ENDOMETRIAL RECEPTIVITY TO EMBRYO IMPLANTATION: MOLECULAR CUES FROM FUNCTIONAL GENOMICS

Abstract

The endometrium is the mucous lining the uterine cavity comprised of a basal and a functional layer being the latter the one that sheds during menses and regenerates from the basal portion. The main cell populations within the functional stratus are epithelial and stromal cells accompanied by a variable number of leukocytes. Epithelial cells are found covering the luminal surface and tubular glands in basal and functional layers. Endometrial stroma contains reticular connective tissue comprised mainly by uterine fibroblasts that rapidly differentiate into decidualized cells when stimulated by an implanting blastocyst. The stromal compartment contains also abundant lymphocytes, granulocytes and macrophages during luteal phase of the menstrual cycle. These cells along with epithelial and stromal fibroblasts are source and target of paracrine signals of proliferation and differentiation. Both components respond to ovarian steroid hormones and depend on each other for their structure, function and responsiveness to estrogen (E2) and progesterone (P4) (Tabibzadeh, 1998, review). During a normal menstrual cycles, human endometrium display unique features for an adult tissue: undergoes cyclic construction and sloughing. The outer layer of the endometrium is loss while the basal layer containing the deep glandular epithelium gets preserved. Later on, stem cells located in this layer will originate the various endometrial cell types in response to the appropriate hormonal stimulus, regenerating the whole endometrium (Padykula, 1991). The endometrial cycle is driven by the ovarian steroidal hormones and can be divided in three phases: proliferative, secretory and menstrual. Proliferative phase lasts around 10 – 20 days averaging 14 days. During this phase, glands grow and become winding due to the active mitosis of the epithelial cells driven by rising levels of serum E2 resulting in growing about 10 times the original thickness of the endometrium. Indeed, extensive DNA synthesis in epithelial cells and some in stromal cells is seen during this stage (Padykula, 1991). Once ovulation has taken place, the increase of circulating P4 triggers the transition to the secretory phase. During this phase, mitotic activity is inhibited and a complex secretory activity is induced beginning with glycogen vesicles polarization in glandular epithelial cells, locating subnuclearly which is further transported by microfilaments to the apical region where glycogen is actively secreted to the lumen of glands. In addition, epithelial cells initiate a complex secretory activity along with the establishment of an adequate environment for embryo implantation that take place only during a restricted time frame called ‘window of implantation’ (Psychoyos, 1986). During this period, morphological and molecular changes take place leading to a coordinated expression or repression of key molecules that ultimately enable the blastocyst to attach and invade the endometrial tissue. Such changes occur independently of the presence of a blastocyst; however the endometrium undergoes further biochemical and morphological changes induced by signals from the blastocyst and the following trophoblast invasion. With no embryo implantation, the endometrium undergoes a series of processes that end toward late secretory phase with sloughing and menses. When a successful embryo implantation takes place, luteolysis is prevented and the endometrium is not just maintained but differentiates to decidua and undergoes dramatic vascular changes at the implantation site. Therefore, gene expression in the human endometrium is likely to exhibit neat and distinct changes throughout the various stages of the menstrual cycle in accordance with the oscillations in estrogen and progesterone serum levels and their tissue receptor levels. Since these ovarian steroid hormones drive these processes eliciting an array of cellular and biochemical responses, mostly through genomic pathways (O'malley & Tsai, 1992), current thinking suggests that at the onset of receptivity, expression of some genes in given cell types of this tissue, is temporarily turned on or increased while some others are temporarily turned off or decreased (Tabibzadeh, 1998). Some of these changes are essential for establishing and maintaining pregnancy. Likewise, when implantation has occurred, another program of gene expression takes place in the endometrium, not only maintaining it, but also triggering further differentiation to decidua and facilitating and regulating trophoblast invasion and placenta development. The endometrium is the mucous lining the uterine cavity comprised of a basal and a functional layer being the latter the one that sheds during menses and regenerates from the basal portion. The main cell populations within the functional stratus are epithelial and stromal cells accompanied by a variable number of leukocytes. Epithelial cells are found covering the luminal surface and tubular glands in basal and functional layers. Endometrial stroma contains reticular connective tissue comprised mainly by uterine fibroblasts that rapidly differentiate into decidualized cells when stimulated by an implanting blastocyst. The stromal compartment contains also abundant lymphocytes, granulocytes and macrophages during luteal phase of the menstrual cycle. These cells along with epithelial and stromal fibroblasts are source and target of paracrine signals of proliferation and differentiation. Both components respond to ovarian steroid hormones and depend on each other for their structure, function and responsiveness to estrogen (E2) and progesterone (P4) (Tabibzadeh, 1998, review). During a normal menstrual cycles, human endometrium display unique features for an adult tissue: undergoes cyclic construction and sloughing. The outer layer of the endometrium is loss while the basal layer containing the deep glandular epithelium gets preserved. Later on, stem cells located in this layer will originate the various endometrial cell types in response to the appropriate hormonal stimulus, regenerating the whole endometrium (Padykula, 1991). The endometrial cycle is driven by the ovarian steroidal hormones and can be divided in three phases: proliferative, secretory and menstrual. Proliferative phase lasts around 10 – 20 days averaging 14 days. During this phase, glands grow and become winding due to the active mitosis of the epithelial cells driven by rising levels of serum E2 resulting in growing about 10 times the original thickness of the endometrium. Indeed, extensive DNA synthesis in epithelial cells and some in stromal cells is seen during this stage (Padykula, 1991). Once ovulation has taken place, the increase of circulating P4 triggers the transition to the secretory phase. During this phase, mitotic activity is inhibited and a complex secretory activity is induced beginning with glycogen vesicles polarization in glandular epithelial cells, locating subnuclearly which is further transported by microfilaments to the apical region where glycogen is actively secreted to the lumen of glands. In addition, epithelial cells initiate a complex secretory activity along with the establishment of an adequate environment for embryo implantation that take place only during a restricted time frame called ‘window of implantation’ (Psychoyos, 1986). During this period, morphological and molecular changes take place leading to a coordinated expression or repression of key molecules that ultimately enable the blastocyst to attach and invade the endometrial tissue. Such changes occur independently of the presence of a blastocyst; however the endometrium undergoes further biochemical and morphological changes induced by signals from the blastocyst and the following trophoblast invasion. With no embryo implantation, the endometrium undergoes a series of processes that end toward late secretory phase with sloughing and menses. When a successful embryo implantation takes place, luteolysis is prevented and the endometrium is not just maintained but differentiates to decidua and undergoes dramatic vascular changes at the implantation site. Therefore, gene expression in the human endometrium is likely to exhibit neat and distinct changes throughout the various stages of the menstrual cycle in accordance with the oscillations in estrogen and progesterone serum levels and their tissue receptor levels. Since these ovarian steroid hormones drive these processes eliciting an array of cellular and biochemical responses, mostly through genomic pathways (O'malley & Tsai, 1992), current thinking suggests that at the onset of receptivity, expression of some genes in given cell types of this tissue, is temporarily turned on or increased while some others are temporarily turned off or decreased (Tabibzadeh, 1998). Some of these changes are essential for establishing and maintaining pregnancy. Likewise, when implantation has occurred, another program of gene expression takes place in the endometrium, not only maintaining it, but also triggering further differentiation to decidua and facilitating and regulating trophoblast invasion and placenta development.