Diagnostic Performance of Desmopressin Stimulation Test in Pediatric Cushing’s Disease

Posted on January 13, 2026 by MaryO

Abstract

Objective

To evaluate the diagnostic performance of the desmopressin (DDAVP) stimulation test in pediatric patients with Cushing’s disease (CD), and to compare its accuracy and safety profile to the ovine corticotropin-releasing hormone (oCRH) stimulation test.

Design

A retrospective cohort study.

Methods

Pediatric patients with CD who underwent peripheral or bilateral inferior petrosal sinus sampling (BIPSS) stimulation testing with either DDAVP or oCRH were included. Patients were matched 1:1 for age, sex, and tumor size. The performance of each test was assessed by evaluating ACTH and cortisol responses and calculating test sensitivities.

Results

In peripheral stimulation testing, DDAVP demonstrated 96.9% sensitivity for cortisol and 81.3% for ACTH, while oCRH showed 93.8% and 96.9% sensitivities respectively (p > 0.05). Percentage change of ACTH was higher in the CRH group compared to DDAVP. In BIPSS, the DDAVP stimulation showed sensitivity 73.3% for baseline and 80% for post-stimulation results, while oCRH had sensitivity 93.3% and 100% respectively. Central-to-peripheral ACTH ratios were similar across groups. No major adverse events were reported, and both tests were well tolerated.

Conclusion

Although the DDAVP stimulation test demonstrates lower diagnostic accuracy compared to the CRH test, it still provides sufficient sensitivity and given its availability and lower cost, it represents a pragmatic alternative to CRH stimulation.

Significance statement

The diagnosis of pediatric CD is challenging due to the rarity of the condition and limited access to dynamic testing agents such as ovine corticotropin-releasing hormone (oCRH). This study provides the largest pediatric evaluation of the desmopressin (DDAVP) stimulation test, demonstrating its diagnostic accuracy and safety profile comparable to oCRH stimulation. The findings support the use of DDAVP as a reliable and practical alternative for diagnosing CD in children, particularly in settings where oCRH is unavailable. This work addresses a critical gap in pediatric endocrinology and has the potential to improve diagnostic pathways and outcomes in this population.

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Introduction

ACTH-secreting pituitary adenomas (PAs) causing Cushing’s disease (CD) represent the majority (~ 70–80%) of cases of endogenous Cushing’s syndrome (CS) in children older than 5 years of age [1, 2]. The diagnosis of CS can be complex and often requires multiple dynamic tests [3]. The Pituitary and Endocrine Societies recommend a stepwise diagnostic approach for suspected CS, starting with screening tests and proceeding to localization studies if hypercortisolism is confirmed [4, 5]. However, variability in assay performance, limited test availability, and the high incidence of incidental findings (such as pituitary incidentalomas), continue to pose challenges in selecting the most appropriate diagnostic tools and interpreting their results.

For patients with ACTH-dependent hypercortisolism, the diagnostic workup focuses on localizing the source of ACTH excess, most commonly a PA, though ectopic ACTH-secreting neuroendocrine tumors are also possible [5]. This becomes particularly challenging when pituitary MRI fails to reveal a visible tumor, which may occur in up to one third of patients [6]. ACTH-secreting PAs express receptors for corticotropin-releasing hormone (CRH) and administration of ovine-CRH (oCRH) stimulates ACTH and cortisol release [7]. The oCRH stimulation test, performed either in peripheral sampling or during bilateral inferior petrosal sinus sampling (BIPSS), has long been validated as a minimally invasive method to differentiate CD from ectopic sources of ACTH [8, 9]. However, the discontinuation of manufacturing of oCRH in the United States and the lower cost of alternative stimulants such as desmopressin (DDAVP, a synthetic arginine vasopressin analogue) have led to increased use of the DDAVP stimulation test.

DDAVP stimulates ACTH release via AVPR1b receptors found in corticotroph PAs, but not typically expressed in normal pituitary tissue or ectopic ACTH-secreting tumors [10]. Therefore, a rise in ACTH and cortisol following DDAVP is suggestive of CD [11, 12]. However, the lack of pediatric specific safety and accuracy data limit its use in the pediatric population.

In this study we describe the procedure of DDAVP stimulation test performed with peripheral sampling or in the context of BIPSS, and we compare its performance with the CRH test in a pediatric cohort.

Methods

Study design and patient selection

This was a single-center, retrospective study conducted at the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) in Bethesda, Maryland. All patients were enrolled under an IRB-approved protocol (Protocol ID: NCT 00001595) and they were evaluated at the National Institutes of Health (NIH) Clinical Center (CC). Written informed consent was provided by all parents and assent by pediatric patients if developmentally appropriate for all research procedures.

We identified patients with a final diagnosis of CD who have undergone peripheral DDAVP stimulation test (n = 32) or BIPSS with DDAVP stimulation (n = 15) between 2021 and 2025 (DDAVP group). We then reviewed our historic cohort and identified patients who have undergone peripheral oCRH stimulation test or BIPSS with oCRH stimulation during their diagnostic workup, matched 1:1 for age, sex and tumor size (CRH group).

The diagnosis of CS was based on clinical features and standard biochemical testing, including a 1 mg (or weight-based adjusted dose) overnight oral dexamethasone suppression test, late-night serum cortisol, and/or 24-hour (24h) urinary free cortisol (UFC), in accordance with current guidelines and adjusted for the pediatric population [3, 5]. All patients were eventually diagnosed with CD either by histologic confirmation of the diagnosis on the resected tumor, or clinical and biochemical remission after transsphenoidal surgery (TSS). Demographic, clinical, biochemical, imaging, surgical, and histopathology data were collected for analysis. Tumor size was recorded based on the MRI report, or if no adenoma was reported at the MRI, tumor size was recorded as 0.5 mm since the thinnest slice of the images we obtain are 1 mm, acknowledging that this assumption could underestimate the size of a larger tumor which lacked radiographic characteristics to be distinguished in the MR images. Cortisol was measured with solid-phase, competitive chemiluminescent enzyme immunoassay (CMIA) on Siemens Immulite 2500 analyzer (Malvern, PA) until 2020 and on Abbott Architect from 2020 until 2025. ACTH was measured with CMIA on Siemens Immulite 2500 analyzer until 2012 and on Immulite 200 XPi analyzer from 2012 until 2025. UFC was measured with chemiluminescent enzyme immunoassay until 2011 and with High Performance Liquid Chromatography/Tandem Mass Spectrometry since 2011 (LC-MS/MS). UFC is reported as both absolute values (mcg/24h) and as the fold change from the upper limit of normal (ULN), to account for variable reference range per age and assay.

Peripheral stimulation test

Patients were admitted at the inpatient pediatric floor of NIH CC at least one day prior to the procedure. An intravenous (IV) catheter was placed in the forearm at least one hour prior to the test initiation (most commonly 1–2 days prior to testing). Patients were fasting and remained lying in bed for the duration of the test. Samples were collected at times − 15 and 0 min prior to administration of stimulant at approximately 8:00am.

In the DDAVP group, 10mcg of DDAVP (2.5mL of 4mcg/mL solution) was administered via IV push over 30 s, followed by a 2mL normal saline flush. Samples were then collected at additional timepoints after administration of DDAVP at + 15, +30, + 45, and + 60 min. In a subset of patients, samples were collected at + 10, +20, + 30, +45, and + 60 min but results were not considered significantly different and eventually protocol was adjusted to sampling every 15 min. For this subset of patients (n = 7) the highest value of samples at + 10 and + 20 min was used as the + 15 min value. Patients were advised to follow moderate fluid restriction after DDAVP administration (max 40oz/1.2 L) for 24 h post-procedure, unless otherwise indicated by the treating physician. Intake/output monitoring was recommended for 24 h, and a repeat basic metabolic panel was obtained the following day.

In the CRH group, after baseline samples were obtained, patients received 1mcg/kg, max 100mcg, of oCRH via IV push, and samples were collected at times + 15, +30, and + 45 min after administration [3].

Samples were analyzed for cortisol and ACTH and the percentage change from baseline was calculated as: [(peak level after stimulation – baseline level)/baseline level]*100. The DDAVP test was considered consistent with CD based on previously published criteria: >18% increase in cortisol and >33% increase in ACTH [12]. The CRH test was considered consistent with CD if there was >20% increase in cortisol and >35% increase in ACTH [3].

Bilateral inferior petrosal sinus sampling (BIPSS)

BIPSS was performed based on standard protocols by an interventional radiologist under anesthesia as previously described [13]. Briefly, catheters were advanced to bilateral petrosal sinuses via radiological guidance through femoral veins. Blood samples were collected at all timepoints simultaneously from each of the petrosal sinus catheter (right, left) and peripheral samples drawn from a vascular catheter introducer sheath in a femoral vein. Baseline samples were collected at − 5 and 0 min. In the DDAVP group, after collecting samples at time 0 min, 10mcg of DDAVP (2.5mL of 4mcg/mL solution) was administered as an IV push over 30 s, followed by a 2mL normal saline flush. In the CRH group, after collecting samples at time 0 min, 1mcg/kg, max 100mcg, of oCRH was administered as an IV push over 30 s via peripheral IV catheter. Post-stimulation blood samples were collected at + 3, +5, and + 10 min. Patients who received DDAVP were advised to follow moderate fluid restriction as described above. Test results were considered consistent with CD if the baseline central:peripheral (C:P) ACTH ratio was >2 and/or the stimulated C:P ratio >3 [14,15,16].

Statistical analysis

Baseline characteristics were summarized using descriptive statistics. Non-normally distributed data are shown as median [Q1, Q3] and were compared between groups with the Wilcoxon rank-sum test. Normally distributed data are shown as mean (standard deviation, SD) and were compared between groups with student’s t-test. Categorical data are shown as counts and proportions and were compared between groups using χ2 test or Fisher’s exact test as appropriate. To assess whether hormone levels or ratios changed significantly over time and differed between the CRH and DDAVP groups, variables were log-transformed to achieve approximately normal distribution, and two-way repeated measures analysis of variance (ANOVA) was performed with time and stimulation group as fixed effects. Area under the curve (AUC) was calculated for timepoints from 0 min to 45 min for the peripheral stimulation test, and from 0 min to 10 min for BIPSS. Sensitivity was calculated using predefined criteria, and Fisher’s exact test was employed to compare sensitivity between the CRH and DDAVP groups. Missing data were considered as missing by chance and were not replaced. A p-value < 0.05 was considered statistically significant. Analyses were conducted using R/RStudio software.

Results

Cohort characteristics

In the peripheral stimulation test cohort, a total of 64 patients were included, consisting of 34 males (53%) and 30 females (47%). In accordance with the selection criteria, the two groups (DDAVP and CRH) were similar in age at time of testing, tumor size, and proportions of negative MRI at diagnosis. Markers of hypercortisolemia were also similar between the two groups, including late night serum cortisol, 24h UFC, and morning ACTH levels.

In the BIPSS analysis, a total of 30 patients were included, consisting of 18 males (60%) and 12 females (40%). The two groups were similar in age at time of testing, tumor size, and proportions of negative MRI at diagnosis. Markers of hypercortisolemia were also similar between the two groups. All corresponding results have been summarized in Table 1.

Table 1 Characteristics of patients undergoing Desmopressin (DDAVP) and oCRH stimulation test

Stimulation test results

In the peripheral stimulation test results, although screening markers of hypercortisolemia were overall similar between the two groups, baseline serum cortisol at the time of the stimulation test was lower in the DDAVP group (14.1 mcg/dL [12.4, 16.8]) compared to the CRH group (18.7 mcg/dL [15.5, 24.7], p < 0.001), while baseline ACTH levels were similar between the two groups (47.5 pg/mL [27.5, 58.0] in the DDAVP group vs. 48.5 pg/mL [33.4, 58.6] in the CRH group, p = 0.73).

In the repeated measures analysis of cortisol during the stimulation test, significant main effect of time (p < 0.001) and group (p < 0.001) were noted, suggesting that cortisol values were significantly different over time and between the two groups. The time-by-group interaction was also significant (p = 0.031), suggesting that the pattern of change over time also differed. Furthermore, AUCs were also different between the two groups, with the CRH group having a higher AUC compared to the DDAVP group (p < 0.001). In the analysis of ACTH between the two groups, there was significant effect of time (p < 0.001), but group (p = 0.05), and the time-by-group (p = 0.11) interaction did not reach statistical significance suggesting that ACTH levels changed overtime but retained a similar overall pattern between the groups. When analyzing AUCs for the ACTH secretion, the CRH group had higher AUC compared to the DDAVP group (p < 0.001). Peak cortisol levels occurred more frequently at 30 min in the DDAVP group and at 45 min in the CRH group, while peak ACTH levels occurred more frequently at 15 min post-stimulation in both groups (Fig. 1)

Fig. 1

figure 1

Hormonal responses to desmopressin (DDAVP) and ovine corticotropin-releasing hormone (oCRH) stimulation in pediatric Cushing’s disease. (A) Serum cortisol concentrations over time following peripheral stimulation, (B) Plasma ACTH levels over time following peripheral stimulation, (C) Central: Peripheral, (C:P) ACTH ratios over time during bilateral inferior petrosal sinus sampling, (BIPSS). Lines follow median values at each timepoint for CRH (red) or DDAVP (blue) group

When looking into the percentage change from baseline, the median percentage change in cortisol was 58.2% [40.6, 85.7] after DDAVP and 82.3% [44.1, 110.0] after oCRH stimulation (p = 0.21), while the median percentage change in ACTH was 122% [53.5, 206.0] and 188.0% [117.0, 342.0] after DDAVP and oCRH stimulation respectively (p = 0.037, Fig. 2).

Fig. 2

figure 2

Group comparison of cortisol and ACTH levels in response to desmopressin (DDAVP) and ovine corticotropin-releasing hormone (oCRH) stimulation in pediatric Cushing’s disease. Percentage change from baseline in cortisol (A) and ACTH (B) levels following peripheral stimulation. Central:Peripheral (C:P) ACTH ratios at baseline (C) and post-stimulation (D) during bilateral inferior petrosal sinus sampling (BIPSS). Box plots display medians, interquartile ranges, and 1.5× IQR whiskers. Dashed lines represent diagnostic thresholds

In the BIPSS stimulation test, the repeated measures analysis noted that in both groups there was significant effect of time (p < 0.001), but group and time-by-group interaction did not differ (p > 0.05), suggesting that overall, there was a similar change of the C:P ACTH ratios between the two groups post-stimulation (Fig. 1). AUCs for C:P ratios did not reach statistical significance between the two groups (p = 0.21). Peak ratios occurred more frequently at 3 min post-stimulation in both groups. Baseline C:P ACTH ratios were similar between the two groups (5.6 [2.1, 10.6] in the DDAVP group vs. 7.5 [4.2, 20.2] in the CRH group, p = 0.20) and the maximum C:P ratios post-stimulation remained similar (17.1 [8.9, 22.1] in the DDAVP group vs. 18.5 [12.3, 65.4] in the CRH group, p = 0.37, Fig. 2).

Sensitivity analysis

Using the diagnostic thresholds specified above for the peripheral stimulation test, sensitivity in the DDAVP group was 96.9% for cortisol and 81.3% for ACTH. In comparison, the CRH group showed 93.8% sensitivity for cortisol and higher sensitivity for ACTH (96.9%, Fig. 3), which however did not differ statistically between the two groups (p > 0.05).

Fig. 3

figure 3

Sensitivity of desmopressin (DDAVP) and ovine corticotropin-releasing hormone (oCRH) stimulation tests in pediatric Cushing’s disease. Sensitivity for cortisol and ACTH results in the peripheral stimulation test (A); and the Central:Peripheral (C:P) ACTH ratio in bilateral inferior petrosal sinus sampling (B)

Eight patients (12.5%) had a false negative response in either cortisol (range of percentage change of cortisol from baseline: 1–13%) or ACTH (range of percentage change of ACTH from baseline: −31-30%). Of these, six patients underwent DDAVP and two patients had oCRH stimulation test. Only two patients had inadequate response in both cortisol and ACTH and would have been misclassified (one in each of the DDAVP and CRH groups). Of the seven patients with false negative stimulation tests, only one was documented to have a hemolyzed blood sample. All patients who underwent DDAVP stimulation had an ACTH response of > 19%.

In the BIPSS analysis, using the thresholds above, sensitivity was 73.3% and 93.3% in the DDAVP and CRH group respectively (p = 0.33) for the baseline ratios, and 80% and 100% in for the stimulated ratios (p = 0.22, Fig. 3). Five (5) patients showed an inadequate response at baseline and three of them also had a false low response post-stimulation. All three of the patients who failed both the baseline and the post-stimulation cutoffs, and who would have been misclassified as possible ectopic CS, were in the DDAVP group and were previously described in a study of negative BIPSS results [13]. Two of these three patients were noted on venograms to have poorly developed inferior petrosal veins that suggested BIPSS might not yield reliable results.

Side effects

Overall patients tolerated the procedures without significant adverse events or complications. One patient in the CRH group reported mild headache, which resolved spontaneously within a few hours. No episodes of hyponatremia or venous thrombosis were recorded.

Discussion

The diagnostic workup of CS can be challenging and complex involving many baseline and dynamic tests. Especially in the pediatric population, the rarity of the disease makes the diagnostic process more difficult. We herein present the DDAVP stimulation test in pediatric patients with CD. We report the performance of the test which although lower than oCRH, still yields sufficient sensitivity overall without significant side effects.

DDAVP stimulation test is used for the differential diagnosis of pituitary versus ectopic sources of hypercortisolemia in ACTH-dependent CS. Although rare in children, infrequent cases of ectopic pediatric CS have been reported, some of which have led to devastating results, even death [2, 17, 18]. In a recent study on a non-invasive approach to differential diagnosis of ACTH-dependent CS, Frete et al. incorporated the CRH or DDAVP stimulation test in their diagnostic algorithm [12]. We have also recently described that in our cohort, pediatric patients with positive high dose dexamethasone suppression test and peripheral CRH or DDAVP stimulation test consistent with pituitary source ended up having CD irrespective of the MRI findings [2]. This could suggest that in this population, especially when IPSS would delay evaluation or is not available, DDAVP stimulation test can assist in important decisions for the management of the patient. The sensitivity of DDAVP test was lower than that of CRH for the diagnosis of CD. Similar findings were noted in a metanalysis by Ceccato et al., where CRH showed higher sensitivity than DDAVP [19]. In the absence of oCRH in some countries, DDAVP remains a safe and effective alternative for this patient population.

The utility of DDAVP stimulation test expands beyond the differential diagnosis of ACTH-dependent CS. Studies have shown that it can be used for the differential diagnosis of non-malignant hypercortisolism as well as a marker of post-operative remission, which have not been explored in this study [20, 21].

False negative and recently false positive results to DDAVP stimulation test have been reported in the literature. Although initially thought that AVPR1b receptors are located only on corticotroph tumors, some ectopic tumors show response [22]. Our false negative results are contingent to the cutoff values we used in this study. For the peripheral stimulation test, we used the latest cutoff values suggested by Frete et al. Initial descriptions of the test suggested the use of >50% change for ACTH and >20% change for cortisol, which would lead to 8 patients in our group being misclassified (instead of 6 with the current criteria). However, if we use a combination of either cortisol or ACTH response, then one patient would still be misclassified due to inadequate response to both cortisol (13%) and ACTH (26.6%). A threshold for ACTH of >20% would have identified all patients with CD in our cohort, but would potentially yield false positive results in patients with ectopic CS. In the BIPSS interpretation, we used the cutoff criteria of >2 for baseline and >3 for stimulated values. Recently a study suggested that cutoffs of C:P ACTH ratio >1.4 for baseline and >2.8 for post-stimulation results would yield better accuracy [23]. If we used those cutoffs, then one patient at baseline and two patients at post-stimulation would have been misclassified. Only one patient would have both ratios below the cutoff criteria (baseline: 1.1, post-stimulation: 1.5) and eventually be considered as ectopic CS. In the pediatric population, one major factor to consider is that technical limitations may pose difficulties in reaching the petrosal sinuses; in these cases, results are not dependent on the stimulant used.

Additional possible explanations for negative results in patients with CD may be a cyclical pattern of cortisol secretion. We have ruled out this possibility in our patients since all of them had midnight serum cortisol the night(s) prior to the test and all were elevated suggesting they had active hypercortisolemia. Technical difficulties could explain some cases where administration of the medication may not have been complete or appropriately delivered. However, most patients had decreased urine output as evidence of an effective dose of DDAVP in their circulation. Finally, as tumors may have pulsatility on ACTH secretion, it is possible that the test coincided with an endogenous pulse of the tumor ACTH secretion that further masked the effect of DDAVP administration.

Certain limitations exist for this study. We had limited patients with ectopic CS and thus we could not compare the performance of the test between patients with CD and patients with ECS. However, we did not aim to define the diagnostic cutoffs of each test but rather to assess the safety and concordance to the CRH stimulation test. Furthermore, ectopic CS is quite rare in the pediatric population that it would be very difficult to recruit enough patients. Although this is the largest to our knowledge cohort of pediatric patients with DDAVP stimulation test, the number of patients may still have been too low to detect significant differences between the tests. Finally, the historic CRH group were evaluated with variable cortisol and ACTH assays which may affect the comparison of absolute values between the two groups. Thus, we present our results also as percentage changes to compare the performance of the tests.

In conclusion, we show the performance of DDAVP stimulation test performed either peripherally or during BIPSS. The test is well tolerated, and no significant side effects were noted. The test shows comparable sensitivity and a valid alternative to the oCRH stimulation test, in the absence of this agent.

Data availability

All raw data used in this study will be deposited in data repository listed in References [24].

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Acknowledgements

This research was supported by the Intramural Research Program of the National Institutes of Health (NIH). The contributions of the NIH authors are considered Works of the United States Government. The findings and conclusions presented in this paper are those of the authors and do not necessarily reflect the views of the NIH or the U.S. Department of Health and Human Services.

Funding

Open access funding provided by the National Institutes of Health. The work was supported by the Intramural Research Program of the National Institutes of Health, Grant ZIA HD009017.

Author information

Authors and Affiliations

  1. Unit on Hypothalamic and Pituitary Disorders, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, 10 Center Drive, Building 10, Rom 1-3330, MSC1103, Bethesda, MD, 20892, USA

    Yetunde B. Omotosho & Christina Tatsi

  2. Endocrine and Venous Services Section, Interventional Radiology Section, Clinical Center, National Institutes of Health, Bethesda, MD, 20892, USA

    Richard Chang & Michael Kassin

  3. Department of Pharmacy, Clinical Center, National Institutes of Health, Bethesda, MD, 20892, USA

    Erna Groat

  4. Department of Pediatrics, Clinical Center, National Institutes of Health, Bethesda, MD, 20892, USA

    Alan Quillian, Ruth Parker & Christina Tatsi

Contributions

YOB collected data, analyzed data and wrote the manuscript, RC and MK performed clinical procedures, EG reviewed clinical procedures regarding medication safety and administration, AQ and RP provided clinical care to participants, CT designed the study, procedures, data collection, data analysis, and interpretation of results. All authors reviewed the manuscript.

Corresponding author

Correspondence to Christina Tatsi.

Ethics declarations

Disclosures

CT received research funding by Pfizer and Recordati for unrelated studies.

Competing interests

The authors declare no competing interests.

ClinicalTrials.gov ID

NCT00001595.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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Inferior Petrosal Sinus Sampling (IPSS) Tumor Lateralization and The Surgical Treatment of Cushing’s Disease

Posted on December 22, 2025 by MaryO

ABSTRACT

Objective

To determine whether accurate inferior petrosal sinus sampling (IPSS) tumor lateralization is associated with improved clinical outcomes following the surgical treatment of Cushing’s disease.

Methods

The presented study was performed in accordance with PRISMA 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).

Results

Seventeen eligible articles were identified, yielding data on 461 patients. Within average follow-up duration (∼59 months), 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 MRI 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.

Conclusions

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’s 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.

From https://www.sciencedirect.com/science/article/abs/pii/S187887502301745X

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Consecutive Resections of Double Pituitary Adenoma for Resolution of Cushing Disease

Posted on December 20, 2025 by MaryO

BACKGROUND

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.

OBSERVATIONS

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.

LESSONS

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.

ABBREVIATIONS

ACTH = adrenocorticotrophic hormone;  BMI = body mass index;  DHEA-S = dehydroepiandrosterone sulfate;  FSH = follicle-stimulating hormone;  GH = growth hormone;  IHC = immunohistochemical;  IPSS = inferior petrosal sinus sampling;  LH = luteinizing hormone;  MRI = magnetic resonance imaging;  POD = postoperative day;  T4 = thyroxine;  TF = transcription factor;  TSH = thyroid-stimulating hormone;  UFC = urinary free cortisol

Pituitary adenomas are adenohypophyseal tumors that can cause endocrinopathies, such as pituitary hormone hypersecretion or anterior hypopituitarism. Cell lineages are used to classify these tumors on the basis of immunohistochemical (IHC) staining of transcription factors, hormones, and other biomarkers.1 Pituitary adenomas differentiate from pluripotent stem cells along one of three lineage pathways, depending on the following active transcription factors (TFs): pituitary transcription factor 1 (PIT-1), T-box transcription factor (TPIT), or steroidogenic factor-1 (SF-1). Rarely, two or more discrete pituitary adenomas from different lineages are identified in patients; however, the etiology remains unclear.2 The incidence of multiple pituitary adenomas has been reported to be 1%–2% of all resected pituitary adenomas but is likely underestimated based on data from large autopsy series.1–4 Pluri-hormonal adenomas are also rare entities in which a single tumor contains multiple TF lineages with one or more hormonal excesses.1–3 Preoperative recognition of multiple or pluri-hormonal pituitary adenomas is rare, and most tumors are discovered incidentally upon autopsy, intraoperatively, or on histological analysis.2,3,5

In cases of multiple synchronous pituitary adenomas, only one hormone excess syndrome is most frequently evident on clinical presentation and endocrine workup. Silent pituitary tumors positive for prolactin on immunohistochemistry are the most prevalent additional, incidentally found tumor in cases of multiple pituitary adenomas.5 This is particularly true in Cushing disease.6,7 It is important to recognize the presence of multiple pituitary adenomas especially in the setting of hormonally active pituitary adenomas to provide optimal management for this subset of patients. Complete resection is curative for Cushing disease with the standard of care achieved through a transsphenoidal approach. Localization of the tumor presents a challenge because of suboptimal sensitivity of magnetic resonance imaging (MRI) in demonstrating microadenomas, the inconsistency of lateralization with inferior petrosal sinus sampling (IPSS), and delays in pathological analysis.1,8,9 Additionally, the presence of an additional pituitary adenoma can obscure the microtumor through its large size and mass effect and can act as a “decoy lesion” during MRI, IPSS, and resection.6

Consideration of multiple pituitary tumors is necessary for successful resection. In a patient with a biochemical picture of Cushing disease, the demonstration of an adenoma with negative adrenocorticotrophic hormone (ACTH) immunostaining and the absence of postoperative hypoadrenalism may indicate the existence of a double adenoma. Few cases have described a lack of remission of an endocrinopathy after transsphenoidal resection due to the presence of an additional adenoma,2,6,10 and even less so in the instance of the persistence of Cushing disease.6 We present a rare case of double pituitary adenomas in a patient presenting with Cushing disease who underwent two endoscopic endonasal transsphenoidal resections and immunostaining for prolactin and ACTH, respectively, with long-term normalization of her hypothalamic-pituitary-adrenal (HPA) axis.

Illustrative Case

History and Presentation

A 32-year-old female, gravida 0 para 0, with a history of a pituitary lesion and hyperprolactinemia presented to our institution for the evaluation for Cushing disease. Ten years earlier, the patient had presented to a gynecologist with hirsutism, galactorrhea, and oligomenorrhea. Her endocrine workup was remarkable for an elevated prolactin at 33.8 ng/mL (2.3–23.3 ng/mL), while follicle-stimulating hormone (FSH), luteinizing hormone (LH), and thyroid-stimulating hormone (TSH) levels were normal. No ACTH or cortisol levels were available. MRI demonstrated a 5 × 6 × 5–mm T1-weighted isointense pituitary lesion protruding into the suprasellar cistern due to a small sella size. She was treated with bromocriptine 2.5 mg daily for 5 years, with normalization of her prolactin level. Subsequent MRI demonstrated a stable lesion size and T1 and T2 hyperintensity in the region of the known pituitary lesion, considered to be posttreatment cystic change with proteinaceous contents and blood. After the normalization of her prolactin levels, she continued to have oligomenorrhea and abnormal hair growth. Polycystic ovaries were not visualized on ultrasound. She was started on oral contraceptives and then switched to the etonorgestrel implant.

A decade after initial presentation, she presented to endocrinology at our institution with 3 years of weight gain, hirsutism, and potential oligomenorrhea. Vital signs were stable (blood pressure: 122/86; heart rate: 72 beats/min), and facial fullness and striae on her bilateral breasts were appreciated on physical examination. She was taking isoniazid and pyridoxine for a recent diagnosis of latent tuberculosis and had discontinued bromocriptine 5 years earlier. Her weight was 66.3 kg and body mass index (BMI) was 23.9 kg/m2. She reported that her maternal uncle had a pituitary tumor. Laboratory analysis was positive for elevated urinary free cortisol (UFC) of 109 µg per 24 hours (2.5–45 µg/24 h; Table 1) and nighttime salivary cortisol of 142 ng/mL (<100 ng/dL) with high-normal prolactin of 22.8 ng/mL (2.3–23.3 ng/dL) and normal FSH, LH, TSH, and thyroxine (T4). Dehydroepiandrosterone sulfate (DHEA-S) was 128 µg/dL (98.8–340.0 µg/dL). Imaging demonstrated a 4 × 4 × 4–mm pituitary lesion with decreased T1-weighted and increased central T2-weighted signal intensity in the left lateral pituitary (Fig. 1A–C). Desmopressin (Ferring Pharmaceuticals DDAVP) stimulation increased a basal ACTH of 49.9 pg/mL to ACTH of 91.2 pg/mL, and cortisol increased from 13.7 µg/dL to 21.2 µg/dL, consistent with neoplastic hypercortisolism. IPSS was performed, which showed a right-sided, central-to-peripheral ACTH gradient (Table 2). The patient elected to undergo endoscopic endonasal resection with the initial target as the left-lateral pituitary mass to achieve a cure for Cushing disease.

TABLE 1Urinary free cortisol at baseline and 3, 5, and 7 months after the primary resection

Variable Baseline 3 Mos 5 Mos 7 Mos on Osilodrostat
Urinary free cortisol (4–50 µg/24 hrs) 109 134.2 125.4 40.3
Urinary creatinine (0.5–2.5 g/24 hrs) 0.995 1.17 1.42 1.11
Urinary vol (mL) 1950 2300 2100 2125
FIG. 1
FIG. 1

Preoperative coronal precontrast (A) and postcontrast (B) T1-weighted magnetic resonance imaging (MRI) and T2-weighted MRI (C) demonstrated a 4-mm3 lesion (arrows) with decreased T1 and increased central T2 signal intensity in the left lateral pituitary. Two days after surgery, coronal precontrast (D) and postcontrast T1-weighted (E) and T2-weighted (F) MRI demonstrated the unchanged adenoma.

TABLE 2Preoperative inferior petrosal sinus sampling with corticorelin ovine triflutate 68 µg

Time (mins) ACTH (pg/mL) Prolactin (ng/mL)
Peripheral Petrosal Sinus ACTH Ratio Peripheral Petrosal Sinus Prolactin Ratio
Rt Lt Rt Lt Rt Lt Rt Lt
−5 50.6 225 1586 4.45 31.34 21 124 295 5.90 14.05
0 48.8 389 1376 7.97 28.20 22.2 185 198 8.33 8.92
3 69.8 4680 1333 67.05 19.1 22.1 396 32.5 17.92 1.47
5 80.9 4590 1623 56.74 20.06 22.1 436 32.2 19.73 1.46
10 112 4160 1660 37.14 14.82 20.2 367 42 17.90 2.05

ACTH or prolactin ratio = inferior petrosal sinus ACTH or prolactin/peripheral blood ACTH or prolactin.

Primary Resection and Outcomes

During the primary resection, abnormal tissue was immediately visible after a linear incision along the bottom of the dura, with an excellent plane of dissection. The inferomedial adenoma was distinct from the known left lateral lesion, and the resection was considered complete by the primary neurosurgeon. Subsequently, the left-sided adenoma was not pursued because of the historical prolactinoma diagnosis and an assumption that the newly discovered adenoma was the cause of ACTH hypersecretion. However, pathology of the inferomedial tumor was strongly and diffusely positive for prolactin (Fig. 2B), synaptophysin, and cytokeratin, with an Mindbomb Homolog-1 (MIB-1) proliferative index of 2.4%. ACTH, growth hormone (GH), FSH, LH, and TSH immunostaining were negative. TF immunohistochemistry was not available. On postoperative day (POD) 1, pituitary MRI was performed and demonstrated the unchanged 4-mm3 T1-weighted hypointense lesion with small central T2-weighted hyperintensity in the left lateral gland (Fig. 1D–F). Cortisol levels ranged from 9.7 to 76.2 µg/dL (4.8–19.5 µg/dL), and ACTH was 19.5 pg/mL (7.2–63.3 pg/mL) on POD 1.

FIG. 2
FIG. 2

Histological examination of surgical specimens from the inferomedial (A–C) and left lateral (D–F) lesions. The initial resection (hematoxylin and eosin [H&E], A) was strongly and diffusely positive for prolactin (B) with normal reticulin levels (C) indicating a lactotrophic pituitary adenoma. The second operation (H&E, D) was diagnostic for a corticotropic pituitary adenoma with diffusely positive adrenocorticotrophic hormone (ACTH) (E) and decreased reticulin (F). Original magnification ×100.

Early reoperation was discussed with the patient based on the pathology and persistent hypercortisolism; however, she elected to pursue conservative management with close follow-up. Postoperative cortisol nadir was 4.8 µg/dL (4.8–19.5 µg/dL) on POD 2 during her 4-day hospital stay. DHEA-S was significantly decreased from baseline at 22.3 µg/dL (98.8–340.0 µg/dL) and a prolactin level of 3.4 ng/mL (2.3–23.3 ng/dL) was low-normal. No glucocorticoids were administered during her hospital course. There was no clinical evidence of vasopressin deficiency while she was an inpatient.

Three months postoperatively, the patient reported insomnia, poor hair quality, fatigue, nocturnal sweating, and continued increasing weight gain with fat accumulation in the supraclavicular and dorsal cervical area. She had one spontaneous menstrual period despite the use of etonogestrel implant. UFC was increased at 134.2 µg/24 hours (4–50 µg/24 h; Table 1). The 8:00 am serum cortisol was 10.2 µg/dL (5.0–25.0 µg/dL). She was started on osilodrostat 2 mg twice daily for her persistent hypercortisolism, and she reported some clinical improvement; however, she had continued elevation in her late-night salivary cortisol levels up to 7.0 nmol/L. Other endocrine lab work was normal, with a prolactin of 13.5 ng/mL (2.8–23.3 ng/mL) and TSH of 3.67 µIU/mL (0.4–4.0 µIU/mL). Her weight had increased by 4.9 kg to 71.2 kg with a BMI of 25.3 kg/m2. Approximately 6 months postoperatively, she was amenable to a secondary resection targeting the remaining left lateral pituitary adenoma.

Secondary Resection and Outcomes

After obtaining adequate exposure for the secondary resection, the lesion in the left lateral aspect of the pituitary was targeted. The tumor was clearly identified and completely resected without intraoperative complication. IHC staining was diffusely positive for ACTH (Fig. 2E), synaptophysin, and cytokeratin with decreased reticulin and an MIB-1 index of 3.3%. Prolactin, GH, TSH, LH, and FSH immunostaining were negative. Postoperative cortisol monitoring demonstrated decreased levels, with a nadir of 2.0 µg/dL on POD 0. Levels of ACTH and DHEA-S were decreased at 4.4 pg/mL (7.2–63.3 pg/mL) and 13.3 µg/dL (98.8–340 µg/dL), respectively, on POD 1. Prolactin remained within the normal range at 8.2 ng/mL (2.8–23.3 ng/mL). The patient was started on intravenous hydrocortisone 50 mg every 8 hours for adrenal insufficiency. Postoperative symptoms of nausea, headache, and muscle weakness resolved with hydrocortisone administration. She was discharged on hydrocortisone 60 mg daily in divided doses for adrenal insufficiency and had no signs of vasopressin deficiency during her 2-day hospital course.

By 3 months, the patient reported decreased fatigue, myalgia, and insomnia and improved overall well-being and physical appearance. She was weaned down to a total daily dose of 20 mg of hydrocortisone and had lost 5.2 kg. Her menstruation returned while having an etonogestrel implant. Rapid ACTH stimulation was abnormal, with decreased cortisol at 30 minutes of 4.1 µg/dL (7.2–63.3 pg/mL) demonstrating continued adrenal insufficiency. Follow-up MRI demonstrated miniscule remaining left pituitary adenoma (Fig. 3). Seven months after her second surgery, she was started on 50 µg levothyroxine for primary hypothyroidism in the setting of slightly elevated TSH of 4.1 µIU/mL (0.4–4.0 µIU/mL) and a low-normal T4 of 0.8 ng/dL (0.7–1.5 ng/dL).

FIG. 3
FIG. 3

Postoperative imaging 3 months after the second operation demonstrates near gross-total resection (yellow arrows: surgical cavity) of the left lateral pituitary adenoma on coronal precontrast (A) and postcontrast T1-weighted (B) and T2-weighted (C) MRI.

Two years after the second resection, the patient lost 10.1 kg (weight, 61.1 kg; BMI, 21.76 kg/m2). Her ACTH stimulation test became normal, and hydrocortisone therapy was discontinued. At the 2-year time point, the patient and her husband successfully conceived a child.

Patient Informed Consent

The necessary patient informed consent was obtained in this study.

Discussion

Double or multiple pituitary adenomas are discovered in 0.37%–2.6% of resected pituitary lesions.3,4,6,11,12 A majority of multiple pituitary adenomas are not suspected before surgery with an inconclusive clinical presentation or endocrine laboratory workup.6 The presentation of multiple synchronous neoplasms is thought to be more common than having a single neoplasm with multiple lineages.1 Studies have shown that additional pituitary adenomas are seen at a rate of 1.6%–3.3% in Cushing disease in studies including both contiguous and noncontiguous double pituitary adenomas.6 Additional pituitary adenomas that are hormonally active make up 40% of resected double pituitary adenomas, with most staining for gonadotroph adenoma.13 Overall, the most common incidental pituitary adenoma is prolactinoma,6 which occurs most frequently with GH or ACTH adenomas.5 In very rare instances, Cushing cases can present with hyperprolactinemia and Cushing synchronously.6 Hormonal secretion and clinical presentation are variable, with the pathology most often attributed to only one component of double pituitary adenoma.3,14 The multiple-hit theory is the most common hypothesis for double pituitary adenoma etiology with coincidental monoclonal expansion of two or more lineages, which present with separate pseudo-capsules for each lesion.15

Observations

On presenting with Cushing disease, the differential diagnosis before the initial operation considered that the known left lateral pituitary adenoma could be a mixed tumor with both prolactin and ACTH lineages. Therefore, it was the initial target of the resection until discovering the second adenoma intraoperatively. With two distinct adenomas, the inferomedial adenoma was presumed to be the source of the ACTH hypersecretion and was subsequently resected. The left lesion was thought to be a prolactinoma and hormonally inactive after historical dopaminergic therapy and thus was not pursued during the initial surgery. However, pathology confirmed that the opposite was true. Few cases have also involved incidental pituitary tumors that look like the hormonally active adenoma and encourage resection of it, leaving the primary pituitary adenoma behind.6,7 It has been reported that these “decoy lesions” can cause surgical failure and require secondary operations.6,7,10,16 Intraoperative localization and confirmation of the adenoma classification may have also been helpful during the case, including tissue-based ACTH antibody assay,9 plasma ACTH measurements with a immunochemiluminometric method,17 or intraoperative ultrasound.5,6

The inferomedial second tumor was not appreciated or reported throughout her serial MRI studies from 2010 to 2020. Interestingly, imaging did demonstrate the left pituitary adenoma that was medically treated as a prolactinoma, although it was later diagnosed as an ACTH-secreting lesion on IHC staining. Preoperative visualization of a pituitary adenoma in Cushing disease is reported to be limited, with a reported 50% incidence with negative MRI with standard 1.5 T.1,18,19 MRI technical refinements in magnet strength, slice thickness, or enhanced spin sequences have increased sensitivity, but one-third of patients with Cushing disease still have negative scans.20 Small prolactinomas, especially those near the cavernous sinus, are also notoriously difficult to visualize on MRI, although recent advances using co-registration of 11C-methionine positron emission tomography–computed tomography with MRI (Met-PET/MRICR) may prove useful.21 Difficulty with preoperative visualization complicates a diagnosis of multiple adenomas, with or without multiple endocrinopathies, and negatively affects surgical planning. In a single-institution retrospective review of MRI in all cases of double pituitary tumors, only one of eight patients (12.5%) over 16 years of age had a positive MRI for double pituitary tumors and was diagnosed preoperatively.2

The patient’s preoperative IPSS demonstrated a right central-to-peripheral gradient. This was incongruent with the MRI demonstrating the single left-sided tumor. While IPSS is useful in confirming Cushing disease, its sensitivity for lateralization has been reported at only 59%–71%.9 With this in mind and a known left-sided adenoma on MRI, exploration of the right side of the pituitary was not originally planned. Ultimately, the left-sided adenoma was the source of ACTH hypersecretion, which remains incongruent with preoperative IPSS. It has been suggested that multiple pituitary adenomas in Cushing disease could further decrease its accuracy.1,6

The patient’s initial historical prolactin levels (33.8 ng/dL) were lower than reported levels of 100–250 ng/dL for microadenoma and >250 ng/dL in cases of macroadenoma. Normally, in active single prolactinoma, prolactin secretion is correlated to size. We do not suspect that the presence of more than one pituitary adenoma would affect the level of prolactin hypersecretion.6 Slight elevations in prolactin can be attributed to causes such as pituitary stalk effect, medications, and physiological stimulation. During the 5 years of bromocriptine therapy, the effect on the inferomedial prolactinoma was unknown, as it was not appreciated on MRI. There are reports of prolactinomas being less responsive to dopaminergic agonist therapy in cases of double adenomas.14,22 Upon resection of the inferomedial prolactinoma during the initial operation, there was no further change in the patient’s prolactin levels, which could most likely be attributed to prior dopaminergic therapy. Unfortunately, the initial endocrine laboratory workup did not include levels of ACTH or cortisol. In addition to hyperprolactinemia, Cushing disease can also present with changes in menstruation. After the secondary resection and removal of the ACTH-secreting pituitary adenoma, the patient’s oligomenorrhea resolved and she achieved pregnancy. Retrospectively, it remains unclear if the prolactinoma was once truly active hormonally.

Lessons

The rare presence of two pituitary adenomas can complicate the diagnosis, medical and surgical management, and long-term outcomes for patients. A complete endocrine workup is essential when a pituitary adenoma is suspected and can help screen for pluri-hormonal and multiple pituitary adenomas. In our patient, it is unknown when the onset of hypercortisolism was with the limited initial hormonal workup.

Currently, localizing and resecting the hormonally active adenoma in double or multiple pituitary adenomas remain a challenge, with limitations in preoperative imaging and intraoperative measures. After encountering the additional inferomedial lesion during surgery, resection of both adenomas during the initial surgery may have been prudent to ensure the resolution of Cushing disease. Although exploration for additional pituitary adenomas is not usually recommended, it could be considered in cases of multiple pituitary adenomas and uncertainty of the culprit of Cushing disease.

The current characterization of pituitary tumors by the World Health Organization includes immunohistochemistry for both transcription factors and pituitary hormones, with clinical usefulness to be determined by future studies. Multiple lineages can occur mixed in a single pituitary adenoma or across different noncontiguous adenomas and can only be determined by TF immunostaining. The left ACTH-staining lesion in our patient had some shrinkage and MRI changes, which may have been a response to dopaminergic therapy. Full characterization of the tumor cell lineages in this case remains undetermined without staining for TFs.

In conclusion, we report a rare case of Cushing disease concurrent with a prolactinoma leading to the need for repeat resection. This is one of the few reported cases of a double pituitary adenoma leading to a lack of biochemical remission of hypercortisolism after the initial surgery. Strategies for localization of the active tumor in double pituitary adenomas are essential for primary surgical success and the resolution of endocrinopathies.

Author Contributions

Conception and design: Zwagerman, Tavakoli, Shah, Findling. Acquisition of data: Zwagerman, Armstrong, Tavakoli, Shah, Ioachimescu, Findling. Analysis and interpretation of data: Zwagerman, Armstrong, Tavakoli, Shah, Coss, Ioachimescu, Findling. Drafting of the article: Zwagerman, Armstrong, Shah. Critically revising the article: Zwagerman, Armstrong, Tavakoli, Shah, Ioachimescu, Findling. Reviewed submitted version of the manuscript: Zwagerman, Armstrong, Tavakoli, Shah, Laing, Ioachimescu, Findling. Approved the final version of the manuscript on behalf of all authors: Zwagerman. Statistical analysis: Armstrong, Shah. Administrative/technical/material support: Zwagerman, Armstrong, Shah. Study supervision: Zwagerman, Tavakoli, Shah, Laing.

References

Filed under: Cushing's, pituitary, Rare Diseases, symptoms, Treatments | Tagged: , , , , , , , | Leave a comment »

Approach to the Patient with Cushing’s Syndrome: Use of Anticoagulation Therapy

Posted on December 19, 2025 by MaryO

Abstract

There is an increased awareness on the higher hypecoagulability risks in patients with Cushing’s syndrome (CS) but management remains controversial. Here, we present four illustrative cases of CS that exemplify some “grey areas” on venous thromboembolism (VTE) prevention—when to start, how long to continue, what to use, and when to stop.

The cases span: initiation of prophylaxis at diagnosis of active CS; periprocedural management around inferior petrosal sinus sampling; peri-operative prophylaxis after transsphenoidal surgery (TSS); and discontinuation decisions in medically controlled disease. We synthesise current evidence and expert practice and recommend considering low-molecular-weight heparin at diagnosis of active CS, continuing through surgery, and extending for approximately three months after biochemical remission in selected patients to address the highest-events risk window.

Based on recent data, we discourage routine use of graduated compression stockings for VTE prevention. Though bleeding complications appear uncommon, they need to be carefully considered on an individualized basis. Finally, scenarios where prophylaxis can be safely discontinued once eucortisolaemia is achieved are outlined. This case-anchored framework translates heterogeneous data into actionable guidance and highlights priorities for prospective evaluation.

The Journal of Clinical Endocrinology & Metabolism, dgaf671, https://doi.org/10.1210/clinem/dgaf671

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Ultrasound-Guided Jugular Vein Access for Inferior Petrosal Sinus Sampling: A Safe and Feasible Technique

Posted on December 11, 2025 by MaryO

Abstract

Pituitary Cushing’s disease (CD) results from excessive adrenocorticotropic hormone (ACTH) secretion, usually due to a pituitary adenoma. This report describes the diagnostic approach and management of a complex case of CD in a patient with multiple comorbidities, highlighting a hybrid technique for inferior petrosal sinus sampling (IPSS) when standard access fails.

A woman with poorly controlled diabetes, obesity, chronic kidney disease (CKD), and hypertension presented with suspected Cushing’s syndrome. Despite normal urinary free cortisol (UFC) levels (likely influenced by renal dysfunction), clinical suspicion prompted further testing, which revealed an inverted cortisol rhythm and lack of suppression on low-dose dexamethasone. High-dose suppression indicated a pituitary source. MRI findings were inconclusive. To confirm the diagnosis, bilateral IPSS was attempted. Right petrosal sinus catheterization via femoral access was successful; however, left-sided access failed. An alternative, ultrasound-guided direct left internal jugular puncture was performed, allowing complete sampling. A central-to-peripheral ACTH gradient >2 at baseline and >3 after desmopressin confirmed a pituitary source. The patient subsequently underwent successful transsphenoidal resection, achieving postoperative biochemical remission.

IPSS remains the gold standard for distinguishing central from ectopic ACTH production. While bilateral femoral access is standard, anatomical variants may necessitate alternative routes. This case demonstrates the feasibility and safety of combining femoral and direct jugular access to complete IPSS when conventional approaches are limited.

This is the first reported case of IPSS performed using a hybrid right femoral and left ultrasound-guided jugular approach, offering a practical alternative when femoral access is not feasible and reinforcing the diagnostic value of IPSS in challenging cases.

Introduction

Pituitary Cushing’s disease (CD) is caused by excessive secretion of adrenocorticotropic hormone (ACTH), typically due to a pituitary adenoma. It represents the most common cause of endogenous Cushing’s syndrome, accounting for approximately 70% of ACTH-dependent cases [1,2]. The diagnostic approach often requires dynamic hormonal testing and neuroimaging; however, distinguishing pituitary from ectopic ACTH secretion remains a clinical challenge [3].

Inferior petrosal sinus sampling (IPSS), first described by Oldfield EH and Doppman JL in 1977, is considered the gold standard for confirming a pituitary origin when biochemical and imaging findings are inconclusive [4-6]. Bilateral catheterization via femoral venous access is the usual approach, guided by digital subtraction angiography (DSA) [4,5]. However, anatomical variants, thrombosis, and technical difficulties can impede standard catheterization, necessitating alternative strategies such as direct ultrasound-guided internal jugular puncture [7].

This report presents a patient with multiple comorbidities and suspected CD in whom a hybrid IPSS approach was successfully performed after failed standard access.

Case Presentation

A female patient with a history of poorly controlled diabetes, obesity, chronic kidney disease (CKD), and hypertension was admitted with suspected Cushing’s syndrome. Initial evaluation revealed normal urinary free cortisol (UFC), likely underestimated due to renal dysfunction. Because of high clinical suspicion, circadian cortisol rhythm was assessed, showing inversion with higher evening than morning levels, supporting hypercortisolism.

A low-dose dexamethasone suppression test (LDDST; 1 mg) failed to suppress cortisol, confirming endogenous hypercortisolism. A high-dose dexamethasone suppression test (HDDST; 8 mg) demonstrated 80% cortisol suppression, suggesting a pituitary source of ACTH overproduction.

Pituitary MRI revealed a poorly defined hypointense nodular area, inconclusive for microadenoma (Figure 1A). To confirm the central origin, bilateral inferior petrosal sinus sampling (IPSS) was performed (Figures 1B–1E).

(A)-Contrast-enhanced-pituitary-MRI-showing-a-hypointense-nodule-in-the-left-half-of-the-gland,-which-was-inconclusive;-(B)-right-internal-jugular-vein-access-achieved,-while-left-jugular-access-was-not-possible-via-this-route;-(C-and-D)-dual-inferior-petrosal-sinus-catheterization-with-right-sided-access-via-the-femoral-vein-and-left-sided-access-via-direct-jugular-puncture;-(E)-ultrasound-guided-placement-of-the-venous-sheath.
Figure 1: (A) Contrast-enhanced pituitary MRI showing a hypointense nodule in the left half of the gland, which was inconclusive; (B) right internal jugular vein access achieved, while left jugular access was not possible via this route; (C and D) dual inferior petrosal sinus catheterization with right-sided access via the femoral vein and left-sided access via direct jugular puncture; (E) ultrasound-guided placement of the venous sheath.

Initial access was established via the bilateral femoral veins with placement of 5 Fr introducer sheaths in both. Due to anatomical complexity and inability to access the left internal jugular vein via the femoral route, a direct ultrasound-guided left jugular puncture was performed. A separate 5 Fr introducer sheath was placed directly into the left internal jugular vein under ultrasound guidance (US guidance). Catheterization was performed using 5 Fr vertebral diagnostic catheters, facilitated by a micro-guidewire.

Correct positioning within the petrosal sinuses was subsequently confirmed by contrast injection. The results demonstrated accurate catheter placement in the inferior petrosal sinuses (adequate prolactin levels), with an ACTH central-to-peripheral gradient greater than 2 at baseline and greater than 3 after desmopressin, thus confirming a pituitary source for the pathology (Tables 1–2).

Peripheral Right IPS Left IPS
16.5 ng/mL 41.2 ng/mL 63.7 ng/mL
Table 1: Prolactin concentrations obtained via inferior petrosal sinus sampling at baseline.

IPS: Inferior Petrosal Sinus.

Time Point Peripheral Right IPS Left IPS
Basal 27.5 pg/mL 77.1 pg/mL 106 pg/mL
Desmopressin 5 min 28.3 pg/mL 168 pg/mL 221 pg/mL
Desmopressin 10 min 27.9 pg/mL 32 pg/mL 80 pg/mL
Table 2: ACTH concentrations obtained via inferior petrosal sinus sampling at baseline and at 5 and 10 minutes after desmopressin stimulation.

IPS: Inferior Petrosal Sinus; ACTH: Adrenocorticotropic hormone.

The patient underwent endonasal transsphenoidal resection of an ACTH-secreting pituitary microadenoma. Postoperatively, serum cortisol fell to <5 µg/dL, indicating secondary adrenal insufficiency, and physiologic glucocorticoid replacement was initiated. Urine output remained normal (no evidence of vasopressin deficiency), and steroid replacement was titrated without adrenal crisis.

Discussion

Diagnostic considerations

CKD can lead to falsely normal UFC values due to impaired renal clearance of cortisol metabolites [8]. Therefore, alternative biochemical tests such as late-night serum cortisol or dexamethasone suppression are recommended in these patients [1,3]. The high-dose dexamethasone suppression observed here supported a pituitary origin, but confirmation by IPSS was critical given the inconclusive MRI findings.

Inferior petrosal sinus sampling

Since its introduction, IPSS has become the reference standard for distinguishing pituitary from ectopic ACTH production, with reported sensitivity and specificity of approximately 96% and 100%, respectively [4-6,9]. The test involves measuring ACTH gradients between central (petrosal) and peripheral samples, values ≥2 at baseline or ≥3 after corticotropin-releasing hormone (CRH) or desmopressin stimulation indicate a central source [5,9].

Desmopressin stimulation

Although CRH has traditionally been used, desmopressin is an effective and safe alternative that achieves comparable diagnostic accuracy [10]. In our case, desmopressin successfully elicited a diagnostic gradient, confirming the pituitary source.

Technical challenges and hybrid approach

Although the conventional IPSS technique uses bilateral femoral access, the procedure was originally performed via direct jugular puncture [2]. Variations in venous anatomy, hypoplasia, or catheterization failure may necessitate alternative routes. Direct ultrasound-guided jugular puncture offers an effective solution, minimizing procedural time and radiation exposure, and reducing the risk of complications such as cervical hematoma. Our case illustrates that combining femoral and direct jugular access allows complete bilateral sampling without compromising safety.

Conclusions

This case demonstrates the feasibility and safety of a hybrid IPSS approach combining right femoral and ultrasound-guided direct left jugular access. This method enabled successful completion of bilateral sampling when standard femoral catheterization failed. The case reinforces IPSS as a critical diagnostic tool for confirming pituitary Cushing’s disease, even in technically challenging circumstances.

References

  1. Nieman LK, Biller BM, Findling JW, Newell-Price J, Savage MO, Stewart PM, Montori VM: The diagnosis of Cushing’s syndrome: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2008, 93:1526-1540. 10.1210/jc.2008-0125
  2. Perlman JE, Johnston PC, Hui F, et al.: Pitfalls in performing and interpreting inferior petrosal sinus sampling: personal experience and literature review. J Clin Endocrinol Metab. 2021, 106:e1953-e1967. 10.1210/clinem/dgab012
  3. Findling JW, Raff H: Diagnosis and differential diagnosis of Cushing’s syndrome. Endocrinol Metab Clin North Am . 2021, 30:729-747. 10.1016/s0889-8529(05)70209-7
  4. Oldfield EH, Doppman JL, Nieman LK, et al.: Petrosal sinus sampling with and without corticotropin-releasing hormone for the differential diagnosis of Cushing’s syndrome. N Engl J Med. 1991, 325:897-905. 10.1056/NEJM199109263251301
  5. Zampetti B, Grossrubatscher E, Dalino Ciaramella P, Boccardi E, Loli P: Bilateral inferior petrosal sinus sampling. Endocr Connect. 2016, 5:R12-R25. 10.1530/EC-16-0029
  6. Vassiliadi DA, Mourelatos P, Kratimenos T, Tsagarakis S: Inferior petrosal sinus sampling in Cushing’s syndrome: usefulness and pitfalls. Endocrine. 2021, 73:530-539. 10.1007/s12020-021-02764-4
  7. Yeh CH, Wu YM, Toh CH, Chen YL, Wong HF: A safe and efficacious alternative: sonographically guided internal jugular vein puncture for intracranial endovascular intervention. AJNR Am J Neuroradiol. 2012, 33:E7-E12. 10.3174/ajnr.A2416
  8. Kidambi S, Raff H, Findling JW: Limitations of nocturnal salivary cortisol and urine free cortisol in the diagnosis of mild Cushing’s syndrome. Eur J Endocrinol. 2007, 157:725-731. 10.1530/EJE-07-0424
  9. Wind JJ, Lonser RR, Nieman LK, DeVroom HL, Chang R, Oldfield EH: The lateralization accuracy of inferior petrosal sinus sampling in 501 patients with Cushing’s disease. J Clin Endocrinol Metab. 2013, 98:2285-2293. 10.1210/jc.2012-3943
  10. Malerbi DA, Mendonça BB, Liberman B, et al.: The desmopressin stimulation test in the differential diagnosis of Cushing’s syndrome. Clin Endocrinol (Oxf). 1993, 38:463-472. 10.1111/j.1365-2265.1993.tb00341.x

From https://www.cureus.com/articles/429423-ultrasound-guided-jugular-vein-access-for-inferior-petrosal-sinus-sampling-a-safe-and-feasible-technique#!/

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