POSTER VIEWING SESSION - FEMALE (IN) FERTILITY

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Aim: To explore the molecular basis of clinically observed volume reduction in uterine leomyoma, exposed to mifepristone.Background: Treatment of uterine leiomyomas with a selective progesterone receptor modulator (SPRM) as an alternative to surgery is of considerable clinical interest.Steroid homone receptors are overexpressed in leiomyoma tumor tissue compared to adjacent myometrium and involved in the process of leiomyoma growth.Progesterone receptor modulators such as mifepristone are effective and well tolerated in reducing myoma volume and vaginal bleeding.In a previously reported study we observed a significant volume reduction in the dominant myoma in response to mifepristone, but with a wide individual variation (median -23%, range: -81 to + 19%) in response to treatment.Thus, a study was conducted to explore the molecular basis of good response to mifepristone treatment.Material and Methods: Premenopausal women with uterine leiomyoma (n = 12) received treatment with mifepristone 50 mg every other day for 12 weeks.Among them, eight women were sub grouped as good (N = 4, median -49%, range -64 to -31%) or poor (N = 4, median -22%, range -23 to -21%) respnders.At surgery, biopsies were taken from the periphery of the dominant leiomyoma and total RNA was extracted to study the gene expression by microarray.The result was further analysed by Ingenuity Pathway Analysis (IPA, Ingenuity® Systems, www.ingenuity.com) to explore the leading molecular pathway mediating the response to mifepristone.The result from the microarray was confirmed by real time-PCR.Proliferation marker MKI67 and apoptosis marker TP53 were analysed along with apoptotic index by TUNEL assay.Ethical permission for this study was obtained prior to start of the study.Results: Twenty one canonical pathways showed significantly different expression (p < 0,05) on comparing between good and poor responders.The most differently expressed pathway was Metabolism of Xenobiotics by Cytochrome P450 pathway.The second most significant pathway and the pathway more relevant to uterine leomyoma growth is the glutathione pathway harboring glutathione-s tranferases (p = 0.0001, ratio 5%).One of the genes was downregulated (GPX2 -1.7 fold) and 4 genes belonging to this family were upregulated (GSTM1 + 8.0-fold), GSTM2(+ 1.5 fold), GSTM3(+ 2.3 fold), GSTM5(+ 2.2 fold) among the good responders.Further analysis by real time PCR showed GSTM1 was not detectable in biopsies from non responders.No correlations were seen for GSTM1, MKI67 or TP53 versus percentual myoma volume reduction.TUNEL analysis showed no difference in the degree of apoptosis between good or bad responders to mifepristone.Conclusion: Our findings indicate that glutothione pathway is involved in the action of mifepristone on leiomyoma volume reduction.GSTM1 positive fenotype is of importance for uterine leiomyoma volume reduction in response to mifepristone exposure in vivo.The mechanism behind the difference in growthregulation is still not clear, but could be suggested to interfere with proliferation or repression co-regulators related to the degree of metabolism of steroids regulated by GSTMs.The finding in the present study of a tentative prognostic marker for leiomyoma volume reduction during mifepristone treatment is of potential importance for the clinical management of millions of women suffering from symptoms from uterine leiomyomas.

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