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Published on: August 13, 2019
RAD001 (Everolimus) Can prevent tamoxifen-related endometrial and stromal hyperplasia
Evrim Erdemoglu1, Mehmet Güney, Gülnur Take
1Department of Obstetrics and Gynecology, Süleyman Demirel University, Isparta, Turkey. erdemoglu@med.sdu.edu.tr
Abstract:
The mechanism of tamoxifen-associated endometrial hyperplasia and cancer is not elicited. RAD001 inhibits a target protein in phosphatidyl kinase pathway, which is involved in endometrial hyperplasia and cancer. We investigated whether endometrial hyperplasia can be prevented through inhibition of the target of rapamycin by RAD001. Sixty BALB/c mice underwent oophorectomy and were divided into 6 groups: group 1, placebo group; group 2, tamoxifen-treated (4 mg/kg per 24 hours); group 3, estradiol-treated (4 mg/kg per 24 hours); group 4, RAD001-treated (1.5 mg/kg per 24 hours); group 5, tamoxifen (4 mg/kg per 24 hours)-and-RAD001 (1.5 mg/kg per 24 hours)-treated; and group 6, estradiol (4 mg/kg per 24 hours)-and-RAD001 (1.5 mg/kg per 24 hours)-treated. The count of glands, the length of epithelium, and immunohistochemical staining of proliferating cell nuclear antigen were analyzed. The count of total glands and the epithelial length were 30.8 (7.1) and 126 (43.4) microm, 53 (8.1) and 162.5 (34.8) microm, 65.2 (13.6) and 401.4 (44.0) microm, and 82.0 (5.2) and 444.7 (57.8) microm in the placebo-, the RAD001-, the tamoxifen-, and the estradiol-treated groups, respectively (P < 0.05). Although addition of RAD001 to estradiol did not decrease the count of total glands and the epithelial length, addition of RAD001 to tamoxifen did (43.3 [13.3] and 218.0 [29.2] microm, P < 0.05). The immunoreactive score of proliferating cell nuclear antigen is significantly decreased by the addition of RAD001 to either tamoxifen or estradiol in the epithelial and glandular cells. RAD001 can prevent tamoxifen-associated and estrogen-related endometrial hyperplasias in mice. RAD001 also decreases stromal cell proliferation in the tamoxifen-treated mice.
Insights
RAD001, an inhibitor of the target of rapamycin pathway, prevents tamoxifen-associated and estrogen-related endometrial hyperplasia in mice. This study demonstrates RAD001
Area of Science:
- Gynecology
- Oncology
- Pharmacology
Background:
- Tamoxifen is associated with endometrial hyperplasia and cancer, but the underlying mechanisms remain unclear.
- The phosphatidyl kinase pathway, involving the target of rapamycin (TOR), plays a role in endometrial proliferation.
- RAD001 is a TOR inhibitor with potential therapeutic applications.
Purpose of the Study:
- To investigate whether RAD001 can prevent tamoxifen-associated and estrogen-related endometrial hyperplasia.
- To evaluate the effect of RAD001 on endometrial gland count, epithelial length, and cell proliferation markers.
Main Methods:
- Sixty oophorectomized BALB/c mice were divided into six groups: placebo, tamoxifen, estradiol, RAD001, tamoxifen + RAD001, and estradiol + RAD001.
- Treatments were administered daily for 24 hours at specified dosages.
- Endometrial tissue was analyzed for gland count, epithelial length, and immunohistochemical staining for proliferating cell nuclear antigen (PCNA).
Main Results:
- Tamoxifen and estradiol significantly increased endometrial gland count and epithelial length compared to placebo (P < 0.05).
- RAD001 co-administration significantly reduced tamoxifen-induced increases in gland count and epithelial length (P < 0.05).
- RAD001 significantly decreased PCNA immunoreactivity in epithelial and glandular cells with both tamoxifen and estradiol treatments, and also reduced stromal cell proliferation in tamoxifen-treated mice.
Conclusions:
- RAD001 effectively prevents tamoxifen-associated and estrogen-related endometrial hyperplasias in a mouse model.
- RAD001 inhibits cell proliferation in endometrial tissues, suggesting a therapeutic role in preventing hormone-driven endometrial changes.
- The findings support the potential of TOR inhibition as a strategy to mitigate tamoxifen-induced endometrial risks.
