On the Horizon: Nonsteroidal Contraceptive Targets in the Female Ovary and Reproductive Tract.

Abstract

Half of all unintended pregnancies in the United States occur among contraceptive users. There is an urgent need for non-coitally related methods that are free of undesirable hormone-related side effects to control fertility. Novel contraceptive agents could be targeted to specific sites in the female reproductive tract to alter gamete (inhibit oocyte maturation, fertilization), ovarian (suppress follicle rupture, oocyte release) and uterine (prevent implantation) function to prevent pregnancy. During the gonadotropin surge, cAMP levels rise in granulosa cells and decrease in the oocyte prior to the resumption of meiosis. Hydrolysis of cAMP is achieved intracellularly via phosphodiesterases (PDE). PDE4 is expressed in granulosa cells, while PDE3 exists in the oocyte. This compartmentalization suggests a novel contraceptive strategy wherein selective inhibition of PDE3 maintains elevated cAMP levels and prevents meiotic maturation of the oocyte without affecting follicle rupture, a concept demonstrated in rodents and recently applied to primates. Immature, GV-intact macaque oocytes obtained from large pre-ovulatory follicles during gonadotropin-stimultated cycles in the absence of an ovulatory hCG bolus were exposed in vitro to various doses of PDE3 inhibitors or a selective PDE4 inhibitor. Resumption of meiosis was specifically blocked by PDE3 inhibitors, but not the PDE4 inhibitor. To determine whether PDE3 inhibitors prevent oocyte maturation in vivo, oocytes were collected after an ovulatory stimulus (hCG) from macaques either receiving no further treatment (control) or the PDE3 inhibitor, ORG 9935 (NV Organon) during gonadotropin-stimulated and natural menstrual cycles. In gondaotropin-stimulated cycles, 85% of oocytes from controls were mature compared to 13% from treated animals. In natural cycles, all oocytes from controls resumed meiosis, whereas 83% from treated animals were GV-intact. Although 60% of GV oocytes from treated animals progressed to metaphase I during culture, none fertilized in vitro compared with 67% fertilization in controls. Thus, the ability of PDE3 inhibitors to block primate oocyte maturation in vitro and in vivo suggests a potential clinical use as contraceptives in women. Very low doses of the antiprogestin, ZK 137 316 (Schering AG), permit ovarian and menstrual cyclicity when administered daily for up to 6 months in rhesus monkeys, but disrupt endometrial growth. This antiprogestin regimen was 100% effective in preventing pregnancy in female macaques during cohabitation with males. The contraceptive efficacy and reversiblility with respect to subsequent fertility was tested in macaques receiving vehicle or antiprogestin daily for 1 year. Antiprogestin-treated females cohabitating with males did not become pregnant. After 1 year, live offspring were born in 80% and 60% of females previously treated with vehicle or antiprogestin, respectively. Antiprogestin exposure during follicular development in macaques altered oocyte functions necessary for normal preimplantation embryogenesis that may contribute to pregnancy prevention. Thus, chronic, low dose antiprogestin permits continued ovarian cyclicity and prevents pregnancy in primates. The rapid reversal of anti-fertility effects and live births after antiprogestin treatment increases confidence in the feasibility of this regimen as a potential contraceptive in women. HD18185, HD031398, RR00163, HD01243-03 (JJ), HD042710 (JJ), HD31633 (MZ)