Implantation (nidation) is the stage in the
embryonic development
An embryo is an initial stage of development of a multicellular organism. In organisms that reproduce sexually, embryonic development is the part of the life cycle that begins just after fertilization of the female egg cell by the male sperm ...
of
mammals
Mammals () are a group of vertebrate animals constituting the class Mammalia (), characterized by the presence of mammary glands which in females produce milk for feeding (nursing) their young, a neocortex (a region of the brain), fur or ...
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
An embryo is an initial stage of development of a multicellular organism. In organisms that reproduce sexually, embryonic development is the part of the life cycle that begins just after fertilization of the female egg cell by the male spe ...
, adheres, and invades into the wall of the female's
uterus
The uterus (from Latin ''uterus'', plural ''uteri'') or womb () is the organ in the reproductive system of most female mammals, including humans that accommodates the embryonic and fetal development of one or more embryos until birth. The uter ...
.
Implantation is the first stage of
gestation
Gestation is the period of development during the carrying of an embryo, and later fetus, inside viviparous animals (the embryo develops within the parent). It is typical for mammals, but also occurs for some non-mammals. Mammals during pregna ...
, and when successful the female is considered to be
pregnant
Pregnancy is the time during which one or more offspring develops (gestation, gestates) inside a woman, woman's uterus (womb). A multiple birth, multiple pregnancy involves more than one offspring, such as with twins.
Pregnancy usually occur ...
.
In a woman, an implanted embryo is detected by the presence of increased levels of
human chorionic gonadotropin
Human chorionic gonadotropin (hCG) is a hormone for the maternal recognition of pregnancy produced by trophoblast cells that are surrounding a growing embryo (syncytiotrophoblast initially), which eventually forms the placenta after implantation ...
(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 ...
.
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
The placenta is a temporary embryonic and later fetal organ that begins developing from the blastocyst shortly after implantation. It plays critical roles in facilitating nutrient, gas and waste exchange between the physically separate mater ...
across the different species of mammals.
Of the five recognised stages of implantation including two pre-implantation stages that precede
placentation
Placentation refers to the formation, type and structure, or arrangement of the placenta. The function of placentation is to transfer nutrients, respiratory gases, and water from maternal tissue to a growing embryo, and in some instances to remove ...
, 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
Hatching (french: hachure) is an artistic technique used to create tonal or shading effects by drawing (or painting or scribing) closely spaced parallel lines. (It is also used in monochromatic representations of heraldry to indicate what the ...
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
The endometrium is the inner epithelial layer, along with its mucous membrane, of the mammalian uterus. It has a basal layer and a functional layer: the basal layer contains stem cells which regenerate the functional layer. The functional laye ...
. 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
![2904_Preembryonic_Development-02](https://upload.wikimedia.org/wikipedia/commons/7/75/2904_Preembryonic_Development-02.jpg)
There are two stages of migration involved in implantation, the first is the migration of the
zygote
A zygote (, ) is a eukaryotic cell formed by a fertilization event between two gametes. The zygote's genome is a combination of the DNA in each gamete, and contains all of the genetic information of a new individual organism.
In multicellula ...
, and the second is the migration of the
trophoblast
The trophoblast (from Greek : to feed; and : germinator) is the outer layer of cells of the blastocyst. Trophoblasts are present four days after fertilization in humans. They provide nutrients to the embryo and develop into a large part of the p ...
.
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
The fallopian tubes, also known as uterine tubes, oviducts or salpinges (singular salpinx), are paired tubes in the human female that stretch from the uterus to the ovaries. The fallopian tubes are part of the female reproductive system. In ot ...
, and the zygote is transported along the tube to the uterus. The fallopian tube is lined with ciliated epithelium, and it is the
cilia
The cilium, plural cilia (), is a membrane-bound organelle found on most types of eukaryotic cell, and certain microorganisms known as ciliates. Cilia are absent in bacteria and archaea. The cilium has the shape of a slender threadlike projecti ...
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
A morula (Latin, ''morus'': mulberry) is an early-stage embryo consisting of a solid ball of cells called blastomeres, contained in mammals, and other animals within the zona pellucida shell. The blastomeres are the daughter cells of the zygote ...
.
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 ...
that will go on to develop into the
embryo
An embryo is an initial stage of development of a multicellular organism. In organisms that reproduce sexually, embryonic development is the part of the life cycle that begins just after fertilization of the female egg cell by the male spe ...
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 me ...
).
The blastocyst is still enclosed in the egg-coat known as the
zona pellucida
The zona pellucida (plural zonae pellucidae, also egg coat or pellucid zone) is a specialized extracellular matrix that surrounds the plasma membrane of mammalian oocytes. It is a vital constitutive part of the oocyte. The zona pellucida first ...
, 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
protease
A protease (also called a peptidase, proteinase, or proteolytic enzyme) is an enzyme that catalyzes (increases reaction rate or "speeds up") proteolysis, breaking down proteins into smaller polypeptides or single amino acids, and spurring the ...
s that are stimulated by various
growth factor
A growth factor is a naturally occurring substance capable of stimulating cell proliferation, wound healing, and occasionally cellular differentiation. Usually it is a secreted protein or a steroid hormone. Growth factors are important for regu ...
s.
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 autocrin ...
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
Matrix metalloproteinases (MMPs), also known as matrix metallopeptidases or matrixins, are metalloproteinases that are calcium-dependent zinc-containing endopeptidases; other family members are adamalysins, serralysins, and astacins. The MMPs b ...
,
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 encode ...
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
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 t ...
of the
menstrual cycle
The menstrual cycle is a series of natural changes in hormone production and the structures of the uterus and ovaries of the female reproductive system that make pregnancy possible. The ovarian cycle controls the production and release of eggs a ...
, 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
The trophoblast (from Greek : to feed; and : germinator) is the outer layer of cells of the blastocyst. Trophoblasts are present four days after fertilization in humans. They provide nutrients to the embryo and develop into a large part of the p ...
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 ...
(also embryoblast), inside the
trophoblast
The trophoblast (from Greek : to feed; and : germinator) is the outer layer of cells of the blastocyst. Trophoblasts are present four days after fertilization in humans. They provide nutrients to the embryo and develop into a large part of the p ...
layer, is aligned closest to the
decidua
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 influ ...
. 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. Th ...
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
Mucin short variant S1, also called polymorphic epithelial mucin (PEM) or epithelial membrane antigen (EMA), is a mucin encoded by the ''MUC1'' gene in humans. Mucin short variant S1 is a glycoprotein with extensive O-linked glycosylation of its e ...
, 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
Glycoproteins are proteins which contain oligosaccharide chains covalently attached to amino acid side-chains. The carbohydrate is attached to the protein in a cotranslational or posttranslational modification. This process is known as glycos ...
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
L-selectin, also known as CD62L, is a cell adhesion molecule found on the cell surface of leukocytes, and the blastocyst. It is coded for in the human by the ''SELL'' gene. L-selectin belongs to the selectin family of proteins, which recognize s ...
, 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
The internal surface of the uterus is lined by uterine epithelial cells which undergo dramatic changes during pregnancy. The role of the uterine epithelial cells is to selectively allow the blastocyst to implant at a specific time (the time of imp ...
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 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
A syncytium (; plural syncytia; from Greek: σύν ''syn'' "together" and κύτος ''kytos'' "box, i.e. cell") or symplasm is a multinucleate cell which can result from multiple cell fusions of uninuclear cells (i.e., cells with a single nucleus) ...
known as the syncytiotrophoblast
Syncytiotrophoblast (from the Greek 'syn'- "together"; 'cytio'- "of cells"; 'tropho'- "nutrition"; 'blast'- "bud") is the epithelial covering of the highly vascular embryonic placental villi, which invades the wall of the uterus to establish nut ...
. 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 embryo ...
.
When the syncytiotrophoblast reaches the basal membrane beneath the decidual cell
Before the fertilized ovum reaches the uterus, the mucous membrane of the body of the uterus undergoes important changes and is then known as the decidua. The thickness and vascularity of the mucous membrane are greatly increased; its Uterine gland ...
s, 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
In biology, the extracellular matrix (ECM), also called intercellular matrix, is a three-dimensional network consisting of extracellular macromolecules and minerals, such as collagen, enzymes, glycoproteins and hydroxyapatite that provide stru ...
. 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 transcripti ...
. The extracellular matrix is degraded by metalloproteinase
A metalloproteinase, or metalloprotease, is any protease enzyme whose catalytic mechanism involves a metal. An example is ADAM12 which plays a significant role in the fusion of muscle cells during embryo development, in a process known as myogen ...
s such as collagenases, gelatinases and matrix metalloproteinase
Matrix metalloproteinases (MMPs), also known as matrix metallopeptidases or matrixins, are metalloproteinases that are calcium-dependent zinc-containing endopeptidases; other family members are adamalysins, serralysins, and astacins. The MMPs b ...
s, and by serine protease
Serine proteases (or serine endopeptidases) are enzymes that cleave peptide bonds in proteins. Serine serves as the nucleophilic amino acid at the (enzyme's) active site.
They are found ubiquitously in both eukaryotes and prokaryotes. ...
s.[ The collagenases digest Types I, II, III, ]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
Serine proteases (or serine endopeptidases) are enzymes that cleave peptide bonds in proteins. Serine serves as the nucleophilic amino acid at the (enzyme's) active site.
They are found ubiquitously in both eukaryotes and prokaryotes. ...
and metalloproteinase
A metalloproteinase, or metalloprotease, is any protease enzyme whose catalytic mechanism involves a metal. An example is ADAM12 which plays a significant role in the fusion of muscle cells during embryo development, in a process known as myogen ...
s. 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
Placentation refers to the formation, type and structure, or arrangement of the placenta. The function of placentation is to transfer nutrients, respiratory gases, and water from maternal tissue to a growing embryo, and in some instances to remove ...
. 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 deri ...
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
Human chorionic gonadotropin (hCG) is a hormone for the maternal recognition of pregnancy produced by trophoblast cells that are surrounding a growing embryo (syncytiotrophoblast initially), which eventually forms the placenta after implantation ...
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
The immune system is a network of biological processes that protects an organism from diseases. It detects and responds to a wide variety of pathogens, from viruses to parasitic worms, as well as cancer cells and objects such as wood splinte ...
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
Human chorionic gonadotropin (hCG) is a hormone for the maternal recognition of pregnancy produced by trophoblast cells that are surrounding a growing embryo (syncytiotrophoblast initially), which eventually forms the placenta after implantation ...
, 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
Prostaglandin E2 (PGE2), also known as dinoprostone, is a naturally occurring prostaglandin with oxytocic properties that is used as a medication. Dinoprostone is used in labor induction, bleeding after delivery, termination of pregnancy, and ...
, 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
Interleukin 6 (IL-6) is an interleukin that acts as both a pro-inflammatory cytokine and an anti-inflammatory myokine. In humans, it is encoded by the ''IL6'' gene.
In addition, osteoblasts secrete IL-6 to stimulate osteoclast formation. Smooth ...
, interferon
Interferons (IFNs, ) are a group of signaling proteins made and released by host cells in response to the presence of several viruses. In a typical scenario, a virus-infected cell will release interferons causing nearby cells to heighten the ...
-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
Human chorionic gonadotropin (hCG) is a hormone for the maternal recognition of pregnancy produced by trophoblast cells that are surrounding a growing embryo (syncytiotrophoblast initially), which eventually forms the placenta after implantation ...
(hCG) not only acts as an immunosuppressive,[ but also signals to the mother that she is pregnant, preventing luteolysis 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 t ...
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
Tissue plasminogen activator (abbreviated tPA or PLAT) is a protein involved in the breakdown of blood clots. It is a serine protease () found on endothelial cells, the cells that line the blood vessels. As an enzyme, it catalyzes the conversion ...
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 f ...
* β1-integrin
Integrins are transmembrane receptors that facilitate cell-cell and cell-extracellular matrix (ECM) adhesion. Upon ligand binding, integrins activate signal transduction pathways that mediate cellular signals such as regulation of the cell cycle, ...
s
* 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 their ...
* 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 CD34 ...
* Transforming growth factor alpha
* 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 ...
* Preimplantation factor
Uterus receptivity
To enable implantation, the uterus
The uterus (from Latin ''uterus'', plural ''uteri'') or womb () is the organ in the reproductive system of most female mammals, including humans that accommodates the embryonic and fetal development of one or more embryos until birth. The uter ...
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. Th ...
s that help to absorb uterine fluid; changes in the thickness of the endometrium
The endometrium is the inner epithelial layer, along with its mucous membrane, of the mammalian uterus. It has a basal layer and a functional layer: the basal layer contains stem cells which regenerate the functional layer. The functional laye ...
and its blood supply development, and the formation of the decidua
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 influ ...
. Collectively these changes are known as plasma membrane transformation The plasma membrane transformation is a concept introduced by Christopher R. Murphy of The University of Sydney to encapsulate the idea that a series of changes in the plasma membrane of uterine epithelial cells is essential to the development of ...
, 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, induc ...
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 ...
-ligand
In coordination chemistry, a ligand is an ion or molecule (functional group) that binds to a central metal atom to form a coordination complex. The bonding with the metal generally involves formal donation of one or more of the ligand's electr ...
-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
The cytoskeleton is a complex, dynamic network of interlinking protein filaments present in the cytoplasm of all cells, including those of bacteria and archaea. In eukaryotes, it extends from the cell nucleus to the cell membrane and is compos ...
of decidual cells
Before the fertilized ovum reaches the uterus, the mucous membrane of the body of the uterus undergoes important changes and is then known as the decidua. The thickness and vascularity of the mucous membrane are greatly increased; its glands are el ...
. 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 ba ...
, 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
The menstrual cycle is a series of natural changes in hormone production and the structures of the uterus and ovaries of the female reproductive system that make pregnancy possible. The ovarian cycle controls the production and release of eggs a ...
when luteinizing hormone
Luteinizing hormone (LH, also known as luteinising hormone, lutropin and sometimes lutrophin) is a hormone produced by gonadotropic cells in the anterior pituitary gland. The production of LH is regulated by gonadotropin-releasing hormone (GnRH) ...
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. Th ...
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
In obstetrics, gestational age is a measure of the age of a pregnancy which is taken from the beginning of the woman's last menstrual period (LMP), or the corresponding age of the gestation as estimated by a more accurate method if available. Su ...
, 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
Progesterone (P4) is an endogenous steroid and progestogen sex hormone involved in the menstrual cycle, pregnancy, and embryogenesis of humans and other species. It belongs to a group of steroid hormones called the progestogens and is the m ...
, and inhibited by estrogens
Estrogen or oestrogen is a category of sex hormone responsible for the development and regulation of the female reproductive system and secondary sex characteristics. There are three major endogenous estrogens that have estrogenic hormonal acti ...
. During the window of implantation, cell to cell adhesion is inhibited by MUC1
Mucin short variant S1, also called polymorphic epithelial mucin (PEM) or epithelial membrane antigen (EMA), is a mucin encoded by the ''MUC1'' gene in humans. Mucin short variant S1 is a glycoprotein with extensive O-linked glycosylation of its e ...
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 cells ...
. 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 ...
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 splitting ...
and its glands
In animals, a gland is a group of cells in an animal's body that synthesizes substances (such as hormones) for release into the bloodstream (endocrine gland) or into cavities inside the body or its outer surface (exocrine gland).
Structure
De ...
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 fertilized ...
.
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 cell
Before the fertilized ovum reaches the uterus, the mucous membrane of the body of the uterus undergoes important changes and is then known as the decidua. The thickness and vascularity of the mucous membrane are greatly increased; its Uterine gland ...
s, which emphasises that the whole layer of them is shed off in every menstruation
Menstruation (also known as a period, among other colloquial terms) is the regular discharge of blood and mucosal tissue from the inner lining of the uterus through the vagina. The menstrual cycle is characterized by the rise and fall of hor ...
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, aft ...
. 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 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 influ ...
. 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
Decidualization is a process that results in significant changes to cells of the endometrium in preparation for, and during, pregnancy. This includes morphological and functional changes (the decidual reaction) to endometrial stromal cells (ESCs), ...
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 channel ...
. 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 contractio ...
(Ca2+) and phosphorylation of CREB. Phosphorylation of CREB upregulates the expression of COX2
Cytochrome c oxidase subunit 2, also known as cytochrome c oxidase polypeptide II, is a protein that in humans is encoded by the MT-CO2 gene. Cytochrome c oxidase subunit II, abbreviated COXII, COX2, COII, or MT-CO2, is the second subunit of c ...
, 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
The placenta is a temporary embryonic and later fetal organ that begins developing from the blastocyst shortly after implantation. It plays critical roles in facilitating nutrient, gas and waste exchange between the physically separate mater ...
. 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
Not only the lining of the uterus transforms, but the secretion from its glands changes. This change is induced by increased levels of progesterone
Progesterone (P4) is an endogenous steroid and progestogen sex hormone involved in the menstrual cycle, pregnancy, and embryogenesis of humans and other species. It belongs to a group of steroid hormones called the progestogens and is the m ...
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 t ...
. 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 a ...
-dependent proteins, important for growth and implantation. Cholesterol
Cholesterol is any of a class of certain organic molecules called lipids. It is a sterol (or modified steroid), a type of lipid. Cholesterol is biosynthesized by all animal cells and is an essential structural component of animal cell mem ...
, 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'' (franchis ...
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 n ...
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) f ...
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 autocrin ...
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
Female infertility refers to infertility in women. It affects an estimated 48 million women, with the highest prevalence of infertility affecting women in South Asia, Sub-Saharan Africa, North Africa/Middle East, and Central/Eastern Europe and Cen ...
. 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 simple ...
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 cons ...
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 (anatomy), organ produced in vitro in three dimensions that shows realistic micro-anatomy. They are derived from one or a few Cell (biology), cells from a Tissue (biology), tissue, ...
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 ...
, a review of several small randomized controlled studies 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 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 simple ...
by approximately 80%. Luteal phase support can include the use of progesterone
Progesterone (P4) is an endogenous steroid and progestogen sex hormone involved in the menstrual cycle, pregnancy, and embryogenesis of humans and other species. It belongs to a group of steroid hormones called the progestogens and is the m ...
and human chorionic gonadotropin
Human chorionic gonadotropin (hCG) is a hormone for the maternal recognition of pregnancy produced by trophoblast cells that are surrounding a growing embryo (syncytiotrophoblast initially), which eventually forms the placenta after implantation ...
(hCG) to improve the chances of a successful implantation.
Zinc deficiency
Zinc
Zinc is a chemical element with the symbol Zn and atomic number 30. Zinc is a slightly brittle metal at room temperature and has a shiny-greyish appearance when oxidation is removed. It is the first element in group 12 (IIB) of the periodi ...
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
Vaginal bleeding is any expulsion of blood from the vagina. This bleeding may originate from the uterus, vaginal wall, or cervix. Generally, it is either part of a normal menstrual cycle or is caused by hormonal or other problems of the reproductiv ...
or spotting that can occur in early pregnancy due to the fertilized egg
A zygote (, ) is a eukaryotic cell formed by a fertilization event between two gametes. The zygote's genome is a combination of the DNA in each gamete, and contains all of the genetic information of a new individual organism.
In multicellula ...
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. I ...
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