Abstract
Proper action of the female sex steroids 17β-estradiol (E2) and progesterone (P4) on the endometrium is essential for fertility. Beyond its role in regulating the cell cycle, cyclin A2 (CCNA2) also mediates E2 and P4 signaling in vitro, but a potential role in modulating steroid action for proper endometrial tissue development and function is unknown. To fill this gap in our knowledge, we examined human endometrial tissue from fertile and infertile cisgender women for CCNA2 expression and correlated this with pregnancy outcome. Functional assessment of CCNA2 was validated in vivo using a conditional Ccna2 uterine-deficient mouse model, while in vitro function was assessed using human cell culture models. We found that CCNA2 expression was significantly reduced in endometrial tissue, specifically the stromal cells, from women undergoing in vitro fertilization who failed to achieve pregnancy. Conditional deletion of Ccna2 from mouse uterine tissue resulted in an inability to achieve pregnancy, which appeared to be due to alterations in the process of decidualization, which was confirmed using in vitro models. From these studies, we conclude that CCNA2 expression during the proliferative/regenerative stage of the menstrual cycle allows for proper steroid responsiveness, decidualization, and pregnancy. When CCNA2 expression levels are insufficient, there is impaired endometrial responsiveness, aberrant decidualization, and loss of pregnancy.
Authors
Fatimah Aljubran, Katelyn Schumacher, Amanda Graham, Sumedha Gunewardena, Courtney Marsh, Michael Lydic, Kristin Holoch, Warren B. Nothnick
Figure 4
Select impaired estrogen action in Ccna2d/d uteri.
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ISSN: 0021-9738 (print), 1558-8238 (online)