Food-Dependent Cushing’s Syndrome: Possible Involvement of Leptin in Cortisol Hypersecretion*

Abstract Stimulation of cortisol secretion by food intake has been implicated in the pathogenesis of some cases of ACTH-independent Cushing’s syndrome, via an aberrant response of the adrenal glands to gastric inhibitory polypeptide (GIP). We report here a novel case of food-dependent Cushing’s syndrome in a patient with bilateral macronodular adrenal hyperplasia. In this patient we were able to confirm a paradoxical stimulation of cortisol secretion by GIP in vivo as well as in vitro on dispersed tumor adrenal cells obtained at surgery. In addition to GIP, in vitro stimulation of these cultured tumor adrenal cells with leptin, the secreted product of the adipocyte, induced cortisol secretion. By comparison, no such stimulation was observed in vitro in adrenal cells obtained from another patient with bilateral macronodular adrenal hyperplasia and Cushing’s syndrome that did not depend on food intake, in tumor cells obtained from a solitary cortisol-secreting adrenal adenoma, and in normal human adrenocortical cells. 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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Incidentally discovered ACTH-dependent adrenal adenoma presenting as 'Pre-Cushing's syndrome'

Acta Endocrinologica ◽

10.1530/acta.0.1110089 ◽

1986 ◽

Vol 111 (1) ◽

pp. 89-92 ◽

Cited By ~ 27

Author(s):

U. Bogner ◽

U. Eggens ◽

J. Hensen ◽

W. Oelkers

Keyword(s):

Cushing’S Syndrome ◽

Adrenal Mass ◽

Adrenal Adenoma ◽

Clinical Signs ◽

Cushing's Syndrome ◽

Cortisol Secretion ◽

Adrenal Tumour ◽

Urinary Cortisol

Abstract. An adrenal tumour was incidentally discovered with no clinical signs of Cushing's syndrome. The endocrine evaluation revealed the unique hormonal constellation of an increased urinary cortisol excretion rate, unequivocal suppressibility of plasma and urinary cortisol by dexamethasone, but only to a residual level in the low normal range which probably reflected ACTH-independent 'autonomous' cortisol secretion. After removal of the adrenal mass, urinary cortisol secretion and dexamethasone suppressibility were normalized. In vitro, the tumour cells were as sensitive towards ACTH as 'normal' human adrenal cells, but showed a reduced cortisol production rate per cell. We suppose that the adrenal mass participated in the diurnal rhythm of ACTH-mediated cortisol secretion in vivo, which resulted in an increased cortisol secretion. During the night, when ACTH levels were low, the cortisol production decreased and the hormone levels were probably too low to suppress ACTH. We regard the hormonal findings in our patients as 'Pre-Cushing's syndrome', although the absence of clinical features of Cushing's syndrome remains unclear. We suggest that every patient with an incidentally discovered adrenal mass should have an endocrinological evaluation because the results may help to decide whether or not the adrenal tumour should be removed.

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Primary adrenocortical micronodular adenomatosis causing Cushing's syndrome. Effects of ketoconazole on steroid production and in vitro performance of adrenal cells

Acta Endocrinologica ◽

10.1530/acta.0.1130370 ◽

1986 ◽

Vol 113 (3) ◽

pp. 370-377 ◽

Cited By ~ 26

Author(s):

W. Oelkers ◽

V. Bähr ◽

J. Hensen ◽

H. Pickartz ◽

P. Exner ◽

...

Keyword(s):

Cushing’S Syndrome ◽

Plasma Cortisol ◽

Venous Blood ◽

Clinical Signs ◽

Cushing's Syndrome ◽

Cortisol Secretion ◽

Urinary Cortisol ◽

Adrenal Cells

Abstract. Mild Cushing's syndrome was diagnosed in a 35 year old woman. Elevated plasma and urinary cortisol levels were unsuppressible with up to 32 mg dexamethasone per day. Aldosterone, 18-OH-corticosterone and testosterone in plasma were normal and dehydroepiandrosterone-sulphate was low. No adrenal tumour was found by CT or adrenal venography, and bilateral cortisol secretion was demonstrated by steroid measurements in adrenal venous blood. A circadian rhythm of plasma cortisol was absent. Plasma ACTH was suppressed, even after injection of CRH, during insulininduced hypoglycaemia and after metyrapone administration, which led to a large fall in plasma cortisol but to a subnormal rise of plasma 11-deoxy-cortisol. The clinical diagnosis of primary micronodular adenomatosis of the adrenal gland was histologically confirmed, when the patient finally underwent bilateral adrenalectomy. In vitro, the adrenal cells did not produce more cortisol and aldosterone than adrenal cells from cadaver kidney donors. In vivo and in vitro, cortisol was slightly less than normally responsive to ACTH. Intermittent treatment of the patient with 800 mg/day of ketoconazole led to a rapid fall of cortisol secretion and clinical signs of adrenocortical insufficiency. Treatment for 7 weeks with 200–400 mg ketoconazole per day reduced plasma and urinary cortisol less dramatically into the normal range. This case unequivocally documents autonomous dysfunction of the adrenal cortex in this rare form of Cushing's syndrome and the efficacy of ketoconazole in the treatment of ACTH-independent hypercortisolism.

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Hypercortisolism with non-pigmented micronodular adrenal hyperplasia: transition from pituitary-dependent to adrenal-dependent Cushing's syndrome

Acta Endocrinologica ◽

10.1530/acta.0.1280120 ◽

1993 ◽

Vol 128 (2) ◽

pp. 120-125 ◽

Cited By ~ 18

Author(s):

Berthold Hocher ◽

Volker Bähr ◽

Severin Dorfmüller ◽

Wolfgang Oelkers

Keyword(s):

Cushing’S Syndrome ◽

Cushing’S Disease ◽

Cushing's Syndrome ◽

Cushing's Disease ◽

Zona Fasciculata ◽

Adrenal Hyperplasia ◽

Adrenal Cells ◽

Before And After ◽

Suppression Test

We report on a female patient with Cushing's syndrome in whom we observed the transition from pituitary dependency to adrenal dependency. Basal ACTH and cortisol values, the CRH test, the dexamethasone suppression test as well as CT of the pituitary and the adrenal gland all reflected pituitary-dependent Cushing's disease in 1985. The patient refused treatment, but presented again five years later. At that time ACTH was suppressed before and after CRH injection. Plasma cortisol did not respond to CRH. After ketoconazole therapy, ACTH was within the high normal range. The patient underwent bilateral adrenalectomy. The adrenals exhibited a bilateral micronodular hyperplasia of the zona fasciculata. In vitro examination of adrenal cells revealed a maintained ACTH response. Some weeks postoperatively, the patient died from pneumonia. Histological examination later showed a chromophobe pituitary microadenoma; ACTH was demonstrated immunohistologically in the adenoma. We postulate that some cases of pituitary Cushing's disease initially exhibit a bilateral homogeneous adrenal hyperplasia which then develops into a nodular hyperplasia; in the next stage of the disease, single micronodules may become autonomous and elevated cortisol levels suppress ACTH secretion of the pituitary adenoma.

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In Vivo and in Vitro Screening for Illegitimate Receptors in Adrenocorticotropin-Independent Macronodular Adrenal Hyperplasia Causing Cushing’s Syndrome: Identification of Two Cases of Gonadotropin/Gastric Inhibitory Polypeptide-Dependent Hypercortisolism

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2004-1256 ◽

2005 ◽

Vol 90 (3) ◽

pp. 1302-1310 ◽

Cited By ~ 61

Author(s):

Jérôme Bertherat ◽

Vincent Contesse ◽

Estelle Louiset ◽

Gaëlle Barrande ◽

Céline Duparc ◽

...

Keyword(s):

Cushing’S Syndrome ◽

Gastric Inhibitory Polypeptide ◽

Cushing's Syndrome ◽

Cortisol Secretion ◽

Adrenal Hyperplasia ◽

Adrenocortical Cells ◽

Normal Cells ◽

H1 Cells

In ACTH-independent macronodular adrenal hyperplasia (AIMAH) causing Cushing’s syndrome, cortisol production can be controlled by illegitimate membrane receptors. The aim of the present study was to evaluate in vivo and in vitro the sensitivity of AIMAH to various regulatory factors to detect the expression of illegitimate receptors by the tissues. Four consecutive patients with AIMAH and hypercortisolism (H1–H4) preoperatively underwent a series of pharmacological and/or physiological tests. After adrenalectomy, in vitro studies were conducted to investigate the cortisol responses of cultured cells, derived from hyperplastic tissues, to various membrane receptor ligands. The adrenal tissues of the two patients who responded in vivo to food intake (H2 and H4) were stimulated in vitro by gastric inhibitory polypeptide. GnRH and human chorionic gonadotropin, but not FSH, stimulated cortisol secretion in patients H2 and H4. In these two cases, human chorionic gonadotropin but not GnRH stimulated cortisol production from cultured adrenocortical cells. Cisapride induced a significant increase in cortisol levels in patient H1. In addition, serotonin (5-HT) was more efficient to stimulate cortisol production in H1 cells than in normal adrenocortical cells. Upright stimulation test provoked an increase in cortisol levels in patients H1, H2, and H3. H1 and H2 cells were more sensitive to the stimulatory action of angiotensin II than normal cells. Similarly, arginine vasopressin (AVP) more efficiently activated steroidogenesis in H1 cells than in normal cells. In H1 tissue, immunohistochemical studies revealed the presence of 5-HT- and AVP-like immunoreactivities within clusters of steroidogenic cells, suggesting that these two factors acted through an autocrine/paracrine mechanism to stimulate cortisol secretion. The present study provides the first demonstration of primary adrenal Cushing’s syndrome dependent on both gonadotropin and gastric inhibitory polypeptide. Our data also show a hyperresponsiveness of hyperplastic adrenal tissues to 5-HT, angiotensin II, and AVP. Finally, they reveal for the first time the presence of paracrine regulatory signals in adrenal hyperplasia tissues.

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Cellular and molecular abnormalities of a macronodular adrenal hyperplasia causing beta-blocker-sensitive Cushing's syndrome

Arquivos Brasileiros de Endocrinologia & Metabologia ◽

10.1590/s0004-27302007000900007 ◽

2007 ◽

Vol 51 (9) ◽

pp. 1452-1462 ◽

Cited By ~ 21

Author(s):

Tânia L. Mazzuco ◽

Michaël Thomas ◽

Monique Martinie ◽

Nadia Cherradi ◽

Nathalie Sturm ◽

...

Keyword(s):

Cushing’S Syndrome ◽

Cultured Cells ◽

Cushing's Syndrome ◽

Screening Tests ◽

Adrenal Hyperplasia ◽

Hormone Production ◽

Autocrine Loop ◽

Molecular Alterations ◽

Molecular Abnormalities

Cushing's syndrome due to ACTH-independent macronodular adrenal hyperplasia (AIMAH) can be associated with abnormal responses of aberrantly expressed adrenocortical receptors. This study aimed to characterize in vitro the pathophysiology of hypercortisolism in a b-blocker-sensitive Cushing's syndrome due to AIMAH. Cortisol secretion profile under aberrant receptors stimulation revealed hyperresponsiveness to salbutamol (beta2-adrenoceptor agonist), cisapride (5-HT4 receptor agonist), and vasopressin in AIMAH cultured cells, but not in normal adrenocortical cells. By RT-PCR, AIMAH tissues revealed beta2-adrenoceptor overexpression rather than ectopical expression. MC2R expression was similar in both AIMAH and normal adrenocortical tissues. Curiously, cortisol levels of AIMAH cells under basal condition were 15-fold higher than those of control cells and were not responsive to ACTH. Analysis of culture medium from AIMAH cells could detect the presence of ACTH, which was immunohistochemically confirmed. Finally, the present study of AIMAH cells has identified: a) cortisol hyperresponsiveness to catecholamines, 5-HT4 and vasopressin in vitro, in agreement with clinical screening tests; b) abnormal expression of beta2-adrenoceptors in some areas of the hyperplastic adrenal tissue; c) autocrine loop of ACTH production. Altogether, the demonstration of aberrant responses to hormonal receptors and autocrine hormone production in the same tissue supports the assumption of multiple molecular alterations in adrenal macronodular hyperplasia.

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cAMP signaling in cortisol-producing adrenal adenoma

Acta Endocrinologica ◽

10.1530/eje-15-0353 ◽

2015 ◽

Vol 173 (4) ◽

pp. M99-M106 ◽

Cited By ~ 19

Author(s):

Davide Calebiro ◽

Guido Di Dalmazi ◽

Kerstin Bathon ◽

Cristina L Ronchi ◽

Felix Beuschlein

Keyword(s):

Signaling Pathway ◽

Cushing’S Syndrome ◽

Cell Function ◽

Adrenal Adenoma ◽

Cushing's Syndrome ◽

Camp Signaling ◽

Common Finding ◽

Adrenocortical Adenomas ◽

Camp Signaling Pathway

The cAMP signaling pathway is one of the major players in the regulation of growth and hormonal secretion in adrenocortical cells. Although its role in the pathogenesis of adrenocortical hyperplasia associated with Cushing's syndrome has been clarified, a clear involvement of the cAMP signaling pathway and of one of its major downstream effectors, the protein kinase A (PKA), in sporadic adrenocortical adenomas remained elusive until recently. During the last year, a report by our group and three additional independent groups showed that somatic mutations of PRKACA, the gene coding for the catalytic subunit α of PKA, are a common genetic alteration in patients with Cushing's syndrome due to adrenal adenomas, occurring in 35–65% of the patients. In vitro studies revealed that those mutations are able to disrupt the association between catalytic and regulatory subunits of PKA, leading to a cAMP-independent activity of the enzyme. Despite somatic PRKACA mutations being a common finding in patients with clinically manifest Cushing's syndrome, the pathogenesis of adrenocortical adenomas associated with subclinical hypercortisolism seems to rely on a different molecular background. In this review, the role of cAMP/PKA signaling in the regulation of adrenocortical cell function and its alterations in cortisol-producing adrenocortical adenomas will be summarized, with particular focus on recent developments.

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SEMIQUANTITATIVE ESTIMATION OF URINARY PREGNANETRIOL, PREGNANETRIOLONE AND TETRAHYDRO S IN THE INVESTIGATION OF ADRENOCORTICAL FUNCTION

Acta Endocrinologica ◽

10.1530/acta.0.0600645 ◽

1969 ◽

Vol 60 (4) ◽

pp. 645-656 ◽

Cited By ~ 2

Author(s):

Frances J. Thomas ◽

A. W. Steinbeck

Keyword(s):

Congenital Adrenal Hyperplasia ◽

Cushing’S Syndrome ◽

Adrenal Adenoma ◽

Cushing's Syndrome ◽

Adrenocortical Function ◽

Endocrine Disorders ◽

Adrenal Carcinoma ◽

Adrenal Hyperplasia ◽

Validity And Reliability ◽

Diagnostic Significance

ABSTRACT Following β-glucuronidase hydrolysis, pregnanetriol, pregnanetriolone and tetrahydro S were extracted from urine, chromatographed on florosil and in two paper systems before semiquantitative estimation of pregnanetriol and pregnanetriolone with the phosphoric acid reaction and of tetrahydro S with blue tetrazolium. The chemical validity and reliability of the method were studied and excretions measured in normal subjects and endocrine disorders. Pregnanetriol excretions were compared with published values. Normal pregnanetriol excretions were found in »idiopathic« hirsutism, with Stein-Leventhal ovaries and in Cushing's syndrome due to adrenal adenoma and hyperplasia; increased excretions were found in congenital adrenal hyperplasia and Cushing's syndrome with adrenal carcinoma. Pregnanetriolone was detected only in congenital adrenal hyperplasia, Cushing's syndrome from hyperplasia and one carcinoma. Large amounts of tetrahydro S were found in Cushing's syndrome with adrenal carcinoma. The possible diagnostic significance of the findings is discussed.

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Cushing’s Syndrome in a Patient with Bilateral Macronodular Adrenal Hyperplasia Responding to Cisapride: An in Vivo and in Vitro Study

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2002-021949 ◽

2003 ◽

Vol 88 (10) ◽

pp. 4616-4622 ◽

Cited By ~ 24

Author(s):

Massimo Mannelli ◽

Pietro Ferruzzi ◽

Paola Luciani ◽

Clara Crescioli ◽

Lisa Buci ◽

...

Keyword(s):

Cushing’S Syndrome ◽

In Vitro Study ◽

Cushing's Syndrome ◽

Vitro Study ◽

Adrenal Hyperplasia

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Cushing syndrome secondary to late onset adrenal hyperplasia: presentation and challenges of management

Pyramid Journal of Medicine ◽

10.4081/pjm.2018.8 ◽

2018 ◽

Vol 1 (1) ◽

Author(s):

Muzzammil Abdullahi ◽

Mamuda Atiku ◽

Imam Mohammed Ibrahim

Keyword(s):

Cushing’S Syndrome ◽

Cushing Syndrome ◽

Late Onset ◽

Adrenal Adenoma ◽

Protein Structures ◽

Cushing's Syndrome ◽

Response To Treatment ◽

Adrenal Tumors ◽

Adrenal Hyperplasia ◽

Supraclavicular Fossa

Cushing’s syndrome is a clinical disorder caused by overproduction of cortisol. Adrenal adenoma is the cause in 5% of cases of Cushing syndrome. ACTH-independent Cushing’s syndrome in 90% is caused by unilateral adrenal tumors. Of these, adenomas are the cause in 80% of the cases, while the others are adrenocortical carcinoma. Rare causes of Cushing’s syndrome include adrenal hyperplasia. Overproduction of cortisol results in weakened protein structures leading to protuberant abdomen and poor wound healing, glucose is converted to fat and deposited in the abdomen, supraclavicular fossa and cheeks. Other presentations are diabetes, hypertension, osteoporosis, fractures, impaired immune function, glucose intolerance, and psychosis. We report a 21-year-old female who presented with clinical symptoms of newly diagnosed hypertension and diabetes mellitus which after poor response to treatment she was evaluated and diagnosed to have Cushing syndrome. She subsequently had left adrenalectomy and did very well with resolution of patients’ symptoms. The histology came out to be diffuse adrenal hyperplasia.

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