The combination of Everolimus with Verapamil reduces ovarian weight and vascular permeability on ovarian hyperstimulation syndrome: a preclinical experimental randomized controlled study

Abstract

The efficacy of pathways inhibition and the combined effect of Everolimus (mTOR inhibitor) and Verapamil (CYP3A inhibitor) in ovarian hyperstimulation syndrome (OHSS) need to be tested. Therefore, the impact of a leucotriene receptor antagonist, an anticoagulant, a GnRH antagonist as well as Everolimus plus Verapamil (at various doses and days of administration) on an OHSS rat model was tested. Sixty three female Wistar rats were randomly divided into seven groups. The control group received saline, while the OHSS group received rec-FSH for four consecutive days. The other five groups received rec-FSH for four days and Montelukast daily, Heparin daily, GnRH antagonist daily, Everolimus plus Verapamil in the last two days (half days group) and Everolimus plus Verapamil (half dose group) daily, respectively. All groups received also hCG at the fifth day. Significantly reduced ovarian weight was observed in the Everolimus plus Verapamil groups (half days and half-dose groups) and the Montelukast group compared to the OHSS group (p = 0.001 and p = 0.001, respectively). The vascular permeability was significantly reduced in the Everolimus plus Verapamil group (half dose group) and the GnRH antagonist group compared to the OHSS group (p < 0.001 and p = 0.011, respectively). However, estradiol and progesterone levels did not differ significantly between the groups. Studying the inhibition of different pathways, we concluded that the co-administration of Everolimus and Verapamil (at half dose) is beneficial for reducing ovarian weight and vascular permeability in an OHSS animal model.

Chinese abstract

通路抑制的效力和依维莫司 (mTOR抑制剂) 联合维拉帕米 (CYP3A抑制剂) 在卵巢过度刺激综合征 (OHSS) 的效应需要被测试。因此, 白三烯受体拮抗剂, 抗凝剂, GnRH拮抗剂以及依维莫司联合维拉帕米 (在不同剂量和给药天数处理) 的对OHSS大鼠模型的影响被检测。将63只雌Wistar大鼠随机分为7组。对照组接受生理盐水, 而OHSS组连续四天接受rec-FSH。其他五组接受rec-FSH四天, 分别为每天给予孟鲁司特, 每天给予肝素, 每天给与GnRH拮抗剂, 最后两天给予依维莫司加维拉帕米 (半日组) 及每天给予依维莫司和维拉帕米 (半剂量组) 。所有组在第五天接受hCG。相比OHSS组依维莫司联合维拉帕米组 (半日和半剂量组) 和孟鲁司特组观察到了卵巢重量的显著降低 (分别为p = 0.001和p = 0.001) 。相比OHSS组依维莫司加维拉帕米 (半剂量组) 和GnRH拮抗剂组血管通透性显著降低 (分别为p＜0.001和p = 0.011) 。然而, 雌二醇和孕酮水平在组间没有显着差异。通过研究不同抑制途径, 我们得出结论, 依维莫司和维拉帕米联合给药 (半剂量) 有益于降低OHSS动物模型中的卵巢重量和血管通透性。

Keywords:

• Everolimus
• ovarian hyperstimulation
• ovarian weight
• vascular permeability
• verapamil

Declaration of interest

The authors report no declarations of interest.