Horm Metab Res 2011; 43(5): 337-342
DOI: 10.1055/s-0031-1271693
Original Basic

© Georg Thieme Verlag KG Stuttgart · New York

Melatonin Exerts Direct Inhibitory Actions on ACTH Responses in the Human Adrenal Gland

C. Campino1 , [*] , F. J. Valenzuela2 , [*] , C. Torres-Farfan2 , H. E. Reynolds2 , L. Abarzua-Catalan2 , E. Arteaga1 , C. Trucco3 , S. Guzmán3 , G. J. Valenzuela4 , M. Seron-Ferre2 , 5
  • 1Departamento de Endocrinología, Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile
  • 2Programa de Fisiopatología, Instituto de Ciencias Biomédicas (ICBM), Facultad de Medicina, Universidad de Chile, Santiago, Chile
  • 3Departamento de Urología, Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile
  • 4Department of Women's Health, Arrowhead Regional Medical Center, Colton, CA, USA
  • 5Universidad de Tarapaca, Arica, Chile
Further Information

Publication History

received 18.11.2010

accepted 12.01.2011

Publication Date:
17 February 2011 (online)

Abstract

In nonhuman primates and rodents, melatonin acting directly on the adrenal gland, inhibits glucocorticoid response to ACTH. In these species, an intrinsic adrenal circadian clock is involved in ACTH-stimulated glucocorticoid production. We investigated whether these findings apply to the human adrenal gland by determining i) expression of clock genes in vivo and ii) direct effects of melatonin in ACTH-stimulated adrenal explants over a) expression of the clock genes PER1 (Period 1) mRNA and BMAL1 [Brain-Muscle (ARNT)-like] protein, ACTH-induced steroidogenic acute regulatory protein (StAR), and 3β-hydroxysteroid dehydrogenase (3β-HSD) and b) over cortisol and progesterone production. Adrenal tissue was obtained from 6 renal cancer patients undergoing unilateral nephrectomy-adrenalectomy. Expression of the clock genes PER1, PER2, CRY2 (Cryptochrome 2), CLOCK (Circadian Locomotor Output Cycles Kaput) and BMAL1, was investigated by RT-PCR in a normal adrenal and in an adenoma. In independent experiments, explants from 4 normal adrenals were preincubated in culture medium (6 h) followed by 12 h in: medium alone; ACTH (100 nM); ACTH plus melatonin (100 nM); and melatonin alone. The explants’ content of PER1 mRNA (real-time PCR) and StAR, 3β-HSD, BMAL1 (immuno slot-blot), and their cortisol and progesterone production (RIA) were measured. The human adrenal gland expresses the clock genes PER1, PER2, CRY2, CLOCK, and BMAL1. ACTH increased PER1 mRNA, BMAL1, StAR, and 3β-HSD protein levels, and cortisol and progesterone production. Melatonin inhibited these ACTH effects. Our study demonstrates, for the first time, direct inhibitory effects of melatonin upon several ACTH responses in the human adrenal gland.

References

  • 1 Reiter RJ, Tan DX, Fuentes-Broto L. Melatonin: a multitasking molecule.  Prog Brain Res. 2010;  181 127-151
  • 2 Dubocovich ML, Markowska M. Functional MT1 and MT2 melatonin receptors in mammals.  Endocrine. 2005;  27 101-110
  • 3 Ekmekcioglu C. Melatonin receptors in humans: biological role and clinical relevance.  Biomed Pharmacother. 2006;  60 97-108
  • 4 Torres-Farfan C, Richter HG, Rojas-Garcia P, Vergara M, Forcelledo ML, Valladares LE, Torrealba F, Valenzuela GJ, Seron-Ferre M. mt1 Melatonin receptor in the primate adrenal gland: inhibition of adrenocorticotropin-stimulated cortisol production by melatonin.  J Clin Endocrinol Metab. 2003;  88 450-458
  • 5 Torres-Farfan C, Valenzuela FJ, Mondaca M, Valenzuela GJ, Krause B, Herrera EA, Riquelme R, Llanos AJ, Seron-Ferre M. Evidence of a role for melatonin in fetal sheep physiology: direct actions of melatonin on fetal cerebral artery, brown adipose tissue and adrenal gland.  J Physiol. 2008;  586 4017-4027
  • 6 Richter HG, Torres-Farfan C, Garcia-Sesnich J, Abarzua-Catalan L, Henriquez MG, Alvarez-Felmer M, Gaete F, Rehren GE, Seron-Ferre M. Rhythmic expression of functional MT1 melatonin receptors in the rat adrenal gland.  Endocrinology. 2008;  149 995-1003
  • 7 Campino C, Valenzuela FJ, Arteaga E, Torres-Farfan C, Trucco C, Velasco A, Guzmán S, Seron-Ferre M. Melatonin reduces cortisol response to ACTH in humans.  Rev Med Chile. 2008;  136 1390-1397
  • 8 Torres-Farfan C, Abarzua-Catalan L, Valenzuela FJ, Mendez N, Richter HG, Valenzuela GJ, Seron-Ferre M. Cryptochrome 2 expression level is critical for adrenocorticotropin stimulation of cortisol production in the capuchin monkey adrenal.  Endocrinology. 2009;  150 2717-2722
  • 9 Son GH, Chung S, Choe HK, Kim HD, Baik SM, Lee H, Lee HW, Choi S, Sun W, Kim H, Cho S, Lee KH, Kim K. Adrenal peripheral clock controls the autonomous circadian rhythm of glucocorticoid by causing rhythmic steroid production.  Proc Nat Acad Sci USA. 2008;  105 20970-20975
  • 10 Oster H, Damerow S, Kiessling S, Jakubcakova V, Abraham D, Tian J, Hoffmann MW, Eichele G. The circadian rhythm of glucocorticoids is regulated by a gating mechanism residing in the adrenal cortical clock.  Cell Metabolism. 2006;  4 163-173
  • 11 Nakao N, Yasuo S, Nishimura A, Yamamura T, Watanabe T, Anraku T, Okano T, Fukada Y, Sharp PJ, Ebihara S, Yoshimura T. Circadian clock gene regulation of steroidogenic acute regulatory protein gene expression in preovulatory ovarian follicles.  Endocrinology. 2007;  148 3031-3038
  • 12 Sewer MB, Waterman MR. ACTH modulation of transcription factors responsible for steroid hydroxylase gene expression in the adrenal cortex.  Microsc Res Tech. 2003;  61 300-307
  • 13 Valenzuela FJ, Torres-Farfan C, Richter HG, Mendez N, Campino C, Torrealba F, Valenzuela GJ, Seron-Ferre M. Clock gene expression in adult primate suprachiasmatic nuclei and adrenal: is the adrenal a peripheral clock responsive to melatonin?.  Endocrinology. 2008;  149 1454-1461
  • 14 Torres-Farfan C, Richter HG, Germain AM, Valenzuela GJ, Campino C, Rojas-García P, Forcelledo ML, Torrealba F, Seron-Ferre M. Maternal melatonin selectively inhibits cortisol production in the primate fetal adrenal gland.  J Physiol. 2004;  554 841-856
  • 15 Torres-Farfan C, Rocco V, Monsó C, Valenzuela FJ, Campino C, Germain A, Torrealba F, Valenzuela GJ, Seron-Ferre M. Maternal melatonin effects on clock gene expression in a nonhuman primate fetus.  Endocrinology. 2006;  147 4618-4626
  • 16 Morgan PJ, Ross AW, Graham ES, Adam C, Messager S, Barrett P. oPer1 is an early response gene under photoperiodic regulation in the ovine pars tuberalis.  J Neuroendocrinol. 1998;  10 319-323
  • 17 Lomax MA, Sadiq F, Karamanlidis G, Karamitri A, Trayhurn P, Hazlerigg DG. Ontogenic loss of brown adipose tissue sensitivity to beta-adrenergic stimulation in the ovine.  Endocrinology. 2007;  148 461-468
  • 18 Torres-Farfan C, Valenzuela FJ, Germain AM, Viale ML, Campino C, Torrealba F, Valenzuela GJ, Richter HG, Serón-Ferré M. Maternal melatonin stimulates growth and prevents maturation of the capuchin monkey fetal adrenal gland.  J Pineal Res. 2006;  41 58-66
  • 19 Lemos DR, Downs JL, Urbanski HF. Twenty-four-hour rhythmic gene expression in the rhesus macaque adrenal gland.  Mol Endocrinol. 2006;  20 1164-1176
  • 20 Fahrenkrug J, Hannibal J, Georg B. Diurnal rhythmicity of the canonical clock genes Per1, Per2 and Bmal1 in the rat adrenal gland is unaltered after hypophysectomy.  J Neuroendocrinol. 2008;  20 323-329
  • 21 Kume K, Zylka MJ, Sriram S, Shearman LP, Weaver DR, Jin X, Maywood ES, Hastings MH, Reppert SM. mCRY1 and mCRY2 are essential components of the negative limb of the circadian clock feedback loop.  Cell. 1999;  98 193-205
  • 22 Gekakis N, Staknis D, Nguyen HB, Davis FC, Wilsbacher LD, King DP, Takahashi JS, Weitz CJ. Role of the CLOCK protein in the mammalian circadian mechanism.  Science. 1998;  280 1564-1569
  • 23 Yu W, Nomura M, Ikeda M. Interactivating feedback loops within the mammalian clock: BMAL1 is negatively autoregulated and upregulated by CRY1, CRY2, and PER2.  Biochem Biophys Res Commun. 2002;  290 933-941
  • 24 Rahman SA, Kollara A, Brown TJ, Casper RF. Selectively filtering short wavelengths attenuates the disruptive effects of nocturnal light on endocrine and molecular circadian phase markers in rats.  Endocrinology. 2008;  149 6125-6135
  • 25 Ratajczak CK, Boehle KL, Muglia LJ. Impaired steroidogenesis and implantation failure in Bmal1-/-mice.  Endocrinology. 2009;  150 1879-1885
  • 26 Alvarez JD, Hansen A, Ord T, Bebas P, Chappell PE, Giebultowicz JM, Williams C, Moss S, Sehgal A. The circadian clock protein BMAL1 is necessary for fertility and proper testosterone production in mice.  J Biol Rhythms. 2008;  23 26-36
  • 27 Doi M, Takahashi Y, Komatsu R, Yamazaki F, Yamada H, Haraguchi S, Emoto N, Okuno Y, Tsujimoto G, Kanematsu A, Ogawa O, Todo T, Tsutsui K, van der Horst GT, Okamura H. Salt-sensitive hypertension in circadian clock-deficient Cry-null mice involves dysregulated adrenal Hsd3b6.  Nat Med. 2010;  16 67-74
  • 28 Imbesi M, Arslan AD, Yildiz S, Sharma R, Gavin D, Tun N, Manev H, Uz T. The melatonin receptor MT1 is required for the differential regulatory actions of melatonin on neuronal ‘clock’ gene expression in striatal neurons in vitro.  J Pineal Res. 2009;  46 87-94
  • 29 Ansurudeen I, Kopprasch S, Ehrhart-Bornstein M, Willenberg HS, Krug AW, Funk RH, Bornstein SR. Vascular-adrenal niche–endothelial cell-mediated sensitization of human adrenocortical cells to angiotensin II.  Horm Metab Res. 2006;  38 476-480
  • 30 Dickmeis T. Glucocorticoids and the circadian clock.  J Endocrinol. 2009;  200 3-22
  • 31 Engeland WC, Arnhold MM. Neural circuitry in the regulation of adrenal corticosterone rhythmicity.  Endocrine. 2005;  28 325-332

1 Both authors contributed equally to this work.

Correspondence

M. Seron-FerrePhD 

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