Tuesday, July 8, 2008

Testing 101: IPSS aka BIPSS

Once the biochemical evidence for Cushing's Disease/Syndrome confirms the diagnosis, differentiation of the source or reason for the high cortisol must be ascertained. There are numerous possible scenarios for questionable source(s). I'll try to outline a few of the more common ones.

Scenario 1: Normal or high ACTH, high cortisol with abnormal circadian rhythm, no evident pituitary tumor on MRI or questionable hypointense area which may or may not mean a tumor, no evident adrenal tumor.

Possible sources of high cortisol: ACTH-secreting pituitary adenoma, ectopic ACTH-secreting tumor

Scenario 2: Normal or high ACTH, high cortisol with abnormal circadian rhythm, visible pituitary tumor on MRI, no evident adrenal tumor.

Possible sources of high cortisol: ACTH-secreting pituitary adenoma, ectopic ACTH-secreting tumor

Scenario 3: Normal ACTH, high cortisol with abnormal circadian rhythm, visible pituitary tumor on MRI, visible adrenal tumor.

Possible sources of high cortisol: ACTH-secreting pituitary adenoma, adrenal tumor

There are more possible scenarios. The point I'm trying to make is that the evidence is not always cut-and-dry, and the source of high cortisol needs to be determined. One tool for doing this is the Bilateral Inferior Petrosal Sinus Sampling (BIPSS) aka IPSS.

In CLINICAL REVIEW: Cushing’s Syndrome: Important Issues in Diagnosis and Management
[The Journal of Clinical Endocrinology & Metabolism 91(10):3746–3753, © 2006 by The Endocrine Society], the authors state:

....mild to moderate hypercortisolism, a normal or slightly elevated plasma
ACTH, and normokalemia has at least a 95% likelihood of having Cushing’s
disease. In contrast, a patient with prodigious hypercortisolism, hypokalemia, and marked elevations of plasma ACTH may be more likely to have an occult ectopic ACTH-secreting tumor.

Approximately 40-50% of pituitary tumors do not show on MRI, although the dynamic protocol used in some specialty centers increases the odds. Couple that with the 10% chance of an incidentaloma and diagnosticians find the need for more validation.

The aforementioned authors also say "Inferior petrosal sinus ACTH sampling with CRH stimulation is the only study having the potential to yield a diagnostic sensitivity and specificity for Cushing’s disease higher than its pretest probability". They are talking about the IPSS.

What is an IPSS?

An IPSS is a test to sample the amount of ACTH draining into the inferior (vs. the superior) petrosal sinuses from the pituitary. Two catheters (one on each side) are threaded from the groin area up each side of the body to a major vein in the petrosal sinus area.

Corticotropin-releasing hormone (CRH), a natural hormone secreted by the hypothalamus, naturally stimulates the anterior pituitary gland to produce ACTH. If only the pituitary, not a tumor, is secreting ACTH, the levels of ACTH in the petrosal sinus area and in the rest of the body should be very close. If the levels of ACTH in the petrosal sinus area is higher than in samples from a peripheral area of the body , then an adenoma/tumor on or close to the pituitary is probably secreting ACTH.

Since CRH is released in pulses naturally and will not be active all the time, CRH is added during the IPSS to stimulate the pituitary to secrete ACTH during the testing period. After drawing blood from the catheters and from a peripheral area (arm or leg) to give a baseline level of ACTH and cortisol, CRH is injected. So that levels of ACTH are recorded from both the petrosal sinus area and the peripheral area, blood is drawn from each area at a specified interval (5-15 minutes, usually) to determine these levels over time. This usually takes about 2 hours.

The blood samples are kept on ice and sent immediately to the lab for determination of ACTH levels. There will be three major comparisons: 1) Right petrosal sinus samples 2) Left petrosal sinus samples 3) Peripheral samples

If the ratio of the right-to-peripheral sample OR the ratio of the left-to-peripheral sample is greater than 2 before the addition of CRH, the value is diagnostic for Cushing's Disease (pituitary source).

If the ratio of the right-to-peripheral sample OR the ratio of the left-to-peripheral sample is greater than 3 after the addition of CRH, the value is diagnostic for Cushing's Disease (pituitary source).

The IPSS may also be used tentatively for lateralization. This means it can help predict which side the tumor may be on. However, this is only about 70% accurate. For this to work, the tumor will drain more on one side than the other. However, some tumors drain into both sides, or there are multiple tumors. Sometimes, the anatomy is not predictable and the tumor may drain into the sinus on the opposite side.

How valid is the IPSS?

Multiple studies cite the usefulness of the IPSS in determining source, but not as a diagnostic tool. Biochemical evidence needs to show there is hypercortisolism prior to the use of the IPSS. The rate of false-positives is relatively nil, but there are false-negatives. In other words, some patients who have had proven Cushing's Disease had a negative IPSS. This is usually due to the infamous episodic/cyclic/subclinical/mild "version" of Cushing's.

In the article, Petrosal sinus sampling for diagnosis of Cushing's disease: evidence of false negative results, [Clin Endocrinol (Oxf). 1996 Aug;45(2):147-56], the authors say:

Only when a significant IPS:P ACTH ratio is present can Cushing's disease tbe established by IPS sampling. The absence of a significant IPS: P ACTH ratio does not necessarily imply ectopic secretion of ACTH, nor does it exclude Cushing's disease. The results of lateralization by IPS sampling do not remove the need for a thorough transsphenoidal examination of the contents of the sella turcica.

In the Endocrinologist [11(5):388-398, September/October 2001] researchers at the University of Virginia say " In experienced centers, the diagnostic sensitivity and specificity of IPSS approaches 100%. The indications for IPSS are debated, with some advocating use when standard dynamic tests are inconclusive, and others advocating use only when pituitary magnetic resonance imaging (MRI) is inconclusive. "

My IPSS was done at UCLA's Medical Center by Dr. Gary Duckwiler. I was sedated prior to the IPSS, and then, due to my extreme sleep apnea, went under general anesthesia and was intubated. Not all folks have to be completely knocked out and intubated. Some centers use a mild sedative and the patient is awake for the process. However, I was not an easy case, and I chose to go to someone with a lot of experience in my type of difficulties, even if it meant flying all the way across the country. (OK, I admit...I was going to be in LA anyway teaching at UCLA the following week, but I still would have done that.)

I woke up well, had no problems at all after the IPSS, and was allowed to leave that evening. I did have two hematomas in my groin area, one on each side. They were sore for a few days, but not sore enough to really bother me. My sore throat was probably the worst part of the whole process.

If you are interested, here are my IPSS results. As an interesting side-note, my tumor was on the posterior side of my pituitary on the floor and wall of the cavernous sinuses. So, the lateralization was correct in my case.

Tomorrow, I'll talk about testing for growth hormone function.


  1. Robin I just wanted to thank you for the information. I just took the overnight cortisol test. it came back fine. I have so many symptoms of cushings too numerous to go into. I had a breast reduction and a tummy tuck a year ago. I exercise sometimes to excess and when i eat i eat very healthy...Well my breasts are getting huge again and my mid section just keeps expanding. My dr. says i do not have cushings even though i have almost all the symptoms along w/ a benign tumor on my left adrenal gland...Any thoughts? Any advice would be greatly appreciated.Thank you.

  2. Unfortunately, most of the symptoms and signs of Cushing's syndrome may be present in people without the disorder. The most specific signs are abnormal stria (stretch marks) that are red and purplish and don't fade with time as normal weight related stria do, easy bruising, and progressive muscle weakness. There are some people with cyclic cushings whose levels of cortisol fluctuate such that repeated testing is needed. If the symptoms are progressing you could ask to repeat the test or use an alternative test such as 24 hour urine free cortisol or midnight salivary cortisol. good luck



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