Nintedanib Treatment After Ovulation is an Effective Therapeutic Strategy for the Alleviation of Ovarian
Shutian Jiang1, Wenzhi Li1, Xinxi Zhao1
1Department of Assisted Reproduction, Shanghai Ninth People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, People's Republic of China.
Purpose:
Ovarian hyperstimulation syndrome (OHSS) is a serious complication of controlled ovarian hyperstimulation. In this study, we hope to explore whether nintedanib, a tyrosine kinase inhibitor, can inhibit OHSS by blocking signaling of vascular endothelial growth factor in a mouse model. Considering that nintedanib been approved for the treatment of some diseases. We believe that nintedanib has important potential in the treatment of OHSS.
Methods:
Female ICR mice aged 6-8 weeks with similar initial weights were used to establish the OHSS model. At 12 and 24 hours after human chorionic gonadotropin (hCG) trigger, we administered nintedanib by subcutaneous injection and analyzed the OHSS-related physiological characteristics and biochemical indices of the model mice within 48 hours after hCG-trigger.
Results:
Nintedanib significantly alleviated the symptoms of OHSS after hCG-trigger compared with those of OHSS group (weight change, P < 0.0001; ovarian weight, P < 0.0001, peritoneal exudation level, P < 0.01). Further investigation proved that the corpus luteum (number, P < 0.001; diameter, P < 0.0001) and luteal vessel (P < 0.0001) development were inhibited in the nintedanib administration group. Then, the vascular permeability test showed that the capillary bleeding points (P < 0.0001) were also significantly reduced in nintedanib administration group. Gene expression tests demonstrated that the intercellular connection-related genes expression in the nintedanib administration group was similar to that in the no-OHSS induced group. Further detection of coagulation and thrombosis indices indicated that the nintedanib administration in the OHSS model did not increase the risk of thrombosis or bleeding.
Conclusion:
Our study demonstrated that nintedanib can alleviate and manage the symptoms of OHSS in a mouse model. These findings identify a feasible scheme for the prevention and treatment of OHSS in clinical practice in the future. Moreover, since the scheme can be implemented after ovulation, it will not cause potential adverse effects on gametogenesis, fertilization or embryonic development.
Insights
Nintedanib effectively treats ovarian hyperstimulation syndrome (OHSS) in mice by reducing vascular permeability and inflammation. This tyrosine kinase inhibitor shows promise for clinical OHSS management without increasing thrombosis risk.
Area of Science:
- Reproductive endocrinology
- Pharmacology
- Vascular biology
Background:
- Ovarian hyperstimulation syndrome (OHSS) is a significant complication of controlled ovarian hyperstimulation.
- Vascular endothelial growth factor (VEGF) signaling is implicated in OHSS pathogenesis.
- Nintedanib, a tyrosine kinase inhibitor, targets VEGF signaling pathways.
Purpose of the Study:
- To investigate the efficacy of nintedanib in inhibiting OHSS in a mouse model.
- To explore nintedanib's mechanism of action by assessing its impact on VEGF signaling and related physiological parameters.
- To evaluate the therapeutic potential of nintedanib for OHSS management.
Main Methods:
- Establishment of an OHSS mouse model using female ICR mice.
- Subcutaneous administration of nintedanib at 12 and 24 hours post-human chorionic gonadotropin (hCG) trigger.
- Analysis of OHSS-related physiological characteristics and biochemical indices within 48 hours post-hCG trigger.
Main Results:
- Nintedanib significantly alleviated OHSS symptoms, including reduced weight gain, ovarian weight, and peritoneal fluid accumulation.
- Treatment with nintedanib inhibited corpus luteum and luteal vessel development and decreased vascular permeability.
- Gene expression analysis indicated normalized intercellular connections, and coagulation/thrombosis indices remained unaffected.
Conclusions:
- Nintedanib effectively alleviates and manages OHSS symptoms in a preclinical mouse model.
- This study suggests a potential clinical application for nintedanib in OHSS prevention and treatment.
- Nintedanib administration post-ovulation avoids adverse effects on gametogenesis, fertilization, and embryonic development.
