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.
