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The Journal of Clinical Endocrinology & Metabolism Vol. 85, No. 10 3531-3536
Copyright © 2000 by The Endocrine Society

Special Articles

Are Ectopic or Abnormal Membrane Hormone Receptors Frequently Present in Adrenal Cushing’s Syndrome?1

Hortensia Mircescu, Jose Jilwan, Nina N'Diaye, Isabelle Bourdeau, Johanne Tremblay, Pavel Hamet and André Lacroix

Division of Endocrinology, Department of Medicine, Research Center, Hôtel-Dieu du Centre Hospitalier de l’Université de Montréal, Montréal, Canada H2W 1T8

Address correspondence and requests for reprints to: André Lacroix, M.D., Division of Endocrinology, Research Center, Hôtel-Dieu du Centre Hospitalier de l’Université de Montréal, 3850 Saint-Urbain Street, Montréal, Québec, Canada H2W 1T8. E-mail: andre.lacroix{at}umontreal.ca


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Twenty consecutive patients with adrenal Cushing’s syndrome were studied with an in vivo protocol to determine the prevalence and diversity of the presence of ectopic or abnormal hormone receptors in their adrenal tissues. All six patients with bilateral ACTH-independent macronodular adrenal hyperplasia were found to have one or two abnormal adrenal receptors, including those for gastric inhibitory polypeptide, vasopressin (V1-vasopressin), ß-adrenergic agonists, LH/human CG, or serotonin 5-HT4. The presence of abnormal hormone receptors was found to be less frequently present in unilateral adenomas or carcinomas (3 of 14). The identification of abnormal adrenal hormone receptors can allow new pharmacological therapies of hypercortisolism. We suggest that the clinical screening for the presence of abnormal hormone receptors should be conducted in patients with adrenal Cushing’s syndrome and, more particularly, in those with ACTH-independent macronodular adrenal hyperplasia, in the hope of offering medical therapy as an alternative to bilateral adrenalectomy.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
PRIMARY ADRENAL etiologies represent 15–20% of endogenous Cushing’s syndromes, and their molecular pathophysiologies are still poorly understood (1, 2, 3). Unilateral benign or malignant adrenocortical tumors are the most frequent, whereas bilateral adrenal hyperplasias are responsible for only 10% of adrenal Cushing’s syndrome. Approximately half the cases of bilateral primary pigmented (micro) nodular adrenal disease are part of Carney’s complex and are linked to unknown genes on chromosome 2 or to mutations of protein kinase A type I-{alpha} regulatory subunit on chromosome 17 (4). In McCune-Albright’s syndrome, an activating mutation of {alpha}- subunit of stimulatory protein G leads to constitutive steroidogenesis in the affected adrenal nodules (5).

Until recently, the regulatory mechanisms of cortisol synthesis in ACTH-independent Cushing’s syndrome were not well understood. Several groups have now shown that the previously believed autonomous cortisol-secreting adrenal tumors may actually be under the control of ectopic (also termed aberrant, illicit) or abnormal hormone receptors. The initial in vitro studies of Ney et al. (6, 7) suggested the presence of ectopic receptors for epinephrine, norepinephrine, TSH, LH, and FSH in some adrenocortical tumors. Subsequent in vitro studies of human adrenocortical benign and malignant tumors have supported a functional relationship between steroidogenesis and various hormone receptors, mostly members of the G-protein-linked superfamily (8, 9, 10, 11, 12, 13, 14). However, it remained unclear whether these ectopic receptors were functional and responsible for Cushing’s or other clinical syndromes. This hypothesis found an in vivo clinical significance following the description of three cases of food- or gastric inhibitory polypeptide (GIP)-dependent Cushing’s syndrome in patients with either unilateral adenomas or bilateral macronodular adrenal hyperplasia (15, 16, 17); this new etiology resulted from the ectopic expression of nonmutated GIP receptor in the abnormal adrenal tissues (18, 19, 20, 21, 22, 23). This finding raised the hypothesis that a diversity of other hormone receptors could be expressed and regulate cortisol secretion abnormally in other cases of adrenal Cushing’s syndrome. This has now been supported by several reports of increased ACTH-independent cortisol secretion after stimulation by vasopressin in patients with unilateral adenomas, carcinomas, or bilateral macronodular adrenal hyperplasia (24, 25, 26, 27, 28); the V1-vasopressin receptor probably mediates this effect. In two other patients with bilateral macronodular adrenal hyperplasia and Cushing’s syndrome, cortisol secretion was found to be regulated by the ectopic adrenocortical expression of ß-adrenergic receptor (ß-AR) in one case (29) and a combination of LH/human (h)CG and 5-HT4 receptors in another case (30).

Despite these case reports indicating the abnormal presence or function of hormone receptors in adrenal Cushing’s syndrome, the precise prevalence and diversity of this pathophysiology remains unknown. It is important to determine whether this pathophysiology is frequently implicated in adrenal Cushing’s syndrome, because it could lead to major changes in the investigation and therapy of this disease. In this article, we wish to report the experience of our center, where 20 consecutive patients with adrenal Cushing’s syndrome were investigated in vivo with a protocol designed to identify the presence of abnormal adrenocortical hormone receptors.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Patients and investigation protocol

After the study of the first patient with GIP-dependent Cushing’s syndrome (16), 19 consecutive patients with adrenal Cushing’s syndrome have been investigated between March 1993 and December 1999. The diagnosis was confirmed after demonstration of elevated daily urinary free cortisol, nonsuppressibility of plasma cortisol during iv dexamethasone testing (16, 26, 29), and suppressed plasma ACTH (both basally and after administration of 1 µg/kg of ovine CRH). Abdominal computed tomography scans showed unilateral or bilateral lesions in all patients. The characteristics of the study population are presented in Table 1Go. There were 6 patients with bilateral ACTH-independent macronodular adrenal hyperplasia (AIMAH), 13 patients with unilateral cortisol-secreting adenomas, and 1 patient with adrenocortical carcinoma. Pathological confirmation could not be obtained for patients 6 and 8, because they have been treated medically. Detailed case reports have been published for patients 1 (16), 2 (26), 3 (29), 5 (23), and 6 (30).


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  		Table 1. Characteristics of the patients with adrenal Cushing’s syndrome

 
Patient 4, a 50-yr-old woman, was referred for AIMAH and Cushing’s syndrome manifested by a 40-kg weight gain with central distribution, high blood pressure, hirsutism, emotional lability, and insomnia over the last 5 yr. Investigations at the referring center yielded urinary cortisol levels between 395–607 nmol/day (normal range, 28–221 nmol/day), nonsuppressible by dexamethasone administration, plasma ACTH levels less than 1 pmol/L (normal, 2–12 pmol/L), basally and after CRH administration. An iodocholesterol scan showed bilateral adrenal uptake. Before our investigation, the patient was treated, during 1 yr, with 750-1000 mg daily of aminoglutethimide, resulting in clinical improvement and a 20-kg weight loss.

The investigation protocol has been described previously (31); it was conducted over a 3-day period, after discontinuing potential interfering medications at least 1 week before the studies. It was approved by the institutional review committee, and informed written consent was obtained from all patients. The strategy consists of inducing transient modulation of ligands for potentially abnormal adrenocortical receptors and monitoring the steroidogenic responses. On day 1, a supine-to-upright posture test evaluated the potential modulation by angiotensin-II, vasopressin, catecholamines, endothelin, or atrial natriuretic peptide. This was followed by a standard mixed meal, assessing the presence of abnormal adrenal receptors for gastrointestinal hormones. Subsequent iv injection of 250 µg ACTH 1–24 provided a reference for the adrenal steroidogenic response. On the second day, administration of 100 µg GnRH iv was used to evaluate for potential modulation of cortisol by FSH, LH, or GnRH. A bolus injection of 200 µg TRH iv assessed the adrenal presence of TSH, PRL, or TRH receptors. Possible steroidogenic responses to 1 mg glucagon iv, 10 IU arginine-vasopressin (AVP) im, and 10 mg cisapride, a serotonin 5HT4 receptor agonist, orally, were evaluated sequentially on the third day. To interpret the response to the above tests, we chose to express plasma cortisol concentrations, at the peak or nadir time point during the various tests, as percentages of the basal levels. A change in plasma cortisol less than 25% from baseline (100%) was arbitrarily defined as no response; a 25–49% change, as a partial response; and a change of 50% or greater, as a positive response. The test was repeated, if a partial or a positive cortisol response was observed, to ensure consistency of the response. If any of the screening tests yielded positive results, further evaluations were undertaken to identify the receptor involved, as described previously (23, 26, 29, 30, 31).


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Abnormal hormone receptors in Cushing’s syndrome secondary to bilateral AIMAH

In all six patients with AIMAH, the investigation protocol detected the presence of abnormal adrenal hormone receptors (Table 2Go). As expected, the administration of ACTH 1–24 resulted in a large increase of plasma cortisol in all patients with AIMAH (454 ± 248%, mean ± 1 SD). None of the patients with AIMAH had plasma cortisol increases after the administration of TRH or glucagon. In two patients with AIMAH (patients 1 and 5), plasma cortisol levels increased 398 and 236% after the mixed meal. They had no abnormal responses to the other stimulation tests, and GIP-dependent Cushing’s syndrome was confirmed in both, based on stimulation of cortisol secretion during in vivo infusion of GIP and demonstration of GIP receptor overexpression in adrenal hyperplasia tissues (16, 19, 23).


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  		Table 2. Plasma cortisol responses to the various screening tests and associated abnormal hormone receptor in patients with AIMAH and Cushing’s syndrome

 
In three patients, plasma cortisol increased after AVP administration and upright posture. In patient 2, in whom plasma cortisol increased 3.4-fold after AVP administration and 1.4- to 2.4-fold during three different posture tests, an increased adrenal responsiveness to vasopressin, mediated by a V1-vasopressin receptor, was documented by in vitro steroidogenic response, intracellular Ca++ flux, binding studies, and messenger RNA assays after RT-PCR amplification (26). A prolonged vasoconstrictive response to vasopressin, of arterioles isolated from a fat biopsy, was also found in this patient, who also suffered from postural hypotension.

In patient 3, plasma cortisol increased 177% after upright posture (165% and 157% in repeat tests) and only partially after AVP administration. Stimulation of cortisol secretion after insulin-induced hypoglycemia, isoproterenol infusion, and correction of hypercortisolism with propranolol suggested the presence of ectopic ß-adrenergic receptors in this patient’s adrenal tissues (29). Confirmation was obtained by in vitro binding studies and stimulation of adenylyl cyclase activity after incubation of the patient’s adrenal membranes with isoproterenol, whereas this was not found in normal adrenal tissue. The stimulation of cortisol secretion during upright posture could not be abolished by a V1-vasopressin receptor antagonist (SR 49059), and modulation of endogenous vasopressin levels by water load and hypertonic saline did not modify plasma cortisol levels (29); the V1-vasopressin receptor messenger RNA could not be detected in this patient’s adrenal tissues (unpublished). This suggests that the partial cortisol response to exogenous pharmacological levels of vasopressin was mediated by AVP-induced catecholamine release.

Interestingly, some patients had mixed abnormal responses related to the inappropriate adrenal expression of more than one receptor. Plasma cortisol levels in patient 4 were stimulated both by increases of catecholamines (upright posture, insulin-induced hypoglycemia, and isoproterenol) and of vasopressin (upright posture, pharmacological doses of AVP, and modulation of endogenous vasopressin with water load and hypertonic saline). Plasma cortisol levels increased from 374 to 925 nmol/L, 60 min after AVP administration, and from 355 to 599 nmol/L after 2-h of upright posture (Table 2Go). Administration of 2.5 µg sc of desmopressin, a preferential V2-vasopressin receptor agonist, did not modify the plasma cortisol levels, suggesting that the receptor involved is a V1- or V3-vasopressin receptor. Plasma cortisol levels declined from 337 to 257 nmol/L (24% decrease) during a 20-cc/kg water loading test (Fig. 1Go), whereas plasma vasopressin levels remained below the limit of detection (<0.5 pg/mL). The infusion of 3% hypertonic saline increased serum sodium from 138 to 150 mmol/L, plasma vasopressin from <0.5 to 0.74 pg/mL, and plasma cortisol from 257 to 442 nmol/L (172% increase). The role of catecholamines, suggested by the positive response to posture, was further assessed by insulin-induced hypoglycemia, which increased plasma cortisol from 363 to 989 nmol/L, whereas ACTH remained suppressed. Plasma cortisol also increased from 323 to 630 nmol/L during a 30-min infusion of isoproterenol and returned rapidly to baseline when the infusion was discontinued (Fig. 2Go). Pretreatment of the patient, with the angiotensin receptor type-1 antagonist losartan, administered at the dose of 100 mg, 12- and 2-h before upright posture, did not prevent the elevation of plasma cortisol from 427 to 646 nmol/L during a 2-h period of ambulation. There were no positive responses to the mixed meal, GnRH, TRH, glucagon, or cisapride. It was concluded that the cortisol secretion was mediated by the abnormal presence and function of ß-adrenergic and V1-vasopressin receptors, and medical therapy with the ß-blocker propranolol (Inderal, Wyeth-Ayerst Laboratories, Inc., Montreal, Québec, Canada) was proposed to the patient. Propranolol was progressively increased to 60 mg orally, four times daily, over a 3-week period, under supervision of her referring physician in Seattle, WA. Treatment was discontinued because of the appearance of fatigue and dyspnea on exertion. The patient elected to undergo surgical therapy before further monitoring of free urinary cortisol levels. Unfortunately, the adrenal tissues were not available for in vitro studies.



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  		Figure 1. Plasma cortisol and Na+ concentrations during an oral water load and an infusion of hypertonic saline, in patient 4 (with Cushing’s syndrome secondary to AIMAH). An oral water load of 20 cc/kg was administered between 0- and 45-min time points and was followed by an iv infusion of 3% sodium chloride between the 120- and 240-min time points. The patient was in supine posture during 60 min before and during the entire test.

 


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  		Figure 2. Plasma cortisol levels during an infusion of isoproterenol, in patient 4 (with Cushing’s syndrome secondary to AIMAH). The isoproterenol dose was 20 ng/kg·min during 30 min (shaded area). In a previous study (29 ), infusion of isoproterenol at the same dose did not increase plasma cortisol levels in two normal individuals in whom ACTH had been suppressed by the administration of dexamethasone (not shown).

 
In patient 6, GnRH administration increased plasma cortisol 214%, whereas oral cisapride increased it by 476%. She had a history of transient central obesity during her four pregnancies and developed sustained Cushing’s syndrome only after menopause. Stimulation of steroidogenesis by hCG and recombinant hLH, but not by purified FSH, suggested that the LH/hCG receptor was coupled to cortisol production (30). Metoclopramide, another serotonin 5-HT4 receptor agonist, like cisapride, also stimulated cortisol production. This stimulation with cisapride was not observed in other patients or normal controls. These findings suggested the abnormal coupling of both LH/hCG and 5-HT4 receptors to steroidogenesis. The normalization of cortisol production after the suppression of LH levels by chronic administration of the long-acting GnRH agonist leuprolide acetate further supported the major role played by the LH/hCG receptor in the hypercortisolism.

Abnormal hormone receptors in Cushing’s syndrome secondary to unilateral adenomas or carcinomas

In the group of 13 patients with adenomas, plasma cortisol responses to the screening tests were observed less frequently (Fig. 3Go). Upright posture increased plasma cortisol (155%) in 1 patient and partially (126%) in a second one. The mixed meal induced an 136% increase of plasma cortisol in 1 of 12 patients, whereas AVP increased cortisol levels 128% in 1 of 12 patients tested. There were no responses after stimulation with GnRH, TRH, glucagon, or cisapride. In contrast, a significant cortisol increase (216 ± 75%, mean ± SD) was observed in 12 of 13 patients after administration of ACTH 1–24, indicating the presence of ACTH receptors in their tumors. In view of the limited aberrant responses in patients with adenoma, no further characterizations were done before surgery.



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  		Figure 3. Plasma cortisol responses to the various tests in the group of 13 patients with Cushing’s syndrome secondary to unilateral cortisol-secreting adenomas. During each test, plasma cortisol levels were monitored at 30-min intervals during periods up to 3 h. Results are expressed as percentages of the plasma cortisol concentrations observed at the peak or nadir time point during the various tests, as compared with basal levels (100%). Tests included a 2-h ambulation posture test, a standard mixed meal, administration of GnRH (100 µg iv), TRH (200 µg iv), glucagon (1 mg iv), AVP (10 IU im), and cisapride (10 mg orally). The 2 lines indicate the thresholds for partial (125%) and positive (150%) responses.

 
Our experience with adrenocortical carcinoma was very limited, because only one patient studied with this protocol was found to have an adrenal carcinoma at the time of surgery. In this patient, none of the screening tests, nor the administration of ACTH 1–24, induced changes in plasma cortisol levels. The patient died 6 months later because of rapidly progressing pulmonary metastasis.


   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
The most striking result of this investigation was the demonstration of a very high prevalence (6 out of 6) of adrenal expression of aberrant hormone receptors in patients with AIMAH. The pathophysiology of this unusual etiology of adrenal Cushing’s syndrome was previously largely unknown (1, 32, 33) but now seems to be frequently associated with the concept of abnormal adrenal expression of hormone receptors coupled to steroidogenesis. The screening protocol used in this study allowed us to identify patients in whom the adrenal hyperplasia seemed to express either a single abnormal receptor (GIP receptor, V1-AVPR, or ß-AR) or two receptors (LH/hCG and 5-HT4, or V1-AVPR and ß-AR). The various stimulation tests produced sufficient fluctuations in endogenous levels of ligands for the abnormal receptors, such as the elevation of LH after GnRH, to allow the detection of the abnormal receptors. Because chronic elevations of cortisol and other steroids in adrenal Cushing’s syndrome may blunt the response of some of the ligands for the aberrant receptors (i.e. relative suppression of LH by sex steroids), it is important to monitor the levels of the ligands in parallel with plasma cortisol during the various screening tests.

In the patients with unilateral cortisol-secreting adrenal adenoma or carcinoma, a lower prevalence (3 out of 14) of abnormal hormone receptors expression or function was identified in this relatively small series. However, previous studies have clearly demonstrated the abnormal presence and function of hormone receptors in unilateral adrenal cortisol-secreting adenomas or carcinomas in up to 27% of patients for vasopressin (24, 28) and in an undefined percentage of patients for GIP (15, 18, 20, 21, 22) or catecholamines (11, 12). In addition, our investigation protocol may have missed the presence of ectopic receptors for factors such as interleukin-1 (14), leptin (34), and many other G-protein-coupled membrane receptors not assessed specifically (such as PTH, calcitonin, or PGs). Larger series of patients investigated in several centers will be necessary to define more precisely the true prevalence and diversity of this pathophysiology.

Most patients with unilateral adrenal adenomas have retained the presence of ACTH receptors in their tumors. Those with AIMAH displayed exaggerated responses to ACTH 1–24, as compared with the patients with adrenal adenomas, which is probably related to the larger tissue mass seen in AIMAH (Table 1Go). The search for activating mutations of the ACTH receptor in cortisol-secreting adrenal tumors or hyperplasias has been unsuccessful to date (35, 36).

The majority of ectopic or abnormal hormone receptors in adrenocortical tumors or hyperplasia (6, 7, 8, 9, 10, 11, 12, 13, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30) belong to the G-protein-coupled receptor superfamily. We hypothesize that ectopic expression of any adenylyl-cyclase-coupled receptor could induce the stimulation of adrenal cells by trophic factors lacking regulatory negative feedback. This stimulus may lead to increased function and possibly confer a proliferative advantage. GIP has been shown to stimulate the production of cAMP and thymidine incorporation in GIP-dependent cortisol-secreting adenoma cells, in a manner similar to ACTH (20). Hormone-stimulated LH/CG receptors can induce adrenocortical cell hyperplasia and Cushing’s syndrome when expressed ectopically in the adrenal cortex of mice transgenic for the pituitary production of a chimeric bovine LHß/carboxy terminal of hCGß (37).

Because V1-AVPR and 5-HT4 receptor are present in the normal adrenal cortex and modulate modest effects of vasopressin and serotonin on steroidogenesis (38, 39), the exaggerated steroidogenic responses to vasopressin in these patients would be secondary to the abnormal function of an eutopic receptor-effector system, rather than to the presence of an ectopic receptor. The demonstration of an exaggerated cortisol response to pharmacological levels of exogenous vasopressin does not constitute direct evidence that fluctuations of AVP endogenous levels are the main regulator of steroidogenesis in these patients. This was illustrated in patient 3 with AIMAH, who increased plasma cortisol in response to exogenous AVP but not to modulations of endogenous vasopressin (29). In fact, this patient was found to have ectopic ß-adrenergic receptors in his adrenal tissues. It is believed that pharmacological AVP levels stimulated catecholamine release, including from the adrenal medulla (40), and then mediated cortisol release. The response of plasma cortisol levels, in patient 4, to water load and hypertonic saline represents the first demonstration of parallel fluctuations in plasma cortisol levels with small physiological changes in endogenous vasopressin levels. All previously reported cases of cortisol stimulation by lysine-vasopressin (24, 25, 27, 28) or AVP (26) were related to exogenous pharmacological amounts. In this patient, as in patient 2 (26), plasma levels of vasopressin were found to be undetectable basally and showed only a very modest increase upon potent physiological stimulation. This may be attributable to the suppressive effects of cortisol on vasopressin gene expression (41). It has also been postulated that an abnormal V1-vasopressin receptor may modify vasopressin production via a short loop mechanism in the hypothalamus (26).

The molecular mechanisms responsible for the ectopic adrenal expression of hormone receptors or for the abnormal response of the eutopic V1-AVPR and 5-HT4 receptor or their effectors are still unknown. A plausible explanation for the overexpression of a single receptor could be a mutation in its promoter, leading to increased expression. In contrast, when several abnormal adrenal receptors are present, a mutation in a factor regulating cell differentiation may be more likely. The diffuse and bilateral adrenal hyperplasia seen in AIMAH suggests a putative mutation in early embryogenesis, whereas later somatic mutations of a single cell would be responsible for unique adenomas.

The presence of abnormal receptors in cortisol-secreting hyperplasias or tumors can lead to innovative pharmacological therapies as alternatives to adrenalectomy. These approaches may include suppression of the ligands or the use of specific receptor antagonists. Short-term improvement of hypercortisolism was achieved with triiodothyronine treatment in a TSH-dependent cortisol-secreting adrenal adenoma (7) and by the use of octreotide in GIP-dependent Cushing’s syndrome (17, 18). Long-term control has also been obtained, in patient 3, by blockade of ectopic ß-adrenergic receptor with propranolol (29) and by inhibition of LH secretion with leuprolide acetate, in patient 6 (with LH/hCG-dependent adrenal Cushing’s) (30).

The testing procedure used in our study is not part of the approved labeling of the compounds and should be conducted as research protocols. There were no significant side effects observed in this study. The entire screening protocol can be easily performed in an ambulatory setting, rendering it accessible to most centers.


   Acknowledgments
 
We thank the various physicians for referring the patients and also Ms. Marie-Thérèse Caron, R.N.; Ms. Marthe Ménard, R.N.; and Ms. Manon Landry, R.N., for conducting the endocrine tests. Thanks also to Ms. Sylvie Sauvé for illustrations, Ms. Victoria Barranga for preparation of the manuscript, and Mr. Ovid Da Silva for editing this text.


   Footnotes
 
1 Presented in part at the 80th Annual Meeting of The Endocrine Society, New Orleans, Louisiana, 1998. This work was supported by Grant MT-13189 from the Medical Research Council of Canada. Back

Received January 10, 1999.

Revised June 23, 2000.

Accepted June 29, 2000.


   References
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 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

  1. Nieman L, Cutler Jr GB. 1995 Cushing’s syndrome. In: De Groot LJ, Besser M, Burger HG, et al., eds. Endocrinology. Philadelphia: W.B. Saunders; 1741–1769.
  2. Latronico AC, Chrousos GP. 1997 Extensive personal experience: adrenocortical tumors. J Clin Endocrinol Metab. 82:1317–1324.[Free Full Text]
  3. Bornstein SR, Stratakis CA, Chrousos GP. 1999 Adrenocortical tumors: recent advances in basic concepts and clinical management. Ann Intern Med. 130:759–771.[Abstract/Free Full Text]
  4. Kirschner LS, Canney JA, Pack SD, et al. 2000 Mutations of the gene encoding the protein kinase A type I-{alpha} regulatory subunit in patients with the Carney complex. Nat Genet. 26:89–92.[CrossRef][Medline]
  5. Weinstein LS, Shenker A, Gejman PV, Merino MJ, Friedman E, Spiegel AM. 1991 Activating mutations of the stimulatory G protein in the McCune Albright syndrome. N Engl J Med. 325:1688–1695.
  6. Schorr I, Ney RL. 1971 Abnormal hormone responses of an adrenocortical cancer adenylyl cyclase. J Clin Invest. 50:1296–1300.
  7. Hingshaw HT, Ney RL. 1974 Abnormal control in the neoplastic adrenal cortex. In: McKerns KW, ed. Hormones and cancer. New York: Academic Press; 309–327.
  8. Williams LT, Gore TB, Lefkowitz RJ.1977 Ectopic ß-adrenergic receptor binding sites. J Clin Invest. 59:319–324.
  9. Millington DS, Golder MP, Cowley T, et al. 1976 In vitro synthesis of steroids by a feminising adrenocortical carcinoma: effect of prolactin and other protein hormones. Acta Endocrinol (Copenh). 82:561–571.[Medline]
  10. Matsukura S, Kakita T, Sueko S, et al. 1980 Multiple hormone receptors in the adenylate cyclase of human adrenocortical tumors. Cancer Res. 40:3768–3771.[Abstract/Free Full Text]
  11. Hirata Y, Uchihashi M, Sueko S, Matsukura S, Fujita T. 1981 Presence of ectopic ß-adrenergic receptors on human adrenocortical cortisol producing adenomas. J Clin Endocrinol Metab. 53:953–957.[Abstract]
  12. Katz MS, Kelly TM, Dax EM, Pineyro MA, Partilla JS, Gregerman RI. 1985 Ectopic ß-adrenergic receptors coupled to adenylate cyclase in human adrenocortical carcinomas. J Clin Endocrinol Metab. 60:900–909.[Abstract]
  13. Leinonen P, Ranta T, Siegberg R, Pelkonen R, Heikkila T, Kahri A. 1991 Testosterone-secreting virilizing adrenal adenoma with human chorionic gonadotrophin receptors, and 21-hydroxylase deficiency. Clin Endocrinol (Oxf). 34:31–35.[Medline]
  14. Willenberg HS, Stratakis CA, Marx C, Erhart-Bornstein M, Chrousos GP, Bornstein SR. 1998 Aberrant interleukin-1 receptors in a cortisol-secreting adrenal adenoma causing Cushing’s syndrome. N Engl J Med. 339:27–31.[Free Full Text]
  15. Hamet P, Larochelle P, Franks DJ, Cartier P, Bolté E. 1987 Cushing’s syndrome with food-dependent periodic hormonogenesis. Clin Invest Med. 10:530–533.[Medline]
  16. Lacroix A, Bolté E, Tremblay J, et al. 1992 Gastric inhibitory polypeptide-dependent cortisol hypersecretion: a new cause of Cushing’s syndrome. N Engl J Med. 327:974–980.[Abstract]
  17. Reznik Y, Allali-Zerah V, Chayvialle JA, et al. 1992 Food-dependent Cushing’s syndrome mediated by aberrant adrenal sensitivity to gastric inhibitory polypeptide. N Engl J Med. 327:981–986.[Abstract]
  18. De Herder WW, Hofland LJ, Usdin TB, et al. 1996 Food-dependent Cushing’s syndrome resulting from abundant expression of gastric inhibitory polypeptide receptors in adrenal adenoma cells. J Clin Endocrinol Metab. 81:3168–3172.[Abstract]
  19. N'Diaye N, Tremblay J, De Herder WW, Hamet P, Lacroix A. 1998 Adrenal overexpression of gastric inhibitory polypeptide receptor underlies food-dependent Cushing’s syndrome. J Clin Endocrinol Metab. 83:2781–2785.[Abstract/Free Full Text]
  20. Chabre O, Liakos P, Vivier J, et al. 1998 Cushing’s syndrome due to a gastric inhibitory polypeptide-dependent adrenal adenoma: insights into hormonal control of adrenocortical tumorigenesis. J Clin Endocrinol Metab. 83:3134–3143.[Abstract/Free Full Text]
  21. Lebrethon MC, Avallet O, Reznik Y, et al. 1998 Food-dependent Cushing’s syndrome: characterization and functional role of gastric inhibitory polypeptide receptor in the adrenals of three patients. J Clin Endocrinol Metab. 83:4514–4519.[Abstract/Free Full Text]
  22. Luton JP, Bertherat J, Kuhn JM, Bertagna X. 1998 Aberrant expression of GIP (gastric inhibitory polypeptide) receptor in an adrenal cortical adenoma responsible for a case of food-dependent Cushing’s syndrome. Bull Acad Natl Med. 182:1839–1850.[Medline]
  23. N'Diaye N, Hamet P, Tremblay J, Boutin J-M, Gaboury L, Lacroix A. 1999 Asynchronous development of bilateral nodular adrenal hyperplasia in GIP-dependent Cushing’s syndrome. J Clin Endocrinol Metab. 84:2616–2622.[Abstract/Free Full Text]
  24. Perraudin V, Delarue C, De Keyzer Y, et al. 1995 Vasopressin-responsive adrenocortical tumor in a mild Cushing’s syndrome: in vivo and in vitro studies. J Clin Endocrinol Metab. 80:2661–2667.[Abstract]
  25. Horiba N, Suda T, Aioba M, et al. 1995 Lysine vasopressin stimulation of cortisol secretion in patients with adrenocorticotropin-independent macronodular adrenal hyperplasia. J Clin Endocrinol Metab. 80:2336–2341.[Abstract]
  26. Lacroix A, Tremblay J, Touyz R, et al. 1997 Abnormal adrenal and vascular responses to vasopressin mediated by a V1-vasopressin receptor in a patient with adrenocorticotropin-independent macronodular adrenal hyperplasia, Cushing’s syndrome and orthostatic hypotension. J Clin Endocrinol Metab. 82:2414–2422.[Abstract/Free Full Text]
  27. Iida K, Kaji H, Matsumoto H, et al. 1997 Adrenocorticotrophin-independent macronodular adrenal hyperplasia in a patient with lysine vasopressin responsiveness but insensitivity to gastric inhibitory polypeptide. Clin Endocrinol (Oxf). 47:739–745.[CrossRef][Medline]
  28. Arnaldi G, Gasc JM, De Keyzer Y, et al. 1998 Variable expression of the V1 vasopressin receptor modulates the phenotypic response of steroid-secreting adrenocortical tumors. J Clin Endocrinol Metab. 83:2029–2035.[Abstract/Free Full Text]
  29. Lacroix A, Tremblay J, Rousseau G, Bouvier M, Hamet P. 1997 Propranolol therapy for ectopic ß-adrenergic receptors in adrenal Cushing’s syndrome. N Engl J Med. 337:1429–1434.[Free Full Text]
  30. Lacroix A, Hamet P, Boutin JM. 1999 Control of hypercortisolism with leuprolide acetate therapy in LH-dependent adrenal Cushing’s syndrome. N Engl J Med. 341:1577–1581.[Free Full Text]
  31. Lacroix A, Mircescu H, Hamet P. 1999 Clinical evaluation of the presence of abnormal hormone receptors in adrenal Cushing’s syndrome. Endocrinologist. 9:9–15.
  32. Lieberman SA, Eccleshall TR, Feldman D. 1994 ACTH-independent massive bilateral adrenal disease (AIMBAD): a subtype of Cushing’s syndrome with major diagnostic, and therapeutic implications. Eur J Clin Endocrinol. 131:67–73.[Abstract]
  33. Stratakis CA, Kirschner LS. 1998 Clinical, and genetic analysis of primary bilateral adrenal diseases (micro- and macronodular disease) leading to Cushing’s syndrome. Horm Metab Res. 30:456–463.[Medline]
  34. Pralong FP, Gomez F, Guillou L, Mosimann F, Franscella S, Gaillard RC. 1999 Food-dependent Cushing’s syndrome: possible involvement of leptin in cortisol hypersecretion. J Clin Endocrinol Metab. 84:3817–3822.[Abstract/Free Full Text]
  35. Latronico AC, Reincke M, Mendonca BB, et al. 1995 No evidence for oncogenic mutations in the adrenocorticotropin receptor gene in human adrenocortical neoplasms. J Clin Endocrinol Metab. 80:875–877.[Abstract]
  36. Light K, Jenkins PJ, Weber A, et al. 1995 Are activating mutations of the ACTH receptor involved in adrenal cortical neoplasia? Life Sci. 56:1523–1527.[CrossRef][Medline]
  37. Kero J, Poutanen M, Zhang F-P, et al. 2000 Elevated luteinizing hormone induces expression of its receptor and promotes steroidogenesis in the adrenal cortex. J Clin Invest. 105:633–641.[Medline]
  38. Perraudin V, Delarue C, Lefevre H, Comtesse V, Kuhn VM, Vaudry H. 1993 Vasopressin stimulates cortisol secretion from human adrenocortical tissues through activation of V1 receptors. J Clin Endocrinol Metab. 76:1522–1528.[Abstract]
  39. Lefebvre H, Contesse V, Delarue C, Vaudry K, Kuhn JM. 1998 Serotonergic regulation of adrenocortical function. Horm Metab Res. 30:398–403.[Medline]
  40. Guillon G, Grazzini E, Andrez M, et al. 1998 Vasopressin: a potent autocrine/paracrine regulator of mammal adrenal functions. Endocr Res. 24:703–710.[Medline]
  41. Eckland DJA, Todd K, Lightman SL. 1988 Immunoreactive vasopressin, and oxytocin in hypothalamo-hypophysial portal blood of the Brattleboro and Long Evans rat: effect of adrenalectomy and dexamethasone. J Endocrinol. 117:27–34.[Abstract]



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