The neurotoxic effects of estradiol on hypothalamic arcuate neurons were examined in a model of chronic estrogenization induced by means of a single injection of estradiol valerate (EV). Eight weeks after EV treatment, a 60% decrease in the total number of beta-endorphin-immunoreactive neurons was detected in the arcuate nucleus. In contrast, the numbers of neurotensin-, somatostatin-, and tyrosine hydroxylase-immunoreactive neurons were unchanged, suggesting that the effects of estradiol were selective for beta-endorphin neurons. Further evidence for the selectivity of estradiol's actions was provided by RIAs indicating decreases in hypothalamic beta-endorphin concentrations, but not in Metenkephalin or neuropeptide-Y concentrations. Cell counts performed in Nissl-stained material using unbiased stereological methods revealed a reduction in the total number of neurons in the EV-treated group compared to that in the controls. The estimated number of neurons lost (approximately 3500) corresponded precisely with the total number of beta-endorphin neurons lost (approximately 3600), as estimated using quantitative immunocytochemistry. These results confirm the selectivity of estradiol's effect on the beta-endorphin cell population and demonstrate that the observed decrease in beta-endorphin immunoreactivity reflects actual cell loss. The evidence indicates that the selective neurotoxic effect of estradiol on hypothalamic beta-endorphin neurons contributes to reproductive senescence, suggesting that steroids may participate in disruption of the biological functions that they normally facilitate.

Estradiol provides physiological signals to the brain throughout life that are indispensable for the development and regulation of reproductive function. In addition to its multiple physiological actions, we have shown that estradiol is also selectively cytotoxic to beta-endorphin neurons in the hypothalamic arcuate nucleus. The mechanism underlying this neurotoxic action appears to involve the conversion of estradiol to catechol estrogen and subsequent oxidation to o-semiquinone free radicals. The estradiol-induced loss of beta-endorphin neurons engenders a compensatory increment in mu opioid binding in the medial preoptic area rendering this region supersensitive to residual beta-endorphin or to other endogenous opioids. The consequent persistent opioid inhibition results in a cascade of neuroendocrine deficits that are ultimately expressed as a chronically attenuated plasma LH pattern to which the ovaries respond by becoming anovulatory and polycystic. This neurotoxic action of estradiol may contribute to a number of reproductive disorders in humans and in animals in which aberrant hypothalamic function is a major component.

The neurotoxic effects of estradiol on hypothalamic arcuate neurons were examined in a model of chronic estrogenization induced by means of a single injection of estradiol valerate (EV). Eight weeks after EV treatment, a 60% decrease in the total number of beta-endorphin-immunoreactive neurons was detected in the arcuate nucleus. In contrast, the numbers of neurotensin-, somatostatin-, and tyrosine hydroxylase-immunoreactive neurons were unchanged, suggesting that the effects of estradiol were selective for beta-endorphin neurons. Further evidence for the selectivity of estradiol's actions was provided by RIAs indicating decreases in hypothalamic beta-endorphin concentrations, but not in Metenkephalin or neuropeptide-Y concentrations. Cell counts performed in Nissl-stained material using unbiased stereological methods revealed a reduction in the total number of neurons in the EV-treated group compared to that in the controls. The estimated number of neurons lost (approximately 3500) corresponded precisely with the total number of beta-endorphin neurons lost (approximately 3600), as estimated using quantitative immunocytochemistry. These results confirm the selectivity of estradiol's effect on the beta-endorphin cell population and demonstrate that the observed decrease in beta-endorphin immunoreactivity reflects actual cell loss. The evidence indicates that the selective neurotoxic effect of estradiol on hypothalamic beta-endorphin neurons contributes to reproductive senescence, suggesting that steroids may participate in disruption of the biological functions that they normally facilitate.