Uses of Corticotropin-Releasing Hormone in the
Evaluation of Patients with Cushing's Syndrome
M. K. Biller, M.D.
& Pituitary Center |
Guestbook | Neurosurgery
Home | Links
(CRH), the hypothalamic peptide which stimulates ACTH release
from the pituitary gland, has been available for investigational
use for nearly a decade. The formulation of greatest clinical
utility, ovine CRH, is currently under evaluation by the United
States Food and Drug Administration for approval as a new drug.
Because approval is anticipated in the near future, it is important
to define the clinical indications for this peptide. A key utilization
of CRH will be in patients with Cushing's syndrome. Three settings
in which oCRH testing has been useful in the evaluation of patients
with Cushing's syndrome are: 1) the differential diagnosis of
ACTH dependent versus ACTH independent Cushing's syndrome, 2)
to enhance the diagnostic accuracy of bilateral inferior petrosal
sinus sampling, and 3) distinguishing between Cushing's syndrome
and pseudo-Cushing's syndrome.
To perform a CRH test, blood is
drawn for baseline ACTH and cortisol levels at -15 and 0 minutes
followed by a 1 mg/kg dose of oCRH administered as an IV bolus.
Samples for ACTH and cortisol are then drawn at 15, 30, 60,
90 and 120 minutes. The test is well tolerated, with the most
common side effects being transient facial flushing occurring
in 20% of subjects, and rare dyspnea and hypotension. Normal
subjects experience a rapid rise in ACTH and cortisol, with
a gradual decline over the subsequent two hours.
CRH Testing - Differential
Diagnosis of Cushing's Syndrome
The first use of oCRH is in the
differential diagnosis of Cushing's syndrome to establish the
site of hormone excess in patients with documented cortisol
excess (Fig. 1). The use of CRH in this setting is based on
the principle that pituitary tumors are responsive to exogenous
CRH, whereas ectopic and adrenal tumors are not. In Cushing's
disease, at least a 50% rise in ACTH and a 20% rise in cortisol
compared to baseline have been described as criteria providing
a 91% sensitivity and 95% specificity for pituitary Cushing's.
It has also been shown that using both the CRH test and the
high dose dexamethasone suppression test enhances diagnostic
accuracy. In adrenal Cushing's, the low ACTH and high cortisol
levels at baseline are not affected by CRH injection. In ectopic
Cushing's, typically due to carcinoid or oat cell tumors of
the lung but reported for a wide variety of tumor types, the
high ACTH and high cortisol levels at baseline are usually not
altered by the CRH administration. However, a few cases of ectopic
Cushing's in which some response was seen to CRH have been reported.
Interestingly, in nearly all of those cases, ACTH rises without
a concomitant increase in cortisol, suggesting that the cortisol
response to CRH may be the most specific biochemical test differentiating
between pituitary and ectopic Cushing's syndrome. It has been
theorized that this discrepancy between ACTH and cortisol release
may be due to the secretion of "big ACTH" by ectopic
tumors, with these abnormal forms of ACTH being less bioactive,
resulting in a smaller adrenal response to a given amount of
Reprinted by permission of the
New England Journal of Medicine Vol. 310, page 622, 1984
CRH Testing - Bilateral Inferior
Petrosal Sinus Sampling
The second use of CRH is to enhance
the diagnostic accuracy of bilateral inferior petrosal sinus
sampling (BIPSS) for ACTH. BIPSS is performed via femoral catheterization
to sample blood from the inferior petrosal sinuses draining
from the pituitary. This provides for comparison between central
and peripheral ACTH values, allowing definitive confirmation
of the site of hormone excess. It is also possible, by comparing
right versus left side ACTH values to predict the tumor location
and provide this information to the pituitary neurosurgeon.
(See Vol. 1 of newsletter). The rationale for using CRH during
BIPSS is that false negative test results may occur in up to
18% of patients subsequently proven to have pituitary Cushing's.
This is due to the fact that secretion of ACTH from corticotroph
adenomas can be episodic, and a low value may be measured from
the petrosal sinuses if the blood is collected between ACTH
pulses. Use of CRH stimulates ACTH release from the corticotroph
adenoma, producing a higher pituitary-to- peripheral ratio,
and thereby allowing better discrimination between pituitary
and ectopic Cushing's. If the pituitary to peripheral ratio
is >3 with CRH, the patient has Cushing's disease. In contrast,
if it is <3, the patient has ectopic Cushing's. The sensitivity
and specificity of BIPSS each reach 100% if CRH is used. Approximately
100 BIPSS's have been performed at the Massachusetts General
Hospital with results very similar to those reported by the
NIH and with no neurologic complications. An example of data
from a BIPSS with CRH performed at the Massachusetts General
Hospital is shown in Table 1.
CRH Test - Cushing Syndrome versus
The most recently described use
of CRH in the evaluation of patients with Cushing's has been
a new test designed to distinguish Cushing's syndrome from pseudo-Cushing's
states. Differentiating between hypercortisolemia associated
with endogenous depression (pseudo-Cushing's) versus depression
associated with true Cushing's syndrome can be extremely difficult.
Insulin tolerance tests, in which patients with primary depression
have a normal cortisol response and patients with Cushing's
syndrome have a blunted response, and CRH tests, in which patients
with primary depression have a blunted response and patients
with Cushing's syndrome have a normal to exaggerated response,
have been advocated to make the distinction between these diagnoses.
However, the data show substantial overlap between groups. Therefore,
although these tests have been useful in studying the physiology
of these disorders, they have not been as useful diagnostically
as initially hoped. It has often been necessary to follow patients
with depression versus Cushing's for many years with improvement
in primary endogenous depression (either spontaneously or with
pharmacotherapy) indicating absence of Cushing's syndrome. A
recent study has suggested that it is possible to distinguish
patients with pseudo-Cushing's from those with Cushing's syndrome
by performing a CRH test immediately following a standard low
dose dexamethasone suppression test. The last dose of the eight
0.5 dexamethasone pills is given at 6 a.m., followed by an 8
a.m. injection of CRH. A plasma cortisol greater than 1.4 mg/dl
measured 15 minutes after the CRH injection differentiated all
patients with Cushing's syndrome from those with pseudo-Cushing's.
The values for plasma cortisol in the 39 patients with Cushing's
syndrome and the 19 patients with pseudo-Cushing's who had elevated
urine free cortisol are shown in the Figure 2. This test had
100 % specificity, sensitivity and diagnostic accuracy and is
extremely promising for the diagnosis of Cushing's syndrome
in this difficultsituation.
In summary, the CRH test is a
safe, well-tolerated diagnostic tool which will have a beneficial
impact on our ability to diagnose accurately patients with Cushing's
JAMA, 1993; 269: 2232-2238
- Yanovski JA, et al. Corticotropin-releasing
hormone stimulation following low-dose dexamethasone administration.
JAMA. 1993; 269: 2232.
- Chrousos GP, et al. The corticotropin-releasing
factor stimulation test: An aid in the evaluation of patients
with Cushing's syndrome. N Engl J Med. 1984; 310:622.
- Oldfield EH, et al. Petrosal
sinus sampling with and without corticotropin-releasing hormone
for the differential diagnosis of Cushing's syndrome. N Engl
J Med. 1991; 325:897.
- Nieman LK, et al. The ovine
corticotropin-releasing hormone stimulation test and the dexamethasone
suppression test in the differential diagnosis of Cushing's
syndrome. Ann Int Med. 1986; 105:862.
|CRH 2-3 min.
|CRH 5 min.
|CRH 10 min.
|CRH 10 min.
& Pituitary Center |
Bulletin Archive | Guestbook
Home | Links