A systematic review of the plasminogen activator system in the endometrium and its role in menstruation and abnormal uterine bleeding

Objective

To evaluate the role of the plasminogen activator (PA) system throughout the endometrial cycle, including the effects of intrauterine contraception, and assess the contribution of genetic mutations in the PA system to the clinical problem of heavy menstrual bleeding (HMB).

Evidence Review

This was a systematic review of the PubMed, Embase, ClinicalTrials.gov, and Cochrane Library databases from 1966 until the search date in October 2021. The publications included were cohort studies, observational studies, case reports, case studies, and case-control studies. Literature reviews were excluded. Abstracts were screened by 3 investigators independently, with subsequent review by the senior investigator to assess study quality. The Risk of Bias In Non-Randomized Studies of Interventions assessment tool was used to evaluate potential sources of bias in the included studies.

Results

A total of 2,021 unique articles were identified, 38 of which qualified for full review, with 17 excluded during that process, leaving 21 articles that met all criteria. Studies reported that the activity of the PA system in the endometrium changed throughout the menstrual cycle, with increases in tissue PA and PA inhibitor 1 (PAI-1) activity surrounding the menstrual phase. Greater fibrinolytic activity was also observed in the endometrial samples of women with HMB as well as those with copper intrauterine devices. Conversely, levonorgestrel intrauterine devices were associated with a decrease in the tissue PA–to–PAI-1 ratio, hence reduced fibrinolysis. Mutations of the PAI-1 and α₂-antiplasmin genes were found to affect the PA system and are associated with HMB.

Conclusion

Genetic mutations that affect the PA system and are linked to alterations in menstrual bleeding, such as PAI-1 and α₂-antiplasmin, have been identified. Further research is needed to ascertain whether additional mutations, and genetic polymorphisms, not only affect the PA system but may also explain some cases of HMB that are yet to be classified.