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Division of Endocrinology, Department of Medicine, Research Center, Hôtel-Dieu du Centre Hospitalier de l’Université de Montréal, Montréal, Canada H2W 1T8
Address correspondence and requests for reprints to: André Lacroix, M.D., Division of Endocrinology, Research Center, Hôtel-Dieu du Centre Hospitalier de l’Université de Montréal, 3850 Saint-Urbain Street, Montréal, Québec, Canada H2W 1T8. E-mail: andre.lacroix{at}umontreal.ca
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Abstract |
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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regulatory subunit on chromosome 17 (4). In
McCune-Albright’s syndrome, an activating mutation of - subunit of
stimulatory protein G leads to constitutive steroidogenesis in the
affected adrenal nodules (5). Until recently, the regulatory mechanisms of cortisol synthesis in ACTH-independent Cushing’s syndrome were not well understood. Several groups have now shown that the previously believed autonomous cortisol-secreting adrenal tumors may actually be under the control of ectopic (also termed aberrant, illicit) or abnormal hormone receptors. The initial in vitro studies of Ney et al. (6, 7) suggested the presence of ectopic receptors for epinephrine, norepinephrine, TSH, LH, and FSH in some adrenocortical tumors. Subsequent in vitro studies of human adrenocortical benign and malignant tumors have supported a functional relationship between steroidogenesis and various hormone receptors, mostly members of the G-protein-linked superfamily (8, 9, 10, 11, 12, 13, 14). However, it remained unclear whether these ectopic receptors were functional and responsible for Cushing’s or other clinical syndromes. This hypothesis found an in vivo clinical significance following the description of three cases of food- or gastric inhibitory polypeptide (GIP)-dependent Cushing’s syndrome in patients with either unilateral adenomas or bilateral macronodular adrenal hyperplasia (15, 16, 17); this new etiology resulted from the ectopic expression of nonmutated GIP receptor in the abnormal adrenal tissues (18, 19, 20, 21, 22, 23). This finding raised the hypothesis that a diversity of other hormone receptors could be expressed and regulate cortisol secretion abnormally in other cases of adrenal Cushing’s syndrome. This has now been supported by several reports of increased ACTH-independent cortisol secretion after stimulation by vasopressin in patients with unilateral adenomas, carcinomas, or bilateral macronodular adrenal hyperplasia (24, 25, 26, 27, 28); the V1-vasopressin receptor probably mediates this effect. In two other patients with bilateral macronodular adrenal hyperplasia and Cushing’s syndrome, cortisol secretion was found to be regulated by the ectopic adrenocortical expression of ß-adrenergic receptor (ß-AR) in one case (29) and a combination of LH/human (h)CG and 5-HT4 receptors in another case (30).
Despite these case reports indicating the abnormal presence or function of hormone receptors in adrenal Cushing’s syndrome, the precise prevalence and diversity of this pathophysiology remains unknown. It is important to determine whether this pathophysiology is frequently implicated in adrenal Cushing’s syndrome, because it could lead to major changes in the investigation and therapy of this disease. In this article, we wish to report the experience of our center, where 20 consecutive patients with adrenal Cushing’s syndrome were investigated in vivo with a protocol designed to identify the presence of abnormal adrenocortical hormone receptors.
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Subjects and Methods |
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After the study of the first patient with GIP-dependent
Cushing’s syndrome (16), 19 consecutive patients with adrenal
Cushing’s syndrome have been investigated between March 1993 and
December 1999. The diagnosis was confirmed after demonstration of
elevated daily urinary free cortisol, nonsuppressibility of plasma
cortisol during iv dexamethasone testing (16, 26, 29), and suppressed
plasma ACTH (both basally and after administration of 1 µg/kg of
ovine CRH). Abdominal computed tomography scans showed unilateral or
bilateral lesions in all patients. The characteristics of the study
population are presented in Table 1
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There were 6 patients with bilateral ACTH-independent macronodular
adrenal hyperplasia (AIMAH), 13 patients with unilateral
cortisol-secreting adenomas, and 1 patient with adrenocortical
carcinoma. Pathological confirmation could not be obtained for patients
6 and 8, because they have been treated medically. Detailed case
reports have been published for patients 1 (16), 2 (26), 3 (29), 5
(23), and 6 (30).
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The investigation protocol has been described previously (31); it was conducted over a 3-day period, after discontinuing potential interfering medications at least 1 week before the studies. It was approved by the institutional review committee, and informed written consent was obtained from all patients. The strategy consists of inducing transient modulation of ligands for potentially abnormal adrenocortical receptors and monitoring the steroidogenic responses. On day 1, a supine-to-upright posture test evaluated the potential modulation by angiotensin-II, vasopressin, catecholamines, endothelin, or atrial natriuretic peptide. This was followed by a standard mixed meal, assessing the presence of abnormal adrenal receptors for gastrointestinal hormones. Subsequent iv injection of 250 µg ACTH 1–24 provided a reference for the adrenal steroidogenic response. On the second day, administration of 100 µg GnRH iv was used to evaluate for potential modulation of cortisol by FSH, LH, or GnRH. A bolus injection of 200 µg TRH iv assessed the adrenal presence of TSH, PRL, or TRH receptors. Possible steroidogenic responses to 1 mg glucagon iv, 10 IU arginine-vasopressin (AVP) im, and 10 mg cisapride, a serotonin 5HT4 receptor agonist, orally, were evaluated sequentially on the third day. To interpret the response to the above tests, we chose to express plasma cortisol concentrations, at the peak or nadir time point during the various tests, as percentages of the basal levels. A change in plasma cortisol less than 25% from baseline (100%) was arbitrarily defined as no response; a 25–49% change, as a partial response; and a change of 50% or greater, as a positive response. The test was repeated, if a partial or a positive cortisol response was observed, to ensure consistency of the response. If any of the screening tests yielded positive results, further evaluations were undertaken to identify the receptor involved, as described previously (23, 26, 29, 30, 31).
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Results |
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In all six patients with AIMAH, the investigation protocol
detected the presence of abnormal adrenal hormone receptors (Table 2). As expected, the administration of
ACTH 1–24 resulted in a large increase of plasma cortisol in all
patients with AIMAH (454 ± 248%, mean ± 1 SD).
None of the patients with AIMAH had plasma cortisol increases after the
administration of TRH or glucagon. In two patients with AIMAH (patients
1 and 5), plasma cortisol levels increased 398 and 236% after the
mixed meal. They had no abnormal responses to the other stimulation
tests, and GIP-dependent Cushing’s syndrome was confirmed in both,
based on stimulation of cortisol secretion during in vivo
infusion of GIP and demonstration of GIP receptor overexpression in
adrenal hyperplasia tissues (16, 19, 23).
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In patient 3, plasma cortisol increased 177% after upright posture (165% and 157% in repeat tests) and only partially after AVP administration. Stimulation of cortisol secretion after insulin-induced hypoglycemia, isoproterenol infusion, and correction of hypercortisolism with propranolol suggested the presence of ectopic ß-adrenergic receptors in this patient’s adrenal tissues (29). Confirmation was obtained by in vitro binding studies and stimulation of adenylyl cyclase activity after incubation of the patient’s adrenal membranes with isoproterenol, whereas this was not found in normal adrenal tissue. The stimulation of cortisol secretion during upright posture could not be abolished by a V1-vasopressin receptor antagonist (SR 49059), and modulation of endogenous vasopressin levels by water load and hypertonic saline did not modify plasma cortisol levels (29); the V1-vasopressin receptor messenger RNA could not be detected in this patient’s adrenal tissues (unpublished). This suggests that the partial cortisol response to exogenous pharmacological levels of vasopressin was mediated by AVP-induced catecholamine release.
Interestingly, some patients had mixed abnormal responses related
to the inappropriate adrenal expression of more than one receptor.
Plasma cortisol levels in patient 4 were stimulated both by increases
of catecholamines (upright posture, insulin-induced hypoglycemia, and
isoproterenol) and of vasopressin (upright posture, pharmacological
doses of AVP, and modulation of endogenous vasopressin with water load
and hypertonic saline). Plasma cortisol levels increased from 374 to
925 nmol/L, 60 min after AVP administration, and from 355 to 599 nmol/L
after 2-h of upright posture (Table 2
). Administration of 2.5 µg sc
of desmopressin, a preferential V2-vasopressin
receptor agonist, did not modify the plasma cortisol levels, suggesting
that the receptor involved is a V1- or
V3-vasopressin receptor. Plasma cortisol levels
declined from 337 to 257 nmol/L (24% decrease) during a 20-cc/kg water
loading test (Fig. 1), whereas plasma
vasopressin levels remained below the limit of detection (<0.5 pg/mL).
The infusion of 3% hypertonic saline increased serum sodium from 138
to 150 mmol/L, plasma vasopressin from <0.5 to 0.74 pg/mL, and plasma
cortisol from 257 to 442 nmol/L (172% increase). The role of
catecholamines, suggested by the positive response to posture, was
further assessed by insulin-induced hypoglycemia, which increased
plasma cortisol from 363 to 989 nmol/L, whereas ACTH remained
suppressed. Plasma cortisol also increased from 323 to 630 nmol/L
during a 30-min infusion of isoproterenol and returned rapidly to
baseline when the infusion was discontinued (Fig. 2). Pretreatment of
the patient, with the angiotensin receptor type-1 antagonist losartan,
administered at the dose of 100 mg, 12- and 2-h before upright posture,
did not prevent the elevation of plasma cortisol from 427 to 646 nmol/L
during a 2-h period of ambulation. There were no positive responses to
the mixed meal, GnRH, TRH, glucagon, or cisapride. It was
concluded that the cortisol secretion was mediated by the abnormal
presence and function of ß-adrenergic and
V1-vasopressin receptors, and medical therapy
with the ß-blocker propranolol (Inderal, Wyeth-Ayerst Laboratories, Inc., Montreal, Québec, Canada) was proposed
to the patient. Propranolol was progressively increased to 60 mg
orally, four times daily, over a 3-week period, under supervision of
her referring physician in Seattle, WA. Treatment was discontinued
because of the appearance of fatigue and dyspnea on exertion. The
patient elected to undergo surgical therapy before further monitoring
of free urinary cortisol levels. Unfortunately, the adrenal tissues
were not available for in vitro studies.
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Abnormal hormone receptors in Cushing’s syndrome secondary to unilateral adenomas or carcinomas
In the group of 13 patients with adenomas, plasma cortisol
responses to the screening tests were observed less frequently (Fig. 3). Upright posture increased plasma cortisol (155%) in 1 patient and
partially (126%) in a second one. The mixed meal induced an 136%
increase of plasma cortisol in 1 of 12 patients, whereas AVP increased
cortisol levels 128% in 1 of 12 patients tested. There were no
responses after stimulation with GnRH, TRH, glucagon, or
cisapride. In contrast, a significant cortisol increase
(216 ± 75%, mean ± SD) was observed in 12 of
13 patients after administration of ACTH 1–24, indicating the presence
of ACTH receptors in their tumors. In view of the limited aberrant
responses in patients with adenoma, no further characterizations were
done before surgery.
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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In the patients with unilateral cortisol-secreting adrenal adenoma or carcinoma, a lower prevalence (3 out of 14) of abnormal hormone receptors expression or function was identified in this relatively small series. However, previous studies have clearly demonstrated the abnormal presence and function of hormone receptors in unilateral adrenal cortisol-secreting adenomas or carcinomas in up to 27% of patients for vasopressin (24, 28) and in an undefined percentage of patients for GIP (15, 18, 20, 21, 22) or catecholamines (11, 12). In addition, our investigation protocol may have missed the presence of ectopic receptors for factors such as interleukin-1 (14), leptin (34), and many other G-protein-coupled membrane receptors not assessed specifically (such as PTH, calcitonin, or PGs). Larger series of patients investigated in several centers will be necessary to define more precisely the true prevalence and diversity of this pathophysiology.
Most patients with unilateral adrenal adenomas have retained the
presence of ACTH receptors in their tumors. Those with AIMAH displayed
exaggerated responses to ACTH 1–24, as compared with the patients with
adrenal adenomas, which is probably related to the larger tissue mass
seen in AIMAH (Table 1). The search for activating mutations of the
ACTH receptor in cortisol-secreting adrenal tumors or hyperplasias has
been unsuccessful to date (35, 36).
The majority of ectopic or abnormal hormone receptors in adrenocortical tumors or hyperplasia (6, 7, 8, 9, 10, 11, 12, 13, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30) belong to the G-protein-coupled receptor superfamily. We hypothesize that ectopic expression of any adenylyl-cyclase-coupled receptor could induce the stimulation of adrenal cells by trophic factors lacking regulatory negative feedback. This stimulus may lead to increased function and possibly confer a proliferative advantage. GIP has been shown to stimulate the production of cAMP and thymidine incorporation in GIP-dependent cortisol-secreting adenoma cells, in a manner similar to ACTH (20). Hormone-stimulated LH/CG receptors can induce adrenocortical cell hyperplasia and Cushing’s syndrome when expressed ectopically in the adrenal cortex of mice transgenic for the pituitary production of a chimeric bovine LHß/carboxy terminal of hCGß (37).
Because V1-AVPR and 5-HT4 receptor are present in the normal adrenal cortex and modulate modest effects of vasopressin and serotonin on steroidogenesis (38, 39), the exaggerated steroidogenic responses to vasopressin in these patients would be secondary to the abnormal function of an eutopic receptor-effector system, rather than to the presence of an ectopic receptor. The demonstration of an exaggerated cortisol response to pharmacological levels of exogenous vasopressin does not constitute direct evidence that fluctuations of AVP endogenous levels are the main regulator of steroidogenesis in these patients. This was illustrated in patient 3 with AIMAH, who increased plasma cortisol in response to exogenous AVP but not to modulations of endogenous vasopressin (29). In fact, this patient was found to have ectopic ß-adrenergic receptors in his adrenal tissues. It is believed that pharmacological AVP levels stimulated catecholamine release, including from the adrenal medulla (40), and then mediated cortisol release. The response of plasma cortisol levels, in patient 4, to water load and hypertonic saline represents the first demonstration of parallel fluctuations in plasma cortisol levels with small physiological changes in endogenous vasopressin levels. All previously reported cases of cortisol stimulation by lysine-vasopressin (24, 25, 27, 28) or AVP (26) were related to exogenous pharmacological amounts. In this patient, as in patient 2 (26), plasma levels of vasopressin were found to be undetectable basally and showed only a very modest increase upon potent physiological stimulation. This may be attributable to the suppressive effects of cortisol on vasopressin gene expression (41). It has also been postulated that an abnormal V1-vasopressin receptor may modify vasopressin production via a short loop mechanism in the hypothalamus (26).
The molecular mechanisms responsible for the ectopic adrenal expression of hormone receptors or for the abnormal response of the eutopic V1-AVPR and 5-HT4 receptor or their effectors are still unknown. A plausible explanation for the overexpression of a single receptor could be a mutation in its promoter, leading to increased expression. In contrast, when several abnormal adrenal receptors are present, a mutation in a factor regulating cell differentiation may be more likely. The diffuse and bilateral adrenal hyperplasia seen in AIMAH suggests a putative mutation in early embryogenesis, whereas later somatic mutations of a single cell would be responsible for unique adenomas.
The presence of abnormal receptors in cortisol-secreting hyperplasias or tumors can lead to innovative pharmacological therapies as alternatives to adrenalectomy. These approaches may include suppression of the ligands or the use of specific receptor antagonists. Short-term improvement of hypercortisolism was achieved with triiodothyronine treatment in a TSH-dependent cortisol-secreting adrenal adenoma (7) and by the use of octreotide in GIP-dependent Cushing’s syndrome (17, 18). Long-term control has also been obtained, in patient 3, by blockade of ectopic ß-adrenergic receptor with propranolol (29) and by inhibition of LH secretion with leuprolide acetate, in patient 6 (with LH/hCG-dependent adrenal Cushing’s) (30).
The testing procedure used in our study is not part of the approved labeling of the compounds and should be conducted as research protocols. There were no significant side effects observed in this study. The entire screening protocol can be easily performed in an ambulatory setting, rendering it accessible to most centers.
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Acknowledgments |
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Footnotes |
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Received January 10, 1999.
Revised June 23, 2000.
Accepted June 29, 2000.
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regulatory subunit in patients with the Carney complex. Nat Genet. 26:89–92.[CrossRef][Medline]
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