Original Article
Gastric Inhibitory Polypeptide–Dependent Cortisol Hypersecretion — A New Cause of Cushing's Syndrome
N Engl J Med 1992; 327:974-980October 1, 1992
- Abstract
- Abstract
Background.
Corticotropin-independent nodular adrenal hyperplasia is a rare cause of Cushing's syndrome, and the factors responsible for the adrenal hyperplasia are not known.
Methods.
We studied a 48-year-old woman with Cushing's syndrome, nodular adrenal hyperplasia, and undetectable plasma corticotropin concentrations in whom food stimulated cortisol secretion.
Results.
Cortisol secretion had an inverse diurnal rhythm in this patient, with low-to-normal fasting plasma cortisol concentrations and elevated postprandial cortisol concentrations that could not be suppressed with dexamethasone. The cortisol concentrations increased in response to oral glucose (4-fold increase) and a lipid-rich meal (4.8-fold increase) or a protein-rich meal (2.6-fold increase), but not intravenous glucose. The infusion of somatostatin blunted the plasma cortisol response to oral glucose. Intravenous infusion of gastric inhibitory polypeptide (GIP) for one hour increased the plasma cortisol concentration in the patient but not in four normal subjects. Fasting plasma GIP concentrations in the patient were similar to those in the normal subjects; feeding the patient test meals induced increases in plasma GIP concentrations that paralleled those in plasma cortisol concentrations. Cell suspensions of adrenal tissue from the patient produced more cortisol when stimulated by GIP than when stimulated by corticotropin. In contrast, adrenal cells from normal adults and fetuses or patients with cortisol-producing or aldosterone-producing adenomas responded to corticotropin but not to GIP.
Conclusions.
Nodular adrenal hyperplasia and Cushing's syndrome may be food-dependent as a result of abnormal responsiveness of adrenal cells to physiologic secretion of GIP. "Illicit" (ectopic) expression of GIP receptors on adrenal cells presumably underlies this disorder. (N Engl J Med 1992;327:974–80.)
Media in This Article
Figure 1
Plasma Cortisol Concentrations in a Patient with Food-Induced Cushing's Syndrome during Fasting and after Eating.Figure 2
Plasma Cortisol and GIP Responses to Oral Glucose Administration (○), Intravenous Glucose Administration (●), and Protein-Rich (□) and Lipid-Rich (
) Meals in a Patient with Food-Induced Cushing's Syndrome.Article Activity
- Article
CUSHING'S SYNDROME is usually caused by excess corticotropin secretion, in which both adrenal glands are diffusely enlarged, or by an adrenal tumor. The tumor is usually autonomous and corticotropin-independent, but we have described a patient in whom cortisol secretion was food-dependent.1 Other patients with Cushing's syndrome have nodular adrenal hyperplasia, which may be due to long-standing corticotropin hypersecretion by a corticotroph adenoma2 3 4 5 6 7 8 9 10 or which may be corticotropin-independent, as demonstrated by the absence of corticotroph adenomas at autopsy11 and undetectable corticotropin concentrations in plasma from the petrosal sinus12 , 13 or peripheral blood obtained after metyrapone administration, insulin-induced hypoglycemia, or corticotropin-releasing hormone infusion.14 15 16 17 Some of the patients with primary pigmented nodular adrenocortical disease have adrenal-stimulating immunoglobulins,18 but in most the cause of the nodular adrenal hyperplasia is not known.
We describe a woman with Cushing's syndrome and corticotropin-independent nodular adrenal hyperplasia in whom cortisol secretion was food-dependent; further studies demonstrated that the excess cortisol secretion was due to abnormal responsiveness of the patient's adrenal glands to endogenously secreted gastric inhibitory polypeptide (GIP).
Case Report
A 48-year-old woman was evaluated because of a two-year history of a weight gain of 40 lb (18 kg), easy bruising, high blood pressure, and emotional lability. Physical examination revealed central obesity, mild facial hirsutism, proximal muscle weakness, and paranoid behavior. There was no family history of Cushing's syndrome. Initial studies of pituitary—adrenal function showed that plasma cortisol concentrations were low to normal in the morning and elevated in the evening and that plasma corticotropin concentrations were undetectable both basally and after stimulation with corticotropin-releasing hormone (Table 1Table 1
Plasma Cortisol and Corticotropin Concentrations and Urinary Cortisol Excretion during Studies of Pituitary—Adrenal Function in a Patient with Food-Induced Cushing's Syndrome.*). The patient's urinary cortisol excretion was normal or slightly elevated and was not suppressed by 2 or 8 mg of dexamethasone (each dose was given orally for two days in divided doses). Abdominal computerized tomography revealed multinodular enlargement of both adrenal glands (overall dimensions: right gland, 5 by 3.5 cm; left gland, 4.5 by 3.7 cm). Scintigraphy with 131I-labeled 6-beta-iodomethyl-19-norcholesterol showed symmetrical bilateral uptake of the tracer by the glands. Findings on computerized tomography and magnetic resonance imaging of the pituitary gland were normal.Plasma corticotropin could not be detected in blood samples obtained from each petrosal sinus before and after intravenous injection of ovine corticotropin-releasing hormone (1 μg per kilogram of body weight) (Ferring, Willowdale, Ont.). The patient then underwent bilateral adrenalectomy. Both adrenal glands contained multiple nodules 1.4 to 2.8 cm in diameter; the right gland weighed 35 g and measured 7 by 4 by 3 cm, and the left weighed 20 g and measured 6.5 by 3.8 by 2.3 cm. Microscopical examination showed nodules composed mainly of acidophilic cuboidal cells; the internodular spaces contained cells with clear cytoplasm mixed with darker cells, forming smaller microscopic nodules. The areas that contained no nodules were hyperplastic, and no atrophic adrenocortical cells were seen. Postoperatively, the patient was treated with replacement doses of cortisone and fludrocortisone, and the signs of Cushing's syndrome progressively disappeared.
Methods
Clinical Studies
Pituitary—adrenal function was studied in the patient, four normal subjects (one woman and three men, 35 to 60 years old), and five patients with Cushing's disease (pituitary-dependent) (four women and one man, 23 to 54 years old). Most of the studies were performed after an overnight fast. The study protocols were approved by the local institutional review committee, and informed consent was obtained from all subjects.
Scintigraphy with [123I]GIP
Human GIP (Bachem Fine Chemicals, Torrance, Calif.) was labeled with sodium iodide I-123 by the chloramine-T method. Monoiodotyrosyl [10Tyr]GIP, isolated from the reaction mixture by high-performance liquid chromatography, was diluted in 1 ml of physiologic saline containing 10 mg of human albumin and then sterilized by membrane filtration. Two millicuries of the 123I-labeled GIP (specific activity, 11,000 Ci per millimole) was administered intravenously after an 8-hour fast, and adrenal scintiscans were obtained continuously during the first 60 minutes and after 2 and 15 hours.
In Vitro Studies with Dispersed Adrenal Cells
Portions of both of the patient's adrenal glands were digested with collagenase (3 mg per milliliter; type 1A, Sigma, St. Louis), elastase (0.125 mg per milliliter; type IIA, Sigma), soybean trypsin inhibitor (0.375 mg per milliliter; type 1S, Sigma), and bovine serum albumin (3 mg per milliliter) in Dulbecco's modified Eagle's medium (Gibco, Burlington, Ont.) at 37°C for 30 minutes. The dispersed cells were incubated in medium containing 10 percent fetal-calf serum at a concentration of 1 × 106 cells per milliliter; 1-ml aliquots were incubated with various peptides in duplicate for two hours at 37°C in an atmosphere of 5 percent carbon dioxide and 95 percent air. After incubation, the aliquots of the medium were collected and stored at -20°C for measurement of cortisol concentrations by radioimmunoassay.
Cells from adrenal adenomas removed from one patient with Cushing's syndrome and one patient with hyperaldosteronism were processed and incubated in the same way. Adrenal tissue was also excised from the fetuses of four women who had undergone voluntary termination of their pregnancies at 12 to 16 weeks of gestation, after the women had given informed consent. The glands were pooled, after which cell suspensions were prepared from them and incubated as described above.
Assays
Plasma, urinary, and suspension concentrations of cortisol were measured by radioimmunoassay with commercial kits (Kallestad Diagnostics, Chaska, Minn.), as was plasma insulin (Immunocorp, Montreal). Plasma corticotropin was measured by immunoradiometric assay with commercial kits (Nichols Diagnostics, San Juan Capistrano, Calif; assay sensitivity, 1.0 ng per liter). Plasma GIP was measured by radioimmunoassay19 using rabbit anti-GIP serum R65 (Novo Research Institute, Bagsvaerd, Denmark). All plasma GIP values were determined in duplicate in one assay with a coefficient of variation of 5.4 percent. The intraassay coefficient of variation for the other assays ranged from 2.9 to 4.3 percent, and the interassay coefficient of variation from 6.8 to 11.3 percent.
Statistical Analysis
Changes in the plasma concentrations of cortisol, glucose, and insulin in the normal subjects were examined by contrast analysis with Bonferroni's t-test, after repeated measures of analysis of variance.
Results
Postprandial Cortisol Secretion
Since the patient's plasma cortisol concentrations were higher in the evening than in the morning (Table 1), the relation between meals and plasma cortisol concentrations was studied while the patient received 8 mg of dexamethasone daily for two days, after having received 2 mg of dexamethasone daily for two days. During the first day of the larger dose (Fig. 1Figure 1
Plasma Cortisol Concentrations in a Patient with Food-Induced Cushing's Syndrome during Fasting and after Eating.A), her fasting plasma cortisol concentration was 11.5 μg per deciliter (317 nmol per liter). The concentration increased substantially after breakfast and remained high until late afternoon. The patient then fasted until 11 p.m. on the second day; at that time her plasma cortisol concentration was approximately 7 μg per deciliter (193 nmol per liter) (Fig. 1B). It rose considerably after each of three nighttime meals, despite continued dexamethasone administration. Similarly, two days later the cortisol concentration remained normal when the patient was fasting and changed little during a four-hour intravenous infusion of dexamethasone20; however, it increased after meals at 3 p.m. and 5 p.m. (Fig. 1C). In contrast, the plasma cortisol concentrations of the four normal subjects decreased while they received similar infusions of dexamethasone (Fig. 1C, shaded area), and remained low for more than 24 hours. The concentrations in the four patients with pituitary-dependent Cushing's disease were partly and transiently suppressed by dexamethasone, but did not increase after meals.The influence of the composition of meals on cortisol secretion was studied in the patient (Fig. 2Figure 2
Plasma Cortisol and GIP Responses to Oral Glucose Administration (○), Intravenous Glucose Administration (●), and Protein-Rich (□) and Lipid-Rich () Meals in a Patient with Food-Induced Cushing's Syndrome.). After she received 75 g of glucose by mouth her plasma cortisol concentration increased fourfold within 60 minutes. A lipid-rich meal (125 ml of 35 percent cream) evoked a 4.8-fold increase in the plasma cortisol concentration within 60 minutes, and a protein-rich meal (150 g of lean chicken meat) evoked a 2.6-fold increase within 180 minutes. The plasma corticotropin concentration was undetectable during all the postprandial increases in plasma cortisol. The cortisol concentration did not increase after the intravenous administration of 25 g of glucose. When the patient was given 75 g of glucose orally while she was receiving somatostatin intravenously (500 μg given over a 60-minute period), the increase in plasma cortisol was reduced to 1.9 times the base-line level; when she received 64 g of glucose orally at the end of the somatostatin infusion, the increase was 2.2 times the value at the end of the infusion.The patient's plasma GIP concentrations increased substantially after the lipid-rich meal and oral glucose administration, to a lesser degree after the protein-rich meal, and not at all after intravenous glucose administration (Fig. 2); the somatostatin infusion blunted the plasma GIP response to oral glucose. The changes in plasma GIP concentrations closely paralleled those in plasma cortisol concentrations. When three sisters of the patient were given 75 g of glucose orally, none of them had an increase in their plasma cortisol.
GIP-Dependent Cortisol Secretion in Vivo
The responses of the plasma concentrations of cortisol, insulin, and GIP to intravenous infusions of glucose with or without GIP in the patient and the four normal subjects are shown in Figure 3Figure 3
Plasma Cortisol, Insulin, and GIP Concentrations during Intravenous Glucose Infusion with and without an Intravenous GIP Infusion in a Patient with Food-Induced Cushing's Syndrome (Solid Square) and Four Normal Subjects (Open Symbols).. The patient's plasma cortisol concentration did not change significantly during the glucose infusion, nor did the concentrations of the normal subjects (mean [±SD] at 0 minutes, 6.0±1.8 μg per deciliter [166±50 nmol per liter]; at 60 minutes, 8.8±1.3 μg per deciliter [243±36 nmol per liter]; P>0.05). The addition of GIP (0.6 μg per kilogram per hour) induced a rapid increase in the patient's cortisol concentration. The peak value was six times higher than the base-line value and was reached at 45 minutes. Plasma corticotropin concentrations were undetectable at all times during these studies. The plasma cortisol concentrations of the normal subjects did not increase significantly during the GIP infusion (10.0±3.8 μg per deciliter [276±105 nmol per liter] at 90 minutes). Similarly, the cortisol concentration of one patient with Cushing's disease did not change during GIP infusion (data not shown). Plasma insulin concentrations increased 2.5-fold in the patient and 3.0-fold in the normal subjects during the GIP infusion. Plasma GIP concentrations increased to the same extent in the patient and the normal subjects during the GIP infusions (Fig. 3).The patient's plasma cortisol concentrations increased 5.1-fold in response to corticotropin (250 μg given intravenously), but neither the corticotropin nor the cortisol concentration increased in response to intravenous corticotropin-releasing hormone (1 μg per kilogram), glucagon (1 mg), insulin (0.2 U per kilogram), or pentagastrin (0.5 μg per kilogram) or to intramuscular vasopressin (10 U) (data not shown).
Adrenal Uptake of [123I]GIP
Scintiscans obtained during the first 60 minutes after the intravenous administration of [123I]GIP showed a distribution phase with imaging of the kidneys, the stomach, and the liver. Those obtained after 15 hours revealed uptake by both adrenal glands, with residual uptake in the intestine.
GIP-Dependent Cortisol Secretion in Adrenal Cells
GIP induced a dose-dependent increase in cortisol secretion in adrenal cells from the patient. The minimal effective dose was 1 nmol per liter (Table 2Table 2
Cortisol Production by Adrenal-Cell Suspensions after Incubation with Various Peptides.*), and the response to GIP was greater than that to corticotropin. In contrast, corticotropin but not GIP stimulated cortisol secretion in the adrenal cells from the fetuses. The dispersed cells from adrenal adenomas secreting either cortisol or aldosterone secreted cortisol in response to corticotropin but not in response to GIP (Table 2), as did the normal adrenal cells from the patient with the aldosteronoma.Discussion
The most striking features of the abnormal cortisol secretion in this patient with corticotropin-independent Cushing's syndrome and nodular adrenal hyperplasia were the inverse circadian rhythm of cortisol secretion and the food-dependent cortisol secretion. The identification of the modulator of cortisol secretion was facilitated by measuring cortisol secretion in response to various test meals and inhibition of glucose-stimulated cortisol secretion by somatostatin. These studies strongly suggested that the mediator was one of the gastrointestinal hormones, only a few of which are secreted in response to oral glucose; among them, GIP secretion increases the most.21 GIP is also released in response to the ingestion of lipids and proteins, but not in response to intravenous glucose21 22 23 24 25 26; the secretion of GIP is inhibited by somatostatin.27 , 28 Although basal plasma GIP concentrations were similar in the patient in this study and in normal subjects in this and other investigations,23 24 25 26 27 28 plasma GIP concentrations measured after a meal showed a striking correlation with cortisol concentrations in our patient but not in normal subjects in a previous study.29 The importance of GIP as an in vivo modulator of cortisol production in this patient was demonstrated by the similarity of her plasma cortisol responses to GIP infusion and to meals. The dose of GIP infused produced plasma GIP concentrations similar to those recorded after meals30 in both the normal subjects and the patient, but only in the patient did the GIP infusion stimulate cortisol secretion. The stimulatory effect of GIP on cortisol secretion in the patient was specific; she had no adrenal response to any other stimuli tested besides corticotropin, to which most patients with either corticotropin-dependent or corticotropin-independent nodular adrenal hyperplasia respond.4 , 13 , 17 Of 15 patients with Cushing's disease, 6 with cortisol-secreting adrenal adenomas, and 4 with ectopic corticotropin secretion whom we have studied during dexamethasone testing (unpublished results, exemplified in the four patients with Cushing's disease shown in Figure 1C), none have had increases in plasma cortisol concentrations after a meal. In addition, GIP infusion did not alter the plasma cortisol concentration in one patient with Cushing's disease.
The suggestion that GIP exerted a direct effect on cortisol secretion in our patient is supported by two lines of evidence. [123I]GIP uptake was detected in the patient's adrenal glands in vivo, and dispersed adrenal cells from the patient responded to GIP but not to any other gastrointestinal hormone or any neuropeptide.
The stimulatory action of GIP in the patient implies the existence of specific membrane receptors on adrenal cells, as demonstrated in insulinomas and gastric cancers.31 32 33 The receptor is a glycoprotein monomer of 59 kd that is functionally coupled to adenylate cyclase.34 Since GIP had no stimulatory effect on adrenal tissue from normal adults or fetuses or from two adrenal adenomas, the abnormal responsiveness of the patient's adrenal glands to physiologic levels of GIP is probably due to the ectopic, or "illicit," expression of GIP receptors in her adrenal glands.
Ectopic expression of membrane receptors for various hormones has been observed in adrenal tumors of rats and patients35 , 36 and in other endocrine tumors.37 In the patient with a food-dependent cortisol-producing adrenal adenoma whom we described previously,1 vasopressin and corticotropin but not several other hormones stimulated the production of adenylate cyclase in the tumor cells. In the corticotropin-independent hyperadrenocorticism associated with the McCune–Albright syndrome, activating mutations of the Gsα gene in various tissues, including nodular adrenal glands, result in the activation of steroidogenesis without the requirement of a ligand,38 which is distinct from GIP-dependent activation of steroidogenesis. Acquired somatic mutations inducing the expression of an ectopic receptor may generate tumors of clonal origin. However, the presence of bilateral nodular hyperplasia suggests that the abnormality in our patient affected all adrenocortical cells and that the initial mutation was present during fetal development. It is unclear why long-standing stimulation of the adrenal glands by corticotropin or GIP leads to nodule formation in addition to diffuse hyperplasia.10 Genetic mutations, present on chromosome 10 in type 2 multiple endocrine neoplasia39 , 40 or on chromosome 11 in type 1 multiple endocrine neoplasia,41 may require several decades before they lead to thyroid C-cell, adrenal medullary, or parathyroid-cell hyperplasia. The recent report of familial cases of nodular adrenal hyperplasia42 supports the notion that the disease may be transmitted genetically and not be expressed clinically before adulthood, although food-dependent hypercortisolism was not studied in those patients.
In conclusion, we suggest that in the patient with nodular adrenal hyperplasia described here, Cushing's syndrome resulted from the ectopic expression of GIP receptors in both adrenal glands (Fig. 4Figure 4
Outline of the Function of the Hypothalamic—Pituitary—Adrenal Axis in Food-Induced Cushing's Syndrome.), as in the patient described by Reznik et al. in the following article.43 Similarly, the adrenal adenoma in the previously reported patient with food-dependent cortisol secretion may have resulted from the ectopic expression of receptors for GIP or another gastrointestinal hormone acquired as a somatic mutation in one adrenal gland.1 Plasma cortisol concentrations should be measured in patients with corticotropin-independent Cushing's syndrome after they have eaten, to identify the frequency of this disorder.We are indebted to Lawrence E. Gilchrist, M.D., for referring the patient; to Robert Benoit, M.D., and Jean-Louis Chiasson, M.D., for providing several peptides and helpful suggestions; to Hélène Latendresse, M.D., and Louis Lamarre, M.D., for their pathological studies; to Cynthia Goodyer, Ph.D., and Yves Lefèbvre, M.D., for providing fetal adrenal tissues; to Marie-Thérèse Caron, R.N., and the nursing staff of the Endocrine Unit for performing the endocrine tests; to Carole Long, B.Sc, and the Endocrine Laboratory staff for technical assistance; and to Ms. Sylvie de Grandpré for assistance in the preparation of the manuscript.
Source Information
From the Division of Endocrinology, Metabolism and Nutrition (A.L., E.B., J.T., H.F., J.G., D.G., P.H.), the Laboratory of Molecular Pathophysiology, Research Center (F.B., J.T., P.H.), and the Department of Nuclear Medicine (R.T.), Hôtel-Dieu de Montréal, Montreal; the Division of Gastroenterology, Hôpital Saint-Luc, Montreal (P.P.); Merck Frosst Canada Inc., Montreal (R.J.F.); the Laboratory of Nutrition and Cancer, Clinical Research Institute of Montreal, Montreal (A.L.); and the Departments of Medicine and Radiology, Université de Montréal, Montreal, and University Hospital, London, Ont. (J.D.). Address reprint requests to Dr. Lacroix at the Division of Endocrinology, Metabolism and Nutrition, Hôtel-Dieu de Montréal, 3840 Saint-Urbain St., Montreal QC H2W 1T8, Canada.
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