Corticotropin-Releasing Hormone Inhibits Melatonin Secretion in Healthy Volunteers – A Potential Link to Low-Melatonin Syndrome in Depression?

Abstract

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 µg human CRH, 1 µg 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.

Changes of Sleep Architecture, Spectral Composition of Sleep EEG, the Nocturnal Secretion of Cortisol, ACTH, GH, Prolactin, Melatonin, Ghrelin, and Leptin, and the DEX-CRH Test in Depressed Patients during Treatment with Mirtazapine

“…This effect may be explained by the alpha-adrenergic action of the substance. Furthermore, it is of interest that nocturnal melatonin levels were blunted after repetitive CRH administration in normal controls (Kellner et al, 1997). Therefore, suppression of HPA activity may have contributed to the increase of melatonin after mirtazapine.…”

“…Besides CRH overactivity, elevated glucocorticoid levels may lead to sleep-EEG changes in patients with depression (Antonijevic and Steiger, 2003). Furthermore, enhanced HPA activity is thought to contribute to blunted melatonin levels (Kellner et al, 1997) and to elevated leptin levels (Antonijevic et al, 1998) in depression. To further elucidate the effects of mirtazapine on sleep and endocrine activity and the related mechanisms including HPA system changes, we performed a study in patients with depression.…”

Chronic Melatonin Treatment Counteracts Glucocorticoid-Induced Dysregulation of the Hypothalamic-Pituitary-Adrenal Axis in the Rat

“…major depression) [11, 12, 13] led to the view that links may exist between impairment of MEL-sensitive mechanisms and behavioral and neuroendocrine symptoms in stress-related and affective disorders, dementia and aging [14, 15]. While earlier studies emphasized the potential importance of impaired MEL secretion for the pathogenesis of sleep disturbances and shifts in circadian rhythmicity in these conditions [16], a recent work demonstrated a direct influence of the principal stimulator of the HPA axis, corticotropin-releasing hormone (CRH), on MEL secretion in humans, thus suggesting a possibility for a mutual feedback between the HPA axis and pineal gland [17]. However, the interactions of MEL with the regulation of the HPA axis are far from clarified: despite the documented abundance of MEL binding sites in the pars tuberalis of the pituitary gland and reports of direct influences of MEL on the adrenal cortex [18, 19], other studies suggest that the relationship between MEL and HPA activity may not be that simple [20].…”

Hypothalamic-pituitary-adrenal axis in the night eating syndrome

“…In this way, melatonin treatment may protect against disruptions caused by stress and thereby may reestablish homeostasis (16). Moreover, as reported earlier, CRH may also inhibit secretion of melatonin in humans (13). Therefore, the disturbances observed in the melatonin secretion in the night eaters may reflect an apparent overexpressed HPA axis.…”