Inferior Petrosal Sinus Sampling (IPSS)

What is inferior petrosal sinus sampling?

Inferior petrosal sinus sampling (IPSS) is a catheter-based diagnostic procedure that measures adrenocorticotropic hormone (ACTH) levels in the veins that drain the pituitary gland — the inferior petrosal sinuses — and compares them with ACTH levels in a peripheral vein. Because the pituitary drains directly into these small sinuses before that blood joins the general circulation, a sample taken there closely reflects what the pituitary gland itself is secreting, making it possible to tell a pituitary source of excess ACTH apart from a source somewhere else in the body.

The technique was first described by Oldfield and Doppman in the early 1980s and, performed bilaterally (BIPSS), remains the reference standard investigation for this specific diagnostic question.

Why is this test needed? Understanding ACTH-dependent Cushing's syndrome

Cushing's syndrome results from prolonged exposure to excess cortisol, and most cases are ACTH-dependent — driven by too much adrenocorticotropic hormone, which in turn overstimulates the adrenal glands. The great majority of ACTH-dependent cases are Cushing's disease, caused by a small ACTH-secreting pituitary adenoma. A minority are due to ectopic ACTH syndrome, in which a tumour outside the pituitary — most often in the lung, pancreas, or thymus — secretes ACTH.

Both conditions can look very similar on standard blood tests, and the culprit pituitary adenoma is often too small to be seen clearly on MRI. Choosing the right treatment — pituitary surgery versus a search for an ectopic tumour elsewhere in the body — depends entirely on getting this distinction right, which is exactly the question IPSS is designed to answer.

When is IPSS recommended?

IPSS is not a first-line test. It is reserved for situations where simpler tests haven't given a clear answer:

ACTH-dependent Cushing's syndrome has already been confirmed biochemically, but

Pituitary MRI is normal, or shows only a very small (typically under 6 mm) or equivocal lesion, or

Biochemical tests (such as high-dose dexamethasone suppression or CRH stimulation) give discordant or borderline results.

In these situations, IPSS distinguishes a pituitary source from an ectopic one before any surgery is planned, avoiding an operation on a gland that may not actually be the cause.

How is the procedure performed?

Vascular access: under sedation or light general anaesthesia, catheters are inserted through both femoral veins in the groin and, under fluoroscopic (X-ray) guidance, are advanced up into both inferior petrosal sinuses — the small veins draining each side of the pituitary.

Baseline sampling: blood is drawn simultaneously from the left sinus, the right sinus, and a peripheral vein, and sent for ACTH measurement.

CRH stimulation: a synthetic corticotropin-releasing hormone is injected intravenously, which sharply increases ACTH release from a genuine pituitary adenoma. Paired samples are then drawn again at fixed intervals — typically at 3, 6, and 10 minutes.

Interpretation: a central-to-peripheral ACTH ratio of 2 or higher at baseline, or 3 or higher after CRH stimulation, points to a pituitary source. A ratio below this threshold points away from the pituitary and toward an ectopic source.

Lateralisation: comparing ACTH levels between the left and right sinus can hint at which side of the pituitary the adenoma sits, though this is considerably less reliable than the central-versus-peripheral distinction and is not used on its own to decide how much of the gland to operate on.

The whole procedure is typically completed within one to two hours, and most patients are observed overnight before going home the following day.

Why is CRH stimulation important?

A resting (baseline) sample alone can occasionally miss a true pituitary source, because ACTH secretion from a small adenoma can vary from moment to moment. Stimulating the pituitary with CRH accentuates the difference between a pituitary and a non-pituitary source, which is why current protocols combine baseline sampling with CRH-stimulated sampling rather than relying on baseline values alone.

Is the procedure safe?

IPSS is minimally invasive and generally very safe when performed by an experienced interventional team. It is done entirely through small punctures in the groin, without any incision near the head or neck. Reported risks are low and include bruising or minor bleeding at the puncture site and, rarely, a blood clot in the vein used for access; serious complications such as injury to the brainstem or cranial nerves are exceedingly rare in experienced hands. Because the procedure uses X-ray guidance, there is a small amount of radiation exposure, kept as low as reasonably achievable throughout.

What determines accuracy?

Accuracy depends heavily on correct catheter placement in both sinuses and on the experience of the team performing and interpreting the test. Confirming that both catheters are genuinely positioned in the petrosal sinuses — sometimes cross-checked using a simultaneous prolactin measurement, since prolactin is also concentrated in this venous drainage — helps reduce the small but recognised false-negative rate, which is largely attributable to anatomical variation in the venous drainage of the pituitary rather than to a failure of the underlying principle of the test.

Why this needs a multidisciplinary team

IPSS sits at the intersection of endocrinology, interventional neuroradiology, and laboratory medicine. Its value depends on close coordination: the endocrine team confirms ACTH-dependent Cushing's syndrome and selects the right patients for the test, the interventional radiology team performs precise bilateral catheterisation, and the laboratory needs to be ready to process time-critical, simultaneously-drawn samples at each stimulation interval. This is why IPSS is offered only at centres equipped to run all three strands of care together, and why the result is always interpreted in the context of the patient's full clinical and biochemical picture rather than in isolation.