maximum size. they appear between day 19 and day 21 of gestational age, and are fully formed at day 20. this corresponds to a fertilization age of approximately five to seven days, which corresponds well with the time of implantation. pinopodes only persist for a maximum of two days, and are seen as the ultrastructural markers of receptivity. their development is enhanced by progesterone, and inhibited by estrogens. during the window of implantation, cell to cell adhesion is inhibited by muc1 a cell surface glycoprotein, belonging to the glycocalyx. the pinopodes are taller than the microvilli and protrude through the glycocalyx enabling direct contact with the adhering trophoblast. the most important attribute of pinopodes is this removal of glycoproteins from the cell surfaces of the uterine epithelial cells. muc16 has also been shown to disappear from the cell surfaces with the development of the pinopodes. some studies have reported that pinopodes entrap cilia, which prevents embryo movement, and during implantation allows close contact and adherence of the embryo. pinopodes bring uterine fluid and its macromolecules into the cells by the process of endocytosis. this decreases the volume of the uterus, taking the walls closer to the blastocyst floating in it. thus, the period of active pinopodes might limit the implantation window. pinopodes continue to absorb fluid, removing most of it during the early stages of implantation. predecidualization the endometrium increases thickness, becomes vascularized and its glands grow to be tortuous and boosted in their secretions. these changes reach their maximum about seven days after ovulation. furthermore, the surface of the endometrium produces a kind of rounded cells, which cover the whole area toward the uterine cavity. this happens about 9 to 10 days after ovulation. these cells are called decidual cells, which emphasises that the whole layer of them is shed off in every menstruation if no pregnancy occurs, just as leaves of deciduous trees. the uterine glands, on the other hand, decrease in activity and degenerate around 8 to 9 days after ovulation in absence of pregnancy. the decidual cells originate from the stromal cells that are always present in the endometrium, and make up a new layer, the decidua. the rest of the endometrium, in addition, expresses differences between the luminal and the basal sides. the luminal cells form the stratum compactum of the endometrium, in contrast to the basalolateral stratum spongiosum, which consists of the rather spongy stromal cells. decidualization decidualization expands if pregnancy occurs, further developing the uterine glands, the zona compacta and the epithelium of decidual cells lining it. the decidual cells become filled with lipids and glycogen and take the polyhedral shape characteristic of decidual cells. factors from the blastocyst also trigger the final formation of decidual cells into their proper form. in contrast, some decidual cells in the proximity of the blastocyst degenerate, providing nutrients for it. an indication of embryonic influence is that decidualization occurs at a higher degree in conception cycles than in nonconception cycles. furthermore, similar changes are observed when giving stimuli mimicking the natural invasion of the embryo. the embryo releases serine proteases which causes the epithelial cell membrane to depolarize and activates the epithelial sodium channel. this triggers an influx of calcium ions (ca2+) and phosphorylation of creb. phosphorylation of creb upregulates the expression of cox2, which leads to the release of prostaglandin e2 (pge2) from epithelial cells. pge2 acts on the stroma cells activating camp-related pathways in stromal cell leading to decidualization. parts of decidua the decidua can be organized into separate sections, although they have the same composition. decidua basalis – this is the part of the decidua which is located basalolateral to the embryo after implantation. decidua capsularis – decidua capsularis grows over the embryo on the luminal side, enclosing it into the endometrium. it surrounds the embryo together with decidua basalis. decidua parietalis – all other decidua on the uterine surface belongs to decidua parietalis. decidua throughout pregnancy after implantation the decidua remains, at least through the first trimester. however, its most prominent time is during the early stages of pregnancy, during implantation. its function as a surrounding tissue is replaced by the definitive placenta. however, some elements of the decidualization remain throughout pregnancy. the compacta and spongiosa layers are still observable beneath the decidua in pregnancy. the glands of the spongiosa layer continue to secrete during the first trimester, when they degenerate. however, before that disappearance, some glands secrete unequally much. this phenomenon of hypersecretion is called the arias-stella phenomenon, after the pathologist javier arias-stella. adaptation of secretions proteins, glycoproteins and peptides secreted by the uterine glands matrix-associated: fibronectin laminin entactin type-iv collagen heparan sulfate proteoglycan integrins – others: mucins prolactin igfbp-1 glycodelin endometrial protein 15 albumin beta-lipoprotein relaxin fibroblast growth factor 1 fibroblast growth factor 2 pappalysin-1 stress response protein 27 (srp-27) ca-125 beta-endorphin leu-enkephalin diamine oxidase tissue plasminogen activator renin progesterone-dependent carbonic anhydrase lactoferrin not only the lining of the uterus transforms, but the secretion from its glands changes. this change is induced by increased levels of progesterone from the corpus luteum. the target of the secretions is the embryoblast, and has several functions on it. nourishment the embryo spends approximately 72 hours in the uterine cavity before implanting. in that time, it cannot receive nourishment directly from the blood of the mother, and must rely on secreted nutrients into the uterine cavity, e.g. iron and fat-soluble vitamins. growth and implantation in addition to nourishment, the endometrium secretes several steroid-dependent proteins, important for growth and implantation. cholesterol, and steroids are also secreted. implantation is further facilitated by synthesis of matrix substances, adhesion molecules and surface receptors for the matrix substances. clinical significance implantation failure reproduction in humans is not very efficient. only around 30% of natural conceptions result in successful pregnancies. of the failed pregnancies around 85% are due to implantation failure. implantation failure is considered to be caused by inadequate uterine receptivity in two-thirds of cases, and by problems with the embryo itself in the other third. most ivf procedures fail because of implantation failure accounting for almost half of all pregnancy failures. inadequate uterine receptivity may be caused by abnormal cytokine and hormonal signaling as well as epigenetic alterations. recurrent implantation failure is a cause of female infertility. therefore, pregnancy rates can be improved by optimizing endometrial receptivity for implantation. evaluation of implantation markers may help to predict pregnancy outcome and detect occult implantation deficiency. as part of the organ-on-a-chip program, an endometrium-on-a-chip has been developed to model the functioning of the endometrium that could more clearly identify causes of implantation failure. organoids have also been developed to model the endometrium and its role in implantation. in women with more than three implantation failures in assisted reproduction, a review of several small randomized controlled studies estimated that the use of adjunct low molecular weight heparin improves live birth rate by approximately 80%. luteal phase support can include the use of progesterone and human chorionic gonadotropin (hcg) to improve the chances of a successful implantation. zinc deficiency zinc is crucial in pre-conception, (and successful pregnancy), and its deficiciency can lead to incompetent blastocyst development. once an egg is fertilized zinc is released in a zinc spark which promotes changes that include the hardening of the zona pellucida preventing polyspermy. implantation bleeding bleeding and spotting are common during the luteal phase of the menstrual cycle, and early stages of pregnancy, but are unrelated to implantation. implantation bleeding occurs between 7 and 14 days after fertilization, and is a small amount of light vaginal bleeding or spotting that can occur in early pregnancy due to the blastocyst penetrating the lining of the uterus during implantation. by day 13 the penetration site in the endometrium has usually been closed by a fibrin plug but increased blood flow into the syncytiotrophoblast spaces can sometimes cause bleeding at that site. implantation bleeding may be accompanied by symptoms such as cramping, nausea, breast tenderness, and headaches. implantation bleeding can be distinguished from period bleeding by color, clotting, strength and duration of flow.