Cortisol, melatonin, and leptin are regulatory hormones with typical circadian rhythms that regulate various physiological and metabolic functions. Another main regulator is the hypothalamic-pituitaryadrenal (HPA) axis, which coordinates several biological functions. The circadian rhythms represent the biological endocrine clock, whereas the HPA represents the stress-induced biological response. However, the interplay between these two main regulators of biological functions is not well understood. Therefore, observations of irregular secretions of circadian neuroendocrine secretions inclusive of cortisol are of special interest, as the night eating syndrome most likely represents changes in the HPA axis.
Melatonin is the primary substance secreted by the pineal gland, which modulates the adrenal (HPA) axis during clinical illness, the serotonergic system in psychiatric disease, as well as the body's general response to stress.
Melatonin is synthesized within the pineal gland from tryptophan via the pathway shown in the figure above.2 The secretion pattern is generated within the suprachiasmatic nucleus (SCN). Synthesis occurs upon exposure to darkness, with the increased activity of serotonin-N-acetyltransferase. By the action of hydroxyindole-O-methyltransferase (HIOMT), N-acetylserotonin is converted to melatonin. Melatonin is then rapidly secreted into the vascular system and, possibly, into the cerebrospinal fluid.3
Peripheral tissues, such as the retina and the gut, are also known to synthesize melatonin.4
Dysregulation of the hypothalamo-pituitary-adrenal axis is related to the clinical course of MS
F. Then Bergh, MD, T. Kümpfel, MD, C. Trenkwalder, MD, R. Rupprecht, MD and F. Holsboer, MD, PhD
From the Max Planck Institute of Psychiatry, Neurology, Muenchen, Germany.
Address correspondence and reprint requests to Dr. Florian Then Bergh, Neurologische Klinik, Klinikum Grosshadern, Marchioninistr. 15, D-81377 Muenchen, Germany.
OBJECTIVE: To investigate whether dysregulation of the hypothalamo–pituitary–adrenal (HPA) axis is related to clinical characteristics in MS.
METHODS: The authors performed the combined dexamethasone–corticotropin-releasing hormone test (Dex-CRH test) in 60 MS patients and 29 healthy control subjects. In addition, the short adrenocorticotropic hormone (ACTH) test was performed in 39 consecutive patients. All patients had active disease and none were treated with glucocorticoids, immunosuppressants, or immunomodulators.
RESULTS: The patients had an exaggerated rise in plasma cortisol concentrations in the Dex-CRH test (p < 0.05), indicating hyperactivity of the HPA system. The degree of hyperactivity was moderate in relapsing–remitting MS patients (n = 38; area under the time-course curve for cortisol [AUC-Cort] 226.2 ± 38.9 arbitrary units [AU], mean ± SEM), intermediate in secondary progressive MS patients (n = 16; AUC-Cort, 286.8 ± 60.2 AU), and marked in primary progressive MS patients (n = 6; AUC-Cort, 670.6 ± 148.6 AU). Differences were significant between the three patient groups (p < 0.005), and between control subjects (n = 29; AUC-Cort, 150.8 ± 34.1 AU) and each patient group. Indicators of HPA axis activation correlated with neurologic disability (Kurtzke’s Expanded Disability Status Scale), but not with the duration of the disease, number of previous relapses, previous corticosteroid treatments, or depressed mood (Hamilton Depression Scale). The ACTH test was normal in 31 of the 33 patients studied.
CONCLUSION: HPA axis hyperactivity in MS is related to the clinical type of disease, with a suggestion of increasing HPA axis dysregulation with disease progression.
Maestroni, G. J. (2001). "The immunotherapeutic potential of melatonin." Expert Opin Investig Drugs 10(3): 467-76.
The interaction between the brain and the immune system is essential for the adaptive response of an organism against environmental challenges. In this context, the pineal neurohormone melatonin (MEL) plays an important role. T-helper cells express G-protein coupled cell membrane MEL receptors and, perhaps, MEL nuclear receptors. Activation of MEL receptors enhances the release of T-helper cell Type 1 (Th1) cytokines, such as gamma-interferon (gamma-IFN) and IL-2, as well as of novel opioid cytokines. MEL has been reported also to enhance the production of IL-1, IL-6 and IL-12 in human monocytes. These mediators may counteract stress-induced immunodepression and other secondary immunodeficiencies and protect mice against lethal viral encephalitis, bacterial diseases and septic shock. Therefore, MEL has interesting immunotherapeutic potential in both viral and bacterial infections. MEL may also influence haemopoiesis either by stimulating haemopoietic cytokines, including opioids, or by directly affecting specific progenitor cells such as pre-B cells, monocytes and NK cells. MEL may thus be used to stimulate the immune response during viral and bacterial infections as well as to strengthen the immune reactivity as a prophylactic procedure. In both mice and cancer patients, the haemopoietic effect of MEL may diminish the toxicity associated with common chemotherapeutic protocols. Through its pro-inflammatory action, MEL may play an adverse role in autoimmune diseases. Rheumatoid arthritis patients have increased nocturnal plasma levels of MEL and their synovial macrophages respond to MEL with an increased production of IL-12 and nitric oxide (NO). In these patients, inhibition of MEL synthesis or use of MEL antagonists might have a therapeutic effect. In other diseases such as multiple sclerosis the role of MEL is controversial. However, the correct therapeutic use of MEL or MEL antagonists should be based on a complete understanding of their mechanism of action. It is not yet clear whether MEL acts only on Th1 cells or also on T-helper Type 2 cells (Th2). This is an important point as the Th1/Th2 balance is of crucial importance in the immune system homeostasis. Furthermore, MEL being the endocrine messenger of darkness, its endogenous synthesis depends on the photoperiod and shows seasonal variations. Similarly, the pharmacological effects of MEL might also be season-dependent. No information is available concerning this point. Therefore, studies are needed to investigate whether the immunotherapeutic effect of MEL changes with the alternating seasons.
Neuroendocrinology. 1997 Apr;65(4):284-90.Links
Corticotropin-releasing hormone inhibits melatonin secretion in healthy volunteers--a potential link to low-melatonin syndrome in depression?
Kellner M, Yassouridis A, Manz B, Steiger A, Holsboer F, Wiedemann K.
Department of Psychiatry, Max Planck Institute of Psychiatry, Munich, Germany. email@example.com
Interactions between the hypothalamic-pituitary-adrenocortical (HPA) system and melatonin secretion have been demonstrated, but only the effects of melatonin on the activity of the HPA system have been studied in man. Alterations of melatonin secretion described as low-melatonin syndrome have been demonstrated in patients suffering from a major depressive episode, and an inhibitory factor on melatonin secretion has been postulated. We investigated whether corticotropin-releasing hormone (CRH), which is thought to be involved in HPA abnormalities in depressed patients, can also suppress melatonin secretion in healthy volunteers. Ten healthy male human volunteers in a double-blind study design received randomized hourly intravenous injections from 08.00 to 18.00 h that contained 10 micrograms human CRH, 1 microgram adrenocorticotropic hormone (ACTH), or placebo to simulate pulsatile hormone secretion. Plasma melatonin and cortisol responses during the treatment and nocturnal sleep electroencephalograms after the treatment were recorded. Administration of CRH reduced melatonin secretion significantly below values obtained after administration of placebo and ACTH. Cortisol secretion was significantly enhanced by ACTH in comparison to both placebo and CRH. Electroencephalographic sleep parameters revealed no treatment effects. Our findings suggest that CRH has an inhibitory effect on the pineal secretion of melatonin in normal man. A mechanism via a release of cortisol was not supported by our results. Secondary hormonal effects from changes in nocturnal sleep architecture were excluded. Further investigation of the action of CRH on melatonin secretion as well as the mutual feedback between the HPA system and the pineal gland may extend our knowledge of neuroendocrine alterations mediating the adaptive response to stress and the eventual involvement in the pathogenesis of depression.
Neurol Sci. 2001 Apr;22(2):159-62. Related Articles, Links
Stress, glucocorticoids and the susceptibility to develop autoimmune disorders of the central nervous system.
Morale C, Brouwer J, Testa N, Tirolo C, Barden N, Dijkstra CD, Amor S, Marchetti B.
Neuropharmacology Unit, OASI (IRCCS), Institute for Research and Care on Mental Retardation and Brain Aging, Troina (EN), Italy.
Alterations of the immunoendocrine circuit along the hypothalamic-pituitary-adrenocortical (HPA) axis in various autoimmune diseases have recently been observed, suggesting a modulatory role of this feedback regulation in the pathogenesis of autoimmune diseases. Susceptibility to experimental autoimmune encephalomyelitis (EAE) may be influenced by variations in the production of endogenous glucocorticoid hormones (GC). The adrenocortical response is central to recovery from EAE in the Lewis rat, as reflected by increased severity of the disease in adrenalectomized animals. The key role of GC in modifying the induction and progression of EAE is also emphasized by a reversal of corticoid-mediated effects through treatment with glucocorticoid receptor (GR) antagonists. We studied the relationship between defective GR function and susceptibility to EAE in transgenic (Tg) mice expressing GR antisense RNA. EAE was induced with the encephalitogenic myelin oligodendrocyte peptide (pMOG 36-50) in wild type (Wt) and transgenic (Tg) female mice bearing GR antisense RNA. pMOG 36-50 induced typical EAE in Wt mice but not in Tg mice. Histological examination of brains and spinal cords of Wt mice showed the presence of inflammation and/or demyelination, whereas in Tg mice neither were present. Although the mechanisms underlying the resistance of Tg mice to EAE induction are not yet clarified, compensatory changes at different levels of the HPA-immune axis in response to the potent immunogenic challenge are likely to participate in the observed effects. This work underlies the plasticity of the HPA-immune axis and suggests that pharmacological manipulation of neuroendocrine-immune networks may be a therapy of multiple sclerosis.
PMID: 11603619 [PubMed - indexed for MEDLINE]
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