Implantation is a phenomenon in prenatal development, i.e. early in pregnancy. It is the event where the embryo, at this stage a blastocyst, adheres to the wall of uterus. It is by this adhesion the fetus receives the oxygen and the nutrients from the mother to be able to grow. Prenatal development is the process in which an embryo or fetus (or foetus) gestates during pregnancy, from the times of fertilization until birth. ... For other uses, see Embryo (disambiguation). ... The blastocyst is the structure formed in early mammalian embryogenesis, after the formation of the blastocele, but before implantation. ... The uterus or womb is the major female reproductive organ of most mammals, including humans. ...

The implantation window

There are many perimeters that have to be in order for a successful implantation to take place. Actually, it is only in a specific period of time that implantation is possible^[1], creating an "implantation window". A reason for these limits in time to enable implantation is, that if a process occurs not in the right time, then it is an omen of that something is wrong. And when there is a risk of that something is wrong, the body rather performs miscarriage than wasting energy on a malformed fetus. Miscarriage or spontaneous abortion is the natural or accidental termination of a pregnancy at a stage where the embryo or the fetus is incapable of surviving, generally defined at a gestation of prior to 20 weeks. ...

The implantation window is started by preparations in the endometrium of the uterus, both structurally and in the composition of its secretions.

Adaption of uterus

To enable implantation, the uterus goes through changes in order to be able to receive the embryo.

Predecidualization

Predecidualization is a preparation of the endometrium of the uterus, prior to implantation, to facilitate it. The endometrium is the inner membrane of the mammalian uterus. ...

The endometrium of the uterus increases in thickness, becomes more vascularized and its glands grow to be tortuous and boosted in their secretions. These changes reaches their maximum about 7 days after ovulation. Ovulation is the process in the menstrual cycle by which a mature ovarian follicle ruptures and discharges an ovum (also known as an oocyte, female gamete, or casually, an egg) that participates in reproduction. ...

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 ^[1]. 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 already 8 to 9 days^[1] after ovulation in absence of pregnancy. Menstrual cycle. ... Deciduous means temporary or tending to fall off (deriving from the Latin word decidere, to fall off). ...

The stromal cells originate from the stromal cells that are always present in the endometrium. However, the decidual cells 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 zona compacta of the endometrium, in contrast to the basalolateral zona spongiosa, which consists of the rather spongy stromal cells^[1]. Stroma can refer to: 1) The connective supportive framework of a biological cell, tissue, or organ. ... Decidua is the term for the uterine lining (endometrium) during a pregnancy. ...

Decidualization

Decidualization succeeds predecidualization if pregnancy occurs. This is an expansion of it, 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 for decidual cells.

Trigger

It is likely that the blastocyst itself makes the main contribution to this additional growing and sustaining of the decidua. An indication of this is that decidualization occurs at a higher degree in conception cycles than in nonconception cycles^[1]. Furthermore, similar changes are observed when giving stimuli mimicing the natural invasion of the embryo^[1].

Parts of decidua

The decidua can be organised 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 ofter 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 the first trimester^[1]. However, its most prominent time is during the early stages of pregnancy, meanwhile as implantation. Its function as a surrounding tissue is replaced by the definitive placenta. However, some elements of the decidualization remains through the whole pregnancy^[1]. The human gestation period of approximately 40 weeks between the time of the last menstrual cycle and delivery is traditionally divided into three periods of three months, or trimesters. ... The placenta is an ephemeral (temporary) organ present in female placental vertebrates during gestation (pregnancy), but a placenta has evolved independently also in other animals as well, for instance scorpions and velvet worms. ...

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^[1], after the pathologist Javier Arias-Stella.

Pinopodes

Pinopodes are small, finger-like protrusions from the endometrium. They appear between day 19 and day 21^[1] of gestational age. This corresponds to a fertilization age of approximately 5 to 7 days, which corresponds well with the time of implantation. They only persist for 2 to 3 days^[1]. The development of them is enhanced by progesterone but inhibited by estrogens. Gestational age is age of a fetus (or newborn infant) from presumed conception. ... Gestational age is usually considered to be the age of an embryo or fetus (or newborn infant) from the first day of the womans last menstrual period (LMP). ... Progesterone is a C-21 steroid hormone involved in the female menstrual cycle, pregnancy (supports gestation) and embryogenesis of humans and other species. ... Estrogens (or oestrogens) are a group of steroid compounds that function as the primary female sex hormone. ...

Function in implantation

Pinopodes endocytose uterine fluid and macromolecules in it. By doing so, the volume of the uterus decreases, taking the walls closer to the embryoblast floating in it. Thus, the period of active pinocytes might also limit the implantation window^[1].

Function during implantation

Pinopodes continue to absorb fluid, and removes most of ut during the early stages of implantation.

Adaption of secretions

Not only the lining of the uterus transforms. In addition, the secretion from its epithelial 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. Lactoferrin is a globular protein found in milk and many mucosal secretions such as tears. ... Progesterone is a C-21 steroid hormone involved in the female menstrual cycle, pregnancy (supports gestation) and embryogenesis of humans and other species. ... The corpus luteum (Latin for yellow body) is a small, temporary endocrine structure in animals. ...

Nourishment

The embryoblast spends approximately 72^[1] 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^[1] and fat-soluble vitamins^[1].

Growth and implantation

In addition to nourishment, the endometrium secretes several steroid-dependent proteins^[1], important for growth and implantation. Cholesterol^[1] and steroids^[1] are also secreted. Implantation is further facilitated by synthesis of matrix substances, adhesion molecues and surface receptors for the matrix substances. Steroid skeleton of lanosterol. ... Cholesterol is a sterol (a combination steroid and alcohol) and a lipid found in the cell membranes of all body tissues, and transported in the blood plasma of all animals. ... In biology, the word matrix is used for the material between animal or plant cells, or generally the material (or tissue) in which more specialized structures are embedded, and also specifically for one part of the mitochondrion. ... In biochemistry, a receptor is a protein on the cell membrane or within the cytoplasm or cell nucleus that binds to a specific molecule (a ligand), such as a neurotransmitter, hormone, or other substance, and initiates the cellular response to the ligand. ...

Mechanism

Implantation occurs approximately 7 days after fertilisation, and is initiated when the blastocyst comes into contact with the uterine wall. A sperm cell fertilizing an ovum This article is about reproduction in organisms. ...

Zona hatching

Main article: Zona hatching

To be able to perform implantation, the blastocyst first needs to get rid of its zona pellucida. This process can be called "hatching". Zona hatching is a phenomenon occuring during prenatal development. ... The zona pellucida (or zona striata in older texts) is a glycoprotein membrane surrounding the plasma membrane of an oocyte. ...

Factors

Lytic factors in the uterine cavity, as well as factors from the blastocyst itself are essential for this process. Mechanisms in the latter are indicated by that the zona pellucida remains intact if an unfertilized egg is placed in the uterus under the same conditions^[1]. A substance probably involved is plasmin. Plasminogen, the plasmin precursor, is found in the uterine cavity, and blastocyst factors contribute to its conversion to active plasmin. This hypothesis is supported by lytic effects in vitro by plasmin^[1]. Furthermore, plasmin inhibitors also inhibit the entire zona hatching in rat experiments^[1]. Plasmin is an important degrading enzyme (EC 3. ... Plasmin is an important degrading enzyme (EC 3. ... Wiktionary has a definition of: In vitro In vitro (Latin: within glass) means within a test tube, or, more generally, outside a living organism or cell. ...

Apposition

The very first, albeit loose, connection between the blastocyst and the endometrium is called the apposition^[1].

Location

On the endometrium, the apposition is usually made where there is a small crypt in it, perhaps because it increases the area of contact with the rather spherical blastocyst.

On the blastocyst, on the other hand, it occurs at a location where there has been enough lysis of the zona pellucida to have created a rupture to enable direct contact between the underlying trophoblast and the decidua of the endometrium^[1]. However, ultimately, the inner cell mass, inside the trophoblast layer, is aligned closest to the decidua. Nevertheless, the apposition on the blastocyst is not dependent on if it is on the same side of the blastocyst as the inner cell mass. Rather, the inner cell mass rotates inside the trophoblast to align to the apposition^[1]. In short, the entire surface of the blastocyst has a potential to form the apposition to the decidua. The trophoblast (from Greek threphein: to feed) is considered to be the first of all embryonic annexes. ... The inner cell mass is surrounded by the single cell layer of cells called trophoblast. ... The trophoblast (from Greek threphein: to feed) is considered to be the first of all embryonic annexes. ...

Adhesion

Adhesion is a much stronger attachment to the endometrium than the loose apposition.

The trophoblasts adhere by penetrating the endometrium, with protrusions of trophoblast cells.

Communication

There is massive communication between the blastocyst and the endometrium at this stage. The blastocyst signals to the endometrium to adapt further to its precense, e.g. by changes in the cytoskeleton of decidual cells. This, in turn, dislodges the decidual cells from their connection to the underlying basal lamina, which enables the blastocyst to perform the succeeding invasion^[1]. The eukaryotic cytoskeleton. ... The basal lamina (often erroneously called basement membrane) is a layer on which epithelium sits. ...

This communication is conveyed by receptor-ligand-interactions, both integrin-matrix and proteoglycan ones. In biochemistry, a receptor is a protein on the cell membrane or within the cytoplasm or cell nucleus that binds to a specific molecule (a ligand), such as a neurotransmitter, hormone, or other substance, and initiates the cellular response to the ligand. ... It has been suggested that this article or section be merged with ligand. ...

Integrin-matrix

Integrins are cell-membrane-spanning receptors with the ability to react with extracellular matrix-proteins, e.g. collagen, laminin, fibronectin and vitronectin. An integrin, or integrin receptor, is an integral membrane protein in the plasma membrane of cells. ...

In this case, integrins are found on the surface of the trophoblast-cells of the blastocyst, as well as on the decidual cells on the uterine wall. The integrins on the trophoblast reacts with collagen, laminin and fibronectin surrounding decidual cells. It is probably fibronectin that guides the blastocyst inbetween the decidual cells down to the basal lamina^[1].

On the other hand, integrins are also found on the decidual cells, reacting with matrix proteins around decidual cells, also in this case fibronectin for instance. Experimentally, implantation is blocked when small peptides with sequences similar to fibronectin is present, because they occupy the integrins of the decidua, making them unable to attach to blastocyst fibronectins^[1].

However, the integrins are only present on the decidua for a limited period of time, more specifically between day 20 to 24 of gestational age, contributing to the implantation window-phenomenon.

proteoglycan receptors

Another ligand-receptor system involved in adhesion is proteoglycan receptors, found on the surface of the decidua of the uterus. Their counterparts, the proteoglycans, are found around the trophoblast cells of the blastocyst. This ligand-receptor system also is present just at the implantation window^[1].

Invasion

Invasion is an even further establishment of the blastocyst in the endometrium.

Syncytiotrophoblasts

The protrusions of trophoblast cells that adhere into the endometrium continue to proliferate and penetrate into the endometrium. These penetrating cells differentiate to become a new type of cells, syncytiotrophoblast. The prefix syn- refers to that the boundaries between these cells disappears, forming a single mass of a multitude of cell nuclei. The rest of the trophoblasts, surrounding the inner cell mass, are hereafter called cytotrophoblasts. Syncytiotrophoblasts are cells found in the placenta of human embryos. ... HeLa cells stained for DNA with the Blue Hoechst dye. ... The introduction to this article provides insufficient context for those unfamiliar with the subject matter. ...

Invasion continues with the syncytiotrophoblasts reaching the basal membrane beneath the decidual cells, penetrating it and further invading into the uterine stroma. Finally, the whole embryo is embedded in the endometrium. Eventually, the syncytiotrophoblasts come into contact with maternal blood and form chorionic villi. This is the initiation of forming the placenta. Chorionic villi are villi that sprout from the chorion, in order to give a maximum area of contact with the maternal blood. ... The placenta is an ephemeral (temporary) organ present in female placental vertebrates during gestation (pregnancy), but a placenta has evolved independently also in other animals as well, for instance scorpions and velvet worms. ...

Secretions

The blastocyst secretes factors for a multitude of purposes during invasion. It secretes several autocrine factors, targeting itself and stimulating it to further invade the endometrium^[1]. Furthermore, secretions loosen decidual cells from each other, prevent the embryo from being rejected by the mother, trigger the final decidualization and prevent menstruation. Autocrine signalling is a form of signalling in which the target cell is the secretory cell itself. ...

Autocrine

Human chorionic gonadotropin is an autocrine growth factor for the blastocyst^[1]. Insulin-like growth factor type 2^[1], on the other hand, stimulates the invasiveness of it. Human chorionic gonadotropin (hCG) is a peptide hormone produced in pregnancy, that is made by the embryo soon after conception and later by the syncytiotrophoblast (part of the placenta). ... The insulin-like growth factors (IGFs) are polypeptides with high sequence similarity to insulin. ...

Dislodging

The syncytiotrophoblasts dislodges decidual cells in their way, both by degradation of cell adhesion molecules linking the decidual cells together as well as degradation of the extracellular matrix between them. Cell Adhesion Molecules (CAMs) are proteins located on the cell surface involved with the binding with other cells or with the extracellular matrix (ECM) in the process called cell adhesion. ...

Cell adhesion molecules are degraded by syncytiotrophoblast secretion of Tumor necrosis factor-alpha. This inhibits the expression of cadherins and beta-catenin^[1]. Cadherins is a cell adhesion molecule and beta-catenin helps anchoring it to the cell membrane. Inhibited expression of these molecules thus loosens the connection between decidual cells, permitting the syncytotrophoblasts and the whole embryo with them to invade into the endometrium. In medicine, tumor necrosis factor alpha (TNFα, cachexin or cachectin) is an important cytokine involved in systemic inflammation and the acute phase response. ... Cadherins are a class of proteins which are expressed on the surface of cells. ... Beta-catenin is a subunit of the cadherin protein complex. ...

The extracellular matrix is degraded by serine endopeptidases and metalloproteinases. Examples of such metalloproteinases are collagenases, gelatinases and stromelysins^[1]. These collagenases digest Type-I collagen, Type-II collagen, Type-III collagen, Type-VII collagen and Type-X collagen^[1]. The gelatinases exist in two forms; one digesting Type-IV collagen and one digesting gelatin^[1]. Crystal structure of Trypsin, a typical serine protease. ... Metalloproteinases (or metalloproteases) constitute a family of enzymes from the group of proteinases, classified by the nature of the most prominent functional group in their active site. ... Collagenases are enzymes that break the peptide bonds in collagen. ... In biology and chemistry, gelatinase is an proteolytic enzyme that allows a living organism to hydrolyse gelatin[1] into its sub-compounds (polypeptides, peptides, and aminoacids) that can cross the cell membrane and be used by the organism. ... Cell surface-associated MT1-MMP (MMP14), Green fluorescent protein (GFP) fused to the C-term produces a signal on the surface of the cell[1] Matrix metalloproteinases (MMPs) are zinc-dependent endopeptidases; other family members are adamalysins, serralysins, and astacins. ... Type-I collagen is the most abundant collagen of the human body. ... Type-II collagen is the basis for articular cartilage and hyaline cartilage. ... Type-III collagen is a fibrous scleroprotein in bone and cartilage and tendon and other connective tissue; yields gelatin on boiling. ... Type-IV collagen is a type of collagen found primarily in the basal lamina There are six genes associated with it: COL4A1, COL4A2, COL4A3, COL4A4, COL4A5, COL4A6 Mutations to the genes coding for collagen type IV lead to Alport syndrome. ... Gelatin (also gelatine, from French gélatine) is a translucent brittle solid substance, colorless or slightly yellow, nearly tasteless and considered foul smelling, extracted from the collagen inside animals connective tissue. ...

Immunosuppressive

The embryo differs from the cells of the mother, and would be rejected as a parasite by the immune system of the mother if it didn't secrete immunosuppresive agents. Such agents are Platelet-activating factor, human chorionic gonadotropin, early pregnancy factor, immunosuppressive factor, Prostaglandin E2, Interleukin 1-alpha, Interleukin 6, interferon-alpha, leukemia inhibitory factor and Colony-Stimulating Factor. A scanning electron microscope image of a single neutrophil (yellow), engulfing anthrax bacteria (orange). ... A platelet-activating factor, also known as a PAF or paf-acether is a potent phospholipid activator and mediator of many leucocyte functions, including platelet aggregation, inflammation, and anaphylaxis. ... Human chorionic gonadotropin (hCG) is a peptide hormone produced in pregnancy, that is made by the embryo soon after conception and later by the syncytiotrophoblast (part of the placenta). ... Early pregnancy factor (EPF) or early conception factor (ECF) is a protein associated with mammalian embryos shortly after fertilization. ... Prostaglandin E is a family of naturally occurring prostaglandins. ... Interleukin-1 (IL-1) is secreted by the macrophages, monocytes and dendritic cells. ... Interleukin-6 (IL-6) is a pro-inflammatory cytokine secreted by T cells and macrophages to stimulate immune response to trauma, especially burns or other tissue damage leading to inflammation. ... Interferons (IFNs) are natural proteins produced by the cells of the immune system of most vertebrates in response to challenges by foreign agents such as viruses, bacteria, parasites and tumor cells. ... Leukemia inhibitory factor, or LIF, an interleukin-6 class cytokine, is a chemical in cells that affects their growth and development. ...

Decidualization

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^[1].

Prevention of menstruation

Human chorionic gonadotropin (hCG) not only acts as an immunosuppressive^[1], but also "notifies" the mother's body that she is pregnant, preventing menstruation by sustaining the function of the corpus luteum. Human chorionic gonadotropin (hCG) is a peptide hormone produced in pregnancy, that is made by the embryo soon after conception and later by the syncytiotrophoblast (part of the placenta). ... A pregnant woman Pregnancy is the process by which a mammalian female carries a live offspring from conception until it develops to the point where the offspring is capable of living outside the womb. ... The corpus luteum (Latin for yellow body) is a small, temporary endocrine structure in animals. ...

Other factors

Other factors secreted by the blastocyst are;

• ovum factor
• Embryo-derived histamine-releasing factor
• Tissue plasminogen activator as well as its inhibitors
• Estradiol
• β1-integrins
• Fibroblast growth factor
• Transforming growth factor alpha
• inhibin

In blood coagulation, tissue plasminogen activator (tPA) is an enzyme (EC 3. ... Estradiol (17β-estradiol) (also oestradiol) is a sex hormone. ... An integrin, or integrin receptor, is an integral membrane protein in the plasma membrane of cells. ... Fibroblast growth factor, or FGF, is a family growth factors involved in wound healing. ... Transforming growth factor (TGF) is one of many characterized growth factors that exist in nature. ... Inhibin is a peptide that is an inhibitor of FSH synthesis and secretion and participates in the regulation of the menstrual cycle. ...

References

1. ^ ^{a b c d e f g h i j k l m n o p q r s t u v w x y z aa ab ac ad ae af ag ah ai aj ak al} Medical Physiology, Boron & Boulpaep, ISBN 1-4160-2328-3, Elsevier Saunders 2005. Updated edition. 1300 pages.