1. Determining the type of Cushing’s syndrome: Not as hard as it seems
Theodore C. Friedman, M.D., Ph.D.
Professor of Medicine-Charles Drew University
Professor of Medicine-UCLA
Magic Foundation
Symposium on Cushing’s Syndrome
February 22, 2009
Las Vegas, NV

2. Types of Cushing’s a. Pituitary Adenoma (Cushing’s Disease) 80%, 95%
b. Ectopic ACTH Syndrome 5%, 1%
c. Adrenal adenoma 13%, 3%
d. Adrenal carcinoma 2%, 1%
Literature-%, Friedman %
Men are more likely to have ectopic
Ectopics are almost always more hypercortisolemic and probably easier to pick up.
Episodic hypercortisolism has not particularly been associated with any type of Cushing’s.

3. Determine Hypercortisolism
Last lecture
UFC, 17OHS
Night-time salivary cortisols
Night-time serum cortisols

4. Distinguishing Type of Cushing’s
Distinguish between ACTH-independent (adrenal) and ACTH-dependent Cushing syndrome (pituitary or ectopic) by measuring an 8 AM fasting plasma ACTH (remember time zone effect)
ACTH < 10 pg/mL-probably adrenal disease
ACTH > 100 pg/mL-likely ectopic
ACTH between 10 pg/mL-100 pg/mL-probably pituitary, but there are overlaps
ACTH needs to be collected in a chilled tube and spun immediately.
Could be in a low
Get a simultaneous serum cortisol to see if in a low.

5. Imaging Get a pituitary MRI, if not already
Pituitary tumor makes pituitary Cushing’s much more likely, but could still have pituitary incidentaloma and non-pituitary Cushing’s
Needs to be confirmed with other test (dexamethasone test, ACTH level)
If low ACTH-get adrenal imaging
Adrenal MRI and CT are somewhat equivalent, usually CT is cheaper, but more radiation exposure

6. Imaging (2)
Patients with pituitary Cushing’s can have a dominant nodule on adrenal imaging, making it look like adrenal disease

7. Dexamethasone suppression tests
Classically, non-Cushing’s patients suppressed to overnight (1 mg at midnight) or low dose (0.5 mg given every 6 hrs for 2 days) dexamethasone.
Patients with pituitary Cushing’s disease did not suppress to overnight or low dose dexamethasone, but did suppress to high dose dexamethasone (2 mg given every 6 hrs for 2 days).
Patients with adrenal or ectopic Cushing’s suppress to high dose dexamethasone.

8. Dexamethasone suppression tests
I found that most patients with mild pituitary Cushing’s disease do suppress to overnight or low dose dexamethasone.
Thus the overnight or low-dose dexamethasone test can be used to distinguish between pituitary and adrenal or ectopic Cushing’s, so patients who suppress to low-dose dexamethasone are unlikely to have adrenal or ectopic Cushing’s.
Isadori et al. (JCEM, 2003, 88: ) agreed with this approach.
Still some concern with being periodic.

9. Distinguishing Type of Cushing’s
oCRH test is also possible as pituitary Cushing’s disease patients respond to oCRH, while adrenal or ectopic do not.
oCRH is expensive
My approach: Patient with ACTH between pg/mL, a pituitary tumor on MRI and suppression to overnight or low dose dexamethasone: I send to pituitary surgery.
Odds of having pituitary disease are already high.

10. Distinguishing Type of Cushing’s
Patients with an ACTH < 10 pg/mL, a clean pituitary MRI and a tumor on adrenal imaging: send to adrenal surgery.
Patients with severe Cushing’s, edema or low potassium, high ACTH and cortisol levels and who do not suppress to dexamethasone: ectopic Cushing’s: IPSS, lung/ thymic imaging, octreotide scan

11. Inferior Petrosal Sinus Sampling (IPSS)
IPSS involves sampling the inferior petrosal sinuses which drain the pituitary for ACTH. Petrosal blood levels of ACTH are compared to peripheral levels.
oCRH is given which usually helps to further distinguish between pituitary and ectopic sources.
Test involves catheterization through the femoral vein, going through the heart into the carotid vein and then to the petrosal sinus.
But do at an experienced center.
Safe and not as bad as it sounds
Cavernous sinus sampling is probably about as good.
Hard to interpret if one petrosal sinus is bigger than the other

12. Inferior Petrosal Sinus Sampling (IPSS) (2)
IPSS has been found to be very useful to distinguish pituitary Cushing disease from ectopic ACTH syndrome. It is also somewhat helpful for determining lateralization of the pituitary tumor.
IPSS depends on the suppression of normal corticotropes by hypercortisolism.
It was hypothesized that patients with pseudo-Cushing states or normal individuals would have lower ACTH concentrations in their petrosal sinuses and lower petrosal to peripheral gradients than those patients with Cushing disease. Additionally, it was expected that patients with pseudo-Cushing states or normal individuals would have symmetric drainage of ACTH into each petrosal sinus.

13. Inferior Petrosal Sinus Sampling (IPSS) (3)
Yanovski et al. (JCEM, 1993, 77: ) performed petrosal sinus sampling in 7 eucortisolemic volunteers, 8 hypercortisolemic patients with pseudo-Cushing states and 40 patients with Cushing disease.
All three groups of patients had similar petrosal ACTH before and after CRH. There was considerable overlap between the three groups precluding this test to diagnose Cushing syndrome.
All three groups had elevated petrosal to peripheral gradients. Again there was too much of an overlap between the three groups to use this test to diagnose Cushing syndrome.
All three groups exhibited significant lateralization of ACTH.
IPSS should not be used to make the diagnosis of Cushing syndrome.

14. So what is IPSS good for?
Distinguishing between pituitary or ectopic Cushing’s
Very good at this, but can usually be done on other grounds
Distinguishing between pituitary and adrenal
Often can been done on other grounds as well, but sometimes needed in hard cases.
Determining if a questionable spot on MRI corresponds to lateralization on IPSS
If you have a right sided questionable lesion and get a right sided lateralization, that would support that the pituitary lesion is the source of the ACTH and might support the diagnosis of Cushing’s
If no tumor is seen on pituitary MRI, yet pituitary Cushing’s is expected.
If ectopic is expected.
Medical-legal reasons
I rarely see the need for it

15. Do you need to be hypercortisolemic during IPSS?
Test works on suppression of normal corticotropes during high cortisol levels-so technically yes
In episodic patents, hard to predict when high.
I get a 24 hr UFC or night-time salivary cortisol the day/night before to determine cortisol status.
If clear-cut central to peripheral gradient, then its probably interpretable and supports pituitary.
But if low ACTH levels and no central to peripheral gradient, then I could be mislead into either concluding adrenal or ectopic, then I would repeat it.

16. On to surgery