Mifepristone induced progesterone withdrawal reveals novel regulatory pathways in human endometrium

Abstract

In women, a single dose of the antiprogestin mifepristone (RU486) in the secretory phase rapidly renders the endometrium unreceptive and is followed by endometrial breakdown and menstruation within 72 h. This model provides a system to identify progesterone-regulated genes, which may be involved in endometrial receptivity and the induction of menstruation. We used cDNA microarrays to monitor the response of the endometriuim over 24 h following administration of mifepristone in the mid-secretory phase. We identified 571 transcripts whose expression was significantly altered, representing 131 biochemical pathways. These include new progesterone regulated members of the Wnt, matrix metalloproteinase (MMP), prostaglandin (PG) and chemokine regulatory pathways. Transcripts involved in thyroid hormone metabolism and signalling such as type II iodothyronine deiodinase and thyroid receptors were also found to be highly regulated by progesterone antagonism in the endometrium. Transcripts required for thyroid hormone synthesis such as thyroid peroxidase (TPO) and thyroglobulin (TG) were also expressed, indicating that the endometrium may be a site of thyroxin production. These results add to the existing knowledge of the role of the Wnt, chemokine, MMP and PG pathways in receptivity and early menstrual events. They provide in vivo evidence supporting direct or indirect regulation of many new transcripts by progesterone. We have also identified for the first time the very early transcriptional changes in vivo in response to progesterone withdrawal. This greatly increases our understanding of the pathways leading to menstruation and may provide new approaches to diagnose and treat menstrual disorders.

Effect of low-dose mifepristone administration on day 2 after ovulation on transcript profiles in implantation-stage endometrium of rhesus monkeys

“…Table 6 gives a list of common gene products that appeared to be regulated by progesterone in previous reports and those reported to display differential abundance in the present study. Now, we report for the first time that a new cohort of 28 gene products were affected in implantation-stage endometrium, following early luteal-phase administration of mifepristone in the present study, and those that were not reported to be affected by progesterone in earlier array-based studies using the model of comparative study between prereceptive and receptive stage endometria (Carson et al 2002, Kao et al 2002, Borthwick et al 2003, Riesewijk et al 2003, Giudice 2004, Mirkin et al 2005, Talbi et al 2006, Sherwin et al 2007). Out of nine gene products that were subjected to realtime RT-PCR quantification, seven (CD44, CSF1, distal less homeobox 4 (DLX4), enigma, KDR, leptin receptor, macrophage migration inhibitory factor (MIF)) are reported here as novel candidates, while two (mucin 1 (MUC1) and uteroglobin) have been reported earlier (Table 6).…”

Aberrant expression and regulation of NR2F2 and CTNNB1 in uterine fibroids

“…In contrast, CTNNB1 expression in myometrial and fibroid cells were not affected by progesterone and/or RA treatments. Several studies report that members of the Wnt signalling pathway, but not CTNNB1 itself, are regulated by progesterone in human endometrial cells (Tulac et al 2006, Catalano et al 2007, Kane et al 2008. Therefore, the progesterone-associated effects on the CTNNB1 pathway in the endometrium may be cell-type specific and not affect myometrial cells.…”

Effect of single post-ovulatory administration of mifepristone (RU486) on transcript profile during the receptive period in human endometrium

“…However, this model does not reflex the steroids dynamics occurring in vivo. Tissue explants are appropriate for evaluating immediate responses in human endometrium to ovarian steroids ex vivo but do not fully address the entire set of genes associated to embryo implantation (Catalano et al 2007, Dassen et al 2007a. The endometrial response to 200 mg of mifepristone in day LHC8 was evaluated in women after 6 or 24 h of treatment (Catalano et al 2007).…”

“…Tissue explants are appropriate for evaluating immediate responses in human endometrium to ovarian steroids ex vivo but do not fully address the entire set of genes associated to embryo implantation (Catalano et al 2007, Dassen et al 2007a. The endometrial response to 200 mg of mifepristone in day LHC8 was evaluated in women after 6 or 24 h of treatment (Catalano et al 2007). Although this model was designed to identify P 4 -regulated genes involved in the endometrial receptivity, also pinpoints transcripts related to the induction of menstruation, introducing a confounding factor in the determination of uterine receptivity genes.…”