Inhibition of ovulation by administration of estetrol in combination with drospirenone or levonorgestrel: Results of a phase II dose-finding pilot study

Abstract Objectives The aim of the study was to evaluate the efficacy of different dosages of estetrol (E4) combined with one of two progestins in suppressing the pituitary–ovarian axis and ovulation in healthy premenopausal women. Methods This was an open, parallel, phase II, dose-finding, pilot study performed in healthy women aged 18 to 35 years with a documented ovulatory cycle before treatment. For three consecutive cycles in a 24/4-day regimen, participants received 5 mg or 10 mg E4/3 mg drospirenone (DRSP); 5 mg, 10 mg or 20 mg E4/150 μg levonorgestrel; or 20 μg ethinylestradiol (EE)/3 mg DRSP as comparator. Pituitary–ovarian axis activity and the occurrence of ovulation were evaluated by monitoring follicular size, serum levels of follicle-stimulating hormone, luteinising hormone, estradiol and progesterone during treatment cycles 1 and 3. Endometrial thickness was evaluated throughout the trial, and the return of ovulation was evaluated after the last intake of medication. Results A total of 109 women were included in the trial. No ovulation occurred in any treatment group. Ovarian activity inhibition seemed proportional to the E4 dosage: the highest suppression was observed in the 20 mg E4 group and was very similar to that observed with EE/DRSP. Endometrial thickness was suppressed to the same extent in all groups. Post-treatment ovulation occurred in all participants between 17 and 21 days after the last active treatment. The study combinations were well tolerated and safe. Conclusions Combined with a progestin, E4 adequately suppresses ovarian activity, particularly when given at a dosage above 10 mg/day. Chinese Abstract 摘要 目的 这项研究的目的是评估不同剂量的雌四醇联合两种孕激素中的其中一种对垂体-卵巢轴以及健康的绝经前妇女的排卵方面的抑制疗效。 方法 这是一个在18到35岁的健康女性中进行的开放的、平行的，关于II期药物剂量探索的初步研究，这些女性均有治疗前的排卵周期记录。连续三个周期的24/4-天方案,参与者接受5毫克或10毫克的雌四醇/3毫克屈螺酮;5毫克,10毫克或20毫克的雌四醇/150 μg左炔诺孕酮;或用20 μg炔雌醇/3毫克屈螺酮作比较。在第1和第3个治疗周期，通过监测卵泡的大小,血清促卵泡激素、黄体生成素、雌二醇和孕激素的水平对垂体-卵巢轴的活动和排卵进行评估。对子宫内膜厚度的评估贯穿于整个试验过程中，对排卵抑制的评估在用完药物之后。 结果 总共有109名妇女参与试验。任何一个治疗组都没有出现排卵。对卵巢活动的抑制似乎与雌四醇的剂量成正比：最严重的抑制出现在20毫克的雌四醇组，与在炔雌醇/屈螺酮组观察到的情况非常相似。所有组的子宫内膜厚度的抑制程度是相同的。在最后一次积极治疗后的第17到21天之间，所有参与者均出现了治疗后的排卵。所有的试验组合均有良好的耐受性和安全性。 结论 雌四醇联合一种雌激素能够充分的抑制卵巢活动，尤其是当雌四醇的剂量大于10毫克/天的时候。 关键词 雌四醇；雌激素；口服避孕药；排卵抑制；孕激素