Original Article
Food-Dependent Cushing's Syndrome Mediated by Aberrant Adrenal Sensitivity to Gastric Inhibitory Polypeptide
N Engl J Med 1992; 327:981-986October 1, 1992
- Abstract
- Abstract
Background.
Some patients with Cushing's syndrome have nodular adrenal hyperplasia. In most the disease is corticotropin-dependent, but in others it is corticotropin-independent. The cause of the adrenal hyperplasia in the latter patients is not known.
Methods.
We studied a 49-year-old woman with Cushing's syndrome and nodular adrenal hyperplasia in whom food stimulated cortisol secretion. Plasma cortisol concentrations were measured in response to the ingestion of mixed meals, glucose, protein, and fat and after the administration of various gastrointestinal and other types of hormones. We also studied the ability of the long-acting somatostatin analogue octreotide to prevent the food-induced increase in plasma cortisol concentrations and to ameliorate the clinical manifestations of Cushing's syndrome in this patient.
Results.
The patient's fasting plasma cortisol concentrations were subnormal, ranging from 3.0 to 7.5 μg per deciliter (83 to 207 nmol per liter), and they increased to as high as 16.5 μg per deciliter (455 nmol per liter) after a mixed meal. Her urinary cortisol excretion ranged from 164 to 250 μg per day (453 to 690 nmol per day) and could not be suppressed by a large dose of dexamethasone. Plasma corticotropin concentrations were virtually undetectable at all times. The ingestion of glucose, protein, and fat increased plasma cortisol concentrations to 3.6, 2.2, and 4 times the base-line value, respectively; the meal-induced and glucose-induced increases were inhibited by octreotide. The infusion of gastric inhibitory polypeptide (GIP) increased the patient's plasma cortisol concentration to 3.7 times the base-line value, but had no effect in normal subjects. The patient's fasting plasma GIP concentrations were normal both before and after a meal, and there was a close correlation between her plasma cortisol and GIP concentrations. Treatment with octreotide decreased urinary cortisol excretion and ameliorated the clinical manifestations of Cushing's syndrome.
Conclusions.
The development of aberrant adrenal sensitivity to GIP can result in food-dependent adrenal hyperplasia and therefore in Cushing's syndrome. (N Engl JMed 1992;327:981–6.)
Media in This Article
Figure 1
The 24-Hour Profile of Plasma Cortisol and Corticotropin Concentrations on Different Days in a Patient with Food-Induced Cushing's Syndrome.Figure 2
The 24-Hour Profile of Plasma Cortisol (□) and GIP (■) Concentrations in a Patient with Food-Induced Cushing's Syndrome (Panel A) and Three Normal Men (Panel B).Article Activity
- Article
THE most common causes of spontaneous Cushing's syndrome are hypersécrétion of corticotropin, from either a pituitary adenoma or a non-endocrine tumor, and unilateral adrenal tumors.1 , 2 Although they are generally considered autonomous, adrenal tumors that are responsive to various stimuli, including food, corticotropin, and vasopressin, have been reported.3 4 5 Corticotropin-independent Cushing's syndrome due to nodular hyperplasia6 7 8 9 is rare, and its cause is poorly understood, although adrenal stimulation by antibodies has been demonstrated in some cases.10 , 11
We describe a patient with corticotropin-independent Cushing's syndrome, who had low plasma cortisol concentrations during periods of fasting and whose concentrations increased after the ingestion of glucose, fat, or proteins and the intravenous infusion of gastric inhibitory polypeptide (GIP). As exemplified by this patient and the patient described by Lacroix et al. in an abstract12 and in more detail in the preceding article,13 Cushing's syndrome can be food-dependent.
Case Report
A 49-year-old woman had a five-year history of fatigue, muscular weakness, and weight gain (total, 8 kg); these symptoms developed during the year after a hysterectomy with oophorectomy. Physical examination revealed that the patient had a round face, interdigital mycosis, proximal myopathy, hypertension (blood pressure, 180/90 mm Hg), and mild depression. She had no striae, hirsutism, clitorimegaly, or osteoporosis. Her mean daily food intake was estimated to be 1895 kcal, with 16 percent of the calories coming from protein, 42 percent from fat, and 42 percent from carbohydrate. The fasting and post—glucose loading plasma glucose concentrations were normal, as were the results of other routine biochemical tests.
The patient's plasma cortisol concentrations were 4.5 μg per deciliter (124 nmol per liter) at 8 a.m. and 12.0 μg per deciliter (331 nmol per liter) at 8 p.m., and urinary cortisol excretion ranged from 164 to 250 μg (453 to 690 nmol) per day (Table 1Table 1
Plasma and Urinary Steroid Measurements in a Patient with Food-Induced Cushing's Syndrome.*). Plasma corticotropin was undetectable before and after the administration of lysine vasopressin and metyrapone. Plasma and urinary cortisol values did not change in response to either a small or a large dose of dexamethasone. The results of hourly measurements of plasma cortisol for two days revealed prominent meal-related peaks (Fig. 1Figure 1The 24-Hour Profile of Plasma Cortisol and Corticotropin Concentrations on Different Days in a Patient with Food-Induced Cushing's Syndrome.), and plasma corticotropin concentrations were virtually undetectable at all times. The patient's plasma aldosterone concentration was normal (and was not stimulated by glucose ingestion). Abdominal computed tomography revealed enlarged adrenal glands (right, 4.5 cm long and 1.5 cm wide; left, 3.5 cm and 1.5 cm), and the left adrenal gland appeared nodular. There was bilateral uptake of [131I]iodocholesterol by the adrenal glands. Computed tomography of the pituitary gland showed no abnormalities.There was no evidence of familial Cushing's syndrome, and the patient's brother and her three daughters had normal fasting (measured at 8 a.m.) and postprandial (measured at 8 p.m.) plasma cortisol concentrations.
Studies were undertaken to determine the responsiveness of the patient's adrenal glands to corticotropin, GIP, mixed meals, carbohydrate, fat, and protein after a fast lasting overnight or longer. The interval between studies was at least one week. During this period, the patient continued the cyclic transdermal estradiol and oral progesterone therapy that had been initiated when she had a hysterectomy, but she received no other medications. On the morning of each test, she remained supine and had an indwelling catheter placed in a forearm vein to allow repeated blood sampling. The patient subsequently declined to undergo bilateral adrenalectomy and therefore was treated with octreotide, a somatostatin analogue,14 on the basis of its ability to inhibit glucose-induced cortisol secretion in an earlier study. She was treated for 2 weeks with 0.05 mg of octreotide subcutaneously before lunch each day, then for 12 weeks with a dose of 0.05 mg daily before her afternoon snack, and finally with a dose of 0.1 mg three times daily. She was advised to eat normally during treatment.
Human GIP (Bachem, Bubendorf, Switzerland) was dissolved in saline with 1 percent albumin, sterilized by membrane filtration, and stored at —20°C until it was used.
Methods
Normal Subjects
Four normal men ranging in age from 25 to 52 years were studied as described below while being given dexamethasone to suppress corticotropin-dependent cortisol secretion (1 mg orally at 4 p.m. and 11 p.m. the day before the test and at 7 a.m. on the morning of the test). Three normal men ranging in age from 27 to 52 years were studied during a 24-hour fast and then after eating a 1130-kcal meal containing 82 g of carbohydrate, 40 g of protein, and 53 g of fat at 8 p.m.
All the studies were approved by the local ethics committee, and the patient and all the normal subjects gave informed consent.
Hormone Assays
Plasma cortisol, corticotropin, aldosterone, and insulin concentrations were measured by commercial radioimmunoassay kits purchased from Incstar (Stillwater, Minn.), the Nichols Institute (San Juan Capistrano, Calif), Behring-Calbiochem (San Diego, Calif.), and Pharmacia (Uppsala, Sweden), respectively. Plasma GIP was measured by radioimmunoassay as described previously.15 The sensitivity of the corticotropin and GIP assays was 1 pg and 20 pg, respectively. All plasma samples from each study were measured in duplicate in the same assay. Urinary cortisol excretion was measured by radioimmunoassay, and urinary 17-hydroxycorticosteroid and 17-ketosteroid excretion was measured by standard colorimetric methods.
In Vitro Studies
The potential steroidogenic effect of the patient's serum was tested by incubation of serum in vitro with adrenal cells from a normal adult. The cells were cultured in 1 ml of a 1:1 solution of Ham's F12 medium and Dulbecco's modified Eagle's medium.16 On the second day of culture, the medium was removed and replaced by fresh medium that contained corticotropin, serum, or IgG fractions of serum obtained from the patient or a normal subject during periods of fasting. The mixtures were then incubated at 37°C for 24 hours, after which the cortisol concentrations in the medium were measured in quadruplicate by radioimmunoassay.
Results
In Vivo Adrenal Responsiveness to Various Stimuli
The patient's plasma cortisol concentrations increased from 3.7 to 26.0 μg per deciliter (102 to 718 nmol per liter) 60 minutes after the intravenous administration of 0.25 mg of corticotropin at 8 a.m. and from 13.0 to 33.0 μg per deciliter (359 to 911 nmol per liter) when the corticotropin was given at 8 p.m.
After an overnight fast and while the patient continued fasting, her plasma cortisol concentrations, measured hourly, averaged 4.3 μg per deciliter (119 nmol per liter) between 8 a.m. and 8 p.m. Her plasma cortisol concentration increased to 16.5 μg per deciliter (455 nmol per liter) 60 minutes after she ate a 690-kcal mixed meal (116 g of carbohydrate, 27 g of protein, and 14 g of fat) at 8 p.m. (Fig. 2Figure 2
The 24-Hour Profile of Plasma Cortisol (□) and GIP (■) Concentrations in a Patient with Food-Induced Cushing's Syndrome (Panel A) and Three Normal Men (Panel B).A); plasma GIP increased from 245 to 1060 ng per liter (49 to 212 pmol per liter). This evening postprandial increase in plasma cortisol did not occur in the three normal men, although their postprandial increase in plasma GIP was prolonged because of the higher fat content of the meal they received (Fig. 2B).The administration of both oral (75 g) and intravenous (25 g) glucose increased the patient's blood glucose and plasma insulin concentrations. By contrast, only the oral administration of glucose was followed by a rise in both plasma cortisol, from 4.1 to 18.0 μg per deciliter (113 to 497 nmol per liter), and GIP, from 105 to 1100 ng per liter (21 to 220 pmol per liter) (Fig. 3Figure 3
Effects of Intravenous and Oral Glucose Administration (Panel A), Oral Glucose One Hour after the Injection of Octreotide (Panel B), a Protein-Based Meal (Panel C), and a Fat-Based Meal (Panel D) on Plasma Concentrations of Cortisol (□), Glucose (●) or Triglycerides (X), Insulin (
), and GIP (■) in a Patient with Food-Induced Cushing's Syndrome.A). The oral glucose—induced increase in plasma cortisol and GIP concentrations was inhibited when the patient was given 0.1 mg of octreotide subcutaneously one hour before the administration of oral glucose (Fig. 3B). The effects of a protein-based meal (490 kcal; 87 percent protein, 8 percent carbohydrate, 5 percent fat) and a fat-based meal (490 kcal; 82 percent fat, 16 percent carbohydrate, 2 percent protein), each eaten at 10 a.m., are shown in Figures 3C and 3D. Both meals were followed by increases in plasma cortisol and GIP concentrations. Plasma cortisol concentrations did not increase after the intravenous administration of 1 mg of glucagon, 0.1 unit of insulin (and glucose) per kilogram of body weight, or 0.5 μg of pentagastrin per kilogram (data not shown). The intravenous infusion of glucose for three hours with simultaneous infusion of 0.6 μg of GIP per kilogram for the last hour resulted in an increase in plasma cortisol concentrations from 4.0 to 14.8 μg per deciliter (110 to 408 nmol per liter) during the last hour (Fig. 4Figure 4
Effects of the Infusion of Glucose and GIP on Plasma Concentrations of Cortisol (□), Glucose (●), Insulin (), and GIP (■) in a Patient with Food-Induced Cushing's Syndrome (Panel A) and Four Normal Subjects (Panel B).A). In contrast, the same infusions had no effect on plasma cortisol concentrations in four normal subjects who received dexamethasone (Fig. 4B). These subjects and the patient did have an increase in plasma cortisol in response to corticotropin given 90 minutes after the GIP and glucose infusion was stopped. In all subjects, plasma insulin concentrations increased during the infusion of GIP, resulting in transient hypoglycemia after both the glucose and GIP infusions were discontinued.The plasma concentrations of GIP and cortisol were positively correlated (P<0.001) in the samples collected during the studies in which the patient received oral glucose, the protein-based meal, and the fat-based meal.
In Vitro Studies
The human adrenal cells cultured in vitro responded to corticotropin in a dose-dependent manner: the mean (±SD) cortisol content in basal medium after 24 hours of incubation was 4.8±0.2 μg per milligram of protein, and it was 9.2±0.2, 12.5±2.5, and 27.8±3.3 μg per milligram of protein after incubation with 10–12, 10–11, and 10–10 mol of corticotropin per liter, respectively. The patient's serum stimulated cortisol production in these cells (8.5±1.5 and 13.7±2.1 μg per milligram of protein after the addition of 20 and 40 μl of serum, respectively), as did normal serum (7.2±1.1 and 11.9±1.0 μg of cortisol per milligram of protein). The IgG (200 μg and 400 μg) prepared from the patient's serum and from normal serum had no steroidogenic effect. Therefore, this patient's Cushing's syndrome was not due to adrenal-stimulating immunoglobulins.
Therapeutic Effects of Octreotide
The food-induced increase in plasma cortisol in the patient was inhibited for six hours after a subcutaneous injection of 0.05 mg of octreotide (data not shown). The effectiveness of the subsequent treatment was initially monitored by measurements of urinary cortisol excretion in the evening (6 to 10 p.m.). Urinary cortisol excretion ranged from 240 to 440 μg (662 to 1214 nmol) per gram of creatinine before treatment (normal, 8 to 30 μg [22 to 83 nmol] per gram of creatinine), 36 to 310 μg (99 to 856 nmol) per gram of creatinine when octreotide was injected before lunch, and 72 to 153 μg ( 199 to 422 nmol) per gram of creatinine when octreotide was injected before the patient's afternoon snack. After three months of treatment, her clinical condition improved: she had lost 5 kg, her well-being and strength improved, and her face became less round. However, her 24-hour urinary cortisol excretion remained elevated, ranging from 240 to 320 μg (662 to 883 nmol) per day. During the fourth month of therapy, clinical signs of Cushing's syndrome recurred; increasing the dose of octreotide to 0.1 mg three times daily resulted in clinical improvement and the return of urinary cortisol excretion to normal levels (100 μg [276 nmol] per day).
Discussion
In our patient, Cushing's syndrome, which was manifested by both clinical symptoms and increased urinary cortisol excretion, was clearly due to food ingestion. Her plasma cortisol concentrations were subnormal when she fasted, and they increased after meals, whether she ate mixed meals or meals largely consisting of protein, fat, or carbohydrate. The increases in plasma cortisol concentrations were not mediated by corticotropin secretion, since plasma corticotropin concentrations were virtually undetectable at all times and dexamethasone did not suppress plasma cortisol concentrations or urinary cortisol excretion. Plasma cortisol concentrations increased in response to the administration of oral glucose, but not intravenous glucose, and this increase was suppressed by octreotide, a somatostatin analogue that is known to decrease the plasma concentrations of various peptides in patients with endocrine tumors of the digestive tract.17 These results strongly suggested that the adrenal glands of this patient were stimulated by some hormone or hormones of the gastrointestinal tract. As in the report by Lacroix et al.,12 GIP was a likely candidate, since the secretion of this peptide is normally stimulated by the ingestion of protein, fat, and glucose.18 , 19 The intravenous infusion of GIP resulted in an increase in the plasma cortisol concentrations of the patient, but not of four normal subjects receiving dexamethasone. GIP stimulated insulin secretion in all subjects, as previously reported.20
The mechanism of the GIP-mediated adrenal stimulation in this patient is not known. Hypersecretion of GIP is unlikely, since the patient's endogenous plasma GIP concentrations were normal, both during periods of fasting and after meals. The most likely explanation is direct or indirect stimulation of the adrenal glands by GIP due to aberrant sensitivity of the glands to this peptide or to a metabolite. This unexpected sensitivity to GIP must be due to the presence of ectopic GIP receptors on the adrenal glands that are not expressed in normal subjects, or to abnormal corticotropin receptors capable of binding GIP as well as corticotropin. Whether or not other peptides can stimulate our patient's adrenal glands is unknown. The failure of lysine vasopressin, glucagon, insulin, and pentagastrin to produce such an effect does not rule out the possibility that some other known or unknown peptides contribute to the patient's adrenal hypersecretion.
Whatever the mechanism involved, it must differ from that which elicits the food-dependent increase in plasma cortisol concentrations that occurs in some normal subjects. Although some investigators have not found any effect of meals on cortisol secretion in normal subjects,21 22 23 others have found a lunch-related increase in plasma cortisol concentrations.24 25 26 This increase is due to the ingestion of proteins, mainly those containing tyrosine and tryptophan; fat and carbohydrate have no discernible effect.27 The sight and taste of food, without ingestion, do not evoke an increase in plasma cortisol.27 This after-lunch cortisol secretion in normal subjects is suppressed by dexamethasone28 and is therefore a corticotropin-dependent phenomenon.29 Gastrin-releasing peptide may participate in the corticotropin-dependent postprandial peak, since this peptide and its receptors are present in the hypothalamus, and the concentrations of both corticotropin and cortisol are increased, in a dose-dependent manner, by the infusion of this peptide.30 The increase in plasma cortisol concentrations induced by the intravenous infusion of vasoactive intestinal polypeptide in patients with Cushing's disease was also related to corticotropin secretion by the pituitary adenomas, and it disappeared after successful adenomectomy.31
The ability of octreotide to block the increase in plasma cortisol concentrations induced by oral glucose in our patient led us to use this drug as an alternative to bilateral adrenalectomy. We believed that this treatment was logical and permissible in our patient, at least for some time, since her Cushing's syndrome was mild and she declined to undergo adrenalectomy. The initial treatment with a single injection before lunch or in the afternoon was designed to reproduce an almost normal diurnal cycle of cortisol secretion by maintaining the meal-stimulated morning peak and inhibiting any cortisol increase later in the day. However, as a result of insufficient cortisol suppression, we had to increase the dose to 0.1 mg three times daily. With this regimen, the patient's urinary cortisol excretion decreased to the upper limit of normal. Therefore, octreotide had an incomplete effect in this patient, and its use as a long-term treatment remains questionable.
We are indebted to Dr. André Lacroix and Dr. J.M. Saez for helpful discussion, to Mrs. Françoise Poiblaud, Mrs. Raymonde Golba, and Mr. Michel Herrou for expert technical assistance, to Miss Annick Le Mouël for dietary advice, and to Mrs. Jacqueline Bouchet and the house staff and nursing staff for their assistance in caring for the patient.
Source Information
From the Département d'Endocrinologic, Centre Hospitalo-Universitaire, Caen, France (Y.R., V.A.-Z., R.L., P.L., G.T., I.B., A.M.B., J.M.), and Institut National de la Santé et de la Recherche Médicale Unité 45 (J.A.C.) and Unité 307 (M.-C.L.), Lyon, France. Address reprint requests to Dr. Reznik at the Département d'Endocrinologie, C.H.U. Côte de nacre, 14000 Caen, France.
- References
References
1
Krieger
CrossRef | Web of Science | Medline2
Rees LH, Landon J. Biochemical abnormalities in some human neoplasms. 5. Inappropriate biosynthesis of hormones by tumours. In: Symington T, Carter RL, eds. Scientific foundations of oncology. London: William Heinemann Medical Books, 1976:112.
3
Schorr
Web of Science | Medline4
Katz
CrossRef | Web of Science | Medline5
Hamet
Web of Science | Medline6
Larsen
CrossRef | Web of Science | Medline7
Carney
CrossRef | Web of Science | Medline8
Hodge
CrossRef | Web of Science | Medline9
Young
Full Text | Web of Science | Medline10
Teding van Berkhout
CrossRef | Web of Science | Medline11
Wulffraat
CrossRef | Web of Science | Medline12
Lacroix A, Bolté E, Poitras P, et al. Gastric inhibitory polypeptide-dependent macronodular adrenal hyperplasia: a new etiology of Cushing's syndrome. In: Program and abstracts of the 73rd Annual Meeting of the Endocrine Society, Washington, D.C., June 19–22, 1991. Bethesda, Md.: Endocrine Society, 1991:91. abstract.
13
Lacroix
Full Text | Web of Science | Medline14
O'Donnell
CrossRef | Web of Science | Medline15
Miazza
Web of Science | Medline16
Penhoat
CrossRef | Web of Science | Medline17
Woltering
Web of Science | Medline18
Jaffe BM. Hormones of the gastrointestinal tract. In: DeGroot LJ, Cahill GF Jr, Odell WD, et al., eds. Endocrinology. Vol. 3. New York: Grune & Stratton, 1979:1669–98.
19
Cataland
CrossRef | Web of Science | Medline20
Dupre
CrossRef | Web of Science | Medline21
Weitzman
CrossRef | Web of Science | Medline22
de Lacerda
CrossRef | Web of Science | Medline23
Vagnucci
CrossRef | Web of Science | Medline24
Brandenburger
Medline25
Quigley
CrossRef | Web of Science | Medline26
Follenius
CrossRef | Web of Science | Medline27
Ishizuka
CrossRef | Web of Science | Medline28
Larochelle
CrossRef | Web of Science | Medline29
Al-Damluji
CrossRef | Web of Science | Medline30
Knigge
CrossRef | Web of Science | Medline31
Ambrosi
Medline
- Citing Articles (53)
Citing Articles
1
Yoshinari Obata, Yuya Yamada, Megu Yamaguchi Baden, Yoshiya Hosokawa, Kenji Saisho, Sachiko Tamba, Koji Yamamoto, Yuji Matsuzawa. (2011) Long-term Efficacy of Trilostane for Cushing's Syndrome due to Adrenocorticotropin-Independent Bilateral Macronodular Adrenocortical Hyperplasia. Internal Medicine 50:21, 2621-2625
CrossRef2
Livia M. Mermejo, Tânia L. Mazzuco, Solange Grunenwald, Maria Candida B. V. Fragoso, Isabelle Bourdeau, André Lacroix. (2011) ACTH-Independent Macronodular Adrenal Hyperplasia. Endocrinology and Metabolism 26:1, 1
CrossRef3
Xavier Bertagna, Laurence Guignat, Marie-Charles Raux-Demay, Brigitte Guilhaume, François Girard. 2011. Cushing's disease. , 533-617.
CrossRef4
Delphine Vezzosi, Jérôme Bertherat, Lionel Groussin. (2010) Pathogenesis of benign adrenocortical tumors. Best Practice & Research Clinical Endocrinology & Metabolism 24:6, 893-905
CrossRef5
S. Galac, V.J. Kars, S. Klarenbeek, K.J. Teerds, J.A. Mol, H.S. Kooistra. (2010) Expression of receptors for luteinizing hormone, gastric-inhibitory polypeptide, and vasopressin in normal adrenal glands and cortisol-secreting adrenocortical tumors in dogs. Domestic Animal Endocrinology 39:1, 63-75
CrossRef6
Rossella Libé, Lionel Groussin, Jérôme Bertherat, Xavier Bertagna. 2010. Genetics of Adrenocortical Tumors (ACT) and Hypersecretory Syndromes. , 173-179.
CrossRef7
André Lacroix. (2009) ACTH-independent macronodular adrenal hyperplasia. Best Practice & Research Clinical Endocrinology & Metabolism 23:2, 245-259
CrossRef8
Tânia L. MAZZUCO, Philippe CHAFFANJON, Monique MARTINIE, Nathalie STURM, Olivier CHABRE. (2009) Adrenal Cushing’s Syndrome Due to Bilateral Macronodular Adrenal Hyperplasia: Prediction of the Efficacy of β-blockade Therapy and Interest of Unilateral Adrenalectomy. Endocrine Journal 56:7, 867-877
CrossRef9
ALAN M. RICE, SCOTT A. RIVKEES. 2008. Receptor Transduction of Hormone Action. , 26-73.
CrossRef10
T.L. Mazzuco, O. Chabre, J.J. Feige, M. Thomas. (2007) Aberrant GPCR expression is a sufficient genetic event to trigger adrenocortical tumorigenesis. Molecular and Cellular Endocrinology 265-266, 23-28
CrossRef11
Jérôme Bertherat, Lionel Groussin, Xavier Bertagna. (2006) Mechanisms of Disease: adrenocortical tumors—molecular advances and clinical perspectives. Nature Clinical Practice Endocrinology & Metabolism 2:11, 632-641
CrossRef12
John Newell-Price, Xavier Bertagna, Ashley B Grossman, Lynnette K Nieman. (2006) Cushing's syndrome. The Lancet 367:9522, 1605-1617
CrossRef13
Sihoon Lee, Ranjoo Hwang, Junho Lee, Yumie Rhee, Dae Jung Kim, Ung-il Chung, Sung-Kil Lim. (2005) Ectopic expression of vasopressin V1b and V2 receptors in the adrenal glands of familial ACTH-independent macronodular adrenal hyperplasia. Clinical Endocrinology 63:6, 625-630
CrossRef14
Hau Liu, Lawrence Crapo. (2005) Update on the Diagnosis of Cushing Syndrome. The Endocrinologist 15:3, 165-179
CrossRef15
Abdullah Alarifi, Ali S. Alzahrani, Suzan Abdel Salam, Mohammed Ahmed, Imaduddin Kanaan. (2005) Repeated Remissions of Cushing's Disease Due to Recurrent Infarctions of an ACTH-Producing Pituitary Macroadenoma. Pituitary 8:2, 81-87
CrossRef16
Nicoletta Sonino, Marco Boscaro, Francesco Fallo. (2005) Pharmacologic Management of Cushing Syndrome. Treatments in Endocrinology 4:2, 87-94
CrossRef17
Stavroula Christopoulos, Isabelle Bourdeau, André Lacroix. (2004) Aberrant Expression of Hormone Receptors in Adrenal Cushing's Syndrome. Pituitary 7:4, 225-235
CrossRef18
André Lacroix, Valérie Baldacchino, Isabelle Bourdeau, Pavel Hamet, Johanne Tremblay. (2004) Cushing's syndrome variants secondary to aberrant hormone receptors. Trends in Endocrinology & Metabolism 15:8, 375-382
CrossRef19
Y. Reznik, H. Lefebvre, V. Rohmer, B. Charbonnel, A. Tabarin, P. Rodien, P. Lecomte, S. Bardet, C. Coffin, J. Mahoudeau. (2004) Aberrant adrenal sensitivity to multiple ligands in unilateral incidentaloma with subclinical autonomous cortisol hypersecretion: a prospective clinical study. Clinical Endocrinology 61:3, 311-319
CrossRef20
S.R. Antonini, N. N’Diaye, V. Baldacchino, P. Hamet, J. Tremblay, A. Lacroix. (2004) Analysis of the putative regulatory region of the gastric inhibitory polypeptide receptor gene in food-dependent Cushing’s syndrome. The Journal of Steroid Biochemistry and Molecular Biology 91:3, 171-177
CrossRef21
Ichiro Tatsuno, Daigaku Uchida, Tomoaki Tanaka, Hisashi Koide, Azusa Shigeta, Tomohiko Ichikawa, Hironobu Sasano, Yasushi Saito. (2004) Vasopressin responsiveness of subclinical Cushing's syndrome due to ACTH-independent macronodular adrenocortical hyperplasia. Clinical Endocrinology 60:2, 192-200
CrossRef22
Mitsuhiko UMAHARA, Shuichi OKADA, Kihachi OHSHIMA, Masatomo MORI. (2003) Glucose-Dependent Insulinotropic Polypeptide Induced Growth Hormone Secretion in Acromegaly. Endocrine Journal 50:5, 643-650
CrossRef23
ISABELLE BOURDEAU, CONSTANTINE A. STRATAKIS. (2002) Cyclic AMP-Dependent Signaling Aberrations in Macronodular Adrenal Disease. Annals of the New York Academy of Sciences 968:1, 240-255
CrossRef24
D. ROSENBERG, L. GROUSSIN, E. JULLIAN, K. PERLEMOINE, X. BERTAGNA, J. BERTHERAT. (2002) Role of the PKA-Regulated Transcription Factor CREB in Development and Tumorigenesis of Endocrine Tissues. Annals of the New York Academy of Sciences 968:1, 65-74
CrossRef25
Isabelle Bourdeau, André Lacroix. (2002) Aberrant hormone receptors in adrenal Cushing's syndrome. Current Opinion in Endocrinology & Diabetes 9:3, 230-236
CrossRef26
Catherine Beauregard, Gabriel Dickstein, Andr?? Lacroix. (2002) Classic and Recent Etiologies of Cushing??s Syndrome. Treatments in Endocrinology 1:2, 79-94
CrossRef27
HIROKAZU SHINOJIMA, HIDEHIRO KAKIZAKI, TOMOAKI USUKI, TORU HARABAYASHI, KANAME AMEDA, TOMOHIKO KOYANAGI. (2001) CLINICAL AND ENDOCRINOLOGICAL FEATURES OF ADRENOCORTICOTROPIC HORMONE- INDEPENDENT BILATERAL MACRONODULAR ADRENOCORTICAL HYPERPLASIA. The Journal of Urology1639-1642
CrossRef28
HIROKAZU SHINOJIMA, HIDEHIRO KAKIZAKI, TOMOAKI USUKI, TORU HARABAYASHI, KANAME AMEDA, TOMOHIKO KOYANAGI. (2001) CLINICAL AND ENDOCRINOLOGICAL FEATURES OF ADRENOCORTICOTROPIC HORMONE- INDEPENDENT BILATERAL MACRONODULAR ADRENOCORTICAL HYPERPLASIA. The Journal of Urology 166:5, 1639-1642
CrossRef29
V. Hana, M. Dokoupilova, J. Marek, R. Plavka. (2001) Recurrent ACTH-independent Cushing's syndrome in multiple pregnancies and its treatment with metyrapone. Clinical Endocrinology 54:2, 277-281
CrossRef30
Q Zhong, R.J Bollag, D.T Dransfield, J Gasalla-Herraiz, K.-H Ding, L Min, C.M Isales. (2000) Glucose-dependent insulinotropic peptide signaling pathways in endothelial cells. Peptides 21:9, 1427-1432
CrossRef31
F. Beuschlein, M. Borgemeister, J. Schirra, B. Goke, M. Fassnacht, W. Arlt, B. Allolio, M. Reincke. (2000) Oral glucose tolerance testing but not intravenous glucose administration uncovers hyper-responsiveness of hypothalamo-pituitary-adrenal axis in patients with adrenal incidentalomas. Clinical Endocrinology 52:5, 617-623
CrossRef32
Christine Gicquel, Jerome Bertherat, Yves Le Bouc, Xavier Bertagna. (2000) PATHOGENESIS OF ADRENOCORTICAL INCIDENTALOMAS AND GENETIC SYNDROMES ASSOCIATED WITH ADRENOCORTICAL NEOPLASMS. Endocrinology & Metabolism Clinics of North America 29:1, 1-13
CrossRef33
Ronald J. M. Croughs, Pierre M. J. Zelissen, Theo J. M. V. van Vroonhoven, Leo J. Hofland, Nina N'diaye, Andre Lacroix, Wouter W. de Herder. (2000) GIP-dependent adrenal Cushing's syndrome with incomplete suppression of ACTH. Clinical Endocrinology 52:2, 235-240
CrossRef34
Gastone G Nussdorfer, Meltem Bahçelioglu, Giuliano Neri, Ludwik K Malendowicz. (2000) Secretin, glucagon, gastric inhibitory polypeptide, parathyroid hormone, and related peptides in the regulation of the hypothalamus– pituitary–adrenal axis. Peptides 21:2, 309-324
CrossRef35
Atkinson. (2000) New causes of Cushing's syndrome: abnormal adrenal regulation of cortisol production. Clinical Endocrinology 52:2, 137-137
CrossRef36
Rupert G.C. Yip, M.Michael Wolfe. (1999) GIF biology and fat metabolism. Life Sciences 66:2, 91-103
CrossRef37
Lacroix, André, Hamet, Pavel, Boutin, Jean-Marie, . (1999) Leuprolide Acetate Therapy in Luteinizing Hormone–Dependent Cushing's Syndrome. New England Journal of Medicine 341:21, 1577-1581
Full Text38
Giuseppina Mazzocchi, Piera Rebuffat, Virgilio Meneghelli, Ludwik K Malendowicz, Cinzia Tortorella, Giuseppe Gottardo, Gastone G Nussdorfer. (1999) Gastric inhibitory polypeptide stimulates glucocorticoid secretion in rats, acting through specific receptors coupled with the adenylate cyclase-dependent signaling pathway. Peptides 20:5, 589-594
CrossRef39
Michael O Boylan, Lisa I Jepeal, M.Michael Wolfe. (1999) Structure of the rat glucose-dependent insulinotropic polypeptide receptor gene. Peptides 20:2, 219-228
CrossRef40
Daidoh, Morita, Hanafusa, Mune, Murase, Sato, Shibata, Suwa, Ishizuka, Yasuda. (1998) In vivo and in vitro effects of AVP and V1a receptor antagonist on Cushing's syndrome due to ACTH-independent bilateral macronodular adrenocortical hyperplasia. Clinical Endocrinology 49:3, 403-409
CrossRef41
Willenberg, Holger S., Stratakis, Constantine A., Marx, ChristianEhrhart-Bornstein, Monika, Chrousos, George P., Bornstein, Stefan R., . (1998) Aberrant Interleukin-1 Receptors in a Cortisol-Secreting Adrenal Adenoma Causing Cushing's Syndrome. New England Journal of Medicine 339:1, 27-31
Full Text42
A. Haidan, U. Hilbers, S.R. Bornstein, M. Ehrhart–Bornstein. (1998) Human adrenocortical NCI-H295 cells express VIP receptors. steroidogenic effect of vasoactive intestinal peptide (VIP). Peptides 19:9, 1511-1517
CrossRef43
Lacroix, André, Tremblay, Johanne, Rousseau, Guy, Bouvier, Michel, Hamet, Pavel, . (1997) Propranolol Therapy for Ectopic β-Adrenergic Receptors in Adrenal Cushing's Syndrome. New England Journal of Medicine 337:20, 1429-1434
Full Text44
W.W. de Herder, S.W.J. Lamberts. (1996) Is there a role for somatostatin and its analogs in Cushing's syndrome?. Metabolism 45, 83-85
CrossRef45
Aarno Hautanen, Herman Adlercreutz. (1996) Pituitary-adrenocortical function in abdominal obesity of males: Evidence for decreased 21-hydroxylase activity. The Journal of Steroid Biochemistry and Molecular Biology 58:1, 123-133
CrossRef46
Nigel D. C. Sturrock, Linda Morgan, William J. Jeffcoate. (1995) Autonomous nodular hyperplasia of the adrenal cortex: tertiary hypercortisolism?. Clinical Endocrinology 43:6, 753-758
CrossRef47
Orth, David N., . (1995) Cushing's Syndrome. New England Journal of Medicine 332:12, 791-803
Full Text48
P. J. Jenkins, S. L. Chew, D. G. Lowe, R. H. Reznek, J. A. H. Wass. (1994) Adrenocorticotrophin-independent unilateral macronodular adrenal hyperplasia occurring with myelolipoma: an unusual cause of Cushing's syndrome. Clinical Endocrinology 41:6, 827-830
CrossRef49
André Lacroix, Edouard Bolté, Johanne Tremblay, Pavel Hamet. (1993) Gastrointestinal peptides and neoplasia ectopic gastric inhibitory polypeptide (GIP) receptors in adrenal glands causing food-dependent Cushing's syndrome. Trends in Endocrinology & Metabolism 4:10, 307
CrossRef50
Mark L. Silen, Jerry D. Gardner. (1993) Response. Trends in Endocrinology & Metabolism 4:10, 307-308
CrossRef51
C. F. Close, M. C. Mann, J. F. Watts, K. G. Taylor. (1993) ACTH-independent Cushing's syndrome in pregnancy with spontaneous resolution after delivery: control of the hypercortisolism with metyrapone.. Clinical Endocrinology 39:3, 375-379
CrossRef52
Bertagna, Xavier, . (1992) New Causes of Cushing's Syndrome. New England Journal of Medicine 327:14, 1024-1025
Full Text53
Lacroix, André, Bolté, Edouard, Tremblay, Johanne, Dupré, John, Poitras, Pierre, Fournier, Hélène, Garon, Jean, Garrel, Dominique, Bayard, Francis, Taillefer, Raymond, Flanagan, Richard J., Hamet, Pavel, . (1992) Gastric Inhibitory Polypeptide–Dependent Cortisol Hypersecretion — A New Cause of Cushing's Syndrome. New England Journal of Medicine 327:14, 974-980
Full Text
