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Original Studies |
Division of Endocrinology, Diabetology, and Metabolism, Department of Medicine, Institute of Pathology (F.M.), and the Department of Surgery (L.G.), University Hospital and Lausanne Medical School, 1011 Lausanne, Switzerland
Address all correspondence and requests for reprints to: François P. Pralong, M.D., Division of Endocrinology, BH 19707, Centre Hospitalier Universitaive Vaudois, 1011 Lausanne, Switzerland. E-mail: francois.pralong{at}chuv.hospvd.ch
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Abstract |
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These results demonstrate that as in previously described cases of food-dependent Cushing’s syndrome, GIP stimulated cortisol secretion from the adrenals of the patient reported here. Therefore, they indicate that such a paradoxical response probably represents the hallmark of this rare condition. In addition, they suggest that leptin, which normally inhibits stimulated cortisol secretion in humans, participated in cortisol hypersecretion in this case. Further studies in other cases of food-dependent Cushing’s syndrome, however, will be necessary to better ascertain the pathophysiological significance of this finding.
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Introduction |
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TopAbstractIntroductionCase ReportsMaterials and MethodsResultsDiscussionReferences |
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In the present study, we describe two patients with ACTH-independent Cushing’s syndrome and bilateral macronodular adrenal hyperplasia, the first one of the food-dependent type and the second with no evidence of food dependency. In the first patient, circulating GIP levels were found to correlate with food-stimulated cortisol secretion in vivo. Furthermore, GIP directly stimulated cortisol secretion from dispersed tumor adrenal cells obtained at surgery, confirming the existence of a paradoxical response to GIP in food-dependent Cushing’s syndrome (6, 9, 10). In addition to GIP, leptin was found to stimulate cortisol secretion by the same adrenal tumor cells, whereas no such in vitro effect of leptin was observed in cells obtained from the case with food-independent Cushing’s syndrome, in cells obtained from a cortisol-secreting solitary adrenal adenoma, or in normal human adrenocortical cells. Taken together, these results confirm the existence of a paradoxical response to GIP in food-dependent adrenal Cushing’s syndrome. Such a paradoxical response, therefore, seems to represent a hallmark of this pathophysiological condition. Moreover, they suggest that leptin, which inhibits cortisol secretion by normal human adrenocortical cells (12, 13), may have played an additional role to stimulate cortisol secretion in this particular case. However, the true pathophysiological significance of this in vitro effect of leptin remains to be elucidated.
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Case Reports |
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TopAbstractIntroductionCase ReportsMaterials and MethodsResultsDiscussionReferences |
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A 36-yr-old woman presented with a pathological fracture of the femoral neck. She had gained 14.7 kg of weight over the previous 3 yr and suffered from recent-onset hypertension. Physical findings included moon-like face, truncal obesity (weight, 86.7 kg; height, 161.5 cm; body mass index, 33.4), the presence of cervicodorsal fat pads, red striae over abdomen and thighs, multiple bruises, and high blood pressure (148/110 mm Hg). Investigations revealed marked osteopenia (L2–L4, 0.82 g/cm2, corresponding to a T score of -2.28 SD; femoral neck, 0.63 g/cm2, corresponding to a T score of -2.32 SD). Endocrine work-up confirmed the suspected diagnosis of Cushing’s syndrome, with elevated urinary free cortisol levels of 1673 and 1346 nmol/24 h on two separate occasions (normal, 28–220). While the patient was taking an estrogen-containing oral contraceptive agent, the morning fasting plasma cortisol was elevated at 988 nmol/L (normal, 200–700), and ACTH was undetectable (<3 ng/L), thus leading to the diagnosis of ACTH-independent Cushing’s syndrome. During an overnight dexamethasone suppression test (1 mg dexamethasone at 2300 h), plasma cortisol at 0800 h was 1211 nmol/L. The absence of a circadian rhythm was demonstrated by the stable values of plasma cortisol after meals of 892, 886, and 834 nmol/L at 000, 1200, and 1700 h, respectively, whereas ACTH was undetectable. An abdominal computed tomography scan revealed the presence of bilateral macronodular adrenal hyperplasia, and In111 octreotide scintigraphy showed marked abnormal diffuse accumulation in both hyperplastic glands.
The patient underwent bilateral adrenalectomy. The right and left
adrenal glands weighed 62.5 and 51.5 g and measured 7 x
5 x 2.5 and 8 x 4.5 x 2.8 cm, respectively. Cut
section revealed multiple yellowish, well delineated but
nonencapsulated, coalescent nodules measuring up to 5 and 1.3 cm in
maximal diameter in the right and left (Fig. 1A
) adrenals, respectively. On
microscopic examination, these nodules were composed predominantly of
large clear cells, which focally exhibited some degree of nuclear
atypia. Clusters of small clear cells as well as tiny foci of
nonpigmented large eosinophilic cells were found within or adjacent to
large clear cell nodules, with transition from one cell type to the
other. Mitotic figures and features of vascular invasion were not
observed. Hyperplastic clear cells occasionally formed pseudoglandular
spaces and also extended into periadrenal fat. The nonnodular
adrenocortical tissue was somewhat atrophic, mostly composed of
nonhyperplastic clear cells. The pathological findings were
consistent with bilateral macronodular adrenocortical hyperplasia.
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A 59-yr-old woman presented with recent onset hypertension, weight gain (10 kg over 1 yr), hirsutism, type 2 diabetes mellitus, and proximal leg weakness. Physical examination revealed truncal obesity (weight, 77 kg; height, 164 cm; body mass index, 28.6), cervicodorsal fat pads, generalized amyotrophia, multiple bruises but no red striae, and high blood pressure (170/120 mm Hg). Endocrine work-up confirmed the suspected diagnosis of Cushing’s syndrome, with elevated urinary free cortisol levels of 524 and 445 nmol/24 h on two separate occasions (normal, 28–220). Morning fasting plasma cortisol was elevated at 723 nmol/L, with undetectable ACTH, thus leading to the diagnosis of ACTH-independent Cushing’s syndrome. An abdominal computed tomography scan revealed bilateral macronodular adrenal hyperplasia.
The patient underwent bilateral adrenalectomy. The right and left
adrenals weighed 35 and 52 g and measured 5 x 6.5 x
1.5 and 7.5 x 5 x 2.3 cm, respectively. On section, both
glands contained multiple yellowish or brownish, well circumscribed,
nonencapsulated coalescent nodules measuring up to 2 cm (right side;
Fig. 1B
) and 2.5 cm (left side) in maximal diameter. Microscopically,
yellow nodules were predominantly composed of large clear cells admixed
with small clusters of either small clear cells or large eosinophilic
pigmented cells (Fig. 2A). Brownish
nodules, the largest measuring 1 cm in maximal diameter, were composed
of large eosinophilic cells with lipofuscin-laden cytoplasm. Nuclear
atypia was a frequent finding in those brownish nodules (Fig. 2B).
Mitoses and features of vascular invasion were not found. Bilateral
extracapsular extension of hyperplastic adrenocortical cells into
periadrenal adipose tissue was present. Pathological findings were
consistent with bilateral macronodular adrenocortical hyperplasia
(14).
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Materials and Methods |
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TopAbstractIntroductionCase ReportsMaterials and MethodsResultsDiscussionReferences |
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The responsiveness of cortisol secretion to food ingestion was assessed before adrenalectomy in both patients. After an overnight fast, an indwelling venous catheter was inserted into an antecubital vein. At 1200 h, the patients were given a standardized meal consisting of 29 g protein (25% of total energy intake), 18 g lipid (35% of total energy intake), and 47 g carbohydrate (40% of total energy intake). Total energy intake was 466 calories. Blood for plasma cortisol was drawn at 0, 30, 45, 60, 90, and 120 min after the start of the meal. In patient 2, who demonstrated a significant rise in plasma cortisol after meal ingestion, the study was repeated after acute blockade with octreotide (200 mg, sc, administered 1 h before the meal). In patient 2, who did not show any cortisol response to meal ingestion, cortisol secretion after an oral glucose tolerance test (100 g) was also evaluated.
In vitro studies
Cortisol secretion from human adrenal cells was studied in vitro. Adrenal glands were obtained after surgery from the two patients described above as well as from one patient with ACTH-independent Cushing’s syndrome resulting from a cortisol-secreting solitary adrenal adenoma. In addition, normal human adrenals were obtained from cadaveric kidney transplant donors.
Dispersion of adrenal cells was performed as previously described (13). Briefly, adrenals were minced with a scalpel blade and then subjected to combined enzymatic and mechanical dispersion; tissue fragments were placed in a Bellco flask (Bellco Glass, Inc., Vineland, NJ) to allow constant trituration and were incubated for 90 min at 37 C in the presence of collagenase type I (Sigma Chemical Co., St. Louis, MO), followed by neuraminidase type V (Sigma Chemical Co.). After complete dissociation of the tissue, cells were resuspended in medium containing 2.5% FCS and plated at a concentration of 106 cells/well in six-well plates pretreated with poly-D-lysine (Sigma Chemical Co.). Viability was assessed by trypan blue exclusion and ranged between 60–80%.
Cells were incubated for 48 hat 37 C in 95% O2-5% CO2. Medium was then changed to serum-free medium, and cells were stimulated for 90 min with 10-9 mol/L ACTH, 10-7 mol/L leptin, 10-9 and 10-8 mol/L GIP, 10-9 and 10-8 mol/L , glucagon-like polypeptide-1. Controls consisted of cells incubated in parallel for 90 min in serum-free medium. All conditions were tested in triplicate.
Hormone assays
Cortisol was measured by RIA in duplicate, using a commercially available kit (Coat-a-Count, Diagnostic Products, Los Angeles, CA). All samples from a single experiment were measured in duplicate in the same assay, and the intra- and interassay coefficients of variation ranged from 3–5.1% and 4–6.4%, respectively. Plasma leptin was measured by RIA, using a kit purchased from Linco Research, Inc. (St. Charles, MO). Intra- and interassay coefficients of variation were between 2.1–2.5% and 3.8–8.2%, respectively. Serum GIP was measured by RIA as previously described (15), using an antiserum generously provided by S. R. Bloom (London, UK) and commercially available peptide (Bachem, Torrance, CA). ACTH was measured by a chemiluminescent assay (Nichols Institute Diagnostics, San Juan Capistrano, CA).
Statistical analysis
The results are expressed as the mean ± SEM. Correlations between circulating GIP and cortisol levels were made by Pearson’s analysis. A stepwise, multiple regression analysis was also performed using a statistical program (JMP, SAS Institute, Inc., Cary, NC) running on a Compaq PC under Windows 95. Comparisons of in vitro results were made using nonparametric testing (van der Waerden test).
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Results |
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TopAbstractIntroductionCase ReportsMaterials and MethodsResultsDiscussionReferences |
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Basal and stimulated cortisol secretion in both patients is
summarized in Table 1. In patient 1,
morning fasting cortisol was elevated on repeated occasions, including
when the patient had discontinued oral estrogens for several weeks
(cortisol, 864 nmol/L), and there was also an abolition of the normal
diurnal rhythm. There was no ACTH or cortisol response to CRH in this
patient, but the adrenals were able to respond to further stimulation
with ACTH-(1–24) (Cosyntropin). In patient 2, morning fasting cortisol
secretion was also elevated on several occasions with an abolition of
the normal diurnal rhythm. There was no response to a standard ovine
CRH test, and neither an oral glucose tolerance test nor the
administration of a standardized meal resulted in cortisol
stimulation.
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: an elevated circulating
cortisol value of 886 nmol/L was further stimulated by meal ingestion
to a maximum of 1184 nmol/L, occurring 30 min after the start of
food intake (Fig. 3A). This increase in cortisol secretion paralleled
the expected stimulation of GIP secretion (16, 17) from 60 pmol/L at
baseline to 510 pmol/L at the time of peak cortisol secretion (30 min).
Circulating cortisol and GIP levels were highly significantly
correlated throughout the test (r2 = 0.5723;
P = 0.0044). After acute octreotide treatment (Fig. 3B), food-stimulated GIP secretion was completely inhibited, and the
acute stimulation of cortisol secretion by food intake was
abolished.
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).
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). In vitro studies
Cortisol secretion from dispersed adrenal cells in response
to ACTH, GIP, and leptin is shown in Fig. 4. There was some variability in the
level of cortisol production by unstimulated cells, but ACTH
stimulation (10-9 mol/L) could elicit a rise in
cortisol secretion in each instance. The lowest baseline production was
observed in cells obtained from a solitary adrenal adenoma (232 ±
6 nmol/L), and the highest was found in adrenal cells obtained form
case 1 (867 ± 82 nmol/L).
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). GIP at
10-9 mol/L did not affect baseline cortisol
secretion (732 ± 43 vs. 867 ± 82 nmol/L for GIP
and controls, respectively), whereas at 10-8
mol/L GIP stimulated cortisol secretion to 1135 ± 152 nmol/L, an
effect comparable to that of 10-9 mol/L ACTH
(1287 ± 229 nmol/L). GIP had no effect on cortisol secretion in
the other cases (Fig. 4, B–D).
Similar to what was observed with GIP, 10-7
mol/L leptin stimulated cortisol secretion to 1162 ± 104 nmol/L
in cells obtained from case 1 compared with that in unstimulated
controls (867 ± 82 nmol/L) or ACTH-stimulated cells (1287 ±
229 nmol/L; Fig. 4A). There was a statistically significant correlation
between GIP-stimulated and leptin-stimulated in vitro
cortisol production in this case (P < 0.041). Such a
correlation was not found in any of the other cases studied. Moreover,
despite the small number of points (triplicates of one experiment), the
differences in cortisol production between controls, on the one hand,
and 10-9 mol/L ACTH, 10-8
mol/L GIP, or 10-7 mol/L leptin, on the other
hand, almost reached statistical significance (P =
0.0612). In the other cases (Fig. 4, B–D), neither leptin nor GIP was
found to affect in vitro cortisol secretion.
Finally, glucagon-like polypeptide-1 at two different concentrations (10-8 and 10-9 mol/L) had no effect on cortisol secretion by cells obtained from case 1 (data not shown).
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Discussion |
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TopAbstractIntroductionCase ReportsMaterials and MethodsResultsDiscussionReferences |
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Leptin normally exerts an inhibition on the activity of the hypothalamo-pituitary-adrenal axis in rodents. This inhibition is probably mediated centrally, via an effect on hypothalamic CRH secretion (20, 21), as well as peripherally, as direct inhibition of cortisol secretion by leptin at the level of the adrenal gland has also been described (13, 22). These various effects of leptin on the activity of the hypothalamo-pituitary-adrenal axis of rodents are consistent with a physiological inhibitory role suggested by the inverse relationship existing in normal humans between circulating leptin and cortisol levels (23). In light of the recent demonstration that leptin can directly inhibit cortisol secretion from human adrenocortical cells (12, 13), we hypothesized that a pathological shift from an inhibition toward a stimulation of cortisol secretion by leptin in adenomatous tissue might play an additional role in the pathogenesis of hypercortisolism in food-dependent Cushing’s syndrome.
The results presented here are consistent with this hypothesis. Tumor cells obtained from the adrenal tissue of the patient with food-dependent Cushing’s syndrome exhibited a responsiveness to acute leptin stimulation that mirrored perfectly their abnormal responsiveness to GIP. Remarkably, such a stimulation of cortisol secretion by leptin was never seen in normal human adrenal tissue (Ref. 13 and the present study) or in adenomatous adrenal tissue obtained from patients with ACTH-independent Cushing’s syndrome that was not dependent upon food ingestion (present study). The contrast in leptin responsiveness existing between cells obtained from the food-dependent case and the other cases of adrenal Cushing’s syndrome therefore suggests that such a stimulation of cortisol secretion is not only abnormal, but is also specific to this rare condition.
Circulating leptin levels were thereafter assessed in blood samples obtained after the test meals in patients 1 (food-dependent Cushing’s syndrome) and 2 to correlate our in vitro finding with in vivo data. In a multivariate regression analysis, GIP and leptin were both identified as independent determinants of plasma cortisol levels, together accounting for most of cortisol variability after meal ingestion. Despite the fact that these results represent a single observation, taken together they are suggestive of the existence of an abnormal response to leptin in the case of food-dependent Cushing’s syndrome reported here.
Leptin levels were pathologically elevated in the two patients with macronodular adrenal hyperplasia reported here, confirming earlier observations made in Cushing’s syndrome (24, 25). However, leptin was not secreted acutely in response to food ingestion in either of these two patients, and this could also be anticipated from previous data (26). It seems very unlikely, therefore, that leptin participated in the acute stimulation of cortisol secretion by food intake, and our data do not indicate that this was the case. Rather, they demonstrate that much like in previously described cases, GIP was an important trigger of this acute secretion.
There was, nevertheless, one major difference between the clinical presentation of previously described cases (5, 6, 7, 8, 9, 10) and that of the patient reported here; other cases with food-dependent Cushing’s syndrome all had low fasting cortisol levels, whereas our patient exhibited permanently elevated fasting total cortisol values, including when she was not taking oral estrogens, and the cortisol-binding globulin level was presumed to be normal. This difference can possibly be explained by our in vitro finding of an abnormal response to leptin in this case. Indeed, one could speculate that constantly elevated leptin levels secondary to the hypercortisolism (24, 25) resulted in a paradoxical chronic stimulation of the adrenal glands and, hence, elevated fasting plasma cortisol values. If this were true, the acute stimulation of cortisol secretion by food intake would then occur on top of these chronically elevated levels, as was indeed the case in this patient. However, this possibility remains purely hypothetical at this time and would require testing and confirmation in vivo in other cases of food-dependent Cushing’s syndrome.
The mechanism(s) possibly underlying the in vitro effect observed also remains unclear. There is a growing list of aberrant receptor expression by adrenal glands that eventually lead to adrenal Cushing’s syndrome due to abnormal responses to hormones such as GIP (8, 9, 10, 11), LH (27), or vasopressin (28, 29); to cytokines such as interleukin-1 (30); or to catecholamines (31). However, the long isoform of the leptin receptor (OB-Rb) is expressed by normal adrenal tissue (12, 13, 32), and leptin has a physiological inhibitory role in cortisol secretion (13, 22). Therefore, unlike other hormones, a paradoxical response to leptin cannot be explained solely by receptor overexpression.
The effect that we have observed is reminiscent of the aberrant responsiveness to hypothalamic releasing factors occurring in some pituitary tumors (33, 34), which might be due to mutations either in their respective receptor or in some step of the secondary messenger cascade. However, it is not known at this time whether the leptin receptor expressed by our patient’s adrenal nodules was normal or mutated.
In conclusion, our results demonstrate that a paradoxical response to GIP probably represents the hallmark of all cases of food-dependent Cushing’s syndromes. Furthermore, they suggest that leptin may represent yet another factor that could participate in the ACTH-independent increased cortisol secretion from hyperplastic or adenomatous adrenal glands. This observation is in agreement with the emerging hypothesis that corticotropin-independent adrenal hyperplasia and hypercortisolism can arise from stimulation by an array of hormones or factors, sometimes secondary to the aberrant expression of their cognate receptor (35). However, because OB-R is normally expressed by adrenal tissue (13, 32), and because leptin plays a physiological role to inhibit cortisol secretion from the adrenal gland (13, 22), the pathophysiological mechanism underlying the paradoxical stimulation described in the present paper cannot be attributed solely to overexpression of OB-R.
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Acknowledgments |
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Footnotes |
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2 Recipient of a Research Development Carrier Award from the Prof.
Dr. Max Cloëtta Foundation.
Received December 30, 1998.
Revised June 24, 1999.
Accepted July 2, 1999.
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