PATHOLOGICAL EFFECT OF ESTRADIOL ON THE HYPOTHALAMUS

Estradiol provides physiological signals to the brain throughout life that are indispensable for the development and regulation of reproduct ive function. In addition to its multiple physiological actions, we ha ve shown that estradiol is also selectively cytotoxic to beta-endorphi n neurons in the hypothalamic arcuate nucleus. The mechanism underlyin g this neurotoxic action appears to involve the conversion of estradio l to catechol estrogen and subsequent oxidation to o-semiquinone free radicals. The estradiol-induced loss of beta-endorphin neurons engende rs a compensatory increment in mu opioid binding in the medial preopti c area rendering this region supersensitive to residual beta-endorphin or to other endogenous opioids. The consequent persistent opioid inhi bition results in a cascade of neuroendocrine deficits that are ultima tely expressed as a chronically attenuated plasma LH pattern to which the ovaries respond by becoming anovulatory and polycystic. This neuro toxic action of estradiol may contribute to a number of reproductive d isorders in humans and in animals in which aberrant hypothalamic funct ion is a major component.