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Journal of the Society for Gynecologic Investigation, Vol. 13, No. 6, 459-465 (2006)
DOI: 10.1016/j.jsgi.2006.05.004

Progestagenic Effects of Tibolone are Target Gene—Specific In Human Endometrial Cells

Wei Zhang, MD

James Mazella, BS

Helenius J. Kloosterboer, PhD

Department of Obstetrics/Gynecology and Reproductive Medicine, SUNY-Stony Brook, Stony Brook, New York; and N.V. Organon, Oss, the Netherlands. Supported by grants NIH HD 19247-16 and Organon 31480

Linda Tseng, PhD

Department of Obstetrics/Gynecology and Reproductive Medicine, SUNY-Stony Brook, Stony Brook, New York; and N.V. Organon, Oss, the Netherlands. Supported by grants NIH HD 19247-16 and Organon 31480; litseng{at}notes.cc.sunysb.edu

Objectives: 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 17ßhydroxy steroid dehydrogenase (17ßHSD, 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 {Delta}4-tibolone ({Delta}4Tib) significantly increased the content of 17ßHSD and SULT1E1 mRNA. In stromal cells, Tib and {Delta}4Tib increased PRL mRNA (~ 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 3ßOHTib, showed some progestagenic effects.

Conclusions: The data showed that Tib and {Delta}4Tib exhibited clear progestagenic effects in endometrial glandular cells by inducing 17ßHSD and SULT1E1, while in stromal cells the response was weaker in the induction of PRL and had little effect on IGFBP1. In addition, the 3ßOHTib metabolite expressed progestagenic activity. These disparate effects in two types of cells may be beneficial for maintaining endometrial cells in a quiescent state.

Key Words: Tibolone • progesterone • 17ßHSD • SULT1E1 • PRL • endometrium


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