scholarly journals Are Ectopic or Abnormal Membrane Hormone Receptors Frequently Present in Adrenal Cushing’s Syndrome?1

2000 ◽  
Vol 85 (10) ◽  
pp. 3531-3536 ◽  
Author(s):  
Hortensia Mircescu ◽  
Jose Jilwan ◽  
Nina N′Diaye ◽  
Isabelle Bourdeau ◽  
Johanne Tremblay ◽  
...  
Keyword(s):  
Medical Therapy ◽  
Cushing’S Syndrome ◽  
Hormone Receptors ◽  
Gastric Inhibitory Polypeptide ◽  
Cushing's Syndrome ◽  
Adrenergic Agonists ◽  
Adrenal Hyperplasia ◽  
Clinical Screening ◽  
Adrenal Hormone

Twenty consecutive patients with adrenal Cushing’s syndrome were studied with an in vivo protocol to determine the prevalence and diversity of the presence of ectopic or abnormal hormone receptors in their adrenal tissues. All six patients with bilateral ACTH-independent macronodular adrenal hyperplasia were found to have one or two abnormal adrenal receptors, including those for gastric inhibitory polypeptide, vasopressin (V1-vasopressin),β -adrenergic agonists, LH/human CG, or serotonin 5-HT4. The presence of abnormal hormone receptors was found to be less frequently present in unilateral adenomas or carcinomas (3 of 14). The identification of abnormal adrenal hormone receptors can allow new pharmacological therapies of hypercortisolism. We suggest that the clinical screening for the presence of abnormal hormone receptors should be conducted in patients with adrenal Cushing’s syndrome and, more particularly, in those with ACTH-independent macronodular adrenal hyperplasia, in the hope of offering medical therapy as an alternative to bilateral adrenalectomy.

scholarly journals Aberrant cortisol regulations in bilateral macronodular adrenal hyperplasia: a frequent finding in a prospective study of 32 patients with overt or subclinical Cushing's syndrome

2010 ◽  
Vol 163 (1) ◽  
pp. 129-138 ◽  
Author(s):  
Rossella Libé ◽  
Joël Coste ◽  
Laurence Guignat ◽  
Frédérique Tissier ◽  
Hervé Lefebvre ◽  
...  
Keyword(s):  
Functional Status ◽  
Cushing’S Syndrome ◽  
Hormone Receptors ◽  
Cushing's Syndrome ◽  
Receptor Expression ◽  
Adrenal Hyperplasia ◽  
Cortisol Responses ◽  
A Prospective Study ◽  
Underlying Pathophysiology

ContextACTH-independent macronodular adrenal hyperplasia (AIMAH) is a rare and heterogeneous condition characterized by abnormal steroid production. Cortisol secretion can be regulated by aberrant hormone receptors.ObjectiveA large series of patients with AIMAH were evaluated to provide information on the prevalence and profile of aberrant regulations, in relation with the functional status.Design and patientsThirty-two consecutive patients with AIMAH were prospectively studied: 10 had a Cushing's syndrome (CS), and 22 had a subclinical CS (SCS).MethodsA baseline endocrine evaluation was followed by an in vivo protocol in search of aberrant cortisol responses (seven provocative tests). An acute inhibition test with the somatostatin analog octreotide was also performed.ResultsAt least one aberrant cortisol response was identified in 28 of 32 (87%) patients. The overall prevalence of aberrant responses was independent of the functional status. Responses to the upright posture and to metoclopramide were frequently observed (67 and 56% respectively). A glucagon response was frequently observed in the SCS group (58%). A cortisol inhibition by octreotide was specifically found in the three CS patients who positively responded to the mixed meal, and was observed also in 12 of 13 (92%) patients with SCS.ConclusionsCortisol responses indicative of aberrant receptor expression were highly prevalent in AIMAH. Thorough phenotyping of AIMAH may help uncover the underlying pathophysiology.

scholarly journals Aberrant Membrane Hormone Receptors in Incidentally Discovered Bilateral Macronodular Adrenal Hyperplasia with Subclinical Cushing’s Syndrome

2001 ◽  
Vol 86 (11) ◽  
pp. 5534-5540 ◽  
Author(s):  
Isabelle Bourdeau ◽  
Pierre D’Amour ◽  
Pavel Hamet ◽  
Jean-Marie Boutin ◽  
André Lacroix
Keyword(s):  
Cushing’S Syndrome ◽  
Plasma Cortisol ◽  
Hormone Receptors ◽  
Gastric Inhibitory Polypeptide ◽  
Urinary Free Cortisol ◽  
Cushing's Syndrome ◽  
Cortisol Secretion ◽  
Adrenal Hyperplasia ◽  
Free Cortisol ◽  
Cortisol Levels

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.

scholarly journals Aberrant expression of multiple hormone receptors in ACTH-independent macronodular adrenal hyperplasia causing Cushing's syndrome

2010 ◽  
Vol 163 (2) ◽  
pp. 293-299 ◽  
Author(s):  
J W B de Groot ◽  
T P Links ◽  
A P N Themmen ◽  
L H Looijenga ◽  
R R de Krijger ◽  
...  
Keyword(s):  
Cushing’S Syndrome ◽  
Hormone Receptors ◽  
Immunohistochemical Analysis ◽  
Cushing's Syndrome ◽  
Adrenal Hyperplasia ◽  
Aberrant Expression ◽  
Adrenal Tissue ◽  
The Individual

ObjectiveAberrant adrenal expression of various hormone receptors has been identified in ACTH-independent macronodular adrenal hyperplasia (AIMAH) causing cortisol hypersecretion regulated by hormones other than ACTH. We aimed to determine aberrant expression of multiple hormone receptors in vivo and in vitro in adrenal tissue of a patient with AIMAH.DesignThe design of the study includes clinical case description, and biochemical and immunohistochemical analysis to demonstrate aberrant expression of multiple hormone receptors in AIMAH.MethodsThe subject of the study is a male diagnosed with Cushing's syndrome because of AIMAH. Directly after laparoscopic removal of the adrenals, adrenal tissue was incubated with and without test substances (ACTH, forskolin, arginine vasopressin (AVP), desmopressin, epinephrine, norepinephrine, purified human chorionic gonadotropin (hCG), metoclopramide and the combinations of AVP with ACTH, epinephrine and metoclopramide). LH/hCG-receptor (hCG-R) immunohistochemistry and RT-PCR analyses were performed to demonstrate aberrant expression of LH/hCG-R and V1–3-AVPR.ResultsAIMAH was characterized by in vivo cortisol responsiveness to AVP and in vitro cortisol responses to AVP, hCG, epinephrine, and norepinephrine suggesting aberrant adrenal expression of the receptors for AVP (the V1–3-AVPRs), catecholamines (the β-AR), and LH (the LH/hCG-R). Incubation with combinations of AVP and ACTH and of AVP with epinephrine induced a stronger cortisol response compared with incubation with the individual agents. Moreover, we demonstrated adrenal V1–3-AVPR and LH/hCG-R expression.ConclusionsAIMAH tissue may simultaneously express multiple aberrant hormone receptors, and individual ligands may potentiate each other regarding cell proliferation and cortisol production.

scholarly journals Cushing's syndrome secondary to ACTH-Independent macronodular adrenal hyperplasia

2007 ◽  
Vol 51 (8) ◽  
pp. 1226-1237 ◽  
Author(s):  
Marcia Helena Soares Costa ◽  
André Lacroix
Keyword(s):  
Cushing’S Syndrome ◽  
Hormone Receptors ◽  
Cushing's Syndrome ◽  
Adrenal Hyperplasia ◽  
Sexual Steroids ◽  
Acth Receptor ◽  
The Family ◽  
Cycle Regulation ◽  
G Protein Coupled

ACTH-Independent macronodular adrenal hyperplasia (AIMAH) is a rare cause of endogenous Cushing's syndrome (CS), in which clinical features usually become apparent only after several decades of life. This form of adrenal hyperplasia typically produces excess cortisol with overt or subclinical CS, but concurrent secretion of mineralocorticoids or sexual steroids can also occur. The diagnosis is suspected by bilateral adrenal nodules larger than 1 cm on incidental imaging studies or following the demonstration of ACTH-independent hormonal hypersecretion. The pathophysiology of this entity is heterogeneous and has been intensely explored in recent years. Several G-protein coupled receptors aberrantly expressed in the adrenal cortex have been implicated in the regulation of steroidogenesis and in the initial cell proliferation in AIMAH. Several familial cases of AIMAH have been recently described with the same pattern of aberrant hormone receptors in all affected members of the family. It is probable that additional somatic genetic events related to cell cycle regulation, adhesion and transcription factors occur in addition over time in the various nodules; other mechanisms, as Gsp or ACTH receptor mutations and paracrine adrenal hormonal secretion have been rarely identified as the molecular mechanism in some cases. When systematically screened, most patients with AIMAH exhibit an in vivo aberrant cortisol response to one or various ligands suggesting the presence of aberrant adrenal receptors. The identification of these receptors creates the possibility of a specific pharmacological treatment isolated or associated with adrenalectomy.

scholarly journals 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

2005 ◽  
Vol 90 (3) ◽  
pp. 1302-1310 ◽  
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.

scholarly journals Long-term low-dose ketoconazole treatment in bilateral macronodular adrenal hyperplasia

2014 ◽  
Vol 2014 ◽  
Author(s):  
Sophie Comte-Perret ◽  
Anne Zanchi ◽  
Fulgencio Gomez
Keyword(s):  
Medical Therapy ◽  
Cushing’S Syndrome ◽  
Clinical Signs ◽  
Cushing's Syndrome ◽  
List Type ◽  
Adrenal Hyperplasia ◽  
Benign Condition ◽  
Steroid Secretion ◽  
Free Cortisol

Summary Medical therapy for Cushing's syndrome due to bilateral macronodular adrenal hyperplasia (BMAH) is generally administered for a limited time before surgery. Aberrant receptors antagonists show inconsistent efficacy in the long run to prevent adrenalectomy. We present a patient with BMAH, treated for 10 years with low doses of ketoconazole to control cortisol secretion. A 48-year-old woman presented with headaches and hypertension. Investigations showed the following: no clinical signs of Cushing's syndrome; enlarged lobulated adrenals; normal creatinine, potassium, and aldosterone; normal urinary aldosterone and metanephrines; elevated urinary free cortisol and steroid metabolites; and suppressed plasma renin activity and ACTH. A screening protocol for aberrant adrenal receptors failed to show any illegitimate hormone dependence. Ketoconazole caused rapid normalisation of cortisol and ACTH that persists over 10 years on treatment, while adrenals show no change in shape or size. Ketoconazole decreases cortisol in patients with Cushing's syndrome, and may prevent adrenal overgrowth. Steroid secretion in BMAH is inefficient as compared with normal adrenals or secreting tumours and can be controlled with low, well-tolerated doses of ketoconazole, as an alternative to surgery. Learning points Enlarged, macronodular adrenals are often incidentally found during the investigation of hypertension in patients harboring BMAH. Although laboratory findings include low ACTH and elevated cortisol, the majority of patients do not display cushingoid features. Bilateral adrenalectomy, followed by life-long steroid replacement, is the usual treatment of this benign condition, and alternative medical therapy is sought. Therapy based on aberrant adrenal receptors gives disappointing results, and inhibitors of steroidogenesis are not always well tolerated. However, ketoconazole at low, well-tolerated doses appeared appropriate to control adrenal steroid secretion indefinitely, while preventing adrenal overgrowth. This treatment probably constitutes the most convenient long-term alternative to surgery.

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

2003 ◽  
Vol 88 (10) ◽  
pp. 4616-4622 ◽  
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

scholarly journals MON-LB44 Cushing’s Syndrome and Illegal Receptors

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Caroline Poku ◽  
Randa Sharag Eldin ◽  
Abubakr Hassab Elrasoul Babiker Mohamed ◽  
Sadiq Sobia
Keyword(s):  
Cushing’S Syndrome ◽  
Hormone Receptors ◽  
Age Distribution ◽  
Cushing's Syndrome ◽  
Endocrine Surgery ◽  
Adrenal Hyperplasia ◽  
Unilateral Adrenalectomy ◽  
Production Studies ◽  
Bilateral Adrenal Hyperplasia ◽  
Adrenal Masses

Abstract Case presentation: A 48-year-old female with HTN presented to the endocrinology clinic for the evaluation of incidental bilateral adrenal masses noted on chest CT for dyspnea workup. At the time of the presentation, she reported generalized fatigue, significant weight gain in the past year and shortness of breath. Her physical exam was remarkable for central obesity. Lab work showed elevated cortisol after 1 mg dexamethasone suppression test x 2 and elevated 24- hour urine cortisol. Plasma free metanephrine levels and aldosterone/ renin ratio were normal. MRI abdomen was done and showed bilateral adrenal masses (left: 5.6 cm, right: 3.2 cm). Patient was diagnosed with Cushing’s syndrome secondary to primary bilateral adrenal hyperplasia and was referred to endocrine surgery who recommended unilateral adrenalectomy. The decision was made to remove the larger left side adrenal mass. On post-operative day one her am cortisol decreased to 2.1 and she was started on hydrocortisone 20 mg in the morning and 10 mg in the evening. Discussion: Primary bilateral adrenal hyperplasia is a rare cause (< 2 %) of endogenous Cushing’s syndrome, usually occurs in a bimodal age distribution, in childhood and in the fifth- sixth decades. Presentation is variable with most patients having no symptoms or subclinical Cushing’s. The theory is the larger nodule size corelates with the higher cortisol production. Studies have shown between 60-70% of cases has aberrant ectopic hormone receptors which leads to increased cortisol production not only from ACTH but also from other ligands such as serotonin and vasopressin. Aberrant receptor testing examines whether cortisol or other steroid production increases in response to either physiologic or pharmacologic stimulus. Multiple genetic mutations have been associated, the most frequent is mutations in the Armadillo repeat- containing 5 gene identified in 2013. Treatment can either be medical or surgical. Medical therapy can be initiated if testing for an aberrant receptor is positive. In recent years there has been a trend towards doing unilateral adrenalectomy instead of bilateral, with initial remission of symptoms reported in about 84% of cases after unilateral adrenalectomy although there is a small risk of recurrence. Post operatively after unilateral adrenalectomy patients should be monitored for adrenal insufficiency. Our patient declined aberrant receptor testing and opted for surgery and is doing well post operatively. Conclusion: Primary bilateral adrenal hyperplasia is a rare cause of endogenous Cushing’s syndrome which can be treated either medically or surgically.

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