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: 6181669
• 负责人: Mary B Zelinski
• 金额: $ 36.24万
• 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/6181669
• 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.

持续服用小剂量抗孕激素，ZK 137 316， 对雌性猕猴来说，允许卵巢/月经周期，但 充分改变生殖道功能(S)以抑制 生育能力。对配对饲养的公猴和母猴的研究 证实了小剂量抗孕激素的避孕效果。 连续六个疗程。一项初步实验表明， 停止妊娠后，可能发生正常妊娠和活着的后代 6个月的方案，但在停药后恢复生育能力 在较长的治疗间隔后，抗孕激素需要严格的测试。 有人建议进行研究，以检验慢性、低剂量ZK 137 316在持续的卵巢/月经周期期间 在生殖道上的位置，以提供怀孕保护。 使用雌性恒河猴，这一提议的具体目的是 为了确定这种新的抗孕激素方案：1)是否可逆 关于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 3)干扰配子/胚胎通过输卵管的运输； 以及4)阻止子宫容受性/着床。女性将获得 赋形剂或小剂量抗孕激素一年，然后配对 男性将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 体外受精后的胚胎发育 在体外与体细胞共培养的囊胚将被 猕猴体内卵泡刺激后的评价 促性腺激素单独或与抗孕激素联合治疗。 妊娠率与生殖道组织学分析 将未经处理的胚胎移植到输卵管和宫内后 接受抗孕激素治疗的患者将描绘出输卵管和 子宫内膜对胚胎及时转运和支持的能力 分别植入。胚胎暴露在环境中的能力 体内的抗孕激素将被运输和植入进行测试 输卵管和宫内移植给未经治疗的受者。 通过留置导管收集的输卵管液体将被检查 人工授精后的精子和输卵管的变化 分泌蛋白质。恢复生育能力和鉴定 生殖道内潜在的避孕作用部位 在持续、小剂量治疗后，ZK 137 316将支持 进一步研究防止怀孕的生化机制， 并支持将这一方案发展为一种新的避孕方式 为女性准备的。