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29-01-2025 | Dexamethasone | Original Article

Melatonin modulation of the chronic dexamethasone-induced adrenal insufficiency

Authors: Banalata Mohanty, Brijesh Kumar Mishra

Published in: Endocrine

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Abstract

Purpose

Chronic exposure to synthetic glucocorticoids/GCs, widely in use to treat many diseases, may compromise the hypothalamic-pituitary-adrenal/HPA axis leading to a condition of adrenal insufficiency/AI. This study demonstrates the efficacy of the melatonin/MEL in amelioration of chronic dexamethasone (DEX)-induced AI.

Methods

Mice (Parkes Strain/Male/8 weeks old/30–33 g) were maintained in four groups (10 mice/group) for 30 days: Group 1/Control received intraperitoneal (i.p) vehicle (alcoholic 0.9% normal saline); Group II/DEX (400 µg/kg BW/day/i.p), Group III/(DEX + MEL 750 µg/kg BW/day/subcutaneous), and Group IV received only MEL. Adrenal, pituitary, and blood samples were collected from six mice/groups. Four mice/groups were subjected to the Lipopolysaccharide (LPS) challenge. Adrenal histology, ACTH immunohistochemistry, and plasma ACTH and corticosterone/CORT levels were measured.

Results

DEX exposure suppressed the pituitary ACTH expression significantly from control as revealed by morphometry and circulating hormones (Density, p < 0.01; size, immunointensity, plasma ACTH, and CORT; p < 0.001). Increased adrenal histopathology indicated probable AI. MEL co-supplementation significantly increased the corticotropes’ density (p < 0.05), size (p < 0.001), immunointensity (<0.01), and plasma level of ACTH (p < 0.01) compared to the DEX group. The adreno-cortical width, zona fasciculata cell density and size, and the plasma CORT level (p < 0.001) were also significantly increased. The enhanced CORT response of the HPA axis in the DEX + MEL group compared to the DEX group on the LPS challenge provides support for the MEL restoration of the HPA axis functioning.

Conclusion

Further research on the MEL modulation of the HPA axis may support its role in preventing AI.
Literature
1.
go back to reference M. Martinac, D. Pehar, D. Karlović, D. Babić, D. Marcinko, M. Jakovljević, Metabolic syndrome, activity of the hypothalamic-pituitary-adrenal axis and inflammatory mediators in depressive disorder. Acta Clin. Croat. 53, 55–71 (2014)PubMed M. Martinac, D. Pehar, D. Karlović, D. Babić, D. Marcinko, M. Jakovljević, Metabolic syndrome, activity of the hypothalamic-pituitary-adrenal axis and inflammatory mediators in depressive disorder. Acta Clin. Croat. 53, 55–71 (2014)PubMed
7.
go back to reference L.H Broersen, A.M Pereira, J.O.L Jørgensen, O.M Dekkers, Adrenal insufficiency in corticosteroids use: systematic review and meta-analysis. J. Clin. Endocrinol. Metab. 100(6), 2171–2180 (2015)CrossRefPubMed L.H Broersen, A.M Pereira, J.O.L Jørgensen, O.M Dekkers, Adrenal insufficiency in corticosteroids use: systematic review and meta-analysis. J. Clin. Endocrinol. Metab. 100(6), 2171–2180 (2015)CrossRefPubMed
8.
go back to reference S.W Borresen, M Klose, D Glintborg, T Watt, M.S Andersen, U Feldt-Rasmussen, Approach to the patient with glucocorticoid-induced adrenal insufficiency. J. Clin. Endocrinol. Metab. 107(7), 2065–2076 (2022)CrossRefPubMed S.W Borresen, M Klose, D Glintborg, T Watt, M.S Andersen, U Feldt-Rasmussen, Approach to the patient with glucocorticoid-induced adrenal insufficiency. J. Clin. Endocrinol. Metab. 107(7), 2065–2076 (2022)CrossRefPubMed
10.
go back to reference R Pofi, C Feliciano, E Sbardella, N Argese, C.P Woods, A.B Grossman, J.W Tomlinson, The short Synacthen (corticotropin) test can be used to predict recovery of hypothalamo-pituitary-adrenal axis function. J. Clin. Endocrinol. Metab. 103(8), 3050–3059 (2018)CrossRefPubMed R Pofi, C Feliciano, E Sbardella, N Argese, C.P Woods, A.B Grossman, J.W Tomlinson, The short Synacthen (corticotropin) test can be used to predict recovery of hypothalamo-pituitary-adrenal axis function. J. Clin. Endocrinol. Metab. 103(8), 3050–3059 (2018)CrossRefPubMed
11.
go back to reference J. Cipolla-Neto, F.G.D. Amaral, Melatonin as a hormone: new physiological and clinical insights. Endocr. Rev. 39, 990–1028 (2018)CrossRefPubMed J. Cipolla-Neto, F.G.D. Amaral, Melatonin as a hormone: new physiological and clinical insights. Endocr. Rev. 39, 990–1028 (2018)CrossRefPubMed
12.
go back to reference J. Falcón, L. Besseau, M. Fuentès, S. Sauzet, E. Magnanou, G. Boeuf, Structural and functional evolution of the pineal melatonin system in vertebrates. Ann. N. Y. Acad. Sci. 1163, 101–111 (2009)CrossRefPubMed J. Falcón, L. Besseau, M. Fuentès, S. Sauzet, E. Magnanou, G. Boeuf, Structural and functional evolution of the pineal melatonin system in vertebrates. Ann. N. Y. Acad. Sci. 1163, 101–111 (2009)CrossRefPubMed
14.
go back to reference R.J. Reiter, J.C. Mayo, D.X. Tan, R.M. Sainz, M. Alatorre-Jimenez, L. Qin, Melatonin as an antioxidant: under promises but over delivers. J. Pineal Res. 61, 253–278 (2016)CrossRefPubMed R.J. Reiter, J.C. Mayo, D.X. Tan, R.M. Sainz, M. Alatorre-Jimenez, L. Qin, Melatonin as an antioxidant: under promises but over delivers. J. Pineal Res. 61, 253–278 (2016)CrossRefPubMed
15.
go back to reference R. Konakchieva, Y. Mitev, O.F. Almeida, V.K. Patchev, Chronic melatonin treatment and the hypothalamo-pituitary-adrenal axis in the rat: attenuation of the secretory response to stress and effects on hypothalamic neuropeptide content and release. Biol. Cell 89, 587–596 (1997)PubMed R. Konakchieva, Y. Mitev, O.F. Almeida, V.K. Patchev, Chronic melatonin treatment and the hypothalamo-pituitary-adrenal axis in the rat: attenuation of the secretory response to stress and effects on hypothalamic neuropeptide content and release. Biol. Cell 89, 587–596 (1997)PubMed
16.
go back to reference R. Konakchieva, Y. Mitev, O.F. Almeida, V.K. Patchev, Chronic melatonin treatment counteracts glucocorticoid-induced dysregulation of the hypothalamic-pituitary-adrenal axis in the rat. Neuroendocrinology 67, 171–180 (1998)CrossRefPubMed R. Konakchieva, Y. Mitev, O.F. Almeida, V.K. Patchev, Chronic melatonin treatment counteracts glucocorticoid-induced dysregulation of the hypothalamic-pituitary-adrenal axis in the rat. Neuroendocrinology 67, 171–180 (1998)CrossRefPubMed
17.
go back to reference C. Torres-Farfan, F.J. Valenzuela, R. Ebensperger, N. Méndez, C. Campino, H.G. Richter, M. Serón-Ferré, Circadian cortisol secretion and circadian adrenal responses to ACTH are maintained in dexamethasone suppressed capuchin monkeys (Cebus apella). Am. J. Primatol. 70, 93–100 (2008)CrossRefPubMed C. Torres-Farfan, F.J. Valenzuela, R. Ebensperger, N. Méndez, C. Campino, H.G. Richter, M. Serón-Ferré, Circadian cortisol secretion and circadian adrenal responses to ACTH are maintained in dexamethasone suppressed capuchin monkeys (Cebus apella). Am. J. Primatol. 70, 93–100 (2008)CrossRefPubMed
18.
go back to reference Y.H. Wu, J.N. Zhou, R. Balesar, U. Unmehopa, A. Bao, R. Jockers, J. Van Heerikhuize, D.F. Swaab, Distribution of MT1 melatonin receptor immunoreactivity in the human hypothalamus and pituitary gland: colocalization of MT1 with vasopressin, oxytocin, and corticotropin-releasing hormone. J. Comp. Neurol. 499, 897–910 (2006). https://doi.org/10.1002/cne.21152CrossRefPubMed Y.H. Wu, J.N. Zhou, R. Balesar, U. Unmehopa, A. Bao, R. Jockers, J. Van Heerikhuize, D.F. Swaab, Distribution of MT1 melatonin receptor immunoreactivity in the human hypothalamus and pituitary gland: colocalization of MT1 with vasopressin, oxytocin, and corticotropin-releasing hormone. J. Comp. Neurol. 499, 897–910 (2006). https://​doi.​org/​10.​1002/​cne.​21152CrossRefPubMed
20.
go back to reference K Ekthuwapranee, A Sotthibundhu, C Tocharus, P Govitrapong, Melatonin ameliorates dexamethasone-induced inhibitory effects on the proliferation of cultured progenitor cells obtained from adult rat hippocampus. J. Steroid Biochem. Mole Biol. 14, 538–548 (2015a) K Ekthuwapranee, A Sotthibundhu, C Tocharus, P Govitrapong, Melatonin ameliorates dexamethasone-induced inhibitory effects on the proliferation of cultured progenitor cells obtained from adult rat hippocampus. J. Steroid Biochem. Mole Biol. 14, 538–548 (2015a)
21.
go back to reference D.M. Mokhtar, M.T. Hussein, A.H. Hassan, Melatonin elicits stimulatory action on the adrenal gland of Soay ram: morphometrical, immunohistochemical, and ultrastructural study. Microsc. Microanal. 23, 1173–1188 (2017)CrossRefPubMed D.M. Mokhtar, M.T. Hussein, A.H. Hassan, Melatonin elicits stimulatory action on the adrenal gland of Soay ram: morphometrical, immunohistochemical, and ultrastructural study. Microsc. Microanal. 23, 1173–1188 (2017)CrossRefPubMed
22.
go back to reference M.T. Hussein, D.M. Mokhtar, A.H.S. Hassan, Melatonin activates the vascular elements, telocytes, and neuroimmune communication in the adrenal gland of Soay rams during the non-breeding season. Protoplasma 257, 353–369 (2020)CrossRefPubMed M.T. Hussein, D.M. Mokhtar, A.H.S. Hassan, Melatonin activates the vascular elements, telocytes, and neuroimmune communication in the adrenal gland of Soay rams during the non-breeding season. Protoplasma 257, 353–369 (2020)CrossRefPubMed
23.
go back to reference W. Tongjaroenbuangam, N. Ruksee, T. Mahanam, P. Govitrapong, Melatonin attenuates dexamethasone-induced spatial memory impairment and dexamethasone-induced reduction of synaptic protein expressions in the mouse brain. Neurochem. Int. 63, 482–491 (2013)CrossRefPubMed W. Tongjaroenbuangam, N. Ruksee, T. Mahanam, P. Govitrapong, Melatonin attenuates dexamethasone-induced spatial memory impairment and dexamethasone-induced reduction of synaptic protein expressions in the mouse brain. Neurochem. Int. 63, 482–491 (2013)CrossRefPubMed
24.
go back to reference N. Ruksee, W. Tongjaroenbuangam, T. Mahanam, P. Govitrapong, Melatonin pretreatment prevented the effect of dexamethasone negative alterations on behavior and hippocampal neurogenesis in the mouse brain. J. Steroid Biochem. Mole Biol. 14, 372–380 (2014) N. Ruksee, W. Tongjaroenbuangam, T. Mahanam, P. Govitrapong, Melatonin pretreatment prevented the effect of dexamethasone negative alterations on behavior and hippocampal neurogenesis in the mouse brain. J. Steroid Biochem. Mole Biol. 14, 372–380 (2014)
26.
go back to reference B. Mohanty, S.P. Pandey, K. Tsutsui, Thyroid disrupting pesticides impair the hypothalamic-pituitary-testicular axis of a wildlife bird. Amandava amandava. Reprod. Toxicol. 71, 32–41 (2017)CrossRefPubMed B. Mohanty, S.P. Pandey, K. Tsutsui, Thyroid disrupting pesticides impair the hypothalamic-pituitary-testicular axis of a wildlife bird. Amandava amandava. Reprod. Toxicol. 71, 32–41 (2017)CrossRefPubMed
27.
go back to reference S.P. Pandey, B. Mohanty, Role of the testicular capsule in seasonal modulation of the testis. J. Exp. Zool. A Ecol. Integ. Physiol. 339, 898–910 (2023)CrossRef S.P. Pandey, B. Mohanty, Role of the testicular capsule in seasonal modulation of the testis. J. Exp. Zool. A Ecol. Integ. Physiol. 339, 898–910 (2023)CrossRef
28.
go back to reference B. Mohanty, Seasonality of reproduction in a subtropical free living finch Amandava amandava: plasticity of adenohypophyseal gonadotropes, lactotropes and thyrotropes. Neuroendocrinology 114, 538–552 (2024)CrossRefPubMed B. Mohanty, Seasonality of reproduction in a subtropical free living finch Amandava amandava: plasticity of adenohypophyseal gonadotropes, lactotropes and thyrotropes. Neuroendocrinology 114, 538–552 (2024)CrossRefPubMed
29.
go back to reference A.B. Ginsberg, S. Campeau, H.E. Day, R.L. Spencer, Acute glucocorticoid pretreatment suppresses stress-induced hypothalamic-pituitary-adrenal axis hormone secretion and expression of corticotropin-releasing hormone hnRNA but does not affect c-fos mRNA or fos protein expression in the paraventricular nucleus of the hypothalamus. J. Neuroendocrinol. 15, 1075–1083 (2003)CrossRefPubMed A.B. Ginsberg, S. Campeau, H.E. Day, R.L. Spencer, Acute glucocorticoid pretreatment suppresses stress-induced hypothalamic-pituitary-adrenal axis hormone secretion and expression of corticotropin-releasing hormone hnRNA but does not affect c-fos mRNA or fos protein expression in the paraventricular nucleus of the hypothalamus. J. Neuroendocrinol. 15, 1075–1083 (2003)CrossRefPubMed
30.
go back to reference C. Tsigos, G.P. Chrousos, Hypothalamic–pituitary–adrenal axis, neuroendocrine factors and stress. J. Psychosom. Res. 53, 865–871 (2002)CrossRefPubMed C. Tsigos, G.P. Chrousos, Hypothalamic–pituitary–adrenal axis, neuroendocrine factors and stress. J. Psychosom. Res. 53, 865–871 (2002)CrossRefPubMed
31.
go back to reference N. Sousa, J.J. Cerqueira, O.F. Almeida, Corticosteroid receptors and neuroplasticity. Brain Res. Rev. 57, 561–570 (2008)CrossRefPubMed N. Sousa, J.J. Cerqueira, O.F. Almeida, Corticosteroid receptors and neuroplasticity. Brain Res. Rev. 57, 561–570 (2008)CrossRefPubMed
33.
go back to reference P. Szot, C.W. Wilkinson, S.S. White, J.B. Leverenz, J.L. Greenup, E.A. Colasurdo, M.A. Raskind, Chronic cortisol suppresses pituitary and hypothalamic peptide message expression in pigtailed macaques. Neuroscience 126, 241–246 (2004)CrossRefPubMed P. Szot, C.W. Wilkinson, S.S. White, J.B. Leverenz, J.L. Greenup, E.A. Colasurdo, M.A. Raskind, Chronic cortisol suppresses pituitary and hypothalamic peptide message expression in pigtailed macaques. Neuroscience 126, 241–246 (2004)CrossRefPubMed
34.
36.
go back to reference C. Grossmann, T. Scholz, M. Rochel, C. Bumke-Vogt, W. Oelkers, A.F. Pfeiffer, S. Diederich, V. Bahr, Transactivation via the human glucocorticoid and mineralocorticoid receptor by therapeutically used steroids in CV-1 cells: a comparison of their glucocorticoid and mineralocorticoid properties. Eur. J. Endocrinol. 1, 397–406 (2004). https://doi.org/10.1530/eje.0.1510397CrossRef C. Grossmann, T. Scholz, M. Rochel, C. Bumke-Vogt, W. Oelkers, A.F. Pfeiffer, S. Diederich, V. Bahr, Transactivation via the human glucocorticoid and mineralocorticoid receptor by therapeutically used steroids in CV-1 cells: a comparison of their glucocorticoid and mineralocorticoid properties. Eur. J. Endocrinol. 1, 397–406 (2004). https://​doi.​org/​10.​1530/​eje.​0.​1510397CrossRef
38.
go back to reference W. Pierpaoli, G.J. Maestroni, Melatonin: a principal neuroimmunoregulatory and anti-stress hormone: its anti-aging effects. Immunol Lett. 16, 355–361 (1987)CrossRefPubMed W. Pierpaoli, G.J. Maestroni, Melatonin: a principal neuroimmunoregulatory and anti-stress hormone: its anti-aging effects. Immunol Lett. 16, 355–361 (1987)CrossRefPubMed
39.
42.
go back to reference J.B Zawilska, M Sadowska, Prolonged treatment with glucocorticoid dexamethasone suppresses melatonin production by the chick pineal gland and retina. Pol. J. Pharm. 54, 61–66 (2002) J.B Zawilska, M Sadowska, Prolonged treatment with glucocorticoid dexamethasone suppresses melatonin production by the chick pineal gland and retina. Pol. J. Pharm. 54, 61–66 (2002)
47.
go back to reference I. Quiros, J.C. Mayo, O. Garcia-Suarez, D. Hevia, V. Martin, C. Rodríguez, R.M. Sainz, Melatonin prevents glucocorticoid inhibition of cell proliferation and toxicity in hippocampal cells by reducing glucocorticoid receptor nuclear translocation. J. Steroid Biochem. Mole Biol. 110, 116–124 (2008). https://doi.org/10.1016/j.jsbmb.2008.02.009CrossRef I. Quiros, J.C. Mayo, O. Garcia-Suarez, D. Hevia, V. Martin, C. Rodríguez, R.M. Sainz, Melatonin prevents glucocorticoid inhibition of cell proliferation and toxicity in hippocampal cells by reducing glucocorticoid receptor nuclear translocation. J. Steroid Biochem. Mole Biol. 110, 116–124 (2008). https://​doi.​org/​10.​1016/​j.​jsbmb.​2008.​02.​009CrossRef
48.
go back to reference K Ekthuwapranee, A Sotthibundhu, P Govitrapong, Melatonin attenuates methamphetamine-induced inhibition of proliferation of adult rat hippocampal progenitor cells in vitro. J. Pineal Res. 58, 418–428 (2015b)CrossRefPubMed K Ekthuwapranee, A Sotthibundhu, P Govitrapong, Melatonin attenuates methamphetamine-induced inhibition of proliferation of adult rat hippocampal progenitor cells in vitro. J. Pineal Res. 58, 418–428 (2015b)CrossRefPubMed
Metadata
Title
Melatonin modulation of the chronic dexamethasone-induced adrenal insufficiency
Authors
Banalata Mohanty
Brijesh Kumar Mishra
Publication date
29-01-2025
Publisher
Springer US
Published in
Endocrine
Print ISSN: 1355-008X
Electronic ISSN: 1559-0100
DOI
https://doi.org/10.1007/s12020-025-04175-1

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