Selektive Östrogen-Rezeptor-Modulatoren (SERM) und ihre Wirkung auf die Proliferation und Differenzierung des Rattenendometriums

Selective estrogen receptor modulators (SERM) are a class of new therapeutic substances that are approved for the treatment of breast cancer as well as for the prevention of atraumatic vertebral fractures in postmenopausal women with a high risk for osteoporosis. Some candidates are still in the clinical development. They have different estrogenagonistic and estrogenantagonistic effects. Both SERMs tamoxifen and raloxifene are strong antiestrogens in-vivo. In-vitro they show different estrogenic effects. The endometrium is an important target of estrogenic effects. Depending on the estrogenic potential of the pharmaceutical it can be stimulated leading in rare cases to the development of an endometrium carcinoma. The aim of this study was to evaluate the effects of the two different nonsteroidal SERMs tamoxifen and raloxifene on the proliferation and the differentiation of the endometrium of the female, ovarectomized (ovex) rat. The ovex rat is a well established and valid model for the determination of estrogenic effects. Two different dose regimens, a single dose subcutaneous application and a multiple dose subcutaneous application for 14 days with relevant therapeutic doses of tamoxifen, raloxifene and 17ß estradiol as positive control and with the vehicle as negative control were chosen for the studies. The following endpoints were selected for the evaluation of the estrogenic effects: the relative uterine wet weight, the uterine histology, the luminal endometrial height, the protooncogenes fos and jun (immunohistochemistry and mRNA levels), the cell cycle parameters cyclin D1 (mRNA) and cdc2 (immunohistochemistry)and the proliferation marker PCNA (immunohistochemistry). The results show that raloxifene stimulates the ovex rat endometrium in a similar way as tamoxifen. Especially after the single dose application of raloxifene the increase of the relative uterine wet weight and of the luminal endometrial height, the expression of the fos and jun mRNA in the rat uterus and the increase in positive staining by immunohistochemistry of the proliferation marker PCNA in the epithelium of the luminal endometrium and the glandular endometrium are significant compared to the control. Even after a short time interval (2- 8 hours) after the last application of raloxifene in the multiple dose regimen there occured a small increase in the relative uterine wet weight and the luminal endometrial height as well as an increase in PCNA positive epithelial cells in the glandular endometrium. To conclude not only tamoxifen but also raloxifene shows significant estrogenic effects in-vivo in the ovex rat endometrium. Furthermore there are differences in the proliferation of the luminal epithelial and the glandular endometrium, especially after the multiple dose application of the compounds.

Grantor dc:publisher

Publikationsserver der RWTH Aachen University

Year dc:date

2001

Author dc:creator

• Schneider, Marion

Contributors dc:contributor

• Hegele-Hartung, Christa

• info:eu-repo/classification/ddc/610
• Medizin

Statement dc:rights

• info:eu-repo/semantics/openAccess

Language dc:language

ger

Identifier

https://publications.rwth-aachen.de/search?p=id:%22RWTH-CONV-120815%22

OAI identifier oai:identifier

oai:publications.rwth-aachen.de:58994