Prevention of ovarian hyperstimulation syndrome in a rat model: comparison of the efficacy of tocilizumab with that of ranibizumab, cabergoline, and a gonadotropin-releasing hormone antagonist

The aim of the study is to investigate the effects of the interleukin-6 (IL-6) blocker tocilizumab in a hyperstimulated rat model and compare it with ranibizumab, a gonadotropin-releasing hormone antagonist (GnRHA), and cabergoline. Forty-seven rats were randomly divided into the following seven groups: Group 1: OHS; Group 2: OHS+ GnRHA; Group 3: OHS + ranibizumab; Group 4: OHS + cabergoline; Group 5: OHS + low-dose tocilizumab (TL); Group 6: OHS + high-dose tocilizumab (TH); Group 7: sham. Ovarian weight was significantly lower only in the ranibizumab group than in the OHS group. Estrogen levels were significantly lower in the GnRHA group than in the OHS and the treatment groups. Progesterone levels were significantly lower in the ranibizumab, cabergoline, and TL groups than in the OHS group. Among the treatment groups, corpus luteum counts were lower than in the OHS group. Corpus luteum counts were lowest in the tocilizumab groups. IL-6 intensity was lower in all treatment groups than in the OHS group. In the ranibizumab group IL-6 intensity was the lowest. The TL group did not significantly differ from the GnRHA and cabergoline groups regarding IL-6 expression. Ovarian VEGF expression was significantly lower in all treatment groups. For the TL, ranibizumab, and cabergoline groups VEGF intensity was similar. Tocilizumab may be a new strategy for preventing ovarian hyperstimulation syndrome by inhibition of IL-6.

本研究旨在探究白细胞介素-6（interleukin-6, IL-6）阻滞剂托珠单抗（tocilizumab）在卵巢过度刺激综合征（Ovarian Hyperstimulation Syndrome, OHS）大鼠模型中的干预效应，并将其与雷珠单抗（ranibizumab）、促性腺激素释放激素拮抗剂（gonadotropin-releasing hormone antagonist, GnRHA）及卡麦角林（cabergoline）进行对比。将47只大鼠随机分为7组：第1组为OHS模型组；第2组为OHS+GnRHA组；第3组为OHS+雷珠单抗组；第4组为OHS+卡麦角林组；第5组为OHS+低剂量托珠单抗（TL）组；第6组为OHS+高剂量托珠单抗（TH）组；第7组为假手术组。实验结果显示：仅雷珠单抗组的卵巢重量较OHS模型组显著降低；促性腺激素释放激素拮抗剂组的雌激素水平显著低于OHS模型组与各治疗组；雷珠单抗组、卡麦角林组与低剂量托珠单抗组的孕酮水平均显著低于OHS模型组；各治疗组的黄体计数均低于OHS模型组，其中托珠单抗组的黄体计数最低；所有治疗组的IL-6表达强度均低于OHS模型组，且雷珠单抗组的IL-6表达强度最低，低剂量托珠单抗组的IL-6表达水平与GnRHA组、卡麦角林组无显著统计学差异；所有治疗组的卵巢血管内皮生长因子（vascular endothelial growth factor, VEGF）表达水平均显著降低，低剂量托珠单抗组、雷珠单抗组与卡麦角林组的VEGF表达强度相近。本研究表明，托珠单抗通过抑制IL-6通路，有望成为预防卵巢过度刺激综合征的新型治疗策略。