title: Estrogen-induced hypothalamic beta-endorphin neuron loss: a possible model of hypothalamic aging.
abstract: Over the course of normal aging, all female mammals with regular cycles display an irreversible arrest of cyclicity at mid-life. Males, in contrast, exhibit gametogenesis until death. Although it is widely accepted that exposure to estradiol throughout life contributes to reproductive aging, a unified hypothesis of the role of estradiol in reproductive senescence has yet to emerge. Recent evidence derived from a rodent model of chronic estradiol-mediated accelerated reproductive senescence now suggests such a hypothesis. It has been shown that chronic estradiol exposure results in the destruction of greater than 60% of all beta-endorphin neurons in the arcuate nucleus while leaving other neuronal populations spared. This loss of opioid neurons is prevented by treatment with antioxidants indicating that it results from estradiol-induced formation of free radicals. Furthermore, we have shown that this beta-endorphin cell loss is followed by a compensatory upregulation of mu opioid receptors in the vicinity of LHRH cell bodies. The increment in mu opioid receptors presumably renders the opioid target cells supersensitive to either residual beta-endorphin or other endogenous mu ligands, such as met-enkephalin, thus resulting in chronic opioid suppression of the pattern of LHRH release, and subsequently that of LH. Indeed, prevention of the neuroendocrine effects of estradiol by antioxidant treatment also prevents the cascade of neuroendocrine aberrations resulting in anovulatory acyclicity. The loss of beta-endorphin neurons along with the paradoxical opioid supersensitivity which ensues, provides a unifying framework in which to interpret the diverse features that characterize the reproductively senescent female.
authors.affiliation: Department of Psychiatry, Montreal Neurological Institute, Douglas Hospital Research Center, Quebec, Canada.
authors.forename: G C
authors.initials: GC
authors.lastname: Desjardins
authors.forename: A
authors.initials: A
authors.lastname: Beaudet
authors.forename: M J
authors.initials: MJ
authors.lastname: Meaney
authors.forename: J R
authors.initials: JR
authors.lastname: Brawer
mesh_terms: D000375:Aging / Q000473:pathology / Q000502:physiology*; D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D004958:Estradiol / Q000633:toxicity*; D004967:Estrogens / Q000502:physiology; D005260:Female; D006801:Humans; D007031:Hypothalamus / Q000187:drug effects* / Q000473:pathology; D008297:Male; D008954:Models, Biological; D009474:Neurons / Q000187:drug effects / Q000473:pathology; D010902:Pituitary Gland / Q000187:drug effects / Q000502:physiology; D017450:Receptors, Opioid, mu / Q000378:metabolism; D012098:Reproduction / Q000187:drug effects / Q000502:physiology; D001615:beta-Endorphin / Q000502:physiology
chemical_list: D000975:Antioxidants; D004967:Estrogens; D017450:Receptors, Opioid, mu; D004958:Estradiol; D001615:beta-Endorphin