REVERSIBLE SUPPRESSION OF MENSTRUATION W/ ANTIPROGESTINS

我们在这项研究中的目标是开发一种安全，可逆的方法， 抑制月经的药物， 抗孕激素 之前我们曾指出，短期系统性 用先灵抗胰蛋白酶ZK 137 316（ZK 316）治疗将 抑制月经。 我们现在进行了一项长期研究， 用ZK 316处理的骑自行车的恒河猴。 在这项研究中，所有 动物表现出正常的治疗前月经周期（平均值_ SE; 28.3_ 1.4天）。 注射ZK 316 0.05和0.1 mg/kg，持续100 天阻止月经，并显着延长 所有猴子的月经间期。 经间期 对照组、0.05组和0.1组的间期分别为28.1 ± 0.83、131.1 ± 0.84和131.1 ± 0.83。 10.1 134 ~ 8.7天（P < 0.001）。 在过去30 给药30天后，对照组猴表达正常 雌二醇（E2）和孕酮（P）的月经周期模式。 在 此外，0.05 mg/kg ZK 316格鲁组所有猴（n = 4） 卵泡期E2水平正常（包括E2激增）， 正常黄体期P水平。在该组中，ZK 316抑制 月经，尽管在黄体期P结束时正常下降， 循环 然而，0.1 mg/kg组的所有猴子都失败了 出现正常的E2激增（E2水平升高至200 pg/ml以上），或 正常黄体期水平的P（>1 ng/ml）在过去30天的 治疗 尽管在这一组中有排卵阻滞，但所有的 猴子显示正常的非激增水平的E2水平（~30-100 pg/ml）。 所有ZK 316治疗的猴子在40天内恢复正常的周期性 治疗后周期长度均正常（29.8 _ 3.0天）。 未检测到治疗的不良反应， 猴子在研究中 总之，我们现在已经表明， 长期抗孕酮治疗将可逆地抑制月经 在恒河猴身上。 国防部分包合同 出版物Slayden OD，Chwalisz K，Vidgoff J，Brenner RM. 剂量 新一代抗白细胞介素ZK 137 - 316的相关作用 切除卵巢和骑自行车的恒河猴。 生物生殖学（增刊1）58：186，1998 （摘要365）。 Slayden OD，Zelinski-Wooten MB，Chwalisz K，Stouffer RL，Brenner RM. 慢性治疗骑自行车的恒河猴低 剂量的抗白细胞介素ZK 137 316的形态学评估 子宫和输卵管。 Reprod 13：269-277，1998. Zelinski-Wooten MB， Chwalisz K，Illiff SA，Niemeyer CL，Eaton GG，Loriaux DL，Slayden OD， Brenner RM，Stouffer RL. 一种慢性、低剂量的 antiresistin ZK 137 316可预防恒河猴怀孕。 嗡嗡声 Reprod 13：2132-2138，1998。 Zelinski-Wooten MB，Slayden OD，Chwalisz K，Hess DL，Brenner RM，Stouffer RL. 慢性治疗骑自行车 恒河猴与低剂量的抗白细胞介素ZK 137 316 建立允许正常月经周期的方案。 Reprod 13：259-267，1998.

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.