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Estrogen Is Not Essential for Full Endometrial Restoration after Breakdown: Lessons from a Mouse Model

Prince Henry’s Institute of Medical Research (T.J.K.-L., N.B.M., L.A.S.) and Department of Obstetrics and Gynecology (T.J.K.-L.), Monash University, Clayton, Victoria 3168, Australia

Address all correspondence and requests for reprints to: T. J. Kaitu’u-Lino, Prince Henry’s Institute of Medical Research, Level 4, Block E, Monash Medical Centre, 246 Clayton Road, Clayton, Victoria 3168, Australia. E-mail: tuuhevaha.kaituu{at}princehenrys.org.

The current dogma surrounding endometrial regeneration after menses includes a critical need for estrogen-primed proliferation. Although some evidence suggests that estrogen may not be required for the initial reepithelialization of the uterine surface, it is widely believed that it is essential for successful stromal renewal. This study aimed to identify proliferating cell types during endometrial repair and to examine whether estrogen is required for successful repair using a previously developed mouse model. In the model, decidualization is artificially induced, and progesterone support withdrawn; the endometrial tissue progressively breaks down by 24 h after progesterone withdrawal and by 48 h has usually undergone complete repair. Although the mice are ovariectomized, restoration of both the stromal and epithelial components proceeds rapidly after breakdown and results in what appears to be a normal endometrium. However, potential estrogenic influences from extraovarian sources (particularly the diet and fat) remain. In this study, complete removal of extraovarian estrogen was achieved by maintenance of animals on a soy-free diet and administration of aromatase inhibitor letrozole. No significant differences in uterine weight or estrogen-responsive genes lactoferrin and progesterone receptor were observed compared with control ovariectomized but otherwise untreated mice, whereas significantly higher measurements were obtained from an estrogen-added group. Importantly, no significant difference in the rate of endometrial repair was observed in the complete absence of estrogen, demonstrating that estrogen is not essential for complete endometrial restoration in this model.