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Division of Endocrinology, Department of Medicine, Research Center, Hôtel-Dieu du Centre Hospitalier de lUniversité de Montréal (CHUM), Montréal, Québec, Canada H2W 1T8
| Abstract |
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I. Introduction
II. Hormonal Regulation of the Normal Adrenal Cortex
III. Primary Adrenal Cushings 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 |
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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 |
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1-adrenoreceptor agonists,
serotonin (5-HT1A) receptor agonists, muscarinic
and nicotinic receptor agonists of acetylcholine, histamine, and
-aminobutyric acid
(GABAA), whereas it
is inhibited by GABAB 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 (P450scc) 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).
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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 (60260%) 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 ETA 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 Cushings Syndrome (CS) |
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Primary adrenal etiologies account for 1520% of endogenous CS in adults and are secondary to unilateral tumors in 9098% 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 34 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 (Carneys 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 Liddles
dexamethasone suppression test (171). In McCune-Albright syndrome,
activating mutations of Gs
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 Gs
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 patients fifth or sixth decade and has a
relatively even gender distribution when compared with Cushings
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
Gs
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 |
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-, adrenergic agonists. Further
studies (Table 1
- adrenergic receptors stimulating guanylate
cyclase and cGMP production was also demonstrated in rat adrenal
carcinoma 494 (188, 189).
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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 Cushings 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 patients 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 |
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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 23 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 patients 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
patients 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).
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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 Carneys 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.
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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 Cushings 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
).
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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. NDiaye 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 Cushings 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 Cushings 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 1822 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 23
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.
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