0021-972X/99/$03.00/0
The Journal of Clinical Endocrinology & Metabolism
Copyright © 1999 by The Endocrine Society
Vol. 84, No. 10
Printed in U.S.A.
Food-Dependent Cushing’s Syndrome: Possible
Involvement of Leptin in Cortisol Hypersecretion*
FRANÇOIS P. PRALONG†, FULGENCIO GOMEZ, LOUIS GUILLOU,
FRANÇOIS MOSIMANN, SEBASTIANO FRANSCELLA, AND ROLF C. GAILLARD
Division of Endocrinology, Diabetology, and Metabolism, Department of Medicine, Institute of
Pathology (F.M.), and the Department of Surgery (L.G.), University Hospital and Lausanne Medical
School, 1011 Lausanne, Switzerland
ABSTRACT
Stimulation of cortisol secretion by food intake has been implicated
in the pathogenesis of some cases of ACTH-independent Cushing’s
syndrome, via an aberrant response of the adrenal glands to gastric
inhibitory polypeptide (GIP). We report here a novel case of fooddependent Cushing’s syndrome in a patient with bilateral macronodular adrenal hyperplasia. In this patient we were able to confirm a paradoxical stimulation of cortisol secretion by GIP in vivo as
well as in vitro on dispersed tumor adrenal cells obtained at surgery.
In addition to GIP, in vitro stimulation of these cultured tumor adrenal cells with leptin, the secreted product of the adipocyte, induced
cortisol secretion. By comparison, no such stimulation was observed
in vitro in adrenal cells obtained from another patient with bilateral
macronodular adrenal hyperplasia and Cushing’s syndrome that did
A
CTH-PRODUCING pituitary adenomas or primary adrenal tumors (benign or malignant) account for the
vast majority of patients presenting with Cusing’s syndrome
(1). Occasional patients with ACTH-independent hypercortisolism and bilateral adrenal hyperplasia have been described (1– 4), and in rare instances food intake was found to
stimulate cortisol secretion (5–10). This food-dependent form
of Cushing’s syndrome results at least partially from an
abnormal adrenal response to gastric inhibitory polypeptide
(GIP) (6, 7) via overexpression of GIP receptors in adrenal
tissue (8 –11).
In the present study, we describe two patients with ACTHindependent Cushing’s syndrome and bilateral macronodular adrenal hyperplasia, the first one of the food-dependent
type and the second with no evidence of food dependency.
In the first patient, circulating GIP levels were found to
correlate with food-stimulated cortisol secretion in vivo. Furthermore, GIP directly stimulated cortisol secretion from
dispersed tumor adrenal cells obtained at surgery, confirming the existence of a paradoxical response to GIP in fooddependent Cushing’s syndrome (6, 9, 10). In addition to GIP,
Received December 30, 1998. Revision received June 24, 1999. Accepted July 2, 1999.
Address all correspondence and requests for reprints to: François
P. Pralong, M.D., Division of Endocrinology, BH 19707, Centre Hospitalier Universitaive Vaudois, 1011 Lausanne, Switzerland. E-mail:
[email protected].
* This work was supported by a grant from the Swiss National Science
Foundation (no. 3100 – 050748.97/1).
† Recipient of a Research Development Carrier Award from the Prof.
Dr. Max Cloëtta Foundation.
not depend on food intake, in tumor cells obtained from a solitary
cortisol-secreting adrenal adenoma, and in normal human adrenocortical cells.
These results demonstrate that as in previously described cases of
food-dependent Cushing’s syndrome, GIP stimulated cortisol secretion from the adrenals of the patient reported here. Therefore, they
indicate that such a paradoxical response probably represents the
hallmark of this rare condition. In addition, they suggest that leptin,
which normally inhibits stimulated cortisol secretion in humans, participated in cortisol hypersecretion in this case. Further studies in
other cases of food-dependent Cushing’s syndrome, however, will be
necessary to better ascertain the pathophysiological significance of
this finding. (J Clin Endocrinol Metab 84: 3817–3822, 1999)
leptin was found to stimulate cortisol secretion by the same
adrenal tumor cells, whereas no such in vitro effect of leptin
was observed in cells obtained from the case with foodindependent Cushing’s syndrome, in cells obtained from a
cortisol-secreting solitary adrenal adenoma, or in normal
human adrenocortical cells. Taken together, these results
confirm the existence of a paradoxical response to GIP in
food-dependent adrenal Cushing’s syndrome. Such a paradoxical response, therefore, seems to represent a hallmark of
this pathophysiological condition. Moreover, they suggest
that leptin, which inhibits cortisol secretion by normal human adrenocortical cells (12, 13), may have played an additional role to stimulate cortisol secretion in this particular
case. However, the true pathophysiological significance of
this in vitro effect of leptin remains to be elucidated.
Case Reports
Case 1
A 36-yr-old woman presented with a pathological fracture of the
femoral neck. She had gained 14.7 kg of weight over the previous 3 yr
and suffered from recent-onset hypertension. Physical findings included
moon-like face, truncal obesity (weight, 86.7 kg; height, 161.5 cm; body
mass index, 33.4), the presence of cervicodorsal fat pads, red striae over
abdomen and thighs, multiple bruises, and high blood pressure (148/
110 mm Hg). Investigations revealed marked osteopenia (L2–L4, 0.82
g/cm2, corresponding to a T score of 22.28 sd; femoral neck, 0.63 g/cm2,
corresponding to a T score of 22.32 sd). Endocrine work-up confirmed
the suspected diagnosis of Cushing’s syndrome, with elevated urinary
free cortisol levels of 1673 and 1346 nmol/24 h on two separate occasions
(normal, 28 –220). While the patient was taking an estrogen-containing
oral contraceptive agent, the morning fasting plasma cortisol was elevated at 988 nmol/L (normal, 200 –700), and ACTH was undetectable
(,3 ng/L), thus leading to the diagnosis of ACTH-independent Cush-
3817
3818
JCE & M • 1999
Vol 84 • No 10
PRALONG ET AL.
ing’s syndrome. During an overnight dexamethasone suppression test
(1 mg dexamethasone at 2300 h), plasma cortisol at 0800 h was 1211
nmol/L. The absence of a circadian rhythm was demonstrated by the
stable values of plasma cortisol after meals of 892, 886, and 834 nmol/L
at 000, 1200, and 1700 h, respectively, whereas ACTH was undetectable.
An abdominal computed tomography scan revealed the presence of
bilateral macronodular adrenal hyperplasia, and In111 octreotide scintigraphy showed marked abnormal diffuse accumulation in both hyperplastic glands.
The patient underwent bilateral adrenalectomy. The right and left
adrenal glands weighed 62.5 and 51.5 g and measured 7 3 5 3 2.5 and
8 3 4.5 3 2.8 cm, respectively. Cut section revealed multiple yellowish,
well delineated but nonencapsulated, coalescent nodules measuring up
to 5 and 1.3 cm in maximal diameter in the right and left (Fig. 1A)
adrenals, respectively. On microscopic examination, these nodules were
composed predominantly of large clear cells, which focally exhibited
some degree of nuclear atypia. Clusters of small clear cells as well as tiny
foci of nonpigmented large eosinophilic cells were found within or
adjacent to large clear cell nodules, with transition from one cell type to
the other. Mitotic figures and features of vascular invasion were not
observed. Hyperplastic clear cells occasionally formed pseudoglandular
spaces and also extended into periadrenal fat. The nonnodular adreno-
cortical tissue was somewhat atrophic, mostly composed of nonhyperplastic clear cells. The pathological findings were consistent with bilateral macronodular adrenocortical hyperplasia.
Case 2
A 59-yr-old woman presented with recent onset hypertension, weight
gain (10 kg over 1 yr), hirsutism, type 2 diabetes mellitus, and proximal
leg weakness. Physical examination revealed truncal obesity (weight, 77
kg; height, 164 cm; body mass index, 28.6), cervicodorsal fat pads,
generalized amyotrophia, multiple bruises but no red striae, and high
blood pressure (170/120 mm Hg). Endocrine work-up confirmed the
suspected diagnosis of Cushing’s syndrome, with elevated urinary free
cortisol levels of 524 and 445 nmol/24 h on two separate occasions
(normal, 28 –220). Morning fasting plasma cortisol was elevated at 723
nmol/L, with undetectable ACTH, thus leading to the diagnosis of
ACTH-independent Cushing’s syndrome. An abdominal computed tomography scan revealed bilateral macronodular adrenal hyperplasia.
The patient underwent bilateral adrenalectomy. The right and left
adrenals weighed 35 and 52 g and measured 5 3 6.5 3 1.5 and 7.5 3
5 3 2.3 cm, respectively. On section, both glands contained multiple
yellowish or brownish, well circumscribed, nonencapsulated coalescent nodules measuring up to 2 cm (right side; Fig. 1B) and 2.5 cm (left
side) in maximal diameter. Microscopically, yellow nodules were
predominantly composed of large clear cells admixed with small
clusters of either small clear cells or large eosinophilic pigmented
cells (Fig. 2A). Brownish nodules, the largest measuring 1 cm in
maximal diameter, were composed of large eosinophilic cells with
lipofuscin-laden cytoplasm. Nuclear atypia was a frequent finding in
those brownish nodules (Fig. 2B). Mitoses and features of vascular
invasion were not found. Bilateral extracapsular extension of hyperplastic adrenocortical cells into periadrenal adipose tissue was
present. Pathological findings were consistent with bilateral macronodular adrenocortical hyperplasia (14).
Family history was negative for Cushing’s syndrome in both patients.
Materials and Methods
In vivo studies
The responsiveness of cortisol secretion to food ingestion was assessed before adrenalectomy in both patients. After an overnight fast, an
indwelling venous catheter was inserted into an antecubital vein. At
1200 h, the patients were given a standardized meal consisting of 29 g
protein (25% of total energy intake), 18 g lipid (35% of total energy
intake), and 47 g carbohydrate (40% of total energy intake). Total energy
intake was 466 calories. Blood for plasma cortisol was drawn at 0, 30, 45,
60, 90, and 120 min after the start of the meal. In patient 2, who demonstrated a significant rise in plasma cortisol after meal ingestion, the
study was repeated after acute blockade with octreotide (200 mg, sc,
administered 1 h before the meal). In patient 2, who did not show any
cortisol response to meal ingestion, cortisol secretion after an oral glucose tolerance test (100 g) was also evaluated.
In vitro studies
FIG. 1. A (Case 1), The multinodular growth pattern of the left adrenal gland is illustrated; each macronodule is generally separated
from the other by adipose septa. B (Case 2), Macronodular adrenocortical hyperplasia of the right adrenal gland consisting of multiple
coalescent yellowish and brownish/pigmented (arrow) nodules of
varying sizes distorting the gland.
Cortisol secretion from human adrenal cells was studied in vitro.
Adrenal glands were obtained after surgery from the two patients described above as well as from one patient with ACTH-independent
Cushing’s syndrome resulting from a cortisol-secreting solitary adrenal
adenoma. In addition, normal human adrenals were obtained from
cadaveric kidney transplant donors.
Dispersion of adrenal cells was performed as previously described
(13). Briefly, adrenals were minced with a scalpel blade and then subjected to combined enzymatic and mechanical dispersion; tissue fragments were placed in a Bellco flask (Bellco Glass, Inc., Vineland, NJ) to
allow constant trituration and were incubated for 90 min at 37 C in the
presence of collagenase type I (Sigma Chemical Co., St. Louis, MO),
followed by neuraminidase type V (Sigma Chemical Co.). After complete dissociation of the tissue, cells were resuspended in medium containing 2.5% FCS and plated at a concentration of 106 cells/well in
six-well plates pretreated with poly-d-lysine (Sigma Chemical Co.). Viability was assessed by trypan blue exclusion and ranged between
60 – 80%.
ABNORMAL RESPONSE TO LEPTIN IN ADRENAL CUSHING
Cells were incubated for 48 hat 37 C in 95% O2-5% CO2. Medium was
then changed to serum-free medium, and cells were stimulated for 90
min with 1029 mol/L ACTH, 1027 mol/L leptin, 1029 and 1028 mol/L
GIP, 1029 and 1028 mol/L , glucagon-like polypeptide-1. Controls consisted of cells incubated in parallel for 90 min in serum-free medium. All
conditions were tested in triplicate.
3819
Hormone assays
Cortisol was measured by RIA in duplicate, using a commercially
available kit (Coat-a-Count, Diagnostic Products, Los Angeles, CA). All
samples from a single experiment were measured in duplicate in the
same assay, and the intra- and interassay coefficients of variation ranged
from 3–5.1% and 4 – 6.4%, respectively. Plasma leptin was measured by
RIA, using a kit purchased from Linco Research, Inc. (St. Charles, MO).
Intra- and interassay coefficients of variation were between 2.1–2.5% and
3.8 – 8.2%, respectively. Serum GIP was measured by RIA as previously
described (15), using an antiserum generously provided by S. R. Bloom
(London, UK) and commercially available peptide (Bachem, Torrance,
CA). ACTH was measured by a chemiluminescent assay (Nichols Institute Diagnostics, San Juan Capistrano, CA).
Statistical analysis
The results are expressed as the mean 6 sem. Correlations between
circulating GIP and cortisol levels were made by Pearson’s analysis. A
stepwise, multiple regression analysis was also performed using a statistical program (JMP, SAS Institute, Inc., Cary, NC) running on a Compaq PC under Windows 95. Comparisons of in vitro results were made
using nonparametric testing (van der Waerden test).
Results
In vivo studies
FIG. 2. A (Case 2), Microscopically, yellowish nodules were composed
predominantly of large clear cells, but also contained foci of large
pigmented eosinophilic cells (hematoxylin and eosin stain; magnification, 380. B (Case 2), A brownish nodule composed of eosinophilic
cells that showed copious lipofuscin-laden cytoplasm and nuclear
atypia (hematoxylin and eosin stain; magnification, 3330).
Basal and stimulated cortisol secretion in both patients is
summarized in Table 1. In patient 1, morning fasting cortisol
was elevated on repeated occasions, including when the
patient had discontinued oral estrogens for several weeks
(cortisol, 864 nmol/L), and there was also an abolition of the
normal diurnal rhythm. There was no ACTH or cortisol
response to CRH in this patient, but the adrenals were able
to respond to further stimulation with ACTH-(1–24) (Cosyntropin). In patient 2, morning fasting cortisol secretion
was also elevated on several occasions with an abolition of
the normal diurnal rhythm. There was no response to a
standard ovine CRH test, and neither an oral glucose tolerance test nor the administration of a standardized meal
resulted in cortisol stimulation.
The food dependency of cortisol secretion in patient 1 is
demonstrated in Fig. 3: an elevated circulating cortisol value
of 886 nmol/L was further stimulated by meal ingestion to
a maximum of 1184 nmol/L, occurring 30 min after the start
of food intake (Fig. 3A). This increase in cortisol secretion
paralleled the expected stimulation of GIP secretion (16, 17)
from 60 pmol/L at baseline to 510 pmol/L at the time of peak
cortisol secretion (30 min). Circulating cortisol and GIP levels
were highly significantly correlated throughout the test (r2 5
0.5723; P 5 0.0044). After acute octreotide treatment (Fig. 3B),
TABLE 1. Basal and stimulated cortisol secretion in two patients with Cushing’s syndrome and bilateral macronodular adrenal
hyperplasia
Stimulation
Basal cortisol
(nmol/L)
309 cortisol
(nmol/L)
459 cortisol
(nmol/L)
609 cortisol
(nmol/L)
909 cortisol
(nmol/L)
Case 1
Fasting, AM and PM (1700 h)
CRH test (1 mg/kg)
ACTH test (250 mg)
556, 864, 988, 834
1260
710
1052
1538
—
—
1002
1924
962
—
Case 2
Fasting, AM and PM (1700 h)
CRH test (1 mg/kg)
OGTT
Standard meal
730, 723, 743, 687
650
530
730
—
602
480
—
—
—
—
742
—
593
387
717
—
567
485
688
3820
JCE & M • 1999
Vol 84 • No 10
PRALONG ET AL.
food-stimulated GIP secretion was completely inhibited, and
the acute stimulation of cortisol secretion by food intake was
abolished.
Circulating leptin levels were elevated in this patient,
ranging between 32–35 mg/L throughout the test (normal
range in nonobese women, 7.4 6 3.7 mg/L), and they were
not affected by meal ingestion. However, in a stepwise multiple regression analysis, circulating leptin was recognized as
an independent determinant of cortisol levels, explaining up
to 55% of cortisol variability (Table 2).
In patient 2, in contrast with patient 1, neither the administration of a standard meal nor an oral glucose tolerance test
stimulated cortisol secretion over its elevated baseline (Table 1).
unstimulated cells, but ACTH stimulation (1029 mol/L)
could elicit a rise in cortisol secretion in each instance. The
lowest baseline production was observed in cells obtained
from a solitary adrenal adenoma (232 6 6 nmol/L), and the
highest was found in adrenal cells obtained form case 1
(867 6 82 nmol/L).
As expected (6, 7, 9, 10), GIP dose dependently stimulated
cortisol secretion in cells obtained from case 1 (Fig. 4A). GIP
at 1029 mol/L did not affect baseline cortisol secretion (732 6
43 vs. 867 6 82 nmol/L for GIP and controls, respectively),
whereas at 1028 mol/L GIP stimulated cortisol secretion to
1135 6 152 nmol/L, an effect comparable to that of 1029
In vitro studies
Cortisol secretion from dispersed adrenal cells in response to ACTH, GIP, and leptin is shown in Fig. 4. There
was some variability in the level of cortisol production by
FIG. 3. Cortisol and GIP secretion in a patient with food-dependent
Cushing’s syndrome. A, Without octreotide; B, after octreotide. **, P ,
0.01.
FIG. 4. In vitro cortisol secretion of dispersed adrenal cells. A, Case
1; B, case 2; C, solitary adrenal adenoma; D, normal adrenal glands.
For statistical analysis, see text. Note the break in the y-axis of B.
TABLE 2. Multiple stepwise regression analysis (case 1), with circulating cortisol values after the ingestion of a standardized meal as the
dependent variable. After octreotide blockage, this regression analysis did not reach statistical significancy
Before octreotide
After octreotide
Whole model test
Step
Parameter
P
R2
F ratio
P 5 0.0367
P 5 0.4608
1
2
Leptin
GP
0.0893
0.0571
0.555
0.889
12.405
9.078
ABNORMAL RESPONSE TO LEPTIN IN ADRENAL CUSHING
mol/L ACTH (1287 6 229 nmol/L). GIP had no effect on
cortisol secretion in the other cases (Fig. 4, B–D).
Similar to what was observed with GIP, 1027 mol/L leptin
stimulated cortisol secretion to 1162 6 104 nmol/L in cells
obtained from case 1 compared with that in unstimulated
controls (867 6 82 nmol/L) or ACTH-stimulated cells
(1287 6 229 nmol/L; Fig. 4A). There was a statistically significant correlation between GIP-stimulated and leptin-stimulated in vitro cortisol production in this case (P , 0.041).
Such a correlation was not found in any of the other cases
studied. Moreover, despite the small number of points (triplicates of one experiment), the differences in cortisol production between controls, on the one hand, and 1029 mol/L
ACTH, 1028 mol/L GIP, or 1027 mol/L leptin, on the other
hand, almost reached statistical significance (P 5 0.0612). In
the other cases (Fig. 4, B–D), neither leptin nor GIP was found
to affect in vitro cortisol secretion.
Finally, glucagon-like polypeptide-1 at two different concentrations (1028 and 1029 mol/L) had no effect on cortisol
secretion by cells obtained from case 1 (data not shown).
Discussion
Food-dependent Cushing’s syndrome has been reported
in association with either bilateral macronodular adrenal
hyperplasia (6, 7, 10) or isolated adrenal adenoma (5, 8, 9). A
pathophysiological role of GIP has been well documented in
this syndrome (18); it has been demonstrated that abnormal
expression of GIP receptors by adenomatous adrenal tissue
(8 –11) mediates an abnormal (paradoxical) stimulation of
cortisol secretion in response to the physiological postprandial rise in circulating GIP. In the present study, we report
a novel patient displaying significant elevations of circulating cortisol after meal ingestion in whom we found in vivo
and in vitro evidence demonstrating that GIP participated in
this paradoxical stimulation. Therefore, these results
strongly suggest that GIP-stimulated cortisol secretion is a
generalized feature of this rare entity. Moreover, we were
able to provide novel in vitro data suggestive of the participation of leptin, the secreted product of the adipocyte (19),
in the pathogenesis of adrenal hypercortisolism in this case.
Leptin normally exerts an inhibition on the activity of the
hypothalamo-pituitary-adrenal axis in rodents. This inhibition is probably mediated centrally, via an effect on hypothalamic CRH secretion (20, 21), as well as peripherally, as
direct inhibition of cortisol secretion by leptin at the level of
the adrenal gland has also been described (13, 22). These
various effects of leptin on the activity of the hypothalamopituitary-adrenal axis of rodents are consistent with a physiological inhibitory role suggested by the inverse relationship
existing in normal humans between circulating leptin and
cortisol levels (23). In light of the recent demonstration that
leptin can directly inhibit cortisol secretion from human adrenocortical cells (12, 13), we hypothesized that a pathological shift from an inhibition toward a stimulation of cortisol
secretion by leptin in adenomatous tissue might play an
additional role in the pathogenesis of hypercortisolism in
food-dependent Cushing’s syndrome.
The results presented here are consistent with this hypothesis. Tumor cells obtained from the adrenal tissue of the
3821
patient with food-dependent Cushing’s syndrome exhibited
a responsiveness to acute leptin stimulation that mirrored
perfectly their abnormal responsiveness to GIP. Remarkably,
such a stimulation of cortisol secretion by leptin was never
seen in normal human adrenal tissue (Ref. 13 and the present
study) or in adenomatous adrenal tissue obtained from patients with ACTH-independent Cushing’s syndrome that
was not dependent upon food ingestion (present study). The
contrast in leptin responsiveness existing between cells obtained from the food-dependent case and the other cases of
adrenal Cushing’s syndrome therefore suggests that such a
stimulation of cortisol secretion is not only abnormal, but is
also specific to this rare condition.
Circulating leptin levels were thereafter assessed in blood
samples obtained after the test meals in patients 1 (fooddependent Cushing’s syndrome) and 2 to correlate our in
vitro finding with in vivo data. In a multivariate regression
analysis, GIP and leptin were both identified as independent
determinants of plasma cortisol levels, together accounting
for most of cortisol variability after meal ingestion. Despite
the fact that these results represent a single observation,
taken together they are suggestive of the existence of an
abnormal response to leptin in the case of food-dependent
Cushing’s syndrome reported here.
Leptin levels were pathologically elevated in the two patients with macronodular adrenal hyperplasia reported here,
confirming earlier observations made in Cushing’s syndrome (24, 25). However, leptin was not secreted acutely in
response to food ingestion in either of these two patients, and
this could also be anticipated from previous data (26). It
seems very unlikely, therefore, that leptin participated in the
acute stimulation of cortisol secretion by food intake, and our
data do not indicate that this was the case. Rather, they
demonstrate that much like in previously described cases,
GIP was an important trigger of this acute secretion.
There was, nevertheless, one major difference between the
clinical presentation of previously described cases (5–10) and
that of the patient reported here; other cases with fooddependent Cushing’s syndrome all had low fasting cortisol
levels, whereas our patient exhibited permanently elevated
fasting total cortisol values, including when she was not
taking oral estrogens, and the cortisol-binding globulin level
was presumed to be normal. This difference can possibly be
explained by our in vitro finding of an abnormal response to
leptin in this case. Indeed, one could speculate that constantly elevated leptin levels secondary to the hypercortisolism (24, 25) resulted in a paradoxical chronic stimulation
of the adrenal glands and, hence, elevated fasting plasma
cortisol values. If this were true, the acute stimulation of
cortisol secretion by food intake would then occur on top of
these chronically elevated levels, as was indeed the case in
this patient. However, this possibility remains purely hypothetical at this time and would require testing and confirmation in vivo in other cases of food-dependent Cushing’s
syndrome.
The mechanism(s) possibly underlying the in vitro effect
observed also remains unclear. There is a growing list of
aberrant receptor expression by adrenal glands that eventually lead to adrenal Cushing’s syndrome due to abnormal
responses to hormones such as GIP (8, 9 –11), LH (27), or
3822
PRALONG ET AL.
vasopressin (28, 29); to cytokines such as interleukin-1 (30);
or to catecholamines (31). However, the long isoform of the
leptin receptor (OB-Rb) is expressed by normal adrenal tissue
(12, 13, 32), and leptin has a physiological inhibitory role in
cortisol secretion (13, 22). Therefore, unlike other hormones,
a paradoxical response to leptin cannot be explained solely
by receptor overexpression.
The effect that we have observed is reminiscent of the
aberrant responsiveness to hypothalamic releasing factors
occurring in some pituitary tumors (33, 34), which might be
due to mutations either in their respective receptor or in some
step of the secondary messenger cascade. However, it is not
known at this time whether the leptin receptor expressed by
our patient’s adrenal nodules was normal or mutated.
In conclusion, our results demonstrate that a paradoxical
response to GIP probably represents the hallmark of all cases
of food-dependent Cushing’s syndromes. Furthermore, they
suggest that leptin may represent yet another factor that
could participate in the ACTH-independent increased cortisol secretion from hyperplastic or adenomatous adrenal
glands. This observation is in agreement with the emerging
hypothesis that corticotropin-independent adrenal hyperplasia and hypercortisolism can arise from stimulation by an
array of hormones or factors, sometimes secondary to the
aberrant expression of their cognate receptor (35). However,
because OB-R is normally expressed by adrenal tissue (13,
32), and because leptin plays a physiological role to inhibit
cortisol secretion from the adrenal gland (13, 22), the pathophysiological mechanism underlying the paradoxical stimulation described in the present paper cannot be attributed
solely to overexpression of OB-R.
Acknowledgments
The authors thank Dr. Charlotte Eberlé, Ph.D., for the measurement
of GIP, Dr. François Rey, Ph.D., for cortisol and ACTH measurements,
and Dr. Gérard Waeber, M.D., for stimulating discussions. The expert
technical assistance of Evelyne Temler and Marco Giacomini is also
gratefully acknowledged.
References
1. Orth DN. 1995 Cushing’s syndrome. N Engl J Med. 332:791– 802.
2. Zeiger MA, Nieman LK, Cutler GB, Chrousos GP, Doppman JL, Travis WD.
1991 Primary bilateral adrenocortical causes of Cushing’s syndrome. Surgery.
110:1106 –1115.
3. Larsen JL, Cathey JW, Odell WD. 1986 Primary adrenocortical nodular dysplasia, a distinct subtype of Cushing’s syndrome. Am J Med. 80:976 –984.
4. Malchoff CD, Rosa J, DeBold CR, et al. 1989 Adrenocortical-independent
bilateral macronodular adrenal hyperplasia: an unusual cause of Cushing’s
syndrome. J Clin Endocrinol Metab. 68:855– 860.
5. Hamet P, Larochelle P, Franks DJ, Cartier P, Bolte E. 1987 Cushing’s syndrome with food-dependent periodic hormonogenesis. Clin Invest Med.
10:530 –533.
6. Lacroix A, Bolté E, Tremblay J, et al. 1992 Gastric inhibitory polypeptidedependent cortisol hypersecretion–a new cause of Cushing’s syndrome.
N Engl J Med. 327:974 –980.
7. Reznik Y, Allali-Zerah V, A. CJ, et al. 1992 Food-dependent Cushing’s syndrome mediated by aberrant adrenal sensitivity to gastric inhibitory polypeptide. N Engl J Med. 327:981–986.
8. de Herder WW, Hofland LJ, Usdin TB, et al. 1996 Food-dependent Cushing’s
syndrome resulting from abundant expression of gastric inhibitory polypeptide receptors in adrenal adenoma cells. J Clin Endocrinol Metab. 81:3168 –3172.
9. Chabre O, Liakos P, Vivier J, et al. 1998 Cushing’s syndrome due to a gastric
inhibitory polypeptide-dependent adrenal adenoma: insights into hormonal
control of adrenocortical tumorigenesis. J Clin Endocrinol Metab.
83:3134 –3143.
JCE & M • 1999
Vol 84 • No 10
10. Lebrethon MC, Avallet O, Reznik Y, et al. 1998 Food-dependent Cushing’s
syndrome: characterization and functional role of gastric inhibitory polypeptide receptor in the adrenals of three patients. J Clin Endocrinol Metab.
83:4514 – 4519.
11. N*Diaye N, Tremblay J, Hamet P, De Herder WW, Lacroix A. 1998 Adrenocortical overexpression of gastric inhibitory polypeptide receptor underlies
food-dependent Cushing’s syndrome. J Clin Endocrinol Metab. 83:2781–2785.
12. Glasgow A, Haidan A, Hilbers U, et al. 1998 Expression of Ob receptor in
normal human adrenals: differential regulation of adrenocortical and adrenomedullary function by leptin. J Clin Endocrinol Metab. 83:4459 – 4466.
13. Pralong FP, Roduit R, Waeber G, et al. 1998 Leptin inhibits directly glucocorticoid secretion by normal human and rat adrenal gland. Endocrinology.
139:4264 – 4268.
14. Aiba M, Hirayama A, Iri H, et al. 1991 Adrenocorticotropic hormone-independent bilateral adrenocortical macronodular hyperplasia as a distinct subtype of Cushing’s syndrome. Enzyme histochemical and ultrastructural study
of four cases with a review of the literature. Am J Clin Pathol. 96:334 –340.
15. Sarson DL. 1982 Radioimmunoassay of gut regulatory peptides. In: Bloom SR,
Long RG, eds. London, Philadelphia, Toronto: Saunders; 101–110.
16. Krarup T, Holst JJ, Larsen KL. 1995 Responses and molecular heterogeneity
of IR-GIP after intraduodenal glucose and fat. Am J Physiol. 249:E195–E200.
17. Lucey MR, Fairclough PD, Wass JA, Kwasoeski P, Medback S, Rees LH. 1984
Responses of circulating somatostatin, insulin, gastrin and GIP, to intraduodenal infusion of nutrients in normal man. Clin Endocrinol (Oxf). 21:209 –217.
18. Bertagna X. 1992 New causes of Cushing’s snydrome. N Engl J Med.
327:1024 –1025.
19. Zhang Y, Proenca R, Maffei M, Barone M, Leopold L, Friedman JM. 1994
Positional cloning of the mouse obese gene and its human homologue. Nature.
372:425– 432.
20. Heiman ML, Ahima RS, Craft LS, Schoner B, Stephens TW, Flier JS. 1997
Leptin inhibition of the hypothalamo-pituitary-adrenal axis in response to
stress. Endocrinology. 138:3859 –3863.
21. Ahima RS, Prabakaran D, Mantzoros C, et al. 1996 Role of leptin in the
neuroendocrine response to fasting. Nature. 382:250 –252.
22. Bornstein RS, Uhlmann K, Haidan A, Ehrhart-Bornstein M, Scherbaum WA.
1997 Evidence for a novel peripheral action of leptin as a metabolic signal to
the adrenal gland. Leptin inhibits cortisol release directly. Diabetes.
46:1235–1238.
23. Licino J, Mantzoros C, Negrao AB, et al. 1997 Human leptin levels are pulsatile
and inversely related to pituitary-adrenal function. Nat Med. 3:575–579.
24. Leal-Cerro A, Considine RV, Peino R, et al. 1996 Serum immunoreactiveleptin levels are increased in patients with Cushing’s syndrome. Horm Metab
Res. 28:711–713.
25. Masuzaki H, Ogawa Y, Hosoda K, et al. 1997 Glucocorticoid regulation of
leptin synthesis and secretion in humans: elevated plasma leptin levels in
Cushing’s syndrome. J Clin Endocrinol Metab. 82:2542–2547.
26. Schoeller DA, Cella LK, Sinha MK, Caro JF. 1997 Entrainment of the diurnal
rythm of plasma leptin to meal timing. J Clin Invest. 100:1882–1887.
27. Lacroix A, N*Diaye N, Hamet P, Tremblay J, Boutin J-M, Sairam MR. LHdependent Cushing’s syndrome (CS) in a woman with bilateral macronodular
adrenal hyperplasia: control of hypercortisolism with leupride. Proc of the 80th
Annual Meet of The Endocrine Society. 1998 Abstract 2303.
28. Horiba N, Suda T, Aiba M, et al. 1995 Lysine vasopressin stimulation of
cortisol secretion in patients with adrenocorticotropin-independent macronodular adrenal hyperplasia. J Clin Endocrinol Metab. 80:2336 –2341.
29. Arnaldi G, Gasc JM, De Keyzer Y, et al. 1998 Variable expression of the V1
vasopressin receptor modulates the phenotypic response of steroid-secreting
adrenocortical tumors. J Clin Endocrinol Metab. 83:2029 –2035.
30. Willenberg HS, Stratakis CA, Marx C, Ehrhart-Bornstein M, Chrousos GP,
Bornstein SR. 1998 Aberrant Interleukin-1 receptors in a cortisol-secreting
adrenal adenoma causing Cushing’s syndrome. N Engl J Med. 339:27–31.
31. Lacroix A, Tremblay J, Rousseau G, Bouvier M, Hamet P. 1997 Propranolol
therapy for ectopic Symbol“ § 12-adrenergic receptors in adrenal Cushing’s
syndrome. N Engl J Med. 337:1429 –1434.
32. Hoggard N, Mercer JG, Rayner DV, Moar K, Trayhurn P, Williams LN. 1997
Localization of leptin receptor mRNA splice variants in murine peripheral
tissues by RT-PCR and in situ hybridization. Biochem Biophys Res Commun.
232:383–387.
33. Irie M, Tsushima T. 1972 Increase of serum growth hormone concentration
following thyrotropin-releasing hormone injection in patients with acromegaly or gigantism. J Clin Endocrinol Metab. 35:97–100.
34. Hanew K, Kokubun M, Sasaki A, Mouri T, Yoshinaga K. 1980 The spectrum
of pituitary growth hormone responses to pharmacological stimuli in acromegaly. J Clin Endocrinol Metab. 51:292–297.
35. Mircescu H, Jilwan J, Hamet P, Lacroix A. 1998 Systematic clinical screening
for abnormal hormone receptors in adrenal Cushing’s syndrome. Proc of the
80th Annual Meet of The Endocrine Soc. 1998 Abstract 2300.