CHARACTERIZATION OF MOLECULARLY CLONED SIMIAN HUMAN IMMUNODEFICIENCY VIRUSES

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Our goal in this research is to develop a safe, reversible method of menstrual suppression with a class of compounds called antiprogestins. Previously we showed that short-term systemic treatment with the Schering antiprogestin ZK 137 316 (ZK316) will suppress menstruation. We have now conducted a long-term study of cycling rhesus monkeys treated with ZK316. In this study, all of the animals exhibited normal pretreatment menstrual cycles (mean _ SE; 28.3 _ 1.4 days). Injection with ZK316 at 0.05 and 0.1 mg/kg for 100 days blocked menstruation and significantly extended the intermenstrual interval in all of the monkeys. Intermenstrual interval in the control, 0.05 and 0.1 groups were 28.1 _ 0.83, 131.1 _ 10.1 and 134 _ 8.7 days, respectively (P < 0.001). During the last 30 days of treatment, the monkeys in the control group expressed normal menstrual cycle patterns of estradiol (E2) and progesterone (P). In addition, all of the monkeys in the 0.05 mg/kg ZK316 grou p (n = 4) had normal follicular phase levels of E2 (including an E2 surge) and normal luteal phase levels of P. In this group, ZK316 suppressed menstruation despite a normal decline in luteal phase P at the end of the cycle. However, all of the monkeys in the 0.1 mg/kg group failed to develop a normal E2 surge (E2 levels rising above 200 pg/ml) or normal luteal phase levels of P (>1 ng/ml) during the last 30 days of treatment. Despite blockade of ovulation in this group, all of the monkeys showed normal nonsurge levels of E2 levels (~30-100 pg/ml). All ZK316-treated monkeys returned to normal cyclicity within 40 days and posttreatment cycle lengths were normal in all of the groups (29.8 _ 3.0 days). No untoward effects of treatment were detected in the monkeys during the study. In summary, we have now shown that long-term antiprogestin treatment will reversibly inhibit menstruation in rhesus monkeys. FUNDING Department of Defense Subcontract PUBLICATIONS Slayden OD, Chwalisz K, Vidgoff J, Brenner RM. Dose related effects of the new generation antiprogestin ZK 137 316 in spayed and cycling rhesus macaques. Biol Reprod (Suppl 1) 58:186,1998 (abstract 365). Slayden OD, Zelinski-Wooten MB, Chwalisz K, Stouffer RL, Brenner RM. Chronic treatment of cycling rhesus monkeys with low doses of the antiprogestin ZK 137 316 Morphometric assessment of the uterus and oviduct. Hum Reprod 13:269-277, 1998. Zelinski-Wooten MB, Chwalisz K, Illiff SA, Niemeyer CL, Eaton GG, Loriaux DL, Slayden OD, Brenner RM, Stouffer RL. A chronic, low dose regimen of the antiprogestin ZK 137 316 prevents pregnancy in rhesus monkeys. Hum Reprod 13:2132-2138, 1998. Zelinski-Wooten MB, Slayden OD, Chwalisz K, Hess DL, Brenner RM, Stouffer RL. Chronic treatment of cycling rhesus monkeys with low doses of the antiprogestin ZK 137 316 Establishment of a regimen that permits normal menstrual cyclicity. Hum Reprod 13:259-267, 1998.