0021-972x/961$03.00/0
Journal
of Cbmcal Endocrinology
and Metabolism
Copyright
0 1996 by The Endocrine
Society
PRISMATIC
Vol
Printed
81, No. 9
LE U.S.A.
CASE
Food-Dependent
Cushing’s
Syndrome
Resulting
from
Abundant
Expression
of Gastric Inhibitory
Polypeptide
Receptors
in Adrenal
Adenoma
Cells
WOUTER
W. DE HERDER,
LEO J. HOFLAND,
TED B. USDIN,
PIET UITTERLINDEN,
PETER VAN KOETSVELD,
EVA MEZEY,
H. JAAP BONJER,
AND STEVEN
W. J. LAMBERTS
FRANK
H. DE JONG,
TOM I. BONNER,
Departments
of Internal Medicine (W.W.d.H., L.J.H., F.H.d.J., P.U., P.u.K., H.J.B.) and Surgery
(H.J.B.), University Hospital Rotterdam,
Rotterdam,
The Netherlands;
and the Laboratory
of Cell
Biology, National
Institute of Mental Health (T.B.U., T.I.B.) and Laboratory
of Clinical Science,
National
Institute of Neurological
Diseases and Stroke (E.M.), National
Institutes
of Health, Bethesda,
Maryland
20892
ABSTRACT
We studied a 45yr-old
woman with food-dependent
Cushing’s
syndrome. Plasma cortisol
levels were subnormal
(4-47 nmol/L)
after an
overnight
fast and increased
after a mixed meal to values between
500-1000
nmol/L.
There was a close correlation
between
circulating
gastric inhibitory
polypeptide
(GIP) and cortisol levels during normal
food intake (r = 0.92; P < 0.0002). Plasma corticotropin
(ACTH)
levels
were undetectable.
Nonfasting
plasma
cortisol
levels were not suppressed by low or high doses of dexamethasone.
Plasma ACTH and
cortisol levels did not increase after human
CRH administration,
but
fasting plasma cortisol
levels increased
after ACTH treatment.
The
infusion
of GIP increased
plasma
cortisol
levels to 7.8 times above
baseline.
Radiological
and cholesterol
uptake
studies
pointed
to a
unilateral
adrenal
adenoma.
Treatment
with octreotide
initially
prevented
the meal-induced
increases
in cortisol
and GIP levels and
decreased
urinary
cortisol
excretion.
Unilateral
adrenalectomy
was
performed.
Cortisol
production
by cultured
adrenal
adenoma
cells
from the patient
was stimulated
by GIP and ACTH. In situ hybridization
studies using a GIP receptor
probe showed an abundant
expression
of GIP receptor
messenger
ribonucleic
acid in the adrenocortical
adenoma.
We conclude that food-dependent
Cushing’s
syndrome
results from
the expression
of GIP receptors
on adrenocortical
adenoma
cells.
(J Clin Endocrinol Metab 81: 3168-3172,
1996)
H
tisolemia was related to abundant
expression
tors in the adrenal adenoma cells.
ISTORICALLY,
endogenous
Cushing’s
syndrome
is
divided
into two major
variants:
corticotropin
(ACTH)-dependent
and ACTH-independent.
ACTH-independent Cushing’s syndrome is usually caused by an adrenal
adenoma
or carcinoma.
Occasionally,
ACTH-independent
bilateral macronodular
or micronodular
adrenal hyperplasia
is found. Food-dependent
Cushing’s syndrome is a new variant in this spectrum. To date, three patients with the clinical
picture of food-dependent
Cushing’s
syndrome have been
reported.
One male patient presented
with a unilateral
adrenal mass (l), and two female patients presented
with bilaterally enlarged nodular adrenals (2,3). In these two female
patients, it was concluded
from in vitro and in vivo studies
that Cushing’s
syndrome
was caused by an abnormal
responsiveness
of the patients’
adrenal glands to gastric inhibitory polypeptide
(GIP) (2,3). We report a female patient
with food-dependent
Cushing’s
syndrome
due to a unilateral adrenal adenoma. We demonstrated
that the hypercor-
of GIP recep-
Case Report
A 45.yr-old
woman
was admitted
for suspected
hypercortisolism.
Her main complaints
were severe tiredness
and a weight gain of 7 kg
over the last 10 months. She had developed
a round plethoric
face and
acne. There was no family history
of endocrine
abnormalities
and no
history of prior steroid administration.
At physical examination
she had
central obesity,
increased
supraclavicular
fat accumulation,
plethora,
mild alopecia, proximal
muscle weakness,
and numerous
ecchymoses.
The patient’s
height was 1.71 m, and weight was 76 kg (body surface
area, 1.87 m’). Blood pressure was 160190 mm Hg while recumbent.
The
serum sodium level was 143 mmol/L,
potassium
was 3.8 mmol/L,
and
fasting glucose was 5.0 mmol/L.
Endocrine
testing, described
in Results, demonstrated
meal-induced,
ACTH-independent
hypercortisolemia,
and hypocortisolemia
during
fasting. Furthermore,
ACTHand insulin-independent
stimulation
of
cortisol secretion by GIP was demonstrated.
Plasma cortisol levels also
increased
after administration
of ACTH. Dual photon absorptiometry
showed
decreased
spinal bone mass. Radiological
findings
were consistent with spinal osteopenia,
and an osteoporotic
fracture
of the 11th
thoracic vertebral
was diagnosed.
Abdominal
computed
tomography
showed a left-sided
adrenal mass
of 3 cm diameter,
whereas
the contralateral
gland seemed atrophic.
[‘“‘I]Iodonorcholesterol
(NP-59) adrenal scintigraphy
showed unilateral
uptake of the radiolabel
at the left side. “‘In diethylene
triamine
pentaacetic acid (DTPA)-pentetreotide
scintigraphy
showed no pathological
uptake of the radiolabel.
The patient was successfully
treated with 0.100
Received
March 1, 1996. Revision
received
April 16, 1996. Accepted
April 25, 1996.
Address
all correspondence
and requests for reprints
to: W. W. de
Herder,
M.D., Department
of Internal
Medicine
III and Clinical Endocrinology,
University
Hospital
Rotterdam,
Dr. Molewaterplein
40, 3015
GD Rotterdam,
The Netherlands.
3168
A PRISMATIC
mg octreotide,
three times daily before each meal, in combination
with
hydrocortisone
replacement
(30 mg daily (16 mg hydrocortisone/m’,
divided into 20 mg in the morning
and 10 mg at night). She was advised
to eat normally
during
treatment,
and she initially
showed
clinical improvement.
After 3.5 months of treatment,
however,
the clinical signs of
Cushing’s
syndrome
recurred.
Therefore,
a left adrenalectomy
(diameter, 3 cm) was performed
through
a retroperitoneal
endoscopic
approach. Macroscopic
and histological
examinations
were typical of an
adrenocortical
adenoma
with clear cells.
Postoperatively,
the patient was treated with 0.75 mg dexamethasane/day,
divided
over two doses of 0.5 and 0.25 mg, respectively.
Postoperatively,
very low plasma cortisol
levels (<lo
nmol/L)
were
found after an overnight
fast, which did not respond to iv administration
of 0.6 pg/kg
BW GIP. However,
plasma cortisol levels increased
from
9 to 279 nmol/L
60 min after the im administration
of 0.250 mg synthetic
ACTH-(1-24).
Replacement
treatment
with hydrocortisone
was required for 7 months.
The features of Cushing’s
syndrome
rapidly
disappeared.
With normal food intake, cortisoluria
normalized,
and a normal
cortisol
diurnal
rhythm
was
observed.
Eight
months
postoperatively,
the nonfasting
plasma cortisol concentration
after administration
of 1 mg dexamethasone
overnight
was 7 nmol/L.
After an
overnight
fast, plasma cortisol levels (169 nmol/L)
did not respond
to
the iv administration
of 0.6 pg/kg
BW GIP in 60 min. During
a postoperative
follow-up
period of 11 months,
there was no recurrence
of
Cushing’s
syndrome.
Materials
and Methods
All studies were performed
according
to the rules of the hospital
medical
ethics committee.
The patient gave informed
consent.
Plasma cortisol levels and urinary
cortisol excretion
were measured
by a RIA with a commercial
kit (obtained
from Diagnostic
Products
Corp., Los Angeles,
CA). Plasma ACTH-(1-39)
was measured
by an
immunoradiometric
assay with a commercially
available
kit (obtained
from CIS Biointernational,
Gif-sur-Yvette,
France). The detection limit of
the assay was 2 rig/L ACTH.
Plasma insulin
was measured
using a
commercially
available immunoradiometric
assay (obtained
from Medgenix Diagnostics,
Fleurus, Belgium).
Plasma GIP was measured
by RIA
with commercial
kits (obtained
from Peninsula
Laboratories,
Belmont,
CA).
Cell dispersion
and incubations
CASE
3169
Dektol at 15 C, followed
by counterstaining
with Giemsa. No hybridization was detected
with the sense probes.
A sample from an adrenocortical
adenoma
obtained
from a 35.yr-old
woman
with classical ACTH-independent
(nonfood-dependent)
Cushing’s syndrome
was used as a control and processed
in the same way.
Results
Endocrine
testing
Diurnal rhythm. Plasma cortisol levels were decreased(4-47
nmol/L) after an overnight fast and increased after food
intake to values between 500-1000nmol/ L (Fig. 1). During a
15-h fast, persistently decreasedplasma cortisol levels (32-53
nmol/L) were found (Fig. 1). Fasting was accompanied by
complaints suggestive of glucocorticoid withdrawal, such as
diffuse muscle aches, painful joints, and anorexia, whereas
subfebrile temperature also developed. These complaints
rapidly disappeared after oral food intake. There was a close
correlation between plasma GIP and cortisol levels during
normal food intake (r = 0.92; P < 0.0002;Fig. 2). Basalplasma
ACTH concentrations were below the detection limit of the
assay (<2 q/L), as were ACTH levels after meals.
ACTH, and CRH. Nonfasting plasma
cortisol levels were not suppressed in the low dose (1 mg)
overnight dexamethasone test or in the high dose iv dexamethasone test (7 mg/7 h) (8). There was no response of
plasma ACTH and cortisol levels to the iv administration of
Effects ofdexamefkasone,
e
5
E
s
.Y
E
3
Portions of the patient’s
adrenocortical
tumor were transferred
to the
laboratory
within 30 min after removal.
The tissue was minced into small
pieces and dissociated
with collagenase
(type I; Sigma Chemical
Co., St.
Louis, MO), as described
previously
(4, 5). Viability
of the cells was
determined
by trypan blue exclusion
and was greater than 80%. Subsequently,
the cells were resuspended
in incubation
buffer
(KrebsRinger bicarbonate
buffer containing
5.4 pmol/L
calcium),
and a 2-h
incubation
without
or with test substances
was performed
in quadruplicate using 300,000 cells/ ml-tube.
At the end of the incubation,
0.5 mL
distilled water was added to each tube, and the resulting suspension
was
stored at -20 C until determination
of hormone
concentrations,
as
described
previously
(5). The following
substances
were added: ACTH(l-24) (Synacthen,
Ciba-Geigy,
Basel, Switzerland)
in a final concentration of lo-ii
mol/L;
human GIP (Bachem,
Bubendorf,
Switzerland)
in
final concentrations
of lo-“,
10m9, lo-‘, and 10m7 mol/L;
insulin in a
final concentration
of 10m9 mol/L;
bombesin
(Bissendorf,
Hannover,
Germany)
in a final concentration
of 10e9 mol/L;
and octreotide
(Sandoz, Basel, Switzerland)
in a final concentration
of lo-* mol/L.
Receptor
900
600
300
0
2000
[
studies
Tumor samples obtained
during surgery
were rapidly
frozen on dry
ice and stored at -70 C until sectionin
Twelve-micron
cryostat sections
were prepared
and hybridized
to [35S]UTP-labeled
riboprobes
made
from a fragment
of the human
Gil’ receptor
(bases l-1507,
GenBank
U39231) subcloned
into the vector pBluescript
II (SK-) (Stratagene,
San
Diego, CA), as previously
described
(6, 7). Slides were dipped in nondiluted NTB3 nuclear track emulsion
(Eastman
Kodak, Rochester,
NY)
and stored desiccated
at 4 C for 28 days before development
using Kodak
6
9
12
15
18
21
24
time of day (h)
FIG. 1. Plasma
cortisol,
GIP, and insulin
levels on a control day with
normal
food intake
at 0800,1200,
and 1730 h (Cl); during
fasting (A);
and during
treatment
with 0.1 mg octreotide
SC at 0730, 1130, and
1700 h (0).
DE HERDER
3170
2
500
2
r
8
0
0
1000
500
1500
GIP (w/L)
FIG.
2. Correlation
els. Fifteen
samples
JCE & M . 1996
Volt31 . No 9
excretion. Urinary cortisol excretion in the nonfasting state
ranged from 2200-3100 nmol/24 h (n < 850), from 140-150
nmol/24 h in the fasting state, and from 700-800 nmo1/24
h during octreotide treatment (0.3 mg daily) in the nonfasting
state.
Octreotide treatment in combination with hydrocortisone
replacement initially resulted in marked clinical improvement. After 3.5 months of octreotide treatment, the clinical
signs of Cushing’s syndrome recurred, and a significant difference between the plasma cortisol levels on and off octreotide therapy during normal food intake could was no
longer present (Fig. 4). Also, GIP levels were lesssuppressed
by octreotide (compare Fig. 1).
1000
E
%
ET AL.
between
nonfasting
plasma GIP and cortisol
were collected
between
0800-2200
h.
lev-
In vitro studies
1.0 Fg/kg BW synthetic human (h) CRH. Fasting plasma
cortisol levels increased from 55 to 1239 nmol/L within 60
min after the im administration of 0.250 mg synthetic
ACTH-(1-24).
Effects ofglucose,GIP, and insulin.
After an overnight fast, the
oral administration of 75 g glucose did not result in a significant increase in blood glucose levels. However, it was
followed by an increase in insulin levels from 11.8 to 34.4
mU/ L after 60 min, an increasein plasma GIP levels from 500
to 829 rig/L after 60 min, and an increase in plasma cortisol
levels from 103 to 512 nmol/L after 90 min. After an overnight fast, the response of plasma cortisol levels to the iv
infusion of glucose 10% for 11 h with the simultaneous administration of 0.6 pg/ kg BW*h hGIP for the last hour was
measured. Plasmacortisol levels did not change significantly
during the glucose infusion. The addition of GIP resulted in
a rapid increasein plasma cortisol levels from 110nmol/L to
a peak of 864nmol/ L after 60 min. Glucose and insulin levels
did not change during the GIP infusion (Fig. 3). The iv administration of 0.1 IU/ kg BW insulin produced hypoglycemia of 18 mg/dL after 20 min, but did not produce an
increase in plasma cortisol, ACTH, or GIP levels.
Adrenocortical adenoma cells in culture produced 76.5 +
1.5 pmol/ tube (mean 2 SD) cortisol? h. The administration
of lo-” mol/L synthetic ACTH-(1-24) stimulated cortisol
production to 644 t 19.5 pmol/tube (mean 2 SD; Fig. 5). GIP
stimulated cortisol production in a dose-dependent fashion
to a maximum of 570 ? 19.5 pmol/tube (mean ? SD) at lop7
mol/L GIP (Fig. 5). Octreotide (lo-’ mol/L), insulin (10e9
mol / L), and bombesin (lop9 mol / L) had no significant effect
on cortisol production in vitro (data not shown).
The meal-induced increase in plasma cortisol and GIP levels was completely prevented after the administration of 0.1 mg octreotide, SC,three times daily before
each meal (Fig. 1). The effectiveness of subsequenttreatment
was initially monitored by measurementsof urinary cortisol
Effects ofoctreotide.
20
-GIP
0.6 ug/kg
6
-60
0
60
120
insulin
12
15
18
21
24
time of day (h)
180
time (min)
FIG. 3. Plasma
cortisol
(W), glucose
(O), and
response
to the iv infusion
of 0.6 Kg/kg GIP.
9
levels
(A)
in
FIG. 4. Plasma
cortisol,
GIP, and insulin
levels during
treatment
with 0.1 mg octreotide,
SC, three times daily ( 0 ; after 3.5 months
of
octreotide
treatment),
after stopping
octreotide
on a day with normal
food intake
(01, and during
fasting
(A). Compare
also with Fig. 1.
A PRISMATIC
F
2
a
CASE
3171
Cushing’s syndrome. However, the expression of GIP receptor mRNA was not above background in the sample
obtained from the adrenal adenoma of another patient with
nonfood-/non-ACTH-dependent
Cushing’s syndrome (Fig.
6). Preliminary investigation by reverse transcription-PCR
suggestedthat in addition to full-length GIP receptor mRNA,
a larger amount of inappropriately spliced GIP receptor
mRNA was present (data not shown).
800
Discussion
0
.OlO
.l
1
10
100
Dose (nmol/l)
FIG. 5. In vitro responses
ofdispersed
adrenal
adenoma
cells to lo-ii
moliL ACTH and increasing
concentrations
of GIP (10-10-10-7
mol/
L). Control,
Basal cortisol release (76.5 -+ 1.5 pmoUtube2
h). Values
are expressed
as the mean + SD.
Receptor
studies
The in situ hybridization studies using the GIP receptor
probe showed abundant expression of GIP receptor messenger ribonucleic acid (mRNA) in the adrenocortical adenoma
sample obtained from the patient with food-dependent
In Cushing’s syndrome, the plasma cortisol pattern usually lacks diurnal rhythmicity. Food intake produces some
secondary increase in plasma cortisol levels in normal subjects, but the cortisol diurnal rhythm is maintained (9). To
date, three cases of food-dependent Cushing’s syndrome
have been reported. Hamet et al. (1) studied a 41-yr-old male
with food-dependent, ACTH-independent hypercortisolemia causedby an unilateral cortisol-producing adrenal adenoma. ACTHindependent, food-dependent Cushing’s syndrome has also been reported in two postmenopausal
women by Reznik et al. (2) and Lacroix et al. (3). In these two
patients, the adrenals were bilaterally enlarged and nodular
on computed tomography. Both adrenals took up radiola-
FIG. 6. GIP receptor
mRNA distribution
in human
adrenal
tumors.
Sections
from the adrenal
of the patient
described
in the report are shown
in the left two panels, and sections from a patient with a primary
adrenal
cortisol-secreting
tumor are shown on the right. Sections were prepared
and hybridized
to 35S-labeled
antisense
riboprobes
directed
to human
GIP receptor
mRNA as described
in Materials and Methods. Brightfield
(A and C) and darkfield
(B and D) photomicrographs
are shown. The bar represents
100 pm.
3172
DE HERDER
beled cholesterol.
The iv infusion
of GIP induced
a rapid
insulin-independent
increase in plasma cortisol levels in
these two patients, but not in normal subjects or in a patient
with Cushing’s
disease (2, 3).
GIP,
also
called
glucose-dependent
insulinotropic
polypeptide,
is a 42-amino acid peptide involved
in the enteroinsular
axis. The GIP receptor is a member of the secretinvasoactive intestinal
polypeptide
family of G protein-coupled receptors and is normally
present in pancreatic p-cells
(10, 11).
In the two female patients with ACTH-independent,
fooddependent
Cushing’s
syndrome,
octreotide
and somatostatin blunted the plasma GIP response to the oral administration of glucose or a meal (2, 3). In the patient described by
Lacroix et al. (3), scintigrams
obtained after iv administration
of [‘231]GIP showed bilateral adrenal uptake of radioactivity.
This patient subsequently
underwent
bilateral
adrenalectomy (3). In vitro, GIP also produced
a dose-dependent
increase in cortisol secretion in the patient’s dispersed adrenal
cells, but not in dispersed
cells derived from fetal adrenals,
a normal human adrenal, or an adrenal adenoma
from a
patient with nonfood-dependent
Cushing’s syndrome (3). In
the other patient described by Reznik et al. (2), treatment with
the somatostatin
analog octreotide
for more than 4 months
normalized
urinary cortisol excretion, accompanied
by amelioration
of the clinical
manifestations
of Cushing’s
syndrome.
We report a fourth case of food-dependent
Cushing’s syndrome. The importance
of GIP as a direct modulator
of cortisol production
by the adrenocortical
adenoma
was demonstrated
both in uivo and in vitro. The patient’s
plasma
cortisol levels increased after ACTH, but not in response to
CRH. This has also been reported in one of the other patients
with GIP-dependent
Cushing’s
syndrome
(3). In parallel,
dispersed
adenoma
cells of our patient responded
to both
GE’ and ACTH. These findings imply that the hypothalamopituitary-adrenal
axis in patients with GIP-dependent
Cushing’s syndrome is suppressed by the hypercortisolemic
state.
However, the abnormal
adrenal cells retained their sensitivity to ACTH.
GIP receptors have been localized in the rat adrenal cortex,
but until now, no information
has been available
on the
presence or absence of GIP receptors on human adrenal cells
(10). As GIP exerts no stimulatory
effect on cultured
cells
derived from adrenal tissue from normal adults or fetuses or
from cortisol-producing
adrenal adenomas, it has been postulated that the abnormal
responsiveness
of the patients’
adrenal glands was due to ectopic or “illicit”
expression
of
GIP receptors on the adrenocortical
cells (2, 3). We found
abundant
expression
of GIP receptor mRNA in the adrenocortical adenoma from our patient and no expression above
background
in an adrenocortical
adenoma
obtained
from
JCE BE M . 1996
Vol81 . No 9
ET AL.
another
patient
with
nonfood-dependent
Cushing’s
syndrome.
From the limited information
in three cases of GIP-dependent Cushing’s
syndrome, it seems that there are at least two
subtypes of this variant of Cushing’s
syndrome. One variant
presents with bilateral nodular
hyperplasia
and may result
from a mutation
acquired
during
adrenal embryogenesis.
The other variant presents with unilateral
adrenal adenoma,
suggestive of a somatic mutation
in one adrenal gland. Probably in this last case, either the adenoma
represents
the
expansion
of a single cell clone, expressing
GIP receptors in
an aberrant way, or these cells normally
express the GIP
receptor, but are usually too small a fraction of the adrenal
mass to give rise to a detectable GIP-induced
signal.
In conclusion,
GIP-dependent
Cushing’s
syndrome
is a
new variant of ACTH-independent
Cushing’s syndrome that
results from the expression
of GIP receptors on adrenocortical cells.
Acknowledgments
We thank Drs. R. A. Vos, I’. T. E. Postema, and R. J. Erdtsieck,
Mrs.
P. C. van Sintmaartensdijk-Schuijff,
and the nursing
staff of Ward 4
Noord
for their excellent
patient care, and Dr. R. P. L. M. Hoogma
for
referring
the patient.
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