We propose to continue and extend ongoing behavioral and biological studies of alcohol effects on female reproductive function to examine mechanisms of alcohol-induced menstrual cycle abnormalities. A model of alcoholism developed in rhesus monkeys, using operant behavioral techniques, will be used to study the hormonal correlates of amenorrhea, anovulation, luteal phase dysfunction and pathological changes of the ovaries and uterus associated with chronic alcohol intoxication. A major goal is to determine the primary site of alcohol's toxic effects on the hypothalamic-pituitary-ovarian axis. Alcohol's effects on the functional capacity of the hypothalamus, pituitary and ovary will be evaluated with provocative tests used in clinical endocrinology. The degree of impairment of gonadotropin release following stimulation with synthetic LHRH and naloxone will be compared in alcoholic, normal and ovariectomized females. Alcohol induced changes in episodic release patterns of gonadotropins will also be measured in ovariectomized females in which ovarian steroid regulation of gonadotropin release is eliminated. Integrated plasma samples will be collected for radioimmunoassay of pituitary and gonadal hormones. The possible reversibility of amenorrhea and anovulation induced by chronic alcohol self-administration will be examined by attempting to induce ovulation with pulsatile synthetic LHRH administration and/or clomiphene stimulation. The capacity of the reproductive system to develop """"""""tolerance"""""""" to chronic alcohol intoxication will also be evaluated. In those monkeys that self-administer moderate doses of alcohol and continue to menstruate, luteal phase adequacy and the frequency of ovulation will be assessed with pituitary-gonadal hormone profiles and laparoscopic examinations. The critical dose of alcohol and duration of exposure necessary to consistently disrupt menstrual cycle regularity will be studied in a programmed alcohol infusion model. The vulnerability of the mid-follicular and mid-luteal phase of the menstrual cycle to alcohol toxicity will also be compared in monkeys with normal ovulatory menstrual cycles. Finally, the effects of chronic alcohol intoxication on hypothalamic-pituitary function will be examined in ovariectomized female monkeys and the relative reinforcing effects of alcohol in ovariectomized and intact monkeys will be compared.
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