1. Inferior Petrosal Sinus Sampling in Cushing’s Syndrome
Lia Neto
Neuroradiology Department – Santa Maria University Hospital, Lisbon - Portugal

2. IPSS in Cushing’s Syndrome
Cortisol
Cushing’s syndrome is a clinically recognizable entity. It is characterized by a variety of symptoms, the
most important of which include hypertension, diabetes
mellitus, weight gain with central obesity, moon
faces, purple abdominal striae, hirsutism, hyperpigmentation,
and osteoporosis. The common denominator
of Cushing’s syndrome is hypercortisolemia.

3. IPSS in Cushing’s Syndrome
- ACTH Dependent Vs ACTH Independent -
80%
The
causes of the syndrome may be classified as ACTHdependent
or ACTH-independent. Overproduction of cortisol alone is typically
due to an adrenal lesion. Approximately 5% of
patients with Cushing’s syndrome have an adrenal
lesion that demonstrates autonomous function—it
does not require stimulation by ACTH to produce
cortisol. These non-ACTH-dependent lesions include
hyperfunctioning adrenal adenomas, adrenocorticalcarcinomas, primary pigmented nodular adrenal
disease (PPNAD), and macronodular hyperplasia of
the adrenals. ACTH-independent Cushing’s syndrome
can also occur as a result of exogenous steroid
administration. There is no role for IPSS in patients
with ACTH-independent Cushing’s syndrome.
The remaining patients with Cushing’s syndrome
have an ACTH-dependent cause. Approximately 80%
of these patients have an ACTH-secreting pituitary
adenoma. This etiology (and only this specific etiology)
is referred to as Cushing’s disease. An additional 15%
of patients with Cushing’s syndrome have an ACTHsecreting
tumor at a site other than the pituitary gland.
Most of these patients have an obvious primary malignancy
with ectopic hormone production, typically in
the lung.

4. IPSS in Cushing’s Syndrome
- Biochemical Tests -
80%
Patients
with ACTH-dependent disease require further
endocrinologic evaluation to determine whether the
ACTH is from a pituitary source (Cushing’s disease)
or an ectopic source of ACTH. A number of biochemical
tests have been developed to aid in this effort.
These include suppression tests with dexamethasone
and stimulation tests with CRHIn general,
pituitary tumors retain some capacity to demonstrate
suppression of ACTH in response to high levels of
exogenous steroids and some ability to demonstrate
stimulation of ACTH in response to exogenous CRH,
while ectopic tumors do not respond. Unfortunately,
none of these biochemical tests is 100% sensitive and
100% specific. The tests shown in table 1 rely on the assumption
that although they are autonomous neoplastic
lesions, pituitary corticotroph adenomas retain at least
partial responsiveness to suppression by elevated glucocorticoid
levels or stimulation by CRH or desmopressin,
and conversely that ectopic ACTH-producing
tumors do not have such regulation. While this is generally
true, variability in the responsiveness of both
types of tumors underlies the lack of 100% accuracy
with these tests.

5. IPSS in Cushing’s Syndrome
- Imaging Tests -
80%
Sensitivity (40-50%)
Adenoma Dimensions
May enhance = parenchyma
“Incidentalomas” (6-10%)
Magnetic resonance imaging (MRI) of the pituitary
gland has become a routine test for evaluating
patients with ACTH-dependent Cushing’s syndrome.
MRI has proven useful not only for establishing the
presence of an adenoma but also for demonstrating its
location within the gland. This information is of
paramount importance for surgical planning, since
preservation of pituitary function after successful
resection of the adenoma is a cardinal objective of
the operation. The sensitivity of MRI in detecting
pituitary adenomas primarily depends on tumor
size. The sensitivity to ACTH-secreting adenomas
has been reported to be as low as 45% in postcontrast
scans. In other type of adenomas the sensitivity is
considerably higher, since they become clinically
apparent when larger in size. Difficulties in demonstrating ACTH-secreting
pituitary adenomas have several other causes that
are less amenable to correction. First, these tumors
are usually very small when patients first present. The
spatial resolution limitations of current MRI scanners
may cause them to be obscured by averaging artifacts.
Second, pituitary adenomas often enhance in a fashion
similar to normal pituitary parenchyma. Finally,
detection of functioning pituitary adenomas is also
confounded by the fact that identical-appearing, small
focal space–occupying lesions can be encountered
within the pituitary parenchyma of normal subjects.
Autopsy studies and MR scans of normal volunteers
have demonstrated that there is a 6% to 10% incidence
of nonfunctioning adenomas (incidentalomas) in the pituitary gland. Neither biochemical tests nor imaging studies
can provide an accurate diagnosis in all patients with
Cushing’s syndrome, and an additional diagnostic
method is sometimes required.

6. IPSS in Cushing’s Syndrome
- Inferior Petrous Sinus Sampling -
Sensitivity %
Specificity %
Lateralization 70%
petrosal sinus sampling can be used to confirm or
exclude the presence of a functioning pituitary
adenoma. It is most useful when the results of biochemical
tests and MRI are discrepant. In addition,
when biochemical tests provide a firm indication of
Cushing’s disease but no lesion is identified on pituitary
MRI, IPSS may provide lateralization of the pituitary
adenoma to one side of the pituitary gland. This
lateralization permits the surgeon to perform a hemihypophysectomy
and preserve pituitary function.

7. IPSS in Cushing’s Syndrome
- Inferior Petrous Sinus Sampling -
CRH (100µg)
Pre 5’
10’
15’
R-IPS
L-IPS PV
ACTH
Inferior petrosal sinus sampling (IPSS) is considered to be the gold standard for confirming the origin of ACTH
secretion in patients with Cushing’s syndrome.
IPS / PV ≥ 2 (≥ 3 post CRH) –Pituitary Cushing Synd.
IPS / PV  2 – Ectopic Cushing’s Synd.
R-PS / L-PS ≥ 1,4 - Lateralization

8. IPSS in Cushing’s Syndrome
Objective :
Evaluate the role of simultaneous bilateral catheterization
of the Inferior Petrosal Sinuses:
in the differential diagnosis of Cushing’s Syndrome
in the lateralization assessment of pituitary adenomas

9. IPSS in Cushing’s Syndrome
Material and Methods:
Retrospective analysis: 6 patients with CS (1♂ 5♀); 28 – 70 yr
IPSS between
Sedation & Anticoagulation (5000 U)
Bilateral femoral vein puncture – Bilateral IPS catheterization
Venogram
IPS and peripheral blood sampling pre and post CRH
IPS/peripheral ACTH ratio: Pituitary Vs Ectopic Cushing’s Syndrome
In Cushing’s Disease: lateralization assessment

10. IPSS in Cushing’s Syndrome
Results:
Catheterization and sampling was possible in all patients
No complications (technical or clinical)
2 patients with ectopic ACTH source
4 patients with Cushing’s Disease

11. IPSS in Cushing’s Syndrome
Results:
Clinically (+)
Biochemically (+)
Imaging (-)
35 yr ♀

12. IPSS in Cushing’s Syndrome
Results:
Clinically (+)
Biochemically (+)
Imaging (-)
35 yr ♀

13. IPSS in Cushing’s Syndrome
Results:
Clinically (+)
Biochemically (+)
Imaging (-)
35 yr ♀
Pre 5’
10’
15’
R-IPS 58
132
165 56
L-IPS
175
496
509
218 PV 14 17 16
IPS / PV – 12,5 / 35
L-IPS / R-IPS – 4

14. IPSS in Cushing’s Syndrome
Clinically (+)
Biochemically (+)
Imaging (inconclusive)
Results:
70 yr ♀

15. IPSS in Cushing’s Syndrome
Clinically (+)
Biochemically (+)
Imaging (inconclusive)
Results:
70 yr ♀
Pre 5’
10’
15’
R-IPS
162
235
206
140
L-IPS
33,7
39,5
68,4
101 PV
32,6
43,5
79,8
110
IPS / PV – 5
R-IPS / E-IPS – 6

16. IPSS in Cushing’s Syndrome
Results:
Clinically (+)
Biochemically (+)
Imaging (-)
32 yr ♀

17. IPSS in Cushing’s Syndrome
Results:
Clinically (+)
Biochemically (+)
Imaging (-)
32 yr ♀
Antes
5min
10min
15min
SPI Dto
1142
5104
5916
289
SPI Esq
2114
2461
2363
1169
Veia Perif.
60.7
178
201
202
IPS / PV – 35
R-IPS / E-IPS – inconclusive

18. IPSS in Cushing’s Syndrome
Originally described by Corrigan and colleagues in 1977 (unilateral venous sampling)
Oldfield et al introduced the bilateral IPSS in the 80´s and in the 90´s the IPSS with and without CRH.
Bilateral IPSS was initially introduced at the National
Institutes of Health by Oldfield and Doppman in the early
1980s.37,40 In the early 1990s, Oldfield et al.39 described theuse of bilateral petrosal sinus sampling with and without
administration of CRH for the differential diagnosis of
Cushing’s syndrome.

19. IPSS in Cushing’s Syndrome
Bilateral IPSS was initially introduced at the National
Institutes of Health by Oldfield and Doppman in the early
1980s.37,40 In the early 1990s, Oldfield et al.39 described theuse of bilateral petrosal sinus sampling with and without
administration of CRH for the differential diagnosis of
Cushing’s syndrome.

20. IPSS in Cushing’s Syndrome
The validity of IPSS relies on successful cannulation of the vessels
Anatomic Variations
Alternative Sampling Methods – Cavernous Sinus, Jugular Vein
Possible Complications (0,2%-1,1%) – vein / venule thrombosis or rupture, SAH, ischemia (...)
Bilateral IPSS was initially introduced at the National
Institutes of Health by Oldfield and Doppman in the early
1980s.37,40 In the early 1990s, Oldfield et al.39 described theuse of bilateral petrosal sinus sampling with and without
administration of CRH for the differential diagnosis of
Cushing’s syndrome.

21. IPSS in Cushing’s Syndrome
Conclusion :
IPSS is a safe and well tolerated procedure
Effective in the differential diagnosis of Cushing’s Syndrome
Useful in the localization of microadenomas and surgical planning

22. IPSS in Cushing’s Syndrome
Conclusion :
The high diagnostic sensitivity, specificity, and accuracy of IPSS have made it a gold standard tool in the investigation of ACTH - dependent Cushing´s syndrome.