPSS due to equivocal biochemical tests and imaging results. Blood samples were taken from the right inferior petrosal sinus (IPS), left IPS, and a peripheral vein before and after stimulation with desmopressin (DDAVP). ACTH and prolactin levels were measured. The diagnosis was based on the ACTH ratio between the IPS and the peripheral vein. Also, lateralization of pituitary adenoma in patients with Cushing’s disease (CD) was predicted. No significant complications were observed with BIPSS.ResultsBased on the pathology report, eight patients had CD, and three had ectopic ACTH syndrome (EAS). Unstimulated BIPSS resulted in a sensitivity of 87.5%, specificity of 100%, PPV of 100%, NPV of 75%, and accuracy of 91%. Stimulated BIPSS resulted in a sensitivity of 100%, specificity of 100%, PPV of 100%, NPV of 100%, and accuracy of 100%. However, pituitary magnetic resonance imaging (MRI) had a lower diagnostic accuracy (sensitivity:62.5%, specificity:33%, PPV:71%, NPV:25%, accuracy:54%). BIPSS accurately demonstrated pituitary adenoma lateralization in 75% of patients with CD.ConclusionsThis study suggests that BIPSS may be a reliable and low-complication technique in evaluating patients with ACTH-dependent CS who had inconclusive imaging and biochemical test results. The diagnostic accuracy is improved by DDAVP stimulation. Pituitary adenoma lateralization can be predicted with the aid of BIPSS.

FRI187 Increased Prolactin Secretion In Inferior Petrosal Sinus Sampling Following Desmopressin Administration In Patients With ACTH-Dependent Cushing’s Syndrome

Abstract Disclosure: M. Guay-Gagnon: None. N. Younes: None. A. La Fontaine: None. S. Larose: None. É. Thérasse: None. A. Lacroix: None. Background: Previous studies have described an increase in central prolactin (PRL) secretion in response to corticotropin-releasing hormone (CRH) during inferior petrosal sinus sampling (IPSS) in a proportion of patients with Cushing’s disease (CD). Desmopressin is used during IPSS instead of CRH because of its wider availability, lower cost, and similar accuracy. It is unknown whether central PRL secretion can also increase after desmopressin as it does after CRH. Objective: Evaluate the central PRL response to desmopressin administration in patients with ACTH-dependent Cushing’s syndrome (CS) undergoing IPSS. Method: We conducted a retrospective study of patients who underwent IPSS in our center between January 2015 and May 2022. IPSSs using desmopressin were collected, as well as those using either CRH (1 mcg/kg IV bolus) or CRH + desmopressin for comparison. ACTH and PRL were measured in bilateral petrosal sinuses at −5, 0, and 3, 5, 10 minutes after a 10 mcg IV desmopressin bolus; simultaneous peripheral ACTH, PRL and cortisol were measured at -5, 0, 3, 5, 10, 30, 45 and 60 minutes. A &amp;gt;50% central PRL increase from the average of −5 and 0 minutes values to peak value was considered a positive response. Results: 30 IPSSs performed with desmopressin were included: 24 patients with CD and 6 patients with ectopic ACTH secretion (EAS). 73.3% were women and mean age was 48.2 ± 14.8 y.o. 12 patients with CD (50%) had a &amp;gt;50% PRL increase on at least one side. The peak PRL value and highest central/peripheral (C/P) ACTH ratio after desmopressin were ipsilateral in 10 out of 12 patients (83%). Among the 9 patients whose pathology was available, only one showed co-expression of ACTH and PRL on immunohistochemistry (IHC), along with GH. In contrast, among the 12 patients with no PRL response, 2 had ACTH and PRL co-expression, and 1 had PRL expression only. No somatic genetic USP8 analyses were performed. Among the 6 patients with EAS, none had a central or peripheral PRL response after desmopressin. 21 IPSSs with either CRH or CRH + desmopressin were collected. 14 out of 18 patients (77.8%) with CD had a &amp;gt;50% PRL increase after stimulation. For 10 out of these 14 patients (71.4%), peak PRL value and C/P ACTH ratio were ipsilateral. 2 out of 3 IPSSs with CRH or CRH + desmopressin in patients with EAS (one resected pulmonary neuroendocrine tumor and one occult EAS) had a &amp;gt;50% PRL increase after stimulation. Conclusion: In our study, 50% of IPSSs showed a significant central PRL increase after desmopressin in patients with CD, but none in patients with EAS. In IPSSs with CRH or CRH + desmopressin, a significant PRL increase was observed in 77.8% of patients with CD, and 2 out of 3 patients with EAS. On pathology, there was no correlation with PRL expression on IHC. Further research is needed to better understand the mechanisms for prolactin secretion following ACTH secretagogue administration and its potential clinical implications. Presentation: Friday, June 16, 2023

FRI248 A Case of Cyclic Cushing’s Disease With No Peripheral ACTH Response But A Marked Inferior Petrosal Sinus ACTH Response After Desmopressin Administration

Abstract Disclosure: M. Guay-Gagnon: None. R. Cheng: None. N. Younes: None. A. La Fontaine: None. S. Larose: None. É. Thérasse: None. C. Beauregard: None. A. Lacroix: None. Background: Desmopressin is commonly used for the diagnosis of Cushing’s disease (CD) especially when CRH is unavailable. We report a case of CD with no peripheral ACTH response but with an unexpectedly marked ACTH and prolactin (PRL) response in inferior petrosal sinus sampling (IPSS) performed with desmopressin. Following failure of pituitary surgery, cabergoline was introduced, which rapidly induced central adrenal insufficiency (AI). Case Report: A 32-y.o. man was referred to our center for Cushing’s syndrome (CS). Over the last years he had developed diabetes, hypertension, hypokalemia, osteoporosis, obesity, and an overt Cushingoid appearance. Morning cortisol was variable with values up to 8065 nmol/L (292 μg/dL) with elevated ACTH of 63 pmol/L (285 pg/mL). The 1 mg dexamethasone suppression test (DST), 24-hour urinary free cortisol (up to 422 x ULN) and bedtime salivary cortisol (up to 74 x ULN) were elevated. The 4 mg IV DST showed partial cortisol suppression, but a very elevated value of 3750 nmol/L (136 μg/dL) the following morning. Desmopressin (10 mcg IV) stimulation test showed no response: ACTH went from 3.8 pmol/L (17.3 pg/mL) to 3.9 pmol/L, and cortisol, from 688 nmol/L (25 μg/dL) to 622 nmol/L. Pituitary MRI, thoracic CT and DOTATATE PET/CT identified no lesion; abdominal CT showed bilateral adrenal hyperplasia. IPSS with desmopressin stimulation identified a pituitary origin with central/peripheral (C/P) ACTH ratios that rose from 7.1 to 34.2 on the left. PRL increased by 83% in left IPSS after desmopressin, while peripheral ACTH and PRL remained stable. During pituitary exploration, the surgeon suspected a tumor on the left, but pathology showed normal pituitary tissue. Hypercortisolism persisted with partial DI requiring oral desmopressin, and cabergoline 0.5 mg twice weekly was initiated. Two weeks later, he was admitted with nausea, vomiting, lethargy, hypotension, hyponatremia, hyperkalemia and a negative septic evaluation. Morning cortisol was 233 nmol/L (8.4 μg/dL), abnormally low in this context. His condition resolved with IV hydrocortisone and fluid resuscitation. ACTH was not measured initially but was 2 x ULN a few weeks later and 4 mg IV DST showed an early cortisol and ACTH rebound. In view of recurrent hypercortisolism, the patient underwent bilateral adrenalectomy resulting in rapid clinical remission. Under hydrocortisone replacement, his most recent ACTH was 21 pmol/L. Conclusions: This is the first report of a petrosal sinus ACTH response to desmopressin without any peripheral response, suggesting a central source of ACTH. Thus, the use of desmopressin during IPSS should still be attempted in patients with no prior peripheral response. It is unclear whether the acute AI episode was due to a combination of nadir of cyclic CD or partial apoplexy and response to cabergoline of a residual corticotroph tumor with desmopressin induced prolactin co-secretion. Presentation: Friday, June 16, 2023