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ObjectivesThe 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. MethodsThis 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. ResultsA total of 109 women were included in the trial. No ovulation occurred in any treatment group. Ovarian activity inhibition seemed proportional to the E4dosage: the highest suppression was observed in the 20 mg E4group 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. ConclusionsCombined with a progestin, E4adequately 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 [ABSTRACT FROM PUBLISHER]

ObjectivesEstetrol (E4) is a natural estrogen produced by the human fetal liver. In combination with drospirenone (DRSP) or levonorgestrel (LNG), E4blocks ovulation and has less effect on haemostatic biomarkers in comparison with ethinylestradiol (EE) combined with DRSP. This study evaluates the impact of several doses of E4/DRSP and E4/LNG on safety parameters such as liver function, lipid metabolism, bone markers and growth endocrine parameters. MethodsThis was a dose-finding, single-centre, controlled study performed in healthy women aged 18 to 35 years with a documented pretreatment ovulatory cycle. Participants received 5 mg or 10 mg E4/3 mg DRSP; 5 mg, 10 mg or 20 mg E4/150 μg LNG; or 20 μg EE/3 mg DRSP as a comparator for three consecutive cycles in a 24/4-day regimen. Changes from baseline to end of treatment in liver parameters, lipid metabolism, bone markers and growth endocrinology were evaluated. ResultsA total of 109 women were included in the study. Carrier proteins were minimally affected in the E4/DRSP and E4/LNG groups, in comparison with the EE/DRSP group, where a significant increase in sex hormone-binding globulin was observed. Similarly, minor effects on lipoproteins were observed in the E4groups, and the effects on triglycerides elicited by the E4groups were significantly lower than those in the EE/DRSP group. No imbalances in bone markers were observed in any groups. No alterations in insulin-like growth factor were observed in the E4groups. ConclusionsE4-containing combinations have a limited effect on liver function, lipid metabolism, and bone and growth endocrine parameters. Chinese Abstract 摘要 目的雌四醇（E4）是来源于人胎儿肝脏的天然雌激素。雌四醇与屈螺酮（DRSP)或左炔诺孕酮(LNG)配伍的复方口服避孕药制剂，能够抑制排卵，同时相较于炔雌醇(EE)与屈螺酮配伍制剂，它对凝血功能的各项指标影响较小。本研究的目的是为了评估不同剂量的雌四醇与屈螺酮以及左炔诺孕酮的配伍制剂对肝功能、脂代谢、骨骼转换标志物、以及生长激素分泌等安全性指标的影响。 方法本研究为开放的、单中心、剂量定义的对照研究，研究对象为18-35岁、具有良好的排卵周期的健康妇女，受试者分别接受5mg或10mg雌四醇/屈螺酮3mg(E4/DRSP)制剂，5mg、10mg、20mg雌四醇/左炔诺孕酮150ug(E4/LNG)制剂，以及20ug炔雌醇/屈螺酮(EE/DRSP)3mg制剂作为对照，连续三个24/4天周期。自基线到研究结束，测定肝功能、脂代谢、骨转换以及生长激素分泌的各项指标，对其改变进行评估。 结果109名妇女入选该研究。与EE/DRSP组比较，E4/DRSP以及E4/LNG组肝脏产生的运载蛋白受影响很小，但是EE/DRSP组性激素结合蛋白的含量明显增加。同样，E4组的脂蛋白受影响很小，而且对甘油三酯的影响显著低于EE/DRSP组。在所有研究组中，都没有观察到骨转换的失衡。在E4组，没有观察到胰岛素样生长因子的改变。 结论含有E4的复方制剂对肝功能、脂代谢、骨骼转换以及生长内分泌的影响有限。 关键词 骨标记物、屈螺酮、内分泌、雌四醇、左炔诺孕酮、脂代谢、肝功能 [ABSTRACT FROM PUBLISHER]