Progestagenic effects of tibolone are target gene-specific in human endometrial cells.
OBJECTIVE
Tibolone (Tib) exhibits progestagenic activities in addition to its tissue-specific estrogenic activities. The purpose of the current study was to determine the progestagenic actions of Tib and its metabolites using target genes known to be regulated by progestins in human endometrial glandular and stromal cells.


METHODS
Human endometrial glandular and stromal cells were isolated from endometrial tissue fragments and separately incubated with Tib and its metabolites. Real-time polymerase chain reaction (PCR) was used to determine the mRNA content of 17betahydroxy steroid dehydrogenase (17betaHSD, type 2) and sulfotransferase (SULT1E1) in endometrial glandular cells, and prolactin (PRL) and insulin-like growth factor binding protein-1 (IGFBP1) in endometrial stromal cells.


RESULTS
In glandular cells, Tib and Delta4-tibolone (Delta4Tib) significantly increased the content of 17betaHSD and SULT1E1 mRNA. In stromal cells, Tib and Delta4Tib increased PRL mRNA ( approximately 30% of the capacity compared to progesterone) and had little effect on IGFBP1 mRNA. Anti-progestin, RU486, reversed the induction of SULT1E1 and PRL by progesterone or Tib. Also, the two 3 hydroxyl tobolone metabolites, especially 3betaOHTib, showed some progestagenic effects.


CONCLUSIONS
The data showed that Tib and Delta4Tib exhibited clear progestagenic effects in endometrial glandular cells by inducing 17betaHSD and SULT1E1, while in stromal cells the response was weaker in the induction of PRL and had little effect on IGFBP1. In addition, the 3betaOHTib metabolite expressed progestagenic activity. These disparate effects in two types of cells may be beneficial for maintaining endometrial cells in a quiescent state.
Zhang
Wei
W
Department of Obstetrics/Gynecology and Reproductive Medicine, SUNY-Stony Brook, Stony Brook, New York 11794, USA.
Mazella
James
J
Kloosterboer
Helenius J
HJ
Tseng
Linda
L
D015067:17-Hydroxysteroid Dehydrogenases / Q000235:genetics; D002478:Cells, Cultured; D017077:Culture Media, Conditioned / Q000032:analysis; D004717:Endometrium / Q000737:chemistry / Q000187:drug effects* / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D004960:Estradiol Dehydrogenases; D020847:Estrogen Receptor Modulators / Q000494:pharmacology; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D018970:Insulin-Like Growth Factor Binding Protein 1 / Q000235:genetics; D015735:Mifepristone / Q000494:pharmacology; D009652:Norpregnenes / Q000378:metabolism / Q000494:pharmacology*; D016133:Polymerase Chain Reaction; D011372:Progestins / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D011388:Prolactin / Q000032:analysis / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis; D017154:Stromal Cells / Q000737:chemistry / Q000187:drug effects; D015238:Sulfotransferases / Q000235:genetics
D017077:Culture Media, Conditioned; D020847:Estrogen Receptor Modulators; D018970:Insulin-Like Growth Factor Binding Protein 1; D009652:Norpregnenes; D011372:Progestins; D012333:RNA, Messenger; D015735:Mifepristone; D011388:Prolactin; D015067:17-Hydroxysteroid Dehydrogenases; D004960:Estradiol Dehydrogenases; C523763:HSD17B2 protein, human; D015238:Sulfotransferases; C020122:estrone sulfotransferase; C027385:tibolone