Cocaine is a commonly abused drug among reproductive age women. there is emerging clinical evidence that chronic cocaine use in women is associated with reproductive dysfunction, including decreased libido, irregular menstrual cycles and amenorrhea. Despite the growing epidemic of cocaine abuse and evidence associating it with reproductive dysfunction, there are no control studies that have assessed the effects of chronic cocaine use on hypothalamic-pituitary-ovarian axis and menstrual cyclicity in women or subhuman primates. Studies in rats have demonstrated cocaine disrupts estrous cyclicity, decreases ovulation rates and alters hypothalamic neurotransmitters that regulate gonadotropin-releasing hormone release. Extrapolation these findings to women or subhuman primates may not be appropriate because the regulation of reproductive function differs between rodents and primates. Accordingly, this proposal will assess the effects of daily follicular phase cocaine administration on reproductive function in normally cycling rhesus monkeys. The studies proposed will: (1) characterize the dose-response effects of daily follicular-phase cocaine administration on menstrual cyclicity, gonadotropin and ovarian steroid levels, ovulation rates, and corpus luteum function, (2) characterize the effects of daily follicular-phase cocaine administration on gonadotropin pulsatility, (3) determine whether daily follicular-phase cocaine administration directly impairs pituitary gonadotropin secretion, and (4) determine whether daily follicular-phase cocaine administration directly affects ovarian steroid secretion and ovulation. To accomplish these aims, monkeys will be placed in a mobile vest and tether assembly to allow drug administration and blood sampling without anesthesia or stress which are known to impair circulating hormone levels and ovarian/menstrual cyclicity. These studies will define cocaine's disruptive effects on ovarian/menstrual cyclicity and ovulation, and determine the dose of cocaine required to disrupt cyclicity. These studies will also determine cocaine's site of action within the hypothalamic-pituitary-ovarian axis, from which future studies may better determine cocaine's mechanism of action within each site in the axis. This information will be of value in the clinical management of reproductive dysfunction related to cocaine abuse.
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