CONTRACEPTION WITH MINI DOSE ANTIPROGESTIN IN MACAQUES

用小剂量抗孕激素对猕猴进行避孕

• 批准号: 2889114
• 负责人: Mary B Zelinski
• 金额: $ 33.01万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1995
• 资助国家: 美国
• 起止时间: 1995-06-01 至 2002-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2889114
• 关键词: Macaca mulatta; artificial fertilization; cell cycle; contraceptives; drug administration rate /duration; drug adverse effect; drug screening /evaluation; early embryonic stage; egg /ovum; embryo /fetus culture; embryo /fetus transplantation; embryo implantation; embryogenesis; fallopian tubes; female; female antifertility drug; fertility; fertilization; gamete transport; gonadotropins; graafian follicles; histology; hormone inhibitor; in vitro fertilization; menstrual cycle; ovulation; pregnancy; progestins

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.

持续给予低剂量的抗孕激素，ZK 137 316， 雌性恒河猴允许卵巢/月经周期，但是 充分改变生殖道的功能以抑制 生育能力。 对配对饲养的雄性和雌性猴子的研究 证明小剂量抗孕激素的避孕效果优于 连续六个周期的治疗。 一项试点实验表明 停止妊娠后可以正常怀孕并生下后代 六个月的治疗方案，但停药后生育能力恢复 更长的治疗间隔后的抗孕激素需要严格的测试。 提出研究来检验以下假设：慢性、低剂量 ZK 137 316 在持续的卵巢/月经周期期间作用于多个 生殖道中的位点以提供怀孕保护。 使用雌性恒河猴，该提案的具体目标是 确定这种新型抗孕激素治疗方案是否可逆：1) 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 发展; 3) 扰乱配子/胚胎通过输卵管的运输； 4) 阻止子宫容受性/着床。 女性将获得 载体或小剂量抗孕激素一年，然后与 男性评估怀孕作为可逆性的终点 抗孕激素治疗。 恢复卵母细胞减数分裂、受精 体外受精和所得胚胎发育后 囊胚与体细胞体外共培养期间 在用人类对猕猴进行体内卵泡刺激后进行评估 单独使用促性腺激素或与抗孕激素联合治疗。 妊娠率和生殖道的组织学分析 将未经处理的胚胎通过输卵管和宫内移植到 接受抗孕激素治疗的受者将勾勒出输卵管和 子宫内膜及时运输胚胎并支持的能力 分别植入。 胚胎暴露的能力 抗孕激素体内运输和植入物将进行测试 输卵管和宫内转移给未经治疗的受者后。 通过留置导管收集的输卵管液体将进行检查 人工授精后的精子和输卵管的变化 分泌蛋白。 恢复生育力和鉴定 生殖道内潜在的避孕作用部位 使用 ZK 137 316 持续小剂量治疗后将支持 进一步研究防止怀孕的生化机制， 并支持将该方案开发为一种新的避孕方式 对女性来说。