Abstract Intensive research work has been performed to better understand the regulation of the endometrium and its clinical implications to improve implantation. Although many proteins and molecules may influence endometrial development, their co-ordinated contribution to the implantation process is still poorly understood and a translation into clinical use has not sufficiently been performed. Clinical evaluation of the endometrium by ultrasound and other techniques, like endometrial biopsy and analysis of uterine secretions, has been intensively studied and therapeutic options to improve endometrial function have been suggested and tested. Systemic treatment with heparin, aspirin or corticosteroids did not result in improved implantation rates. Gene therapy and cervical treatment, e. Therefore, this review focuses on different aspects of endometrial research, which all contribute to the diagnosis, evaluation and therapy of endometrial function and dysfunction. First, the endometrial development towards a receptive milieu is described. Second, the actual clinical evaluation of endometrial receptivity, possible therapeutic strategies and in particular, the evaluation of endometrial function in the non-natural situation of hormonal stimulation is critically evaluated. In conclusion, the endometrium shall be considered as an important fertility-determining factor and therapeutic options should be developed in near future. On the maternal side, a so-called receptive endometrium is a prerequisite. Although implantation itself is a dynamic process occurring between blastocyst and endometrial layers, the priming of the endometrium towards the window of implantation WOI is of pure maternal origin. A reduced endometrial receptivity is found in an increasing number of unexplained infertilities. Therefore, an inadequate endometrium can be considered as a main fertility-determining factor. The endometrium undergoes precisely defined morphological changes until a receptive endometrium is developed. These morphological changes were described as early as 1950 by Noyes, Hertig and Rock and occur under the control of the sexual steroid hormones, estrogen and progesterone. Estrogen is the dominant hormone of the proliferative phase , whereas progesterone is the determining hormone of the secretory phase, where transformation and stromal decidualization occur. Preparation of the endometrium is directed towards the cycle phase of receptivity, which is known as the WOI. The WOI is described as the period in the mid-luteal phase from day 19 to day 24, when implantation can take place ; and is time limited. Different cell types, which interact to allow a co-ordinated invasion, form the endometrial net. Four groups of resident endometrial cells can be differentiated: stromal cells, epithelial and endothelial cells, and non-resident immune cells. Stromal cells primed by estrogen will differentiate to decidual cells under the influence of progesterone. Epithelial cells are involved in the adhesion process of the embryo. Receptivity of epithelial cells includes structural changes of the plasma membrane Murphy, 2000 and the cytoskeleton ; , causing a transformation of microvilli at the implantation site simultaneous to the stromal decidualization process. Also, at the time of decidualization, increased cytokine production leads to the migration of immune cells into the endometrium, of which the most important are monocytes and uterine natural killer NK cells. Immune competent cells have their specific role in the preparation of endometrial receptivity. Besides cellular changes, decidualization creates an extracellular matrix ECM composition of utmost importance. This matrix is composed mainly of laminin, heparan sulphate proteoglycans and type IV collagens. In the last two decades, a large number of proteins and other molecules, which are expressed in the endometrium in a cycle-dependent manner, have been described. Some of them, such as the insulin-like growth factor binding protein-1 IGFBP-1 , are used as a marker for decidualization at least in in vitro experiments. Nevertheless, the importance of these factors for endometrial regulation, and the interaction of these factors, is far from being understood. Furthermore, new technologies of molecular genetics, in particular the microarrays ; ; ; ; ; , have shown an enormous number of genes being expressed differentially within the endometrium throughout the cycle. However, the actual functions of these individual genes often remain to be determined. Although knowledge on molecular mechanisms in the endometrium has increased tremendously, translation of this basic research into daily clinical routine is rather limited. Therapeutic options remain poor. Therefore, the main purpose of this review is the re-evaluation of the endometrial contribution to fertility. The first section focuses on the endometrial development towards a receptive milieu. To elucidate the possible function of regulatory factors for each phase of endometrial development, we have used a cycle-dependent description. The second section is dedicated to the actual clinical evaluation of endometrial receptivity, possible therapeutic strategies and, in particular, the evaluation of endometrial function in the non-natural situation of hormonal stimulation. The endometrial cycle—towards uterine receptivity Every phase of the endometrial cycle is precisely tuned by many known and unknown genes that are regulated by endocrine, paracrine and autocrine factors. In this section, we have concentrated on some of the more important factors, many of which have been shown to be of relevance in humans. These factors are summarized in Figure. Microarray profiling of endometrial genes may allow a more comprehensive overview of gene encoding factors that are involved in endometrial differentiation. Furthermore, expression profiling of genes during the WOI in endometriosis may be helpful in identifying genes responsible for implantation failure. Up- and down-regulated factors of the proliferative and secretory phase. The proliferative phase The main feature of the endometrial tissue during the proliferative phase is active proliferation and angiogenesis to ensure nutrition of the developing new tissue, while suppressing apoptotic factors. Adequate development of endometrial tissue during this phase of the cycle is crucial for synchronization of the maturation process necessary for implantation during the secretory phase endometrium. One of the key players during the proliferative phase is the rising female hormone estrogen. Estrogen is found to induce the proliferation of cells and demonstrates an indirect effect by stimulating the expression of steroid receptors such as the progesterone receptor PR , which is crucial for progesterone action during the secretory phase, and ERs ERa, ERb , as well as retinoic acid receptor and androgen receptor. Estrogen also acts as a cell survival factor in the late proliferative phase via inhibition of the tumour suppressor gene phosphatase and tensin homologue PTEN. This gene is found to increase apoptosis and contact inhibition in endometrial cells by regulating various factors. PTEN inhibition on the other hand leads to elevated expression of such factors, e. Akt, a cell survival factor which acts via down-regulation of FasL, cell cycle inhibitor p27, cytochrome C release and many others. Anti-apoptotic genes like Bcl-2 are also up-regulated in the proliferative phase. These changes partially reflect the interaction between immune cells and the endometrial cells during this phase. Furthermore, ovarian hormones extensively regulate the growth factor system of insulin-like growth factor IGF and IGF-binding protein; induction of IGF-I by estrogen during the proliferative phase is thought to contribute to the proliferation of the endometrium. In a rece
