This Article Full Text Full Text (PDF) All Versions of this Article: 90/2/973    most recent Author Manuscript (PDF) Submit a related Letter to the Editor Purchase Article View Shopping Cart Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Hanifi-Moghaddam, P. Articles by Blok, L. J. Search for Related Content PubMed PubMed Citation Articles by Hanifi-Moghaddam, P. Articles by Blok, L. J. Related Collections Female Endocrinology

Molecular Portrait of the Progestagenic and Estrogenic Actions of Tibolone: Behavior of Cellular Networks in Response to Tibolone

Departments of Reproduction and Development (P.H.-M., L.J.B.), Obstetrics and Gynecology (S.C.J.P.G., F.H.v.W., C.W.B.), Urology (M.S.), and Bioinformatics (M.M.), Erasmus MC, 3000 CA Rotterdam, The Netherlands; and Research and Development Laboratories, N.V. Organon (H.J.K., M.E.D.G., A.M.S., A.J.v.G.), 5340 BH Oss, The Netherlands

Address all correspondence and requests for reprints to: Dr. P. Hanifi-Moghaddam, Department of Reproduction and Development, Erasmus Medical Center, P.O. Box 1738, 3000 DR Rotterdam, The Netherlands. E-mail: p.hanifi_moghaddam{at}erasmusmc.nl.

Tibolone is a synthetic steroid with estrogenic effects on brain, vagina, and bone without stimulating the endometrium. During tibolone treatment, it is thought that the progestagenic properties of tibolone stimulate cell differentiation, which effectively counterbalances the growth-stimulating effects of the estrogenic properties of tibolone. The objective of this study was to characterize the expression profile that reflects the endometrial responses to the separated estrogenic (growth-inducing) and progestagenic (growth-inhibiting) actions of tibolone, thus gaining insight into the counteracting effect of these properties of tibolone on the endometrium. The estrogenic action of tibolone was studied in the estrogen-responsive ECC1 cell line (expressing estrogen receptor ), and the progestagenic action was studied in the progesterone-responsive cell line Ishikawa PRAB-36 (expressing PRA and PRB). The data showed that the progestagenic and estrogenic effects of tibolone produce different expression profiles with a narrow overlap in genes; however, both properties modulate the same biological processes. The final genetic network analysis indicated that the estrogenic effect of tibolone is potentially counterbalanced by the progestagenic metabolite of tibolone via differential regulation of similar cellular processes. For example, both progestagenic and estrogenic properties stimulate proliferation, but they exert the opposite effect on apoptosis. The apoptosis network was stimulated by the progestagenic properties of tibolone; in contrast, the estrogenic effect of tibolone suppressed the apoptosis network. The current results indicate that this differential regulation is realized through modulation of a different group of genes and rarely via contraregulation of the same set of genes.

This article has been cited by other articles:

				G. C. Rodriguez, B.J. Rimel, W. Watkin, J. M. Turbov, C. Barry, H. Du, G. L. Maxwell, and J.M. Cline Progestin Treatment Induces Apoptosis and Modulates Transforming Growth Factor-{beta} in the Uterine Endometrium Cancer Epidemiol. Biomarkers Prev., March 1, 2008; 17(3): 578 - 584. [Abstract] [Full Text] [PDF]

				S. Bai, G. Grossman, L. Yuan, B. A. Lessey, F. S. French, S. L. Young, and E. M. Wilson Hormone control and expression of androgen receptor coregulator MAGE-11 in human endometrium during the window of receptivity to embryo implantation Mol. Hum. Reprod., February 1, 2008; 14(2): 107 - 116. [Abstract] [Full Text] [PDF]

				C. Barbier, H. J. Kloosterboer, and D. G. Kaufman Effects of Tibolone Metabolites on Human Endometrial Cell Lines in Co-culture Reproductive Sciences, January 1, 2008; 15(1): 75 - 82. [Abstract] [PDF]

				H. A. M. Verheul, L. J. Blok, C. W. Burger, P. Hanifi-Moghaddam, and H. J. Kloosterboer Levels of Tibolone and Estradiol and their Nonsulfated and Sulfated Metabolites in Serum, Myometrium, and Vagina of Postmenopausal Women Following Treatment for 21 Days With Tibolone, Estradiol, or Estradiol Plus Medroxyprogestrone Acetate Reproductive Sciences, February 1, 2007; 14(2): 160 - 168. [Abstract] [PDF]

				P Hanifi-Moghaddam, B Sijmons, M C Ott, W F J van IJcken, D Nowzari, E C M Kuhne, P van der Spek, H J Kloosterboer, C W Burger, and L J Blok The hormone replacement therapy drug tibolone acts very similar to medroxyprogesterone acetate in an estrogen-and progesterone-responsive endometrial cancer cell line J. Mol. Endocrinol., December 1, 2006; 37(3): 405 - 413. [Abstract] [Full Text] [PDF]

				W. Zhang, J. Mazella, H. J. Kloosterboer, and L. Tseng Progestagenic Effects of Tibolone are Target Gene--Specific In Human Endometrial Cells Reproductive Sciences, September 1, 2006; 13(6): 459 - 465. [Abstract] [PDF]

				C. Grohe 'Tib the balance': the search for the optimal hormone replacement therapy Eur. Heart J., July 2, 2005; 26(14): 1345 - 1346. [Full Text] [PDF]