Pitfalls in Performing and Interpreting Inferior Petrosal Sinus Sampling: Personal Experience and Literature Review
Open accessAbstract
Context: Inferior petrosal sinus sampling (IPSS) helps differentiate the source of ACTH-dependent hypercortisolism in patients with inconclusive biochemical testing and imaging, and is considered the gold standard for distinguishing Cushing disease (CD) from ectopic ACTH syndrome. We present a comprehensive approach to interpreting IPSS results by examining several real cases. Evidence Acquisition: We performed a comprehensive review of the IPSS literature using PubMed since IPSS was first described in 1977. Evidence Synthesis: IPSS cannot be used to confirm the diagnosis of ACTH-dependent Cushing syndrome (CS). It is essential to establish ACTH-dependent hypercortisolism before the procedure. IPSS must be performed by an experienced interventional or neuroradiologist because successful sinus cannulation relies on operator experience. In patients with suspected cyclical CS, it is important to demonstrate the presence of hypercortisolism before IPSS. Concurrent measurement of IPS prolactin levels is useful to confirm adequate IPS venous efflux. This is essential in patients who lack an IPS-to-peripheral (IPS:P) ACTH gradient, suggesting an ectopic source. The prolactin-adjusted IPS:P ACTH ratio can improve differentiation between CD and ectopic ACTH syndrome when there is a lack of proper IPS venous efflux. In patients who have unilateral successful IPS cannulation, a contralateral source cannot be excluded. The value of the intersinus ACTH ratio to predict tumor lateralization may be improved using a prolactin-adjusted ACTH ratio, but this requires further evaluation. Conclusion: A stepwise approach in performing and interpreting IPSS will provide clinicians with the best information from this important but delicate procedure.
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IPS prolactin measurements can be used as a surrogate marker of appropriate catheterization or normal IPS venous efflux to prevent a false-negative result.
“However, IPS prolactin measurements can be used as a surrogate marker of appropriate catheterization or normal IPS venous efflux to prevent a false-negative result (77).”
From Approach to the Patient: Diagnosis of Cushing Syndrome (2022) · cites this paper as [77]
Prolactin-adjusted intersinus ACTH ratios can be used for tumor lateralization.
“Studies have also shown how prolactin-adjusted intersinus ACTH ratios can be used for tumor lateralization (77, 79).”
From Approach to the Patient: Diagnosis of Cushing Syndrome (2022) · cites this paper as [77]
The most common complications of BIPSS include groin hematomas and transient headaches.
“The most common complications of the procedure include groin hematomas and transient headaches.”
From Approach to the Patient: Diagnosis of Cushing Syndrome (2022) · cites this paper as [77]
BIPSS cannot be used to establish the diagnosis of ACTH-dependent CS, and the presence of hypercortisolism must be confirmed immediately before and at the time of the procedure.
“The test, however, cannot be used to establish the diagnosis of ACTH-dependent CS and the presence of hypercortisolism must be confirmed immediately before and at the time of the procedure (77).”
From Approach to the Patient: Diagnosis of Cushing Syndrome (2022) · cites this paper as [77]
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“There can also be serious complications, including stroke and subarachnoid hemorrhage, thought to be related to anatomical variations causing transient hypotension and/or vascular injury during the procedure (77).”
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“However, further evaluation of the prolactin-adjusted ACTH ratio is needed to prove reliable surgical guidance [50].”
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“1 3 ratio of central to peripheral cortisol felt to be diagnostic, and the use of concomittent prolactin sampling to maximize specificity also varies between centers, making the absolute sensitivity and specificity of the test unknown [34].”
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“IPSS helps differentiate the source of ACTH‐dependent hypercortisolism in patients with inconclusive biochemical testing and imaging, and is considered the gold standard for distinguishing Cushing disease from ectopic ACTH syndrome.(29,30) It can achieve 81%–100% sensitivity with CRH stimulation and is superior to pit…”
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“To avoid pitfalls in results interpretation, cor-tisol-lowering medications should be withdrawn at least 48-72 h before the procedure and overt hypercortisolism must be assured before BIPSS [30].”
Method68Ga-DOTATOC PET/CT in the Localization of Pituitary Tumors in Cushing’s Disease
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“An intersinus ACTH ratio of ≥ 1.4 was used for the lateralization of pituitary adenomas [12,13].”
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“8 A central diagnosis is suspected by an inferior petrosal sinus (IPS) to peripheral ACTH ratio of greater than 2 prestimulation or greater than 3 poststimulation.”
BackgroundFinding the Culprit: Cushing Syndrome Secondary to Lung Carcinoid Tumor
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“to improve the stepwise (noninvasive) diagnostic approach in ACTH-dependent CS [37,38].”
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“CRH stimulation is necessary to ensure the accuracy of the algorithm [21]; therefore, we used CRH in all the IPSS procedures.”
MethodValizadeh, M., Abiri, B., Hosseinpanah, F., & Grossman, A. (2024) · Journal of Internal Medicine · doi:10.1111/joim.13789 · Cited by 5 · see citing works
“ACTH ratio could also mimic CD in the EAS [140].”
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“Notably, there are studies reporting that IPSS may not be required in patients with a sellar mass and a bio-chemical testing suggestive of CD [26, 27].”
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“It has been demonstrated that the sensitivity of BIPSS can vary from 88 to 100%, and its specificity from 67 to 100% in the diagnosis of CD [24].”
BackgroundRare case of renal Ewing sarcoma presenting as ectopic Cushing syndrome in a 12-year-old girl
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“On the day of BIPSS procedure, 8 am plasma cortisol was elevated (>10 µ g/dL) in all the patients, thus excluding the possibility of cyclical CS. [22] The BIPSS procedure was performed by a single interventional neurologist at our hospital.”
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Grineva, E. N., Tsoy, U. A., & Рыжкова, Д. В. (2024) · Annals of the Russian academy of medical sciences · doi:10.15690/vramn12677 · Cited by 2 · see citing works
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“They can be differentiated by inferior petrosal sinus sampling [5].”
BackgroundParro, I. M., Ortiz-Sánchez, D., Moreno, R. G. G., Gómez-Rioja, R., Martínez, R. F., & Álvarez-Escolá, C. (2022) · Advances in laboratory medicine · doi:10.1515/almed-2022-0088 · Cited by 2
“Other publications [23, 24] suggest that this standardization could not be applicable to patients with ectopic CS and recommend the use of prolactin ratio only to identify the informative points of the test.”
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“Pearlman et al. suggested prolactin-normalized ratio as a surrogate for proper catheterization and normal venous efflux of the IPSS [33].”
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“2,6,9,14,15 Consequently, IPSS should ideally be standardized and performed in experienced centers to minimize variability.”
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Self-citationIPSS does not impact management in Cushing's Disease when a pituitary tumor is visible on MRI
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“However, it needs to be done in the hypercortisolemic phase, as performing it during the trough phase increases the rate of false negative results, extending the time to diagnosis and exposing the patient to avoidable risk (5, 20, 21).”
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“Although the conventional IPSS technique uses bilateral femoral access, the procedure was originally performed via direct jugular puncture [2].”
Diagnostik und Therapie des endogenen Hypercortisolismus (Cushing-Syndrom)
Andereggen, L., & Christ, E. (2025) · Journal für Endokrinologie, Diabetologie und Stoffwechsel · doi:10.1007/s41969-025-00276-4
“Ein hoher zentraler/peripherer Prolaktin-Quo-tient (>1,8–2,0) spricht für eine korrek-te selektive Drainage aus dem Sellage-biet, was essenziell für die valide Inter-pretation der ACTH-Werte ist [19, 31, 32].”
Prolactinoma localization by inferior petrosal sinus sampling: illustrative case
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Self-citationSyndrome de Cushing paranéoplasique par sécrétion ectopique d’hormone adrénocorticotrope
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“Otras publicaciones [23, 24] sugieren que esta normalización podría ser errónea en pacientes con CE y recomiendan exclusivamente el uso de la ratio de prolactina para identificar los puntos informativos de la prueba.”
BackgroundSelective Venous Sampling for Hypercortisolism
Ho, J. P., & Solander, S. (2022) · Diagnosis and Management of Endocrine Disorders in Interventional Radiology · doi:10.1007/978-3-030-87189-5_9
- Authors
- Perlman, J. E., Johnston, P. C., Hui, F., Mulligan, G., Weil, R. J., Recinos, P. F., Yogi-Morren, D., Salvatori, R., Mukherjee, D., Gallia, G., Kennedy, L., & Hamrahian, A. H.
- Affiliations
- Johns Hopkins University (US)
- Royal Victoria Hospital (GB)
- Cleveland Clinic (US)
- Rhode Island Hospital (US)
- Corresponding author
- Hamrahian, Amir H
- ORCID
- Venue
- The Journal of Clinical Endocrinology & Metabolism
- Publisher
- The Endocrine Society
- Published
- 2021-01-09
- Volume
- 106
- Issue
- 5
- Pages
- e1953-e1967
- ISSN
- 0021-972X (ISSN-L)
- 1945-7197
- PMC
- PMC8599872
- OpenAlex
- W3118576125
- Cited by
- 50
- References
- 0
- Citations by year
- 2026: 8 · 2025: 9 · 2024: 7 · 2023: 10 · 2022: 10 · 2021: 6
- FWCI
- 1.27
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model (vor)
- Locations
- The Journal of Clinical Endocrinology & Metabolism (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- NIH
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Pituitary Gland Disorders and Treatments
- Health Sciences › Medicine › Surgery › Adrenal and Paraganglionic Tumors
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adrenal Hormones and Disorders
- Keywords
- inferior petrosal sinus sampling, ACTH-dependent hypercortisolism, Cushing's disease, ectopic ACTH syndrome, ACTH-dependent Cushing's syndrome, diagnostic pitfalls
- MeSH terms
- ACTH Syndrome, Ectopic, Diagnosis, Differential, Humans, Petrosal Sinus Sampling, Pituitary ACTH Hypersecretion
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