| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
Clinical Studies |
Divisions of Endocrinology (A.L., J.T., P.H.) and Internal Medicine (J.R.C, E.S.), Research Center (A.L., J.T., J.R.C., P.H.) Hôtel-Dieu de Montréal, Montréal H2W 1T8; Multidisciplinary Research Group on Hypertension (R.M.T., L.Y.D., R.L., E.L.S.), Institut de Recherches Cliniques de Montréal, Montréal H2W 1R7; and Department of Medicine (A.L., J.T., R.M.T., L.Y.D., R.L., J.R.C., E.L.S., P.H.), Université de Montréal, Montréal, Quebec, Canada
Address all correspondence and requests for reprints to: Dr. André Lacroix, Centre de Recherche, Hôtel-Dieu de Montréal, 3850 St-Urbain, Montréal (Québec) H2W 1T8, Canada.
 |
Abstract |
|---|
 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
|
Introduction |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
in adrenal nodules results in a constitutive
stimulation of steroidogenesis (4). Recently, we (5) and others (6, 7)
described food-dependent cortisol production in three women with
ACTH-independent macronodular bilateral adrenal hyperplasia (AIMAH) and
in one man (8) and one woman (9) with adrenal adenomas; this syndrome
was secondary to an ectopic expression or increased responsiveness of
gastric inhibitory polypeptide receptors in the adrenals. These
findings raised the hypothesis that adrenal proliferation and function
in adrenocortical hyperplasia or tumors may be secondary to
abnormalities of receptors for various other hormones or growth
factors. We now describe a patient with Cushing’s syndrome in whom
steroid production from AIMAH was stimulated by upright posture and
administration of arginine vasopressin (AVP); in addition, orthostatic
hypotension and abnormal vascular response to AVP was present in the
same patient. |
Materials and Methods |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
A 36-yr-old woman was referred for evaluation of Cushing’s syndrome and AIMAH. Hypercorticism developed during the preceding 5–6 yr, with a 13-kg weight gain, irregular menses, and easy bruising; attacks of discomfort, blurry vision, dizziness, difficulty with concentration, musculoskeletal pain, and palpitations occurred when standing up for more than 30–60 min and were relieved by lying down.
Free urinary cortisol levels were elevated at 386 and 441 nmol/day (normals by high-performance liquid chromatography assay: 13–130 nmol/day); morning plasma cortisol was 789 nmol/L, not suppressed by 1 mg (745 nmol/L) or 8 mg (497 nmol/L) overnight dexamethasone. Morning plasma ACTH was undetectable by RIA and immunoradiometric assay. An abdominal computed tomography (CT) scan revealed macronodular adrenals measuring 5 cm on the right and 8 cm on the left. Oral ketoconazole (400–800 mg daily) was initiated 15 months before referral. Weight decreased from 67 to 50 kg, but fatigue and dizzy spell episodes persisted at a reduced severity. Urinary cortisol normalized, but ACTH levels remained undetectable. Ketoconazole was discontinued 1 week before investigation.
Blood pressure was 120/70 mm Hg, sitting, weight was 48 kg, and height was 160 cm; there were no residual signs of hypercorticism. Pituitary magnetic resonance imaging was normal. After investigation, bilateral adrenalectomy was performed; the left adrenal measured 9 x 4 x 2 cm (36 g), and the right adrenal measured 6.5 x 3 x 1.5 cm (17 g). Both adrenals were diffusely enlarged with alternance of clear and acidophilic micronodules, without internodular atrophy.
The patient was treated with hydrocortisone (30 mg) and fludrocortisone
(0.1 mg) daily. During the following 6 months, weight was stable, but
symptomatic orthostatic hypotension persisted. Support stockings and an
increase of fludrocortisone to 0.15 mg daily did not improve symptoms.
After reevaluation 7 months post adrenalectomy, treatment with an
-adrenergic agonist, midodrine chlorhydrate (Amatine, Boots
Pharmaceuticals, Eobicoke, Ont; 5 mg orally three times daily),
partially improved the control of blood pressure and of symptoms.
Methods
Clinical studies. Pituitary adrenal function was studied in the patient with AIMAH, in seven normal control individuals, and in one woman each with either an adrenal pheochromocytoma or normal pituitary-adrenal function 2 yr after removal of a corticotroph pituitary adenoma or with mild cyclic Cushing’s disease. The study protocols were approved by the institutional review committee, and written informed consent was obtained from all subjects.
Studies were performed, after an overnight fast, in the supine position for 60 min before testing. The protocol included serial measurements at 30–60 min intervals of plasma ACTH, cortisol, aldosterone, free testosterone, dehydroepiandrosterone sulfate, and estradiol during the course of the various tests. On the first day, a combined stimulation with luteinizing hormone release hormone (LHRH) (100 µg; Factrel, Wyeth-Ayerst, Montréal, Québec, Canada), TRH (200 µg; Relefact, Hoechst-Roussel, Montréal, Québec), GHRH 1–27 (1.2 µg/kg; Ferring Inc., North York, Ontario, Canada) iv bolus was performed; this was followed, 180 min later, by a stimulation test with 250 µg iv ACTH 1–24 (Cortrosyn, Organon Canada Ltd, Scarborough, Ontario). On the second day, a posture test was performed in a 2-h supine position, followed by a 2-h ambulation period. One hour later, a mixed meal was administered; this was followed, 2 h later, by stimulation with 1 µg/kg iv ovine CRH (ACTHREL, Ferring Inc). On the third day, stimulation with 10 U im AVP (Pitressin, Parke-Davis, Scarborough, Ontario) was performed, followed, 120 min later, by an insulin-induced hypoglycemia (0.15 U/kg). On the subsequent day, glucagon (Eli Lily Canada Inc. Scarborough, Ontario) 1 mg was injected iv, and this was followed 120 min later by an iv dexamethasone test (1 mg/h from 1100 h to 1500 h), as described previously (5); however, in this study, AVP (10 U) was injected im at 1400 h. A desmopressin stimulation was performed by sc injection of 2.5 µg desmopressin acetate (dDAVP) (Ferring Inc). Angiotensin II (Hypertensin, Ciba-Geigy, Mississauga, Ontario)) was infused at a rate of 1 ng/kg·min during 15 min, and at 3 ng/kg·min during 30 min, to increase blood pressure by 30/15 mm Hg; isoproterenol (Isuprel Sanofi Winthrop, Markham, Ontario) was injected as a 1-µg iv bolus and increased heart rate by 54 beats/min. ACTH 1–24 sensitivity test was performed by sequential injections of 0.1, 1.0, and 5 µg Cortrosyn at 2-h intervals.
Materials. AVP, the V1-AVP receptor antagonist [1-(ß-mercapto-ß, ß-cyclopentamethylene propionic acid), 2-(O-Me)-Tyrosine]- Arg8-vasopressin, dDAVP, endothelin-1 (ET-1), and BQ-123 were from Peninsula Laboratories (Belmont, CA); Sarafotoxin (S6c) from Calbiochem (La Jolla, CA); and Fura-2-acetoxymethylester (Fura-2, AM) and pluronic F-127 from Molecular Probes (Eugene, OR). Other chemicals were obtained from Sigma (St. Louis, MO), Fischer Scientific Co. (Fair Lawn, NJ), and BDH Inc. (Darmstadt, Germany).
In vitro studies with dispersed adrenal cells. Portions of both adrenal glands were dispersed and incubated (1 x 106 cells/mL) in DMEM (Gibco Canada, Mississauga, Ontario), without serum, with various hormones during 2 h at 37 C, as described previously (5); after incubation, medium was collected and frozen at -20 C for assay of cortisol concentration.
Assays. Plasma, urinary, and cell media concentrations of cortisol were measured by a commercial RIA kit (Quanticoat Kallestad Diagnostics, Chaska, MN), as were other steroids, renin, and ACTH (IRMA Allegro, Nichols Diagnostics, San Juan Capistrano, CA). Plasma AVP RIA was performed, as described previously (10), with an assay sensitivity of 0.1 pg/assay tube and a limit of detection in plasma of 0.25 pg/mL. RIA for atrial natriuretic peptide (ANP) and for ET-l levels were performed as described previously (11, 12).
Measurement of calcium in isolated cells. Cells, plated at a density of 106 cells/well and grown for 3 days on glass coverslips, were washed three times with 2 mL modified HBSS; cells were loaded with Fura-2, AM (4 µmol/L) in dimethyl sulfoxide with 0.02% pluronic acid, and incubated for 30 min at 37 C in a humidified incubator (95% air-5% CO2). Cells were then washed three times and [Ca2+]i was measured in multiple cells simultaneously by fluorescent digital imaging using the Attofluor Digital Fluorescence System (Axiovert 135 inverted microscope, Zeiss, West Germany), as described previously (13). Dose response curves for ET-1 (0.01 nmol/L to 1 µmol/L) and AVP (0.01 nmol/L to 1 µmol/L) were obtained. In addition, ET-1-induced responses (10 nmol/L) were determined in the presence of 1.0 µmol/L BQ-123 (a selective ETA receptor antagonist), and AVP-induced responses (10 nmol/L) were assessed in the presence of 1.0 µmol/L V1-AVP receptor antagonist. Effects of 100 nmol/L S6c (a selective ETB receptor agonist) and 100 nmol/L dDAVP (a selective V2 receptor agonist) also were assessed. The maximum peak ratio recorded (40–100 sec) was considered as the maximal response of the agonist. At various intervals throughout the experiment, the effects of 50 µL of vehicle (HBSS) on [Ca2+]i transients were determined.
AVP receptor binding assay. Binding studies were performed using 100 µL of dispersed cells (107 cells/mL) incubated in duplicate with 1 pmol/L [3H]-AVP (Du Pont, Mississauga, Ontario) in the presence of increasing concentrations of unlabeled AVP (0.33 pmol/L to 1 µmol/L), V1-AVP receptor antagonist or dDAVP (1 pmol/L to 1 µmol/L), in a final vol of 250 µL, for 60 min at 22 C, as described previously (14). Binding was stopped by 3 mL ice cold DMEM, followed by rapid filtration through glass fibre filters no. 34 (Schleicher & Schuell, Keene, NH), and counting the radioactivity in washed filters in a Rackgamma ß LKB counter with 40% efficiency.
RT-PCR of vasopressin receptors. Total RNA was extracted by the guanidium thiocyanate/cesium chloride method. Two µg RNA were reverse transcribed with random hexamers. Three sets of specific oligodeoxynucleotides for the vasopressin receptors V1, V2, and V3 were provided by Dr, Yves de Keyzer, Institut Cochin de Génétique Moléculaire, Paris, and are described elsewhere (15). PCR was performed in 20 mmol/L Tris-HCl (pH 8.4), 50 mmol/L KCl, 2 mmol/L MgCl2, and 0.5 mmol/L dNTP with 25 pmol/L of each primer. After 35 cycles (45 sec at 94 C, 45 sec at 58–62 C, 1 min at 72 C), 10% of the reaction was analyzed on a 3% agarose gel, and the bands were revealed by ethidium bromide staining.
In vitro stimulation of small sc arteries.
A biopsy of
gluteal sc fat was obtained; small arteries (
250 µm lumen
diameter) were mounted on a wire myograph and stimulated sequentially
with norepinephrine (0.01–10 µmol/L), AVP (0.01–30 nmol/L),
angiotensin II (0.1–300 nmol/L), and ET-1 (0.01–1 µmol/L), as
described previously (16).
Statistical analysis. Comparison of mean values was performed by ANOVA, followed by Bonferroni’s correction for multiple testing. Concentration-response curves were fitted by nonlinear regression using the Instat and Inplot programs (Graphpad Software, San Diego, CA), and the EC50 (concentration giving 50% of the maximum response) was determined and the pD2 calculated as -log [EC50 (mol/L)]. Receptor affinity and density were estimated by computer analysis using the nonlinear regression, curve-fitting program LIGAND.
|
Results |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
Plasma cortisol varied between 271–543 nmol/L fasting, without
diurnal variations, whereas ACTH was less than 0.2 pmol/L; urinary free
cortisol levels remained between 121–265 nmol/day on days without
stimulation tests (normals: 90–330). Various tests, including a mixed
meal, insulin-induced hypoglycemia, TRH-LHRH-GHRH, or glucagon did not
modify plasma cortisol (Fig. 1
) or ACTH, despite
appropriate fluctuations of glucose, TSH, PRL, FSH, LH, or GH (not
shown). CRH administration provoked a subnormal increase of ACTH
(<0.2–0.95 pmol/L) and cortisolemia (287–466 nmol/L) within 30 min.
Administration of 10 U of AVP im increased plasma cortisol rapidly
(Fig. 1) from 501 to 1445 nmol/L, ACTH from less than 0.2 to 0.87
pmol/L, and 24-h urinary-free cortisol up to 995 nmol/day; this was
associated with abdominal cramping, an increase in blood pressure (mm
Hg) from 105/70 to 125/80 at 30 min, and 132/90 at 120 min, and a heart
rate of 80 beats/min basally, of 64 at 30 min, and of 76 at 120 min.
Administration of dDAVP did not result in any stimulation of cortisol
(Fig. 1). After an iv dexamethasone test, cortisolemia was not
suppressed in the AIMAH patient (Fig. 2), whereas in
normal individuals, it suppressed to less than 51 nmol/L (35 ± 11
nmol/L) at the 0900 h time point on the second day (9D2).
Administration of vasopressin under dexamethasone infusion reproduced
the brisk increase of cortisol in plasma (337%) and urine (1281
nmol/day) in the AIMAH patient despite undetectable ACTH; an important
stimulation of aldosterone (67-fold) and other steroids was also
induced by AVP (Table 1). In contrast, AVP
administration under dexamethasone infusion did not increase plasma
cortisol levels in control patients with normal
hypothalamic-pituitary-adrenal axis or Cushing’s disease (Fig. 2).
|
|
|
); plasma AVP levels were
below the limit of detection during these posture tests, whereas
natremia and osmolarity remained normal. The cortisol response to
orthostasis was not suppressed by dexamethasone infusion (Fig. 1).
Basal supine renin levels were relatively suppressed and did not
increase during orthostatic hypotension (Table 2);
supine aldosterone levels were in the low-to-normal range, but
increased 5- to 6-fold during orthostasis despite decreased renin
response. Plasma ANP decreased normally from supine to upright posture
(14.5 to 6.6 nmol/L); plasma norepinephrine levels increased normally
from 0.16 to 0.91 ng/mL during orthostatic hypotension. Supine plasma
ET levels were in the normal range at 2.1 pmol/L but failed to increase
above 2.4 pmol/L during the postural hypotension.
|
). An iv bolus of 1 µg isoproterenol increased
heart rate 54 beats/min but not plasma cortisol levels (Fig. 1). The
peak cortisol increase, after ACTH 1–24 stimulation in the patient
with AIMAH, was 31% with 0.1 µg, 93% with 1 µg, 90% with 5 µg,
and 314% with 250 µg dose; this was not different from the response
of two other patients with bilateral macronodular adrenal hyperplasia
without Cushing’s syndrome (not shown). In vitro studies
Cortisol production by freshly dispersed cells from the
macronodular adrenals and from normal adult human adrenal.
AVP treatment stimulated cortisol production in a dose-dependent
manner, with a minimal effective concentration of 1 nmol/L and a 424%
maximal response in cells from the patient with AIMAH (Fig. 3); in normal adult human adrenal cells, AVP produced
only a slight, nondose-dependent stimulation (135%). The AVP response
was partially inhibited by the V1-AVPR antagonist, whereas
dDAVP had no effect. ACTH 1–24 induced the largest dose-dependent
increase of cortisol secretion in cells from the patient with AIMAH
(913%) and from the normal adult adrenal (286%).
|
AIMAH adrenal cell Ca++ concentrations in response to
hormone treatment.
Intracellular [Ca++] was
stimulated by AVP, and this was inhibited completely by the
V1-AVPR antagonist, whereas dDAVP had no effect (Fig. 4). Intracellular [Ca++] also was
stimulated by ACTH and ET-1; the latter effects were inhibited, in
part, by the selective ETA antagonist BQ-123, whereas the
selective ETB agonist S6c stimulated
[Ca++]i transients but less than ET-1. The
pD2 values for AVP, ET-1, and ACTH were 9.1 ± 0.52,
8.7 ± 0.26, and 7.9 ± 0.07, respectively.
|
Blood pressure regulation.
The patient was reevaluated 7
months post adrenalectomy under replacement with hydrocortisone (10 mg
orally) twice daily; and fludrocortisone (0.1 mg orally) daily; urinary
free cortisol was normal at 238 nmol/day, with normal serum electrolyte
levels. Orthostatic hypotension persisted, but plasma levels of AVP,
ACTH, and renin now were detectable basally; and AVP and renin
increased, albeit subnormally, during upright posture (Table 3). Blood vols measured after 2 h of recumbency
were (L): total: 3.33; red cell mass: 1.22; plasma vol: 2.11 (normals
for height and weight: 3.16, 1.26, 1.89, respectively). After 2 h
of ambulation without support stockings, they were decreased to total:
2.52; red cell mass: 0.88; plasma vol: 1.64. Plasma ET levels were
normal supine, but failed to increase despite hypotension.
|
), whereas relaxation required only 5 ± 1 min in
this and previously published controls (16).
|
|
Discussion |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
We identified cortisol regulation by posture and by exogenous AVP in this patient. AVP increases cortisol production in normal subjects, by stimulating ACTH secretion directly and by potentiating CRH effects (1). In contrast, a direct effect of AVP on adrenal steroidogenesis was demonstrated in vivo and in vitro in this AIMAH patient. Adrenal response in vivo to lysine-vasopressin were reported in canine (17) or human Cushing’s syndrome from adenoma (15), or macronodular adrenal hyperplasia (18); these reports did not indicate whether posture or endogenous AVP modulated cortisol production and whether blood pressure regulation was altered.
Actions of AVP are mediated by three G protein-coupled receptors: V1 (or V1a) receptor (19) expressed mainly in vascular smooth muscle cells, adrenals, liver, platelets, brain, and mesangial cells; V2 receptor (20) in kidney; and V3 (or V1b) receptor (21) in pituitary, and possibly in kidney. AVP was shown to directly stimulate growth and steroidogenesis in rat, bovine, dog, and frog adrenal cells (22, 23, 24, 25); it inhibits steroidogenesis in Leydig cells (26). AVP also stimulates cortisol secretion from normal human adrenals in vitro (27, 28) via activation of V1-AVP receptors. Our in vivo and in vitro data on cell binding, intracellular [Ca++], and steroid response to AVP, dDAVP, and V1-AVPR antagonist and RT-PCR clearly demonstrate that the adrenal hyperresponsiveness to vasopressin was mediated via a V1-AVP receptor. Binding studies revealed a similar V1-AVPR affinity (2.63 nmol/L) in AIMAH adrenal cells compared with membranes from human glomerulosa-rich normal adrenal cells (3.3 nmol/L) (28) or myometrium (29). The ED50 of AVP on [Ca++]i was similar in the adrenal cells of our patient (0.9 nmol/L) compared with glomerulosa-rich cells (1.4 nmol/L) from normal adrenals (28). Although our RT-PCR assay was not quantitative, there does not seem to be a gross overexpression of the V1-AVPR. Direct sequencing of this receptor will be necessary to clarify whether an activating mutation is present. Activating mutations of the TSH receptor in thyroid toxic nodules (30) or the LH receptor in familial male precocious puberty (31) can lead to target tissue hyperplasia and increased function. The diffuse and bilateral hyperplasia in this and other patients with AIMAH (5, 6, 7) suggest that the putative mutation must have occurred during early embryogenesis, whereas somatic mutations would be responsible for unique adenomas (8, 9).
In vitro evidence of ectopic receptors in adrenocortical tumors were described for catecholamines, TSH, LH, HCG, PRL, GH, glucagon, and AVP (7, 32, reviewed in Ref. 33). Gastric inhibitory polypeptide (GIP)-dependent Cushing’s syndrome (5, 6, 7, 8, 9) constitutes the first clinically recognized demonstration of the role of abnormal hormone receptors in the pathophysiology of adrenal tumors or hyperplasia. Because the V1-AVPR was present in the normal adrenal cortex, the abnormality described here would rather be secondary to the abnormal function of a eutopic receptor-effector system. Recently, the V3-AVP receptor was shown to be expressed ectopically in a bronchial carcinoid secreting ACTH (34); in addition, most patients with Cushing’s disease (but not normal individuals) secrete ACTH in response to dDAVP, suggesting ectopic V2-AVPR or abnormal V3-AVPR response in corticotroph adenoma cells (35).
AVP was a logical candidate endogenous modulator of cortisol secretion during postural hypotension in this patient, because exogenous AVP exerted such a potent effect on cortisol production and should increase during orthostatic hypotension (36). Endogenous AVP was below the limit of detection initially but maintained normal water balance in this patient; thus AVP may have modulated steroidogenesis via hyperresponsive V1-AVPR. Glucocorticoid receptors in the paraventricular nuclei (37) are modulated by osmolarity and mediate cortisol negative feedback on vasopressin transcription; this may explain why AVP levels were undetectable, despite the orthostatic hypotension before adrenalectomy. The puzzling persistence of relatively suppressed AVP levels after bilateral adrenalectomy raises the possibility that an exaggerated feedback V1-AVPR signal may be exerted at the hypothalamic level in this patient; V1-AVPR are present in several brain regions, but it is still unknown whether AVP-producing neurons express such receptors and whether AVP synthesis is regulated by its V1-AVPR. AVP also has been shown to be produced in normal adrenal medulla and cortex in humans, as well as in other species (27, 28), raising the possibility of a paracrine regulatory role of AVP on adrenal steroidogenesis and, possibly, growth in this patient with AIMAH. CRH stimulates AVP release from the adrenal medulla (28); CRH stimulated cortisol secretion in vivo in this patient with only minor changes in ACTH levels, but no direct effect of CRH was found in adrenocortical cells in vitro (not shown).
Alternative mediators of cortisol triggered by upright posture included catecholamine surges, with ectopic ß-adrenergic receptors (32); no response was found to insulin-induced hypoglycemia or isoproterenol administration in vivo or in vitro. Another potential modulator was angiotensin II, but renin was suppressed and infusion of angiotensin II failed to elicit a cortisol production in vivo. The decreased basal levels of aldosterone and renin could have resulted from AVP-dependent regulation of inappropriate cortisol and aldosterone production. ETs have also been shown to be produced in adrenal glands, where their receptors are present (38); ETs stimulate cortisol and aldosterone production (38, 39). The lack of increase of ET-1 levels while cortisol increased during upright posture suggests that ET-1 was not an important regulator of steroidogenesis in vivo in this patient.
The pathophysiology of the orthostatic hypotension in this patient is unclear. Cushing’s syndrome often is accompanied by blood volume expansion and high blood pressure (1); thus, the decreased blood volume and delayed postural hypotension of this patient certainly is most atypical. AVP normally exerts a vasoconstrictor effect on vascular smooth muscle; this patient’s small artery maximal constrictor response to AVP was not increased, but an intriguing prolongation of the constrictor effect of AVP was noted. This may suggest that an abnormal response of V1-AVPR-effector system was present not only in the adrenals, but also in vascular and other tissues. Paradoxical vasodilator effects of high concentrations of vasopressin in certain vascular beds have been described previously (40, 41); however, there was no evidence in vivo of such paradoxical effects of vasopressin in this patient.
ET-1 is a vasoconstrictor peptide synthesized by endothelial cells but also by neurons in the paraventricular and supraoptic nuclear neurons of the hypothalamus, with terminals in posterior pituitary (42). Plasma levels of ET-1 increase concomitantly with vasopressin during upright posture in normal individuals but not in patients with autonomic failure or central diabetes insipidus (43); this suggests that the source of ET-1 during postural changes is from the posterior pituitary, rather than from peripheral endothelial cells. The failure to increase ET levels in this patient during orthostatic hypotension clearly is not related to autonomic failure. The persistence of a lack of response of ET to upright posture, several months after the correction of hypercorticism, raises the possibility that an exaggerated V1-AVPR signal may alter the vasopressin and ET response at the hypothalamic level. A combined contribution of the relatively deficient vasoconstrictor systems AVP, ET, and renin-angiotensin II to the pathophysiology of orthostatic hypotension in this patient certainly is another possibility.
In conclusion, it is proposed that a generalized hyperresponsiveness of the V1-AVPR-effector system underlied the macronodular adrenal hyperplasia, hypercorticism and also may be implicated in the orthostatic hypotension in this patient; this abnormality would lead to AVP-modulated secretion of cortisol and aldosterone and to feedback suppression of the CRH-ACTH-adrenal and renin-angiotensin axis, as well as to decreased hypothalamic AVP and ET release. In addition, abnormal vascular responses of the V1-AVPR-effector system may underlie a redistribution of blood volumes in the upright posture, leading to the delayed-onset orthostatic hypotension. Futher studies to characterize this patient’s AVP receptor-effector systems at the molecular level will be necessary to clarify this hypothesis.
This study lends support to our broader hypothesis that AIMAH or adrenocortical tumors (including cortisol, aldosterone, androgens, or estrogens secreting) may be secondary to either ectopic hormone receptors (such as GIPR, ß-adrenergic receptors) or any other receptor capable of coupling to G proteins and steroidogenesis, or to abnormalities of eutopic receptors such as those for ACTH, AVP, angiotensin ll, serotonin, ANP, or growth factors. This may eventually lead to pharmacological therapy as an alternative to adrenalectomy; it will be interesting to treat patients such as this one with oral V1-AVPR antagonists (44, 45), when they become available for human use.
|
Acknowledgments |
|---|
|
Footnotes |
|---|
Received February 11, 1997.
Revised May 2, 1997.
Accepted May 5, 1997.
|
References |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
This article has been cited by other articles:
 |
|
 |
|
  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]
|
|
|
|
 |
|
 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]
|
|
|
|
 |
|
 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]
|
|
|
|
|
|
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]
|
|
|
|
|
|
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]
|
|
|
|
|
|
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]
|
|
|
|
 |
|
 A. Lacroix, N. N'Diaye, J. Tremblay, and P. Hamet Ectopic and Abnormal Hormone Receptors in Adrenal Cushing's Syndrome Endocr. Rev., February 1, 2001; 22(1): 75 - 110. [Abstract] [Full Text]
|
|
|
|
|
|
H. Mircescu, J. Jilwan, N. N'Diaye, I. Bourdeau, J. Tremblay, P. Hamet, and A. Lacroix Are Ectopic or Abnormal Membrane Hormone Receptors Frequently Present in Adrenal Cushing's Syndrome? J. Clin. Endocrinol. Metab., October 1, 2000; 85(10): 3531 - 3536. [Abstract] [Full Text]
|
|
|
|
 |
|
 J. L. Doppman, G. P. Chrousos, D. A. Papanicolaou, C. A. Stratakis, H. R. Alexander, and L. K. Nieman Adrenocorticotropin-independent Macronodular Adrenal Hyperplasia: An Uncommon Cause of Primary Adrenal Hypercortisolism Radiology, September 1, 2000; 216(3): 797 - 802. [Abstract] [Full Text]
|
|
|
|
 |
|
 A. Lacroix, P. Hamet, and J.-M. Boutin Leuprolide Acetate Therapy in Luteinizing Hormone-Dependent Cushing's Syndrome N. Engl. J. Med., November 18, 1999; 341(21): 1577 - 1581. [Full Text] [PDF]
|
|
|
|
|
|
N. N’Diaye, P. Hamet, J. Tremblay, J.-M. Boutin, L. Gaboury, and A. Lacroix Asynchronous Development of Bilateral Nodular Adrenal Hyperplasia in Gastric Inhibitory Polypeptide-Dependent Cushing's Syndrome J. Clin. Endocrinol. Metab., August 1, 1999; 84(8): 2616 - 2622. [Abstract] [Full Text]
|
|
|
|
|
|
E. Grazzini, C. Breton, S. Derick, M. Andres, D. Raufaste, F. Rickwaert, G. Boccara, P. Colson, N. C. Guérineau, C. Serradeil-Le Gal, et al. Vasopressin Receptors in Human Adrenal Medulla and Pheochromocytoma J. Clin. Endocrinol. Metab., June 1, 1999; 84(6): 2195 - 2203. [Abstract] [Full Text]
|
|
|
|
 |
|
 S. R. Bornstein, C. A. Stratakis, and G. P. Chrousos Adrenocortical Tumors: Recent Advances in Basic Concepts and Clinical Management Ann Intern Med, May 4, 1999; 130(9): 759 - 771. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. R. Bornstein and G. P. Chrousos Adrenocorticotropin (ACTH)- and Non-ACTH-Mediated Regulation of the Adrenal Cortex: Neural and Immune Inputs J. Clin. Endocrinol. Metab., May 1, 1999; 84(5): 1729 - 1736. [Full Text]
|
|
|
|
|
|
C. A. Stratakis, J. A. Carney, L. S. Kirschner, H. S. Willenberg, S. Brauer, M. Ehrhart-Bornstein, and S. R. Bornstein Synaptophysin Immunoreactivity in Primary Pigmented Nodular Adrenocortical Disease: Neuroendocrine Properties of Tumors Associated with Carney Complex J. Clin. Endocrinol. Metab., March 1, 1999; 84(3): 1122 - 1128. [Abstract] [Full Text]
|
|
|
|
|
|
A. Lacroix Five-Year Experience with Laparoscopic Adrenalectomy at Hotel-Dieu in Montreal: Endocrinologist's Perspective J. Clin. Endocrinol. Metab., September 1, 1998; 83(9): 3043 - 3046. [Full Text]
|
|
|
|
|
|
O. Chabre, P. Liakos, J. Vivier, P. Chaffanjon, F. Labat-Moleur, M. Martinie, S. P. Bottari, I. Bachelot, E. M. Chambaz, G. Defaye, et al. Cushing's Syndrome due to a Gastric Inhibitory Polypeptide-Dependent Adrenal Adenoma: Insights into Hormonal Control of Adrenocortical Tumorigenesis J. Clin. Endocrinol. Metab., September 1, 1998; 83(9): 3134 - 3143. [Abstract] [Full Text]
|
|
) was
ambulating or sitting until 2200 h, was supine until 2330 h,
and was upright at the 2400-h time point. Other patients were a woman
with a pheochromocytoma (
), a woman with normal pituitary adrenal
function 2 yr after removal of a pituitary ACTH-secreting adenoma
(
), and a woman with mild cyclic Cushing’s disease (•); the
shaded area indicates the range of cortisol values in
seven normal individuals during the iv dexamethasone test, performed
without the vasopressin stimulation. 9D2 and 9D3: 0900 h on days 2
and 3, after dexamethasone infusion.
