Evolving Paradigms in Diagnosing Cushing’s Disease: Is Bilateral Inferior Petrosal Sinus Sampling Becoming Obsolete?

Highlight

– Bilateral inferior petrosal sinus sampling (BIPSS) has traditionally been the gold standard to differentiate Cushing’s disease (CD) from ectopic ACTH syndrome (EAS).
– Over three decades, the reliance on BIPSS has declined significantly as improved imaging (pituitary MRI) has increased diagnostic confidence.
– An intention-to-diagnose analysis of 229 patients showed stable proportions of confirmed CD despite reduced BIPSS usage.
– The findings support judicious use of BIPSS, reserving it for challenging diagnostic cases where imaging and hormonal tests are inconclusive.

Study Background

Cushing’s syndrome caused by adrenocorticotropic hormone (ACTH)-secreting pituitary adenomas, termed Cushing’s disease (CD), presents a diagnostic challenge. Differentiating CD from ectopic ACTH syndrome (EAS) is critical because management strategies differ significantly. Bilateral inferior petrosal sinus sampling (BIPSS) has been regarded as the gold standard for this differential diagnosis, offering direct venous sampling of ACTH gradients between the pituitary drainage and peripheral veins. However, BIPSS is an invasive procedure requiring technical expertise, and its availability is limited in many centers.

With advances in non-invasive diagnostics, particularly pituitary magnetic resonance imaging (MRI) and refined hormonal testing (including dynamic suppression tests), there is growing debate over the necessity of routine BIPSS. Additionally, even with BIPSS, a proportion of cases remain inconclusive, and procedural complications, although rare, can be serious. This study sought to evaluate whether modern imaging and hormonal techniques can justify reducing BIPSS usage without compromising diagnostic accuracy.

Study Design

This retrospective single-center study analyzed 229 consecutive patients diagnosed with ACTH-dependent Cushing’s syndrome (ACTH-CS) without overt endocrine tumors, who were evaluated between 1992 and 2021. All patients underwent standardized hormonal assays (n=229), and nearly all had pituitary imaging by MRI (n=226) or computed tomography (CT) (n=3). Additional chest/abdominal CT scans were performed in 114 patients to investigate potential ectopic sources. BIPSS was performed in 113 patients.

The diagnostic outcomes were classified using an intention-to-diagnose framework based on final post-therapeutic confirmation or suspicion: confirmed CD (cCD), suspected CD (sCD), confirmed EAS (cEAS), and suspected EAS (sEAS). This classification depended on direct evidence of ACTH tumor presence after intervention or persistent diagnostic uncertainty.

Key Findings

Across three decades segmented into 1992-2001, 2002-2011, and 2012-2021, the study observed significant trends in diagnostic approaches and outcomes:

• BIPSS Utilization: Decreased progressively from 68% (1992-2001) to 49% (2002-2011) and further to 26% (2012-2021).
• Imaging Detection: The frequency of identifying a typical pituitary adenoma on MRI increased from 40% to 58% and finally to 69% across the respective time intervals, reflecting improvements in MRI technology and expertise.
• Diagnostic Confirmation of CD: The proportion of patients with confirmed CD remained stable and high at 83%, 81%, and 93%, respectively.

These data suggest that reduction in BIPSS use did not compromise diagnostic yield for CD. Instead, enhanced pituitary imaging improved non-invasive diagnosis, allowing many patients to avoid the invasive BIPSS procedure.

The intention-to-diagnose analysis also emphasizes that a minority of patients still had inconclusive diagnoses (suspected CD or EAS), indicating a need to maintain BIPSS availability in complex cases.

Expert Commentary

BIPSS has been invaluable in distinguishing pituitary-dependent from ectopic ACTH secretion; however, its invasive nature and procedural risks make it less appealing when non-invasive modalities suffice. Improved spatial resolution of modern MRI and the integration of comprehensive hormonal assessment protocols have shifted clinical practice toward a more selective BIPSS approach.

Nevertheless, clinicians must consider pitfalls such as MRI-negative CD, which occurs due to very small adenomas, and false negatives with hormonal testing due to assay variability or intermittent hormone secretion. In such scenarios, BIPSS remains crucial for accurate localization. Current international guidelines, including those from the Endocrine Society, recommend BIPSS primarily when imaging is negative or discrepant and biochemical testing is inconclusive, reaffirming the findings presented.

One limitation of this study is its retrospective design and single-center scope, which might limit generalizability. Additionally, evolving definitions and techniques in hormonal testing over the decades may have influenced diagnostic outcomes.

Conclusion

This comprehensive temporal evaluation demonstrates that the diagnosis of Cushing’s disease is transitioning beyond routine reliance on bilateral inferior petrosal sinus sampling. Advances in pituitary MRI and hormonal diagnostics enable a substantial reduction in BIPSS utilization without sacrificing diagnostic accuracy.

BIPSS should be reserved for cases with ambiguous imaging or hormonal results, ensuring a patient-tailored approach that balances diagnostic certainty with procedural risks. Future prospective, multicenter studies integrating novel imaging modalities such as 7 Tesla MRI and molecular biomarkers may further refine this diagnostic algorithm.

Funding and ClinicalTrials.gov

Funding details were not specified in the reported study. No clinical trial registry number was provided.

References

1. Newell-Price J, Bertagna X, Grossman AB, Nieman LK. Cushing’s syndrome. Lancet. 2006 May 6;367(9522):1605-17. doi:10.1016/S0140-6736(06)68699-6.
2. Endocrine Society Clinical Practice Guideline. Diagnosis of Cushing’s Syndrome: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2008 May;93(5):1526-40. doi:10.1210/jc.2008-0125.
3. 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 Aug 1;325(13):897-905.
4. Lacroix A, Feelders RA, Stratakis CA, Nieman LK. Cushing’s Syndrome. Lancet. 2015 Feb 7;386(9996):913-27. doi:10.1016/S0140-6736(14)61375-1.