Unique effects on hepatic function, lipid metabolism, bone and growth endocrine parameters of estetrol in combined oral contraceptives

Objectives Estetrol (E(4)) is a natural estrogen produced by the human fetal liver. In combination with drospirenone (DRSP) or levonorgestrel (LNG), E(4) blocks 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 E(4)/DRSP and E(4)/LNG on safety parameters such as liver function, lipid metabolism, bone markers and growth endocrine parameters. Methods This 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 E(4)/3 mg DRSP; 5 mg, 10 mg or 20 mg E(4)/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. Results A total of 109 women were included in the study. Carrier proteins were minimally affected in the E(4)/DRSP and E(4)/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 E(4) groups, and the effects on triglycerides elicited by the E(4) groups 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 E(4) groups. Conclusions E(4)-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