Does loss of REST contribute towards progesterone resistance in endometriosis associated infertility?

Endometriosis is a gynecological condition where endometrial stroma and glandular tissue grow outside the pelvic cavity. It affects 176 million women worldwide including 10% of women in their reproductive age. Endometriosis causes pelvic pain, irregular menses, pain during intercourse and is associated with infertility. The strong correlation of endometriosis with infertility is suggested in studies where 25%-50% infertile women have endometriosis and 30%-50% of women with endometriosis are infertile. One of the few pathologies associated in endometriosis that can contribute to infertility, is the inability of progesterone to suppress the proliferative effects of estrogen. A number of progesterone target genes have been found to be inappropriately expressed in the endometrium of women with endometriosis. Several theories on the molecular basis of progesterone resistance/insensitivity in endometriosis have been proposed yet the exact mechanism remains to be elucidated. Preliminary studies from our lab have found neuron-restrictive silencer factor/RE1-silencing transcription factor (NRSF/REST) protein expression is severely reduced in eutopic endometrial tissue in women with endometriosis. The overall hypothesis of this project is that REST facilitates the eutopic endometrium to fully respond to progesterone and loss of REST contributes to endometriosis associated infertility. To test this hypothesis, we utilized both in vitro and in vivo model systems. Using siRNA approach, we evaluated the effect of loss of REST on human endometrial stromal cells (HESCs) ability to respond to progesterone. To check for progesterone signaling we looked at expression levels of FOXO1, a well-known progesterone target gene, essential for fertility which is also misexpressed in endometriosis. We found reduced transcript expression of FOXO1 upon REST knockdown in HESCs. Additionally, using RESTfl/fl; PGRcre (REST KO) mice in REST was deleted from those cells expressing progesterone receptors, we examined the role of REST in fertility. A 6-month breeding trial revealed impaired fertility in REST KO mice. The mice were subfertile with average litter size of 2 (approx.) compared to control’s average litter size of 8 (approx.). We speculate a role of REST in endometriosis associated sub-fertility and further investigation is required to dissect exact mechanism.