Rat uterine complement C3 expression as a model for progesterone receptor modulators: characterization of the new progestin trimegestone.
Progestins have a wide variety of activities in female reproduction. There are also pharmacological applications for progestins, including hormone replacement therapy and contraception. Here we report the development and characterization of the rat uterine complement component C3 mRNA as a molecular target for the evaluation of the antiestrogenic activity of progestins in the uterus. In this assay, ethinyl estradiol (EE) is used to stimulate C3 expression and progestins are then evaluated for their ability to inhibit this expression. The three reference progestins, progesterone (P4), levonorgestrel (LNG), and medroxyprogesterone acetate (MPA) blocked the increase in C3 mRNA levels induced by EE. Dexamethasone (DEX) and 17alpha-methyl testosterone did not inhibit the estrogen induced C3 mRNA levels; in fact, DEX caused a further increase in C3 mRNA levels. Finally, the antiprogestin RU486 was able to block the MPA inhibition of C3 message. RU486, like DEX, caused an increase in C3 mRNA levels above that of estrogen treatment alone. The model was also used to evaluate trimegestone (TMG), a new steroidal progestin, that has been shown to be a potent and selective progesterone receptor agonist. The activity of TMG in the rat uterine decidualization and ovulation inhibition assays was similar to MPA. However, in the C3 model, TMG caused a dose-dependent inhibition of the EE induced C3 message and was approximately five-fold more potent in this model than MPA (EC(50) of 4.7 microg/kg and 26.5 microg/kg, respectively). Therefore, TMG was a more potent antagonist of estrogenic activity in the uterine endometrium than any of the reference progestins tested and therefore may be more effective in protecting the endometrium in hormone replacement therapy.
Lundeen
S G
SG
Endocrinology Division, Women's Health Research Institute, Wyeth-Ayerst Research, 145 King of Prussia Road, Radnor, PA 19087 USA. slundeen@prius.jnj.com
Zhang
Z
Z
Zhu
Y
Y
Carver
J M
JM
Winneker
R C
RC
D000818:Animals; D001681:Biological Assay; D003176:Complement C3 / Q000096:biosynthesis* / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D020847:Estrogen Receptor Modulators / Q000494:pharmacology*; D005260:Female; D008525:Medroxyprogesterone / Q000494:pharmacology; D045167:Progesterone Congeners / Q000494:pharmacology*; D011372:Progestins / Q000494:pharmacology*; D011397:Promegestone / Q000031:analogs & derivatives / Q000494:pharmacology*; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D011980:Receptors, Progesterone / Q000037:antagonists & inhibitors; D014599:Uterus / Q000187:drug effects*
D003176:Complement C3; D020847:Estrogen Receptor Modulators; D045167:Progesterone Congeners; D011372:Progestins; D012333:RNA, Messenger; D011980:Receptors, Progesterone; C050319:trimegestone; D011397:Promegestone; D008525:Medroxyprogesterone