CONTRACEPTION WITH MINI DOSE ANTIPROGESTIN IN MACAQUES

该项目是IRPG提案的一部分，其总体目标是 临床和实验室科学家一起开发一种新的 基于抗孕激素的避孕策略。IRPG， 由3个相互关联的项目组成，基于支持的假设 通过对几个物种的初步研究，低剂量的抗- 卵泡刺激素允许卵巢周期性，但改变了卵巢的功能。 下丘脑-垂体-卵巢-生殖道避孕 入会仪式本项目的实验将利用成年雌性 恒河猴（1）表征长效亲本形式的抗 并建立最佳途径和低剂量，不诱导 月经过早，（2）确定是否长期暴露于低剂量抗- 睾丸素损害卵巢/生殖道的功能， 引起闭经或月经周期不规则，有明显的毒性作用， 生殖能力的不可逆变化，以及（3）试验低剂量 在骑自行车的猴子中使用抗-resistin的方案， 怀孕研究最初将集中在测试仓库 配方，如 作为用于皮下植入的丸粒， 肌肉注射用微球，输出容量，释放度 动力学和持续时间、局部和全身毒性以及剂量相关性 诱导月经提前的能力。 然后是媒介物和选定剂量的 将对正常的骑自行车的猴子施用抗β-半乳糖苷酶蛋白4个月。 卵巢类固醇、垂体促性腺激素和抗- 卵泡和黄体期长度和月经周期， 以及排卵和子宫成熟的直接指标， 治疗组间和组内比较，作为 治疗间隔。下一个媒介物或一剂或多剂抗-白细胞介素将是 对与雄性关在一起的雌性猴（成对圈养：1只雄性 + （1）整个繁殖季节。怀孕初期， 经超声检查证实， 动物/组分析每个随后的周期。胎儿流产，妊娠 长度和分娩时的胎儿体重将在组间进行比较。 长期暴露于抗-β-胡萝卜素的猴子（及其后代，如果 任何）将用于组织的毒理学评价。额外 接受抗生育剂量的anti-resistin的猴子将 在接下来的繁殖季节用溶剂处理，以评估 行动的可逆性。研制实用的 低剂量的抗孕激素，可以安全有效地避孕， 恒河猴在保持月经周期的同时，将支持这一步骤， 考虑采用这种方法控制妇女生育的广泛计划。

This project is part of an IRPG proposal whose overall goal is to bring together clinical and laboratory scientists to develop a novel contraceptive strategy based upon the anit-progestins. The IRPG, which consists of 3 interlocking projects, is based on the hypothesis supported by preliminary studies in several species that low doses of anti- progestin permit ovarian cyclicity, yet alter the function of the hypothalamus-pituitary-ovary-reproductive tract to prevent pregnancy initiation. Experiments in the current project will utilize adult, female rhesus monkeys to (1) characterize long-acting parental forms of anti- progestin and establish optimal routes and low doses that do not induce premature menses, (2) determine if chronic exposure to low-dose anit- progestin impairs the function of the ovary/reproductive tract without causing amenorrhea or irregular cyclicity, significant toxic effects or irreversible changes in reproductive capacity, and (3) test low-dose regimens of anti-progestin in cycling monkeys for protection against pregnancy. Research will initially concentrate on testing depot formulations, such as pellets for subcutaneous implantation and microspheres for intramuscular injection, for output capacity, release kinetics and duration, local and systemic toxicity, and dose-related ability to induce premature menses. Then vehicle and selected dose of anti-progestin will administered to normal cycling monkeys for 4 months. Circulating levels of ovarian steroids, pituitary gonadotropins and anti- progestin, lengths of follicular and luteal phases and menstrual cycle, as well as direct indices of ovulation and uterine maturation will be compared between treatment groups and within groups as a function of treatment interval. Next vehicle or a dose(s) of anti-progestin will be administered to female monkeys caged with male (paired housing: 1 male + 1 female) throughout the breeding season. Early pregnancy will be confirmed by ultrasonography, with the number and percent of fertile animals/group analyzed for each ensuing cycle. Fetal wastage, gestation length, and fetal weight at delivery will be compared between groups. Monkeys chronically exposed to anti-progestin (and their offspring, if any) will be used for toxicologic evaluation of tissues. Additional monkeys receiving an anti-fertility dose of anti-progestin will be treated with vehicle in the following breeding season to assess reversibility of action. Development of practical delivery system for low-dose anti-progestins that result in safe, effective contraception in rhesus monkeys while retaining menstrual cyclicity will support the step- wide plan to consider this method for controlling fertility in women.