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Plasma DHEA, androstenedione, testosterone and 17-hydroxyprogesterone (17-OHP) profiles on a control day with normal food intake at 0800, 1400, and 2000 h and during a day of fasting with food intake at 1800 h.
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Aberrant gastric inhibitory polypeptide (GIP) receptor expression in bilaterally hyperplastic adrenals or unilateral adrenal adenomas is a rare form of adrenal hyperfunction. So far, only few cases have been described. In all these cases, cortisol was the predominant steroid released in a food-dependent manner, leading to the development of non-ACT...
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... 3 shows the plasma cortisol and ACTH profiles (measured at 1-to 2-h ) during a day when the patient took regular meals and during a day of fasting, up to 1800 h, when a meal was allowed. Figure 4 shows the corresponding androgen (DHEA, androstenedione, testosterone) and 17-hydroxypro- gesterone levels. Persistently decreased cortisol and andro- gen levels were found during fasting, followed by a cortisol and androgen rise when the patient was allowed to eat at 1800 h. ...
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... 5,12,13,20,30,[32][33][34][35][36][37][38][39][41][42][43][45][46][47][48] It was also reported in nine patients (eight woman and one man) with unilateral adenomas (Table 1). 11,19,21,40,50,52,53 As most patients with PBMAH or unilateral cortisol-secreting adenomas with overt CS, and even less frequently for those with mild cortisol excess, are not systematically screened for abnormal cortisol secretion following meals, the number of such cases is probably underestimated, but its real prevalence is unknown. For example, a recent study identified in the adrenal adenoma of a 27-year-old patient with polyposis coli and APC mutation without evidence of CS, abnormal expression of the GIP, 5-HT7, and LH receptors, and cortisol secretion was stimulated in dispersed cells by the ligands, but this potential regulation was not evaluated in vivo before surgery. ...
... The abnormal adrenal regulation of cortisol production by GIP suggested that this aberrant adrenal sensitivity to GIP was secondary either to ectopic expression or activating mutation of GIPR, not normally expressed or functional in human zona fasciculata cells. 56 Ectopic GIPR was confirmed in several cases of GIP-dependent PBMAH 20,30,[33][34][35][36][40][41][42][43]45,46,48 and adenomas 19,20,33,40,41,[50][51][52][53] (Figure 1) and was not identified in non-GIP-dependent CS adrenal tissues 20,33,40,52 or the human adrenocortical carcinoma cell line H295. 41,50 Glucose-dependent insulinotropic peptide-dependent cortisol production results from the ectopic expression of nonmutated GIPR in adrenocortical zona fasciculata 20,21 that can be detected in the early phases of adrenal hyperplasia. ...
... The abnormal adrenal regulation of cortisol production by GIP suggested that this aberrant adrenal sensitivity to GIP was secondary either to ectopic expression or activating mutation of GIPR, not normally expressed or functional in human zona fasciculata cells. 56 Ectopic GIPR was confirmed in several cases of GIP-dependent PBMAH 20,30,[33][34][35][36][40][41][42][43]45,46,48 and adenomas 19,20,33,40,41,[50][51][52][53] (Figure 1) and was not identified in non-GIP-dependent CS adrenal tissues 20,33,40,52 or the human adrenocortical carcinoma cell line H295. 41,50 Glucose-dependent insulinotropic peptide-dependent cortisol production results from the ectopic expression of nonmutated GIPR in adrenocortical zona fasciculata 20,21 that can be detected in the early phases of adrenal hyperplasia. ...
Thirty years ago, we identified that cortisol secretion in some patients with unilateral adenoma or primary bilateral macronodular adrenal hyperplasia (PBMAH) was stimulated by food intake; this was secondary to the abnormal adrenocortical responsiveness to physiological post prandial increase in glucose-dependent insulinotropic peptide (GIP). This resulted from the ectopic expression of non-mutated GIP receptor in the pathological adrenal tissues of those patients. Although ectopic GIPR was confirmed in a relatively limited number of cases to date, its elucidation lead to the identification of a wide diversity of aberrant G-protein-coupled receptors regulating steroidogenesis and cell proliferation in a high proportion of patients with PBMAH or cortisol-secreting adenomas. In addition, ectopic GIPR was identified in other endocrine tumors including somatotroph pituitary tumors with paradoxical growth hormone response to oral glucose, medullary thyroid carcinomas and other neuroendocrine tumors. The first molecular pathogenic mechanism responsible for ectopic GIPR expression was elucidated in unilateral GIP-dependent adenomas in which somatic duplication and rearrangements in chromosome region 19q13.32 containing the GIPR locus lead to increased expression of GIPR which was enhanced by the activity of a glucocorticoid response element. Recently, germline lysine demythylase 1A (KDMIA) mutations combined with somatic chromosome 1p deletions were found to be specifically responsible for ectopic GIPR in sporadic or familial GIP-dependent PBMAH and can be associated with adrenal myelolipoma, MGUS or multiple myeloma. Screening for ectopic GIPR should be conducted in all patients with PBMAH; genetic studies to identify KDM1A mutations should be offered to such patients in order to detect affected members and provide early detection of PBMAH and other potential associated neoplasias. The elucidation of GIP-dependent CS illustrates that careful bedside phenotyping of rare conditions can lead to identification of genetically determined diseases requiring personalized approaches to investigation and therapy.
... Similar results were reported by Ye et al, who failed to identify any differences in GIPR expression in ten aldosteronomas vs five normal adrenals [60]. An aberrant GIPR expression was also reported in a patient with unilateral androgen-producing adrenal tumor, hirsutism and subclinical cortisol secretion, who had increased adrenal androgen and cortisol levels after meals [61]. Molecular and functional tests on the primary tumor cells obtained from a tumor biopsy confirmed the presence of a functional and inducible GIPR. ...
... Molecular and functional tests on the primary tumor cells obtained from a tumor biopsy confirmed the presence of a functional and inducible GIPR. So an aberrant GIPR expression in the zona reticularis may also induce cell proliferation and GIPdependent androgen secretion [61]. ...
... Many other such receptors have been identified in CS due to PBMAH, including vasopressin, b-adrenergic, LH/hCG and HT4 receptors [49]. Although they can be expressed alone, the combination of more than one other aberrant GPCR with GIPR is a common event in FDCS [42,61,[75][76][77], particularly among PBMAH patients [78]. The review by El Ghorayeb [49] nicely summarizes the screening procedures for multiple aberrant GPCR expression used in various systematic studies on patients with subclinical or overt CS, and extends previous considerations [78]. ...
The glucose-dependent insulinotropic polypeptide (GIP) is an incretin hormone produced in the gastrointestinal tract in response to nutrients. GIP has a variety of effects on different systems, including the potentiation of insulin secretion from pancreatic β-cells after food intake (i.e. incretin effect), which is probably the most important. GIP effects are mediated by the GIP receptor (GIPR), a G protein-coupled receptor expressed in several tissues, including islet β-cells, adipocytes, bone cells, and brain. As well as its involvement in metabolic disorders (e.g. it contributes to the impaired postprandial insulin secretion in type 2 diabetes (T2DM), and to the pathogenesis of obesity and associated insulin resistance), an inappropriate GIP/GIPR axis activation of potential diagnostic and prognostic value has been reported in several endocrine tumors in recent years. The ectopic GIPR expression seen in patients with overt Cushing syndrome and primary bilateral macronodular adrenal hyperplasia or unilateral cortisol-producing adenoma has been associated with an inverse rhythm of cortisol secretion, with low fasting morning plasma levels that increase after eating. On the other hand, most acromegalic patients with an unusual GH response to oral glucose suppression have GIPR-positive somatotropinomas, and a milder phenotype, and are more responsive to medical treatment. Neuroendocrine tumors are characterized by a strong GIPR expression that may correlate positively or inversely with the proliferative index MIB-1, and that seems an attractive target for developing novel radioligands. The main purpose of this review is to summarize the role of the GIP/GIPR axis in endocrine neoplasia, in the experimental and the clinical settings.
... GIP, through the activation of the PKA cascade, induces a substantial glucocorticoid secretagogue effect, leading to the identification of a food-dependent Cushing's syndrome [65]. In one reported case, a female patient with hirsutism and a unilateral adenoma, both adrenal androgens and cortisol were found to be stimulated by food intake in vivo and by GIP in vitro [66]. In animal studies, GIP administration increases corticosterone levels in rats, and isolated rat adrenocortical zona fasciculate/reticularis cells respond to GIP in a cAMP-dependent manner [67]. ...
Gastric inhibitory polypeptide (GIP) is best known as an incretin hormone released by enteroendocrine K-cells in response to feeding and stimulates insulin release to regulate blood glucose and nutrient homeostasis. More recently GIP has been ascribed a positive role in lipid metabolism, bone strength, cardiovascular function and cognition. The present paper considers an emerging role of GIP and related gut hormones in fertility and especially polycystic ovarian syndrome (PCOS). Key evidence concerns restoration of fertility in women with gross obesity and PCOS following bariatric surgery. This is considered to reflect indirect effects mediated by alleviation of insulin resistance together with possible direct effects of surgically induced changes of GIP, GLP-1 and related peptide hormones on ovaries and the hypothalamic-pituitary-adrenal axis. Further studies are required to determine inter-relationships between the hormones and cellular mechanisms involved but these observations suggest that GIP and other gut may provide a novel therapeutic approach for PCOS and other reproductive disorders.
... Overexpression of GIPR in the adrenal cortex has been previously demonstrated in patients with ACTH-independent Cushing syndrome resulting from food-dependent adrenal cortisol secretion.21,24,30 GIPR overexpression has also been identified in adrenocortical adenomas with androgen or aldosterone hyperproduction and less frequently in adrenocortical adenomas.23,31 Recently, one study showed that the aberrant expression of a non-mutated GIPR gene was sufficient to initiate the formation of benign adrenocortical tumors and hyperplastic adrenal tissue using an in vivo cell transplantation model in mice.20 ...
... 21,24,30 GIPR overexpression has also been identified in adrenocortical adenomas with androgen or aldosterone hyperproduction and less frequently in adrenocortical adenomas. 23,31 Recently, one study showed that the aberrant expression of a non-mutated GIPR gene was sufficient to initiate the formation of benign adrenocortical tumors and hyperplastic adrenal tissue using an in vivo cell transplantation model in mice. 20 The potential involvement of the GIPR gene in the etiology of adrenocortical hyperplasia occurring in MEN1 syndrome might be supported by this evidence. ...
The molecular mechanisms involved in the genesis of the adrenocortical lesions seen in MEN1 syndrome (ACL-MEN1) remain poorly understood; loss of heterozygosity at 11q13 and somatic mutations of MEN1 are not usually found in these lesions. Thus, additional genes must be involved in MEN1 adrenocortical disorders. Overexpression of the glucose-dependent insulinotropic peptide receptor has been shown to promote adrenocortical tumorigenesis in a mice model and has also been associated with ACTH-independent Cushing syndrome in humans. However, to our knowledge, the status of glucose-dependent insulinotropic peptide receptor expression in adrenocortical lesions in MEN1 has not been previously investigated.
To evaluate glucose-dependent insulinotropic peptide receptor expression in adrenocortical hyperplasia associated with MEN1 syndrome.
Three adrenocortical tissue samples were obtained from patients with previously known MEN1 germline mutations and in whom the presence of a second molecular event (a new MEN1 somatic mutation or an 11q13 loss of heterozygosity) had been excluded. The expression of the glucose-dependent insulinotropic peptide receptor was quantified by qPCR using the DDCT method, and b-actin was used as an endogenous control.
The median of glucose-dependent insulinotropic peptide receptor expression in the adrenocortical lesions associated with MEN1 syndrome was 2.6-fold (range 1.2 to 4.8) higher than the normal adrenal controls (p = 0.02).
The current study represents the first investigation of glucose-dependent insulinotropic peptide receptor expression in adrenocortical lesions without 11q13 loss of heterozygosity in MEN1 syndrome patients. Although we studied a limited number of cases of MEN1 adrenocortical lesions retrospectively, our preliminary data suggest an involvement of glucose-dependent insulinotropic peptide receptor overexpression in the etiology of adrenocortical hyperplasia. New prospective studies will be able to clarify the exact role of the glucose-dependent insulinotropic peptide receptor in the molecular pathogenesis of MEN1 adrenocortical lesions.
... GIP-dependent CS can occur in patients with AIMAH 24,31-40 or with unilateral adenomas. [41][42][43][44][45][46][47] Patients with CS can present low fasting plasma cortisol levels, which increase following meals, despite suppression of ACTH. Cortisol increased following physiological elevation of plasma level of GIP after meals, as the result of the ectopic expression of nonmutated GIP receptor in zona fasciculata-type cells in AIMAH or unilateral adenomas. ...
... Cortisol increased following physiological elevation of plasma level of GIP after meals, as the result of the ectopic expression of nonmutated GIP receptor in zona fasciculata-type cells in AIMAH or unilateral adenomas. 31,33,35,[37][38][39][41][42][43][45][46][47][48][49] This should not be confused with the modest elevation in cortisol after mid-day meal in normal individuals which is mediated by ACTH stimulation by protein content of the diet. 24 To date, more than 30 such cases have been reported in whom adrenal hormonal hypersecretion, including clinical or subclinical CS, was correlated to GIP levels. ...
... In one woman presenting with hirsutism and sub-clinical cortisol secretion from unilateral adrenal adenoma, adrenal androgens (modest elevation of androstenedione, testosterone, DHEA/ DHEAS) and plasma cortisol increased after meals. 47 Octreotide pretreatment was able to block the androgen and cortisol rise after meals. It was shown that GIP receptor was overexpressed in this adrenal adenoma compared with normal adrenal tissue. ...
The aberrant adrenal expression and function of one or several G-protein coupled receptors can lead to cell proliferation and abnormal regulation of steroidogenesis in unilateral adenomas, carcinomas or in ACTH-independent macronodular adrenal hyperplasia (AIMAH). Excess cortisol secretion leading to either sub-clinical or overt Cushing's syndrome is the most prevalent phenotype reported to date. In a few patients, aberrant regulation of androgen excess has been reported. More recently, initial studies suggest that similar mechanisms are involved in the renin-independent regulation of aldosterone secretion in primary aldosteronism. In recent years, cases of familial AIMAH have been identified, and specific aberrant hormone receptors are functional in the adrenal of affected members. The identification of aberrant receptors can offer specific pharmacological approach to prevent disease progression and control abnormal steroidogenesis; alternatively, unilateral or bilateral adrenalectomy remains the treatment of choice.
... Aberrant expression of several G-Protein Coupled Receptors (GPCR) frequently regulates the production of cortisol in ACTH-independent macronodular adrenal hyperplasias (AIMAH) and adrenocortical adenomas causing Cushing's syndrome or androgen excess (1,2). In primary aldosteronism, the mechanisms regulating aldosterone production, while renin and angiotensin II are suppressed, are largely unknown. ...
Primary adrenal Cushing's syndrome can result from the aberrant adrenal expression of several hormone receptors; this mechanism has not been explored in detail in aldosterone-producing tumors.
The objective of the study was to evaluate a 56-yr-old male patient with an aldosteronoma for the regulation of aldosterone secretion by aberrant hormone receptors.
Renin-independent stimulation of aldosterone secretion was observed in vivo after a mixed meal, oral glucose, or administration of glucose-dependent insulinotropic peptide (GIP), vasopressin, and tegaserod. The mixed meal-mediated stimulation of aldosterone was not present in five other cases of aldosteronoma. A smaller response of aldosterone after GIP infusion was observed in a normal subject. Aldosterone secretion was stimulated by GIP in primary cultures of this patient's aldosteronoma. Increased expression of GIP receptor was found in this aldosteronoma by real-time RT-PCR and immunohistochemistry. The GIP receptor protein was also found at lower levels in zona glomerulosa cells of the normal adjacent adrenal gland. Increased expression of serotonin 4 and ACTH receptors was also present in this aldosteronoma.
This case report provides new evidence of the implication of aberrant hormone receptors in the regulation of this aldosteronoma and suggests that further detailed studies of the role of aberrant hormone receptors in this frequent pathology should be undertaken.
... Hamet et al. (3) described the first case of cortisol production stimulated by food intake in a patient with a unilateral adrenal adenoma leading to CS. Several studies have since demonstrated that the abnormal cortisol response in these cases depends on the expression of glucose-dependent insulinotropic polypeptide receptor (GIP-R), which can be expressed in macronodular adrenal hyperplasia (4)(5)(6)(7)(8)(9) and, less frequently, in unilateral adrenal adenoma (10)(11)(12)(13). In the majority of reported cases, cortisol is the main steroid secreted in response to food intake, so most of these patients have a clinical appearance of subclinical or overt CS, though some atypical cases with GIP-mediated cortisol and androgen secretion (12), or a cortisol response to both gonadotropin and GIP stimulation (14), have been described. ...
... Several studies have since demonstrated that the abnormal cortisol response in these cases depends on the expression of glucose-dependent insulinotropic polypeptide receptor (GIP-R), which can be expressed in macronodular adrenal hyperplasia (4)(5)(6)(7)(8)(9) and, less frequently, in unilateral adrenal adenoma (10)(11)(12)(13). In the majority of reported cases, cortisol is the main steroid secreted in response to food intake, so most of these patients have a clinical appearance of subclinical or overt CS, though some atypical cases with GIP-mediated cortisol and androgen secretion (12), or a cortisol response to both gonadotropin and GIP stimulation (14), have been described. ...
... In our case, we demonstrated in vitro the concomitant release of adrenal androgens and cortisol from adrenal tissue perifused with GIP. This situation has been previously described in a patient with an adrenocortical adenoma leading to hirsutism and subclinical CS (12). However, Bertherat et al. (14) identified two patients with CS due to adrenal hyperplasia that responded to both gonadotropin and GIP stimulation, demonstrating that ACTH-independent adrenocortical tissues may simultaneously express multiple illegitimate membrane receptors. ...
Cortisol secretion in ACTH-independent macronodular adrenal hyperplasia (AIMAH) may be regulated by the aberrant expression of several G-protein-coupled receptors. Bilateral adrenalectomy is the treatment of choice in most cases. We searched for aberrant receptor expression in a patient with AIMAH and evaluated the response to medical and surgical treatment.
A 35-year-old woman with amenorrhea, hirsutism, and hypertension presented ACTH-independent cortisol secretion with high androgen levels. Abdominal computed tomography showed bilateral adrenal macronodules (4.5 cm right and 1.0 cm left). Scintigraphy with I(131)-norcholesterol showed bilateral uptake, prevalent on the right side. Several in vivo stimulation tests were assessed before and after treatment and in vitro studies were performed after unilateral adrenalectomy.
Plasma cortisol increased after a standard meal test (60%) and oral glucose loading (147%), and the response was blunted by pretreatment with 100 microg s.c. octreotide. The therapy with long-acting release octreotide (octreotide-LAR) showed an improvement in urinary free cortisol (UFC) levels. Unilateral adrenalectomy was performed and histopathology revealed macronodular AIMAH. Cortisol and androgens increased after perifusion of tumoral tissue with glucose-dependent insulinotropic polypeptide (GIP), and GIP and LH-receptor overexpression was found in both the adrenal nodules and the adjacent cortex. After surgery, UFC and androgen levels normalized followed by clinical improvement.
GIP and LH-receptor expression may coexist in AIMAH, influencing the functional and morphological phenotype. Aberrant hormone receptor expression enables specific pharmacological treatment, but long-term studies are needed to evaluate its real efficacy. Unilateral adrenalectomy may be a safe initial option, particularly for asymmetric bilateral adrenal enlargements.
... Further studies demonstrated the involvement of ectopic GIP-R expression in the adrenal tissues of patients with GIP-dependent Cushing's syndrome and bilateral macronodular hyperplasia (Lacroix et al. 1992, Reznik et al. 1992). GIP-dependent Cushing's syndrome has now been identified in at least 17 patients with adrenocorticotropin (ACTH)-independent macronodular adrenal hyperplasia (Chabre et al. 1998, Lebrethon et al. 1998, N'Diaye et al. 1999, Pralong et al. 1999, Croughs et al. 2000, Gerl et al. 2000, Lacroix et al. 2001, Groussin et al. 2002, Bertagna et al. 2003) and seven with unilateral adenoma (Hamet et al. 1987, De Herder et al. 1996, Chabre et al. 1998, Luton et al. 1998, Tsagarakis et al. 2001). Sequence analysis of the full-length cDNA of GIP-dependent adrenal tissues revealed no GIP-R mutation in the affected adenomas or macronodular hyperplasia of these patients (N'Diaye et al. 1998). ...
The best characterized effect of glucose-dependent insulinotropic polypeptide (GIP) is its stimulatory effect on insulin secretion by pancreatic beta-cells. Recently, it was demonstrated that some cases of primary adrenal Cushing's syndrome were secondary to the ectopic expression of non-mutated GIP receptor (GIP-R) in bilateral adrenal hyperplasias or unilateral adrenal adenomas, resulting in food-dependent steroidogenesis. Using a human multiple-expression tissue array, GIP-R was found to be expressed in a large number of human adult and fetal tissues, but not in the adrenal gland. The analysis of the promoter region of human (h) GIP-R gene revealed six consensus sequences important in regulating the reporter gene activity and capable of binding to Sp1 and Sp3 transcription factors. Data obtained by gene array and semi-quantitative RT-PCR showed an increase in the expression of Sp3 and CRSP9 (co-regulator of Sp1 transcription factor, subunit 9) in the adrenal adenomas or bilateral macronodular hyperplasias of patients with GIP-dependent Cushing's syndrome; they were, however, also increased in some patients with non-GIP-dependent cortisol-secreting adenomas or with ACTH-dependent Cushing's disease. This study represents the first step in our understanding of the mechanisms involved in the regulation of the expression of the hGIP-R gene.
... As expected, V1-R and 5-HT 4 R were expressed in normal adrenal cortex. Overexpression of the mRNAs encoding the eutopic V1a and 5-HT 4 receptors has been described in tissue explants removed from AIMAHs responsive to AVP and cisapride in vivo, respectively (22)(23)(24)(25). Conversely, the present AIMAH tissue presented serotonin and vasopressin hyperresponsivenes unrelated to the degree of mRNA V1-R and 5-HT 4 R expression, which could be explained by differences in receptor sensitivity or in corticosteroidogenesis coupling. ...
... Adrenal macronodular hyperplasia leading to a Cushing's syndrome mediated by LH or hCG secretion was first described in a patient that have manifested marked Cushing's features during her pregnancies and after menopause (12). Occurrence of Cushing's syndrome under excessive plasmatic concentration of hCG during pregnancy was suggested in other cases (25)(26)(27). This condition was believed to be caused by aberrant expression of LHR associated with ligand excess, because in vivo inhibition of hypercortisolism was obtained either by pharmacological suppression of LH levels or naturally by post-partum hCG suppression. ...
... Thereafter, the pathophysiology of this syndrome was characterized by a hypercortisolism induced by physiological post-prandial increase in circulating GIP concentrations 20,21 . Abnormal GIPR expression has been then described in other cases of benign adrenal tumors 12,13,16,19,[22][23][24][25] but was not observed in a small cohort of malignant adrenal tissues 26 . No mutation in GIPR gene coding sequence and promoter could be identified so far 15,27 and the molecular mechanisms of this ectopic GIPR expression remain unclear. ...
Membres du Jury : Pr. André LACROIX Rapporteur, Pr. Eric CLAUSER Rapporteur, Pr. Duarte PIGNATELLI Examinateur, Pr. Jacques YOUNG Examinateur, Dr. Michaël THOMAS Examinateur, Pr. Olivier CHABRE Examinateur.
... In one patient with GIP-dependent AIMAH, plasma ACTH and cortisol responses to CRH were still preserved, presumably because the intermittent fooddependent stimulation of cortisol had not yet completely suppressed the HPA axis (208). In a female patient with hirsutism and a unilateral adenoma, both adrenal androgens and cortisol were found to be stimulated by food intake in vivo and GIP in vitro (213); hypercortisolism was modest and ACTH was not fully suppressed. The abnormal adrenal regulation of cortisol production by GIP suggested that this aberrant adrenal sensitivity to GIP was secondary either to ectopic expression or activating mutation of GIPR, not normally expressed or functional in adrenal cortical tissues. ...
... If the relative suppression of ACTHR in GIP-dependent adrenal tissues is confirmed in further stud- ies, this would indicate that GIP cannot substitute for ACTH in inducing the expression of ACTHR; it must be noted, however, that plasma GIP levels are only elevated transiently postprandially, which is different from conditions where ACTH is elevated chronically. GIPR overexpression was confirmed in other cases (Table 2) of GIP-dependent adrenal macronodular hyperplasias (205, 206, 208, 208a) and adenomas (205, 208a-210, 213) and was not demonstrated in non-GIP-dependent CS adrenal tissues (205,210,213,219) or the human adrenocortical carcinoma cell line H295 (211). GIPR overexpression was detected, even in the early stages of adrenal hyperplasia (206). ...
The mechanism by which cortisol is produced in adrenal Cushing's syndrome, when ACTH is suppressed, was previously unknown and was referred to as being "autonomous." More recently, several investigators have shown that some cortisol and other steroid-producing adrenal tumors or hyperplasias are under the control of ectopic (or aberrant, illicit, inappropriate) membrane hormone receptors. These include ectopic receptors for gastric inhibitory polypeptide (GIP), beta-adrenergic agonists, or LH/hCG; a similar outcome can result from altered activity of eutopic receptors, such as those for vasopressin (V1-AVPR), serotonin (5-HT4), or possibly leptin. The presence of aberrant receptors places adrenal cells under stimulation by a trophic factor not negatively regulated by glucocorticoids, leading to increased steroidogenesis and possibly to the proliferative phenotype. The molecular mechanisms responsible for the abnormal expression and function of membrane hormone receptors are still largely unknown. Identification of the presence of these illicit receptors can eventually lead to new pharmacological therapies as alternatives to adrenalectomy, now demonstrated by the long-term control of ectopic P-AR- and LH/hCGR-dependent Cushing's syndrome by propanolol and leuprolide acetate. Further studies will potentially identify a larger diversity of hormone receptors capable of coupling to G proteins, adenylyl cyclase, and steroidogenesis in functional adrenal tumors and probably in other endocrine and nonendocrine tumors.
