Role of progesterone in structural and biochemical remodeling of endometrium Gracy Rosario Geetanjali Sachdeva William C Okulicz Christopher I Ace

Abstract

The endometrial response to the varying levels of ovarian steroids is exhibited as alterations in its form and function. These changes in endometrial morphology and physiology, especially those observed during the implantation window are prerequisites to support embryo attachment and invasion. However the state of endometrial receptivity to embryo results from an operative network of several molecular events triggered by estrogen, progesterone and probably some other factors, yet to be discovered. It is well established that estrogen and progesterone are the critical endocrine determinants of endometrial functions. However the precise delineation of hormone driven events and their interaction is yet to be ascertained. Several attempts have been made to understand these cascades, however most of these studies have been conducted in vitro using one or the other component of endometrial tissues. We have attempted to investigate in vivo morphological and biochemical/molecular changes in endometrium in response to neutralization of progesterone synthesis/ function in two primate animal models. In one of the models, ovariectomized rhesus monkeys, artificial menstrual cycles were simulated and subsequent effects on the _expression of various genes were investigated in presence and absence of sufficient progesterone levels. The results coincided with those observed in the endometrium of the other model, bonnet monkeys presenting normal hypothalamus-ovarian-pituitary function but displaying retarded endometrial growth due to blocked progesterone receptor. A significant decline was observed in the expression of transforming growth factor beta, transforming growth factor beta receptor, leukaemia inhibitory factor, whereas no remarkable changes were observed in the expression of estrogen receptor and progesterone receptors in response to neutralization of progesterone synthesis/function in these two animal models. Taking support from the inferences drawn from previously published in vitro studies and our data from in vivo studies conducted in these two models, we propose a hypothesis supporting a potential link between the expressions of transforming growth factor beta, leukaemia inhibitory factor, cyclooxygenases and integrins.

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

“…Only 130 transcripts (22%) were common in both the groups and all of them displayed opposite regulatory direction between groups, except for three down-regulated transcripts in the mifepristone group, supporting our main finding. Endometrial receptivity results from the expression and repression of genes controlled by ovarian steroidal hormones and other factors; however it is well established that P 4 is a critical determinant of endometrial function during the window of implantation (Rosario et al 2003). Under this premise, it is surprising that only about a third of the genes that change its expression level at the moment of endometrial receptivity are also regulated under the action of mifepristone.…”

PARP1 during embryo implantation and its upregulation by oestradiol in mice

“…expression of adhesion molecules (von Lukowicz et al 2008), transcriptional regulation of cyclooxygenase-2 (Lin et al 2011), transforming growth factor-b1 (TGF-b1) receptor (Sterling et al 2006), syndecan-4 (Lacal et al 2009), NF-kB (Kauppinen et al 2013), SMAD3 (Huang et al 2011), sex determining region Y-Box-2 (Musard et al 2001) and E-cadherin (McPhee et al 2008), which are essential during embryo implantation (Nakamura et al 2004, San et al 2004, Jha et al 2006, Lin et al 2006, St-Louis et al 2010. Furthermore, cell differentiation, cell proliferation (Lei et al 2009, Kaloglu & Onarlioglu 2010, Macdonald et al 2011, Afshar et al 2012) and the tissue remodelling process also take place in the uterus (Fazleabas & Strakova 2002, Rosario et al 2003, Kaloglu & Onarlioglu 2010, and can be influenced by PARP1 (Pagano et al 2007, Kobayashi 2011. In endometrial carcinoma, PARP1 can regulate the progesterone receptor (PR; Ghabreau et al 2004), suggesting the involvement of PARP1 in ovarian steroid signalling.…”