Información del artículo
En investigaciones recientes se ha demostrado que la producción de cortisol en algunos casos de síndrome de Cushing no dependiente de la corticotropina (previamente descritos como “autónomos”) está regulada por la existencia de receptores de membrana aberrantes que producen un estímulo crónico de las células corticosuprarrenales, no regulado de forma negativa por glucocorticoides, y que conduce a un incremento crónico de la esteroidogénesis y (posiblemente) a la proliferación celular en la glándula. Se han descrito receptores de este tipo en casos de síndrome de Cushing para varias hormonas, entre ellas el péptido inhibidor gástrico (GIP), la arginina vasopresina (AVP), las catecolaminas, la lutropina/gonadotropina coriónica humana, la serotonina y otras. Los mecanismos moleculares que conducen a la aparición de este tipo de receptores en la corteza suprarrenal todavía son desconocidos. Esta nueva variante etiológica del síndrome de Cushing no dependiente de la corticotropina dará lugar (como así está ocurriendo) a la utilización de tratamientos farmacológicos alternativos a la adrenalectomía. Son probables la identificación futura de nuevos receptores aberrantes capaces de inducir la esteroidogénesis que causa el síndrome de Cushing y la descripción de receptores aberrantes en otros órganos endocrinos y no endocrinos.
Palabras clave:
Síndrome de Cushing
Receptores aberrantes
Corticotropina
Recent studies have shown that cortisol production in some cases of adrenocorticotropic hormone (ACTH)- independent Cushing’s syndrome (previously suspected as being “autonomous”) is actually regulated by aberrant membrane receptors. These receptors produce a chronic stimulus on adrenal cells unregulated by the usual glucocorticoid negative feedback, thus increasing chronic steroidogenesis and possibly stimulating cellular hyperplasia. Receptors of this type have been described in cases of Cushing’s syndrome caused by a several hormones: gastric inhibitor peptide (GIP), arginine-vasopressin (AVP), catecholamines, LH/hCG, serotonin (5-HT) and others.
The molecular mechanisms leading to expression of this type of receptors in the adrenal cortex are still unknown. This new etiological variant of ACTH-independent Cushing’s syndrome will lead (as is already happening) to the use of new pharmacological alternatives to adrenalectomy. Potentially, further studies will identify other aberrant receptors that induce steroidogenesis leading to Cushing’s syndrome, as well as the presence of aberrant receptors in other endocrine and non-endocrine organs.
Key words:
Cushing’s syndrome
Aberrant receptors
Adrenocorticotropic hormone
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Bibliografía
[1.]
H. Raff, J.W. Findling.
A physiologic approach to diagnosis of the Cushing’s syndrome.
Ann Intern Med, 138 (2003), pp. 980-991
[2.]
A. Lacroix, N. N’Diaye, J. Tremblay, P. Hamet.
Ectopic and abnormal hormone receptors in adrenal Cushing’s syndrome.
Endocr Rev, 22 (2001), pp. 75-110
[3.]
G. Arnaldi, A. Angeli, A.B. Atkinson, X. Bertagna, F. Cavagnini, G.P. Chrousos, et al.
Diagnosis and complications of Cushing’s syndrome: a consensus statement.
J Clin Endocrinol Metab, 88 (2003), pp. 5593-5602
[4.]
D.N. Orth.
Cushing’s syndrome.
N Engl J Med, 332 (1995), pp. 791-803
[5.]
A. Lacroix, I. Bourdeau.
Bilateral adrenal Cushing’s syndrome: macronodular adrenal hyperplasia and primary pigmented nodular adrenocortical disease.
Endocrinol Metab Clin North Am, 34 (2005), pp. 441-458
[6.]
P. Álvarez, L. Isidro, M. González-Martín, L. Loidi, F. Arnal, F. Cordido.
Ectopic adrenocorticotropic hormone production by a non catecholamine secreting pheochromocytoma.
J Urol, 167 (2002), pp. 2514-2515
[7.]
N.J. Marieb, S. Spangler, M. Kashgarian, A. Heinmann, M.L. Schwartz, P.E. Schwartz.
Cushing’s syndrome secondary to ectopic cortisol production by an ovarian carcinoma.
J Clin Endocrinol Metab, 57 (1983), pp. 737-740
[8.]
J.W. Findling, H. Raff.
Cushing’s syndrome: Important issues in diagnosis and management.
J Clin Endocrinol Metab, 91 (2006), pp. 3746-3753
[9.]
D.N. Orth, W.J. Kovacs.
The adrenal cortex.
Williams’ Textboook of Endocrinology, pp. 517-664
[10.]
J. Newell-Price, P. Trainer, M. Besser, A. Grossman.
The diagnosis and differential diagnosis of Cushing’s syndrome and pseudoCushing’s states.
Endocr Rev, 19 (1998), pp. 647-672
[11.]
J.A. Carney, H. Gordon, P.C. Carpenter.
The complex of myxomas, spotty pigmentation, and endocrine overactivity.
Medicine (Baltimore), 64 (1985), pp. 270-283
[12.]
J.A. Carney, L.S. Hruska, G.D. Beauchamp.
Dominant inheritance of the complex of myxomas, spotty pigmentation and endocrine overactivity.
Mayo Clinic Proc, 61 (1986), pp. 165-172
[13.]
I. Schorr, R.L. Ney.
Abnormal hormone responses of an adrenocortical cancer adenyl cyclase.
J Clin Invest, 50 (1971), pp. 1295-1300
[14.]
H.T. Hihgshaw, RL. Ney.
Abnormal control in the neoplastic adrenal cortex.
Hormones and cancer, pp. 309-327
[15.]
N. N’Diaye, J. Tremblay, P. Hamet, A. Lacroix.
Hormone receptor abnormalities in adrenal Cushing syndrome.
Horm Metab Res, 30 (1988), pp. 440-446
[16.]
E.R. Simpson, M.R. Waterman.
Regulation of the synthesis of steroidogenic enzymes in adrenal cortical cells by ACTH.
Annu Rev Physiol, 50 (1988), pp. 427-440
[17.]
J.G. Lehoux, A. Fleury, L. Ducharme.
The acute and chronic effects of adrenocorticotropin on the levels of messenger ribonucleic acid and protein of steroidogenic enzymes in rat adrenal in vivo.
Endocrinology, 139 (1998), pp. 3913-3922
[18.]
M. Ehrhart-Bornstein, J.P. Hinson, S.R. Bornstein, W.A. Scherbaum, G.P. Vinson.
Intraadrenal interactions in the regulation of adrenocortical steroidogenesis.
Endocr Rev, 19 (1998), pp. 101-143
[19.]
S.W. Walker, E.R. Lightly, C. Clyne, B.C. Williams, I.M. Bird.
Adrenergic and cholinergic regulation of cortisol secretion from the zona fasciculata/reticularis of bovine adrenal cortex.
Endocr Rev, 17 (1991), pp. 237-265
[20.]
G. Mazzocchi, G. Gottardo, G.C. Nussdorfer.
Catecholamines stimulate steroid secretion of dispersed fowl adrenocortical cells, acting through the beta receptor subtyme.
Horm Metab Res, 29 (1997), pp. 190-192
[21.]
G.C. Nussdorfer, L.K. Malendowicz.
Role of VIP, PACAP, and related peptides in the regulation of the hypothalamo-pituitary-adrenal axis.
Peptides, 19 (1998), pp. 1443-1467
[22.]
J.A. Yanovski, G.B. Cutler Jr.
Glucocorticoid action and the clinical features of Cushing’s syndrome.
Endocrinol Metab Clin North Am, 23 (1994), pp. 487-509
[23.]
V. Bodart, W.E. Rainey, A. Fournier, H. Ong, A. De Lean.
The H295R human adrenocortical cell line contains functional atrial natriuretic peptide receptors that inhibit aldosterone biosynthesis.
Mol Cell Endocrinol, 118 (1996), pp. 137-144
[24.]
M. Kawai, M. Naruse, T. Yoshimoto, K. Naruse, K. Shionoya, M. Tanaka, et al.
C-type natriuretic peptide as a possible local modulator of aldosterone secretion in bovine adrenal zona glomerulosa.
Endocrinology, 137 (1996), pp. 42-46
[25.]
J.S. Flier.
Clinical review 94: What’s in a name? In search of leptin’s physiologic role.
J Clin Endocrinol Metab, 83 (1998), pp. 1407-1413
[26.]
S. Christopoulos, I. Bourdeau, A. Lacroix.
Aberrant expression of hormone receptors in adrenal Cushing’s syndrome.
Pituitary, 7 (2004), pp. 225-235
[27.]
F.M. Swords, S. Aylwin, L. Perry, J. Arola, A.B. Grossman, J.P. Monson, et al.
The aberrant expression of the gastric inhibitory polypeptide (GIP) receptor in adrenal hyperplasia: Does chronic acdrenocorticotropin exposure stimulate up-regulation of GIP receptors in Cushing’s disease.
J Clin Endocr Metab, 90 (2005), pp. 3009-3016
[28.]
P. Hamet, P. Larochelle, D.J. Franks, P. Cartier, E. Bolte.
Cushing syndrome with food-dependent periodic hormonogenesis.
Clin Invest Med, 10 (1987), pp. 530-533
[29.]
G. Arnaldi, J.M. Gasc, Y. De Keyzer, M.L. Raffin-Sanson, V. Perraudin, J.M. Kuhn, et al.
Variable expression of the V1 vasopressin receptor modulates the phenotypic response of the steroidsecreting adenocortical tumors.
J Clin Endocrinol Metab, 83 (1998), pp. 2029-2035
[30.]
S. Makino, K. Hashimoto, M. Sugiyama, R. Hirasawa, T. Takao, Z. Ota, et al.
Cushing’s syndrome due to huge nodular adrenocortical hyperplasia with fluctuation of urinary 17-OHCS excretion.
Endocrinol Jpn, 36 (1989), pp. 655-663
[31.]
N. Horiba, T. Suda, M. Aiba, M. Naruse, K. Nomura, M. Imamura, et al.
Lysine vasopressin stimulation of cortisol secretion in patients with adrenocorticotropin-independent macronodular adrenal hyperplasia.
J Clin Endocrinol Metab, 80 (1995), pp. 2336-2341
[32.]
A. Lacroix, J. Tremblay, R.M. Touyz, L.Y. Deng, R. Lariviere, J.R. Cusson, et al.
Abnormal adrenal and vascular responses to vasopressin mediated by a V1-vasopressin receptor in a patient with adrenocorticotropin-independent macronodular adrenal hyperplasia, Cushing’s syndrome, and orthostatic hypontension.
J Clin Endocrinol Metab, 82 (1997), pp. 2414-2422
[33.]
H. Daidoh, H. Morita, J. Hanafusa, T. Mune, H. Murase, M. Sato, et al.
In vivo and in vitro effects of AVP and V1a receptor antagonist on Cushing’s syndrome due to ACTH-independent bilateral macronodular adrenocortical hyperplasia.
Clin Endocrinol (Oxf), 49 (1998), pp. 403-409
[34.]
H. Mircescu, J. Jilwan, N. N’Diaye, I. Bourdeau, J. Tremblay, P. Hamet, et al.
Are ectopic or abnormal membrane hormone receptors frequently present in adrenal Cushing’s syndrome?.
J Clin Endocrinol Metab, 85 (2000), pp. 3531-3536
[35.]
S. Matsukura, T. Kakita, S. Sueoka, H. Yoshimi, Y. Hirata, M. Yokota, et al.
Multiple hormone receptors in the adenilate cyclase of human adrenocortical tumors.
Cancer Res, 40 (1980), pp. 3768-3771
[36.]
Y. Hirata, M. Uchiashi, S. Sueoka, S. Matsukura, T. Fujita.
Presence of ectopic beta adrenergic receptors on human adrenocortical cortisol-producing adenomas.
J Clin Endocrinol Metab, 53 (1981), pp. 953-957
[37.]
M.S. Katz, T.M. Kelly, E.M. Dax, M.A. Pineyro, J.S. Partilla, R.I. Gregerman.
Ectopic beta adrenergic receptors coupled to adenylate cyclase in human adrenocortical carcinomas.
J Clin Endocrinol Metab, 60 (1985), pp. 900-909
[38.]
A. Lacroix, J. Tremblay, G. Rousseau, M. Bouvier, P. Hamet.
Propranolol therapy for ectopic beta-adrenergic receptors in adrenal Cushing’s syndrome.
N Engl J Med, 337 (1997), pp. 1429-1434
[39.]
G.T. Keegan, F. Grabarits, A.S. Roland.
Pregnancy complicated by Cushing’s syndrome.
South Med J, 69 (1976), pp. 1207-1209
[40.]
A. Parra, J. Cruz-Krohn.
Intercurrent Cushing’s syndrome and pregnancy.
Am J Med, 40 (1966), pp. 961-966
[41.]
E. Reschini, G. Giustina, P.G. Crosignani, A. D’Alberton.
Spontaneous remission of Cushing’s syndrome after termination of pregnancy.
Obstet Gynecol, 51 (1978), pp. 598-602
[42.]
L. Calodney, R.P. Eaton, W. Black, F. Cohn.
Exacerbation of Cushing’s syndrome during pregnancy: report of a case.
J Clin Endocrinol Metab, 36 (1973), pp. 81-86
[43.]
K. Kreines, E. Perrin, R. Salzer.
Pregnancy in Cushing’s syndrome.
J Clin Endocrinol Metab, 24 (1964), pp. 75-79
[44.]
C. Wallace, E.L. Toth, R.Z. Lewanczuk, K. Siminoski.
Pregnancy-induced Cushing’s syndrome in multiple pregnancies.
J Clin Endocrinol Metab, 81 (1996), pp. 15-21
[45.]
C.F. Close, M.C. Mann, J.F. Watts, K.G. Taylor.
ACTH-independent Cushing’s syndrome in pregnancy with spontaneous resolution after delivery: control of the hypercortisolism with metyrapone.
Clin Endocrinol (Oxf), 39 (1993), pp. 375-379
[46.]
J. Kero, M. Poutanen, F.P. Zhang, N. Rahman, A.M. McNicol, J.H. Nilson, et al.
Elevated luteinizing hormone induces expression of its receptor and promotes steroidogenesis in the adrenal cortex.
J Clin Invest, 105 (2000), pp. 633-641
[47.]
R.A. Feelders, S.W. Lamberts, L.J. Hofland, P.M. Van Koetsveld, M. Verhoef-Post, A.P. Themmen, et al.
Luteinizing hormone (LH)-responsive Cushing’s syndrome: the demonstration of LH receptor messenger ribonucleic acid in hyperplastic adrenal cells, which respond to chorionic gonadotropin and serotonin agonists in vitro.
J Clin Endocrinol Metab, 88 (2003), pp. 73-77
[48.]
L. Mazzuco Tania, O. Chabre, J.J. Feige, M. Thomas.
Aberrant expression of human luteinizing hormone receptor by adrenocortical cells is sufficient to provoke both hyperplasia and Cushing’s syndrome features.
J Clin Endocrinol Metab, 91 (2006), pp. 196-203
[49.]
H. Lefevre, V. Contesse, C. Derarue, M. Feuilloley, F. Hery, P. Grise, et al.
Serotonin-induced stimulation of cortisol secretion from human adrenocortical tissue is mediated through activation of a serotonin 4 receptor subtype.
Neuroscience, 47 (1992), pp. 999-1007
[50.]
H. Lefevre, V. Contesse, C. Delarue, C. Soubrane, A. Legrand, J.M. Kuhn, et al.
Effect of the serotonin-4 receptor agonist zacopride on aldosterone secretion from the human adrenal cortex: in vivo and in vitro studies.
J Clin Endocrinol Metab, 77 (1993), pp. 1662-1666
[51.]
Lefevre, V. Contesse, C. Delarue, A. Legrand, J.M. Kuhn, H. Vaudry, et al.
The serotonin-4 receptor agonist cisapride and angiotensin II exert additive effects on aldosterone secretion in normal man.
J Clin Endocrinol Metab, 80 (1995), pp. 504-507
[52.]
D. Cartier, I. Lihrmann, F. Parmentier, C. Bastard, J. Bertherat, P. Caron, et al.
Overexpression of serotonin-4 receptors in cisapride- responsive adrenocorticotropin-independent bilateral macronodular hyperplasia causing Cushing’s syndrome.
J Clin Endocrinol Metab, 88 (2003), pp. 248-254
[53.]
C. Bonnin, M. Monsaingeon, V. Bex, M. Duclos, D. Tortigues, H. Lefevre, et al.
Hypercorticism by bilateral adrenal hyperplasia with several paradoxical responses [resumen].
Program and abstracts of the 82nd annual meeting of the Endocrine Society,
[54.]
O. Caticha, W.D. Oddell, D.E. Wilson, L.A. Dowdell, R.H. Noth, A.L. Swislocki, et al.
Estradiol stimulates cortisol production by adrenal cells in estrogen-dependent primary adrenocortical nodular dysplasia.
J Clin Endocrinol Metab, 77 (1993), pp. 494-497
[55.]
C.A. Stratakis, N. Sarlis, L.S. Kirschner, J.A. Carney, J.L. Doppman, L.K. Nieman, et al.
Paradoxical response to dexamethasone in the diagnosis of primary pigmented nodular adrenocortical disease.
Ann Intern Med, 131 (1999), pp. 585-591
[56.]
I. Bourdeau, P. Caron, W. Schürch, N. N’Diaye, T. Antakly, A. Lacroix.
Paradoxical response to dexamethasone correlates with high expression of glucocorticoid receptors in primary pigmented nodular adrenocortical disease [resumen].
Program and abstracts of the 82nd annual meeting of the Endocrine Society,
[57.]
F.P. Pralong, F. Gomez, L. Guillou, F. Mosimann, S. Franscella, R.C. Gaillard.
Food-dependent Cushing’s syndrome: possible involvement of leptin in cortisol hypersecretion.
J Clin Endocrinol Metab, 84 (1999), pp. 3817-3822
[58.]
K. Hashimoto, Y. Kawada, K. Murakami, T. Hattori, S. Suemaru, J. Kageyama, et al.
Cortisol responsiveness to insulin-induced hypoglicemia in Cushing’s syndrome with huge nodular adrenocortical hyperplasia.
Endocrinol Jpn, 33 (1986), pp. 479-487
[59.]
A. Lacroix, H. Mircescu, P. Hamet.
Clinical evaluation of the presence of abnormal hormone receptors in adrenal Cushing’s syndrome.
Endocrinologist, 9 (1999), pp. 9-15
[60.]
L.T. Williams, R.J. Lefkowitz, A.M. Watanabe, D.R. Hathaway, H.R.J. Besch.
Thyroid hormone regulation of b-adrenergic receptor number.
J Biol Chem, 252 (1977), pp. 2787-2789
[61.]
C.C. Malbon, F.J. Moreno, R.J. Cabelli, J.N. Fain.
Fat cell adenylate cyclase and β-adrenergic receptors in altered thyroid states.
J Biol Chem, 253 (1978), pp. 671-678
[62.]
J.R. Hadcock, C.C. Malbon.
Down-regulation of β-adrenergic receptors: agonist-induced reduction in receptor mRNA levels.
Proc Natl Acad Sci U S A, 85 (1988), pp. 5021-5025
[63.]
J.C. Mak, M. Nishikawa, P.J. Barnes.
Glucocorticosteroids increase β-2 adrenergic receptor transcription in human lung.
Am J Physiol, 268 (1995), pp. L41-L46
[64.]
C.C. Malbon, J.R. Hadcock.
Evidence that glucocorticoid response elements in the 5’-noncoding region of the hamster beta 2-adrenergic receptor gene are obligate for glucocorticoid regulation of receptor mRNA levels.
Biochem Biopsy Res Commun, 154 (1988), pp. 676-681
[65.]
X.M. Zhou, P.H. Fishman.
Desensitization of the human beta1-adrenergic receptor. Involvement of the cyclic AMP-dependent but not a receptor-specific protein kinase.
J Biol Chem, 266 (1991), pp. 7462-7468
[66.]
F. Nantel, S. Marullo, S. Krief, A.D. Strosberg, M. Bouvier.
Cellspecific down-regulation of the β-3 adrenergic receptor.
J Biol Chem, 269 (1994), pp. 13148-13155
[67.]
G. Guillon.
Vasopressin, oxytocin and angiotensin receptors in mammals.
Ann Endocrinol (Paris), 50 (1989), pp. 425-433
[68.]
S. Keppens, H. De Wulf.
The activation of liver glycogen phosphorilase by vasopressin.
FEBS Lett, 51 (1975), pp. 29-32
[69.]
J.M. Elalouf, A. Di Stefano, C. De Rouffignac.
Sensitivities of rat kidney thick ascending limbs and collecting ducts to vasopressin in vivo.
Proc Natl Acad Sci U S A, 83 (1986), pp. 2276-2280
[70.]
K.L. Scorecki, D.A. Aussiello.
Vasopressin receptor adenylate cyclase interactions: a model for cAMP metabolism in the kidney.
pp. 55-73
[71.]
A. Lacroix, E. Bolte, J. Tremblay, J. Dupre, P. Poitras, H. Fournier, et al.
Gastric inhibitory polypeptide-dependent cortisol hypersecretion -a new cause of Cushing’s syndrome.
N Engl J Med, 327 (1992), pp. 974-980
[72.]
C. Gicquel, X. Bertagna, Y. Le Bouc.
Recent advances in the pathogenesis of adrenocortical tumors.
Eur J Endocrinol, 133 (1995), pp. 133-144
[73.]
A.C. Latronico, G.P. Chrousos.
Extensive personal experience: Adrenocortical tumors.
J Clin Endocrinol Metab, 82 (1997), pp. 1317-1324
[74.]
J. Kero, M. Poutanen, F.P. Zhang, N. Rahman, A.M. McNicol, J.H. Nilson, et al.
Elevated luteinizing hormone induces expression of its receptor and promotes steroidogenesis in the adrenal cortex.
J Clin Invest, 105 (2000), pp. 633-641
[75.]
D.S. Millington, M.P. Golder, T. Cowley, D. London, H. Roberts, W.R. Butt, et al.
In vitro synthesis of steroids by a feminishing adrenocortical carcinoma: effect of prolactin and other protein hormones.
Acta Endocrinol (Copenh), 82 (1976), pp. 561-571
[76.]
C. Lamas, J.J. Alfaro, T. Lucas, B. Lecumberri, B. Barceló, J. Estrada.
Is unilateral adrenalectomy an alternative treatment for ACTH-independent macronodular adrenal hyperplasia?: Longterm follow-up of four cases.
Eur J Endocr, 146 (2002), pp. 237-240
[77.]
Y. Reznik, V. Allali-Zerah, J.A. Chayvialle, R. Leroyer, P. Leymarie, G. Travert, et al.
Food-dependent Cushing’s syndrome mediated by aberrant adrenal sensitivity to gastric inhibitory polypeptide.
N Eng J Med, 327 (1992), pp. 981-986
[78.]
R.J. Croughs, P.M. Zelissen, Th.J. Van Vroonhoven, L.J. Hofland, N. N’Diaye, A. Lacroix, et al.
GIP-dependent adrenal Cushing’s syndrome with incomplete suppression of ACTH.
Clin Endocrinol (Oxf), 52 (2000), pp. 235-240
[79.]
W. De Herder, L.J. Hofland, T.B. Usdin, F.H. De Jong, P. Uitterlinden, P. Van Koetsveld, et al.
Food-dependent Cushing’s syndrome resulting from abundant expression of gastric inhibitory polypeptide receptors in adrenal adenoma cells.
J Clin Endocrinol Metab, 83 (1996), pp. 3134-3143
[80.]
A. Lacroix, P. Hamet, J.M. Boutin.
Leuprolide acetate therapy in luteinizing hormone-dependent Cushing’s syndrome.
N Engl J Med, 341 (1999), pp. 1577-1581
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