ANTI PROGESTIN CHRONIC LOW DOSE DEPENDENT ENDOMETRIAL ATROPHY: MONKEY

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Antiprogestins are reported to inhibit endometrial maturation in cycling macaques and women. In this study, we investigated the long-term effects of low dose treatment with the new antiprogestin ZK 137 316 on endometrial morphology in intact, naturally cycling rhesus monkeys. Four groups of monkeys were injected daily for 5 cycles with 3 doses of ZK 137 316 (none (vehicle), 0.01, 0.03 and 0.1 mg /kg body weight, i.m.). Oviducts and uteri (n=3/ group) were collected on day 22 of the 5th cycle in the vehicle, 0.01 and 0.03 mg/kg groups, or 6-7 days after the estradiol peak in the 0.1 mg/kg group. Oviduct and uterine tissues were weighed and samples were fixed, embedded in glycolmethacrylate and sectioned for histology. Mean endometrial weight (qSE) from vehicle, 0.01, 0.03 and 0.1 mg kg groups were 510 q 10, 196 q 111, 36 q 3 and 43 q 13 mg, respectively (P<0.05). The endometrium from vehicle-treated monkeys was fully differentiated with large secretory glands and well-developed spiral arteries. The endometrium of all ZK 137 316 treated animals showed glandular atrophy, stromal compaction, artery degradation and venous dilation, and in the 0.1 mg/kg group, almost complete loss of endometrial glands and spiral arteries. These data indicate that ZK 137 316 can profoundly suppress endometrial development in a dose-dependent manner in naturally cycling rhesus monkeys with normal levels of estrogen. There were no significant effects of ZK 137 316 on myometrial or oviductal weights compared to vehicle treated controls. In summary, chronic treatment with low dose ZK 137 316 produced a dramatic "antiproliferative" effect in the rhesus endometrium without signs of unopposed estrogen action in the uterus. Because such atrophied endometria are unlikely to support implantation, our laboratory is now evaluating the contraceptive efficacy of chronic low dose ZK 137 316 treatment in rhesus monkeys.