CONTRACEPTION WITH MINI DOSE ANTIPROGESTIN IN MACAQUES

连续给予低剂量的抗白细胞介素ZK 137 316， 雌性恒河猴允许卵巢/月经周期，但 足以改变生殖道的功能， 生育 对成对圈养的雄性和雌性猴进行的研究 证明了小剂量抗孕酮的避孕效果， 连续六个疗程。 一项试点实验表明， 停止妊娠后，可以正常怀孕并存活后代。 六个月的方案，但恢复生育能力后撤销 在较长的治疗间隔后的抗前列腺素需要严格的测试。 建议进行研究以检验慢性低剂量ZK 137 316在持续的卵巢/月经周期中， 在生殖道的部位，以防止怀孕。 利用雌性恒河猴，本提案的具体目标是 为了确定这种新的抗前列腺素方案是否：1）是可逆的 治疗一年后恢复生育能力; 2)损害卵母细胞核成熟、受精或早期胚胎 破坏配子/胚胎通过输卵管的运输; 和4）防止子宫容受性/着床。 女性将获得 载体或小剂量抗孕酮治疗一年，然后与 将妊娠作为可逆性终点进行评估 抗前列腺素治疗。 恢复卵母细胞减数分裂，受精 在体外授精和发育后， 在与体细胞的体外共培养期间， 在用人类在体内刺激猕猴的卵泡后评价 促性腺激素单独或与抗孕酮治疗组合。 妊娠率和生殖道组织学分析 在输卵管和子宫内移植未处理的胚胎后， 抗孕激素治疗的受体将描绘输卵管和 子宫内膜及时运输胚胎和支持 植入，分别。 胚胎暴露于 将测试体内的抗胰高血糖素转运和植入 在输卵管和子宫内转移到未经治疗的受体后。 将检查通过留置导管收集的输卵管液， 人工授精后精子和输卵管变化 分泌蛋白 恢复生育能力和查明 生殖道内的潜在避孕作用部位 ZK 137 316持续小剂量治疗后， 进一步研究防止怀孕的生化机制， 并支持将这种方案发展为一种新的避孕方式 包女

Continual administration of low doses of the antiprogestin, ZK 137 316, to female rhesus monkeys permits ovarian/menstrual cyclicity, but sufficiently alters the function(s) of the reproductive tract to inhibit fertility. Studies with pair-housed male and female monkeys demonstrated the contraceptive efficacy of minidose antiprogestin over six consecutive cycles of treatment. A pilot experiment suggests that normal pregnancies and live offspring can occur after cessation of the six-month regimen, but restoration of fertility following withdrawal of antiprogestin after longer treatment intervals needs rigorous testing. Studies are proposed to test the hypothesis that chronic, low dose ZK 137 316 during sustained ovarian/menstrual cyclicity acts at multiple sites in the reproductive tract to provide protection from pregnancy. Using the female rhesus monkey, the specific aims of this proposal are to determine whether this novel antiprogestin regimen: 1) is reversible with respect to restoration of fertility after one year of treatment; 2) impairs oocyte nuclear maturation, fertilization or early embryonic development; 3) disrupts gamete/embryo transport through the oviduct; and 4) prevents uterine receptivity/implantation. Females will receive vehicle or minidose antiprogestin for one year, followed by pairing with males to assess pregnancy as an endpoint of the reversibility of antiprogestin treatment. Resumption of oocyte meiosis, fertilization after insemination in vitro and development of resultant embryos of blastocysts during in vitro coculture with somatic cells will be evaluated after follicular stimulation of macaques in vivo with human gonadotropins alone or in combination with antiprogestin treatment. Pregnancy rates and histological analyses of the reproductive tract after oviductal and intrauterine transfer of untreated embryos to antiprogestin-treated recipients will delineate the oviductal and endometrial capacity for timely embryo transport and to support implantation, respectively. The ability of embryos exposed to antiprogestin in vivo to be transported and implant will be tested following oviductal and intrauterine transfer to untreated recipients. Oviductal fluid collected via indwelling catheter will be examined for sperm following artificial insemination and for changes in oviductal secretory protein. Restoration of fertility and identification of potential sites of contraceptive action within the reproductive tract following continual, minidose treatment with ZK 137 316 will support further investigation of biochemical mechanisms that prevent pregnancy, and support development of this regimen as a new mode of contraception for women.