This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Lacroix, A. Articles by Hamet, P. Search for Related Content PubMed PubMed Citation Articles by Lacroix, A. Articles by Hamet, P.

Ectopic and Abnormal Hormone Receptors in Adrenal Cushing’s Syndrome¹

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

	Abstract

Top Abstract I. Introduction II. Hormonal Regulation of... III. Primary Adrenal... IV. Initial in Vitro... V. In Vivo Demonstration... VI. Investigation Strategy VII. Molecular Mechanisms of... VIII. Ectopic/Abnormal Hormone... IX. An Opportunity for... X. Summary and Conclusions References

 
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), ß-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 ß-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.

I. Introduction

II. Hormonal Regulation of the Normal Adrenal Cortex

III. Primary Adrenal Cushing’s Syndrome (CS)

IV. Initial in Vitro Evidence of Ectopic Adrenal Membrane Hormone Receptors

V. In Vivo Demonstration of the Functionality of Ectopic or Abnormal Membrane Hormone Receptors

A. Food- and GIP-dependent CS

B. Vasopressin-responsive CS

C. Catecholamine-dependent CS

D. LH-dependent CS

E. LH-dependent adrenal androgen-secreting tumors

F. Serotonin-responsive CS

G. Steroid-responsive CS

H. Other abnormal hormone responses in adrenal CS

VI. Investigation Strategy

A. Initial clinical screening protocol

B. Further characterization of abnormal hormone receptors

C. Systematic clinical screening for ectopic/abnormal hormone receptors

VII. Molecular Mechanisms of Ectopic/Abnormal Hormone Receptors

A. Tissue-specific expression and regulation of membrane hormone receptors

B. Potential mechanisms of ectopic or abnormal hormone receptors

C. Role of ectopic hormone receptors in adrenocortical cell proliferation

VIII. Ectopic/Abnormal Hormone Membrane Receptors in Nonadrenocortical Tumors

IX. An Opportunity for New Pharmacological Therapeutic Strategies

X. Summary and Conclusions

	I. Introduction

Top Abstract I. Introduction II. Hormonal Regulation of... III. Primary Adrenal... IV. Initial in Vitro... V. In Vivo Demonstration... VI. Investigation Strategy VII. Molecular Mechanisms of... VIII. Ectopic/Abnormal Hormone... IX. An Opportunity for... X. Summary and Conclusions References

 
ENDOGENOUS Cushing’s syndrome (CS) is characterized by clinical symptoms and signs resulting from chronic exposure to increased secretion of glucocorticoids (GCs) and other steroids by the adrenal cortex (1, 2, 3). Most frequently, endogenous CS is ACTH dependent, arising from excess ACTH production by pituitary corticotrope adenoma (Cushing’s disease) or from an extrapituitary tumor secreting POMC and ACTH (ectopic ACTH syndrome); rarely, a CRH-secreting tumor causes excessive ACTH production from the pituitary (ectopic CRH syndrome). Less frequently, CS is ACTH independent, as it results from excess secretion of cortisol by benign and malignant adrenocortical tumors or hyperplasias (1, 2, 3, 4). Rare cases of ectopic cortisol production from ovarian tumors that led to ACTH-independent CS have been described (5). Lastly, cortisol hypersensitivity with variable increases in GC receptor numbers has been proposed to explain the clinical features of CS in two patients with low or dysregulated cortisol and ACTH levels and no exposure to exogenous GC (6, 7).

The mechanisms by which cortisol is produced in adrenal CS, when ACTH is suppressed, were previously unknown and referred to as being "autonomous." Studies by several groups have now shown that some of the cortisol-producing adrenal tumors or hyperplasias may actually be under the control of ectopic (or aberrant, illicit, inappropriate) hormone membrane receptors (8, 9, 10). After a brief overview of the regulation of normal adrenocortical function by its main trophic hormones and of the etiologies of adrenal CS, the present review will focus on in vitro and in vivo findings, identifying abnormalities of expression or function of receptors for various hormones in primary adrenal CS. The mechanisms regulating tissue-specific expression of eutopic membrane receptors in the normal adrenal cortex and the potential molecular alterations leading to the ectopic expression of hormone receptors in adrenocortical tumors and hyperplasias will also be discussed. The identification of abnormal membrane hormone receptors in adrenal CS has now opened the field of new therapeutic strategies to control hypercortisolism by interfering with ligand binding to these receptors and will also be presented.

	II. Hormonal Regulation of the Normal Adrenal Cortex

Top Abstract I. Introduction II. Hormonal Regulation of... III. Primary Adrenal... IV. Initial in Vitro... V. In Vivo Demonstration... VI. Investigation Strategy VII. Molecular Mechanisms of... VIII. Ectopic/Abnormal Hormone... IX. An Opportunity for... X. Summary and Conclusions References

 
The normal regulation of adrenocortical function has been the subject of recent reviews (11, 12) and, hence, will be discussed only briefly here. An important site of regulation of the hypothalamic-pituitary-adrenal axis (HPA) is located in neurons of the medial parvocellular part of the hypothalamic paraventricular nucleus (PVN) where CRH and arginine vasopressin (AVP) are produced and travel along their axons to the median eminence to be released in the hypophyseal portal blood system (13, 14). The binding of CRH or AVP to its respective specific receptors CRH-R1 (15) and AVP V3R (16) on corticotrophs of the anterior lobe stimulates the synthesis and maturation of POMC, leading to ACTH secretion (17). Vasoactive intestinal polypeptide (VIP) and pituitary adenylate cyclase activating peptide (PACAP), which are also produced in hypothalamic neurons, enhance CRH and ACTH release (18, 19). CRH secretion can be stimulated in the PVN by ₁-adrenoreceptor agonists, serotonin (5-HT_1A) receptor agonists, muscarinic and nicotinic receptor agonists of acetylcholine, histamine, and -aminobutyric acid (GABA_A)_, whereas it is inhibited by GABA_B agonists (14). CRH release is also stimulated by angiotensin II (Ang-II), neuropeptide Y (NPY), cholecystokinin (CCK), and gastrin-releasing peptide, or suppressed by atrial natriuretic peptide (ANP), substance P, somatostatin, and nitric oxide (NO) (14). Several cytokines, including interleukin-1 (IL-1), tumor necrosis factor (TNF-), and IL-6, stimulate CRH, possibly through the production of prostaglandins in brain vascular endothelium (20). ACTH secretion can also be modulated by paracrine/autocrine interactions, as corticotroph cells have been shown to express CRH, which can effectively stimulate ACTH release (21).

ACTH binds to its G protein-coupled membrane melanocortin type 2 receptor (22, 23) to elicit short-term (acute) and long-term (chronic) specific responses, as illustrated in Fig. 1 (24, 25). Activation of the adenylyl cyclase (AC)/cAMP/cAMP-dependent protein kinase (PKA) pathway leads to the phosphorylation of proteins that regulate the early and late steps of steroidogenesis (26, 27). ACTH rapidly (within a few minutes) promotes the mobilization and transfer of free cholesterol to the inner mitochondrial membrane (27). Cloning of the steroidogenic acute regulatory (StAR) protein (28), the subsequent finding of mutations in the StAR gene responsible for the steroid deficiency disease, lipoid adrenal congenital hyperplasia (29, 30), as well as the knockout of this gene in the mouse (31) have identified this ACTH-inducible protein as a key modulator of cholesterol transport into mitochondria. A second protein involved in this process is the peripheral-type benzodiazepine receptor (PBR), which completes the final step of cholesterol delivery to CYP11A1 (P450_scc) for transformation into pregnenolone (32, 33). ACTH also up-regulates the immediate early genes c-fos and c-jun via the PKA pathway (25, 34, 35). A positive feedback loop for the long-term effects of ACTH is established by the hormone up-regulating its own receptor (36, 37).

View larger version (54K): [in this window] [in a new window]   Figure 1. Regulation of steroidogenesis by ectopic hormone receptors in fasciculata cells of adrenal CS. ACTH is the physiological modulator of steroidogenesis in the adrenal cortex. Binding to its receptor (ACTHR) activates AC and leads to cAMP production with cAMP-dependent protein kinase (PKA) activation and phosphorylation of specific TFs (SF-1, NGFI-B, Sp-1, Pbx-1, CREB) that regulate free cholesterol availability and steroidogenic enzymes expression. ACTH also regulates the early steps of steroid synthesis by the direct activation of CYP enzymes. The ectopic expression of membrane hormone receptors functionally coupled to steroidogenesis confers inappropriate sensitivity to adrenocortical cells either to GIP, to catecholamines (E, NE), or to other hormones (LH/hCG, TSH, etc...). These ectopic or abnormal receptors probably regulate steroidogenesis in adrenal CS by mimicking the cellular events triggered by ACTHR activation. N, Nucleus; M, mitochondria; E, epinephrine; NE, norepinephrine. [Modified with permission from N. N'Diaye et al.: Horm Metab Res 30: 440–446, 1998 (10 ). © Georg Thieme Verlag.]

Many ACTH effects are mediated by specific transcription factors (TFs), including orphan nuclear receptors such as nur77 (also called NGFI-B) (39) or steroidogenic factor 1 (SF-1) (40, 41). Indeed, stressful stimuli induce SF-1 and nur77 transcription in corticotrophs and in the adrenal cortex (39, 42). Nur77 and SF-1 both modulate the expression of steroidogenic enzyme genes in the adrenal cortex, nur77 being activated by dephosphorylation and SF-1 by putative PKA-dependent phosphorylation (41, 43, 44).

As an example, SF-1 is involved in the regulation of CYP YP11A (45, 46, 47, 48) and CYP17 (49, 50), where it has been postulated to play a role in constitutive and cAMP-regulated expression. The analysis of the promoter regions of these genes has led to the identification of cAMP-responsive sequences (CRS) and TFs that bind them or synergize cAMP-dependent transcription; general TFs, as cAMP response element (CRE)-binding (CREB) protein and the homeodomain protein Pbx1, both bind CRS and drive cAMP-dependent expression of steroidogenic genes (51, 52, 53, 54, 55). Another ubiquitous TF, Sp1, was shown to regulate basal and cAMP-dependent expression of the CYP11A gene (56). Recent data have suggested that SF-1 is able to mediate cAMP-induced transcription of the CYP17 gene: the proximal CRS (CRS2: –80 to –40) has been identified as a SF-1 binding site (57); moreover, a dominant negative mutation preventing SF-1 binding suppresses cAMP-regulated expression of a reporter gene (58). The coactivator CREB-binding protein (CBP/p300) has been proposed to integrate the effects of TFs such as SF-1, Sp1, CREB, and probably Pbx1 for the regulation of CYP11A and CYP17 genes (59, 60). Moreover, nur77 and nurr1 (nur-related factor 1) positively regulate POMC expression in the pituitary (61, 62). SF-1 up-regulates StAR expression and activity (63). Knockout nur77–/– mice demonstrate no remarkable phenotype (64), suggesting that other members of the nur family play redundant roles, perhaps in humans as well. In contrast, SF-1 appears to be essential for the development and survival of steroidogenic organs, as SF-1–/– mice lack adrenal glands and gonads and exhibit male-to-female sex reversal of their genitalia (65, 66).

Increasing evidence indicates that adrenocortical steroidogenesis is modulated not solely by ACTH but also by multiple circulating and local peptide hormones, neuropeptides, neurotransmitters, ions, and cytokines (11, 67, 68, 69, 70). Both in vivo and in vitro studies have clearly demonstrated that AVP stimulates aldosterone and cortisol secretion in bovine adrenals (71, 72); in rat cells, AVP stimulates aldosterone but not corticosterone secretion (73, 74). However, it stimulates aldosterone (250%) and cortisol (60–260%) secretion from normal human adrenals in vitro (75, 76, 77) via activation of V1-AVP receptors (V1-AVPR) localized mainly in compact cells of the zona reticularis and, to a lesser extent, in the zona glomerulosa (ZG) and fasciculata (68, 74, 78, 79). V2-AVPR were not detected initially in human adrenal cortex tissues (68), but were identified recently by RT-PCR studies (79); their stimulation by DDAVP does not modulate steroidogenesis (79, 80). V3-AVPR (or V1bR) are not detected in the normal human adrenal cortex (79), but are expressed in rat and human chromaffin cells (68, 77, 81), where AVP can stimulate catecholamine release from the adrenal medulla. Thus, AVP could exert significant direct effects on adrenal cortex function, both in endocrine and paracrine modes, but its physiological role has not yet been clearly established. However, in patients with congenital central diabetes insipidus, there is no evidence for clinically significant decreased cortisol secretion (82, 83).

Catecholamines have also been shown to stimulate cortisol and aldosterone secretion in vitro in bovine, pig, and fowl via ß1-adrenoreceptors (11, 84, 85), but this does not appear to occur in human adrenocortical cells (86). Serotonin (5-HT) is another neurotransmitter that may play a role in the control of steroidogenesis (87). 5-HT is able to directly trigger cortisol and aldosterone release, as demonstrated in vitro, in rat, frog, and human adrenal cells (87, 88, 89) but also, indirectly, by stimulating adrenal blood flow (90). The receptor subtype involved in these adrenal effects is still controversial in the rat, but was determined to be 5-HT4 receptor (5-HT₄R) in frogs and humans (88, 89). The 5-HT₄R is positively coupled to the cAMP and calcium pathways. In vivo, 5-HT4 agonists such as cisapride or zacopride induce an increase in aldosterone but not in cortisol secretion in humans (91, 92). Possible paracrine control of steroidogenesis by 5-HT can be proposed since its presence has been demonstrated in human perivascular mast cells and in chromaffin cells of the frog, rat, and mouse adrenals (93, 94, 95). Central 5-HT is known to enhance ACTH release from the pituitary and to activate the systemic renin-angiotensin system (RAS) to stimulate aldosterone secretion. However, no study has established whether these secretory responses can occur within the adrenal gland in vivo.

VIP and PACAP have been shown to play a paracrine role in the secretory activity of the adrenal cortex in the rat, human, and cow, as they are synthesized by adrenomedullary chromaffin cells (18). VIP stimulates aldosterone release from ZG through the activation of selective VIP receptors (VIPR2/VIPR3), whereas it stimulates cortisol secretion moderately through the nonspecific activation of ACTH receptor (ACTHR) (96, 97, 98). VIP/PACAP-induced adrenal steroidogenesis can also be enhanced by an indirect mechanism: indeed, both stimulate catecholamine secretion from adrenal chromaffin cells (99, 100), which in turn elicit a ß-adrenoreceptor-mediated aldosterone release (101, 102). Moreover, cortisol secretion can be raised by increasing the intraadrenal blood flow as it is stimulated by VIP and PACAP (103, 104).

Ang-II, the biologically active peptide of the RAS, and potassium ion are the major regulators of aldosterone synthesis and secretion (2). A decrease in potassium balance activates the RAS, leading to Ang-II, and then to aldosterone release. Ang-II mediates its effect on steroidogenesis via AT1 receptors (AT1R), which are coupled to phospholipases C and A₂ (PLC, PLA₂). It has been demonstrated that Ang-II inhibits the expression of P450c17 at the transcriptional level in ovine adrenocortical cells (105). Moreover, it augments the expression of StAR protein (106). In the rat, Ang-II enhances the transcription of AT1R and P450 aldo synthase (CYP 11B2) in vivo and in vitro (107, 108). However, Ang-II seems to inhibit AT1R expression in bovine and human fasciculata cells (109, 110). The presence of a local RAS in the adrenal cortex suggests that Ang-II can regulate aldosterone production in a paracrine fashion (111) (for review see Refs. 112, 113). Inhibitory signals contribute to maintain aldosterone homeostasis. Dopamine and somatostatin blunt Ang-II-induced aldosterone production (114, 115). The natriuretic peptides ANP and C-type natriuretic peptide (CNP), which are present in the circulation but are also expressed in the adrenal medulla, have been demonstrated to exert an inhibitory action on aldosterone release in vitro (116, 117). ANP also inhibits ACTH and Ang-II-induced cortisol production by decreasing the level of StAR expression (118). Other neuropeptides regulate the steroidogenic function of the adrenal cortex by acting both at the central and adrenal levels, as endothelin 1 (ET-1) (119, 120) and NPY (121, 122) enhance cortisol and aldosterone release.

Recent attention has been drawn to leptin as a negative regulator of the HPA axis. Acute injection of leptin in humans (123) and mice (124) counteracts fasting-induced activation of the HPA axis. This effect is proposed to be driven by a direct action of the peptide, both at the hypothalamic and adrenal levels (125). Leptin and its receptor, Ob-R, are expressed in the pituitary (126, 127) and in human, rat, and mouse adrenal glands (128, 129, 130). Moreover, the adrenal is embedded in adipose tissue, the physiological source of leptin, which acts at the transcriptional level to prevent the stress-induced stimulation of CRH and CYP17 mRNAs in the hypothalamus and adrenal, respectively (131, 132, 133). Other studies have shown opposite effects of leptin on the pituitary where CRH (known to suppress appetite and food intake) and ACTH levels are stimulated, leading to cortisol secretion (134, 135). These discrepancies may arise from anatomic and functional differences in CRH neurons in the PVN where leptin might have inhibitory effects on some and stimulatory effects on other populations of cells. Leptin is induced by GCs (136, 137), resulting in higher plasma levels in CS patients (138, 139).

The integrity of adult adrenal size is maintained by a continuous process of cell division in the ZG and centripetal migration and differentiation into fasciculata cells (140). Chronic stimulation by ACTH induces a phenotypic change of glomerulosa cells into fasciculata cells (141) whereas GCs inhibit this differentiation process namely by reducing P450scc expression (142, 143, 144); it was proposed that GCs may play a role in the functional zonation of the adrenal cortex (11). Indeed, high levels of GC (as high as in the inner adrenal cortex owing to centripetal blood flow) were shown to inhibit the 18-hydroxylation step in ACTH-treated cultures of human fetal adrenals, thus decreasing 18-OH-deoxycorticosterone (DOC) and aldosterone levels (11). In contrast to GC, ACTH can lead in vivo to hypertrophy and hyperplasia of the adrenal cortex, a process that is reversible. Paradoxically, it seems to harbor inhibitory effects on cell proliferation in vitro. A trophic effect is observed after a 2-h exposure to ACTH. This is correlated with a PKA-dependent increase of c-Jun and c-Fos expression (145, 146). After 24 h of stimulation, c-Myc expression is decreased, and inhibition of cell growth is observed (145, 147). Recent data suggest a cAMP-independent proliferation-promoting effect of ACTH (148, 149). Indeed, ACTH was shown to stimulate the mitogen-activated protein (MAP)-kinase pathway in vivo and in vitro, leading to the accumulation of c-Fos, c-Jun, and c-Myc (147, 150). Ang-II is another peptidic hormone that can also activate the MAP-kinase cascade in adrenal cells in a PKC-dependent mechanism (146, 151). In vivo, a chronic stimulation with Ang-II induces ZG hypertrophy. ET-1 also augments cell proliferation in the ZG in vitro and in vivo by interacting with its ET_A receptor, which is specifically expressed in the ZG (119). Chronic treatment with VIP exerts a moderate hyperplasia of ZG in vivo (152, 153). Somatostatin exerts direct antiproliferative effects on the ZG in vivo (115). It can also antagonize the mitogenic action of Ang-II. ACTH stimulates the autocrine production of growth factors (GFs) such as insulin-like growth factor I (IGF-I), IGF-II, and transforming growth factor-ß1 (TGF-ß1), which regulate the trophic and steroidogenic functions of the adrenal cortex in vivo (11, 154). IGF-I and IGF-II have mitogenic effects. IGF-II is more highly expressed in fetal than in adult adrenals (155). In addition, it is highly expressed in hormonally active adrenocortical carcinomas but not in benign tumors, which suggests an important role in tumor acquisition or progression (156, 157). In bovine cells, IGF-I and TGF-ß1 exert opposite effects on adrenocortical function by inhibiting the expression of specific adrenal genes; IGF-I enhances the transcription level of ACTH-R, StAR, and specific steroidogenic enzymes, whereas TGF-ß1 inhibits it (158). TGF-ß1 is thought to play a role in human fetal adrenal remodeling, as it inhibits fetal zone cell proliferation and promotes apoptosis in vitro (159, 160). However, this has not been demonstrated in vivo.

	III. Primary Adrenal Cushing’s Syndrome (CS)

Top Abstract I. Introduction II. Hormonal Regulation of... III. Primary Adrenal... IV. Initial in Vitro... V. In Vivo Demonstration... VI. Investigation Strategy VII. Molecular Mechanisms of... VIII. Ectopic/Abnormal Hormone... IX. An Opportunity for... X. Summary and Conclusions References

 
The incidence of CS has not been determined with great precision. The increasing frequency of subclinical cortisol-secreting adrenal lesions, identified during the evaluation of adrenal incidentalomas, renders precise estimation of the true incidence even more difficult. The incidence of clinical CS secondary to unilateral adrenal adenoma is approximately two cases per million per year (161); this estimate is close to that of 1.7 per million per year for adrenocortical carcinoma, where clinically significant hormonal secretion occurs in 30–60% of cases, including clinical hypercortisolism, in approximately half of the hormonally active cases (162, 163, 164). Since pituitary Cushing’s disease is approximately 3-fold more frequent than primary adrenal disease, its incidence would be close to five to six cases per million per year. When clinically detectable ectopic ACTH secretion is also taken into account, the overall incidence of endogenous CS would reach approximately 10 cases per million per year.

Primary adrenal etiologies account for 15–20% of endogenous CS in adults and are secondary to unilateral tumors in 90–98% of cases (1, 2, 163); in contrast, in prepubertal children, primary adrenal causes are responsible for almost 65% of CS. In adults, some case series have suggested that adenomas and carcinomas are equally responsible for adrenal CS, whereas in other series, adenomas were responsible for up to 80% of cases (165, 166). Cortisol-secreting adrenal carcinomas are 3–4 times more frequent than adrenal adenomas in children. For unclear reasons, adrenal tumors are more frequent in females than in males with a ratio of 4:1 for adenomas and 2:1 for carcinomas (161, 162, 163, 164).

Less than 10% of ACTH-independent CS can be secondary to bilateral adrenal lesions, and their pathophysiology is diverse. Primary pigmented nodular adrenocortical disease (PPNAD) or micronodular adrenal dysplasia can be familial, associated with other tumors such as myxomas, schwannomas, pigmented cutaneous lesions, and peripheral endocrine tumors (Carney’s complex), and linked to unknown genes on chromosome 2 or to mutations of protein kinase A Type 1- located on chromosome 17 (167, 168, 169 169A ). In PPNAD, the overall size of the adrenal gland is usually not enlarged, but is occupied by several small black or brown nodules spread in an otherwise atrophic cortex. High synaptophysin expression in PPNAD nodules suggests a neuroendocrine phenotype of these cells (170). A paradoxical increase in cortisol production is often found in these patients during Liddle’s dexamethasone suppression test (171). In McCune-Albright syndrome, activating mutations of G_s occur in some adrenal cells in a mosaic pattern during early embryogenesis and lead to the formation of adrenal nodules, in which constitutive activation of AC and the steroidogenic cascade produce increased cortisol secretion with ACTH suppression; the internodular adrenal cortex, where the G_s mutation is not present, becomes atrophic (172, 173).

ACTH-independent bilateral macronodular adrenal hyperplasia (AIMAH) is a rare cause of CS, as it is estimated to represent less than 1% of all endogenous cases of this syndrome (1, 2, 3, 4). In a review by Lieberman et al. (174) in 1994, only 24 published cases had been identified, but several other cases and series have been reported since then (175, 176, 177, 178). AIMAH has been described by various terms, including massive macronodular adrenocortical disease (MMAD), autonomous macronodular adrenal hyperplasia (AMAH), ACTH-independent massive bilateral adrenal disease (AIMBAD), and "giant" or "huge" macronodular adrenal disease (175). The clinical syndrome becomes evident during the patient’s fifth or sixth decade and has a relatively even gender distribution when compared with Cushing’s disease or unilateral adrenal tumors, which are more prevalent in women. Most cases have been sporadic, but a few familial cases have been reported as well (179, 180, 181, 182). An activating R201S mutation of G_s was found in the AIMAH tissues of a patient without any other features of McCune-Albright syndrome (183).

	IV. Initial in Vitro Evidence of Ectopic Adrenal Membrane Hormone Receptors

Top Abstract I. Introduction II. Hormonal Regulation of... III. Primary Adrenal... IV. Initial in Vitro... V. In Vivo Demonstration... VI. Investigation Strategy VII. Molecular Mechanisms of... VIII. Ectopic/Abnormal Hormone... IX. An Opportunity for... X. Summary and Conclusions References

 
The concept of ectopic adrenal membrane receptor expression was proposed initially by Robert Ney and his collaborators in 1971 (8, 9, 184). In studying the role of AC in mediating the effects of ACTH in rat adrenal steroidogenesis, only ACTH was capable of stimulating AC in normal cortex membrane preparations; however, in corticosterone-producing rat adrenocortical carcinoma 494, they demonstrated that AC was stimulated by hormones other than ACTH, such as epinephrine, norepinephrine, and TSH (8). Catecholamine effects on AC were induced by ß-, but not by -, adrenergic agonists. Further studies (Table 1) indicated that AC from this tumor was also stimulated by FSH, LH, and slightly by PGE₁) (184), but not by glucagon, insulin, vasopressin, PTH, or calcitonin. Propranolol was able to block the effects of catecholamines but not of other hormones on AC. The illicit hormones exerted no additive or synergistic actions, suggesting that the tumor possessed multiple specific receptors which activated a common AC (Fig. 1). The presence of ectopic and functional ß-adrenergic receptors was also confirmed by other groups (185, 186); high-affinity ß-adrenergic binding sites and AC stimulation were observed in rat adrenocortical carcinoma 494 membranes, but not in normal adrenal membranes (185). A direct effect on steroidogenesis could not be verified in these initial studies, as AC was not efficiently coupled to steroidogenesis in rat adrenal carcinoma 494 (186). The aberrant response of AC to various hormones is not a universal phenomenon, as the AC of the Y1 mouse adrenocortical tumor cell line was found to be stimulated by ACTH, but not by epinephrine, PTH, insulin, glucagon, TSH, or PGE₁ (187). The presence of ectopic - adrenergic receptors stimulating guanylate cyclase and cGMP production was also demonstrated in rat adrenal carcinoma 494 (188, 189).

Other in vitro studies have further supported the functional coupling of several, most frequently G protein-linked, membrane hormone receptors to steroidogenesis in some human adrenocortical benign and malignant tumors (Table 1). Millington et al. (190) investigated the effects of various hormones on the secretion of steroids in a human feminizing adenocarcinoma secreting mostly estrogens and androgens, but also some GC. AC activity was stimulated more by PRL, human placental lactogen, LH, and FSH preparations than by ACTH; insulin inhibited AC slightly, while TSH was without effect. In tumor explant culture, estrone and estradiol secretion was stimulated by PRL, insulin, and ACTH, but little by LH or GH. Androstenedione secretion was augmented by LH, GH, PRL, and ACTH. The synthesis of 11-hydroxycorticosteroids was stimulated by LH, GH, and PRL, but very little by ACTH. It must be stressed that hormone preparations available at that time were not pure and that contamination was quite possible. Matsukura et al. (191) studied AC activity in human cortisol-secreting adrenal tissues from adenomas, adenocarcinoma, and primary nodular hyperplasia (AIMAH), compared with normal adrenals and bilateral hyperplasias from pituitary Cushing’s disease. In normal tissues, only ACTH and PGE₁ stimulated AC activity; in most adenomas, AC activity was increased by norepinephrine, in some by epinephrine, and in a few by TSH, LH, or Ang-II. In a case of AIMAH, AC was stimulated by glucagon and ACTH only. No stimulation of AC was found in adrenal carcinoma tissue. Hirata et al. (192) demonstrated the presence of high-affinity ß-adrenergic binding sites in two of three cortisol-secreting adenomas, but not in the normal adrenal cortex or in one case of aldosterone-producing adenoma; furthermore, epinephrine stimulated cortisol secretion in cultured tumor cells from one of the patients with an adenoma, and Katz et al. (193) studied six human adrenal carcinomas with diversified steroidogenic activities and compared them with the normal adrenal cortex from three individuals; AC was stimulated by ß-adrenergic agonists in four of six tumors but not in normal tissues. In one tumor examined for other hormone responses, AC was also stimulated by TSH, but not by glucagon or hCG. In two cases, membranes from metastatic adrenocortical cancer were compared with the primary tumor and had lost stimulation of AC by epinephrine or ACTH. Specific high-affinity ß-adrenergic binding sites were detected only in tumors in which AC was stimulated by ß-adrenergic agonists. In contrast, Saez et al. (194) did not find any AC responsiveness to norepinephrine, glucagon, and TSH in crude adrenal membranes from 11 patients with adenomas and carcinomas.

The aberrant expression of LH/hCG receptors was also previously reported in vitro in androgen-secreting adrenal adenomas (195, 196). Testosterone production was stimulated by hCG and ACTH in adrenal adenoma cells in culture, while only ACTH but not hCG was able to stimulate secretion of cortisol, testosterone, and other steroids from the adjacent normal adrenal cortex (195); binding studies performed on cell membranes from hCG-responsive adrenal adenoma demonstrated high-affinity (0.14 nM) binding capacity (198 fmol/g). A preliminary report of the presence of LH/hCG receptor in a cortisol-secreting adrenocortical carcinoma was presented recently (197).

Willenberg et al. (198) investigated the adrenal adenoma of a 62-yr-old woman who presented CS with no particular clinical characteristics; striking lymphocytic infiltration of the adenoma was identified at histology. In contrast to normal control human adrenals or other cortisol-secreting adenomas or carcinomas, immunostaining revealed CD45 and CD68-positive macrophage-like cells in this patient’s adenoma, and these cells are a major source of IL-1. Type I IL-1 receptor, which is not a seven-transmembrane G-coupled-receptor, was also found to be aberrantly expressed in the adenoma, by in situ hybridization and RT-PCR, but not in the normal adrenal cortex or other tumors. In cells dispersed from the adenoma, cortisol secretion was stimulated 2.6-fold by IL-1ß, but poorly by ACTH (198); in normal adrenocortical cells or other cortisol-secreting adenomas, cortisol secretion was increased by approximately 1.5-fold during incubation with IL-1ß. Since infiltration of mononuclear cells occurs in 15% of adrenal tumors, it will be of interest to further explore the prevalence of abnormal cytokine receptor expression in adrenal hyperplasias and tumors.

	V. In Vivo Demonstration of the Functionality of Ectopic or Abnormal Membrane Hormone Receptors

Top Abstract I. Introduction II. Hormonal Regulation of... III. Primary Adrenal... IV. Initial in Vitro... V. In Vivo Demonstration... VI. Investigation Strategy VII. Molecular Mechanisms of... VIII. Ectopic/Abnormal Hormone... IX. An Opportunity for... X. Summary and Conclusions References

 
The proposed concept of ectopic hormone receptors had been demonstrated in vitro only, until it found a clinical manifestation of its significance, in vivo, with the description of food-dependent CS (199); this resulted from ectopic adrenal expression of the receptor for a gastrointestinal hormone called gastric inhibitory polypeptide or GIP (200, 201).

A. Food- and GIP-dependent CS
Hamet et al. (199) were the first to identify "food-dependent" cortisol production in a 41-yr-old male patient presenting with CS secondary to a unilateral adrenal adenoma and periodic hormonogenesis. Plasma cortisol was consistently low in the morning or during fasting, but increased to abnormal levels after meals; food-induced elevations of plasma cortisol were not suppressed by high oral doses of dexamethasone. AC activity in the resected adrenal adenoma membrane preparation was stimulated 27% by ACTH and 62% by vasopressin, but not by FSH, glucagon, or Ang-II; the effects of various gastrointestinal hormones were not examined in this case. Another female patient with CS secondary to an adrenal adenoma had been previously reported to have "persistent diurnal cortisol secretory rhythm" (202); the low fasting plasma cortisol levels in the morning increased during the day at the presumed, but not indicated, meal times, suggesting that this patient also had food-dependent CS.

Two patients with bilateral AIMAH and food-dependent cortisol production were studied in detail a few years later and allowed to clarify the pathophysiology of this syndrome (200, 201). The first patient, a 48-yr-old French-Canadian woman, presented with typical symptoms of CS, which had become manifest during the previous 2–3 yr (200). Initial investigation revealed low plasma cortisol levels, fasting in the morning, and higher levels during the day, whereas plasma ACTH was always suppressed. The suspicion that cortisol production was regulated by a gastrointestinal hormone came from the observation that plasma cortisol was stimulated by oral administration of glucose or by lipid-rich or protein-rich meals, but not by intravenous glucose. In addition, somatostatin pretreatment inhibited the cortisol-stimulatory effect of oral glucose. A review of the various secretagogues of gastrointestinal hormones indicated that only GIP and the glucagon-like peptides (GLPs) were stimulated significantly by oral glucose and lipids, and to a lesser extent by proteins. Plasma cortisol levels were correlated with plasma GIP concentrations during the various test meals. In vivo GIP infusion, to reproduce physiological postprandial concentrations, augmented cortisol production in the patient, but not in four normal controls. In the patient, plasma cortisol was stimulated by the administration of ACTH but not by CRH, glucagon, insulin-induced hypoglycemia, pentagastrin, or AVP. The presence of GIP receptors (GIPRs) in adrenal tissues was supported by adrenal imaging after the injection of [¹²³I]-GIP in vivo (200). The incubation of dispersed adrenal cells in vitro confirmed GIP-mediated cortisol secretion in the patient’s cells, whereas no cortisol response to GIP was found in normal adult or fetal adrenal cells or in other cortisol- or aldosterone-secreting adenomas (200); there was no stimulation of cortisol production in the patient’s adrenal cells after in vitro incubation with secretin, CCK, VIP, substance P, bombesin, calcitonin gene-related peptide, glucagon, vasopressin, ANP, CRH, TRH, GHRH, neurotensin, or neurokinin A. It was thus concluded that food-dependent cortisol secretion resulted from the abnormal responsiveness of adrenal cells to the physiological secretion of GIP; "illicit" or ectopic GIPR expression on adrenal cells (Figs. 1 and 2) presumably were the basis for this new etiology of CS (200).

View larger version (45K): [in this window] [in a new window]   Figure 2. HPA axis in GIP-dependent CS. The ectopic adrenal expression of the GIPR (in red) has been identified both in bilateral macronodular adrenal hyperplasia (left of figure) or in unilateral adrenal adenomas (right side of figure). After food ingestion, GIP is released in physiological concentrations by K cells from the duodenum and small intestine and binds to the ectopic adrenal GIPR; this results in postprandial supraphysiological increases of plasma cortisol (full black lines) which exerts its negative feedback on CRH and ACTH synthesis. In the absence of food ingestion (low plasma GIP levels), the suppressed levels of plasma ACTH (dashed blue lines) leads to decreased occupation of the ACTHR (decreased expression) and low fasting levels of plasma cortisol. A somatic postzygotic mutation occurring in a single cell leading to GIPR expression would eventually result in the growth of a GIP-dependent monoclonal unilateral cortisol-secreting adenoma with adjacent and contralateral adrenal cortex atrophy (right side of figure). A somatic mutation occurring during early embryonal life and responsible for ectopic GIPR expression in the progenitor cells of the adrenal cortex (polyclonal) would be responsible for the long-term development of nonfamilial GIP-dependent bilateral macronodular adrenal hyperplasia and CS (left hand side of figure).

Food- or GIP-dependent CS has now been identified in 13 patients with AIMAH (139, 200, 201, 205, 206, 207, 208) and in seven with unilateral adenoma (199, 205 208A, 213), as summarized in Table 2. At pathological examination, no distinctive features were reported, compared with non-GIP-dependent cortisol-secreting adenomas or bilateral macronodular hyperplasia, except in one case (207). This patient was described in a preliminary report to have facial pigmented spots, a blue nevus on one leg, lipofuscin pigments in bilateral adrenal macronodules, and a periadrenal schwannoma suggestive of Carney’s complex without any family history; a full description has not yet been published, but in vitro studies clearly confirmed GIP-induced stimulation of cortisol secretion by adrenal cells (205). In two cases of AIMAH, the patient initially presented with a unilateral lesion and developed contralateral enlargement only later in time (206 208A ). Except for three patients [the first patient described with food-dependent CS but not proven to be GIP-dependent (199) and two recent ones with AIMAH (GIPR overexpression not yet confirmed)], all other patients are females; adrenal CS is more frequent in females (161), but it remains to be seen whether an even higher female frequency will be found in GIP-dependent CS and what molecular mechanism underlies this sex distribution. Average age at the time of diagnosis may be somewhat greater in patients with AIMAH than in patients with unilateral adrenal adenoma (Table 2) (174, 175); the youngest patient with a unilateral adenoma was only 15 yr old. In GIP-dependent CS, chronic GIP-induced hypercortisolism eventually leads to suppression of CRH and ACTH; this suppression, coupled with low GIP levels in the fasting state, is responsible for the decreased plasma cortisol levels, which can be accompanied by symptoms of relative cortisol insufficiency (201, 209). However, in certain patients (Table 2), fasting plasma cortisol levels were not particularly low, indicating that GIP-dependent CS should not be excluded without performing a test meal (139, 206); this finding could indicate that subpopulations of adrenal cells in the tumor or hyperplasia have lost their GIP dependency and are secreting cortisol under different mechanisms, or that more than one abnormal receptor regulating cortisol production are expressed in these cells. In one patient with food-dependent AIMAH but in whom fasting plasma cortisol was relatively elevated, Pralong et al. (139) reported that, in addition to GIP, leptin also aberrantly stimulated cortisol secretion in dispersed adrenal cells; thus, the potential presence of more than one abnormal receptor may modify the phenotypic appearance. The potential presence of ectopic GLP-1 receptors has been excluded to date by the lack of stimulation of cortisol production after GLP-1 administration, either in vivo or in vitro (139, 206, 210). In one patient with GIP-dependent AIMAH, plasma ACTH and cortisol responses to CRH were still preserved, presumably because the intermittent food-dependent 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.

De Herder et al. (209) used in situ hybribization to demonstrate abundant GIPR mRNA in adrenal adenoma cells from their patient with GIP-dependent CS; this signal was not present in the adenoma from a patient with non-food-dependent CS, but was not examined in the normal adrenal cortex in this initial study. Using RT-PCR amplification, N'Diaye et al. (219) demonstrated pronounced adrenal GIPR overexpression in adrenal adenoma or hyperplastic tissues from GIP-dependent CS compared with the normal human pancreas, normal adult or fetal adrenal cortex, or non-GIP-dependent adrenal CS tissues. A small amount of GIPR mRNA was detected in normal fetal and adult adrenal tissues after at least 35 cycles of amplification and hybridization with the labeled cDNA but was not coupled efficiently to steroidogenesis. Sequence analysis of the full-length cDNA of normal and GIP-dependent adrenal tissues revealed no mutation of GIPR in the affected adrenal tissues (219); similar proportions of isoforms lacking exons 4 and 9 were identified in normal and GIP-dependent adrenals. Chabre et al. (210) confirmed the presence of the same overexpressed GIPR isoforms in a GIP-dependent adenoma by RT-PCR and sequencing; no GIPR bands could be detected in the atrophic adrenal cortex adjacent to the tumor or in normal adult adrenals, but only ethidium bromide staining was used. The ACTHR was found to be expressed at a lower level in GIP-dependent adenoma compared with normal tissues (210); this may be secondary to the chronic suppression of endogenous ACTH, which is known to up-regulate ACTHR expression (36, 37). If the relative suppression of ACTHR in GIP-dependent adrenal tissues is confirmed in further studies, 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 small amount of GIPR mRNA sometimes found in normal fetal or adult adrenal tissues after amplification was not efficiently coupled to steroidogenesis (219) and may reflect a low number of GIPR in endothelial cells (214) rather than in adrenocortical cells. Thus, the concept of functional ectopic receptors remains valid in explaining the pathophysiology of GIP-dependent CS (Figs. 1 and 2).

It has been reported that the in vitro cortisol-stimulating effects of GIP are coupled to an increase of cAMP, but not of IP₃ production (205, 210). In studying GIP-dependent adrenal cells in primary culture, GIPR down-regulation by its own ligand has been demonstrated, as assessed by the induction of steroidogenic enzyme expression, cortisol secretion, or GIPR mRNA levels by in situ hybridization and RT-PCR studies (205, 220). By stimulating steroidogenic enzyme activity, ACTH pretreatment of cells increased the GIP-induced cortisol response but did not appear to modify GIPR expression directly (205).

Stimulation of thymidine incorporation into newly synthesized DNA by GIP was observed in primary cultures of adrenal cells from GIP-dependent CS, but not in normal cells (210). Activation of p42-p44 MAP kinases was observed after treatment of pathological cells with GIP (210). Depending on the cell culture conditions used, ACTH can be shown to inhibit or stimulate markers of cell proliferation in adrenal cells. In the studies by Lebrethon et al. (205), under conditions where ACTH inhibited thymidine incorporation in normal and GIP-dependent adrenal cells, GIP was also found to suppress DNA synthesis only in GIP-dependent, and not in normal adrenal cells. Such results suggest that GIP is possibly capable of regulating cell proliferation, in addition to steroidogenesis, in these tissues; however, cell growth stimulation by GIP has not yet been clearly demonstrated.

It should be stressed that food-induced cortisol secretion has been reported in some non-GIP-dependent CS. Bercovici et al. (221) described a patient with pituitary Cushing’s disease in whom ACTH and cortisol were increased strikingly after mixed meals. ACTH secretion was stimulated by protein-rich meals, but not by oral glucose or lipid-rich meals. Intravenous infusion of amino acids was capable of inducing this response, while octreotide administration did not modify urinary cortisol levels. It was concluded that the pituitary corticotroph adenoma of this patient retained the capacity that normal corticotroph cells have to enhance their release of ACTH after protein ingestion. It has been shown very clearly that, in normal individuals, mixed meals produce an increase in ACTH release and in plasma cortisol levels; this is more evident at lunchtime than after breakfast, when the diurnal peak of ACTH and cortisol may mask the response (222, 223, 224). This stimulation is of hypothalamic-pituitary origin and is abolished by dexamethasone administration (225). It is believed that the effect may be secondary to the heightened serotonin production and related to tryptophan content in the meal (224). -Adrenergic agonists can also increase postprandial stimulation of ACTH (226).

B. Vasopressin-responsive CS
A large proportion of pituitary corticotroph adenomas have been shown to augment their ACTH release after LVP administration, resulting in increased plasma cortisol levels (227, 228). In contrast, in adrenal CS, where ACTH is suppressed, it is expected that plasma cortisol should not increase after LVP administration (229). However, abnormal adrenal stimulation of cortisol secretion in response to exogenous AVP or LVP administration has been described in canine (230) and human ACTH-independent CS, secondary to unilateral adrenal adenomas, carcinomas, or AIMAH (Table 3).

Horiba et al. (234) reported two male Japanese patients with bilateral macronodular adrenal hyperplasia and clinical CS in whom im injection of 10 IU LVP increased plasma cortisol 2.3- to 2.6-fold, while plasma ACTH remained undetectable; there were no ACTH or cortisol responses to CRH or dexamethasone. Upon pathological examination, the glands were replaced by macronodules composed of compact and clear cells, but there were some regions of cortical internodular atrophy. In dispersed adrenal cells from both patients, LVP stimulated cortisol secretion (2.8- to 3.2-fold) more efficiently than ACTH. In seven other patients with CS and unilateral adenoma, LVP injection resulted in small increases of plasma cortisol, varying between 9.8 and 25.3%. In four normal subjects pretreated with 2 mg dexamethasone at bedtime and 0.5 mg on the morning of the test, LVP injection elevated plasma cortisol 1.6- to 1.8-fold (up to 45 nmol/liter from basal levels of 20.9 nmol/liter). An exaggerated 2.6-fold rise in plasma cortisol after 10 IU of LVP was also reported in a patient with a unilateral cortisol-secreting adenoma and mild ACTH-independent CS (235). Intracellular calcium flux in dispersed tumor cells was stimulated by AVP and inhibited by a V1-AVPR antagonist. Using RT-PCR amplification, the V1-AVPR signal was stronger in the cortisol-secreting tumor than in the normal gland; there was a faint V2-AVPR signal in normal and tumoral adrenal tissues, and no V3-AVPR in either.

A 36-yr-old female American patient with CS and AIMAH presented an unusual association with orthostatic hypotension (80). Exogenous AVP, but not desmopressin, triggered large elevations of plasma cortisol (3.4-fold) and aldosterone (67-fold) levels. During upright posture and hypotension, cortisol and aldosterone secretion increased, despite the suppression of ACTH and renin levels. AVP, which normally rises during upright posture and even further in orthostatic hypotension, remained below the limit of assay detection, until the correction of hypercortisolism. Under dexamethasone suppression, plasma cortisol, aldosterone, and androgens were elevated by exogenous AVP in the patient, but not in the controls. Cells freshly dispersed from the diffuse adrenal hyperplasia displayed higher cortisol stimulation (4.2-fold) during incubation with AVP than normal adrenal cells (1.3-fold); the cortisol response was mediated by V1-AVPR, as shown by the effects of V1 antagonists and the lack of effect of V2 agonists. The presence of V1-AVPR was supported by binding studies, intracellular Ca²⁺ flux studies, and RT-PCR amplification of mRNA for all three AVPR. The binding studies revealed a similar V1-AVPR affinity (2.63 nM) in AIMAH adrenal cells, compared with membranes from human glomerulosa-rich normal adrenal cells or myometrium (236). The ED₅₀ of AVP on [Ca²⁺]_i was similar in the adrenal cells of the patient (0.9 nM) compared with glomerulosa-rich cells (1.4 nM) from normal adrenals (76). Interestingly, CRH administration stimulated cortisol in vivo but not in vitro without any stimulation of ACTH; it is possible that CRH increased the adrenal production of vasopressin (68) and cortisol in a paracrine manner. Alteration of the V1-receptor-effector system was not limited to the adrenal tissues of this patient, as there was also an abnormal, prolonged vascular vasoconstrictive response to AVP, compared with the arterioles of normal or hypertensive subjects. The persistence of decreased stimulation of plasma vasopressin and endothelin levels during postural hypotension, several months after correction of the hypercortisolism, also raised the possibility of an exaggerated V1-AVPR signal at the hypothalamic level in this patient. The causal relationship between abnormal V1-AVPR-mediated-responses and postural hypotension remains uncertain (80). Another male Japanese patient with AIMAH and CS was found to have a 1.8-fold increase in plasma cortisol after LVP injection (237); food intake, GIP infusion, octreotide, and CRH were without effects. Removal of the large bilateral macronodular adrenals showed no areas of internodular atrophy; LVP stimulated cortisol production in cells freshly dispersed from a macronodule. Stimulation of plasma cortisol by administration of 0.2 IU AVP was noted in a Japanese man with AIMAH and coincident multiple adenomatous polyps and colon cancer (238); a point mutation of the APC gene was revealed in the colon cancer but not in the adrenal nodules.

In a retrospective study of 26 patients with CS secondary to unilateral cortisol-secreting tumors, Arnaldi et al. (79) observed an increase of plasma cortisol greater than 30 ng/ml after LVP testing in 27% of cases (five adenomas and two carcinomas). Quantitative RT-PCR assay of V1-AVPR showed that the levels of message were similar in 20 cortisol-secreting adenomas, compared with three normal adult adrenals; the levels were lower in 19 adrenocortical carcinomas, but there was a large overlap with adrenal adenomas. The normal adrenal glands and the majority of tumors also expressed low amounts of V2-AVPR, but no V3-AVPR. Only six of the patients for whom adrenal tumor material was available had undergone LVP testing; responders had somewhat higher V1-AVPR concentrations in their tumors than nonresponders, but the levels were not higher than in normal adrenal tissues. In one patient with an in vivo cortisol response (1.6-fold) to LVP, the AVP-induced cortisol secretion (2-fold) of perifused adrenal cells was inhibited by V1-AVPR antagonists.

The demonstration of an exaggerated cortisol response to pharmacological levels of exogenous vasopressin does not constitute direct evidence that fluctuations of endogenous AVP levels are the main regulator of steroidogenesis in these patients. This was illustrated in a male patient with AIMAH who was shown to have increased plasma cortisol in response to upright posture and administration of 10 IU AVP (86); however, the modulation of endogenous AVP levels by water dilution or hypertonic saline infusion did not modify plasma cortisol levels. In addition, in vivo administration of a V1-AVPR antagonist inhibited the response of cortisol to exogenous AVP, but not to upright posture. In fact, this patient was found to have ectopic ß-adrenergic receptors (see Section V.C.) in his adrenal tissues; it is believed that pharmacological AVP levels stimulated catecholamine release, including from the adrenal medulla (68), and then mediated cortisol release in this case. Further support comes from the fact that there was no evidence of V1-AVPR in his adrenal tissues (N. N’Diaye and A. Lacroix, unpublished observation).

Daidoh et al. (239) studied a 49-yr-old man with very large bilateral AIMAH and severe CS; intravenous injection of small amounts of AVP (0.3 IU) increased plasma cortisol 3.7-fold without any detectable rise in ACTH. Similarly, insulin-induced hypoglycemia elevated plasma AVP and cortisol without any increase in plasma ACTH; catecholamine effects were not studied however. Upright posture augmented plasma AVP and cortisol. Oral administration of the V1-AVPR antagonist OPC-21268 for 8 days decreased urinary free cortisol levels, but potential spontaneous fluctuations of cortisol secretion were not evaluated for long periods. It was further shown, in dispersed adrenal cells, that AVP stimulated cortisol secretion in AIMAH cells but not in normal control cells, and that this effect was inhibited by OPC-21268; GIP was without effects on AIMAH cells, but catecholamine and insulin were not tested directly. We recently studied a 50-yr-old American woman with CS and AIMAH in whom plasma cortisol was stimulated by upright posture (1.7-fold) and exogenous AVP (3.4-fold), but not by dDVAP (240). In this patient, we were able to demonstrate that plasma cortisol was inhibited by water loading (24% decrease), and elevated during hypertonic saline infusion (1.7-fold). This patient was also found to have abnormal responses to ß-adrenergic receptor agonists (see Section V.C.), in addition to the abnormal V1-AVPR response in her adrenals. These last two cases represent the first demonstrations of fluctuations in plasma cortisol levels in parallel with small physiological changes in endogenous vasopressin levels. All the previously reported cases of cortisol stimulation by lysine- (231, 232, 233, 234, 235, 237) or arginine-vasopressin (80) were related to exogenous pharmacological amounts. In these last two patients, as in another patient (80), plasma vasopressin was found to be suppressed to undetectable levels basally and showed only a very modest increase upon potent physiological stimulation. This may be due to the suppressive effects of hypercortisolism on vasopressin gene expression (241). It has also been postulated that abnormal V1-AVPR may modify vasopressin production via a short loop regulation mechanism in hypothalamic nuclei (80).

An abnormal increase of plasma cortisol in response to vasopressin administration was also noted in patients with preclinical bilateral macronodular adrenal hyperplasia (242). Recently, an exaggerated plasma cortisol response to LVP was seen in a 67-yr-old woman with CS and bilateral macronodular adrenal hyperplasia, whose brother had died after bilateral adrenalectomy for CS and AIMAH (182); the precise nature of the abnormal hormone receptor implicated is unknown, but this constitutes the first demonstration of abnormal hormone responsiveness in familial AIMAH.

Since V1-AVPR are present in the normal adrenal cortex and modulate modest effects of vasopressin on steroidogenesis, 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. V1-AVPR mRNA levels were found to be expressed either at higher (235) or similar (79, 80) levels, compared with normal control adrenal tissues. The binding affinity and dose response of intracellular calcium flux for V1-AVPR noted in the adrenal tissues of a patient with AIMAH (80) were not different from those reported in other normal tissues. Thus, no evidence of ectopic receptor or gross overexpression of the eutopic V1-AVPR has been presented to date; the molecular mechanisms leading to the abnormal response of V1-AVPR or its effector system, which would increase the response to AVP, remain to be elucidated.

Recently, V3-AVPR were shown to be expressed ectopically in a series of bronchial carcinoids secreting ACTH (243). A large proportion of patients with Cushing’s disease, but not normal individuals, secrete ACTH in response to DDAVP (244, 245). V3-AVPR were found to be overexpressed in corticotroph adenomas (229); as DDAVP can also bind in part to V3-AVPR, this may explain the effects of DDAVP on ACTH release in Cushing’s disease. Thus, stimulation of cortisol levels after vasopressin administration in CS cannot directly distinguish between pituitary corticotroph adenoma, ACTH-independent primary adrenal tumor or hyperplasia, or relatively well differentiated carcinoid tumors producing ACTH.

C. Catecholamine-dependent CS
Catecholamines are known to modulate HPA activity. Activation of _1-adrenoreceptors in the PVN leads to CRH release with increased plasma levels of ACTH and cortisol (14). Administration of ß₁- or ß₂-adrenergic agonists or antagonists has no effect on ACTH or cortisol secretion (246). Peripherally administered _1-adrenoreceptor agonists fail to activate the HPA, as the blood-brain barrier prevents their access to the PVN. Direct adrenal stimulatory or inhibitory effects of catecholamines on GC or mineralocorticoid secretion have been noted in several species, but are limited to aldosterone secretion in humans, where cortisol secretion is unaffected (11).

As discussed in Section IV, the abnormal presence of ß- adrenergic receptors or the activation of AC activity by catecholamines has been reported in vitro in several cases of human adrenal tumors associated with CS (191, 192, 193); no evidence of such receptors has been found in the normal adrenal cortex. However, the clinical expression of this abnormality was appreciated only recently in two patients. A 56-yr-old French-Canadian man with AIMAH and CS (86) was shown to have ACTH-independent overproduction of cortisol and aldosterone during elevations of endogenous catecholamines level (upright posture, insulin-induced hypoglycemia, and EKG stress test). Augmented plasma cortisol during upright posture was decreased after pretreatment with the ß-adrenergic antagonist, propranolol; in contrast, this did not occur after inhibition of the RAS system with captopril or losartan, or of AVP with a V1-AVPR antagonist. Isoproterenol infusion stimulated cortisol (2.1-fold) and aldosterone (2.2-fold) secretion in the patient, but not in normal subjects, in whom ACTH had been suppressed by dexamethasone. Plasma cortisol was not influenced by mixed meals, or administration of TRH, GnRH, glucagon, or cisapride; as discussed previously, a late increase of cortisol after AVP administration was believed to result from stimulation of release of adrenomedullary catecholamines. High-affinity binding sites compatible with ß₁-adrenergic receptor (ß₁-AR) or ß₂-AR were found in the adrenal tissues of the patient, but not in the controls. They were efficiently coupled to steroidogenesis (Fig. 1), as shown by AC stimulation with isoproterenol in vitro and catecholamine-induced steroidogenesis in vivo (86). Further molecular studies are needed to properly characterize the ß-adrenergic receptor subtype expressed in hyperplastic adrenal tissues and to determine whether or not it is mutated.

Another 50-yr-old American woman with CS and AIMAH (240) was found to have abnormal responses to catecholamines in addition to an exaggerated response to AVP (described previously in Section V.B.). In this patient, plasma cortisol had risen after upright posture (1.7-fold) and exogenous AVP (3.4-fold), but also after insulin-induced hypoglycemia (2.7-fold), while ACTH remained suppressed. Infusion of isoproterenol for 30 min increased plasma cortisol from 323 to 630 nmol/liter, which returned rapidly to baseline when the infusion was discontinued. Pretreatment of the patient with the angiotensin receptor type-1 antagonist losartan did not prevent the elevation of plasma cortisol during upright posture. There were no increases of plasma cortisol after mixed meals, GnRH, TRH, glucagon, or cisapride. It was concluded that cortisol secretion was mediated by the abnormal presence and function of ß-adrenergic and V1-AVPR, and medical therapy with the ß-blocker propranolol was proposed to the patient; she did not tolerate this medication well and elected to undergo surgery in her home city (tissues not available).

D. LH-dependent CS
The LH/hCG receptor (LH/hCGR) normally activates AC and PLC to stimulate gonadal steroidogenesis (247). The receptor is mainly expressed in gonadal tissues, but also in other tissues, including the uterus, fallopian tubes, placenta, brain, hypothalamus, and prostate (248); recently, the presence of LH/hCGR was identified in the zona reticularis of the human adrenal (249) by immunohistochemistry and in situ hybridization. hCG stimulates DHEAS secretion in human fetal adrenal cells (250).

A 63-yr-old French-Canadian woman was studied for CS and AIMAH (251). Retrospectively, she described having gained between 18–22 kg during each of four full-term pregnancies, with Cushingoid fat distribution, but without high blood pressure, purple skin striae, or hirsutism. Her weight returned rapidly to baseline after delivery with symptoms of lack of appetite, nausea, and fatigue, which subsided within 2–3 months. Chronic hypercortisolism became clinically manifest only 10 yr after menopause (Fig. 3). Cortisol production was increased by the in vivo administration of GnRH, hCG, and recombinant human LH (hLH). Plasma free testosterone and estradiol were also augmented by hLH administration. Abnormal stimulation of cortisol, free testosterone, and DHEAS production was also evoked in this patient by oral intake of cisapride and metoclopramide, two 5-HT₄R agonists (251). Administration of the long-acting GnRH analog leuprolide acetate initially increased LH and FSH secretion, which was paralleled by a rise in cortisol secretion; however, this was followed within 10 days by suppression of endogenous LH and FSH levels and normalization of cortisol production. Stimulation of cortisol by hCG and recombinant hLH, but not by FSH, suggests that a functional adrenocortical LH/hCGR was coupled to steroidogenesis (Fig. 3); the lack of stimulation by GnRH, when LH levels were suppressed by chronic administration of leuprolide acetate, excludes an adrenal GnRH receptor. Studies of normal adult controls did not indicate any coupling of LH/hCGR to adrenal synthesis of cortisol or DHEAS. Abnormal stimulation of plasma cortisol after GnRH and LH administration was also found in one woman with bilateral macronodular adrenal hyperplasia and normal urinary cortisol levels, which did not suppress normally with dexamethasone (242). This suggests that diverse ectopic hormone receptors can be present in preclinical bilateral macronodular adrenal hyperplasia.

View larger version (22K): [in this window] [in a new window]   Figure 3. HPA axis in CS secondary to the ectopic adrenal expression of LH/hCGR. Adrenal expression of the LH/hCGR in the adrenal cortex is illustrated. Occupation of this receptor either by hCG of placental origin or by LH of pituitary origin induces cortisol secretion, which exerts negative feedback inhibition on CRH and ACTH production (upper panel). The development of bilateral adrenal hyperplasia and hypercortisolism is produced transiently and reversibly due to occupation of the receptor by hCG during pregnancies; delivery is followed by a transient period of hypocortisolism (upper and lower panels). At the time of menopause, a sustained elevation of LH levels follows a decrease in ovarian estrogen production and results in a progressive increase of bilateral adrenal hyperplasia and hypercortisolism. Administration of long-acting leuprolide acetate initially induced transient stimulation of LH and cortisol, followed by long-term suppression of LH and restoration of normal cortisol production.

Transient corticotropin-independent CS during pregnancy with complete resolution after spontaneous abortion or delivery was described in two patients with mild bilateral adrenal hyperplasia (260, 261) or unknown adrenal pathology (262). A paradoxical increase in cortisol excretion during dexamethasone administration in pregnancy completely returned to normal after delivery (261). One patient developed severe biochemical and clinical evidence of CS during each of three pregnancies, and ACTH or cortisol levels were not stimulated by vasopressin administration (260); there was a transient period of hypocortisolism after each delivery, followed by complete clinical regression. In one case, short-term hCG administration elevated urinary 17-hydroxycorticosteroid levels, while sequential estrogen and progestogen administration had no effect (262).

It is thus possible that some of these patients with transient CS during pregnancy, or in whom hypercortisolism increased during pregnancy, also expressed ectopic LH receptors in their adrenal adenomas or in their adrenal cortex. Specific testing of the regulation of steroidogenesis with LH or estrogens in future cases of transient CS during pregnancy will help in elucidating the pathophysiology. It must be pointed out that spontaneous remission of CS after delivery has also been reported in a patient with ACTH-dependent CS of probable pituitary origin (263); the mechanisms involved in this regression have not been elucidated.

E. LH-dependent adrenal androgen-secreting tumors
Although the regulation of cortisol secretion by LH in adrenal CS was demonstrated only recently in vivo, there have been several reports indicating that the regulation of steroidogenesis in some rare, pure, androgen-secreting tumors was stimulated by hCG or GnRH (195, 264, 265). As plasma LH was found to be relatively suppressed in some of these patients, the role of endogenous LH in maintaining androgen production may be uncertain. In some cases, suppression of endogenous LH levels by administration of estrogens (266, 267) or by ACTH stimulation of GC (268) inhibited androgen production. In other cases, estrogens were unsuccessful in depressing androgen production (264, 269, 270). It has been suggested that gonadal cells localized in the adrenals could explain this phenomenon; however, clear evidence of adrenal origin of the tumors was identified in certain cases (195).

F. Serotonin-responsive CS
5-HT is produced by intraadrenal mast cells in humans and can regulate corticosteroid production via a paracrine mechanism (87, 271); these effects are mediated by the 5-HT₄R subtype, which is expressed mainly in adrenal ZG but also in zona fasciculata cells (89, 91). 5-HT₄R agonists are potent stimulators of aldosterone secretion in humans; they are weak stimulators of cortisol secretion by human adrenocortical cells in vitro, but not of plasma cortisol in normal subjects (87).

In the patient with LH-dependent CS (251), cisapride and metoclopramide, two 5-HT₄R agonists, produced 4.8- and 2.6-fold peak elevations, respectively, in plasma cortisol 120 min after their oral administration. Plasma corticotropin levels remained undetectable during cisapride and metoclopramide testing. Stimulation of plasma cortisol in this patient after treatment with cisapride and metoclopramide was proportional to their respective affinity for 5-HT₄R (87); no such response to cisapride was found in five other patients with bilateral adrenal hyperplasia, 11 with unilateral adenoma, and one with carcinoma and CS (240). A patient with CS and AIMAH was found to increase plasma cortisol in response to cisapride as well as to LVP and CRH, despite suppression of ACTH (272). Recent observations in patients with bilateral macronodular adrenal hyperplasia and preclinical hypercortisolism also documented marked stimulation of cortisol secretion upon cisapride administration (242).

The exaggerated cortisol responses to cisapride in these patients could be secondary to the increased zona fasciculata expression or abnormal function of an "eutopic" 5-HT₄R-effector system, rather than to the presence of an ectopic receptor. The presence of a 5-HT₄R has been detected by RT-PCR in the adrenal tissues of one of these patients and was similar to that found in normal adrenal cortex; however, full receptor sequencing and adrenal zone distribution have not been performed (272).

G. Steroid-responsive CS
Caticha et al. (273) described a 33-yr-old woman who developed transient and reversible clinical and biochemical signs of ACTH-independent CS during three pregnancies and during intake of oral contraceptives. Her adrenal histology was described as being compatible with primary nodular dysplasia, but there were no comments on pigmentation of her adrenal nodules; there was also no family history of adrenal disease and no other features of Carney’s complex. Paradoxical increases in cortisol production were noted during oral dexamethasone suppression tests. Dose-responsive stimulation of cortisol secretion occurred after bilateral adrenalectomy when the cells were exposed to estradiol; the in vitro addition of dexamethasone was not reported, nor were the effects of antiestrogens.

Paradoxical increases in plasma cortisol and urinary free cortisol were observed during the last 2 days of classical Liddle’s 4-day low- and high-dose oral dexamethasone tests in patients with PPNAD with or without Carney’s complex (171). We found no evidence of ectopic membrane hormone receptors in two patients with PPNAD, who showed an increase in cortisol secretion during prolonged dexamethasone administration; GC receptors appeared to be highly expressed by immunohistochemistry in PPNAD micronodules, compared with the adjacent internodular atrophic adrenal or to the normal control adrenal cortex (274). Similar paradoxical elevations of cortisol production during dexamethasone have been reported in several cases of CS during pregnancy (258, 261).

H. Other abnormal hormone responses in adrenal CS
Hashimoto et al. (275) described a 51-yr-old male with large bilateral AIMAH in whom plasma cortisol increased during insulin-induced hypoglycemia, while ACTH, measured by RIA, remained at undetectable levels (<10 pg/ml); in vitro, dispersed adrenal cells stimulated cortisol secretion with ACTH, but not with insulin, catecholamines, vasopressin, or Ang-II. A very similar patient with AIMAH studied by the same group (232) also displayed elevated plasma cortisol during insulin-induced hypoglycemia and combined LVP-CRH tests while plasma ACTH remained undetectable; in vitro studies were not performed in this case. It remained unclear whether insulin itself, a factor increased during hypoglycemia, or subdetectable rises in plasma ACTH were responsible for the regulation of cortisol secretion in these cases.

Leptin synthesis is stimulated by GC (136), and leptin receptors are expressed in normal adrenals as well as in adrenocortical adenomas and carcinomas (128, 276). Plasma leptin has been found to be elevated in patients with CS. The leptin receptor is expressed in the adrenal cortex, where leptin normally inhibits cortisol secretion. Leptin negatively regulates the HPA, both at the pituitary level, where it suppresses CRH secretion, and the adrenal level, where it depresses steroidogenesis (124, 130, 276). Pralong et al. (139) recently reported a 36-yr-old woman with AIMAH and CS in whom a mixed meal heightened plasma cortisol levels, and this effect was decreased by octreotide pretreatment. GIP was not infused, but GIP stimulated cortisol secretion in vitro. Leptin (single dose of 100 nM) increased cortisol secretion in vitro, whereas in normal adrenal tissues, it normally suppresses this parameter. Plasma leptin levels were elevated in this patient with CS but did not increase after meals. GIPR or leptin receptor were not measured directly. Thus, this case raises the possibility of paradoxical stimulation of steroidogenesis by leptin in some cases of AIMAH, but more detailed studies are required in other similar cases to confirm this possibility.

	VI. Investigation Strategy

Top Abstract I. Introduction II. Hormonal Regulation of... III. Primary Adrenal... IV. Initial in Vitro... V. In Vivo Demonstration... VI. Investigation Strategy VII. Molecular Mechanisms of... VIII. Ectopic/Abnormal Hormone... IX. An Opportunity for... X. Summary and Conclusions References

 
A. Initial clinical screening protocol
A protocol has been developed to screen patients with adrenal CS for the presence of ectopic/abnormal adrenal hormone receptors (277); the strategy is based on monitoring plasma levels of steroids during various tests that transiently modulate the levels of ligands for potentially abnormal receptors. The protocol includes serial measurements of plasma ACTH, cortisol, and other steroids or hormones as indicated (aldosterone, free testosterone, DHAS, and estradiol) at 30- to 60-min intervals for 2–3 h during the course of various tests performed after an overnight fast and in a supine posture for at least 1 h. Initial screening includes a posture test performed in a 2-h supine position, followed by a 2-h ambulatory period (to evaluate potential modulation by Ang-II, vasopressin, catecholamines, ANP, etc.); this is followed by a standard mixed meal (to evaluate the response of gastrointestinal hormones) and then by the administration of 250 µg ACTH 1–24 iv, which serves as a reference test. On another day, the administration of 100 µg GnRH iv (modulation by FSH, LH, GnRH) is followed by 200 µg TRH iv (modulation by TSH, PRL, TRH). Responses to 1 mg glucagon iv, 10 IU AVP im, and 10 mg cisapride orally (a serotonin 5-HT₄R agonist; this is now replaced by 10 mg metoclopramide as cisapride was withdrawn from the market) are tested sequentially on the third day. A change of less than 25% plasma cortisol is arbitrarily defined as no response, a 25–49% change is defined as a partial response, and a change of 50% or greater is considered a positive response. If a partial or positive cortisol response is found, the test is repeated to verify its consistency and to determine whether other steroids, such as aldosterone, DHAS, testosterone, and estradiol, are also modified. At the same time, fluctuations of potentially interesting ligand hormones (i.e., catecholamines, vasopressin, renin/Ang-II, and ANP during a posture test) are measured. If a prolonged response to a test masks the evaluation of the following test, it is repeated separately.

B. Further characterization of abnormal hormone receptors
After initial screening, other tests can be performed to confirm the responses or to elucidate which hormone is implicated (Fig. 4). For example, if cortisol stimulation by upright posture is found, the inverse effect, i.e., suppression by assuming a supine posture after ambulation, is verified. The respective contributions of vasopressin, catecholamines, and Ang-II or ANP modifications need to be distinguished. An exaggerated cortisol response to pharmacological levels of exogenous vasopressin is followed by evaluation of whether physiological fluctuations of endogenous vasopressin would modify plasma cortisol levels. An increase of plasma vasopressin during an upright posture test should parallel the elevation of plasma cortisol levels. Endogenous plasma AVP levels can be modulated by a 20 cc/kg water load, followed by infusion of NaCl 3% at 0.1 cc/kg/min for 120 min. The expected result would be an initial suppression of AVP and cortisol during water loading, followed by an increase of AVP and cortisol levels. To determine whether the vasopressin receptor involved in this response is a V1, V2, or V3 receptor type, 2.5 µg desmopressin, a preferential V2 receptor agonist, is administered subcutaneously (80, 86); the absence of a response to desmopressin would suggest a V1 or V1b/V3 receptor-mediated response. Pretreatment with a specific oral V1 receptor antagonist (SR 49049) has been used to demonstrate in vivo the involvement of the V1 receptor in this response (86). In case of no response to exogenous AVP, the role of Ang-II is assessed by repeating the posture test after administration of an AT1R antagonist or by direct infusion of Ang-II. If a catecholamine response is suspected, endogenous catecholamine stimulation is produced by insulin-induced hypoglycemia, and, if positive, by isoproterenol infusion (86). An attempt to block the response and to treat the patient with a ß-blocker would be conducted if the stimulation of cortisol production is reproduced.

View larger version (30K): [in this window] [in a new window]   Figure 4. Outline of the investigation protocol to further characterize abnormal adrenal hormone receptors when a positive response is identified during initial screening. Plasma cortisol levels are monitored during the various tests. [Reproduced with permission from A. Lacroix et al.: The Endocrinologist 9:9–15, 1999 (277 ). © Lippincott Williams & Wilkins, http://lww.com]

Stimulation of cortisol production after GnRH administration could result from the abnormal adrenocortical presence of receptors for LH/hCG, FSH, or GnRH itself. The cortisol response after the administration on different days, of hCG 10,000 U im, purified human FSH 150–300 U im, and recombinant LH 300 U iv can be compared (251). A response to GnRH coupled to an absence of response to FSH, LH, and hCG would suggest an ectopic GnRH receptor; various analogs and antagonists of this receptor are available for testing the hypothesis. In addition, the response to an acute dose of GnRH should persist despite the suppression of endogenous gonadotropins by the administration of supraphysiological doses of gonadal steroids or the use of long-acting GnRH analogs. In the presence of an ectopic LH/hCGR, a response to exogenous hCG or LH, but not to exogenous FSH, should be evident; the response to acute GnRH administration should disappear when the LH response is abolished by exogenous gonadal steroids or after the chronic administration of long-acting GnRH analogs. Therapy with long-acting GnRH analogs should produce eventual suppression of the endogenous LH ligand and normalize cortisol production, as demonstrated recently by our group in one such patient (251). In the presence of an ectopic FSH receptor, there should be no response to hCG or LH, but cortisol production should be increased after the administration of purified FSH. Here again, long-acting GnRH analogs should suppress the biologically active ligand and correct the hypercortisolism.

Stimulation of cortisol synthesis after TRH administration has not yet been reported. However, AC stimulation by TSH has been demonstrated in adrenocortical adenomas in vitro (9). Thus, a response to TRH would suggest the possibility of an ectopic receptor either for TSH, TRH, or PRL. The PRL receptor does not belong to the family of G-coupled seven-transmembrane receptors, which could mimic the ACTHR and activate AC. However, adrenocortical stimulation by PRL has been described in vitro (190), and the presence of this receptor in adrenal tumors has been confirmed (278). Elevation of endogenous PRL levels after a chlorpromazine test and its inhibition by a bromocriptine test would easily clarify the role of endogenous PRL. The potential presence of an ectopic TSH receptor would be assessed directly by the administration of purified human TSH and by inhibiting endogenous TSH production with exogenous T₄. The lack of an ectopic TRH receptor would be confirmed by disappearance of the cortisol response when the response of TSH to TRH has been suppressed by T₄ administration.

The in vitro response of AC to glucagon has been demonstrated previously in a cortisol-secreting adenoma (190), but a clinical case has not yet been reported. If a response to 1 mg of exogenous glucagon is found, it would be necessary to show that fluctuations of endogenous glucagon levels during insulin-induced hypoglycemia, fasting, or oral administration of glucose correlate well with fluctuations of cortisol levels.

The oral administration of 10 mg cisapride, a 5-HT₄R agonist, is expected to induce a large increase in aldosterone, but not in cortisol levels in normal individuals (91). If a cortisol response to cisapride is found, a response to other 5-HT₄R agonists such as zacopride or metoclopramide should be seen, but not to specific 5-HT-1,2,3 agonists. Although some specific 5-HT₄R antagonists are currently under investigation, their availability is limited, but they should become very valuable in confirming the role of this abnormally expressed receptor.

C. Systematic clinical screening for ectopic/abnormal hormone receptors
There has been only one report to date of the systematic clinical screening of patients with adrenal CS for the presence of diverse abnormal hormone receptors (240). In that study, 20 consecutive patients with adrenal CS secondary to either bilateral macronodular adrenal hyperplasia (n = 6), unilateral adenoma (n = 13), or carcinoma (n = 1) were tested for evidence of an abnormal hormone receptor. All six patients with AIMAH had a positive response to at least one test, in addition to ACTH 1–24: two patients, to the mixed meal (GIP-dependent); one patient, to GnRH (LH/hCGR) and cisapride (5-HT₄R); and three patients, to the upright posture and vasopressin (1 ß-AR, 1 V1-AVPR, 1 ß-AR, and V1-AVPR). In patients with unilateral adenoma, only one patient had a positive response to upright posture, while three partial responses to either mixed meals, vasopressin, or posture were also noted but were not further characterized. In the patient with adrenocortical carcinoma or in two patients with micronodular adrenal dysplasia (274), plasma cortisol was not modified by any of the tests. Initial experience suggests that the adrenal expression of various ectopic or abnormal hormone receptors is frequently implicated in the pathophysiology of bilateral macronodular adrenal hyperplasia (240), but less frequently in unilateral adenoma (79). It must be noted that the initial protocol used to date did not screen for many other G protein-coupled membrane receptors, such as those for PTH, calcitonin, acetylcholine, dopamine, opiates, prostaglandins, etc; it may thus become pertinent to investigate these other potential abnormal receptors in the future.

	VII. Molecular Mechanisms of Ectopic/Abnormal Hormone Receptors

Top Abstract I. Introduction II. Hormonal Regulation of... III. Primary Adrenal... IV. Initial in Vitro... V. In Vivo Demonstration... VI. Investigation Strategy VII. Molecular Mechanisms of... VIII. Ectopic/Abnormal Hormone... IX. An Opportunity for... X. Summary and Conclusions References

 
A. Tissue-specific expression and regulation of membrane hormone receptors
The hormonal regulation of adrenal cortex development and function requires the tissue-specific expression of hormone receptors. This implies the existence of fine-tuned mechanisms of regulation that involve cis-acting regulatory elements (promoters) and trans-acting factors (TFs) for these receptors. It is thus pertinent to briefly review which factors regulate the appropriate tissue-specific expression of the membrane hormone receptors of interest in adrenal CS before considering which molecular mechanisms could be responsible for their abnormal adrenal expression and function.

The ACTH MC-2 receptor gene, localized on human chromosome 18 (18p11.2), is highly expressed in the adrenal cortex and, at lower levels, in fat tissue and skin (22, 279, 280). The proximal promoter region (1,000 bp) of the human ACTHR (hACTHR) gene is responsible for the basal transcriptional rate and contains several potential regulatory elements: one SP1 element, four AP1 elements, seven CRE (cAMP-responsive element)-like regulatory elements, and three SF-1-like elements (SF-35, SF-209, and SF-98) (23, 281, 282). Both SF-35 and SF-98 sites were shown to be essential for the cAMP regulation of ACTHR transcription. Although absolutely required, SF-1 is not sufficient for ACTHR expression in the adrenals, since it is not expressed in gonads, whereas both Leydig and ovarian cells express SF-1 (41). The well known up-regulation of the receptor by its own ligand (36, 37, 283, 284, 285) is probably mediated by one of the CREs. The same regulatory elements are present in the proximal promoter of the mouse ACTHR, except for CREs, which have been changed for GRE (GC-responsive element) sites (286). A negative regulatory region (silencer), located between –1,236 and –908 from the transcription start site, prevents expression of the receptor in heterologous systems or in non-SF-1-containing cell sites (286). This suggests that other factors are needed for the receptor to be expressed properly.

ß-Adrenergic receptors (ß-AR) are subject to extremely tight regulation. In addition to short-term regulatory phosphorylation of receptor proteins, their gene expression is also regulated. Cloning of the 5'-flanking region of human ß₁-AR (chromosome 10q24–26) revealed several potential thyroid response elements (TRE), GREs, and CREs (287). These putative response elements support the pathophysiological evidence that thyroid and GC hormones regulate ß₁-AR by affecting receptor expression (287, 288). Hyper- and hypothyroidism have been associated with increases or decreases in ß₁-AR number and activity. Thus, the presence of TRE in the 5'-flanking region of ß₁-AR is consistent with these clinical conditions (289, 290). ß₂-AR (chromosome 5q32) expression is up-regulated by GC in various tissues and is due to a direct increase in the rate of its transcription (291, 292). This is probably mediated by GRE, as demonstrated for hamster ß₂-AR (293). In contrast, ß₁-AR is down-regulated by GC. The stability of ß₁-AR mRNA is not influenced by GC, but nuclear run-on assays have revealed that down-regulation is due to a decline in the relative transcription rate of the receptor (294). Homologous desensitization of ß-AR has been observed for the three receptor types, ß₁-, ß₂-, and ß₃-AR (291, 295, 296). This is compatible with the presence of CRE in the promoters of both ß₁- and ß₂-AR (287). Moreover, ß-adrenergic stimulation causes not only down-regulation of ß-AR but also loss of coupling to G_s/AC effectors (297). In vivo investigations of GC effects on ß-agonist-induced down-regulation of ß₁- and ß₂-AR have shown that GC can prevent down-regulation of ß₂-AR number and mRNA at the transcriptional level; the TF CREB may be involved (294).

LH/hCGR have also been reported in the human adrenal zona reticularis (249), although they are more highly expressed in gonadal tissues. The LH/CGR is one of the largest seven-transmembrane receptors (683 amino acids) as it harbors an unusually long extracellular ligand-binding domain (247). This receptor is encoded by two genes: gene I isolated from a lymphocyte library, and gene II isolated from a placental library (298). The four copies of hLHR genes are localized on chromosome 2p16–21 loci. The two proximal 5'-untranslated regions have been well characterized (299, 300, 301) and differ by several base changes and a 6-bp deletion in the coding region (+55 to +60). The transcription initiation site is localized at position –176 bp for both promoter regions. Additional upstream transcription start sites have been identified in human testicular and choriocarcinoma JAR cells. These data suggest that tissue-selective LHR promoter utilization and gene (I or II) expression may underlie the specific pattern of LHR expression. TATA and CAAT-like boxes have been identified in human, but not in mouse and rat, promoters; the human promoter contains one CRE, seven AP1 sites, and one half-ERE site. Three negative control regions (NCRs), when complexed with proteins of JEG-3 cell nuclear extracts, disable the proximal promoter activity (300); these regions might be very important in nongonadal tissues.

The actions of vasopressin are mediated by three G protein-coupled membrane receptor subtypes. V2 receptors are expressed almost exclusively in renal collecting ducts to promote water permeability via activation of G_s and AC (302, 303). VIa (or VI) receptors are expressed in blood vessels, where they promote vasoconstriction (304), and in the liver, where they promote glycogenolysis (305), while VIb (or V3) receptors are located mainly in the anterior pituitary, but also in the adrenal medulla. VIa and Vlb receptors are coupled to various pertussis toxin-sensitive G proteins and activate PLA₂, PLC, and PLD through activation of ligand-gated calcium channels (306). VIa receptors are also present in the adrenal cortex where they are involved in steroid secretion (see Section II). Dexamethasone increases the expression of VIa receptors in the rat liver and forebrain (307, 308). The elevation of mRNA levels precedes the rise in binding activity, suggesting a transcriptional effect. Isolation and analysis of the 5'-regulatory region of the rat VIa receptor have demonstrated that trans-acting factors such as CREB, AP-2, and GR are involved in the expression of the receptor gene (309, 310). At the protein level, GC have been shown to produce an early decrease in binding site density, followed later by an increase, which becomes more prevalent with time. Perhaps GC initially affects the stability of receptor protein or that of mRNA levels (307, 311). GC can also negatively regulate the stimulated expression of V1a receptor by a mechanism not involving GR-binding to DNA (310). Furthermore, it has been reported that GC amplify the vasopressin-induced transduction signal (increased IP accumulation in the presence of dexamethasone) (312, 313). This mechanism of regulation was demonstrated for the V1b receptor in the anterior pituitary where prolonged exposure to dexamethasone decreased the number of receptors, while increasing their coupling efficiency. Potentiation was found to be due, in part, to an increase in the guanylyl nucleotide-binding protein, Gq (314). The effect of GC on adrenal VIa receptors has not been studied.

The recent cloning of rat (214), hamster (215), and human GIPR (216, 217, 218) has revealed that it is a member of the secretin-VIP family of receptors. This gene is proposed to be involved in the pathogenesis of diabetes as GIPR knockout mice displayed glucose intolerance with impaired insulin secretion (218A ). The human GIPR gene is localized on the chromosome 19q13.3 locus and consists of 14 exons; it is expressed in several tissues, including the rat brain, fat, gut, vascular endothelium, and adrenals (214, 315, 316). In situ hybridization studies indicate that the GIPR is localized in the inner layers of the rat adrenal cortex (214); GIP is also able to stimulate AC and corticosterone synthesis in the rat adrenal cortex (317). In humans, the tissue distribution of GIPR mRNA has not yet been examined extensively, but has been discovered in the pancreas and brain, but not in spleen (210). Several splice variants of the receptor have been described in the human pancreas, of which one with a 27-amino acid insertion in the cytoplasmic tail is functional (216, 219). The rat GIPR has been shown to be desensitized by its own ligand in vivo and in vitro (318). The rat 5'-flanking region of the receptor gene has recently been cloned (319); it is a TATA-less promoter harboring one CRE, an octamer-binding site, three Sp1 sites, and an initiator element (319). Distal negative control sequences, not yet clearly identified, seem to confer cell-specific regulation of GIPR expression (319). The human GIPR promoter, however, has not yet been characterized.

5-HT₄R-mediated stimulation of corticosteroid secretion is the only known endocrine effect mediated by this receptor. Activation of 5-HT₄R augments AC activity and elevates cAMP. Homologous desensitization has been postulated to occur via a specific receptor kinase. Splice variants of 5-HT₄R have been detected in several human tissues, and their tissue distribution suggests some degree of tissue specificity (320). These splice variants differ in their capacity to trigger the signal transduction cascade after receptor activation.

B. Potential mechanisms of ectopic or abnormal hormone receptors
The molecular mechanisms responsible for the ectopic or abnormal expression and function of membrane receptors in adrenal CS have not yet been identified. In fact, the important question of regulation of the tissue-specific expression of genes is raised by this new pathophysiology of adrenal CS. Several hypothesis can be proposed, however (Fig. 5). A gene rearrangement could potentially lead to adrenocortical-specific, inappropriate expression of a hormone receptor gene. Examples of this mechanism in endocrine tumors include rearrangements described in subsets of parathyroid adenomas (321), in GC-remediable aldosteronism (322), and in papillary carcinoma of the thyroid (323). The PTH promoter has been found to be recombined with the cyclin D gene, giving rise to the prad-1 oncogene (321). The aldosterone synthase gene has been shown to be fused with the 11ß-hydroxylase promoter, resulting in ectopic production of aldosterone in zona fasciculata (322). In 25% of human papillary carcinomas (up to 62% after exposure to Chernobyl irradiation), a chromosomal break fuses the intracellular tyrosine kinase domain of the growth factors receptor RET to one of at least eight new promoters including H4, ELE1, R1, NTRK1, RFG, and other genes (324, 325); this results in constitutive dimerization and activation of the tyrosine kinase of RET, bypassing the requirement for ligand binding. None of the ectopic hormone receptors identified to date in adrenal CS is located on the same chromosome as the ACTHR promoter; gross gene rearrangements have not been reported to date. More discrete mutations in the promoter regions of the membrane hormone receptor could also greatly increase the expression of a receptor normally expressed at such a low level that it would not play a significant role in steroidogenesis. A point mutation in the promoter region of the hormone receptor could generate an appropriate binding site for an adrenocortical-specific TF/co-activator complex, leading to ectopic expression (Fig. 5A).

View larger version (17K): [in this window] [in a new window]   Figure 5. The potential molecular mechanisms leading to ectopic expression of G protein-coupled receptor (GPCR) in adrenal CS may include mutations in cis-acting regulatory regions (A) or in trans-acting factors (B). A, Gene rearrangement could fuse a specific GPCR gene that is not expressed in adrenals with an adrenocortical-specific promoter, resulting in ectopic expression of the receptor in the adrenal cortex. More discrete mutations in the GPCR promoter could also lead to abnormal expression. Thus, a point mutation could enhance the transcription of a receptor that is normally weakly expressed in the adrenals and not coupled to steroidogenesis; a point mutation in the promoter of a GPCR gene that is not expressed in the adrenals could generate a new binding site for an adrenocortical-specific TF leading to ectopic expression. B, A gain-of-function mutation of an adrenocortical-specific activator could induce overexpression of an adrenal receptor; the ectopic adrenal expression of a transcription factor (TF) or of its coactivator (not shown) could also result in the ectopic expression of a GPCR. A loss-of-function mutation of a repressor (R) or corepressor (not shown) that prevents the GPCR adrenal expression could result in ectopic expression.

Another interesting hypothesis emerges from a recent study by Kero et al. (327), who observed that transgenic mice expressing bLHß-CTP (a chimeric protein of ß -subunit fragments of bovine LH and hCG) in their pituitary develop adrenal CS in addition to polycystic ovaries and ovarian tumors after chronically elevated serum LH levels. It was shown that this resulted from ectopic expression of LH/CG receptors in the adrenal cortex, not detectable or functional in control mice. Since this induction is abolished by gonadectomy, it was proposed that elevated estrogens and PRL levels were responsible for inducing the illicit expression of the LH/CG receptor in the adrenal cortex. This observation would thus raise the possibility that the "ectopic expression" of a receptor may not require a mutation of cis- or trans-acting regulators, but may result from exaggerated stimulation of a gene that is normally silent.

The presence of abnormal membrane hormone receptors in unilateral cortisol-secreting adenomas may arise from the monoclonal expansion of a primary adrenocortical cell that acquired a somatic mutation, leading to the abnormal expression and function of that receptor at the postzygotic stage of adrenal cortex development (Fig. 2); most studies confirm the monoclonal composition of human adrenocortical tumors (157, 163). In patients with ectopic membrane hormone receptors in bilateral macronodular adrenal hyperplasia, the mutational event must have occurred very early during embryogenesis so that every cortical cell of both adrenals would be affected by the defect, which is polyclonal. There have been rare reports of familial AIMAH (179, 180, 181, 182), and in only one case, an abnormal response to LVP was demonstrated in one sibling (182); thus, abnormalities of receptor expression in these syndromes may frequently be the consequence of somatic mutations but, in some cases, could also be germline mutations. In the case of a very early mutational event resulting in AIMAH, the abnormal expression could affect diverse tissues so that polymorph aberrant manifestations would be expected. This was the case in the patient with vasopressin-dependent CS (80) who also displayed an abnormal vascular response to AVP and decreased hypothalamic AVP release during postural hypotension. One patient with GIP-dependent CS and AIMAH suffered from psychiatric dysfunctions that persisted even after correction of the hypercortisolism (200); since GIPR have been shown to be expressed in the brain (214), it is possible that the brain GIPR is also altered. The McCune-Albright syndrome is an example of a somatic mutation occurring during embryogenesis and leading to defects in the adrenal cortex as well as in several other tissues (172); it is still unclear how a somatic mutation could affect all cells in a polyclonal mode in one case (ectopic hormone receptors in AIMAH and CS) and result in a mosaic or oligoclonal pattern of distribution in another case (McCune-Albright syndrome).

The majority of ectopic or abnormal hormone receptors in adrenocortical tumors or hyperplasias (8, 9, 10) belong to the G protein-coupled receptor superfamily. Studies of the second messengers implicated in ectopic/abnormal hormone receptors in adrenal CS suggest that they regulate steroidogenesis by mimicking the cellular events triggered normally by ACTHR activation (Fig. 1). It is thus expected that only ectopic hormone receptors capable of coupling efficiently to the intracellular signaling systems present in adrenocortical cells (i.e., those for ACTH, V1-AVP, etc.) will be able to regulate steroidogenesis aberrantly. Certain receptors may be involved more frequently than others, however, if they share more characteristics of the promoters or TFs essential for adrenal cell type-specific tissue expression. It is thus noteworthy that GIPR and the ß-AR are expressed normally and are functional in the adrenal fasciculata cells of rodents; it will be interesting to compare the structures of promoters and TFs between species. The LH/hCGR is expressed in the human adrenocortical reticularis during embryonic life; it remains to be seen which events render its expression possible in the fasciculata in adrenal CS (251). Similarly, the 5-HT₄R is usually very efficiently coupled to aldosterone synthesis in the human glomerulosa and already possesses some tropism for fasciculata cells; increased functional coupling to cortisol secretion may require only the inactivation of a relative silencer in fasciculata cells.

C. Role of ectopic hormone receptors in adrenocortical cell proliferation
What is the role of abnormal hormone receptors in altered cell growth and tumorigenesis? One could postulate that the primary event is a mutation resulting in aberrant adrenal expression of the receptor, leading to increased proliferation and eventually to increased hormone production. Alternatively, it can be proposed that the primary event is an unknown proliferative one resulting in cell dedifferentiation with resultant expression of "embryonal" type genes, including one or several hormone receptors. In either hypothesis, it is clear that a relatively long time period is necessary before phenotypic expression of the abnormal hormone receptor becomes evident. This is particularly true for AIMAH, as several decades are necessary before the hyperplasia and hyperfunction become clinically manifest. This may be secondary to the transient occupation of the receptor by the ligand, as illustrated by the cases of GIP (Fig. 2) and LH-dependent (Fig. 3) CS. In GIP-dependent CS, the adrenal tissues are stimulated only briefly but repeatedly after each food ingestion; in LH/hCG-dependent CS, the hyperplasia and hyperfunction occurred only after intense and prolonged exposure to the ligands, i.e., during pregnancy for hCG, or after menopause for LH. Reversal of the hyperplasia between pregnancies would favor the hypothesis that the ectopic receptor is a primary event rather than one that is secondary to another proliferative event; however, this awaits clear demonstration of adenoma or AIMAH regression after complete blockade of the ectopic receptor. There is also indication, based on cases of preclinical cortisol production in bilateral macronodular disease, that steroidogenesis can be relatively inefficient, despite significant proliferation. This suggests poor steroidogenic enzyme activities in the adrenal lesions or that the low expression of abnormal receptors is better coupled to proliferative signals than to hormone synthesis.

The elucidation of this question requires better understanding of the factors regulating normal adrenal gland development. Knowledge of the ontogeny of steroidogenic tissues (adrenals and gonads) was provided by the identification of tissue-specific TFs (328, 329). Indeed, by using SF-1 as a marker, it became possible to trace steroidogenic cells back to the earliest stage of differentiation (330). Investigation of the spatiotemporal expression of SF-1 revealed the existence of the adreno-genital primordium (AGP) which is composed of a SF-1-immunoreactive single cell population (for review see Ref. 331). This structure lies between the coelomic epithelia of the urogenital bridge and the dorsal aorta. The AGP then gives rise to adrenocortical and gonadal primordia, which both express SF-1. Studies in SF-1 knockout mice have shown that the earliest stages of urogenital ridge development occur normally; however, regression of the adrenals and gonads is observed as soon as gonadal sexual differentiation takes place (66). These results suggest a complex cascade of transcriptional events for establishment of the endocrine axis. The adrenocortical primordium gives rise to the adrenal cortex that differentiates into three zonae (glomerulosa, fasciculata, and reticularis). The adrenal medulla is composed of neural cells (SF-1-negative cells) that have migrated from a dorsal root ganglion to the adrenal primordium. In adult mice, SF-1 is expressed in adrenocortical, testicular Leydig, ovarian theca, and granulosa cells, and, at a lower level, in spleen and pituitary gonadotropes (reviewed in Ref. 41).

DAX-1 (dosage-sensitive sex reversal, AHC critical region on the X chromosome, gene 1) is another steroidogenic-specific TF involved in the adrenal cortex and gonads, as demonstrated by disorders due to DAX-1 mutations (332, 333, 334). DAX-1 belongs to the orphan nuclear receptor superfamily as does NGFI-B and SF-1 and it acts as a transcriptional repressor. However, the protein is atypical since it possesses no DNA-binding domain, suggesting possible interactions with other TFs. Indeed, DAX-1 has an expression profile similar to that of SF-1, suggesting a functional correlation between these two proteins (335, 336, 337). Moreover, SF-1 was shown to be a critical regulator of DAX-1 expression, as functional SF-1-binding sites have been identified in the promoter region of DAX-1 gene (338, 339). Another transcriptional repressor has been shown to play a role in adrenal development. Initially designated as an essential actor throughout nephrogenesis (340, 341), the Wilm’s tumor suppressor gene (WT1) has recently been implicated in adrenogenesis (342). Unlike SF-1, WT1 expression is not detectable during adrenal cortex formation (343, 344) but is in the developing kidney and urogenital system. Taken together, these results suggest, first, that the WT1 gene may be expressed in a very transitory manner in adrenocortical precursor cells, and second, that WT1 activity may be required at early steps of adrenal development, probably in the AGP stage. Functional interactions between SF-1, DAX-1, and WT1 have been demonstrated for transcriptional regulation of the Mullerian inhibiting substance (MIS) sex-specific gene in vitro (344). Such combinational regulation may occur for the expression of genes determining the fate of the AGP. It should be interesting to determine whether any alterations in SF-1, DAX-1, or WT1 could be present, particularly in cases of AIMAH with ectopic membrane hormone receptors.

The concept of abnormal G protein-coupled receptors and/or postreceptor events leading to increased cAMP and proliferation is now well established (Table 4, reviewed in Refs. 345, 346, 347), especially in somatotroph and thyroid cells (348, 349). Stimulation of G-protein-coupled receptors, alone or in association with tyrosine kinase receptors, is known to evoke powerful mitogenic signals via G protein-mediated activation of ras (346). Thus, altered activity at any step of the transduction signal cascade may predispose to tumor formation. Transgenic mice with thyroid-specific expression of adenosine A2 receptor (which activates AC via G_s protein) develop thyroid hyperplasia and severe hyperthyroidism (350), clearly demonstrating that in vivo constitutive activation of the cAMP cascade in thyroid cells is sufficient to stimulate autonomous hyperfunction and uncontrolled cell proliferation. There are many examples of hormone receptor mutations involved in endocrine pathologies (Table 4). Some include somatic or germline constitutive mutational activation of the TSH receptor, resulting in hyperfunctionning thyroid adenomas and hyperplasias (351, 352); familial male precocious puberty (characterized by Leydig cell hyperplasia and testosterone production) is due to constitutive activation of LH/hCGR (353). At the G protein level, the mosaic-activating mutation of G_s leads to McCune-Albright syndrome (172); activating mutations of inhibitory G_i protein (Gip) have been identified in some, but not all, adrenocortical and ovarian tumors (355), and G_s overexpression has been shown in insulinomas and other endocrine tumors (356). There are examples of transgenic mice with cardiac overexpression of ß₂-AR or G_s that display enhanced cardiac function and develop myocardial fibrosis (357). However, it must be stressed that cAMP is not mitogenic in all cell types. Counterregulatory mechanisms are initiated in response to persistently elevated cAMP levels. This was the case for transgenic mice expressing gsp in pancreatic ß-cells (358) where inhibitors of phosphodiesterases were required to obtain high cAMP levels and enhanced insulin secretion. In the Y1 mouse adrenocortical cell line transfected with ß₂-AR, ectopic receptors have been found to be efficiently coupled to steroidogenesis, but cell growth has not been studied (359).

What is the cell of origin in which the receptor is expressed abnormally? Based on the profile of steroids produced, it appears that it can occur in well differentiated cells of the fasciculata/reticularis (pure cortisol- or mixed cortisol-/androgen-secreting adenoma), and in cells from the reticularis (pure androgen-secreting adenoma); the three classes of adrenal steroids are sometimes secreted in macronodular hyperplasia, suggesting that all zonae are affected. It remains to be seen whether some cases of unilateral adenomas or bilateral hyperplasia in primary hyperaldosteronism can also be secondary to ectopic hormone receptors.

No constitutive activating mutations of the ACTHR have yet been found in adrenocortical neoplasms or hyperplasias (361). Recent studies suggested that ACTHR could act as a tumor suppressor gene in adrenal tumorigenesis (362) in a way similar to p53, which is involved in many tumor types, including adrenocortical tumors (363). Loss of heterozygosity of the ACTHR gene was shown to be associated with high malignancy or the absence of secretion in a subset of human adrenocortical tumors. Furthermore, lower expression of ACTHR was found in adrenocortical carcinomas compared with adrenocortical adenomas from patients with CS (364, 365). ACTH is known to be a differentiating factor with low potential for promotion of cell proliferation, as demonstrated by in vitro experiments. It has thus been speculated that a defect in the ACTHR signal cascade could result in dedifferentiation and increased cell proliferation (362). Obviously, much work remains to be done to better understand the mechanisms underlying tumorigenesis of the adrenal cortex.

	VIII. Ectopic/Abnormal Hormone Membrane Receptors in Nonadrenocortical Tumors

Top Abstract I. Introduction II. Hormonal Regulation of... III. Primary Adrenal... IV. Initial in Vitro... V. In Vivo Demonstration... VI. Investigation Strategy VII. Molecular Mechanisms of... VIII. Ectopic/Abnormal Hormone... IX. An Opportunity for... X. Summary and Conclusions References

 
The ectopic or abnormal expression of membrane hormone receptors is not limited to endocrine tumors of the adrenal cortex; an extensive review of their abnormal expression in nonadrenal cortex tissues is beyond the objective of this article, but a few examples will be cited. The aberrant stimulation of AC in other human endocrine tumors has been explored initially by Robert Ney and colleagues (366). AC stimulation was induced by glucagon in three of nine pheochromocytomas and in two of three parathyroid adenomas, by LH and TSH in a thyroid follicular carcinoma, and by ACTH in a pituitary chromophobe adenoma (9, 366). The AC of normal adrenal medulla was not stimulated by glucagon, suggesting the ectopic expression of glucagon receptor in pheochromocytoma (9, 367). This finding served, for a prolonged period of time, as a diagnostic provocative test, particularly in periodically secreting pheochromocytomas. With the advent of more sensitive catecholamine determinations, the glucagon provocative test was rarely used, and this may have contributed to the paucity of molecular characterization of the receptor in pheochromocytomas (368). We do not know whether the glucagon receptor structure in pheochromocytomas is normal, or what regulates its expression. The presence of glucagon receptor in pheochromocytomas remains of clinical relevance as glucagon is commonly used in premedication for endoscopic and radiological investigation of the digestive system, and inadvertent crisis still occurs after its administration in unsuspected pheochromocytomas (369).

Matsukura et al. (370) found aberrant AC stimulation in four GH-secreting pituitary adenomas by TRH (two of four), GnRH (two of four), norepinephrine (three of four), dopamine (one of four), glucagon (one of three), or PGE₁ (four of four); in one ACTH-secreting pituitary adenoma, AC was stimulated by GnRH, norepinephrine, and glucagon, but not by TRH. The paradoxical stimulation of GH or ACTH after the GnRH or TRH tests in vivo in patients before surgery correlated well with the AC stimulation in vitro. The AC of two ectopic ACTH secreting tumors (gastric carcinoid and malignant thymoma) was also stimulated by TRH, GnRH, norepinephrine, epinephrine, serotonin, and PGE₁ (370).

The frequently observed paradoxical increase in GH in acromegalic patients after administration of TRH, or in a lesser proportion, of GnRH (371, 372, 373) and the AC stimulation found in vitro (370) suggested the presence of ectopic TRH or GnRH receptors in GH-secreting pituitary tumors. The expression of TRH receptors type 1 has been confirmed in GH-secreting adenomas (374), where the structure of the receptor does not appear to be mutated (375); the TRHR-1 is normally expressed in rat somatotroph cells (376), and it is unknown whether the abnormal response of GH in acromegaly results from ectopic expression of one of the TRH receptors, or rather from abnormal coupling of this receptor to GH secretion in adenoma cells. In a preliminary report, the paradoxical increase in GH following oral glucose in acromegaly was found to result from aberrant GH-tumor response to GIP (376A ); this would suggest that ectopic GIPR could also occur in acromegaly. Epidermal growth factor (EGF) receptor is overexpressed in several types of human cancers including aggressive GH-secreting tumors (377).

As a corollary to the ectopic expression of LH/hCGR in the adrenal cortex, the stimulation of androgen secretion in patients with ovarian arrhenoblastomas, after administration of ACTH, and their suppression by dexamethasone indicate the ectopic expression of ACTHR in some of those tumors (378, 379).

In a sporadic human medullary thyroid carcinoma (MTC), Matsakura et al. (380) found that the AC was activated by TRH, glucagon, epinephrine, norepinephrine, and serotonin, but not by TSH, ACTH, or PRL. A large number of studies have now evaluated the expression and function of hormone and growth factor receptors in MTC (381, 382). It is problematic to distinguish which of the receptors identified are indeed ectopic, as frequently, the search for their expression in normal C cells has not been performed. Mutations of the normally C cell-expressed RET protooncogene (eutopic receptor) are present in almost all cases of genetic forms of familial MTC and MEN-2 (multiple endocrine neoplasia, type 2), and in a proportion of sporadic MTC cases (somatic), and play a crucial role in initiation of C cell proliferation (323). Clearly, other receptors contribute to the development and progression of MTC, e.g., the trk family, neurotrophin receptors, where the type trkB is reduced, while trkC expression is increased during the progression of the disease (381). Some of these proliferative-related receptors are expressed also in normal thyroid; this appears to be the case for transforming growth factor- (TGF- and EGF), as well as for their common EGF receptor (382). However, EGF binding protein, particularly EGFBP-2 and -3, are detected only in MTC (382). Rat MTC cell line 6/23 also expresses GLP-1 receptor, VIP receptor, and PACAP receptor (383); in addition, several splice variants of PACAP were expressed in 6/23 cell line. The GLP-1 receptor expression is responsible for glucagon effect on calcitonin secretion via cAMP stimulation (384). Additional receptors in which ectopic or increased expression may be related to the progression of the disease include progesterone receptors, which are focally detected in all studied cases of MTC without the concurrent presence of estrogen receptors (385). Expression of gastrointestinal hormones and their receptors, particularly those of CCK-B/gastrin, also received attention in MTC. Thus, CCK-B/gastrin receptors were detected in all biopsy specimens, while they were not found in normal thyroid tissues or in other thyroid tumors such as follicular adenoma, papillary carcinoma, or anaplastic carcinoma (386). Therefore, the presence of CCK-B/gastrin receptor in MTC may have clinical implications. Much attention has been paid, over the last decade, to somatostatin receptor expression in MTC and many other tumor types. The genomic structure and transcription regulation of the various types of somatostatin receptors are now better understood in MTC (387).

Many other receptors have been described, during the last decade, as being expressed in the adrenal medulla tumors without apparent clinical evidence of their ectopic activities. Such is the case for the ANP receptor and its effect on catecholamine release in human pheochromocytoma (388). Most of the receptors studied more recently have, at least, a potential relevance for control of proliferation. Thus, IGF-II itself is produced and released by the adrenal and is accompanied by the presence of IGF-II R in pheochromocytomas (389). As the ectopic expression of Src homology 2 (SH2) and SH3-containing oncogenic adaptor protein v-Crk in PC12 cells results in EGF-inducible neuronal differentiation, v-Crk was studied and demonstrated able to regulate the strength of a tyrosine kinase signal that leads to prolonged activation of Ras and MAP kinase, respectively (390). Pheochromocytoma shares the expression of several genes with MTC; one example is TGF gene and its receptor EGFR (391). Both of these tumors express these receptors in vivo and in vitro, and it has been suggested that TGF is involved in the regulation of tumor cell growth. Since the signaling pathway from the TrkA receptor via the MAP kinase is not altered in PC12 cells, it has been proposed that p300 could play a pivotal role in triggering the antimitogenic effect of NGF and neuronal differentiation (392).

Since all cells are regulated in their function and proliferation by a series of hormone and growth factors that signal the cells via membrane receptors, it appears quite plausible that several other examples of ectopic or abnormal membrane receptors will be identified in various hyperplasias and tumors in diverse endocrine and nonendocrine human tissues.

	IX. An Opportunity for New Pharmacological Therapeutic Strategies

Top Abstract I. Introduction II. Hormonal Regulation of... III. Primary Adrenal... IV. Initial in Vitro... V. In Vivo Demonstration... VI. Investigation Strategy VII. Molecular Mechanisms of... VIII. Ectopic/Abnormal Hormone... IX. An Opportunity for... X. Summary and Conclusions References

 
The identification of ectopic or abnormal adrenal hormone receptors in cortisol-secreting hyperplasias or tumors provides new opportunities to use specific pharmacological therapies as alternatives to adrenalectomy. This was initially suggested by the short-term improvement of hypercortisolism when T₃ was administered briefly to a patient before resection of an adrenal adenoma in which AC was stimulated by TSH (9); however, these data were very preliminary and could not clearly distinguish whether the changes in cortisol levels reflected spontaneous fluctuations of cortisol secretion or were truly the result of endogenous TSH suppression.

Pharmacological blockade of postprandial GIP release with octreotide was attempted in a few patients with GIP-dependent CS as an alternative to surgery (Table 2; Refs. 201, 208, 209). During the first months of subcutaneous octreotide administration before each meal, clinical and biological improvements were documented, but long-term treatment proved to be ineffective. It is presumed that the escape of octreotide efficacy was secondary to down-regulation of somatostatin receptors in GIP-secreting intestinal cells. Thus, adrenalectomy remains the long-term treatment of choice for this syndrome until specific GIPR antagonists become available. Short-term use of the oral V1-AVPR antagonist OPC-21268 for 8 days decreased urinary free cortisol levels in a patient with vasopressin-responsive AIMAH and CS (239).

In the patient with catecholamine-dependent CS and bilateral AIMAH (86), initial treatment with propranolol up to 320 mg daily was able to considerably reduce cortisol secretion; however, urinary cortisol levels remained approximately twice the upper limit of normal, and it was decided to remove one of the two very large adrenals surgically. It then became possible, upon restoration of propranolol administration, to completely normalize cortisol production. Interestingly, the control of hypercortisolism was followed by a decreased requirement in the dosage of the ß-blocker from 320 mg to 20 mg of propranolol daily, as higher doses were causing adrenal insufficiency. GC are known to stimulate ß₂-AR transcription (292) via GRE located in promoters of the target genes (293). The normalization of cortisol levels may have decreased ß-AR density, which would explain the lower requirement for the antagonist. Propranolol therapy did not reduce the size of the remaining adrenal even after 3 yr of follow-up; however, the minimal dose of propranolol necessary to maintain normal cortisol production was administered, without blocking the receptors completely. This constituted the first example of long-term pharmacological blockade of an ectopic adrenal membrane hormone receptor.

In the patient with LH/hCG-dependent AIMAH and CS, the suppression of endogenous LH levels with chronic, long-acting leuprolide acetate controlled the hypercortisolism (Fig. 3) and avoided bilateral adrenalectomy (251). Leuprolide acetate, a long-acting GnRH agonist, initially stimulated gonadotropin release, which increased cortisol production for 1 week; this was followed by suppression of endogenous LH levels and normalization of cortisol production. Despite complete suppression of endogenous LH levels, the patient did not present cortisol insufficiency. It is possible that basal cortisol production was maintained by serotonin stimulation, since there was also evidence of abnormal 5-HT₄R function in the same adrenals. The absence of regression of bilateral adrenal hyperplasia, despite chronic suppression of endogenous LH, indicates that its size was maintained by abnormal function of 5-HT₄R, or that aberrant receptors regulate steroidogenesis but not cell proliferation. It will be interesting to study the effects of a specific 5-HT₄R antagonist in this patient when it becomes available. A GnRH analog has previously been used successfully in long-term suppression of testosterone-secreting ovarian tumor (393).

Further studies will probably identify a larger diversity of hormone receptor abnormalities and should eventually allow the use of new pharmacological tools to inhibit either the production of endogenous ligands or block the receptors with appropriate specific antagonists (Table 5). Since it is also possible to detect the presence of ectopic/abnormal hormone receptors at the stage of preclinical steroid hormone production (242), it will be of great interest to investigate whether the progression of adrenal tumors or hyperplasias can be prevented by these new pharmacological approaches.

	X. Summary and Conclusions

Top Abstract I. Introduction II. Hormonal Regulation of... III. Primary Adrenal... IV. Initial in Vitro... V. In Vivo Demonstration... VI. Investigation Strategy VII. Molecular Mechanisms of... VIII. Ectopic/Abnormal Hormone... IX. An Opportunity for... X. Summary and Conclusions References

	Acknowledgments

 
We wish to acknowledge the late Dr. E. Bolté for his initial contributions in elucidating food- and GIP-dependent Cushing’s syndrome. In addition, we thank Drs. J.-M. Boutin, H. Mircescu, W. W. de Herder, I. Bourdeau, R. M. Touyz, L. Y. Deng, R. Larivière, J. R. Cusson, E. L. Schiffrin, G. Rousseau, M. Bouvier, the patients and their referring physicians, CHUM Endocrine Division members, nurses, and laboratory technicians for their contributions to this work. The assistance of Mrs. Victoria Baranga in preparing the manuscript, of Mr. Bruno St-Pierre for medical illustrations, and of Mr. Ovid Da Silva in editing the text is also appreciated.

	Footnotes

 
Address reprint requests to: André Lacroix, M.D., Division of Endocrinology, Research Center, Hôtel-Dieu du CHUM, 3840 St. Urbain Street, Montréal, Québec, Canada H2W 1T8. E-mail: andre.lacroix{at}umontreal.ca

¹ Supported by a grant from the Medical Research Council of Canada (MA-10339).

	References

Top Abstract I. Introduction II. Hormonal Regulation of... III. Primary Adrenal... IV. Initial in Vitro... V. In Vivo Demonstration... VI. Investigation Strategy VII. Molecular Mechanisms of... VIII. Ectopic/Abnormal Hormone... IX. An Opportunity for... X. Summary and Conclusions References

 

1. Nieman L, Cutler Jr GB 1995 Cushing’s syndrome. In: De Groot LJ, Besser M, Burger HG, Jameson JL, Loriaux DL, Marshall JC, Odell WD, Potts Jr JT, Rubenstein AH (eds) Endocrinology. W.B. Saunders Co, Philadelphia, pp 1741–1769
2. Orth DN, Kovacs WJ 1998 The adrenal cortex. In: Wilson JD, Foster DW, Kronenberg HM, Larsen PR (eds) Williams’ Textbook of Endocrinology. W.B. Saunders Co, Philadelphia, pp 517–664
3. Yanovski JA, Cutler Jr GB 1994 Glucocorticoid action and the clinical features of Cushing’s syndrome. Endocrinol Metab Clin North Am 23:487–509[Medline]
4. Newell-Price J, Trainer P, Besser M, Grossman A 1998 The diagnosis and differential diagnosis of Cushing’s syndrome and pseudo-Cushing’s states. Endocr Rev 19:647–672[Abstract/Free Full Text]
5. Marieb NJ, Spangler S, Kashgarian M, Heimann A, Schwartz ML, Schwartz PE 1983 Cushing’s syndrome secondary to ectopic cortisol production by an ovarian carcinoma. J Clin Endocrinol Metab 57:737–740[Abstract/Free Full Text]
6. Iida S, Nakamura Y, Fujii H, Nishimura J, Tsugawa M, Gomi M, Fukata J, Tarui S, Moriwaki K, Kitani T 1990 A patient with hypocortisolism and Cushing’s syndrome-like manifestations: cortisol hyperreactive syndrome. J Clin Endocrinol Metab 70:729–737[Abstract/Free Full Text]
7. Newfield RS, Kalaitzoglou G, Licholai T, Chilton D, Ashraf J, Thompson EB, New MI 2000 Normocortisolemic Cushing’s syndrome initially presenting with increased glucocorticoid receptor numbers. J Clin Endocrinol Metab 85:14–21[Abstract/Free Full Text]
8. Schorr I, Ney RL 1971 Abnormal hormone responses of an adrenocortical cancer adenyl cyclase. J Clin Invest 50:1295–1300
9. Hingshaw HT, Ney RL 1974 Abnormal control in the neoplastic adrenal cortex. In: McKerns KW (ed) Hormones and Cancer. Academic Press, New York, pp 309–327
10. N'Diaye N, Tremblay J, Hamet P, Lacroix A 1998 Hormone receptor abnormalities in adrenal Cushing’s syndrome. Horm Metab Res 30:440–446[Medline]
11. Ehrhart-Bornstein M, Hinson JP, Bornstein SR, Scherbaum WA, Vinson GP 1998 Intraadrenal interactions in the regulation of adrenocortical steroidogenesis. Endocr Rev 19:101–143[Abstract/Free Full Text]
12. Nussdorfer GG, Mazzocchi G 1998 Immune-endocrine interactions in the mammalian adrenal gland: facts and hypotheses. Int Rev Cytol 183:143–184[Medline]
13. Baylis PH 1991 Vasopressin and its neurophysin. In: DeGroot LJ, Besser M, Burger HG, Jameson JL, Loriaux DL, Marshall JC, Odell WD, Potts Jr JT, Rubenstein AH (eds) Endocrinology. W.B. Saunders Co, Philadelphia, pp 406–420
14. Grossman A 1999 Corticotropin-releasing hormone: basic physiology and clinical applications. In: DeGroot LJ, Besser GM, Burger HG, Jameson JL, Loriaux DL, Marshall JC, Odell WD, Potts Jr JT, Rubenstein AH (eds) Endocrinology. W.B. Saunders Co, Philadelphia, pp 341–354
15. Chen R, Lewis KA, Perrin MH, Vale WW 1993 Expression cloning of a human corticotropin-releasing-factor receptor. Proc Natl Acad Sci USA 90:8967–8971[Abstract/Free Full Text]
16. de Keyzer Y, Auzan C, Lenne F, Beldjord C, Thibonnier M, Bertagna X, Clauser E 1994 Cloning and characterization of the human V3 pituitary vasopressin receptor. FEBS Lett 356:215–220[CrossRef][Medline]
17. Bertagna X 1994 Proopiomelanocortin-derived peptides. Endocrinol Metab Clin North Am 23:467–485[Medline]
18. Nussdorfer GG, Malendowicz LK 1998 Role of VIP, PACAP, and related peptides in the regulation of the hypothalamo-pituitary-adrenal axis. Peptides 19:1443–1467[CrossRef][Medline]
19. Watanobe H, Tamura T 1994 Stimulation by peptide histidine methionine (PHM) of adrenocorticotropin secretion in patients with Cushing’s disease: a comparison with the effect of vasoactive intestinal peptide (VIP) and a study on the effect of combined administration of corticotropin- releasing hormone with PHM or VIP. J Clin Endocrinol Metab 78:1372–1377[Abstract]
20. Lacroix S, Rivest S 1998 Effect of acute systemic inflammatory response and cytokines on the transcription of the genes encoding cyclooxygenase enzymes (COX-1 and COX-2) in the rat brain. J Neurochem 70:452–466[Medline]
21. Giraldi FP, Cavagnini F 1998 Corticotropin-releasing hormone is produced by rat corticotropes and modulates ACTH secretion in a paracrine/autocrine fashion. J Clin Invest 101:2478–2484[Medline]
22. Mountjoy KG, Robbins LS, Mortrud MT, Cone RD 1992 The cloning of a family of genes that encode the melanocortin receptors. Science 257:1248–1251[Abstract/Free Full Text]
23. Naville D, Jaillard C, Barjhoux L, Durand P, Begeot M 1997 Genomic structure and promoter characterization of the human ACTH receptor gene. Biochem Biophys Res Commun 230:7–12[CrossRef][Medline]
24. Simpson ER, Waterman MR 1988 Regulation of the synthesis of steroidogenic enzymes in adrenal cortical cells by ACTH. Annu Rev Physiol 50:427–440[CrossRef][Medline]
25. Lehoux JG, Fleury A, Ducharme L 1998 The acute and chronic effects of adrenocorticotropin on the levels of messenger ribonucleic acid and protein of steroidogenic enzymes in rat adrenal in vivo. Endocrinology 139:3913–3922[Abstract/Free Full Text]
26. Miller WL 1988 Molecular biology of steroid hormone synthesis. Endocr Rev 9:295–318[Abstract/Free Full Text]
27. Stocco DM, Clark BJ 1996 Regulation of the acute production of steroids in steroidogenic cells. Endocr Rev 17:221–244[Abstract/Free Full Text]
28. Clark BJ, Wells J, King SR, Stocco DM 1994 The purification, cloning, and expression of a novel luteinizing hormone-induced mitochondrial protein in MA-10 mouse Leydig tumor cells. Characterization of the steroidogenic acute regulatory protein (StAR). J Biol Chem 269:28314–28322[Abstract/Free Full Text]
29. Lin D, Sugawara T, Strauss III JF, Clark BJ, Stocco DM, Saenger P, Rogol A, Miller WL 1995 Role of steroidogenic acute regulatory protein in adrenal and gonadal steroidogenesis. Science 267:1828–1831[Abstract/Free Full Text]
30. Bose HS, Sugawara T, Strauss III JF, Miller WL 1996 The pathophysiology and genetics of congenital lipoid adrenal hyperplasia. International Congenital Lipoid Adrenal Hyperplasia Consortium. N Engl J Med 335:1870–1878[Abstract/Free Full Text]
31. Caron KM, Soo SC, Wetsel WC, Stocco DM, Clark BJ, Parker KL 1997 Targeted disruption of the mouse gene encoding steroidogenic acute regulatory protein provides insights into congenital lipoid adrenal hyperplasia. Proc Natl Acad Sci USA 94:11540–11545[Abstract/Free Full Text]
32. Papadopoulos V 1998 Structure and function of the peripheral-type benzodiazepine receptor in steroidogenic cells. Proc Soc Exp Biol Med 217:130–142[CrossRef][Medline]
33. Amri H, Ogwuegbu SO, Boujrad N, Drieu K, Papadopoulos V 1996 In vivo regulation of peripheral-type benzodiazepine receptor and glucocorticoid synthesis by Ginkgo biloba extract EGb 761 and isolated ginkgolides. Endocrinology 137:5707–5718[Abstract]
34. Lehoux JG, Ducharme L 1995 In vivo effects of adrenocorticotropin on c-jun, jun-B, c-fos and fos-B in rat adrenal. Endocr Res 21:267–274[Medline]
35. Hol EM, Gispen WH, Bar PR 1995 ACTH-related peptides: receptors and signal transduction systems involved in their neurotrophic and neuroprotective actions. Peptides 16:979–993[CrossRef][Medline]
36. Penhoat A, Jaillard C, Saez JM 1989 Corticotropin positively regulates its own receptors and cAMP response in cultured bovine adrenal cells. Proc Natl Acad Sci USA 86:4978–4981[Abstract/Free Full Text]
37. Mountjoy KG, Bird IM, Rainey WE, Cone RD 1994 ACTH induces up-regulation of ACTH receptor mRNA in mouse and human adrenocortical cell lines. Mol Cell Endocrinol 99:R17–R20
38. Di Blasio AM, Voutilainen R, Jaffe RB, Miller WL 1987 Hormonal regulation of messenger ribonucleic acids for P450 scc (cholesterol side-chain cleavage enzyme) and P450c17 (17-hydroxylase/17,20-lyase) in cultured human fetal adrenal cells. J Clin Endocrinol Metab 65:170–175[Abstract/Free Full Text]
39. Murphy EP, Conneely OM 1997 Neuroendocrine regulation of the hypothalamic pituitary adrenal axis by the nurr1/nur77 subfamily of nuclear receptors. Mol Endocrinol 11:39–47[Abstract/Free Full Text]
40. Sugawara T, Kiriakidou M, McAllister JM, Holt JA, Arakane F, Strauss III JF 1997 Regulation of expression of the steroidogenic acute regulatory protein (StAR) gene: a central role for steroidogenic factor 1. Steroids 62:5–9[CrossRef][Medline]
41. Parker KL, Schimmer BP 1997 Steroidogenic factor 1: a key determinant of endocrine development and function. Endocr Rev 18:361–377[Abstract/Free Full Text]
42. Ingraham HA, Lala DS, Ikeda Y, Luo X, Shen WH, Nachtigal MW, Abbud R, Nilson JH, Parker KL 1994 The nuclear receptor steroidogenic factor 1 acts at multiple levels of the reproductive axis. Genes Dev 8:2302–2312[Abstract/Free Full Text]
43. Li Y, Lau LF 1997 Adrenocorticotropic hormone regulates the activities of the orphan nuclear receptor Nur77 through modulation of phosphorylation. Endocrinology 138:4138–4146[Abstract/Free Full Text]
44. Wilson TE, Mouw AR, Weaver CA, Milbrandt J, Parker KL 1993 The orphan nuclear receptor NGFI-B regulates expression of the gene encoding steroid 21-hydroxylase. Mol Cell Biol 13:861–868[Abstract/Free Full Text]
45. Morohashi K, Zanger UM, Honda S, Hara M, Waterman MR, Omura T 1993 Activation of CYP11A and CYP11B gene promoters by the steroidogenic cell-specific transcription factor, Ad4BP. Mol Endocrinol 7:1196–1204[Abstract/Free Full Text]
46. Takayama K, Morohashi K, Honda S, Hara N, Omura T 1994 Contribution of Ad4BP, a steroidogenic cell-specific transcription factor, to regulation of the human CYP11A and bovine CYP11B genes through their distal promoters. J Biochem (Tokyo) 116:193–203[Abstract/Free Full Text]
47. Watanabe N, Inoue H, Fujii-Kuriyama Y 1994 Regulatory mechanisms of cAMP-dependent and cell-specific expression of human steroidogenic cytochrome P450 scc (CYP11A1) gene. Eur J Biochem 222:825–834[Medline]
48. Clemens JW, Lala DS, Parker KL, Richards JS 1994 Steroidogenic factor-1 binding and transcriptional activity of the cholesterol side-chain cleavage promoter in rat granulosa cells. Endocrinology 134:1499–1508[Abstract/Free Full Text]
49. Zhang P, Mellon SH 1996 The orphan nuclear receptor steroidogenic factor-1 regulates the cyclic adenosine 3',5'-monophosphate-mediated transcriptional activation of rat cytochrome P450c17 (17-hydroxylase/c17–20 lyase). Mol Endocrinol 10:147–158[Abstract/Free Full Text]
50. Zhang P, Mellon SH 1997 Multiple orphan nuclear receptors converge to regulate rat P450c17 gene transcription: novel mechanisms for orphan nuclear receptor action. Mol Endocrinol 11:891–904[Abstract/Free Full Text]
51. Inoue H, Watanabe N, Higashi Y, Fujii-Kuriyama Y 1991 Structures of regulatory regions in the human cytochrome P-450 scc (desmolase) gene. Eur J Biochem 195:563–569[Medline]
52. John ME, John MC, Boggaram V, Simpson ER, Waterman MR 1986 Transcriptional regulation of steroid hydroxylase genes by corticotropin. Proc Natl Acad Sci USA 83:4715–4719[Abstract/Free Full Text]
53. Bischof LJ, Kagawa N, Moskow JJ, Takahashi Y, Iwamatsu A, Buchberg AM, Waterman MR 1998 Members of the meis1 and pbx homeodomain protein families cooperatively bind a cAMP-responsive sequence (CRS1) from bovine CYP17. J Biol Chem 273:7941–7948[Abstract/Free Full Text]
54. Kagawa N, Ogo A, Takahashi Y, Iwamatsu A, Waterman MR 1994 A cAMP-regulatory sequence (CRS1) of CYP17 is a cellular target for the homeodomain protein Pbx1. J Biol Chem 269:18716–18719[Abstract/Free Full Text]
55. Ogo A, Waterman MR, Kagawa N 1997 cAMP-dependent transactivation involving the homeodomain protein Pbx1. Arch Biochem Biophys 338:193–200[CrossRef][Medline]
56. Venepally P, Waterman MR 1995 Two Sp1-binding sites mediate cAMP-induced transcription of the bovine CYP11A gene through the protein kinase A signaling pathway. J Biol Chem 270:25402–25410[Abstract/Free Full Text]
57. Bakke M, Lund J 1995 Mutually exclusive interactions of two nuclear orphan receptors determine activity of a cyclic adenosine 3',5'-monophosphate-responsive sequence in the bovine CYP17 gene. Mol Endocrinol 9:327–339[Abstract/Free Full Text]
58. Jacob AL, Lund J 1998 Mutations in the activation function-2 core domain of steroidogenic factor-1 dominantly suppresses PKA-dependent transactivation of the bovine CYP17 gene. J Biol Chem 273:13391–13394[Abstract/Free Full Text]
59. Monte D, DeWitte F, Hum DW 1998 Regulation of the human P450 scc gene by steroidogenic factor 1 is mediated by CBP/p300. J Biol Chem 273:4585–4591[Abstract/Free Full Text]
60. Bischof LJ, Kagawa N, Waterman MR 1998 The bovine CYP17 promoter contains a transcriptional regulatory element cooperatively bound by tale homeodomain proteins. Endocr Res 24:489–495[Medline]
61. Philips A, Lesage S, Gingras R, Maira MH, Gauthier Y, Hugo P, Drouin J 1997 Novel dimeric Nur77 signaling mechanism in endocrine and lymphoid cells. Mol Cell Biol 17:5946–5951[Abstract]
62. Philips A, Maira M, Mullick A, Chamberland M, Lesage S, Hugo P, Drouin J 1997 Antagonism between Nur77 and glucocorticoid receptor for control of transcription. Mol Cell Biol 17:5952–5959[Abstract]
63. Rust W, Stedronsky K, Tillmann G, Morley S, Walther N, Ivell R 1998 The role of SF-1/Ad4BP in the control of the bovine gene for the steroidogenic acute regulatory (StAR) protein. J Mol Endocrinol 21:189–200[Abstract]
64. Lee SL, Wesselschmidt RL, Linette GP, Kanagawa O, Russell JH, Milbrandt J 1995 Unimpaired thymic and peripheral T cell death in mice lacking the nuclear receptor NGFI-B (Nur77). Science 269:532–535[Abstract/Free Full Text]
65. Luo X, Ikeda Y, Parker KL 1994 A cell-specific nuclear receptor is essential for adrenal and gonadal development and sexual differentiation. Cell 77:481–490[CrossRef][Medline]
66. Parker KL 1998 The roles of steroidogenic factor 1 in endocrine development and function. Mol Cell Endocrinol 145:15–20[CrossRef][Medline]
67. Jones MT, Gillham B 1988 Factors involved in the regulation of adrenocorticotropic hormone/ß-lipotropic hormone. Physiol Rev 68:743–818[Free Full Text]
68. Gallo-Payet N, Guillon G 1998 Regulation of adrenocortical function by vasopressin. Horm Metab Res 30:360–367[Medline]
69. Clements JA, Funder JW 1986 Arginine vasopressin (AVP) and AVP-like immunoreactivity in peripheral tissues. Endocr Rev 7:449–460[Abstract/Free Full Text]
70. Turnbull AV, Rivier CL 1999 Regulation of the hypothalamic-pituitary-adrenal axis by cytokines: actions and mechanisms of action. Physiol Rev 79:1–71[Abstract/Free Full Text]
71. Bird IM, Walker SW, Williams BC 1990 Agonist-stimulated turnover of the phosphoinositides and the regulation of adrenocortical steroidogenesis. J Mol Endocrinol 5:191–209[Abstract/Free Full Text]
72. Bird IM, Nicol M, Williams BC, Walker SW 1990 Vasopressin stimulates cortisol secretion and phosphoinositide catabolism in cultured bovine adrenal fasciculata/reticularis cells. J Mol Endocrinol 5:109–116[Abstract/Free Full Text]
73. Hinson JP, Vinson GP, Porter ID, Whitehouse BJ 1987 Oxytocin and arginine vasopressin stimulate steroid secretion by the isolated perfused rat adrenal gland. Neuropeptides 10:1–7[CrossRef][Medline]
74. Gallo-Payet N, Guillon G, Balestre MN, Jard S 1986 Vasopressin induces breakdown of membrane phosphoinositides in adrenal glomerulosa and fasciculata cells. Endocrinology 119:1042–1047[Abstract/Free Full Text]
75. Perraudin V, Delarue C, Lefebvre H, Contesse V, Kuhn JM, Vaudry H 1993 Vasopressin stimulates cortisol secretion from human adrenocortical tissue through activation of V1 receptors. J Clin Endocrinol Metab 76:1522–1528[Abstract]
76. Guillon G, Trueba M, Joubert D, Grazzini E, Chouinard L, Cote M, Payet MD, Manzoni O, Barberis C, Robert M 1995 Vasopressin stimulates steroid secretion in human adrenal glands: comparison with angiotensin-II effect. Endocrinology 136:1285–1295[Abstract]
77. Guillon G, Grazzini E, Andrez M, Breton C, Trueba M, Serradeil-LeGal C, Boccara G, Derick S, Chouinard L, Gallo-Payet N 1998 Vasopressin: a potent autocrine/paracrine regulator of mammal adrenal functions. Endocr Res 24:703–710[Medline]
78. Guillon G, Gallo-Payet N 1986 Specific vasopressin binding to rat adrenal glomerulosa cells. Relationship to inositol lipid breakdown. Biochem J 235:209–214[Medline]
79. Arnaldi G, Gasc JM, de Keyzer Y, Raffin-Sanson ML, Perraudin V, Kuhn JM, Raux-Demay MC, Luton JP, Clauser E, Bertagna X 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]
80. Lacroix A, Tremblay J, Touyz RM, Deng LY, Lariviere R, Cusson JR, Schiffrin EL, Hamet P 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]
81. Grazzini E, Lodboerer AM, Perez-Martin A, Joubert D, Guillon G 1996 Molecular and functional characterization of V1b vasopressin receptor in rat adrenal medulla. Endocrinology 137:3906–3914[Abstract]
82. Mazza E, Goffi S, Barchi P, Arvat E, Bellone J, Limone P, Ghigo E, Camanni F 1994 Enhanced adrenocorticotrophic hormone and cortisol responses to corticotrophin-releasing hormone in central idiopathic diabetes insipidus. Eur J Endocrinol 130:121–124[Abstract/Free Full Text]
83. Elias LL, Antunes-Rodrigues J, Elias PC, Moreira AC 1997 Effect of plasma osmolality on pituitary-adrenal responses to corticotropin-releasing hormone and atrial natriuretic peptide changes in central diabetes insipidus. J Clin Endocrinol Metab 82:1243–1247[Abstract/Free Full Text]
84. Walker SW, Lightly ER, Clyne C, Williams BC, Bird IM 1991 Adrenergic and cholinergic regulation of cortisol secretion from the zona fasciculata/reticularis of bovine adrenal cortex. Endocr Res 17:237–265[Medline]
85. Mazzocchi G, Gottardo G, Nussdorfer GG 1997 Catecholamines stimulate steroid secretion of dispersed fowl adrenocortical cells, acting through the ß-receptor subtype. Horm Metab Res 29:190–192[Medline]
86. Lacroix A, Tremblay J, Rousseau G, Bouvier M, Hamet P 1997 Propranolol therapy for ectopic beta-adrenergic receptors in adrenal Cushing’s syndrome. N Engl J Med 337:1429–1434[Free Full Text]
87. Lefebvre H, Contesse V, Delarue C, Vaudry H, Kuhn JM 1998 Serotonergic regulation of adrenocortical function. Horm Metab Res 30:398–403[Medline]
88. Delarue C, Lefebvre H, Idres S, Leboulenger F, Homo-Delarche G, Lihrmann I, Feuilloley M, Vaudry H 1988 Serotonin stimulates corticosteroid secretion by frog adrenocortical tissue in vitro. J Steroid Biochem 29:519–525[CrossRef][Medline]
89. Lefebvre H, Contesse V, Delarue C, Feuilloley M, Hery F, Grise P, Raynaud G, Verhofstad AA, Wolf LM, Vaudry H 1992 Serotonin-induced stimulation of cortisol secretion from human adrenocortical tissue is mediated through activation of a serotonin4 receptor subtype. Neuroscience 47:999–1007[CrossRef][Medline]
90. Hinson JP, Vinson GP, Pudney J, Whitehouse BJ 1989 Adrenal mast cells modulate vascular and secretory responses in the intact adrenal gland of the rat. J Endocrinol 121:253–260[Abstract/Free Full Text]
91. Lefebvre H, Contesse V, Delarue C, Soubrane C, Legrand A, Kuhn JM, Wolf LM, Vaudry H 1993 Effect of the serotonin-4 receptor agonist zacopride on aldosterone secretion from the human adrenal cortex: in vivo and in vitro studies. J Clin Endocrinol Metab 77:1662–1666[Abstract]
92. Lefebvre H, Contesse V, Delarue C, Legrand A, Kuhn JM, Vaudry H, Wolf LM 1995 The serotonin-4 receptor agonist cisapride and angiotensin-II exert additive effects on aldosterone secretion in normal man. J Clin Endocrinol Metab 80:504–507[Abstract]
93. Delarue C, Leboulenger F, Morra M, Hery F, Verhofstad AJ, Berod A, Denoroy L, Pelletier G, Vaudry H 1988 Immunohistochemical and biochemical evidence for the presence of serotonin in amphibian adrenal chromaffin cells. Brain Res 459:17–26[CrossRef][Medline]
94. Verhofstad AA, Jonsson G 1983 Immunohistochemical and neurochemical evidence for the presence of serotonin in the adrenal medulla of the rat. Neuroscience 10:1443–1453[CrossRef][Medline]
95. Fernandez-Vivero J, Rodriguez-Sanchez F, Verastegui C, Cordoba MF, Romero A, de Castro JM 1993 Immunocytochemical distribution of serotonin and neuropeptide Y (NPY) in mouse adrenal gland. Histol Histopathol 8:509–520[Medline]
96. Bornstein SR, Haidan A, Ehrhart-Bornstein M 1996 Cellular communication in the neuro-adrenocortical axis: role of vasoactive intestinal polypeptide (VIP). Endocr Res 22:819–829[Medline]
97. Bodnar M, Sarrieau A, Deschepper CF, Walker CD 1997 Adrenal vasoactive intestinal peptide participates in neonatal corticosteroid production in the rat. Am J Physiol 273:R1163–R1172
98. Li ZG, Queen G, LaBella FS 1990 Adrenocorticotropin, vasoactive intestinal polypeptide, growth hormone-releasing factor, and dynorphin compete for common receptors in brain and adrenal. Endocrinology 126:1327–1333[Abstract/Free Full Text]
99. Anderova M, Duchene AD, Barbara JG, Takeda K 1998 Vasoactive intestinal peptide potentiates and directly stimulates catecholamine secretion from rat adrenal chromaffin cells. Brain Res 809:97–106[CrossRef][Medline]
100. Guo X, Wakade AR 1994 Differential secretion of catecholamines in response to peptidergic and cholinergic transmitters in rat adrenals. J Physiol (Lond) 475:539–545[Abstract/Free Full Text]
101. Bernet F, Bernard J, Laborie C, Montel V, Maubert E, Dupouy JP 1994 Neuropeptide Y (NPY)- and vasoactive intestinal peptide (VIP)-induced aldosterone secretion by rat capsule/glomerular zone could be mediated by catecholamines via ß 1 adrenergic receptors. Neurosci Lett 166:109–112[CrossRef][Medline]
102. Hinson JP, Kapas S, Orford CD, Vinson GP 1992 Vasoactive intestinal peptide stimulation of aldosterone secretion by the rat adrenal cortex may be mediated by the local release of catecholamines. J Endocrinol 133:253–258[Abstract/Free Full Text]
103. Hinson JP, Cameron LA, Purbrick A, Kapas S 1994 The role of neuropeptides in the regulation of adrenal vascular tone: effects of vasoactive intestinal polypeptide, substance P, neuropeptide Y, neurotensin, Met-enkephalin, and Leu-enkephalin on perfusion medium flow rate in the intact perfused rat adrenal. Regul Pept 51:55–61[CrossRef][Medline]
104. Nussdorfer GG 1996 Paracrine control of adrenal cortical function by medullary chromaffin cells. Pharmacol Rev 48:495–530[Medline]
105. Bird IM, Magness RR, Mason JI, Rainey WE 1992 Angiotensin-II acts via the type 1 receptor to inhibit 17-hydroxylase cytochrome P450 expression in ovine adrenocortical cells. Endocrinology 130:3113–3121[Abstract/Free Full Text]
106. Clark BJ, Pezzi V, Stocco DM, Rainey WE 1995 The steroidogenic acute regulatory protein is induced by angiotensin II and K⁺ in H295R adrenocortical cells. Mol Cell Endocrinol 115:215–219[CrossRef][Medline]
107. Harrison-Bernard LM, El Dahr SS, O’Leary DF, Navar LG 1999 Regulation of angiotensin II type 1 receptor mRNA and protein in angiotensin II-induced hypertension. Hypertension 33:340–346[Abstract/Free Full Text]
108. Giacchetti G, Opocher G, Sarzani R, Rappelli A, Mantero F 1996 Angiotensin II and the adrenal. Clin Exp Pharmacol Physiol Suppl 3:S119–S124
109. Penhoat A, Ouali R, Jaillard C, Langlois D, Begeot M, Saez JM 1991 Characterization and regulation of angiotensin and corticotropin receptors on cultured bovine adrenal cells. Endocr Res 17:1–18
110. Naville D, Lebrethon MC, Kermabon AY, Rouer E, Benarous R, Saez JM 1993 Characterization and regulation of the angiotensin II type-1 receptor (binding and mRNA) in human adrenal fasciculata-reticularis cells. FEBS Lett 321:184–188[CrossRef][Medline]
111. Gupta P, Franco-Saenz R, Mulrow PJ 1995 Locally generated angiotensin II in the adrenal gland regulates basal, corticotropin-, and potassium-stimulated aldosterone secretion. Hypertension 25:443–448[Abstract/Free Full Text]
112. Mulrow PJ 1998 Renin-angiotensin system in the adrenal. Horm Metab Res 30:346–349[Medline]
113. Vinson GP, Ho MM 1998 The adrenal renin/angiotensin system in the rat. Horm Metab Res 30:355–359[Medline]
114. Missale C, Memo M, Liberini P, Spano P 1988 Dopamine selectively inhibits angiotensin II-induced aldosterone secretion by interacting with D-2 receptors. J Pharmacol Exp Ther 246:1137–1143[Abstract/Free Full Text]
115. Kasprzak A, Rebuffat P, Andreis PG, Mazzocchi G, Nussdorfer GG 1991 Effects of prolonged cysteamine administration on the rat adrenal cortex: evidence that endogenous somatostatin is involved in the control of the growth and steroidogenic capacity of zona glomerulosa. J Steroid Biochem Mol Biol 38:469–473[CrossRef][Medline]
116. Bodart V, Rainey WE, Fournier A, Ong H, De Lean A 1996 The H295R human adrenocortical cell line contains functional atrial natriuretic peptide receptors that inhibit aldosterone biosynthesis. Mol Cell Endocrinol 118:137–144[CrossRef][Medline]
117. Kawai M, Naruse M, Yoshimoto T, Naruse K, Shionoya K, Tanaka M, Morishita Y, Matsuda Y, Demura R, Demura H 1996 C-type natriuretic peptide as a possible local modulator of aldosterone secretion in bovine adrenal zona glomerulosa. Endocrinology 137:42–46[Abstract]
118. Cherradi N, Brandenburger Y, Rossier MF, Vallotton MB, Stocco DM, Capponi AM 1998 Atrial natriuretic peptide inhibits calcium-induced steroidogenic acute regulatory protein gene transcription in adrenal glomerulosa cells. Mol Endocrinol 12:962–972[Abstract/Free Full Text]
119. Hinson JP, Kapas S 1998 The role of endothelial cell products in the regulation of adrenocortical function: actions of endothelin, nitric oxide, adrenomedullin and PAMP. Horm Metab Res 30:334–340[Medline]
120. Nussdorfer GG, Rossi GP, Belloni AS 1997 The role of endothelins in the paracrine control of the secretion and growth of the adrenal cortex. Int Rev Cytol 171:267–308[Medline]
121. Mazzocchi G, Malendowicz LK, Macchi C, Gottardo G, Nussdorfer GG 1996 Further investigations on the effects of neuropeptide Y on the secretion and growth of rat adrenal zona glomerulosa. Neuropeptides 30:19–27[CrossRef][Medline]
122. Malendowicz LK, Markowska A, Zabel M 1996 Neuropeptide Y-related peptides and hypothalamo-pituitary-adrenal axis function. Histol Histopathol 11:485–494[Medline]
123. Rohner-Jeanrenaud F, Jeanrenaud B 1996 Obesity, leptin, and the brain. N Engl J Med 334:324–325[Free Full Text]
124. Ahima RS, Prabakaran D, Mantzoros C, Qu D, Lowell B, Maratos-Flier E, Flier JS 1996 Role of leptin in the neuroendocrine response to fasting. Nature 382:250–252[CrossRef][Medline]
125. Flier JS 1998 Clinical review 94: What’s in a name? In search of leptin’s physiologic role. J Clin Endocrinol Metab 83:1407–1413[Free Full Text]
126. Jin L, Burguera BG, Couce ME, Scheithauer BW, Lamsan J, Eberhardt NL, Kulig E, Lloyd RV 1999 Leptin and leptin receptor expression in normal and neoplastic human pituitary: evidence of a regulatory role for leptin on pituitary cell proliferation. J Clin Endocrinol Metab 84:2903–2911[Abstract/Free Full Text]
127. Shimon I, Yan X, Magoffin DA, Friedman TC, Melmed S 1998 Intact leptin receptor is selectively expressed in human fetal pituitary and pituitary adenomas and signals human fetal pituitary growth hormone secretion. J Clin Endocrinol Metab 83:4059–4064[Abstract/Free Full Text]
128. Glasow A, Haidan A, Hilbers U, Breidert M, Gillespie J, Scherbaum WA, Chrousos GP, Bornstein SR 1998 Expression of Ob receptor in normal human adrenals: differential regulation of adrenocortical and adrenomedullary function by leptin. J Clin Endocrinol Metab 83:4459–4466[Abstract/Free Full Text]
129. Cao GY, Considine RV, Lynn RB 1997 Leptin receptors in the adrenal medulla of the rat. Am J Physiol 273:E448–E452
130. Pralong FP, Roduit R, Waeber G, Castillo E, Mosimann F, Thorens B, Gaillard RC 1998 Leptin inhibits directly glucocorticoid secretion by normal human and rat adrenal gland. Endocrinology 139:4264–4268[Abstract/Free Full Text]
131. Heiman ML, Ahima RS, Craft LS, Schoner B, Stephens TW, Flier JS 1997 Leptin inhibition of the hypothalamic-pituitary-adrenal axis in response to stress. Endocrinology 138:3859–3863[Abstract/Free Full Text]
132. Huang Q, Rivest R, Richard D 1998 Effects of leptin on corticotropin-releasing factor (CRF) synthesis and CRF neuron activation in the paraventricular hypothalamic nucleus of obese (ob/ob) mice. Endocrinology 139:1524–1532[Abstract/Free Full Text]
133. Bornstein SR, Uhlmann K, Haidan A, Ehrhart-Bornstein M, Scherbaum WA 1997 Evidence for a novel peripheral action of leptin as a metabolic signal to the adrenal gland: leptin inhibits cortisol release directly. Diabetes 46:1235–1238[Abstract]
134. Schwartz MW, Seeley RJ, Campfield LA, Burn P, Baskin DG 1996 Identification of targets of leptin action in rat hypothalamus. J Clin Invest 98:1101–1106[Medline]
135. Malendowicz LK, Macchi C, Nussdorfer GG, Nowak KW 1998 Acute effects of recombinant murine leptin on rat pituitary-adrenocortical function. Endocr Res 24:235–246[Medline]
136. Slieker LJ, Sloop KW, Surface PL, Kriauciunas A, LaQuier F, Manetta J, Bue-Valleskey J, Stephens TW 1996 Regulation of expression of ob mRNA and protein by glucocorticoids and cAMP. J Biol Chem 271:5301–5304[Abstract/Free Full Text]
137. Spinedi E, Gaillard RC 1998 A regulatory loop between the hypothalamo-pituitary-adrenal (HPA) axis and circulating leptin: a physiological role of ACTH. Endocrinology 139:4016–4020[Abstract/Free Full Text]
138. Cizza G, Lotsikas AJ, Licinio J, Gold PW, Chrousos GP 1997 Plasma leptin levels do not change in patients with Cushing’s disease shortly after correction of hypercortisolism. J Clin Endocrinol Metab 82:2747–2750[Abstract/Free Full Text]
139. 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]
140. Belloni AS, Mazzocchi G, Meneghelli V, Nussdorfer GG 1978 Cytogenesis in the rat adrenal cortex: evidence for an ACTH-induced centripetal cell migration from the zona glomerulosa. Arch Anat Histol Embryol 61:195–205[Medline]
141. Kahri A 1966 Histochemical and electron microscopic studies on the cells of the rat adrenal cortex in tissue culture. Acta Endocrinol (Copenh) 52:[Suppl 108]:1–96
142. Arola J, Heikkila P, Voutilainen R, Kahri AI 1994 Corticosterone regulates cell proliferation and cytochrome P450 cholesterol side-chain cleavage enzyme messenger ribonucleic acid expression in primary cultures of fetal rat adrenals. Endocrinology 135:2064–2069[Abstract]
143. Salmenpera M, Kahri AI, Saure A 1976 Effects of corticosterone on adrenocorticotrophin-induced mitochondrial differentiation with special reference to 11 ß- and 18-hydroxylation. J Endocrinol 70:215–222[Abstract/Free Full Text]
144. Salmenpera M 1976 Comparison of the ultrastructural and steroidogenic properties of mitochondria of fetal rat adrenals in tissue culture. A morphometric and a gas chromatographic analysis. J Ultrastruct Res 56:277–286[CrossRef][Medline]
145. Armelin HA, Lotfi CF, Lepique AP 1996 Regulation of growth by ACTH in the Y-1 line of mouse adrenocortical cells. Endocr Res 22:373–383[Medline]
146. Penhoat A, Ouali R, Viard I, Langlois D, Saez JM 1996 Regulation of primary response and specific genes in adrenal cells by peptide hormones and growth factors. Steroids 61:176–183[CrossRef][Medline]
147. Watanabe G, Pena P, Albanese C, Wilsbacher LD, Young JB, Pestell RG 1997 Adrenocorticotropin induction of stress-activated protein kinase in the adrenal cortex in vivo. J Biol Chem 272:20063–20069[Abstract/Free Full Text]
148. Lotfi CF, Todorovic Z, Armelin HA, Schimmer BP 1997 Unmasking a growth-promoting effect of the adrenocorticotropic hormone in Y1 mouse adrenocortical tumor cells. J Biol Chem 272:29886–29891[Abstract/Free Full Text]
149. Kimura E, Sonobe MH, Armelin MC, Armelin HA 1993 Induction of FOS and JUN proteins by adrenocorticotropin and phorbol ester but not by 3',5'-cyclic adenosine monophosphate derivatives. Mol Endocrinol 7:1463–1471[Abstract/Free Full Text]
150. Karin M 1995 The regulation of AP-1 activity by mitogen-activated protein kinases. J Biol Chem 270:16483–16486[Free Full Text]
151. Watanabe G, Lee RJ, Albanese C, Rainey WE, Batlle D, Pestell RG 1996 Angiotensin II activation of cyclin D1-dependent kinase activity. J Biol Chem 271:22570–22577[Abstract/Free Full Text]
152. Malendowicz LK, Nussdorfer GG 1993 Unusual effect of prolonged vasoactive intestinal peptide (VIP) administration on the adrenal growth and corticosterone secretion in the rat. Neuropeptides 25:145–150[CrossRef][Medline]
153. Rebuffat P, Nowak KW, Tortorella C, Musajo FG, Gottardo G, Mazzocchi G, Nussdorfer GG 1994 Evidence that endogenous vasoactive intestinal peptide (VIP) plays a role in the maintenance of the growth and steroidogenic capacity of rat adrenal zona glomerulosa. J Steroid Biochem Mol Biol 51:81–88[CrossRef][Medline]
154. Mesiano S, Katz SL, Lee JY, Jaffe RB 1997 Insulin-like growth factors augment steroid production and expression of steroidogenic enzymes in human fetal adrenal cortical cells: implications for adrenal androgen regulation. J Clin Endocrinol Metab 82:1390–1396[Abstract/Free Full Text]
155. Voutilainen R, Ilvesmaki V, Ariel I, Rachmilewitz J, de Groot N, Hochberg A 1994 Parallel regulation of parentally imprinted H19 and insulin-like growth factor-II genes in cultured human fetal adrenal cells. Endocrinology 134:2051–2056[Abstract/Free Full Text]
156. Ilvesmaki V, Kahri AI, Miettinen PJ, Voutilainen R 1993 Insulin-like growth factors (IGFs) and their receptors in adrenal tumors: high IGF-II expression in functional adrenocortical carcinomas. J Clin Endocrinol Metab 77:852–858[Abstract]
157. Gicquel C, Bertagna X, Le Bouc Y 1995 Recent advances in the pathogenesis of adrenocortical tumours. Eur J Endocrinol 133:133–144[Abstract/Free Full Text]
158. Le Roy C, Li JY, Stocco DM, Langlois D, Saez JM 2000 Regulation by adrenocorticotropin (ACTH), angiotensin II, transforming growth factor-ß and insulin-like growth factor I of bovine adrenal cell steroidogenic capacity and expression of ACTH receptor steroidogenic acute regulatory protein cytochrome P450c17, and 3ß-hydroxysteroid dehydrogenase. Endocrinology 141:1599–1607[Abstract/Free Full Text]
159. Riopel L, Branchaud CL, Goodyer CG, Adkar V, Lefebvre Y 1989 Growth-inhibitory effect of TGF-B on human fetal adrenal cells in primary monolayer culture. J Cell Physiol 140:233–238[CrossRef][Medline]
160. Spencer SJ, Mesiano S, Lee JY, Jaffe RB 1999 Proliferation and apoptosis in the human adrenal cortex during the fetal and perinatal periods: implications for growth and remodeling. J Clin Endocrinol Metab 84:1110–1115[Abstract/Free Full Text]
161. Ross NS 1994 Epidemiology of Cushing’s syndrome and subclinical disease. Endocrinol Metab Clin North Am 23:539–546[Medline]
162. Bertagna C, Orth DN 1981 Clinical and laboratory findings and results of therapy in 58 patients with adrenocortical tumors admitted to a single medical center (1951 to 1978). Am J Med 71: 855–875
163. Latronico AC, Chrousos GP 1997 Extensive personal experience: adrenocortical tumors. J Clin Endocrinol Metab 82:1317–1324[Free Full Text]
164. 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]
165. Samuels MH, Loriaux DL 1994 Cushing’s syndrome and the nodular adrenal gland. Endocrinol Metab Clin North Am 23:555–569[Medline]
166. Trainer PJ, Grossman A 1991 The diagnosis and differential diagnosis of Cushing’s syndrome. Clin Endocrinol (Oxf) 34:317–330[Medline]
167. Carney JA, Gordon H, Carpenter PC, Shenoy BV, Go VL 1985 The complex of myxomas, spotty pigmentation, and endocrine overactivity. Medicine (Baltimore) 64:270–283[Medline]
168. Stratakis CA, Carney JA, Lin JP, Papanicolaou DA, Karl M, Kastner DL, Pras E, Chrousos GP 1996 Carney complex, a familial multiple neoplasia and lentiginosis syndrome. Analysis of 11 kindreds and linkage to the short arm of chromosome 2. J Clin Invest 97:699–705[Medline]
169. Casey M, Mah C, Merliss AD, Kirschner LS, Taymans SE, Denio AE, Korf B, Irvine AD, Hughes A, Carney JA, Stratakis CA, Basson CT 1998 Identification of a novel genetic locus for familial cardiac myxomas and Carney complex. Circulation 98:2560–2566[Abstract/Free Full Text]
169. Kirschner LS, Carney JA, Pack SD, Taymans SE, Giatzakis C, Cho YS, Cho-Chung YS, Stratakis CA 2000 Mutations of the gene encoding the protein kinase A Type 1- regulatory subunit in patients with the Carney complex. Nat Genet 26:89–92[CrossRef][Medline]
170. Stratakis CA, Carney JA, Kirschner LS, Willenberg HS, Brauer S, Ehrhart-Bornstein M, Bornstein SR 1999 Synaptophysin immunoreactivity in primary pigmented nodular adrenocortical disease: neuroendocrine properties of tumors associated with Carney complex. J Clin Endocrinol Metab 84:1122–1128[Abstract/Free Full Text]
171. Stratakis CA, Sarlis N, Kirschner LS, Carney JA, Doppman JL, Nieman LK, Chrousos GP, Papanicolaou DA 1999 Paradoxical response to dexamethasone in the diagnosis of primary pigmented nodular adrenocortical disease. Ann Intern Med 131:585–591[Abstract/Free Full Text]
172. 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[Abstract]
173. Boston BA, Mandel S, LaFranchi S, Bliziotes M 1994 Activating mutation in the stimulatory guanine nucleotide-binding protein in an infant with Cushing’s syndrome and nodular adrenal hyperplasia. J Clin Endocrinol Metab 79:890–893[Abstract]
174. 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 Endocrinol 131:67–73[Abstract/Free Full Text]
175. Stratakis CA, Kirschner LS 1998 Clinical and genetic analysis of primary bilateral adrenal diseases (micro- and macronodular disease) leading to Cushing syndrome. Horm Metab Res 30:456–463[Medline]
176. Malchoff CD, Rosa J, DeBold CR, Kozol RA, Ramsby GR, Page DL, Malchoff DM, Orth DN 1989 Adrenocorticotropin-independent bilateral macronodular adrenal hyperplasia: an unusual cause of Cushing’s syndrome. J Clin Endocrinol Metab 68:855–860[Abstract/Free Full Text]
177. Doppman JL, Miller DL, Dwyer AJ, Loughlin T, Nieman L, Cutler GB, Chrousos GP, Oldfield E, Loriaux DL 1988 Macronodular adrenal hyperplasia in Cushing disease. Radiology 166:347–352[Abstract/Free Full Text]
178. Doppman JL, Nieman LK, Travis WD, Miller DL, Cutler Jr GB, Chrousos GP, Norton JA 1991 CT and MR imaging of massive macronodular adrenocortical disease: a rare cause of autonomous primary adrenal hypercortisolism. J Comput Assist Tomogr 15:773–779[Medline]
179. Findlay JC, Sheeler LR, Engeland WC, Aron DC 1993 Familial adrenocorticotropin-independent Cushing’s syndrome with bilateral macronodular adrenal hyperplasia. J Clin Endocrinol Metab 76:189–191[Abstract]
180. Minami S, Sugihara H, Sato J, Tatsukuchi A, Sugisaki Y, Sasano H, Wakabayashi I 1996 ACTH independent Cushing’s syndrome occurring in siblings. Clin Endocrinol (Oxf) 44:483–488[CrossRef][Medline]
181. Cooper RJ, Udelsman R, Resta C, Tollin SR, Familial Cushing’s syndrome secondary to bilateral macronodular hyperplasia. Program and Abstracts of The 80th Annual Meeting of The Endocrine Society, New Orleans, LA, 1998 (Abstract P2–397), p 333
182. Grunenberger F, Noal E, Bachellier P, Weber JC, Jaeck D, Schlienger JL 1999 Hypercorticisme familial non ACTH dépendant par hyperplasie macronodulaire bilatérale des surrénales. Ann Endocrinol (Paris) 60:290 (Abstract A04)
183. Fragoso MCB, Latronico AC, Domenice S, Lando VS, Mendonca BB Activation mutation in the stimulatory guanine nucleotide-binding protein in a woman with Cushing’s syndrome by ACTH-independent macronodular adrenal hyperplasia. Program and Abstracts of The 81st Annual Meeting of The Endocrine Society, San Diego, CA, 1999 (Abstract P2–150), p 312
184. Schorr I, Rathnam P, Saxena BB, Ney RL 1971 Multiple specific hormone receptors in the adenylate cyclase of an adrenocortical carcinoma. J Biol Chem 246:5806–5811[Abstract/Free Full Text]
185. Williams LT, Gore TB, Lefkowitz RJ 1977 Ectopic ß-adrenergic receptor binding sites. Possible molecular basis of aberrant catecholamine responsiveness of an adrenocortical tumor adenylate cyclase. J Clin Invest 59:319–324
186. Brush JS, Sutliff LS, Sharma RK 1974 Metabolic regulation and adenyl cyclase activity of adrenocortical carcinoma cultured cells. Cancer Res 34:1495–1502[Abstract/Free Full Text]
187. Taunton OD, Roth J, Pastan I 1969 Studies on the adrenocorticotropic hormone-activated adenyl cyclase of a functional adrenal tumor. J Biol Chem 244:247–253[Abstract/Free Full Text]
188. Perchellet JP, Sharma RK 1980 Ectopic alpha-adrenergic mediated accumulation of guanosine 3',5'- monophosphate in isolated adrenocortical carcinoma cells. Endocrinology 106:1589–1593[Abstract/Free Full Text]
189. Shanker G, Sharma RK 1980 Characterization of ectopic -adrenergic binding receptors of adrenocortical carcinoma cells. Endocrinology 106:1594–1598[Abstract/Free Full Text]
190. Millington DS, Golder MP, Cowley T, London D, Roberts H, Butt WR, Griffiths K 1976 In vitro synthesis of steroids by a feminising adrenocortical carcinoma: effect of prolactin and other protein hormones. Acta Endocrinol (Copenh) 82:561–571[Abstract/Free Full Text]
191. Matsukura S, Kakita T, Sueoka S, Yoshimi H, Hirata Y, Yokota M, Fujita T 1980 Multiple hormone receptors in the adenylate cyclase of human adrenocortical tumors. Cancer Res 40:3768–3771[Abstract/Free Full Text]
192. Hirata Y, Uchihashi M, Sueoka 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/Free Full Text]
193. 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/Free Full Text]
194. Saez JM, Tell GP, Dazord A 1978 Human adrenocortical tumors: alterations in membrane-bound hormone receptors and cAMP protein kinases. In: Sharma RK, Criss WE (eds) Endocrine Control in Neoplasia. Raven Press, New York, pp 53–69
195. Leinonen P, Ranta T, Siegberg R, Pelkonen R, Heikkila P, Kahri A 1991 Testosterone-secreting virilizing adrenal adenoma with human chorionic gonadotrophin receptors and 21-hydroxylase deficiency. Clin Endocrinol (Oxf) 34:31–35[Medline]
196. Pittaway DE, Andersen RN, Givens JR 1973 In vitro on an HCG responsive, testosterone secreting adrenal cortical adenoma. Steroids 22:731–745[CrossRef][Medline]
197. Why L, Carlson HE, Kane P, Li X, Lei ZM, Rao CV Cushing’s syndrome secondary to an hCG/LH receptor-positive adrenal carcinoma presenting in the postpartum period. Program and abstracts of The 82nd Annual Meeting of The Endocrine Society, Toronto Ontario, Canada, 2000 (Abstract 2040), p 493
198. Willenberg HS, Stratakis CA, Marx C, Ehrhart-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]
199. Hamet P, Larochelle P, Franks DJ, Cartier P, Bolte E 1987 Cushing syndrome with food-dependent periodic hormonogenesis. Clin Invest Med 10:530–533[Medline]
200. Lacroix A, Bolte E, Tremblay J, Dupre J, Poitras P, Fournier H, Garon J, Garrel D, Bayard F, Taillefer R, Flanagan RJ, Hamet P 1992 Gastric inhibitory polypeptide-dependent cortisol hypersecretion—a new cause of Cushing’s syndrome. N Engl J Med 327:974–980[Abstract]
201. Reznik Y, Allali-Zerah V, Chayvialle JA, Leroyer R, Leymarie P, Travert G, Lebrethon MC, Budi I, Balliere AM, Mahoudeau J 1992 Food-dependent Cushing’s syndrome mediated by aberrant adrenal sensitivity to gastric inhibitory polypeptide. N Engl J Med 327:981–986[Abstract]
202. Olsen NJ, Fang VS, DeGroot LJ 1978 Cushing’s syndrome due to adrenal adenoma with persistent diurnal cortisol secretory rhythm. Metabolism 27:695–700[CrossRef][Medline]
203. Lacroix A, Bolté E, Poitras P, Fournier H, Garon J, Garrel D, Bayard F, Tremblay J, Taillefer R, Flanagan R, Hamet P 1991 Gastric inhibitory polypeptide-dependent macro-nodular adrenal hyperplasia: a new etiology of Cushing’s syndrome. Program and Abstracts of the 73rd Annual Meeting of The Endocrine Society, Washington, DC, 1991 (Abstract 241), p 91
204. Mahoudeau J, Reznik Y 1993 Appetite comes with eating, cortisol too. A new cause of Cushing’s syndrome (editorial). Presse Méd 22:407–408
205. Lebrethon MC, Avallet O, Reznik Y, Archambeaud F, Combes J, Usdin TB, Narboni G, Mahoudeau J, Saez JM 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]
206. N'Diaye N, Hamet P, Tremblay J, Boutin JM, Gaboury L, Lacroix A 1999 Asynchronous development of bilateral nodular adrenal hyperplasia in gastric inhibitory polypeptide-dependent Cushing’s syndrome. J Clin Endocrinol Metab 84:2616–2622[Abstract/Free Full Text]
207. Archambeaud-Mouveroux F, Comas JM, Tessier MP Food-dependent Cushing’s syndrome associated with the Carney complex. Program and abstracts of the 10th International Congress of Endocrinology, San Francisco, CA, 1996 (Abstract P3–158), p 899
208. Croughs RJ, Zelissen PM, Van Vroonhoven ThJ Hofland LJ, N'Diaye N, Lacroix A, de Herder WW 2000 GIP-dependent adrenal Cushing’s syndrome with incomplete suppression of ACTH. Clin Endocrinol (Oxf) 52:235–240[CrossRef][Medline]
208. Lacroix A, N’Diaye N, de Herder W, Nieman L, Ezzat S, Hermus A, Noordam C, Gerl H, Lochs H, Pico A, Hamet P, Tremblay J Adrenal GIP receptor overexpression in food-dependent Cushing’s Syndrome. Program and Abstracts of the 11th International Congress of Endocrinology, Sydney, Australia, 2000 (Abstract P18), p 99
209. de Herder W, Hofland LJ, Usdin TB, de Jong FH, Uitterlinden P, van Koetsveld P, Mezey E, Bonner TI, Bonjer HJ, Lamberts SW 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]
210. Chabre O, Liakos P, Vivier J, Chaffanjon P, Labat-Moleur F, Martinie M, Bottari SP, Bachelot I, Chambaz EM, Defaye G, Feige JJ 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]
211. Luton JP, Bertherat J, Kuhn JM, Bertagna X 1998 Aberrant expression of the GIP (gastric inhibitory polypeptide) receptor in an adrenal cortical adenoma responsible for a case of food-dependent Cushing’s syndrome. Bull Acad Natl Med 182:1839–1849[Medline]
212. Combes J, Bourrinet-Pellet E, Narboni G, Saez JM, Remy-Martin MA, Mantion G, Cornette C, De Wazières B, Penfornis A 1998 Un nouveau cas de syndrome de Cushing dépendant de l’alimentation associé à un adénome surrénalien unique. Ann Endocrinol (Paris) 59:264 (Abstract A171)
213. Tsagarakis S, Tsigos C, Vassiliou V, Tsiotra P, Pratsinis H, Kletsas D, Trivizas P, Nikou A, Mavromatis T, Sotsiou F, Raptis S, Thalassinos N 2001 Food-dependent androgen and cortisol secretion by a GIP-receptor expressive adrenocortical adenoma leading to hirsutism and subclinical Cushing’s syndrome: in vivo and in vitro studies. J Clin Endocrinol Metab 86:583–589[Abstract/Free Full Text]
214. Usdin TB, Mezey E, Button DC, Brownstein MJ, Bonner TI 1993 Gastric inhibitory polypeptide receptor, a member of the secretin-vasoactive intestinal peptide receptor family, is widely distributed in peripheral organs and the brain. Endocrinology 133:2861–2870[Abstract/Free Full Text]
215. Yasuda K, Inagaki N, Yamada Y, Kubota A, Seino S, Seino Y 1994 Hamster gastric inhibitory polypeptide receptor expressed in pancreatic islets and clonal insulin-secreting cells: its structure and functional properties. Biochem Biophys Res Commun 205:1556–1562[CrossRef][Medline]
216. Gremlich S, Porret A, Hani EH, Cherif D, Vionnet N, Froguel P, Thorens B 1995 Cloning, functional expression, and chromosomal localization of the human pancreatic islet glucose-dependent insulinotropic polypeptide receptor. Diabetes 44:1202–1208[Abstract]
217. Volz A, Goke R, Lankat-Buttgereit B, Fehmann HC, Bode HP, Goke B 1995 Molecular cloning, functional expression, and signal transduction of the GIP-receptor cloned from a human insulinoma. FEBS Lett 373:23–29[CrossRef][Medline]
218. Yamada Y, Hayami T, Nakamura K, Kaisaki PJ, Someya Y, Wang CZ, Seino S, Seino Y 1995 Human gastric inhibitory polypeptide receptor: cloning of the gene (GIPR) and cDNA. Genomics 29:773–776[CrossRef][Medline]
218. Miyawaki K, Yamada Y, Yano H, Niwa H, Ban H, Ihara Y, Kubota A, Fujimoto S, Kajikawa M, Kuroe A, Tsuda K, Hashimoto H, Yamashita T, Jomori T, Tashiro F, Miyazaki J, Seino Y 1999 Glucose intolerance caused by a defect in the entero-insular axis: a study in gastric inhibitory polypeptide receptor knockout mice. Proc Natl Acad Sci USA 96:14843–14847[Abstract/Free Full Text]
219. N'Diaye N, Tremblay J, Hamet P, de Herder WW, Lacroix A 1998 Adrenocortical overexpression of gastric inhibitory polypeptide receptor underlies food-dependent Cushing’s syndrome. J Clin Endocrinol Metab 83:2781–2785[Abstract/Free Full Text]
220. Lacroix A, Bolté É, Tremblay J, Hamet P 1993 Syndrome de Cushing induit par le GIP: expression clinique d’un récepteur ectopique. Med Sci 9:706–715
221. Bercovici JP, Monguillon P, Merceur C, Codet JP, Roger P, Floch HH 1996 Cushing’s disease: role of feeding. Presse Méd 25:1326–1330
222. Follenius M, Brandenberger G, Hietter B 1982 Diurnal cortisol peaks and their relationships to meals. J Clin Endocrinol Metab 55:757–761[Abstract/Free Full Text]
223. Quigley ME, Yen SS 1979 A mid-day surge in cortisol levels. J Clin Endocrinol Metab 49:945–947[Abstract/Free Full Text]
224. Ishizuka B, Quigley ME, Yen SS 1983 Pituitary hormone release in response to food ingestion: evidence for neuroendocrine signals from gut to brain. J Clin Endocrinol Metab 57:1111–1116[Abstract/Free Full Text]
225. Larochelle P, Du SP, Bolte E, Lelorier J, Goyer R 1983 Tixocortol pivalate, a corticosteroid with no systemic glucocorticoid effect after oral, intrarectal, and intranasal application. Clin Pharmacol Ther 33:343–350[Medline]
226. Al Damluji S, Iveson T, Thomas JM, Pendlebury DJ, Rees LH, Besser GM 1987 Food-induced cortisol secretion is mediated by central -1 adrenoceptor modulation of pituitary ACTH secretion. Clin Endocrinol (Oxf) 26:629–636[Medline]
227. Coslovsky R, Wajchenberg BL, Nogueira O 1974 Hyperresponsiveness to lysine-vasopressin in Cushing’s disease. Acta Endocrinol (Copenh) 75:125–132[Abstract/Free Full Text]
228. Raux MC, Binoux M, Luton JP, Gourmelen M, Girard F 1975 Studies of ACTH secretion control in 116 cases of Cushing’s syndrome. J Clin Endocrinol Metab 40:186–197[Abstract/Free Full Text]
229. Arnaldi G, de Keyzer Y, Gasc JM, Clauser E, Bertagna X 1998 Vasopressin receptors modulate the pharmacological phenotypes of Cushing’s syndrome. Endocr Res 24:807–816[Medline]
230. van Wijk PA, Rijnberk A, Croughs RJ, Wolfswinkel J, Selman PJ, Mol JA 1994 Responsiveness to corticotropin-releasing hormone and vasopressin in canine Cushing’s syndrome. Eur J Endocrinol 130:410–416[Abstract/Free Full Text]
231. Demura R, Demura H, Nunokawa T, Baba H, Miura K 1972 Responses of plasma ACTH, GH, LH and 11-hydroxycorticosteroids to various stimuli in patients with Cushing’s syndrome. J Clin Endocrinol Metab 34:852–859[Abstract/Free Full Text]
232. Makino S, Hashimoto K, Sugiyama M, Hirasawa R, Takao T, Ota Z, Saegusa M, Ohashi T, Omori H 1989 Cushing’s syndrome due to huge nodular adrenocortical hyperplasia with fluctuation of urinary 17-OHCS excretion. Endocrinol Jpn 36:655–663[Medline]
233. Itagaki E, Nozaki M, Abe Y, Takizawa M, Furukawa H, Murakawa S 1989 Direct effect of lysine-vasopressin on cortisol production in isolated adrenal cells from nodular adrenocortical hyperplasia. In: Mantero F (ed) Serono Symposia, Raven Press, New York, vol 57:403–408
234. Horiba N, Suda T, Aiba M, Naruse M, Nomura K, Imamura M, Demura H 1995 Lysine vasopressin stimulation of cortisol secretion in patients with adrenocorticotropin-independent macronodular adrenal hyperplasia. J Clin Endocrinol Metab 80:2336–2341[Abstract]
235. Perraudin V, Delarue C, de Keyzer Y, Bertagna X, Kuhn JM, Contesse V, Clauser E, Vaudry H 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]
236. Guillon G, Balestre MN, Roberts JM, Bottari SP 1987 Oxytocin and vasopressin: distinct receptors in myometrium. J Clin Endocrinol Metab 64:1129–1135[Abstract/Free Full Text]
237. Iida K, Kaji H, Matsumoto H, Okimura Y, Abe H, Fujisawa M, Kamidono S, Chihara K 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]
238. Yamakita N, Murai T, Ito Y, Miura K, Ikeda T, Miyamoto K, Onami S, Yoshida T 1997 Adrenocorticotropin-independent macronodular adrenocortical hyperplasia associated with multiple colon adenomas/carcinomas which showed a point mutation in the APC gene. Intern Med 36:536–542[Medline]
239. Daidoh H, Morita H, Hanafusa J, Mune T, Murase H, Sato M, Shibata T, Suwa T, Ishizuka T, Yasuda K 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. Clin Endocrinol (Oxf) 49:403–409[CrossRef][Medline]
240. Mircescu H, Jilwan J, N'Diaye N, Bourdeau I, Tremblay J, Hamet P, Lacroix A 2000 Are ectopic or abnormal membrane hormone receptors frequently present in adrenal Cushing’s Syndrome? J Clin Endocrinol Metab 85:3531–3536[Abstract/Free Full Text]
241. Eckland DJ, 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/Free Full Text]
242. Bourdeau I, D’Amour P, Hamet P, Boutin JM, Lacroix A 2000 Abnormal membrane hormone receptors in subclinical bilateral macronodular adrenal hyperplasia. Program and abstracts of the 82nd Annual Meeting of The Endocrine Society, Toronto, Ontario, Canada, 2000 (Abstract 1934), p 467
243. de Keyzer Y, Lenne F, Auzan C, Jegou S, Rene P, Vaudry H, Kuhn JM, Luton JP, Clauser E, Bertagna X 1996 The pituitary V3 vasopressin receptor and the corticotroph phenotype in ectopic ACTH syndrome. J Clin Invest 97:1311–1318[Medline]
244. Sakai Y, Horiba N, Tozawa F, Sakai K, Kuwayama A, Demura H, Suda T 1997 Desmopressin stimulation test for diagnosis of ACTH-dependent Cushing’s syndrome. Endocr J 44:687–695[Medline]
245. Malerbi DA, Mendonca BB, Liberman B, Toledo SP, Corradini MC, Cunha-Neto MB, Fragoso MC, Wajchenberg BL 1993 The desmopressin stimulation test in the differential diagnosis of Cushing’s syndrome. Clin Endocrinol (Oxf) 38:463–472[Medline]
246. Al Damluji S, Perry L, Tomlin S, Bouloux P, Grossman A, Rees LH, Besser GM 1987 Alpha-adrenergic stimulation of corticotropin secretion by a specific central mechanism in man. Neuroendocrinology 45:68–76[CrossRef][Medline]
247. Segaloff DL, Ascoli M 1993 The lutropin/choriogonadotropin receptor .. 4 years later. Endocr Rev 14:324–347[Abstract/Free Full Text]
248. Rao CV 1996 The beginning of a new era in reproductive biology and medicine: expression of low levels of functional luteinizing hormone/human chorionic gonadotropin receptors in nongondal tissues. J Physiol Pharmacol 47:41–53
249. Pabon JE, Li X, Lei ZM, Sanfilippo JS, Yussman MA, Rao CV 1996 Novel presence of luteinizing hormone/chorionic gonadotropin receptors in human adrenal glands. J Clin Endocrinol Metab 81:2397–2400[Abstract]
250. Seron-Ferre M, Lawrence CC, Jaffe RB 1978 Role of hCG in regulation of the fetal zone of the human fetal adrenal gland. J Clin Endocrinol Metab 46:834–837[Abstract/Free Full Text]
251. Lacroix A, Hamet P, Boutin JM 1999 Leuprolide acetate therapy in luteinizing hormone-dependent Cushing’s syndrome. N Engl J Med 341:1577–1581[Free Full Text]
252. Sheeler LR 1994 Cushing’s syndrome and pregnancy. Endocrinol Metab Clin North Am 23:619–627[Medline]
253. Aron DC, Schnall AM, Sheeler LR 1990 Cushing’s syndrome and pregnancy. Am J Obstet Gynecol 162:244–252[Medline]
254. Buescher MA, McClamrock HD, Adashi EY 1992 Cushing syndrome in pregnancy. Obstet Gynecol 79:130–137[Medline]
255. Keegan GT, Grabarits F, Roland AS 1976 Pregnancy complicated by Cushing’s syndrome. South Med J 69:1207–1209[Medline]
256. Parra A, Cruz-Krohn J 1966 Intercurrent Cushing’s syndrome and pregnancy. Am J Med 40:961–966[CrossRef][Medline]
257. Reschini E, Giustina G, Crosignani PG, D’Alberton A 1978 Spontaneous remission of Cushing syndrome after termination of pregnancy. Obstet Gynecol 51:598–602[Medline]
258. Calodney L, Eaton RP, Black W, Cohn F 1973 Exacerbation of Cushing’s syndrome during pregnancy: report of a case. J Clin Endocrinol Metab 36:81–86[Abstract/Free Full Text]
259. Kreines K, Perrin E, Salzer R 1964 Pregnancy in Cushing’s syndrome. J Clin Endocrinol Metab 24:75–79
260. Wallace C, Toth EL, Lewanczuk RZ, Siminoski K 1996 Pregnancy-induced Cushing’s syndrome in multiple pregnancies. J Clin Endocrinol Metab 81:15–21[CrossRef][Medline]
261. Close CF, Mann MC, Watts JF, Taylor KG 1993 ACTH-independent Cushing’s syndrome in pregnancy with spontaneous resolution after delivery: control of the hypercortisolism with metyrapone. Clin Endocrinol (Oxf) 39:375–379[Medline]
262. Wieland RG, Shaffer MBJ, Glove RP 1971 Cushing’s syndrome complicating pregnancy. A case report. Obstet Gynecol 38:841–843[Medline]
263. Aron DC, Schnall AM, Sheeler LR 1990 Spontaneous resolution of Cushing’s syndrome after pregnancy. Am J Obstet Gynecol 162:472–474[Medline]
264. de Lange WE, Pratt JJ, Doorenbos H 1980 A gonadotrophin responsive testosterone producing adrenocortical adenoma and high gonadotrophin levels in an elderly woman. Clin Endocrinol (Oxf) 12:21–28[Medline]
265. Takahashi H, Yoshizaki K, Kato H, Masuda T, Matsuka G, Mimura T, Inui Y, Takeuchi S, Adachi H, Matsumoto K 1978 A gonadotrophin-responsive virilizing adrenal tumour identified as a mixed ganglioneuroma and adreno-cortical adenoma. Acta Endocrinol (Copenh) 89:701–709[Abstract/Free Full Text]
266. Werk EEJ, Sholiton LE, Kalejs L 1973 Testosterone-secreting adrenal adenoma under gonadotropin control. N Engl J Med 289:767–770
267. Larson BA, Vanderlaan WP, Judd HL, McCullough DL 1976 A testosterone-producing adrenal cortical adenoma in an elderly woman. J Clin Endocrinol Metab 42:882–887[Abstract/Free Full Text]
268. Givens JR, Andersen RN, Wiser WL, Coleman SA, Fish SA 1974 A gonadotropin-responsive adrenocortical adenoma. J Clin Endocrinol Metab 38:126–133[Abstract/Free Full Text]
269. Blichert-Toft M, Vejlsted H, Hehlet H, Albrechtsen R 1975 Virilizing adrenocortical adenoma responsive to gonadotrophin. Acta Endocrinol (Copenh) 78:77–85[Abstract/Free Full Text]
270. Smith HC, Posen S, Clifton-Bligh P, Casey J 1978 A testosterone-secreting adrenal cortical adenoma. Aust NZ J Med 8:171–175[Medline]
271. Lefebvre H, Gonzalez KN, Contesse V, Delarue C, Vaudry H, Kuhn JM 1998 Effect of prolonged administration of the serotonin4 (5-HT4) receptor agonist cisapride on aldosterone secretion in healthy volunteers. Endocr Res 24:749–752[Medline]
272. Bonnin C, Monsaingeon M, Bex V, Duclos M, Tortigues D, Lefebvre H, Tabarin A, Roger P 2000 Hypercorticism by bilateral adrenal hyperplasia with several paradoxical responses. Program and abstracts of the 82nd Annual Meeting of The Endocrine Society, Toronto, Ontario, Canada, 2000 (Abstract 1936), p 467
273. Caticha O, Odell WD, Wilson DE, Dowdell LA, Noth RH, Swislocki AL, Lamothe JJ, Barrow R 1993 Estradiol stimulates cortisol production by adrenal cells in estrogen-dependent primary adrenocortical nodular dysplasia. J Clin Endocrinol Metab 77:494–497[Abstract]
274. Bourdeau I, Caron P, Schürch W, N'Diaye N, Antakly T, Lacroix A 2000 Paradoxical response to dexamethasone correlates with high expression of glucocorticoid receptors in primary pigmented nodular adrenocortical disease. Program and Abstracts of the 82nd Annual Meeting of The Endocrine Society,Toronto, Ontario, Canada, 2000 (Abstract 1935), p 467
275. Hashimoto K, Kawada Y, Murakami K, Hattori T, Suemaru S, Kageyama J, Ota Z, Hayata S, Ohashi T, Omori H 1986 Cortisol responsiveness to insulin-induced hypoglycemia in Cushing’s syndrome with huge nodular adrenocortical hyperplasia. Endocrinol Jpn 33:479–487[Medline]
276. Glasow A, Bornstein SR, Chrousos GP, Brown JW, Scherbaum WA 1999 Detection of Ob-receptor in human adrenal neoplasms and effect of leptin on adrenal cell proliferation. Horm Metab Res 31:247–251[Medline]
277. Lacroix A, Mircescu H, Hamet P 1999 Clinical evaluation of the presence of abnormal hormone receptors in adrenal Cushing’s syndrome. The Endocrinologist 9:9–15
278. Glasow A, Haidan A, Gillespie J, Kelly PA, Chrousos GP, Bornstein SR 1998 Differential expression of prolactin receptor (PRLR) in normal and tumorous adrenal tissues: separation of cellular endocrine compartments by laser capture microdissection (LCM). Endocr Res 24:857–862[Medline]
279. Cammas FM, Kapas S, Barker S, Clark AJ 1995 Cloning, characterization and expression of a functional mouse ACTH receptor. Biochem Biophys Res Commun 212:912–918[CrossRef][Medline]
280. Boston BA, Cone RD 1996 Characterization of melanocortin receptor subtype expression in murine adipose tissues and in the 3T3–L1 cell line. Endocrinology 137:2043–2050[Abstract]
281. Marchal R, Naville D, Durand P, Begeot M, Penhoat A 1998 A steroidogenic factor-1 binding element is essential for basal human ACTH receptor gene transcription. Biochem Biophys Res Commun 247:28–32[CrossRef][Medline]
282. Naville D, Penhoat A, Durand P, Begeot M 1999 Three steroidogenic factor-1 binding elements are required for constitutive and cAMP-regulated expression of the human adrenocorticotropin receptor gene. Biochem Biophys Res Commun 255:28–33[CrossRef][Medline]
283. Lebrethon MC, Naville D, Begeot M, Saez JM 1994 Regulation of corticotropin receptor number and messenger RNA in cultured human adrenocortical cells by corticotropin and angiotensin II. J Clin Invest 93:1828–1833
284. Penhoat A, Jaillard C, Saez JM 1994 Regulation of bovine adrenal cell corticotropin receptor mRNA levels by corticotropin (ACTH) and angiotensin-II (A-II). Mol Cell Endocrinol 103:R7–10
285. Picard-Hagen N, Penhoat A, Hue D, Jaillard C, Durand P 1997 Glucocorticoids enhance corticotropin receptor mRNA levels in ovine adrenocortical cells. J Mol Endocrinol 19:29–36[Abstract/Free Full Text]
286. Cammas FM, Pullinger GD, Barker S, Clark AJ 1997 The mouse adrenocorticotropin receptor gene: cloning and characterization of its promoter and evidence for a role for the orphan nuclear receptor steroidogenic factor 1. Mol Endocrinol 11:867–876[Abstract/Free Full Text]
287. Collins S, Ostrowski J, Lefkowitz RJ 1993 Cloning and sequence analysis of the human ß1-adrenergic receptor 5'-flanking promoter region. Biochim Biophys Acta 1172:171–174[Medline]
288. Tseng YT, Waschek JA, Padbury JF 1995 Functional analysis of the 5' flanking sequence in the ovine ß1-adrenergic receptor gene. Biochem Biophys Res Commun 215:606–612[CrossRef][Medline]
289. Williams LT, Lefkowitz RJ, Watanabe AM, Hathaway DR, Besch HRJ 1977 Thyroid hormone regulation of ß-adrenergic receptor number. J Biol Chem 252:2787–2789[Abstract/Free Full Text]
290. Malbon CC, Moreno FJ, Cabelli RJ, Fain JN 1978 Fat cell adenylate cyclase and ß-adrenergic receptors in altered thyroid states. J Biol Chem 253:671–678[Free Full Text]
291. Hadcock JR, Malbon CC 1988 Down-regulation of ß-adrenergic receptors: agonist-induced reduction in receptor mRNA levels. Proc Natl Acad Sci USA 85:5021–5025[Abstract/Free Full Text]
292. Mak JC, Nishikawa M, Barnes PJ 1995 Glucocorticosteroids increase ß 2-adrenergic receptor transcription in human lung. Am J Physiol 268:L41–L46
293. Malbon CC, Hadcock JR 1988 Evidence that glucocorticoid response elements in the 5'-noncoding region of the hamster beta 2-adrenergic receptor gene are obligate for glucocorticoid regulation of receptor mRNA levels. Biochem Biophys Res Commun 154:676–681[CrossRef][Medline]
294. Mak JC, Nishikawa M, Shirasaki H, Miyayasu K, Barnes PJ 1995 Protective effects of a glucocorticoid on downregulation of pulmonary ß 2-adrenergic receptors in vivo. J Clin Invest 96:99–106
295. Zhou XM, Fishman PH 1991 Desensitization of the human ß1-adrenergic receptor. Involvement of the cyclic AMP-dependent but not a receptor-specific protein kinase. J Biol Chem 266:7462–7468[Abstract/Free Full Text]
296. Nantel F, Marullo S, Krief S, Strosberg AD, Bouvier M 1994 Cell-specific down-regulation of the ß3-adrenergic receptor. J Biol Chem 269:13148–13155[Abstract/Free Full Text]
297. Lohse MJ, Benovic JL, Codina J, Caron MG, Lefkowitz RJ 1990 ß-Arrestin: a protein that regulates ß-adrenergic receptor function. Science 248:1547–1550[Abstract/Free Full Text]
298. Tsai-Morris CH, Geng Y, Buczko E, Dufau ML 1998 A novel human luteinizing hormone receptor gene. J Clin Endocrinol Metab 83:288–291[Abstract/Free Full Text]
299. El Hefnawy T, Krawczyk Z, Nikula H, Vihera I, Huhtaniemi I 1996 Regulation of function of the murine luteinizing hormone receptor promoter by cis- and trans-acting elements in mouse Leydig tumor cells. Mol Cell Endocrinol 119:207–217[CrossRef][Medline]
300. Hu YL, Lei ZM, Rao CV 1996 cis-Acting elements and trans-acting proteins in the transcription of chorionic gonadotropin/luteinizing hormone receptor gene in human choriocarcinoma cells and placenta. Endocrinology 137:3897–3905[Abstract]
301. Hu YL, Lei ZM, Rao CV 1998 Analysis of the promoter of the luteinizing hormone/human chorionic gonadotropin receptor gene in neuroendocrine cells. Life Sci 63:2157–2165[CrossRef][Medline]
302. Elalouf JM, Di Stefano A, de Rouffignac C 1986 Sensitivities of rat kidney thick ascending limbs and collecting ducts to vasopressin in vivo. Proc Natl Acad Sci USA 83:2276–2280[Abstract/Free Full Text]
303. Skorecki KL, Ausiello DA 1998 Vasopressin receptor-adenylate cyclase interactions: a model for cAMP metabolism in the kidney. In: Cowley, AWJ, Liard J-F, Ausiello DA (eds) Vasopressin Cellular and Integrative Functions. Raven Press, New York, vol 7:55–73
304. Guillon G 1989 Vasopressin, oxytocin and angiotensin receptors in mammals. Ann Endocrinol (Paris) 50:425–433[Medline]
305. Keppens S, de Wulf H 1975 The activation of liver glycogen phosphorylase by vasopressin. FEBS Lett 51:29–32[CrossRef][Medline]
306. Briley EM, Lolait SJ, Axelrod J, Felder CC 1994 The cloned vasopressin V1a receptor stimulates phospholipase A2, phospholipase C, and phospholipase D through activation of receptor-operated calcium channels. Neuropeptides 27:63–74[CrossRef][Medline]
307. Watters JJ, Swank MW, Wilkinson CW, Dorsa DM 1996 Evidence for glucocorticoid regulation of the rat vasopressin V1a receptor gene. Peptides 17:67–73[CrossRef][Medline]
308. Watters JJ, Wilkinson CW, Dorsa DM 1996 Glucocorticoid regulation of vasopressin V1a receptors in rat forebrain. Brain Res Mol Brain Res 38:276–284[Medline]
309. Morel A, O’Carroll AM, Brownstein MJ, Lolait SJ 1992 Molecular cloning and expression of a rat V1a arginine vasopressin receptor. Nature 356:523–526[CrossRef][Medline]
310. Iwasaki Y, Oiso Y, Saito H, Majzoub JA 1997 Positive and negative regulation of the rat vasopressin gene promoter. Endocrinology 138:5266–5274[Abstract/Free Full Text]
311. Murasawa S, Matsubara H, Kizima K, Maruyama K, Mori Y, Inada M 1995 Glucocorticoids regulate V1a vasopressin receptor expression by increasing mRNA stability in vascular smooth muscle cells. Hypertension 26:665–669[Abstract/Free Full Text]
312. Colson P, Ibarondo J, Devilliers G, Balestre MN, Duvoid A, Guillon G 1992 Upregulation of V1a vasopressin receptors by glucocorticoids. Am J Physiol 263:E1054–E1062
313. Watanabe Y, Tokuda H, Suzuki A, Shinoda J, Kotoyori J, Ito Y, Oiso Y, Kozawa O 1995 Glucocorticoid amplifies vasopressin-induced phosphoinositide hydrolysis in aortic smooth muscle cells. J Cell Biochem 57:522–529[CrossRef][Medline]
314. Rabadan-Diehl C, Aguilera G 1998 Glucocorticoids increase vasopressin V1b receptor coupling to phospholipase C. Endocrinology 139:3220–3226[Abstract/Free Full Text]
315. Moens K, Heimberg H, Flamez D, Huypens P, Quartier E, Ling Z, Pipeleers D, Gremlich S, Thorens B, Schuit F 1996 Expression and functional activity of glucagon, glucagon-like peptide I, and glucose-dependent insulinotropic peptide receptors in rat pancreatic islet cells. Diabetes 45:257–261[Abstract]
316. Yip RG, Boylan MO, Kieffer TJ, Wolfe MM 1998 Functional GIP receptors are present on adipocytes. Endocrinology 139:4004–4007[Abstract/Free Full Text]
317. Mazzocchi G, Rebuffat P, Meneghelli V, Malendowicz LK, Tortorella C, Gottardo G, Nussdorfer GG 1999 Gastric inhibitory polypeptide stimulates glucocorticoid secretion in rats, acting through specific receptors coupled with the adenylate cyclase-dependent signaling pathway. Peptides 20:589–594[CrossRef][Medline]
318. Tseng CC, Boylan MO, Jarboe LA, Usdin TB, Wolfe MM 1996 Chronic desensitization of the glucose-dependent insulinotropic polypeptide receptor in diabetic rats. Am J Physiol 270:E661–E666
319. Boylan MO, Jepeal LI, Wolfe MM 1999 Structure of the rat glucose-dependent insulinotropic polypeptide receptor gene. Peptides 20:219–228[CrossRef][Medline]
320. Blondel O, Gastineau M, Dahmoune Y, Langlois M, Fischmeister R 1998 Cloning, expression, and pharmacology of four human 5-hydroxytryptamine 4 receptor isoforms produced by alternative splicing in the carboxyl terminus. J Neurochem 70:2252–2261[Medline]
321. Rosenberg CL, Kim HG, Shows TB, Kronenberg HM, Arnold A 1991 Rearrangement and overexpression of D11S287E, a candidate oncogene on chromosome 11q13 in benign parathyroid tumors. Oncogene 6:449–453[Medline]
322. Lifton RP, Dluhy RG, Powers M, Rich GM, Cook S, Ulick S, Lalouel JM 1992 A chimaeric 11 beta-hydroxylase/aldosterone synthase gene causes glucocorticoid-remediable aldosteronism and human hypertension. Nature 355:262–265[CrossRef][Medline]
323. Gagel RF 1998 Multiple endocrine neoplasia. In: Wilson JD, Foster DW, Kronenberg HM, Larsen PR (eds) Williams Textbook of Endocrinology. W.B. Saunders Co, Philadelphia, pp 1627–1649
324. Rabes HM, Demidchik EP, Sidorow JD, Lengfelder E, Beimfohr C, Hoelzel D, Klugbauer S 2000 Pattern of radiation-induced RET and NTRK1 rearrangements in 191 post-Chernobyl papillary thyroid carcinomas: biological, phenotypic, and clinical implications. Clin Cancer Res 6:1093–1103[Abstract/Free Full Text]
325. Salassidis K, Bruch J, Zitzelsberger H, Lengfelder E, Kellerer AM, Bauchinger M 2000 Translocation t(10;14)(q11.2:q22.1) fusing the kinetin to the RET gene creates a novel rearranged form (PTC8) of the RET proto-oncogene in radiation-induced childhood papillary thyroid carcinoma. Cancer Res 60:2786–2789[Abstract/Free Full Text]
326. Tatsumi K, Miyai K, Notomi T, Kaibe K, Amino N, Mizuno Y, Kohno H 1992 Cretinism with combined hormone deficiency caused by a mutation in the PIT1 gene. Nat Genet 1:56–58[CrossRef][Medline]
327. Kero J, Poutanen M, Zhang FP, Rahman N, McNicol AM, Nilson JH, Keri RA, Huhtaniemi IT 2000 Elevated luteinizing hormone induces expression of its receptor and promotes steroidogenesis in the adrenal cortex. J Clin Invest 105:633–641[Medline]
328. Morohashi KI, Omura T 1996 Ad4BP/SF-1, a transcription factor essential for the transcription of steroidogenic cytochrome P450 genes and for the establishment of the reproductive function. FASEB J 10:1569–1577[Abstract]
329. Waterman MR 1994 Biochemical diversity of cAMP-dependent transcription of steroid hydroxylase genes in the adrenal cortex. J Biol Chem 269:27783–27786[Free Full Text]
330. Hatano O, Takakusu A, Nomura M, Morohashi K 1996 Identical origin of adrenal cortex and gonad revealed by expression profiles of Ad4BP/SF-1. Genes Cells 1:663–671[Abstract]
331. Morohashi K 1997 The ontogenesis of the steroidogenic tissues. Genes Cells 2:95–106[Abstract]
332. Zanaria E, Muscatelli F, Bardoni B, Strom TM, Guioli S, Guo W, Lalli E, Moser C, Walker AP, McCabe ER 1994 An unusual member of the nuclear hormone receptor superfamily responsible for X-linked adrenal hypoplasia congenita. Nature 372:635–641[CrossRef][Medline]
333. Muscatelli F, Strom TM, Walker AP, Zanaria E, Recan D, Meindl A, Bardoni B, Guioli S, Zehetner G, Rabl W 1994 Mutations in the DAX-1 gene give rise to both X-linked adrenal hypoplasia congenita and hypogonadotropic hypogonadism. Nature 372:672–676[CrossRef][Medline]
334. Lalli E, Bardoni B, Zazopoulos E, Wurtz JM, Strom TM, Moras D, Sassone-Corsi P 1997 A transcriptional silencing domain in DAX-1 whose mutation causes adrenal hypoplasia congenita. Mol Endocrinol 11:1950–1960[Abstract/Free Full Text]
335. Ikeda Y, Swain A, Weber TJ, Hentges KE, Zanaria E, Lalli E, Tamai KT, Sassone-Corsi P, Lovell-Badge R, Camerino G, Parker KL 1996 Steroidogenic factor 1 and Dax-1 colocalize in multiple cell lineages: potential links in endocrine development. Mol Endocrinol 10:1261–1272[Abstract/Free Full Text]
336. Swain A, Zanaria E, Hacker A, Lovell-Badge R, Camerino G 1996 Mouse Dax1 expression is consistent with a role in sex determination as well as in adrenal and hypothalamus function. Nat Genet 12:404–409[CrossRef][Medline]
337. Giguere V 1999 Orphan nuclear receptors: from gene to function. Endocr Rev 20:689–725[Abstract/Free Full Text]
338. Yu RN, Ito M, Jameson JL 1998 The murine Dax-1 promoter is stimulated by SF-1 (steroidogenic factor-1) and inhibited by COUP-TF (chicken ovalbumin upstream promoter-transcription factor) via a composite nuclear receptor-regulatory element. Mol Endocrinol 12:1010–1022[Abstract/Free Full Text]
339. Kawabe K, Shikayama T, Tsuboi H, Oka S, Oba K, Yanase T, Nawata H, Morohashi K 1999 Dax-1 as one of the target genes of Ad4BP/SF-1. Mol Endocrinol 13:1267–1284[Abstract/Free Full Text]
340. Hastie ND 1994 The genetics of Wilms’ tumor-a case of disrupted development. Annu Rev Genet 28:523–558[Medline]
341. Semenza GL 1994 Transcriptional regulation of gene expression: mechanisms and pathophysiology. Hum Mutat 3:180–199[CrossRef][Medline]
342. Moore AW, McInnes L, Kreidberg J, Hastie ND, Schedl A 1999 YAC complementation shows a requirement for Wt1 in the development of epicardium, adrenal gland and throughout nephrogenesis. Development 126:1845–1857[Abstract]
343. Moore AW, Schedl A, McInnes L, Doyle M, Hecksher-Sorensen J, Hastie ND 1998 YAC transgenic analysis reveals Wilms’ tumour 1 gene activity in the proliferating coelomic epithelium, developing diaphragm and limb. Mech Dev 79:169–184[CrossRef][Medline]
344. Nachtigal MW, Hirokawa Y, Enyeart-VanHouten DL, Flanagan JN, Hammer GD, Ingraham HA 1998 Wilms’ tumor 1 and Dax-1 modulate the orphan nuclear receptor SF-1 in sex-specific gene expression. Cell 93:445–454[CrossRef][Medline]
345. Dhanasekaran N, Heasley LE, Johnson GL 1995 G protein-coupled receptor systems involved in cell growth and oncogenesis. Endocr Rev 16:259–270[Abstract/Free Full Text]
346. Spiegel AM 1996 Mutations in G proteins and G protein-coupled receptors in endocrine disease. J Clin Endocrinol Metab 81:2434–2442[CrossRef][Medline]
347. Farfel Z, Bourne HR, Iiri T 1999 The expanding spectrum of G protein diseases. N Engl J Med 340:1012–1020[Free Full Text]
348. Billestrup N, Swanson LW, Vale W 1986 Growth hormone-releasing factor stimulates proliferation of somatotrophs in vitro. Proc Natl Acad Sci USA 83:6854–6857[Abstract/Free Full Text]
349. Dumont JE, Jauniaux JC, Roger PP 1989 The cyclic AMP-mediated stimulation of cell proliferation. Trends Biochem Sci 14:67–71[CrossRef][Medline]
350. Ledent C, Dumont JE, Vassart G, Parmentier M 1992 Thyroid expression of an A2 adenosine receptor transgene induces thyroid hyperplasia and hyperthyroidism. EMBO J 11:537–542[Medline]
351. Parma J, Duprez L, Van Sande J, Cochaux P, Gervy C, Mockel J, Dumont J, Vassart G 1993 Somatic mutations in the thyrotropin receptor gene cause hyperfunctioning thyroid adenomas. Nature 365:649–651[CrossRef][Medline]
352. Kopp P, Van Sande J, Parma J, Duprez L, Gerber H, Joss E, Jameson JL, Dumont JE, Vassart G 1995 Brief report: congenital hyperthyroidism caused by a mutation in the thyrotropin-receptor gene. N Engl J Med 332:150–154[Free Full Text]
353. Shenker A, Laue L, Kosugi S, Merendino Jr JJ, Minegishi T, Cutler Jr GB 1993 A constitutively activating mutation of the luteinizing hormone receptor in familial male precocious puberty. Nature 365:652–654[CrossRef][Medline]
354. Siffert W, Rosskopf D, Siffert G, Busch S, Moritz A, Erbel R, Sharma AM, Ritz E, Wichmann HE, Jakobs KH, Horsthemke B 1998 Association of a human G-protein ß3 subunit variant with hypertension. Nat Genet 18:45–48[CrossRef][Medline]
355. Lyons J, Landis CA, Harsh G, Vallar L, Grunewald K, Feichtinger H, Duh QY, Clark OH, Kawasaki E, Bourne HR 1990 Two G protein oncogenes in human endocrine tumors. Science 249:655–659[Abstract/Free Full Text]
356. Zeiger MA, Norton JA 1993 Gs—identification of a gene highly expressed by insulinoma and other endocrine tumors. Surgery 114:458–462[Medline]
357. Drazner MH, Koch WJ, Lefkowitz RJ 1997 Potentiation of ß-adrenergic signaling by gene transfer. Proc Assoc Am Physicians 109:220–227[Medline]
358. Ma YH, Landis C, Tchao N, Wang J, Rodd G, Hanahan D, Bourne HR, Grodsky GM 1994 Constitutively active stimulatory G-protein s in ß-cells of transgenic mice causes counterregulation of the increased adenosine 3',5'-monophosphate and insulin secretion. Endocrinology 134:42–47[Abstract/Free Full Text]
359. Allen JM, Baetge EE, Abrass IB, Palmiter RD 1988 Isoproterenol response following transfection of the mouse ß2-adrenergic receptor gene into Y1 cells. EMBO J 7:133–138[Medline]
360. Rilianawati, Paukku T, Kero J, Zhang FP, Rahman N, Kananen K, Huhtaniemi I 1998 Direct luteinizing hormone action triggers adrenocortical tumorigenesis in castrated mice transgenic for the murine inhibin -subunit promoter/simian virus 40 T-antigen fusion gene. Mol Endocrinol 12:801–809[Abstract/Free Full Text]
361. Light K, Jenkins PJ, Weber A, Perrett C, Grossman A, Pistorello M, Asa SL, Clayton RN, Clark AJ 1995 Are activating mutations of the adrenocorticotropin receptor involved in adrenal cortical neoplasia? Life Sci 56:1523–1527[CrossRef][Medline]
362. Reincke M, Mora P, Beuschlein F, Arlt W, Chrousos GP, Allolio B 1997 Deletion of the adrenocorticotropin receptor gene in human adrenocortical tumors: implications for tumorigenesis. J Clin Endocrinol Metab 82:3054–3058[Abstract/Free Full Text]
363. Reincke M, Karl M, Travis WH, Mastorakos G, Allolio B, Linehan HM, Chrousos GP 1994 p53 mutations in human adrenocortical neoplasms: immunohistochemical and molecular studies. J Clin Endocrinol Metab 78:790–794[Abstract]
364. Reincke M, Beuschlein F, Latronico AC, Arlt W, Chrousos GP, Allolio B 1997 Expression of adrenocorticotrophic hormone receptor mRNA in human adrenocortical neoplasms: correlation with P450 scc expression. Clin Endocrinol (Oxf) 46:619–626[CrossRef][Medline]
365. Arnaldi G, Mancini V, Costantini C, Giovagnetti M, Petrelli M, Masini A, Bertagna X, Mantero F 1998 ACTH receptor mRNA in human adrenocortical tumors: overexpression in aldosteronomas. Endocr Res 24:845–849[Medline]
366. Schorr I, Hinshaw HT, Cooper MA, Mahaffee D, Ney RL 1972 Adenyl cyclase hormone responses of certain human endocrine tumors. J Clin Endocrinol Metab 34:447–451[Abstract/Free Full Text]
367. Dexter RN, Allen DO 1970 A glucagon sensitive adenyl cyclase system in pheochromocytoma. Clin Res 18:601 (Abstract)
368. Levey GS, Weiss SR, Ruiz E 1975 Characterization of the glucagon receptor in a pheochromocytoma. J Clin Endocrinol Metab 40:720–723[Abstract/Free Full Text]
369. Barancik M 1989 Inadvertent diagnosis of pheochromocytoma after endoscopic premedication. Dig Dis Sci 34:136–138[CrossRef][Medline]
370. Matsukura S, Kakita T, Hirata Y, Yoshimi H, Fukase M 1977 Adenylate cyclase of GH and ACTH producing tumors of human: activation by non-specific hormones and other bioactive substances. J Clin Endocrinol Metab 44:392–397[Abstract/Free Full Text]
371. Lawrence AM, Goldfine ID, Kirsteins L 1970 Growth hormone dynamics in acromegaly. J Clin Endocrinol Metab 31:239–247[Abstract/Free Full Text]
372. Irie M, Tsushima T 1972 Increase of serum growth hormone concentration following thyrotropin-releasing hormone injection in patients with acromegaly or gigantism. J Clin Endocrinol Metab 35:97–100[Abstract/Free Full Text]
373. Hanew K, Kokubun M, Sasaki A, Mouri T, Yoshinaga K 1980 The spectrum of pituitary growth hormone responses to pharmacological stimuli in acromegaly. J Clin Endocrinol Metab 51:292–297[Abstract/Free Full Text]
374. Yamada M, Hashimoto K, Satoh T, Shibusawa N, Kohga H, Ozawa Y, Yamada S, Mori M 1997 A novel transcript for the thyrotropin-releasing hormone receptor in human pituitary and pituitary tumors. J Clin Endocrinol Metab 82:4224–4228[Abstract/Free Full Text]
375. Faccenda E, Melmed S, Bevan JS, Eidne KA 1996 Structure of the thyrotrophin-releasing hormone receptor in human pituitary adenomas. Clin Endocrinol (Oxf) 44:341–347[CrossRef][Medline]
376. Konaka S, Yamada M, Satoh T, Ozawa H, Watanabe E, Takata K, Mori M 1997 Expression of thyrotropin-releasing hormone (TRH) receptor mRNA in somatotrophs in the rat anterior pituitary. Endocrinology 138:827–830[Abstract/Free Full Text]
376. Ohshima K, Okada S, Onai T, Sato M, Umahara M, Nakamura Y, Kato M, Kakegawa T, Tatemoto K, Mori MProgram of the 76th Annual Meeting of The Endocrine Society, Anaheim, CA, 1994 (Abstract 51C), p 213
377. LeRiche VK, Asa SL, Ezzat S 1996 Epidermal growth factor and its receptor (EGF-R) in human pituitary adenomas: EGF-R correlates with tumor aggressiveness. J Clin Endocrinol Metab 81:656–662[Abstract]
378. Tucci JR, Zah W, Kalderon AE 1973 Endocrine studies in an arrhenoblastoma responsive to dexamethasone, ACTH and human chorionic gonadotropin. Am J Med 55:687–694[CrossRef][Medline]
379. Gallagher TF, Spencer H, Bradlow HL, Allen L, Hellman L 1962 Steroid production and metabolism in metastatic arrhenoblastoma. J Clin Endocrinol Metab 22:970–977
380. Matsukura S, Kakita T, Fukase M, Fujita T 1981 Adenylate cyclase of a human medullary thyroid carcinoma. Experientia 37:523–524[CrossRef][Medline]
381. McGregor LM, McCune BK, Graff JR, McDowell PR, Romans KE, Yancopoulos GD, Ball DW, Baylin SB, Nelkin BD 1999 Roles of trk family neurotrophin receptors in medullary thyroid carcinoma development and progression. Proc Natl Acad Sci U S A 96:4540–4545[Abstract/Free Full Text]
382. van der Laan BF, Freeman JL, Asa SL 1995 Expression of growth factors and growth factor receptors in normal and tumorous human thyroid tissues. Thyroid 5:67–73[Medline]
383. Vertongen P, Ciccarelli E, Woussen-Colle MC, De Neef P, Robberecht P, Cauvin A 1994 Pituitary adenylate cyclase-activating polypeptide receptors of types I and II and glucagon-like peptide-I receptors are expressed in the rat medullary carcinoma of the thyroid cell line 6/23. Endocrinology 135:1537–1542[Abstract]
384. Crespel A, De Boisvilliers F, Gros L, Kervran A 1996 Effects of glucagon and glucagon-like peptide-1-(7–36) amide on C cells from rat thyroid and medullary thyroid carcinoma CA-77 cell line. Endocrinology 137:3674–3680[Abstract]
385. Colomer A, Martinez-Mas JV, Matias-Guiu X, Llorens A, Cabezas R, Prat J, Garcia-Ameijeiras A 1996 Sex-steroid hormone receptors in human medullary thyroid carcinoma. Mod Pathol 9:68–72[Medline]
386. Amiri-Mosavi A, Ahlman H, Tisell LE, Wangberg B, Kolby L, Forssell-Aronsson E, Lundberg PA, Lindstedt G, Nilsson O 1999 Expression of cholecystokinin-B/gastrin receptors in medullary thyroid cancer. Eur J Surg 165:628–631[CrossRef][Medline]
387. Mato E, Matias-Guiu X, Chico A, Webb SM, Cabezas R, Berna L, De Leiva A 1998 Somatostatin and somatostatin receptor subtype gene expression in medullary thyroid carcinoma. J Clin Endocrinol Metab 83:2417–2420[Abstract/Free Full Text]
388. Nakamaru M, Ogihara T, Saito H, Rakugi H, Hashizume K, Yamatodani A, Wada H, Kumahara Y 1989 Effect of atrial natriuretic peptide on catecholamine release from human pheochromocytoma. Acta Endocrinol (Copenh) 120:107–112[Abstract/Free Full Text]
389. Gelato MC, Vassalotti J 1990 Insulin-like growth factor-II: possible local growth factor in pheochromocytoma. J Clin Endocrinol Metab 71:1168–1174[Abstract/Free Full Text]
390. Teng KK, Lander H, Fajardo JE, Hanafusa H, Hempstead BL, Birge RB 1995 v-Crk modulation of growth factor-induced PC12 cell differentiation involves the Src homology 2 domain of v-Crk and sustained activation of the Ras/mitogen-activated protein kinase pathway. J Biol Chem 270:20677–20685[Abstract/Free Full Text]
391. Nilsson O, Wangberg B, Kolby L, Schultz GS, Ahlman H 1995 Expression of transforming growth factor and its receptor in human neuroendocrine tumours. Int J Cancer 60:645–651[Medline]
392. Billon N, van Grunsven LA, Rudkin BB 1996 The CDK inhibitor p21WAF1/Cip1 is induced through a p300-dependent mechanism during NGF-mediated neuronal differentiation of PC12 cells. Oncogene 13:2047–2054[Medline]
393. Barnes RB, Ehrmann DA 1997 Long-term suppression of testosterone after treatment with a gonadotropin-releasing hormone agonist in a woman with a presumed testosterone secreting ovarian tumor. J Clin Endocrinol Metab 82:1746–1748[Free Full Text]
394. Pollak MR, Brown EM, Estep HL, McLaine PN, Kifor O, Park J, Hebert SC, Seidman CE, Seidman JG 1994 Autosomal dominant hypocalcaemia caused by a Ca(2+)-sensing receptor gene mutation. Nat Genet 8:303–307[CrossRef][Medline]
395. Schipani E, Kruse K, Juppner H 1995 A constitutively active mutant PTH-PTHrP receptor in Jansen-type metaphyseal chondrodysplasia. Science 268:98–100[Abstract/Free Full Text]
396. Rodien P, Bremont C, Sanson ML, Parma J, Van Sande J, Costagliola S, Luton JP, Vassart G, Duprez L 1998 Familial gestational hyperthyroidism caused by a mutant thyrotropin receptor hypersensitive to human chorionic gonadotropin. N Engl J Med 339:1823–1826[Free Full Text]
397. McKenzie JM, Zakarija M 1995 Hyperthyroidism. In: De Groot LJ, Besser M, Burger HG, Jameson JL, Loriaux DL, Marshall JC, Odell WD, Potts Jr JT, Rubenstein AH (eds) Endocrinology. W.B. Saunders Co, Philadelphia, pp 676–711
398. Service FJ 1995 Hypoglycemia including hypoglycemia in neonates and children. In: De Groot LJ, Besser M, Burger HG, Jameson JL, Loriaux DL, Marshall JC, Odell WD, Potts Jr JT, Rubenstein AH (eds) Endocrinology.W.B. Saunders Co, Philadelphia, pp 1605–1623
399. Gammaltoft S, Kahn CR 1995 Hormone signaling via membrane receptors. In: De Groot LJ, Besser M, Burger HG, Jameson JL, Loriaux DL, Marshall JC, Odell WD, Potts Jr JT, Rubenstein AH (eds) Endocrinology. W.B. Saunders Co, Philadelphia, pp 17–65
400. Landis CA, Masters SB, Spada A, Pace AM, Bourne HR, Vallar L 1989 GTPase inhibiting mutations activate the alpha chain of Gs and stimulate adenylyl cyclase in human pituitary tumours. Nature 340:692–696[CrossRef][Medline]
401. Russo D, Arturi F, Wicker R, Chazenbalk GD, Schlumberger M, DuVillard JA, Caillou B, Monier R, Rapoport B, Filetti S 1995 Genetic alterations in thyroid hyperfunctioning adenomas. J Clin Endocrinol Metab 80:1347–1351[Abstract]
402. Iiri T, Herzmark P, Nakamoto JM, van Dop C, Bourne HR 1994 Rapid GDP release from Gs in patients with gain and loss of endocrine function. Nature 371:164–168[CrossRef][Medline]

This article has been cited by other articles:

				A. Lampron, I. Bourdeau, S. Oble, A. Godbout, W. Schurch, P. Arjane, P. Hamet, and A. Lacroix Regulation of Aldosterone Secretion by Several Aberrant Receptors Including for Glucose-Dependent Insulinotropic Peptide in a Patient with an Aldosteronoma J. Clin. Endocrinol. Metab., March 1, 2009; 94(3): 750 - 756. [Abstract] [Full Text] [PDF]

				O Zwermann, Y Suttmann, M Bidlingmaier, F Beuschlein, and M Reincke Screening for membrane hormone receptor expression in primary aldosteronism Eur. J. Endocrinol., March 1, 2009; 160(3): 443 - 451. [Abstract] [Full Text] [PDF]

				M. H. S. Costa, A. C. Latronico, R. M. Martin, A. S Barbosa, M. Q Almeida, C. F. P. Lotfi, H. P Lima Valassi, M. Y. Nishi, A. M. Lucon, S. A. Siqueira, et al. Expression profiles of the glucose-dependent insulinotropic peptide receptor and LHCGR in sporadic adrenocortical tumors J. Endocrinol., February 1, 2009; 200(2): 167 - 175. [Abstract] [Full Text] [PDF]

				C Vincent-Dejean, L Cazabat, L Groussin, K Perlemoine, G Fumey, F Tissier, X Bertagna, and J Bertherat Identification of a clinically homogenous subgroup of benign cortisol-secreting adrenocortical tumors characterized by alterations of the protein kinase A (PKA) subunits and high PKA activity. Eur. J. Endocrinol., June 1, 2008; 158(6): 829 - 839. [Abstract] [Full Text] [PDF]

				E Louiset, V Contesse, L Groussin, D Cartier, C Duparc, V Perraudin, J Bertherat, and H Lefebvre Expression of vasopressin receptors in ACTH-independent macronodular bilateral adrenal hyperplasia causing Cushing's syndrome: molecular, immunohistochemical and pharmacological correlates J. Endocrinol., January 1, 2008; 196(1): 1 - 9. [Abstract] [Full Text] [PDF]

				N M Albiger, G Occhi, B Mariniello, M Iacobone, G Favia, A Fassina, D Faggian, F Mantero, and C Scaroni Food-dependent Cushing's syndrome: from molecular characterization to therapeutical results Eur. J. Endocrinol., December 1, 2007; 157(6): 771 - 778. [Abstract] [Full Text] [PDF]

				J R Meinardi, B H R Wolffenbuttel, and R P F Dullaart Cyclic Cushing's syndrome: a clinical challenge Eur. J. Endocrinol., September 1, 2007; 157(3): 245 - 254. [Abstract] [Full Text] [PDF]

				J. Miyamoto, T. Matsumoto, H. Shiina, K. Inoue, I. Takada, S. Ito, J. Itoh, T. Minematsu, T. Sato, T. Yanase, et al. The Pituitary Function of Androgen Receptor Constitutes a Glucocorticoid Production Circuit Mol. Cell. Biol., July 1, 2007; 27(13): 4807 - 4814. [Abstract] [Full Text] [PDF]

				D Vezzosi, D Cartier, C Regnier, P Otal, A Bennet, F Parmentier, M Plantavid, A Lacroix, H Lefebvre, and P Caron Familial adrenocorticotropin-independent macronodular adrenal hyperplasia with aberrant serotonin and vasopressin adrenal receptors Eur. J. Endocrinol., January 1, 2007; 156(1): 21 - 31. [Abstract] [Full Text] [PDF]

				I. Bourdeau, L. Matyakhina, S. G. Stergiopoulos, F. Sandrini, S. Boikos, and C. A. Stratakis 17q22-24 Chromosomal Losses and Alterations of Protein Kinase A Subunit Expression and Activity in Adrenocorticotropin-Independent Macronodular Adrenal Hyperplasia J. Clin. Endocrinol. Metab., September 1, 2006; 91(9): 3626 - 3632. [Abstract] [Full Text] [PDF]

				A. Lampron, I. Bourdeau, P. Hamet, J. Tremblay, and A. Lacroix Whole Genome Expression Profiling of Glucose-Dependent Insulinotropic Peptide (GIP)- and Adrenocorticotropin-Dependent Adrenal Hyperplasias Reveals Novel Targets for the Study of GIP-Dependent Cushing's Syndrome J. Clin. Endocrinol. Metab., September 1, 2006; 91(9): 3611 - 3618. [Abstract] [Full Text] [PDF]

				M. Alevizaki, K. Saltiki, E. Mantzou, E. Anastasiou, and I. Huhtaniemi The adrenal gland may be a target of LH action in postmenopausal women. Eur. J. Endocrinol., June 1, 2006; 154(6): 875 - 881. [Abstract] [Full Text] [PDF]

				M. O. Boylan, L. I. Jepeal, and M. M. Wolfe Sp1/Sp3 binding is associated with cell-specific expression of the glucose-dependent insulinotropic polypeptide receptor gene Am J Physiol Endocrinol Metab, June 1, 2006; 290(6): E1287 - E1295. [Abstract] [Full Text] [PDF]

				V. Perraudin, C. Delarue, H. Lefebvre, J.-L. Do Rego, H. Vaudry, and J.-M. Kuhn Evidence for a Role of Vasopressin in the Control of Aldosterone Secretion in Primary Aldosteronism: in Vitro and in Vivo Studies J. Clin. Endocrinol. Metab., April 1, 2006; 91(4): 1566 - 1572. [Abstract] [Full Text] [PDF]

				K. Saner-Amigh, B. A. Mayhew, F. Mantero, F. Schiavi, P. C. White, C. V. Rao, and W. E. Rainey Elevated Expression of Luteinizing Hormone Receptor in Aldosterone-Producing Adenomas J. Clin. Endocrinol. Metab., March 1, 2006; 91(3): 1136 - 1142. [Abstract] [Full Text] [PDF]

				T. L. Mazzuco, O. Chabre, J.-J. Feige, and M. Thomas Aberrant Expression of Human Luteinizing Hormone Receptor by Adrenocortical Cells Is Sufficient to Provoke Both Hyperplasia and Cushing's Syndrome Features J. Clin. Endocrinol. Metab., January 1, 2006; 91(1): 196 - 203. [Abstract] [Full Text] [PDF]

				R. Libe and J. Bertherat Molecular genetics of adrenocortical tumours, from familial to sporadic diseases Eur. J. Endocrinol., October 1, 2005; 153(4): 477 - 487. [Abstract] [Full Text] [PDF]

				V. Baldacchino, S. Oble, P.-O. Decarie, I. Bourdeau, P. Hamet, J. Tremblay, and A. Lacroix The Sp transcription factors are involved in the cellular expression of the human glucose-dependent insulinotropic polypeptide receptor gene and overexpressed in adrenals of patients with Cushing's syndrome J. Mol. Endocrinol., August 1, 2005; 35(1): 61 - 71. [Abstract] [Full Text] [PDF]

				M. Ascoli Learning New Tricks from an Old Dog: The Processing of the Intracellular Precursor of the Luteinizing Hormone Receptor (LHR) into the Mature Cell-Surface LHR Is a Regulated Process Endocrinology, August 1, 2005; 146(8): 3221 - 3223. [Full Text] [PDF]

				P. M. Apaja, J. T. Aatsinki, H. J. Rajaniemi, and U. E. Petaja-Repo Expression of the Mature Luteinizing Hormone Receptor in Rodent Urogenital and Adrenal Tissues Is Developmentally Regulated at a Posttranslational Level Endocrinology, August 1, 2005; 146(8): 3224 - 3232. [Abstract] [Full Text] [PDF]

				G. Mazzocchi, P. Rebuffat, A. Ziolkowska, G. P. Rossi, L. K. Malendowicz, and G. G. Nussdorfer G Protein Receptors 7 and 8 Are Expressed in Human Adrenocortical Cells, and Their Endogenous Ligands Neuropeptides B and W Enhance Cortisol Secretion by Activating Adenylate Cyclase- and Phospholipase C-Dependent Signaling Cascades J. Clin. Endocrinol. Metab., June 1, 2005; 90(6): 3466 - 3471. [Abstract] [Full Text] [PDF]

				L. Matyakhina, R. J. Freedman, I. Bourdeau, M.-H. Wei, S. G. Stergiopoulos, A. Chidakel, M. Walther, M. Abu-Asab, M. Tsokos, M. Keil, et al. Hereditary Leiomyomatosis Associated with Bilateral, Massive, Macronodular Adrenocortical Disease and Atypical Cushing Syndrome: A Clinical and Molecular Genetic Investigation J. Clin. Endocrinol. Metab., June 1, 2005; 90(6): 3773 - 3779. [Abstract] [Full Text] [PDF]

				V. Contesse, Y. Reznik, E. Louiset, C. Duparc, D. Cartier, F. Sicard, A. Laquerriere, F. Parmentier, J.-M. Kuhn, H. Vaudry, et al. Abnormal Sensitivity of Cortisol-Producing Adrenocortical Adenomas to Serotonin: In Vivo and in Vitro Studies J. Clin. Endocrinol. Metab., May 1, 2005; 90(5): 2843 - 2850. [Abstract] [Full Text] [PDF]

				F. M. Swords, S. Aylwin, L. Perry, J. Arola, A. B. Grossman, J. P. Monson, and A. J. L. Clark The Aberrant Expression of the Gastric Inhibitory Polypeptide (GIP) Receptor in Adrenal Hyperplasia: Does Chronic Adrenocorticotropin Exposure Stimulate Up-Regulation of GIP Receptors in Cushing's Disease? J. Clin. Endocrinol. Metab., May 1, 2005; 90(5): 3009 - 3016. [Abstract] [Full Text] [PDF]

				R. G. Dluhy, M. M. Maher, and C.-L. Wu Case 7-2005 - A 59-Year-Old Woman with an Incidentally Discovered Adrenal Nodule N. Engl. J. Med., March 10, 2005; 352(10): 1025 - 1032. [Full Text] [PDF]

				M. O. van Aken, A. M Pereira, S. W. van Thiel, G. van den Berg, M. Frolich, J. D. Veldhuis, J. A. Romijn, and F. Roelfsema Irregular and Frequent Cortisol Secretory Episodes with Preserved Diurnal Rhythmicity in Primary Adrenal Cushing's Syndrome J. Clin. Endocrinol. Metab., March 1, 2005; 90(3): 1570 - 1577. [Abstract] [Full Text] [PDF]

				J. Bertherat, V. Contesse, E. Louiset, G. Barrande, C. Duparc, L. Groussin, P. Emy, X. Bertagna, J.-M. Kuhn, H. Vaudry, et al. In Vivo and in Vitro Screening for Illegitimate Receptors in Adrenocorticotropin-Independent Macronodular Adrenal Hyperplasia Causing Cushing's Syndrome: Identification of Two Cases of Gonadotropin/Gastric Inhibitory Polypeptide-Dependent Hypercortisolism J. Clin. Endocrinol. Metab., March 1, 2005; 90(3): 1302 - 1310. [Abstract] [Full Text] [PDF]

				M. O. van Aken, A. M. Pereira, M. Frolich, J. A. Romijn, H. Pijl, J. D. Veldhuis, and F. Roelfsema Growth hormone secretion in primary adrenal Cushing's syndrome is disorderly and inversely correlated with body mass index Am J Physiol Endocrinol Metab, January 1, 2005; 288(1): E63 - E70. [Abstract] [Full Text] [PDF]

				G. Mansmann, J. Lau, E. Balk, M. Rothberg, Y. Miyachi, and S. R. Bornstein The Clinically Inapparent Adrenal Mass: Update in Diagnosis and Management Endocr. Rev., April 1, 2004; 25(2): 309 - 340. [Abstract] [Full Text] [PDF]

				P. Rodien, N. Jordan, A. Lefevre, J. Royer, C. Vasseur, F. Savagner, A. Bourdelot, and V. Rohmer Abnormal stimulation of the thyrotrophin receptor during gestation Hum. Reprod. Update, March 1, 2004; 10(2): 95 - 105. [Abstract] [Full Text] [PDF]

				G. Arnaldi, A. Angeli, A. B. Atkinson, X. Bertagna, F. Cavagnini, G. P. Chrousos, G. A. Fava, J. W. Findling, R. C. Gaillard, A. B. Grossman, et al. Diagnosis and Complications of Cushing's Syndrome: A Consensus Statement J. Clin. Endocrinol. Metab., December 1, 2003; 88(12): 5593 - 5602. [Abstract] [Full Text] [PDF]

				M. Mannelli, P. Ferruzzi, P. Luciani, C. Crescioli, L. Buci, G. Corona, M. Serio, and A. Peri Cushing's Syndrome in a Patient with Bilateral Macronodular Adrenal Hyperplasia Responding to Cisapride: An in Vivo and in Vitro Study J. Clin. Endocrinol. Metab., October 1, 2003; 88(10): 4616 - 4622. [Abstract] [Full Text] [PDF]

				M. Bielinska, H. Parviainen, S. B. Porter-Tinge, S. Kiiveri, E. Genova, N. Rahman, I. T. Huhtaniemi, L. J. Muglia, M. Heikinheimo, and D. B. Wilson Mouse Strain Susceptibility to Gonadectomy-Induced Adrenocortical Tumor Formation Correlates with the Expression of GATA-4 and Luteinizing Hormone Receptor Endocrinology, September 1, 2003; 144(9): 4123 - 4133. [Abstract] [Full Text] [PDF]

				I. Bourdeau, A. Lacroix, W. Schurch, P. Caron, T. Antakly, and C. A. Stratakis Primary Pigmented Nodular Adrenocortical Disease: Paradoxical Responses of Cortisol Secretion to Dexamethasone Occur in Vitro and Are Associated with Increased Expression of the Glucocorticoid Receptor J. Clin. Endocrinol. Metab., August 1, 2003; 88(8): 3931 - 3937. [Abstract] [Full Text] [PDF]

				D. Rosenberg, L. Groussin, E. Jullian, K. Perlemoine, S. Medjane, A. Louvel, X. Bertagna, and J. Bertherat Transcription Factor 3',5'-Cyclic Adenosine 5'-Monophosphate-Responsive Element-Binding Protein (CREB) Is Decreased during Human Adrenal Cortex Tumorigenesis and Fetal Development J. Clin. Endocrinol. Metab., August 1, 2003; 88(8): 3958 - 3965. [Abstract] [Full Text] [PDF]

				H. Lefebvre, C. Duparc, N. Chartrel, S. Jegou, A. Pellerin, A. Laquerriere, R. Ivell, H. Vaudry, and J.-M. Kuhn Intraadrenal Adrenocorticotropin Production in a Case of Bilateral Macronodular Adrenal Hyperplasia Causing Cushing's Syndrome J. Clin. Endocrinol. Metab., July 1, 2003; 88(7): 3035 - 3042. [Abstract] [Full Text] [PDF]

				H. Raff and J. W. Findling A Physiologic Approach to Diagnosis of the Cushing Syndrome Ann Intern Med, June 17, 2003; 138(12): 980 - 991. [Full Text] [PDF]

				M. C. B. V. Fragoso, S. Domenice, A. C. Latronico, R. M. Martin, M. A. A. Pereira, M. C. N. Zerbini, A. M. Lucon, and B. B. Mendonca Cushing's Syndrome Secondary to Adrenocorticotropin-Independent Macronodular Adrenocortical Hyperplasia due to Activating Mutations of GNAS1 Gene J. Clin. Endocrinol. Metab., May 1, 2003; 88(5): 2147 - 2151. [Abstract] [Full Text] [PDF]

				M. O. Goodarzi, D. W. Dawson, X. Li, Z. Lei, P. Shintaku, C. V. Rao, and A. J. Van Herle Virilization in Bilateral Macronodular Adrenal Hyperplasia Controlled by Luteinizing Hormone J. Clin. Endocrinol. Metab., January 1, 2003; 88(1): 73 - 77. [Abstract] [Full Text] [PDF]

				R. A. Feelders, S. W. J. Lamberts, L. J. Hofland, P. M. van Koetsveld, M. Verhoef-Post, A. P. N. Themmen, F. H. de Jong, H. J. Bonjer, A. J. Clark, A.-J. van der Lely, et al. Luteinizing Hormone (LH)-Responsive Cushing's Syndrome: The Demonstration of LH Receptor Messenger Ribonucleic Acid in Hyperplastic Adrenal Cells, which Respond to Chorionic Gonadotropin and Serotonin Agonists in Vitro J. Clin. Endocrinol. Metab., January 1, 2003; 88(1): 230 - 237. [Abstract] [Full Text] [PDF]

				D. Cartier, I. Lihrmann, F. Parmentier, C. Bastard, J. Bertherat, P. Caron, J.-M. Kuhn, A. Lacroix, A. Tabarin, J. Young, et al. Overexpression of Serotonin4 Receptors in Cisapride-Responsive Adrenocorticotropin-Independent Bilateral Macronodular Adrenal Hyperplasia Causing Cushing's Syndrome J. Clin. Endocrinol. Metab., January 1, 2003; 88(1): 248 - 254. [Abstract] [Full Text] [PDF]

				C. A. Koch, K. Pacak, and G. P. Chrousos The Molecular Pathogenesis of Hereditary and Sporadic Adrenocortical and Adrenomedullary Tumors J. Clin. Endocrinol. Metab., December 1, 2002; 87(12): 5367 - 5384. [Abstract] [Full Text] [PDF]

				T. Mune, H. Murase, N. Yamakita, T. Fukuda, M. Murayama, A. Miura, T. Suwa, J. Hanafusa, H. Daido, H. Morita, et al. Eutopic Overexpression of Vasopressin V1a Receptor in Adrenocorticotropin-Independent Macronodular Adrenal Hyperplasia J. Clin. Endocrinol. Metab., December 1, 2002; 87(12): 5706 - 5713. [Abstract] [Full Text] [PDF]

				L. Groussin, E. Jullian, K. Perlemoine, A. Louvel, B. Leheup, J. P. Luton, X. Bertagna, and J. Bertherat Mutations of the PRKAR1A Gene in Cushing's Syndrome due to Sporadic Primary Pigmented Nodular Adrenocortical Disease J. Clin. Endocrinol. Metab., September 1, 2002; 87(9): 4324 - 4329. [Abstract] [Full Text] [PDF]

				L. Groussin, K. Perlemoine, V. Contesse, H. Lefebvre, A. Tabarin, P. Thieblot, J. L. Schlienger, J. P. Luton, X. Bertagna, and J. Bertherat The Ectopic Expression of the Gastric Inhibitory Polypeptide Receptor Is Frequent in Adrenocorticotropin-Independent Bilateral Macronodular Adrenal Hyperplasia, but Rare in Unilateral Tumors J. Clin. Endocrinol. Metab., May 1, 2002; 87(5): 1980 - 1985. [Abstract] [Full Text] [PDF]

				M. Ascoli, F. Fanelli, and D. L. Segaloff The Lutropin/Choriogonadotropin Receptor, A 2002 Perspective Endocr. Rev., April 1, 2002; 23(2): 141 - 174. [Abstract] [Full Text] [PDF]

				T. Piltonen, R. Koivunen, L. Morin-Papunen, A. Ruokonen, I.T. Huhtaniemi, and J.S. Tapanainen Ovarian and adrenal steroid production: regulatory role of LH/HCG Hum. Reprod., March 1, 2002; 17(3): 620 - 624. [Abstract] [Full Text] [PDF]

				C. A. Koch and G. P. Chrousos Is the Diminuto/Dwarf1 Gene Involved in Physiologic Adrenocortical Size Regulation and Tumor Formation? J. Clin. Endocrinol. Metab., November 1, 2001; 86(11): 5127 - 5129. [Full Text] [PDF]

				I. Bourdeau, P. D'Amour, P. Hamet, J.-M. Boutin, and A. Lacroix Aberrant Membrane Hormone Receptors in Incidentally Discovered Bilateral Macronodular Adrenal Hyperplasia with Subclinical Cushing's Syndrome J. Clin. Endocrinol. Metab., November 1, 2001; 86(11): 5534 - 5540. [Abstract] [Full Text] [PDF]

				M. Cote, G. Guillon, M. D. Payet, and N. Gallo-Payet Expression and Regulation of Adenylyl Cyclase Isoforms in the Human Adrenal Gland J. Clin. Endocrinol. Metab., September 1, 2001; 86(9): 4495 - 4503. [Abstract] [Full Text] [PDF]

				R. Khardori, M. Boscaro, L. Barzon, and N. Sonino Considerations in Diagnosis of Cushing Syndrome Arch Intern Med, July 23, 2001; 161(14): 1780 - 1780. [Full Text] [PDF]

This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Lacroix, A. Articles by Hamet, P. Search for Related Content PubMed PubMed Citation Articles by Lacroix, A. Articles by Hamet, P.