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Implantation (nidation) is the stage in the embryonic development of mammals in which the
blastocyst The blastocyst is a structure formed in the early embryonic development of mammals. It possesses an inner cell mass (ICM) also known as the ''embryoblast'' which subsequently forms the embryo, and an outer layer of trophoblast cells called the t ...
hatches as the embryo, adheres, and invades into the wall of the female's uterus. Implantation is the first stage of gestation, and when successful the female is considered to be pregnant. In a woman, an implanted embryo is detected by the presence of increased levels of human chorionic gonadotropin (hCG) in a
pregnancy test A pregnancy test is used to determine whether a female is pregnant or not. The two primary methods are testing for the female pregnancy hormone (human chorionic gonadotropin (hCG)) in blood or urine using a pregnancy test kit, and scanning with u ...
. The implanted embryo will receive oxygen and nutrients in order to grow. There is an extensive variation in the type of trophoblast cells, and structures of the placenta across the different species of mammals. Of the five recognised stages of implantation including two pre-implantation stages that precede placentation, the first four are similar across the species. The five stages are migration and hatching, pre-contact, attachment, adhesion, and invasion. The two pre-implantation stages are associated with the pre-implantation embryo. In humans following the stage of hatching that takes place around four to five days after
fertilization Fertilisation or fertilization (see spelling differences), also known as generative fertilisation, syngamy and impregnation, is the fusion of gametes to give rise to a new individual organism or offspring and initiate its development. Proce ...
, the process of implantation begins. By the end of the first week the blastocyst is superficially attached to the uterine endometrium. By the end of the second week implantation has completed.


Implantation stages

There are five recognized stages of implantation in mammals, including two pre-implantation stages that precede the formation of the placenta. They are: migration and hatching, pre-contact, attachment, adhesion, and invasion. The first four stages are similar across the species with the process of invasion being variable. These three stages of ''apposition'', ''attachment'', and ''invasion'' are also alternatively termed ''contact'' (apposition), ''adhesion'' (attachment), and ''penetration'' (invasion), and can only take place during a limited timeframe known as the window of implantation when the uterus is at its most receptive.


Migration and hatching

There are two stages of migration involved in implantation, the first is the migration of the zygote, and the second is the migration of the trophoblast. Following the fertilization of the oocyte that creates the single diploid cell called the zygote, the zygote starts to migrate towards the uterus. Fertilization takes place in the
ampulla An ampulla (; ) was, in Ancient Rome, a small round vessel, usually made of glass and with two handles, used for sacred purposes. The word is used of these in archaeology, and of later flasks, often handle-less and much flatter, for holy water or ...
of the fallopian tube, and the zygote is transported along the tube to the uterus. The fallopian tube is lined with ciliated epithelium, and it is the cilia that move the zygote. During this migration the zygote undergoes a number of cell divisions that creates a ball of 16 compacted
blastomere In biology, a blastomere is a type of cell produced by cell division (cleavage) of the zygote after fertilization; blastomeres are an essential part of blastula formation, and blastocyst formation in mammals. Human blastomere characteristics In ...
s called a morula. The morula enters the uterus after three or four days, and as it does a cavity called the
blastocoel The blastocoel (), also spelled blastocoele and blastocele, and also called cleavage cavity, or segmentation cavity is a fluid-filled or yolk-filled cavity that forms in the blastula during very early embryonic development. At this stage in mammal ...
is formed in the morula to produce the
blastocyst The blastocyst is a structure formed in the early embryonic development of mammals. It possesses an inner cell mass (ICM) also known as the ''embryoblast'' which subsequently forms the embryo, and an outer layer of trophoblast cells called the t ...
. The blastocyst contains the
inner cell mass The inner cell mass (ICM) or embryoblast (known as the pluriblast in marsupials) is a structure in the early development of an embryo. It is the mass of cells inside the blastocyst that will eventually give rise to the definitive structures of t ...
that will go on to develop into the embryo proper, and an outer cell layer of trophoblasts that will develop into the extraembryonic membranes (
fetal membranes The fetal membranes are the four extraembryonic membranes, associated with the developing embryo, and fetus in humans and other mammals.. They are the amnion, chorion, allantois, and yolk sac. The amnion and the chorion are the chorioamniotic memb ...
). The blastocyst is still enclosed in the egg-coat known as the zona pellucida, and for it to be able to implant into the uterine wall it must rid itself of this covering. This stage is known as zona hatching, and when there is sufficient dissolution the blastocyst is able to initiate the apposition stage of implantation. Lytic factors in the uterine cavity, as well as factors from the blastocyst itself are essential for the breakdown of the egg-coat. Mechanisms in the latter are indicated by the fact that the zona pellucida remains intact if an unfertilized egg is placed in the uterus under the same conditions. Among the known molecular regulators that promote hatching are predominantly proteases that are stimulated by various growth factors. The blastocyst also produces
cytokine Cytokines are a broad and loose category of small proteins (~5–25 kDa) important in cell signaling. Cytokines are peptides and cannot cross the lipid bilayer of cells to enter the cytoplasm. Cytokines have been shown to be involved in autoc ...
s, both pro-inflammatory and anti-inflammatory, that have crucial roles during implantation and other stages of pregnancy. Both types of cytokines modulate the activity of proteases, including MMPs,
plasminogen Plasmin is an important enzyme () present in blood that degrades many blood plasma proteins, including fibrin clots. The degradation of fibrin is termed fibrinolysis. In humans, the plasmin protein (in the zymogen form of plasminogen) is encoded ...
activators, and
cathepsin Cathepsins (Ancient Greek ''kata-'' "down" and ''hepsein'' "boil"; abbreviated CTS) are proteases (enzymes that degrade proteins) found in all animals as well as other organisms. There are approximately a dozen members of this family, which are di ...
s. It is unknown whether the cytokines involved in hatching are pro-inflammatory or anti-inflammatory, or which proteases are involved. However, it is well accepted that the pro-inflammatory cytokines are dominant during implantation. Cytokines are also present in the
uterine milk Uterine glands or endometrial glands are tubular glands, lined by ciliated columnar epithelium, found in the functional layer of the endometrium that lines the uterus. Their appearance varies during the menstrual cycle. During the proliferative ph ...
which might regulate the development and function of the blastocyst but there is no evidence to support their involvement in hatching.
Leukemia inhibitory factor Leukemia inhibitory factor, or LIF, is an interleukin 6 class cytokine that affects cell growth by inhibiting differentiation. When LIF levels drop, the cells differentiate. Function LIF derives its name from its ability to induce the terminal ...
(LIF) is a pro-inflammatory cytokine expressed in the endometrium during the luteal phase of the menstrual cycle, with the highest expression seen during the window of implantation. LIF plays a role in adhesion and invasion.
Assisted zona hatching Assisted zona hatching (AZH) is a procedure of assisted reproductive technology in which a small hole is made in the zona pellucida, using a micromanipulator, thereby facilitating zona hatching. Zona hatching is where the blastocyst gets rid of the ...
may take place in assisted reproduction, where the zona pellucida may be artificially pierced to facilitate hatching.


Apposition

Following zona hatching, the very first loose connection or contact between the blastocyst and the endometrium is called apposition. Apposition is usually made where there is a small crypt in the endometrium, and also where there has been enough breakdown of the zona pellucida to allow the blastocyst trophoblast to directly contact the underlying endometrium. Ultimately, the
inner cell mass The inner cell mass (ICM) or embryoblast (known as the pluriblast in marsupials) is a structure in the early development of an embryo. It is the mass of cells inside the blastocyst that will eventually give rise to the definitive structures of t ...
(also embryoblast), inside the trophoblast layer, is aligned closest to the decidua. If the inner cell mass is not aligned with the decidua at apposition, it has the ability to freely rotate within the trophoblast and achieve this alignment. Apposition is only a weak interaction of the trophectoderm with the uterine epithelium that is unstable to shear stress. Apposition is also reversible allowing repositioning of the blastocyst in the uterus.


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. This adhering activity is by microvilli that are on the trophoblast. The trophoblast have binding fiber connections, laminin, collagen type IV, and integrins that assist in this adhesion process.
Mucin-16 Mucin-16 (MUC-16) also known as Ovarian cancer-related tumor marker CA125 is a protein that in humans is encoded by the ''MUC16'' gene. MUC-16 is a member of the mucin family glycoproteins. MUC-16 has found application as a tumor marker or biom ...
is a transmembrane mucin expressed at the apical surface of uterine epithelia. This mucin prevents the blastocyst from implanting in an undesired located on the epithelium. Thus, MUC-16 inhibits cell-cell adhesion. Its removal during
pinopode Pinopodes (also known as pinopods and uterodomes) are protrusions on the apical cellular membrane of uterine epithelial cells. Pinopodes have a pinocytotic role (hence the name pinopode - Greek for "drinking foot"), as well as a secretory role. T ...
formation has been shown to facilitate trophoblast invasion ''in vitro''. The identity of the molecules on the trophoblast and the endometrial epithelia that mediate the initial interaction between the two remain unidentified. However, a number of research groups have proposed that MUC1, a member of the
mucin Mucins () are a family of high molecular weight, heavily glycosylated proteins (glycoconjugates) produced by epithelial tissues in most animals. Mucins' key characteristic is their ability to form gels; therefore they are a key component in most ...
family of glycosylated proteins, is involved. MUC1 is a transmembrane glycoprotein expressed at the apical surface of endometrial epithelial cells during the window of implantation in humans and has been shown to be differentially expressed between fertile and infertile subjects during this time. MUC1 displays carbohydrate moieties on its extracellular domain that are ligands of L-selectin, a
cell adhesion molecule Cell adhesion molecules (CAMs) are a subset of cell surface proteins that are involved in the binding of cells with other cells or with the extracellular matrix (ECM), in a process called cell adhesion. In essence, CAMs help cells stick to each ...
on the surface of trophoblast cells. An in vitro model of implantation gave evidence to support the hypothesis that L-selectin mediates apposition of the blastocyst to the uterine epithelium by interacting with its ligands.


Invasion

Invasion is the further establishment of the blastocyst into the endometrium. The protrusions of trophoblast cells that adhere into the endometrium continue to proliferate and penetrate into the endometrium using
gelatinase A Gelatinase A, also known as MMP2 (, ''72-kDa gelatinase'', ''matrix metalloproteinase 2'', ''type IV collagenase'', ''3/4 collagenase'', ''matrix metalloproteinase 5'', ''72 kDa gelatinase type A'', ''collagenase IV'', ''collagenase type IV'', ''MM ...
and B. Trophoblasts invade the uterus attempting to reach maternal blood supply, for setting up the foundation for fetal blood flow. As these trophoblasts penetrate, they terminally differentiate into a
multinucleated Multinucleate cells (also known as multinucleated or polynuclear cells) are eukaryotic cells that have more than one nucleus per cell, i.e., multiple nuclei share one common cytoplasm. Mitosis in multinucleate cells can occur either in a coordinat ...
tissue, a syncytium known as the syncytiotrophoblast. Between this layer and the blastocyst lies the
cytotrophoblast "Cytotrophoblast" is the name given to both the inner layer of the trophoblast (also called layer of Langhans) or the cells that live there. It is interior to the syncytiotrophoblast and external to the wall of the blastocyst in a developing embry ...
. When the syncytiotrophoblast reaches the basal membrane beneath the decidual cells, it dislodges them to further invade into the uterine stroma. Dislodging is accomplished by degrading the
cell adhesion molecule Cell adhesion molecules (CAMs) are a subset of cell surface proteins that are involved in the binding of cells with other cells or with the extracellular matrix (ECM), in a process called cell adhesion. In essence, CAMs help cells stick to each ...
s (CAMs) that link the decidual cells, and the associated extracellular matrix. Degradation is achieved by the secretion of
tumor necrosis factor-alpha Tumor necrosis factor (TNF, cachexin, or cachectin; formerly known as tumor necrosis factor alpha or TNF-α) is an adipokine and a cytokine. TNF is a member of the TNF superfamily, which consists of various transmembrane proteins with a homolog ...
from the syncytiotrophoblast, which inhibits the expression of CAMs and
beta-catenin Catenin beta-1, also known as beta-catenin (β-catenin), is a protein that in humans is encoded by the ''CTNNB1'' gene. Beta-catenin is a dual function protein, involved in regulation and coordination of cell–cell adhesion and gene transcrip ...
. The extracellular matrix is degraded by metalloproteinases such as
collagenases Collagenases are enzymes that break the peptide bonds in collagen. They assist in destroying extracellular structures in the pathogenesis of bacteria such as ''Clostridium''. They are considered a virulence factor, facilitating the spread of ga ...
, gelatinases and matrix metalloproteinases, and by serine proteases. The collagenases digest Types I, II,
III III or iii may refer to: Companies * Information International, Inc., a computer technology company * Innovative Interfaces, Inc., a library-software company * 3i, formerly Investors in Industry, a British investment company Other uses * ...
,
VII VII or vii may refer to: the Roman numeral 7 Art and entertainment * The Vii, a video game console * vii, leading-tone triad, see diminished triad * ''VII'' (Blitzen Trapper album) * ''VII'' (Just-Ice album) * ''VII'' (Teyana Taylor album) * ...
and X collagen. The gelatinases exist in two forms; one digesting
Type-IV collagen Collagen IV (ColIV or Col4) is a type of collagen found primarily in the basal lamina. The collagen IV C4 domain at the C-terminus is not removed in post-translational processing, and the fibers link head-to-head, rather than in parallel. Also, ...
and one digesting
gelatin Gelatin or gelatine (from la, gelatus meaning "stiff" or "frozen") is a translucent, colorless, flavorless food ingredient, commonly derived from collagen taken from animal body parts. It is brittle when dry and rubbery when moist. It may also ...
. The extracellular matrix is degraded by serine endopeptidases and metalloproteinases. The syncytiotrophoblast can then invade into the endometrium taking the embryo with it where it becomes embedded. Eventually, the syncytiotrophoblast comes into contact with maternal blood and forms
chorionic villi Chorionic villi are villi that sprout from the chorion to provide maximal contact area with maternal blood. They are an essential element in pregnancy from a histomorphologic perspective, and are, by definition, a product of conception. Branche ...
– the beginning of placentation. Following invasion, the breach in the uterine epithelium made by the blastocyst's entry is sealed by a fibrin plug. The fibrin plug is a coagulation of a blood clot and cellular debris.


Extravillous trophoblasts

Extravillous trophoblast Extravillous trophoblasts (EVTs), are one form of differentiated trophoblast cells of the placenta. They are invasive mesenchymal cells which function to establish critical tissue connection in the developing placental-uterine interface. EVTs der ...
s are cells from the invading villi that migrate into the myometrium of the mother’s uterus. These cells remodel the
spiral arteries Spiral arteries are small arteries which temporarily supply blood to the endometrium of the uterus during the luteal phase of the menstrual cycle. In histology, identifying the presence of these arteries is one of the most useful techniques in i ...
to improve and secure maternal blood flow to the growing embryo. There is also evidence that this process occurs with the uterine veins, stabilizing them to improve drainage of fetal blood and metabolic wastes. Trophoblasts have also been documented to migrate into various tissues in the mother. Due to this trophoblasts have been implicated in a phenomenon known as fetomaternal microchimerism where fetal cells establish cell lines in maternal tissues.


Secretions

The blastocyst secretes factors for a multitude of purposes during invasion. It secretes several
autocrine Autocrine signaling is a form of cell signaling in which a cell secretes a hormone or chemical messenger (called the autocrine agent) that binds to autocrine receptors on that same cell, leading to changes in the cell. This can be contrasted with pa ...
factors, targeting itself and stimulating it to further invade the endometrium. Human chorionic gonadotropin is an autocrine growth factor for the blastocyst, while
Insulin-like growth factor 2 Insulin-like growth factor 2 (IGF-2) is one of three protein hormones that share structural similarity to insulin. The MeSH definition reads: "A well-characterized neutral peptide believed to be secreted by the liver and to circulate in the bloo ...
, stimulates its invasiveness. Furthermore, secretions loosen decidual cells from each other, prevent the embryo from being rejected by the mother, trigger the final decidualization and prevent menstruation.


=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 did not secrete
immunosuppressive Immunosuppression is a reduction of the activation or efficacy of the immune system. Some portions of the immune system itself have immunosuppressive effects on other parts of the immune system, and immunosuppression may occur as an adverse reacti ...
agents. Such agents include platelet-activating factor, human chorionic gonadotropin,
early pregnancy factor Heat shock 10 kDa protein 1 (Hsp10), also known as chaperonin 10 (cpn10) or early-pregnancy factor (EPF), is a protein that in humans is encoded by the ''HSPE1'' gene. The homolog in ''E. coli'' is GroES that is a chaperonin which usually works ...
, prostaglandin E2,
interleukin-1 alpha Interleukin-1 alpha (IL-1 alpha) also known as hematopoietin 1 is a cytokine of the interleukin 1 family that in humans is encoded by the ''IL1A'' gene. In general, Interleukin 1 is responsible for the production of inflammation, as well as the p ...
, interleukin 6, interferon-alpha,
leukemia inhibitory factor Leukemia inhibitory factor, or LIF, is an interleukin 6 class cytokine that affects cell growth by inhibiting differentiation. When LIF levels drop, the cells differentiate. Function LIF derives its name from its ability to induce the terminal ...
and
colony-stimulating factor Colony-stimulating factors (CSFs) are secreted glycoproteins that bind to receptor proteins on the surfaces of hemopoietic stem cells, thereby activating intracellular signaling pathways that can cause the cells to proliferate and differentia ...
.


=Prevention of menstruation

= Human chorionic gonadotropin (hCG) not only acts as an immunosuppressive, but also signals to the mother that she is pregnant, preventing
luteolysis Luteolysis (also known as luteal regression) is the structural and functional degradation of the corpus luteum, which occurs at the end of the luteal phase of both the estrous and menstrual cycles in the absence of pregnancy. Prostaglandin F2 al ...
of the
corpus luteum The corpus luteum (Latin for "yellow body"; plural corpora lutea) is a temporary endocrine structure in female ovaries involved in the production of relatively high levels of progesterone, and moderate levels of estradiol, and inhibin A. It is th ...
and menstruation by sustaining the function of the corpus luteum.


=Other factors

= Other factors secreted by the blastocyst are; * Embryo-derived histamine-releasing factor * Tissue plasminogen activator as well as its inhibitors *
Estradiol Estradiol (E2), also spelled oestradiol, is an estrogen steroid hormone and the major female sex hormone. It is involved in the regulation of the estrous and menstrual female reproductive cycles. Estradiol is responsible for the development of ...
* β1- integrins *
Fibroblast growth factor Fibroblast growth factors (FGF) are a family of cell signalling proteins produced by macrophages; they are involved in a wide variety of processes, most notably as crucial elements for normal development in animal cells. Any irregularities in the ...
*
CYTL1 Cytokine-like protein 1 (also protein C17) is a protein that in humans is encoded by the ''CYTL1'' gene. Function Protein C17 is a cytokine-like protein specifically expressed in bone marrow and cord blood mononuclear cells that bear the CD3 ...
*
Transforming growth factor alpha Transforming growth factor alpha (TGF-α) is a protein that in humans is encoded by the TGFA gene. As a member of the epidermal growth factor (EGF) family, TGF-α is a mitogenic polypeptide. The protein becomes activated when binding to receptors ...
*
Inhibin Activin and inhibin are two closely related protein complexes that have almost directly opposite biological effects. Identified in 1986, activin enhances FSH biosynthesis and secretion, and participates in the regulation of the menstrual cy ...
* Preimplantation factor


Uterus receptivity

To enable implantation, the uterus goes through changes in order to be able to receive the conceptus. Receptivity includes changes to endometrial cells in the formation of
pinopode Pinopodes (also known as pinopods and uterodomes) are protrusions on the apical cellular membrane of uterine epithelial cells. Pinopodes have a pinocytotic role (hence the name pinopode - Greek for "drinking foot"), as well as a secretory role. T ...
s that help to absorb uterine fluid; changes in the thickness of the endometrium and its blood supply development, and the formation of the decidua. Collectively these changes are known as plasma membrane transformation, and bring the
blastocyst The blastocyst is a structure formed in the early embryonic development of mammals. It possesses an inner cell mass (ICM) also known as the ''embryoblast'' which subsequently forms the embryo, and an outer layer of trophoblast cells called the t ...
nearer to the endometrium and immobilize it. During this stage the blastocyst can still be eliminated by being flushed out of the uterus. Successful implantation is co-dependent on the viability of the embryo, and the receptivity of the uterus. A critical involved factor is the developmental synchrony between the embryo and the uterus. The synchrony gives a short period of receptivity known as the window of implantation, and involves much
crosstalk In electronics, crosstalk is any phenomenon by which a signal transmitted on one circuit or channel of a transmission system creates an undesired effect in another circuit or channel. Crosstalk is usually caused by undesired capacitive, ind ...
between the blastocyst and the endometrium at this stage. During adhesion this communication is conveyed by
receptor Receptor may refer to: *Sensory receptor, in physiology, any structure which, on receiving environmental stimuli, produces an informative nerve impulse *Receptor (biochemistry), in biochemistry, a protein molecule that receives and responds to a n ...
- ligand-interactions, both integrin-matrix and proteoglycan ones. Proteoglycan receptors are found on the surface of the decidua, and their counterparts, the proteoglycans, are found around the trophoblast cells of the blastocyst. This ligand-receptor system is also present just at the implantation window. The blastocyst signals to the endometrium to adapt further to its presence, for example by changes in the cytoskeleton of decidual cells. This, in turn, dislodges the decidual cells from their connection to the underlying
basal lamina The basal lamina is a layer of extracellular matrix secreted by the epithelial cells, on which the epithelium sits. It is often incorrectly referred to as the basement membrane, though it does constitute a portion of the basement membrane. The bas ...
, which enables the blastocyst to perform the succeeding invasion.


Window of implantation

The window of implantation is a limited timeframe for the successful attachment of the blastocyst. In humans uterine receptivity is optimum on days 20-24 of the secretory phase of the menstrual cycle when luteinizing hormone levels are at their peak. In humans the window of implantation is only available for 24-36 hours. The endometrial microbiome has been indicated as having an important role in successful implantation in controlling endometrial cell function, and the function of the local immunity system that prevents pathogen growth. This is associated with the secretion of protective substances.


Pinopodes

Pinopode Pinopodes (also known as pinopods and uterodomes) are protrusions on the apical cellular membrane of uterine epithelial cells. Pinopodes have a pinocytotic role (hence the name pinopode - Greek for "drinking foot"), as well as a secretory role. T ...
s are formed at the beginning of the window of implantation, and are found in many species. They are mushroom-like protrusions from the apical cell membrane of uterine epithelial cells. Pinopodes are formed by the swelling of these epithelial cells, and the fusing together of a number of microvilli, to reach a 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 Human fertilization is the union of a human egg and sperm, occurring primarily in the ampulla of the fallopian tube. The result of this union leads to the production of a fertilized egg called a zygote, initiating embryonic development. Scient ...
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 glycocalyx, also known as the pericellular matrix, is a glycoprotein and glycolipid covering that surrounds the cell membranes of bacteria, epithelial cells, and other cells. In 1970, Martinez-Palomo discovered the cell coating in animal c ...
. 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 Sixteen or 16 may refer to: *16 (number), the natural number following 15 and preceding 17 *one of the years 16 BC, AD 16, 1916, 2016 Films * '' Pathinaaru'' or ''Sixteen'', a 2010 Tamil film * ''Sixteen'' (1943 film), a 1943 Argentine film dir ...
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 Endocytosis is a cellular process in which substances are brought into the cell. The material to be internalized is surrounded by an area of cell membrane, which then buds off inside the cell to form a vesicle containing the ingested material. E ...
. 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 Angiogenesis is the physiological process through which new blood vessels form from pre-existing vessels, formed in the earlier stage of vasculogenesis. Angiogenesis continues the growth of the vasculature by processes of sprouting and splittin ...
and its glands grow to be tortuous and boosted in their secretions. These changes reach their maximum about seven days after
ovulation Ovulation is the release of eggs from the ovaries. In women, this event occurs when the ovarian follicles rupture and release the secondary oocyte ovarian cells. After ovulation, during the luteal phase, the egg will be available to be fertilize ...
. 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 In the fields of horticulture and Botany, the term ''deciduous'' () means "falling off at maturity" and "tending to fall off", in reference to trees and shrubs that seasonally shed leaves, usually in the autumn; to the shedding of petals, afte ...
. 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 The decidua is the modified mucosal lining of the uterus (that is, modified endometrium) that forms every month, in preparation for pregnancy. It is shed off each month when there is no fertilised egg to support. The decidua is under the influe ...
, 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 Sodium channels are integral membrane proteins that form ion channels, conducting sodium ions (Na+) through a cell's membrane. They belong to the superfamily of cation channels and can be classified according to the trigger that opens the chan ...
. This triggers an influx of
calcium ions Calcium ions (Ca2+) contribute to the physiology and biochemistry of organisms' cells. They play an important role in signal transduction pathways, where they act as a second messenger, in neurotransmitter release from neurons, in contraction ...
(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 Arias-Stella reaction, also Arias-Stella phenomenon, is a benign change in the endometrium associated with the presence of chorionic tissue. Arias-Stella reaction is due to progesterone primarily. Cytologically, it looks like a malignancy and, hi ...
, after the pathologist Javier Arias-Stella.


Adaptation of secretions

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 corpus luteum (Latin for "yellow body"; plural corpora lutea) is a temporary endocrine structure in female ovaries involved in the production of relatively high levels of progesterone, and moderate levels of estradiol, and inhibin A. It is th ...
. 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 A steroid is a biologically active organic compound with four rings arranged in a specific molecular configuration. Steroids have two principal biological functions: as important components of cell membranes that alter membrane fluidity; and ...
-dependent proteins, important for growth and implantation. Cholesterol, and steroids are also secreted. Implantation is further facilitated by synthesis of
matrix Matrix most commonly refers to: * ''The Matrix'' (franchise), an American media franchise ** '' The Matrix'', a 1999 science-fiction action film ** "The Matrix", a fictional setting, a virtual reality environment, within ''The Matrix'' (franchi ...
substances,
adhesion molecules Cell adhesion molecules (CAMs) are a subset of cell surface proteins that are involved in the binding of cells with other cells or with the extracellular matrix (ECM), in a process called cell adhesion. In essence, CAMs help cells stick to each ...
and surface
receptors Receptor may refer to: * Sensory receptor, in physiology, any structure which, on receiving environmental stimuli, produces an informative nerve impulse *Receptor (biochemistry), in biochemistry, a protein molecule that receives and responds to a ...
for the matrix substances.


Clinical significance

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 In vitro fertilisation (IVF) is a process of fertilisation where an egg is combined with sperm in vitro ("in glass"). The process involves monitoring and stimulating an individual's ovulatory process, removing an ovum or ova (egg or eggs) fr ...
procedures fail because of implantation failure accounting for almost half of all pregnancy failures. Inadequate uterine receptivity may be caused by abnormal
cytokine Cytokines are a broad and loose category of small proteins (~5–25 kDa) important in cell signaling. Cytokines are peptides and cannot cross the lipid bilayer of cells to enter the cytoplasm. Cytokines have been shown to be involved in autoc ...
and hormonal signaling as well as
epigenetic alteration In biology, epigenetics is the study of stable phenotypic changes (known as ''marks'') that do not involve alterations in the DNA sequence. The Greek prefix '' epi-'' ( "over, outside of, around") in ''epigenetics'' implies features that are "o ...
s. Recurrent implantation failure is a cause of female infertility. Therefore,
pregnancy rate Pregnancy rate is the success rate for getting pregnant. It is the percentage of all attempts that leads to pregnancy, with attempts generally referring to menstrual cycles where insemination or any artificial equivalent is used, which may be simp ...
s 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 An organ-on-a-chip (OOC) is a multi-channel 3-D microfluidic cell culture, integrated circuit (chip) that simulates the activities, mechanics and physiological response of an entire organ or an organ system, a type of artificial organ. It constit ...
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.
Organoid An organoid is a miniaturized and simplified version of an organ produced in vitro in three dimensions that shows realistic micro-anatomy. They are derived from one or a few cells from a tissue, embryonic stem cells or induced pluripotent ste ...
s have also been developed to model the endometrium and its role in implantation. In women with more than three implantation failures in
assisted reproduction Assisted reproductive technology (ART) includes medical procedures used primarily to address infertility. This subject involves procedures such as in vitro fertilization (IVF), intracytoplasmic sperm injection (ICSI), cryopreservation of gametes o ...
, a review of several small
randomized controlled studies A randomized controlled trial (or randomized control trial; RCT) is a form of scientific experiment used to control factors not under direct experimental control. Examples of RCTs are clinical trials that compare the effects of drugs, surgical te ...
estimated that the use of adjunct
low molecular weight heparin Low-molecular-weight heparin (LMWH) is a class of anticoagulant medications. They are used in the prevention of blood clots and treatment of venous thromboembolism (deep vein thrombosis and pulmonary embolism) and in the treatment of myocardial in ...
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

Implantation bleeding is a small amount of light vaginal bleeding or spotting that can occur in early pregnancy due to the fertilized egg implanting in the uterus. Bleeding and spotting are common during the luteal phase of the menstrual cycle, and early stages of pregnancy, and are unrelated to implantation. Implantation bleeding occurs between 7 to 14 days after fertilization, and 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.


See also

*
Embryonic diapause Embryonic diapause (from late 19th century English: dia- ‘through’ + pause- 'delay') (aka delayed implantation in mammals) is an evolutionary reproductive strategy used by several animal species across a number of kingdoms, including approximate ...
*
Hofbauer cell Hofbauer cells are oval eosinophilic histiocytes with granules and vacuoles found in the placenta, which are of mesenchymal origin, in mesoderm of the chorionic villus, particularly numerous in early pregnancy. Etymology They are named after J. Is ...
s * Reichert’s membrane


References


Books

*


External links


Virtual human embryo detailing stages of development


Further reading


"Implantation of the blastocyst..."

"Implantation "
{{Reproductive physiology Embryology Obstetrics Human reproduction Fertility Midwifery