Effects of SERM (selective estrogen receptor modulator) treatment on growth and proliferation in the rat uterus.
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.
Stygar
Denis
D
Division for Reproductive Endocrinology, Department of Woman and Child Health, Karolinska Institutet, Stockholm, Sweden. denis.stygar@kbh.ki.se
Muravitskaya
Natalia
N
Eriksson
Britt
B
Eriksson
Håkan
H
Sahlin
Lena
L
D000818:Animals; D002455:Cell Division / Q000187:drug effects; D004958:Estradiol / Q000031:analogs & derivatives* / Q000494:pharmacology; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D005260:Female; D000077267:Fulvestrant; D005786:Gene Expression Regulation / Q000187:drug effects; D007334:Insulin-Like Growth Factor I / Q000096:biosynthesis / Q000235:genetics; D019394:Ki-67 Antigen / Q000032:analysis; D009929:Organ Size / Q000187:drug effects; D010052:Ovariectomy; D018809:Proliferating Cell Nuclear Antigen / Q000032:analysis; D012333:RNA, Messenger / Q000096:biosynthesis; D020849:Raloxifene Hydrochloride / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011960:Receptors, Estrogen / Q000096:biosynthesis / Q000235:genetics; D011986:Receptors, Somatotropin / Q000096:biosynthesis / Q000235:genetics; D020845:Selective Estrogen Receptor Modulators / Q000494:pharmacology*; D013629:Tamoxifen / Q000494:pharmacology; D014599:Uterus / Q000033:anatomy & histology / Q000187:drug effects* / Q000378:metabolism
D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D019394:Ki-67 Antigen; D018809:Proliferating Cell Nuclear Antigen; D012333:RNA, Messenger; D011960:Receptors, Estrogen; D011986:Receptors, Somatotropin; D020845:Selective Estrogen Receptor Modulators; D013629:Tamoxifen; D000077267:Fulvestrant; D020849:Raloxifene Hydrochloride; D004958:Estradiol; D007334:Insulin-Like Growth Factor I