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Effects of SERM (selective estrogen receptor modulator) treatment on growth and proliferation in the rat uterus
Denis Stygar1, Natalia Muravitskaya, Britt Eriksson
1Division for Reproductive Endocrinology, Department of Woman and Child Health, Karolinska Institutet, Stockholm, Sweden. denis.stygar@kbh.ki.se
Background:
Selective estrogen receptor modulators (SERMs) have been developed in order to create means to control estrogenic effects on different tissues. A major drawback in treatment of estrogen receptor (ER) positive breast cancer with the antagonist tamoxifen (TAM) is its agonistic effect in the endometrium. Raloxifene (RAL) is the next generation of SERMs where the agonistic effect on the endometrium has been reduced.
Methods:
The aim of the present study was to determine the effect of SERM treatment on the uterus, as assessed by proliferation markers and several factors involved in uterine growth. Ovariectomized (ovx) rats were treated with estradiol (E2), tamoxifen (TAM), RAL, ICI182780 (ICI) or vehicle (OVX-controls). We studied the effects on mRNA levels of the growth hormone (GH) receptor, insulin-like growth factor-I (IGF-I), ERalpha and ERbeta. In addition, by immunohistochemistry the proliferation markers PCNA and Ki-67, as well as ERalpha and ERbeta, were detected.
Results:
The uterine weight of the rats treated with E2 or TAM was increased as compared to OVX-controls. The uterine GH-receptor mRNA level was highest in the E2 treated animals. In ICI treated rats no GH-receptor mRNA could be detected. The IGF-I mRNA level increased 16-fold in uteri of the TAM treated group and 9-fold in the E2 treated rats as compared to OVX-controls. The ERalpha mRNA level was increased in the E2 treated rats, while the ERbeta mRNA level was increased after TAM treatment. The proliferation, as assessed by PCNA, was lowest in ICI treated animals.
Conclusions:
The uterine wet weight, the LE height and the GH-receptor mRNA levels showed similar patterns, indicating that GH is involved in the regulation of uterine weight. Tamoxifen, which has been related to increased incidence of endometrial carcinoma in women, dramatically increased IGF-I mRNA levels in rat uterus. Since proliferation was not higher in TAM and E2 treated rats than in OVX controls, this assay of simple, early proliferation does not give the full explanation of why TAM should enhance the risk of developing endometrial cancer.
Insights
Selective estrogen receptor modulators (SERMs) like tamoxifen can affect uterine growth. This study investigated SERM effects on rat uterus, finding tamoxifen significantly increased IGF-I mRNA, but not early proliferation markers, suggesting complex mechanisms behind endometrial cancer risk.
Area of Science:
- Endocrinology
- Pharmacology
- Oncology
Background:
- Selective estrogen receptor modulators (SERMs) are designed to modulate estrogenic effects across tissues.
- Tamoxifen (TAM), a SERM used for estrogen receptor (ER) positive breast cancer, exhibits undesirable agonistic effects on the endometrium.
- Raloxifene (RAL) represents a newer generation of SERMs with reduced endometrial agonistic activity.
Purpose of the Study:
- To investigate the impact of SERM treatment on uterine tissue.
- To assess proliferation markers and key factors involved in uterine growth.
- To compare the effects of estradiol (E2), tamoxifen (TAM), and raloxifene (RAL) on the uterus.
Main Methods:
- Ovariectomized (ovx) rats were administered E2, TAM, RAL, ICI182780 (ICI), or vehicle.
- mRNA levels of growth hormone (GH) receptor, insulin-like growth factor-I (IGF-I), ERalpha, and ERbeta were analyzed.
- Immunohistochemistry was used to detect proliferation markers (PCNA, Ki-67) and ERalpha/ERbeta.
Main Results:
- Uterine weight increased in rats treated with E2 or TAM compared to controls.
- Insulin-like growth factor-I (IGF-I) mRNA levels were significantly elevated in TAM (16-fold) and E2 (9-fold) treated groups.
- ERbeta mRNA levels increased after TAM treatment, while ERalpha mRNA increased with E2 treatment.
Conclusions:
- Growth hormone (GH) appears to play a role in regulating uterine weight, as indicated by similar patterns in uterine wet weight, LE height, and GH-receptor mRNA levels.
- Tamoxifen markedly increased IGF-I mRNA in rat uteri, a finding associated with increased endometrial carcinoma incidence in women.
- The lack of increased early proliferation markers (PCNA) in TAM and E2 treated rats suggests that simple proliferation assays do not fully explain TAM's enhanced risk for endometrial cancer.
