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Division of Endocrinology, Department of Medicine, Research Center, Hôtel-Dieu and Hôpital Saint-Luc du Centre Hospitalier de l’Université de Montréal, Montréal, Canada H2W 1T8
Address all 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, 3840 Saint-Urbain Street, Montréal, Québec, Canada H2W 1T8.
Abstract
Cortisol secretion in adrenal Cushing’s syndrome can be regulated by the aberrant adrenal expression of receptors for gastric inhibitory polypeptide, vasopressin, catecholamines, LH/human CG (LH/hCG), or serotonin.
Four patients with incidentally discovered bilateral macronodular adrenal hyperplasia without clinical Cushing’s syndrome were evaluated for the possible presence of aberrant adrenocortical hormone receptors. Urinary free cortisol levels were within normal limits, but plasma cortisol levels were slightly elevated at nighttime and suppressed incompletely after dexamethasone administration. Plasma ACTH was partially suppressed basally but increased after administration of ovine CRH.
A 51-yr-old woman had ACTH-independent increases of plasma cortisol after 10 IU AVP im (292%), 100 µg GnRH iv (184%), or 10 mg cisapride orally (310%); cortisol also increased after administration of NaCl (3%), hCG, human LH, and metoclopramide. In a 61-yr-old man, cortisol was increased by AVP (349%), GnRH (155%), hCG (252%), and metoclopramide (191%). Another 53-yr-old male increased plasma cortisol after AVP (171%) and cisapride (142%). Cortisol secretion was also stimulated by vasopressin in a 54-yr-old female.
This study demonstrates that subclinical secretion of cortisol can be regulated via the aberrant function of at least V1-vasopressin, LH/hCG, or 5-HT4 receptors in incidentally identified bilateral macronodular adrenal hyperplasia.
THE REGULATION OF cortisol secretion in patients with adrenal Cushing’s syndrome, secondary either to ACTH-independent bilateral macronodular adrenal hyperplasia (AIMAH) or unilateral adenoma, can be mediated by the aberrant adrenocortical presence and function of membrane receptors for GIP (1, 2, 3, 4, 5, 6), vasopressin (1, 7, 8, 9, 10, 11), catecholamines (11, 12), IL-I (13), leptin (14), LH/human CG (LH/hCG) (15), or serotonin (15). In a recent study of 20 patients with adrenal Cushing’s syndrome, the presence of aberrant membrane hormone receptors was found to be more prevalent in AIMAH than in adenomas (11). We hypothesized that a similar pathophysiology may also be present in subclinical AIMAH.
We report here the study of four consecutive patients, evaluated for bilateral adrenal incidentalomas, in whom we demonstrated the presence of subclinical Cushing’s syndrome and identified that cortisol secretion was regulated by at least one or several aberrant membrane hormone receptors.
Subjects and Methods
Patients
The four patients were referred for bilateral macronodular adrenal hyperplasia, identified incidentally by an abdominal ultrasound. Patient 1, a 51-yr-old woman, reported hirsutism since adolescence, high blood pressure, and weight gain of 18 kg during the last 5 yr. She had four uncomplicated pregnancies without any manifestation of transient Cushing’s syndrome. Her menses had stopped 6 months previously. There was no family history of adrenal disease. An abdominal computed tomography (CT) scan revealed bilateral macronodular adrenal hyperplasia with one large nodule on each gland, which measured 4.4 cm x 3.1 cm on the right and 5.0 cm x 3.3 cm on the left.
Patient 2, a 61-yr-old man, was known for long-term alcohol dependence. On CT scan, multiple bilateral adrenal nodules were present. The right gland measured 3.2 x 6.1 cm; and the left, 7.3 x 4.0 cm. Patient 3, a 53-yr-old man, had suffered a myocardial infarction 4-yr previously, and high blood pressure identified at that time was well controlled under medication. His mother died at age 34, from an adrenal carcinoma confirmed by necropsy, but there was no other family history suggestive of genetic cancers or adrenal disease. Abdominal CT scan showed enlarged nodular adrenals, the right measuring 3.5 cm x 2.5 cm and the left 4.0 cm x 2.3 cm. Patient 4 was a 54-yr-old postmenopausal woman with a past medical history of recurrent superficial bladder carcinoma. An abdominal CT scan revealed the presence of two nodules (2 x 2 cm on the left adrenal, whereas the right adrenal measured 4.0 x 3.8 x 3.0 cm and included small calcifications).
None of the four patients presented any clinical signs of Cushing’s
syndrome, except for hirsutism in patient 1 (but without central
obesity, striae, or proximal muscle weakness). Bilateral adrenal uptake
was shown by scintigraphy with 131 I-6ß-iodomethylnorcholesterol
(NP-59) in the four patients. Further details on clinical
characteristics and initial endocrine investigations are summarized in
Table 1
.
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The protocol used has been described previously (1, 16). The strategy is based on monitoring plasma levels of steroids at 30–60 min intervals for 2–3 h during tests that transiently modulate the levels of ligands for potentially aberrant receptors. Initial screening includes a posture test performed in a 2-h supine position, followed by a 2-h ambulatory period (to evaluate potential modulation by angiotensin-II, vasopressin, catecholamines, atrial natriuretic peptide, and others); this is followed by a standard mixed meal to evaluate the response to fluctuations of gastrointestinal hormones, and then by the administration of 250 µg ACTH 1–24 iv, which serves as a reference test. On another day, the administration of 100 µg GnRH iv (modulation by FSH, LH, GnRH) is followed by 200 µg TRH iv (modulation by TSH, PRL, TRH). Responses to 1 mg glucagon iv, 10 IU AVP im, and 10 mg cisapride or metoclopramide orally [serotonin 5-HT4 receptor (5-HT4R) agonists] are tested sequentially on the third day. A change of less than 25% of plasma cortisol is arbitrarily defined as no response; a 25–49% change, as a partial response; and a change of 50% or greater, as a positive response.
Because abnormal stimulations were found with the initial screening protocol, further tests were performed to characterize the type of receptor involved [including the response of plasma cortisol and other steroids to the sc administration of 2.5 µg desmopressin (DDAVP, a V2-vasopressin receptor agonist; Ferring Pharmaceuticals Ltd., North York, Ontario, Canada]. Modulation of endogenous levels of vasopressin and its effect on plasma cortisol levels was examined by the administration of a 20-cc/kg oral water load, followed 90 min later by an infusion of NaCl 3% at 0.1 cc/kg·min during 120 min, while maintaining the patient in supine posture. An insulin-induced hypoglycemia was performed by iv injection of 0.15 U/kg of regular insulin; isoproterenol was infused at the rate of 20 ng/kg·min, during 30 min, to determine the presence of ß-adrenergic receptors. After a positive response of cortisol to GnRH, further tests included the administration of 300 U recombinant human LH (hLH) (LHadi; Serono Laboratories, Inc., Oakville, Ontario, Canada) iv, the im administration of 10,000 IU hCG (A.P.L.; Wyeth-Ayerst Laboratories, Inc., Montréal, Québec, Canada), or 300 IU purified urinary human FSH (Fertinorm HP; Serono Laboratories, Inc., Oakville, Ontario).
The institutional ethics committee approved the study, and written informed consent was obtained from all subjects.
Assays
Plasma and urinary cortisol, plasma estradiol, FSH, LH, and PRL were measured by immunofluorometric assay (Immuno I system; Bayer Corp., Tarrytown, NY); ACTH, by immunoradiometric assay (Allegro; Nichols Institute Diagnostics, San Juan Capistrano, CA); and other steroid or peptide hormones and renin, by commercial RIA kits.
Results
Initial endocrine evaluation
Despite the normal urinary free cortisol levels (except for one
value in patient 4), subtle abnormalities were found in the diurnal
plasma cortisol cycles in the four patients (Table 1
); their sleeping
plasma cortisol levels at night were slightly elevated (Table 1).
Plasma cortisol decreased only partially after oral 1-mg overnight
(Table 1), or iv 4-mg dexamethasone suppression tests (infusion of 1
mg/h from 1100 h to 1500 h), reaching respective nadirs of
280, 284, 151, and 168 nM at 0900 h on the following
morning [normals, <76 nM (17, 18)]. Plasma
ACTH levels tended to be partially suppressed basally, but plasma ACTH
and cortisol increased normally after iv administration of 1 µg/kg
ovine CRH (oCRH) in patients 1, 3, and 4 but not in patient 2 (Table 1). The administration of 250 µg 1,24-ACTH iv produced large
increases in plasma cortisol (7.5-, 15.1-, 7.0-, and 5.8-fold,
respectively); it also produced 3.6-, 14.9-, 5.3-, and 7.6-fold
increases in plasma aldosterone and larger increases in plasma
17-OH-progesterone concentrations (Table 1).
In vivo evaluation for the presence of aberrant adrenal hormone receptors
In patient 1, there were positive increases in plasma cortisol
after cisapride, vasopressin, and GnRH tests (Table 2). A partial response to the initial
upright posture (Table 2) was repeated twice, with similar results (127
and 123%). There were no changes in plasma cortisol after ingestion of
a mixed meal or administration of TRH or glucagon. Because plasma ACTH
was not completely suppressed, vasopressin administration was performed
3 h after initiation of infusion of dexamethasone (1 mg/h during
4 h); plasma cortisol levels increased from 204 to 596
nM (Fig. 1A), whereas plasma
ACTH did not increase (0.9 to 0.7 pM). The administration
of 2.5 µg desmopressin sc was without effects on plasma cortisol.
Endogenous vasopressin levels were modulated by a 20-cc/kg water load,
followed by an infusion of 3% NaCl; the water load suppressed serum
sodium from 143 to 137 mM and plasma vasopressin to
undetectable levels, and this resulted in a progressive decline of
plasma cortisol from 241 to 200 nM. The infusion of NaCl
(3%) increased plasma sodium to 152 mM and plasma
vasopressin to 18.2 pg/ml (normal basal levels, 0.5–3.5 pg/ml), and
this was followed by an increase of plasma cortisol to 335
nM (Fig. 2), whereas plasma
ACTH levels remained stable (1.2 pM basally and 1.4
pM at 240 min). During an insulin-induced hypoglycemia,
plasma cortisol levels increased from 166 to 969 nM and
ACTH from 1.1 to 18.0 pM. An infusion of 20 ng/kg·min
isoproterenol, during 30 min, did not produce any changes in plasma
cortisol (not shown). Because cisapride had stimulated
cortisol secretion (Table 2 and Fig. 1A), 10 mg metoclopramide (another
5-HT4 receptor agonist) was administered orally,
and it also increased plasma cortisol levels (145%, Fig. 1A).
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and Fig. 1A), as plasma FSH increased from 52
to 80 U/L, and LH from 26 to 116 U/L. We thus investigated whether the
secretion of cortisol was modulated by fluctuations in LH, FSH, or GnRH
itself. There was no variation of cortisol levels after administration
of purified FSH. However, plasma cortisol increased 1.5-fold after im
administration of 10,000 IU hCG, and from 174 to 378 nM 45
min after iv injection of recombinant hLH (Fig. 1A). The hLH injection
also increased plasma levels of aldosterone from 83 to 301
pM, of 17-OH-progesterone from 1.7 to 9.5 nM,
and of androstenedione from 7.5 to 13.6 nM; but it did not
modify plasma levels of estradiol, testosterone, DHEAS, or ACTH (0.9
pM). After this investigation, patient 1 received injections of a long-acting form of leuprolide acetate (3.75 mg im every 4 wk); this resulted in a transient elevation of plasma FSH and LH levels during 12 h, without increases in urinary free cortisol levels. The GnRH stimulation tests were repeated, 4 and 8 wk later, and no longer produced increases in plasma cortisol levels, as FSH and LH were now both suppressed. The patient was treated with leuprolide acetate and estrogen/progesterone replacement therapy during 1 yr and maintains monthly urinary free cortisol levels between 123–283 nmol/d. Plasma androgens have improved to levels of 17-OH-progesterone (4.2 nM), DHEAS (3.2 µM), free testosterone (13.8 pM), but without significant changes in hirsutism, weight, or size of adrenals on repeat CT scan. PRL levels have normalized to 5 µg/L.
In patient 2, there were also significant increases in plasma cortisol
after 10 mg metoclopramide orally (191%). There was a borderline
partial response to the upright posture (121%). Vasopressin
administration, performed under dexamethasone infusion, increased
plasma cortisol levels from 134 to 467 nM; whereas plasma
ACTH remained under 1 pM. The sc administration of 2.5 µg
desmopressin and a water load were without effect. (Fig. 1B). Plasma
cortisol increased after GnRH administration (155%), as plasma FSH
increased from 13.5 to 20.8 U/L and LH from 5.4 to 27.5 U/L. The
secretion of cortisol increased after im administration of 10,000 IU
hCG (252%). The patient deferred hLH stimulation and other tests.
The initial in vivo evaluation of patient 3 demonstrated
positive responses to upright posture and vasopressin administration,
and a partial response to cisapride (Table 2); other
screening tests were without effect. Plasma cortisol increased from 274
to 589 nM during upright posture but was
accompanied by a small increase of ACTH (from 1.1 to 3.1
pM). When the upright posture test was repeated,
under dexamethasone infusion, plasma cortisol did not increase but
failed to suppress normally despite undetectable ACTH levels. The
posture test was repeated after resuming his 100 mg metroprolol daily,
and the increase in plasma cortisol was 1.6-fold, compared with
2.1-fold without the ß-blocker. The administration of vasopressin did
increase plasma cortisol despite the fact that ACTH was completely
suppressed by the dexamethasone (Fig. 1C). Desmopressin administration
did not induce any increase in plasma cortisol. Endogenous levels of
vasopressin were suppressed by a water load, and cortisol levels
decreased from 241 to 160 nM; infusion of NaCl
3% did not result in any increase of cortisol, but plasma vasopressin
concentrations increased from less than 0.25 to only 1.2 pg/ml. The
initial partial response to cisapride in patient 2 (Table 2) was repeated on another occasion and resulted in a larger 3.3-fold
stimulation of plasma cortisol, of 5.4-fold of aldosterone, and
1.8-fold of androstenedione; whereas there was no change in DHEAS
levels. The metoclopramide stimulation also produced a 3-fold increase
in plasma cortisol levels and an 8.8-fold increase in aldosterone
(Fig. 1C).
In patient 4, there were no responses to upright posture, mixed meal,
TRH, GnRH, glucagon, and cisapride tests. Plasma cortisol
increased 2.1-fold, after vasopressin injection, despite suppression of
ACTH under dexamethasone infusion. Plasma aldosterone levels increased
from 116 to 1232 pM, but there were no changes in
others steroids. Administration of desmopressin did not result in any
stimulation of cortisol (Fig. 1C). Urinary free cortisol levels and the
clinical course have remained stable in the last 12 months follow-up
period of patients 3 and 4. However, in patient 4, a repeat vasopressin
stimulation test, under dexamethasone infusion, produced a 3.1-fold
increase in plasma cortisol, compared with a 2.1-fold increase 12
months previously.
Discussion
As in patients with unilateral adrenal incidentalomas, where subclinical cortisol secretion is now frequently recognized (19, 20), patients with bilateral adrenal hyperplasia discovered incidentally may also be detected at a stage of subclinical Cushing’s syndrome. This was the case in the four patients reported here, because they had normal urinary free cortisol levels and only partially suppressed ACTH levels basally; a variable proportion of cortisol secretion was not ACTH-dependent, as shown by the incomplete suppression after dexamethasone tests. In all patients, plasma cortisol levels were also above the normal level of 50 nM when sampled shortly after onset of sleep (21). Despite the fact that urinary free cortisol levels were within the normal range, and that there were no overt clinical signs of Cushing’s syndrome, the presence of hypertension, hirsutism, and osteoporosis suggests that the patients had been exposed to supraphysiological amounts of glucocorticoids and other adrenal steroids. Patients previously described as presenting preclinical Cushing’s syndrome with bilateral macronodular adrenal hyperplasia did have high urinary free cortisol levels, probably placing them in the Cushing’s syndrome category with mild manifestations (22, 23, 24). AIMAH is a rare distinct subtype of adrenal Cushing’s syndrome (25, 26, 27), where cortisol oversecretion can be relatively modest, when taking into account the very large size of abnormal adrenal tissues. Despite affecting both adrenal glands, AIMAH usually occurs in a sporadic form; the familial transmission has been reported only rarely (28, 29, 30). There was no family history of AIMAH in our patients, but there was an intriguing history of adrenal carcinoma in the mother of patient 3.
Until recently, the mechanisms regulating cortisol secretion in
ACTH-independent Cushing’s syndrome were not well understood. Several
groups have now shown that the previously believed autonomous
cortisol-secreting adrenal tumors or hyperplasias may actually be under
the control of a diversity of aberrant hormone receptors, such as those
for GIP, ß-adrenergic, LH/hCG, V1-vasopressin, or
5-HT4 agonists (1). We now
demonstrate, for the first time, that aberrant cortisol regulation can
also occur in subclinical AIMAH. At least one aberrant response was
found in all four cases, but more than one were found in three of the
four patients. Thus, in patients 1 and 2, the initial investigation
indicated the abnormal ACTH-independent secretion of cortisol in
response to cisapride and/or metoclopramide
(5-HT4 receptor agonists), exogenous vasopressin,
and GnRH. Further investigations confirmed that cortisol secretion was
regulated by physiological fluctuations of endogenous vasopressin
levels in patient 1 (Fig. 2); despite several reports of aberrant
responses to the exogenous supraphysiological administration of lysine-
or arginine-vasopressin in adrenal Cushing’s syndrome (1, 7, 8, 9, 10, 11), very few investigations demonstrated that cortisol
secretion was regulated by physiological fluctuations of vasopressin
(11). Because desmopressin, a preferential V2-vasopressin
receptor agonist, was without effect, it is likely that the
V1-vasopressin receptor is implicated, as shown in previous studies
(8, 9, 10, 11). The responses to cisapride and/or
metoclopramide are both in agreement with the abnormal coupling of a
serotonin 5-HT4-receptor to cortisol secretion,
as recently reported in patients with AIMAH and clinical Cushing’s
syndrome (1, 15).
The increased secretion of cortisol after GnRH administration in the first two patients was most probably mediated by the aberrant adrenal expression of an LH/hCG receptor. Stimulation of cortisol secretion by hCG and recombinant hLH (but not by FSH) in patient 1 support this hypothesis; the lack of stimulation of cortisol secretion by GnRH, when LH levels were suppressed by chronic administration of leuprolide acetate, suggests that an adrenal GnRH receptor was not involved. A woman with Cushing’s syndrome secondary to AIMAH was recently reported to have abnormal coupling of LH/hCG receptor to cortisol production (15); in that case, transient Cushing’s syndrome was clinically present during each pregnancy, which was not reported here by our female patient. Interestingly, in the previously reported patient (15), overt clinical syndrome had become manifest only 10 yr after onset of menopause and chronic elevations of LH; the current patient still had normal periods until 6 months before this investigation.
Patient 3 increased cortisol level after cisapride, metoclopramide, and exogenous vasopressin, but not with desmopressin. This patient also increased plasma cortisol during the posture test, but this was an ACTH-dependent variation because the response disappeared when the test was done under dexamethasone suppression. In view of the previous occurrence of a myocardial infarction, we could not test here directly the possibility of ectopic ß-adrenergic receptors by using an insulin-induced hypoglycemia or isoproterenol infusion (11, 12). It remains possible that this patient’s adrenal expressed a V1-vasopressin receptor with an increased coupling to cortisol secretion; however, we cannot exclude the presence of an ectopic ß-adrenergic receptor. Patient 4 showed only a modest response in cortisol to exogenous vasopressin. She probably expresses V1-vasopressin receptor in her adrenal, which is stimulated by supraphysiological levels of vasopressin but not by small endogenous increases during upright posture. Because the aberrant response to exogenous vasopressin increased after 1 yr of follow-up, it will be interesting to follow this and the other patients to assess eventual progression to overt Cushing’s syndrome.
The four patients exhibited a large increase in 17-OH-progesterone after ACTH injection, with a peak value larger than 30 nM at 60 min, which is used as a criteria for late-onset 21-hydroxylase deficiency (31). A high incidence of adrenal incidentalomas is found in homozygous (82%) and in heterozygous (45%) patients with 21-hydroxylase-deficiency (32). Here, the nonsuppressibility of cortisol under dexamethasone suppression and the partially suppressed ACTH levels certainly argue against late onset 21-hydroxylase deficiency; acquired relative deficiency of this enzyme is also frequently present in adrenal tumors (19, 20).
The molecular mechanisms responsible for the aberrant expression of membrane receptors in AIMAH have not been identified yet (1). Several years are necessary before the phenotypic expression of the receptor becomes evident, and this may be secondary to the transient occupation of the receptor by the ligand, as illustrated by the cases of GIP- and LH-dependent Cushing’s syndrome. Because the size of adrenals was not much less in these patients with subclinical disease, compared with that previously described with clear hypercortisolism (1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15), it is also possible that poor steroidogenic enzyme activities or a better coupling of the illicit receptors to proliferative signals than to hormone synthesis could be present in subclinical adrenal lesions. Immunohistochemical studies of steroidogenic enzymes, in two men with AIMAH, revealed that 3ß-HSDII was expressed only in large clear cells; whereas CYP17 (P450C17) was seen only in small compact cells (33). Immunoreactivities for CYP11A1 (P-450scc), CYP21A2 (P-450c21), and CYP11B2 (P-450C11) were present in both cell types (34). Direct molecular studies in the adrenal tissues will be necessary to determine whether several aberrant receptors are present in the same cells or are present in different nodules.
The detection of abnormal receptors in cortisol-secreting hyperplasias or tumors can lead to pharmacological therapies as alternatives to adrenalectomy. These approaches may include suppression of the ligands or the use of specific receptor antagonists. Long-term control was obtained by blockade of ectopic ß-adrenergic receptor with propranolol (12) and by inhibition of LH secretion with leuprolide acetate in the LH/hCG-dependent adrenal Cushing’s syndrome (15). Based on the clinical presence of hirsutism and high blood pressure, we treated patient 1 with long-acting leuprolide acetate to inhibit the ligand occupation of at least one of her three abnormal receptors. After 1 yr of treatment, we noted improvement of blood pressure with reduction of antihypertensive medication, but there were no changes in hirsutism and adrenal size. The eventual availability of an orally active specific blocker of V1-vasopressin and 5-HT4 receptors will be of interest for the potential treatment of such patients.
This study demonstrates that subclinical abnormalities of secretion of cortisol and other steroids can be present in incidentally identified bilateral macronodular adrenal hyperplasia and are likely to be modulated by the abnormal adrenal expression of diversified hormone receptors, including those for V1-vasopressin, LH/hCG, or 5-HT4. It is thus recommended that the presence of these aberrant receptors be examined in vivo in all AIMAH patients with subclinical or clinical Cushing’s syndrome.
Acknowledgments
We thank the physicians who referred the patients; Marie-Thérèse Caron, R.N., for conducting the endocrine tests; and Victoria Baranga for assistance in the preparation of the manuscript.
Footnotes
This work was supported by Grant MT-13189 from the Canadian Institutes of Health Research. This work was presented in part at the 82nd Annual Meeting of The Endocrine Society, Toronto, Canada, June 2000.
Abbreviations: AIMAH, ACTH-independent bilateral macronodular adrenal hyperplasia; CT, computed tomography; 5-HT4R, 5-HT4 receptor; GIP, gastric inhibitory polypeptide; hCG, human CG; hLH, human LH; oCRH, ovine CRH.
Received November 2, 2000.
Accepted September 2, 2001.
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)
concentrations during an oral water load and an infusion of hypertonic
saline in patient 1 (with subclinical Cushing’s syndrome and bilateral
macronodular adrenal hyperplasia). An oral water load of 20 cc/kg was
administered between 0–45 min time points and was followed by an iv
infusion of 3% sodium chloride between 120–240 min time points. The
patient was in supine posture during 60 min before and during the
entire test.