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

Abstract

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 In the model, decidualization is artificially induced, and progesterone support withdrawn; the endometrial tissue progressively breaks down by 24 h after progesterone withdrawal and by 48 h has usually undergone complete repair.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.

DREAM/calsenilin/KChIP3 modulates strategy selection and estradiol-dependent learning and memory

“…3C). This measurement is comparable to uterine weights of mice which received the same dose of subcutaneous injections of estradiol in other studies (Kaitu'u-Lino et al 2007) and of mice on diestrus (Gui et al 2006). This was expected as we did not choose a dose of estradiol that would mimic proestrus levels of estradiol, since we did not want to get a ceiling effect and possibly lose the difference between WT and KO animals.…”

“…Uterine weights of animals that received estradiol injections were significantly higher than those of oilinjected controls (t ¼ 5.2, P , 0.0001, t-test) (Fig. 3C), and they are comparable to uterine weights of mice that received same dose of subcutaneous injections of estradiol in other studies (Kaitu'u-Lino et al 2007) or of mice on diestrus (Gui et al 2006).…”

Reduced Transforming Growth Factor-β Activity in the Endometrium of Women With Heavy Menstrual Bleeding

“…Initiation of endometrial repair therefore occurs during the menstrual phase, when ovarian hormone levels remain low. Indeed, in the mouse model of simulated menstruation, repair occurred without delay when both exogenous and endogenous estrogens were removed (4). …”

Endometrial reconstruction from stem cells

“…After menstruation or parturition the endometrial surface epithelium repairs without scarring (14) in the absence of E (15). In other mucosal surfaces (e.g., intestine), regeneration of damaged mucosa occurs without scarring unless the injury involves the deep muscularis layers.…”