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Endocrine Care |
Service des Maladies Endocriniennes et Métaboliques (J.P.L., X.B., J.B.), Centre National de la Recherche Scientifique, UPR1524 (L.G., K.P., X.B., J.B.), CHU Cochin, 75014 Paris, France; Service d’Endocrinologie (H.L.) et INSERM, U-413 (V.C.), CHU de Rouen, 76000 Rouen, France; Service d’Endocrinologie (A.T.), CHU de Bordeaux, 33000 Bordeaux, France; Service d’Endocrinologie (P.T.), CHU de Clermont Ferrand, 63000 Clermont Ferrand, France; Service de Médecine Interne (J.L.S.), CHU de Strasbourg, 67000 Strasbourg, France; and COMETE Network, 75015 Paris, France
Address all correspondence and requests for reprints to: Dr. Jérôme Bertherat, Service des Maladies Endocriniennes et Métaboliques, Hôpital Cochin, 27 rue du Fg St. Jacques, 75014, Paris, France. E-Mail: . jerome.bertherat{at}cch.ap-hop-paris.fr
Abstract
Control of cortisol secretion by the abnormal expression of the gastric inhibitory polypeptide receptor (GIP-R) have been observed in some rare cases of ACTH-independent, food-dependent Cushing’s syndrome (FD-ACS) due to adrenal adenoma (AA) or bilateral macronodular hyperplasia (AIMAH). This study was performed to determine the prevalence of GIP-R ectopic expression in ACS and its correlation with fasting cortisol levels.
GIP-R expression was studied by RT-PCR in 30 unilateral adrenal tumors [16 AA and 14 adrenocortical cancer (AC)] and 8 AIMAH tissues. Fasting and postprandial cortisol levels were assayed, respectively, at 0800 and 1200 h in AA, AC, and AIMAH, and 1 h after a morning standard meal in 6 AIMAH patients.
Similar expression of 2 GIP-R isoforms was observed in 1 of 16 AA, 0 of 14 AC, and 4 of 8 AIMAH as well as in the 4 insulinomas used as positive controls. In vitro study of the GIP-R-expressing AA showed stimulation of cortisol secretion and cAMP production by GIP. The fasting 0800-h plasma cortisol level was above 276 nmol/liter in all patients except 1 AA case and 1 AIMAH case, both of whom expressed GIP-R. In the 3 additional AIMAH cases that expressed the GIP-R, fasting plasma cortisol levels were above 276 nmol/liter.
This study demonstrates that ectopic expression of GIP-R is rare in AA and is usually associated with the low fasting plasma cortisol levels that characterize FD-ACS. In contrast, GIP-R expression is frequent in AIMAH and might not always be associated with a low fasting plasma cortisol level. This suggests that maintenance of hypercortisolemia in GIP-R- expressing AIMAH does not always depend solely on GIP-R, and that simultaneous abnormal expression of other membrane receptors might be present. The expression of GIP-R could not be observed during malignant transformation of the adrenal cortex.
This study highlighted the major role of cAMP alterations secondary to GIP-R ectopic expression in the pathophysiology of AIMAH and in some rare cases of well differentiated benign adrenocortical tumors.
ADRENAL CUSHING’S SYNDROME (ACS) is usually secondary to a unilateral adrenocortical tumor, either benign [adrenocortical adenoma (AA)] or malignant [adrenocortical carcinoma (AC)]. In no more than 10% of cases ACS can be secondary to ACTH-independent macronodular hyperplasia (AIMAH) or primary pigmented nodular adrenocortical disease (1). In ACS, despite the lack of ACTH stimulation of the cAMP pathway (2), increased adrenocortical mass and glucocorticoid secretion are present. This paradoxical observation has been explained in some rare cases of ACS by molecular alterations of the cAMP pathway; activating somatic mutations of the 
-subunit of the Gs protein have been reported in the McCune-Albright syndrome, in which AIMAH can been observed, and inactivating mutations of the R1A subunit of PKA (PRKAR1A) have been observed in the Carney complex, which typically induces primary pigmented nodular adrenocortical disease (3, 4, 5). Ectopic or abnormal expression of hormone receptors has been observed in human ACS in both in vivo and in vitro studies (recently reviewed in Ref.6). The best example is the food-dependent ACS (FD-ACS) (7). It was first identified in a male patient with a unilateral adrenal adenoma (AA). Yet the final evidence of an abnormal adrenocortical response to gastric inhibitory polypeptide (GIP) in FD-ACS was first demonstrated in two patients with AIMAH, both with low fasting cortisol levels that increased after food intake (8, 9). To date, 12 cases of FD-ACS have been reported, 6 with AIMAH and 6 with AA (7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18). However, the exact prevalence of this syndrome and the role of abnormal GIP-R expression in adrenocortical tumorigenesis is unknown. It is possible that routine investigation of circadian cortisol variations is not sensitive enough to detect all cases of GIP-R expression in ACS and that this situation might be more frequent than previously reported.
We systematically sought clinical evidence of FD-ACS in 30 patients with unilateral tumors (16 AA and 14 AC) and 8 patients with AIMAH by assessing fasting and postprandial cortisol plasma levels and circadian variations in plasma cortisol. Studies of surgically removed tissues were used to detect GIP-R mRNA and the responsiveness of cortisol to GIP perifusion.
Materials and Methods
Patients and endocrinological investigations
Thirty patients had unilateral tumors and eight patients had AIMAH. The diagnosis of ACS was based on the results of laboratory investigations, as previously reported (19). Briefly, the diagnosis of ACS was based on elevated 24-h urinary cortisol excretion (>248 nmol/d), with low ACTH plasma levels (<15 pg/ml; normal range, 20–60 pg/ml), and abnormal response to either the overnight 1-mg dexamethasone suppression test (plasma cortisol, >110 nmol/liter) and/or the classic low dexamethasone (2 mg/d for 2 d) suppression test (urinary cortisol, >28 nmol/d).
Blood samples were collected for the determination of fasting cortisol levels at 0800 h (normal range, 276–552 nmol/liter). Measurements of postprandial cortisol were performed 1 h after the end of a standard meal in patients with AIMAH and at 1200 h (3 h after breakfast) in patients with unilateral adrenal tumors and in AIMAH patients as part of the routine cortisol circadian rhythm investigation. Further studies were performed when FD-ACS was suspected: cortisol response to oral glucose load (patients 1, 32, and 34), somatostatin analog treatment (patients 1 and 34), and fasting (patients 32 and 34).
Tissue collection and culture of H295R cells
Adrenal (16 AA, 14 AC, and 8 AIMAH) or pancreatiD Tissues (4 insulinomas, used as a positive control for GIP-R expression) were obtained during surgery and were immediately dissected by the pathologist, frozen, and stored in liquid nitrogen until use. Adrenal tumors were diagnosed by the use of classical histological criteria and molecular genetics markers as previously reported by the COMETE network (20), which is dedicated to the study of adrenal tumors. Normal adrenal cortex tissue was obtained from 2 normal glands (kidney removal) and from the adjacent cortex of 4 nonsecreting adenomas. Informed consent was given for adrenal tissue collection as part of a protocol approved by the institutional review board of Cochin Hospital. H295R cells were cultured as previously described (21).
GIP-R expression study
Poly(A)+ mRNA was extracted by use of the Micro FastTrack kit (Invitrogen, Groningen, The Netherlands). RT was performed with the cDNA Cycle kit (Invitrogen). cDNA was amplified by PCR using Dynazyme II DNA polymerase (Finnzymes Oy, Espoo, Finland) for 35 cycles (94 C for 1 min, 56 C for 2 min, 72 C for 3 min). Reverse transcriptase was omitted from the reaction mixture as a negative control. The following synthetic oligonucleotides (Life Technologies, Inc., Gaithersburg, MD) were used: for GIP-R cDNA amplification: sense primers located in exon II, 5'-CCTGATCGCCCCTGCACGAAC-3'; antisense primers located in exon VII, 5'-AGGTCGAGGTAGCAGACGGTCTCG-3'; and for actin: sense primer, 5'-GGGCATGGGTCAGAAGGATT-3'; antisense primer, 5'-ATGAGGTAGTCAGTCAGGTC-3'. The PCR products were separated on an agarose gel and stained with ethidium bromide. After electrophoresis, the PCR product was excised from the gel and purified using the Wizard PCR prep purification system (Promega Corp., Madison, WI). PCR products were directly sequenced with an ABI 373A automated DNA sequencer.
In vitro perifusion study
The perifusion technique used to investigate the effects of GIP, glucagon-like peptide 1 (GLP-1), and ACTH on cortisol secretion in adrenal adenoma from patient 1 has been described in detail previously (22, 23). Briefly, tumor fragments obtained at surgery were immediately transported to the laboratory in DMEM. After dissection and preincubation in DMEM at 20 C, tumor slices were mixed with Bio-Gel P2 (Bio-Rad Laboratories, Inc., Richmond, CA) and transferred to perifusion chambers. Each perifusion column contained approximately 100 mg wet tissue. The perifusion chambers were supplied with DMEM at a constant flow rate (300 µl/min). The pH (7.4) and temperature (37 C) were kept constant throughout the experiment. The perifusion medium was continuously gassed with a 95% O2/5% CO2 mixture. The tissues were allowed to stabilize for 2 h before adding the test substances. Secretagogues were dissolved in gassed DMEM and infused at the same flow rate as DMEM alone by means of a multichannel peristaltic pump (Wiz pump, Isco, Lincoln, NE). Fractions of the effluent perfusate were collected every 5 min and immediately frozen until assay. Cortisol levels were determined by an immunoluminescent assay using a commercial kit (Amerlite, Ortho-Clinical Diagnostics, Issy-les-Moulineaux, France). The detection limit of the assay was 3 nmol/liter. The basal and stimulated values were compared by two-tailed Wilcoxon test. Human GIP and GLP-1 were obtained from Bachem Biochimie (Voisins le Bretonneux, France). Synthetic human ACTH was provided by Drs. R. H. Andreatta and V. Rasetti (Novartis, Basel, Switzerland).
cAMP determination
Tumoral adrenocortical fragments from the AA from patient 1 were dissected, sliced into 1- to 2-mm3 pieces, and preincubated for 2 h in DMEM. Adrenal slices were rinsed and incubated for 15 min at room temperature in 180 µl DMEM containing 10 mM 3-isobutyl-1-methylxanthine to inhibit phosphodiesterase activity. Twenty microliters of a solution containing GIP, GLP-1, or ACTH were added to the medium, and the cells were incubated for 10 min. The reaction was stopped by adding 200 µl ice-cold 20% trichloroacetic acid (wt/vol). The tissues were homogenized and centrifuged (13,000 x g, 5 min, 4 C). The supernatant was washed three times with 1 ml water-saturated diethyl ether, dried under vacuum, and reconstituted in RIA buffer (0.05 M sodium acetate, pH 5.8). The concentration of cAMP contained in each sample was determined in duplicate using a commercial cAMP RIA kit (Amersham International, Les Ulis, France). The detection limit of the assay was 12 fmol/tube. The pellet was used for protein quantification by the Lowry method.
Statistical analysis
Statistical significance was assessed by one-way ANOVA with the Tukey-Kramer multiple comparisons test as posttest using the InStat program (GraphPad Software, Inc., San Diego, CA).
Results
Endocrinological investigation (Tables 1
and 2)
Sixteen unilateral tumors were diagnosed as AA (cases 1–16). Twelve of 16 AA were responsible for Cushing’s syndrome, and the remaining 4 of 16 AA were not hypersecreting or were responsible for preclinical Cushing’s syndrome (cases 5, 7, 10, and 14). Fourteen tumors were diagnosed as malignant tumors (cases 17–30). Twelve of 14 AC were responsible for steroid hypersecretion (see details in Table 1).
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Fasting 0800-h cortisol plasma levels were above 276 nmol/liter in all patients except one with AA [case 1, full clinical report previously published (17)] and in one case of AIMAH (case 32). A significant (
60%) cortisol increase after food intake (fasting 0800 h vs. fed 1200 h) was observed in these two patients and in one other AIMAH patient (case 34). These three patients were the only ones in whom FD-ACS was diagnosed and GIP-R expression was suspected before surgery. Low cortisol plasma levels were observed when the two AIMAH patients were subjected to a 24-h period of fasting (Fig. 1). The somatostatin analog, octreotide, inhibited the cortisol response to an oral glucose load or meal in patients 1 (data not shown) and 32 (Fig. 1).
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Two PCR products of similar size (634 and 527 bp) were observed in the insulinomas and the positive adrenal tissues (Fig. 2). Direct sequencing of the PCR product revealed that the 634-bp product was the full-length GIP-R (exons 2–7) and that the 527-bp product corresponded to the previously reported shorter isoform that lacks exon 4 (12, 16). As expected, a 435-bp fragment was observed for all of the samples included in this study when amplified with the actin primers, as a control of the quality of the cDNAs.
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), and 4 of 8 AIMAH (cases 31–34; Fig. 2, B and C). GIP-R mRNA was not detected in the atrophic adrenal cortex adjacent to AA in case 1, the 14 AC (Fig. 2C), the 2 normal adrenal cortex samples, the 4 adrenal cortex samples adjacent to nonsecreting AA, or the H295R cell line. Adrenal tissue from the three patients (no. 1, 32, and 34) in whom FD-ACS was diagnosed before surgery expressed the GIP-R. In addition, GIP-R mRNA was detected in the adrenal tissue from AIMAH cases 31 and 33. An in vivo response to upright posture and vasopressin was also observed in patient 33.
In vitro effects of GIP on a GIP-R-expressing adrenal adenoma (Fig. 3)
Administration of a pulse of ACTH (10-9 M; 20 min) to perifused tumor fragments (AA from patient 1) induced a 36% increase in cortisol secretion (P < 0.05). The effects of graded concentrations of GIP ranging from 10-12–10-7 M on cortisol release are shown in Fig. 3. Cortisol production increased by 217% of the basal level (P < 0.05) after the addition of 10-7 M GIP. In contrast, GLP-1 had no influence on cortisol secretion.
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). In contrast, GLP-1 had no affect on cAMP production. ACTH, used as a control, produced a massive increase in cAMP formation (P < 0.001). Discussion
Systematic in vitro screening for GIP-R expression by RT-PCR showed that this receptor is frequently expressed in AIMAH, whereas it is rare in unilateral adrenal tumors (1 of 30). In AIMAH it could be associated (as in cases 31 and 32) with the asymmetric and delayed development of AIMAH, as previously reported (13). The unilateral adrenal tumor with GIP-R expression was an AA, and no signal was detected in the 14 AC or in the adrenocortical cell line H295R, which was derived from an AC. GIP-R expression has never been reported in AC. According to the recent review by Lacroix et al. (6), the overexpression of the GIP-R has been observed worldwide in 6 cases of AA (including case 1 of this study) and 10 cases of AIMAH. Our series adds 4 new cases of AIMAH with GIP-R ectopic expression, 2 of which showed the typical clinical signs of FD-ACS. Given that AA is much more prevalent than AIMAH in ACS, the results of our systematic screening are in accordance with the prevalence of GIP-R expression determined by the various case reports of FD-ACS in the literature.
In AA, GIP-R expression is associated with an abnormal cortisol rhythm. The 0800 h fasting cortisol plasma level (66 nmol/liter) in the patient presenting with the GIP-R expressing AA of this study was much below the lower limit of the normal range (276 nmol/liter). This seems to be the case in all previously reported AAs (7, 10, 11, 15, 16, 18). Furthermore, none of the other 29 patients with ACS due to unilateral tumor without GIP-R expression had an 0800 h plasma cortisol level below 276 nmol/liter. This suggests that in vivo screening by a single assay of fasting plasma cortisol is a sensitive and specific method for the detection of GIP-R expression in ACS patients with unilateral tumors. The situation appears to differ in patients with AIMAH. The fasting 0800 h cortisol plasma levels were above 276 nmol/liter in 3 of the 4 cases expressing GIP-R. A nonsuppressed fasting cortisol level was previously reported in AIMAH with FD-ACS (14), but GIP-R expression was not studied in this case. This suggests that measuring the fasting plasma cortisol concentration is not a sensitive enough method to screen for GIP-R in AIMAH. Measuring the cortisol response to a mixed meal might improve this sensitivity, although the precise diagnostic criteria might be somewhat arbitrary. Percent increases of 25% and 50% have been proposed (24). In patient 33, a response to upright posture and vasopressin was observed. The simultaneous coexpression of another "illegitimate" receptor in such an AIMAH case might maintain high or normal fasting plasma cortisol levels and obscure the FD-ACS phenotype.
Several conditions are required for a GIP-R to be functional in an adrenal tumor. The sequence data identified two isoforms that are identical to those in the insulinomas. These have previously been characterized in AA and AIMAH (12, 16). Furthermore, an in vitro study of the GIP-R-expressing AA from patient 1 showed that cortisol was secreted and cAMP was stimulated in response to GIP. The mechanisms leading to GIP-R expression remain unknown. Our results support ectopic expression, as it was not detected in the adrenal tissue adjacent to the AA with FD-ACS or in the normal adrenal samples. This is consistent with a previous study in which GIP-R was also detected by RT-PCR and ethidium bromide staining (16). However, another study that used Southern blotting to detect PCR products revealed a low level of GIP-R expression in normal human adrenal tissue (12). GIP-R are present in rat adrenal cortex and are able to stimulate glucocorticoid secretion through PKA (25, 26). However, normal human adrenal tissue does not respond to GIP (12).
Mutation of a cis- or a trans-acting element regulating the expression of the GIP-R has been proposed to trigger ectopic GIP-R expression. Consistently, the GIP-R-expressing AA in this study is monoclonal (Gicquel, C., unpublished observation). However, this hypothesis does not hold when several illegitimate receptors are expressed in the same tumor, as discussed above. Indeed, cortisol control by LH or CRH and cisaprid has been observed in the same AIMAH patients (27). We recently observed an AIMAH patient with FD-ACS who responded to hCG/LH (28). Systematic wide range in vivo and in vitro screening of ACS for abnormal membrane receptor expression might demonstrate that the simultaneous expression of a number of receptors is quite frequent in AIMAH. Ectopic GIP-R expression has never been observed in AC. This suggests that activation of the cAMP pathway by GIP-R might be involved in the tumorigenesis of slow-growing benign tumors (AA or AIMAH).
In conclusion, abnormal expression of the GIP-R is rare in AA and is associated with low fasting cortisol plasma levels. In contrast, GIP-R is frequently expressed in AIMAH and not always associated with low fasting cortisol plasma levels. This may be due to the simultaneous abnormal expression of various membrane receptors, which may be a frequent phenomenon in AIMAH. Abnormal GIP-R expression does not seem to occur in AC, and activation of the cAMP pathway by GIP might be involved in tumorigenesis of benign, slowly growing, and well differentiated adrenocortical tumors.
Acknowledgments
We thank the surgeons (Profs. Y. Chapuis and B. Dousset) and the medical and paramedical staff from our Endocrine Department who managed the patients, Drs. A. Louvel and F. Tissier for carrying out the pathological examinations, and Dr. A. Dugue and the staff of the Laudat laboratory for hormonal assays.
Footnotes
This work was supported in part by the Plan Hospitalier de Recherche Clinique (AOM 95201 to COMETE Network, coordinated by Prof. P. F. Plouin and dedicated to the study of adrenal tumors) and the Association pour la Recherche sur le Cancer (ARC 4225).
L.G. is recipient of a fellowship from the Association pour la Recherche sur le Cancer.
Abbreviations: AA, Adrenal adenoma; AC, adrenocortical cancer; AIMAH, bilateral macronodular hyperplasia; FD-ACS, ACTH-independent, food-dependent Cushing’s syndrome; GIP, gastric inhibitory polypeptide; GIP-R, gastric inhibitory polypeptide receptor; GLP-1, glucagon-like peptide 1.
Received August 29, 2001.
Accepted January 25, 2002.
References
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), during a 24-h period fasting (
), and during octreotide treatment (
; 500 µg, sc, three times per d; not performed in patient 32 shown in B).
