The Journal of Clinical Endocrinology & Metabolism Vol. 83, No. 5 1485-1488
Copyright © 1998 by The Endocrine Society
Plasma Levels of Corticotropin-Releasing Hormone in the Inferior Petrosal Sinuses of Healthy Volunteers, Patients with Cushing’s Syndrome, and Patients with Pseudo-Cushing States
Jack A. Yanovski1,
Lynnette K. Nieman,
John L. Doppman,
George P. Chrousos,
Ronald L. Wilder,
Philip W. Gold and
Konstantine T. Kalogeras
Office of the Director (J.A.Y.) and the Department of Diagnostic
Radiology (J.L.D.), Warren Grant Magnuson Clinical Center; the
Developmental Endocrinology Branch, National Institute of Child Health
and Human Development (J.A.Y., L.K.N., G.P.C.); the Clinical
Neuroendocrinology Branch, National Institute of Mental Health (P.W.G.,
K.T.K.); and the Arthritis and Rheumatism Branch, National Institute of
Arthritis and Musculoskeletal and Skin Diseases (R.L.W.), National
Institutes of Health, Bethesda, Maryland 20892; and the Department of
Psychiatry and Human Behavior (K.T.K.), University of Mississippi
Medical Center School of Medicine, Jackson, Mississippi 39216
Address all correspondence and requests for reprints to: Jack A. Yanovski, M.D., Ph.D., National Institutes of Health, 10 Center Drive, MSC 1862, Building 10, Room 10N262, 9000 Rockville Pike, Bethesda, Maryland 20892-1862. E-mail: jy15i{at}nih.gov
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Abstract
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The objective of this study was to determine whether measurements
of human CRH in the inferior petrosal sinuses could distinguish
patients with Cushing’s syndrome from those with pseudo-Cushing states
or normal physiology. Twenty-five patients with Cushing’s disease, 17
patients with the syndrome of ectopic ACTH, 7 patients with Cushing’s
syndrome of adrenal origin, 6 patients with pseudo-Cushing states, and
11 volunteers believed to have normal hypothalamic-pituitary-adrenal
axes were studied. Basal plasma human CRH and ACTH were measured at two
time points in the petrosal sinuses and in a peripheral vein. Most
subjects were studied after the administration of intravenous diazepam
or midazolam and fentanyl, but because of the known inhibitory effects
of such sedation on CRH secretion, 2 normal volunteers and 3 patients
with pseudo-Cushing states were studied without sedation. Human CRH
levels were near or below the detection limit of the assay in all
subjects. Although the normal volunteers and patients with
pseudo-Cushing states who were studied without sedation had
significantly greater inferior petrosal sinus ACTH levels than those
who received sedation, there were no differences in measured human CRH
levels for any of the groups. We conclude that inferior petrosal sinus
human CRH levels are not easily measured in the inferior petrosal
sinuses and cannot be used to determine whether individual patients may
have hypersecretion of CRH causing their ACTH secretion.
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Introduction
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THE BASIS for all tests used to
differentiate patients with Cushing’s syndrome from those with
pseudo-Cushing states is the presumption that the etiology of the
hypercortisolism in these conditions is different (1). The
hypercortisolism of pseudo-Cushing states is believed to be the result
of increased hypothalamic CRH secretion in the context of a
hypothalamic-pituitary-adrenal (HPA) axis that is otherwise normally
constituted and which is appropriately restrained by cortisol negative
feedback (2, 3). In contrast, hypothalamic CRH secretion is believed to
be suppressed by the hypercortisolism of true Cushing’s syndrome; CRH
levels are low in the cerebrospinal fluid of patients with Cushing’s
disease (4, 5), and hypothalamic CRH secretion remains low for a
substantial time after adenomectomy (5a). However, peripheral venous
CRH levels are generally too low to differentiate between healthy
volunteers and patients with Cushing’s syndrome or pseudo-Cushing
states.
Bilateral, inferior petrosal sinus (IPS) sampling for ACTH measurement
has high accuracy in differentiating between Cushing’s disease and the
syndrome of ectopic ACTH secretion (6), but measurements of IPS ACTH
have not proven useful for discriminating Cushing’s disease from
pseudo-Cushing states or normal physiology (7). As venous blood from
both the hypothalamus and pituitary drains into the IPSs, IPS sampling
provides an opportunity to assess both hypothalamic and pituitary
hormones before their entry into the systemic circulation. In the
horse, CRH levels that increase with exercise and are suppressed by
glucocorticoid administration can be measured from pituitary venous
effluent (8, 9, 10). However, no prior studies have compared levels of
human CRH in the IPS of individuals with Cushing’s syndrome to those
in patients with pseudo-Cushing states or in individuals with normal
physiology.
We hypothesized that patients with Cushing’s syndrome would have low
CRH levels in the IPSs compared to healthy volunteers due to increased
glucocorticoid negative feedback, and patients with pseudo-Cushing
states would have greater IPS CRH levels because their ACTH
hypersecretion is believed to be CRH mediated. To test this hypothesis,
we compared basal IPS CRH levels of patients with Cushing’s syndrome
to those of patients with pseudo-Cushing states and volunteers with
normal HPA axis activity.
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Subjects and Methods
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Patient selection
We studied 25 patients with Cushing’s disease, 17 patients with
the syndrome of ectopic ACTH, 7 patients with Cushing’s syndrome of
adrenal origin, 6 patients with pseudo-Cushing states, and 11 healthy
volunteers believed to have normal HPA axis activity. Patients with
adrenal disorders were studied for the purpose of this protocol and not
for clinical care. All patients with Cushing’s syndrome or
pseudo-Cushing states had clinical and biochemical evidence of
hypercortisolism (including urinary free cortisol excretion of >248
nmol/day; normal, 27–248 nmol/day) before IPS sampling. The diagnosis
of a pseudo-Cushing state was based on the lack of features of severe
Cushing’s syndrome (such as marked central adiposity, cutaneous
atrophy, proximal myopathy, and large purple striae), the presence of
relatively mild hypercortisolism (urinary free cortisol, <1000
nmol/day), preservation of some diurnal variation of plasma cortisol,
and lack of progression of the laboratory values, the clinical signs,
or the symptoms of Cushing’s syndrome over an observation period of at
least 18 months. Of the patients diagnosed with pseudo-Cushing states,
all 6 had a diagnosis of either a current or a previous major
depressive episode. One patient with a pseudo-Cushing state also had
current substance abuse. Volunteers with normal HPA axis activity had
24-h urinary free cortisol measurements within the normal range and
normal results from overnight 1-mg dexamethasone suppression tests. All
subjects were studied at least 2 days after discontinuing any
medication known to affect the HPA axis. The diagnosis of Cushing’s
disease, ectopic ACTH, or primary adrenal disorders was confirmed at
surgery or, in three patients with Cushing disease, by clinical and
biochemical remission after pituitary radiation treatment. None of
these 3 patients had elevated peripheral CRH levels consistent with an
ectopic CRH-secreting tumor. The 17 patients with ectopic ACTH included
9 with bronchial carcinoid tumors, 5 with thymic carcinoid tumors, 2
with pancreatic ACTH-secreting tumors, and 1 with appendiceal
carcinoid. The 7 patients with adrenal disorders included 4 with a
unilateral adrenal adenoma, 1 with primary pigmented nodulocortical
adrenal disease (Carney complex) (11), and 2 with ACTH-independent,
bilateral macronodular adrenal disease (12). Informed consent was
obtained from all subjects, and the IPS sampling protocol was approved
by the NICHHD institutional review board.
Petrosal sinus sampling
IPS sampling was performed essentially as previously described
(13). Because of the known inhibitory effects of benzodiazepines (14)
and narcotics (15) on CRH secretion, a total of five subjects (two
healthy volunteers and three patients with pseudo-Cushing states) were
studied without any sedation. The remainder received sedation with iv
diazepam (1–10 mg) or midazolam (1–2 mg) and fentanyl (50–100 µg).
After systemic anticoagulation with heparin (3000–4000 IU) in all
subjects, catheters were advanced to the inferior petrosal sinuses
under fluoroscopic guidance, and their positions were verified by
contrast injections. Between 0900–1100 h, two blood samples were
obtained simultaneously from each IPS and a peripheral vein. Plasma
samples were centrifuged immediately and frozen at -20 C until assay
of CRH and ACTH.
Hormonal analyses
Plasma CRH and ACTH were measured by RIA after extraction (16).
In general, initial plasma volumes permitted a 2- to 3-fold
concentration of the plasma after reconstitution. Because most of these
patients had a number of other hormones measured in these samples,
sample volume was not equal for each tube. To assure comparable values,
samples were not analyzed when available plasma would not permit more
than a 1-fold concentration of sample content. There were 5 patients (2
patients with adrenal disorders and 1 each with Cushing disease,
ectopic ACTH, and pseudo-Cushing states) for whom no CRH levels could
be measured because inadequate plasma volume was available for
analysis. An additional 11 patients had individual samples that could
not be analyzed for CRH, but had at least 1 plasma sample from each
petrosal sinus and the peripheral vein in which CRH could be measured.
One patient with Cushing’s disease had a single missing peripheral
ACTH value.
The limit of detection for the human CRH assay ranged from 1.5–2.2
pmol/L. The mean intra- and interassay coefficients of variation were
7.0% and 7.9%, respectively. The limit of detection for the ACTH
assay ranged from 0.7–1.1 pmol/L. The mean intra- and interassay
coefficients of variation were 3.8% and 7.2%, respectively. The CRH
and ACTH antibodies exhibited no significant cross-reactivity with
related peptide hormones (<1%; data not shown). All samples from the
same subject were analyzed in one assay.
Statistical analyses
Data from the two basal time points were averaged for the
purpose of analysis. In most samples, CRH levels were below the
detection limit of the assay. In such cases, the detection limit was
used for all statistical analyses. Data were analyzed on a Macintosh
Centris 650 using SuperAnova 1.11 and StatView 4.5 (Abacus Concepts,
Berkeley, CA) software. ANOVA, with repeated measures (ANOVA-R) where
appropriate, was used to compare the hormone concentrations in the
petrosal sinuses and the peripheral vein. Due to heteroscadasticity of
variance, plasma ACTH measurements were subjected to logarithmic
transformation before analysis. Preplanned, paired and unpaired Fisher
least significant difference tests were used. The dominant IPS for each
hormone was defined as the inferior petrosal sinus that had the highest
ACTH concentration. The results of all analyses were essentially
unchanged when the three patients believed to have Cushing’s disease
who entered remission only after pituitary radiation were excluded.
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Results
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Human CRH levels in IPS plasma were either undetectable or quite
near the limit of detectability in all study subjects (Fig. 1
). CRH levels in those who underwent IPS
sampling without sedation were also essentially undetectable.
Statistical analysis of human CRH levels revealed no significant
differences between any of the groups in either the IPSs or the
peripheral vein (ANOVA-R; df = 8; P = 0.47).
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Figure 1. Plasma human CRH concentrations (mean
± SEM) in the dominant petrosal sinus (A; defined as the
petrosal sinus with the highest ACTH level), nondominant petrosal sinus
(B), and peripheral vein (C). AD, Adrenal disorders; EA, ectopic ACTH
secretion; CD, patients with Cushing’s disease; NV+, normal volunteers
sampled with sedation; PCS+, pseudo-Cushing states sampled with
sedation; NV-, normal volunteers sampled without sedation; PCS-,
pseudo-Cushing states sampled without sedation.
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As expected (Fig. 2), ACTH showed
significant differences between patients with ACTH-dependent Cushing’s
syndrome (Cushing’s disease and ectopic ACTH) and those with primary
adrenal disorders for both IPSs and the peripheral vein (ANOVA-R;
df = 8; P < 0.001). ACTH levels were also higher
in patients with ACTH-dependent Cushing’s syndrome than in sedated
patients with pseudo-Cushing states or normal physiology
(P < 0.001). Among the subjects with pseudo-Cushing
states and normal physiology, the dominant and nondominant petrosal
plasma ACTH levels were significantly greater in subjects who received
no sedation than in those who were sedated for the procedure (ANOVA-R;
df = 2; P < 0.01).
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Figure 2. Plasma ACTH concentrations (mean ±
SEM) in the dominant petrosal sinus (A; defined as the
petrosal sinus with the highest ACTH level), nondominant petrosal sinus
(B), and peripheral vein (C). Note the different scale for each figure.
*, P < 0.001 compared to patients with Cushing’s
syndrome of adrenal origin, sedated volunteers with normal physiology,
or sedated patients with pseudo-Cushing states. §,
P < 0.01 compared to sedated patients with
pseudo-Cushing states. AD, Adrenal disorders; EA, ectopic ACTH
secretion; CD, Cushing’s disease; NV+, normal volunteers sampled with
sedation; PCS+, pseudo-Cushing states sampled with sedation; NV-,
normal volunteers sampled without sedation; PCS-, pseudo-Cushing
states sampled without sedation.
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Discussion
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In this study, basal IPS human CRH levels were undetectable in
patients with Cushing’s syndrome, patients with pseudo-Cushing states,
and healthy volunteers with a normally constituted HPA axis. When
sedation was omitted for patients with pseudo-Cushing states or healthy
volunteers, IPS ACTH levels were greater than in those receiving
sedation, but the CRH levels in the petrosal sinuses remained
undetectable. Thus, contrary to our hypothesis, measurements of IPS CRH
appear to be of no value in distinguishing Cushing’s syndrome from
pseudo-Cushing states or from normal physiology unless a much more
sensitive CRH assay becomes available.
These results might be considered surprising given previous studies
finding greater cerebrospinal fluid CRH levels in patients with
pseudo-Cushing states, such as depression or anorexia nervosa, than in
controls (17, 18, 19, 20, 21, 22, 23). However, the diurnal variation in cerebrospinal
fluid CRH is out of phase with that expected of hypothalamic CRH neuron
secretion, and it is likely that cerebrospinal fluid CRH levels are
mainly the result of the secretion of extrahypothalamic CRH-secreting
cells. Thus, cerebrospinal fluid CRH levels are not necessarily
reflective of the activity of the neurons that cause pituitary ACTH
secretion (17, 21).
CRH is secreted by the paraventricular nucleus of the hypothalamus into
the long portal vessels, where it has been measured in nanomolar
concentrations (24, 25, 26, 27, 28) before it reaches the anterior pituitary gland.
However, CRH concentrations were found to be below the detection limit
of the assay (<2.2 pmol/L) in both the petrosal sinuses and periphery
of nearly all of our subjects. This does not appear to be the result of
the pretreatment of most of our subjects with anxiolytics and
narcotics, both of which are known to suppress CRH secretion (14, 15).
As mentioned earlier, five of our subjects (two healthy volunteers and
three patients with pseudo-Cushing states) who were not pretreated with
sedatives also showed undetectable petrosal sinus CRH levels.
The most likely explanation for our findings is that IPS concentrations
of hypothalamic factors such as CRH are already too diluted by
nonpituitary blood to be detected. In this case, measurements of
cavernous sinus CRH may prove informative. Another possibility is that
the pituitary gland disposes of the majority of human hypothalamic CRH
secretion before it enters the pituitary venous effluent. Active
degradation and/or uptake of CRH may be taking place at the anterior
pituitary, contributing to the undetectable petrosal sinus CRH levels.
High levels of CRH-binding protein, are found in the anterior pituitary
(29), which might help bind a portion of endogenous CRH secreted into
the portal circulation.
In this study we found that the petrosal ACTH concentrations of
patients with pseudo-Cushing states who received sedatives during
sampling are lower than those of patients with pseudo-Cushing states
who did not receive sedation, whose results are similar to those of
patients with Cushing’s syndrome who received sedatives. These
findings might seem to suggest that administration of sedation during
petrosal sinus sampling may be of value in assuring accurate
interpretation of sampling data. We have previously found that petrosal
sinus sampling for ACTH in sedated subjects is of limited use to
discriminate pseudo-Cushing states from Cushing’s disease (7) and
cannot be recommended for this purpose. For the differential diagnosis
of Cushing’s syndrome, we recommend that petrosal sinus sampling be
performed with sedation, because the vast majority of petrosal sinus
sampling data have been collected from sedated patients. As part of the
present study, it was our intent to study patients believed to have
true Cushing’s syndrome without sedation. However, our initial
attempts to perform such petrosal sinus samplings in patients with true
Cushing’s syndrome who had previously undergone a sedated sampling
were met with great patient dissatisfaction, and we cannot report any
results from such samplings.
We conclude that IPS CRH levels are undetectable in patients with
Cushing’s syndrome, in patients with pseudo-Cushing states, and in
healthy volunteers and are not made measurably greater when sedation is
withheld. Dilution of the pituitary effluent by nonpituitary blood
entering the cavernous sinuses appears to be the most likely
explanation for the undetectable CRH concentrations in the petrosal
sinuses, although uptake and degradation of CRH by pituitary cells may
contribute to the observed results. We hypothesize that sampling of
cavernous sinus blood, which may be less diluted with
nonpituitary-derived blood, may demonstrate detectable CRH levels in
individuals with a pseudo-Cushing state and possibly provide a tool to
differentiate these patients from individuals with Cushing’s
syndrome.
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Acknowledgments
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The authors thank the nurses of the 10-West NICHHD in-patient
endocrinology unit at the Warren Grant Magnuson Clinical Center, NIH,
and the support staff of the Warren Grant Magnuson Clinical Center
Special Procedures Unit for their care of the patients involved in this
study.
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Footnotes
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1 Commissioned officer in the USPHS. 
Received November 19, 1997.
Revised January 12, 1998.
Accepted January 22, 1998.
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Top
Abstract
Introduction
