Inferior Petrosal Sinus Sampling (IPSS): Testing Procedure for Evaluating Cushing’s Syndrome

Inferior Petrosal Sinus Sampling (IPSS) is a vital diagnostic procedure used to determine the source of excess adrenocorticotropic hormone (ACTH) secretion in patients with Cushing syndrome. This article provides a detailed overview of the IPSS procedure, including the necessary preparation, precautions, and interpretation of the results.

What is IPSS?

IPSS is an invasive radiological procedure that involves catheterization of the inferior petrosal sinuses (IPS) on both sides of the pituitary gland. It is performed to measure ACTH levels and detect a gradient between the IPS and the peripheral circulation. This gradient helps to establish whether the source of excess ACTH secretion is the pituitary gland (Cushing's disease) or an ectopic source (ectopic ACTH syndrome).

Anatomy of the Pituitary Gland

The pituitary gland is a small, pea-sized endocrine organ located at the base of the brain, within a bony structure called the sella turcica. It is connected to the hypothalamus by a stalk called the infundibulum and  is divided into two main parts: the anterior pituitary (adenohypophysis) and the posterior pituitary (neurohypophysis).

Figure 5. Venous and arterial supply of the pituitary gland. AH adenohypophysis, NH neurohypophysis

Figure 5. Venous and arterial supply of the pituitary gland. AH adenohypophysis, NH neurohypophysis

Anterior Pituitary: The anterior pituitary produces and secretes several hormones, including adrenocorticotropic hormone (ACTH), growth hormone (GH), thyroid stimulating hormone (TSH), prolactin (PRL), follicle stimulating hormone (FSH), and luteinizing hormone (LH). These hormones regulate various physiological processes, such as growth, metabolism, reproduction, and stress responses.

Posterior pituitary: The posterior pituitary stores and releases hormones in the hypothalamus, specifically vasopressin (antidiuretic hormone) and oxytocin. Vasopressin regulates the balance of water in the body, while oxytocin plays a role in birth and lactation.

Anatomy of the inferior petrosal sinus

The inferior petrosal sinus (IPS) is a small paired venous channel that drains blood from the cavernous sinus to the internal jugular vein. It runs along the petrous part of the temporal bone, connecting the cavernous sinus (near the pituitary gland) with the jugular bulb.  IPS is of particular importance in IPSS because it collects blood from the pituitary gland, allowing the measurement of hormone levels directly from the source.

Significance of the Pituitary Gland and Inferior Petrosal Sinus in IPSS

IPSS is a vital diagnostic tool to identify the source of excess ACTH secretion in patients with Cushing syndrome. By measuring ACTH levels within the IPS, physicians can differentiate between pituitary and ectopic sources of hormone production.

During IPSS, catheters are inserted into the femoral veins and guided through the venous system to reach the IPS bilaterally. Blood samples are collected from the IPS and peripheral circulation before and after administering corticotropin-releasing hormone (CRH). By analyzing the central to peripheral ACTH gradient, healthcare professionals can determine whether the source of excessive ACTH secretion is the pituitary gland (Cushing's disease) or an ectopic source (ectopic ACTH syndrome).

Preparing for IPSS

To ensure accurate and reliable IPSS results, patients must follow specific guidelines:

Patients should maintain fasting prior to the test to reduce potential confounding factors and ensure consistent physiological conditions during the procedure.

Measure serum cortisol levels on the morning of the scheduled IPSS procedure. The test should only proceed if cortisol levels are > 10 mcg/dL, although most patients with Cushing syndrome have cortisol levels > 15 mcg/dL.

Precautions and Complication Rates

When performed by an experienced radiologist, IPSS has a low incidence of serious complications, such as cerebrovascular accidents, at only 0.2%. Employing the right techniques, thorough preparation, and carefully selecting suitable patients are essential factors in maintaining low complication rates.

Interpreting IPSS Results

A central-to-peripheral plasma ACTH gradient of 2.0 before corticotropin-releasing hormone (CRH) administration or ≥ 3.0 after CRH administration, indicates a pituitary source of ACTH. Generally, the gradient is much higher, particularly after CRH injection.

Key Considerations and Recommendations

If the IPS-to-peripheral (IPS:P) ACTH gradient is inconsistent with a pituitary source, a peripheral ACTH response exceeding 35% to CRH administration may suggest a central etiology rather than an ectopic source.

The reliability of radiological confirmation of catheter tip placement in the IPS may be questionable. IPS:P prolactin ratios greater than 1.8 can confirm accurate catheterization. Prolactin can be measured routinely during IPSS or stored and measured later if the IPS: P ACTH ratio is inconsistent with a pituitary source, reducing associated costs.

IPSS has limited value in distinguishing patients with Cushing syndrome from normal individuals or those with pseudo-Cushing states. Before referring a patient for IPSS, healthcare providers must establish a diagnosis of ACTH-dependent Cushing syndrome.

In the absence of appropriate bilateral IPS catheterization, which can be confirmed by measuring the IPS: P prolactin ratio, the lack of a significant IPS: P ACTH gradient does not exclude a pituitary source as the underlying etiology of Cushing syndrome.

Furthermore, confirming the accurate venous sampling in only one IPS may not exclude a pituitary source on the contralateral side of the pituitary gland due to variable venous drainage.

Additional Key Considerations

The success and safety of IPSS are highly dependent on the expertise of the interventional radioologist performing the procedure. It is crucial to choose a medical center with a team experienced in the implementation of IPSS to ensure the best possible results and minimize complications.

Before undergoing IPSS, patients should undergo preliminary tests to confirm the presence of ACTH-dependent Cushing syndrome. These tests may include a 24-hour urinary free cortisol measurement, a low-dose dexamethasone suppression test, and late-night salivary cortisol measurements.

IPSS may be contraindicated in patients with certain medical conditions, such as severe coagulopathy, uncontrolled hypertension, or active infection. A thorough evaluation of the medical history and overall health of each patient is necessary before proceeding with IPSS.

After the IPSS procedure, patients should be closely monitored for any signs of complications, such as bleeding or infection. They should also receive clear instructions on post-procedure care, including pain management and potential warning signs that may warrant immediate medical attention.

Case study

A 42-year-old woman presents with a 6-month history of rapid weight gain, central obesity, facial rounding, and easy bruising. Laboratory evaluation reveals an elevated 24 hour urinary free cortisol level and a failure to suppress cortisol on a low-dose dexamethasone suppression test. Late-night salivary cortisol levels are also elevated. Magnetic resonance imaging (MRI) scan shows no evidence of pituitary adenoma. The patient undergoes an inferior pseudosal sinus sampling (IPSS) to differentiate between pituitary Cushing disease and ectopic ACTH syndrome. Which of the following IPSS findings suggest pituitary Cushing disease?

A) A central-to-peripheral ACTH gradient of 1.5 before CRH administration. and 2.5 after CRH administration

B) A central-to-peripheral ACTH gradient of 0.5 before CRH administration and 1.5 after CRH administration

C) A central-to-peripheral ACTH gradient of 3.0 before CRH administration and 6.0 after CRH administration

D) A central to peripheral ACTH gradient of 1.0 before CRH administration and 1.0 after CRH administration

Answer: C) A central-to-peripheral ACTH gradient of 3.0 before CRH administration and 6.0 after CRH administration


Inferior Petrosal Sinus Sampling (IPSS) is used to distinguish between pituitary Cushing's disease (CD) and ectopic ACTH syndrome (EAS) in patients with ACTH-dependent Cushing's syndrome.

A central-to-peripheral ACTH gradient of 2.0 before corticotropin-releasing hormone (CRH) administration or 3.0 after CRH administration suggests a pituitary source of ACTH, indicating pituitary Cushing's disease. The gradient is usually much greater, especially after CRH injection.

Option A represents an intermediate finding, with a borderline gradient after CRH administration. This result would be inconclusive and may warrant further evaluation. Option B suggests a low gradient, indicative of ectopic ACTH syndrome. Option D shows no change in the ACTH gradient before and after CRH administration, suggesting ectopic ACTH syndrome.

Option C, with a central-to-peripheral ACTH gradient of 3.0 before CRH administration and 6.0 after CRH administration, is most suggestive of Pituitary Cushing's disease. This result demonstrates a clear increase in ACTH gradient after CRH administration, indicating a pituitary source of excessive ACTH secretion.


Inferior petrosal sinus sampling is a critical diagnostic tool for accurately identifying excess ACTH secretion source in patients with Cushing's Syndrome. By following the proper guidelines and considering key factors, healthcare providers can effectively use IPSS to guide treatment decisions and improve patient outcomes.


Colao A, Faggiano A, Pivonello R, Pecori Giraldi F, Cavagnini F, Lombardi G; Study Group of the Italian Endocrinology Society on the Pathophsiology of the Hypothalamic-Pituitary-Adrenal Axis. Inferior petrosal sinus sampling in the differential diagnosis of Cushing syndrome: results of an Italian multicenter study. Eur J Endocrinol. 2001 May;144(5):499-507.

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