Decidualization

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Decidual reaction
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Sectional plan of the gravid uterus in the third and fourth month.
Anatomical terminology
Micrograph showing decidualization of the endometrium due to exogenous progesterone (oral contraceptive pill). H&E stain. Endometrium ocp use3.jpg
Micrograph showing decidualization of the endometrium due to exogenous progesterone (oral contraceptive pill). H&E stain.

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), the presence of decidual white blood cells (leukocytes), and vascular changes to maternal arteries. The sum of these changes results in the endometrium changing into a structure called the decidua. In humans, the decidua is shed during childbirth. [1]

Contents

Decidualization plays an important role in promoting placenta formation between a mother and her fetus by mediating the invasiveness of trophoblast cells. It also triggers the production of cellular and molecular factors that result in structural changes, or remodeling, of maternal spiral arteries. Decidualization is required in some mammalian species where embryo implantation and trophoblast cell invasion of the endometrium occurs, also known as hemochorial placentation. This allows maternal blood to come into direct contact with the fetal chorion, a membrane between the fetal and maternal tissues, and allows for nutrient and gas exchange. However, decidualization-like reactions have also been observed in some species that don't display hemochorial placentation. [2]

In humans, decidualization occurs after ovulation during the menstrual cycle. After implantation of the embryo, the decidua further develops to mediate the process of placentation. In the event no embryo is implanted, the decidualized endometrial lining is shed or, as is the case with species that follow the estrous cycle, absorbed. [1] In menstruating species, decidualization is spontaneous and occurs as a result of maternal hormones. In non-menstruating species, decidualization is non-spontaneous, meaning it only happens after there are external signals from an implanted embryo. [3]

Overview

After ovulation, the high levels of progesterone initiate the molecular changes leading to decidualization. The process triggers an influx of decidual leukocytes along with morphological and functional changes of ESCs. The changes in the ESCs result in the endometrium developing a secretory lining that produces a variety of proteins, cytokines, and growth factors. These secreted factors will regulate the invasiveness of trophoblast cells that eventually form the placental connection if an embryo implants into the decidua. [4]

Decidual leukocytes

One of the identifying features of the decidua is the presence of large numbers of leukocytes that are mostly made up of specialized uterine natural killer (uNK) cells [5] and some dendritic cells. As the fetus consists of both maternal and paternal DNA, the decidual leukocytes play a role in suppressing the immune response of the mother to prevent treating the fetus as genetically foreign. Outside of their immune functions, the uNK cells and dendritic cells also act as regulators of maternal spiral artery remodeling and ESC differentiation. [6]

Endometrial stromal cells (ESCs)

ESCs are the connective tissue cells of the endometrium that are fibroblastic in appearance. However, decidualization causes them to swell up and adopt an epithelial cell-like appearance due to the accumulation of glycogen and lipid droplets. Furthermore, they begin secreting cytokines, growth factors, and proteins like IGFBP1 and prolactin, along with extracellular matrix (ECM) proteins such as fibronectin and laminin. The increased production of these ECM proteins turns the endometrium into the dense structure known as the decidua, which produces factors that promote trophoblast attachment and inhibit overly aggressive invasion. [7]

During pregnancy

The decidual reaction is seen in very early pregnancy in the generalized area where the blastocyst contacts the endometrial decidua. It consists of an increase in secretory functions of the endometrium at the area of implantation, as well as a surrounding stroma that becomes edematous. [8]

The decidual reaction occurs only in humans and a few other species. The decidual reaction and decidua are not required for implantation. Evidence can be taken from the fact that in ectopic pregnancies and hysterectomies, implantation can occur anywhere in the abdomino-pelvic cavity. [9]

Role in diseases and disorders

Abnormalities in decidualization have been implicated in diseases such as endometriosis, in which impaired decidualization leads to ectopic uterine tissue growth. Lack of decidualization has also been linked to higher rates of miscarriage. [10]

Chronic deciduitis, a chronic inflammation of the decidua, has been linked with premature birth. [11]

In research

The decidualization process is initiated by progesterone, but this requires cyclic adenosine monophosphate (cAMP) to act as the initial signalling molecule to sensitize endometrial cells to progesterone. Consequently, human ESCs have been decidualized in culture with chemical analogs of cAMP and progesterone together. In vitro decidualization results in similar morphological changes to the human ESCs as well as upregulated production of decidualization markers such as IGFBP1 and prolactin. [7]

Mouse models have been extensively used for the identification of the molecular factors required for and involved in decidualization. [12]

See also

Related Research Articles

<span class="mw-page-title-main">Endometrium</span> Inner mucous membrane of the mammalian uterus

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 layer thickens and then is shed during menstruation in humans and some other mammals, including apes, Old World monkeys, some species of bat, the elephant shrew and the Cairo spiny mouse. In most other mammals, the endometrium is reabsorbed in the estrous cycle. During pregnancy, the glands and blood vessels in the endometrium further increase in size and number. Vascular spaces fuse and become interconnected, forming the placenta, which supplies oxygen and nutrition to the embryo and fetus. The speculated presence of an endometrial microbiota has been argued against.

<span class="mw-page-title-main">Placenta</span> Organ that connects the fetus to the uterine wall

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 maternal and fetal circulations, and is an important endocrine organ, producing hormones that regulate both maternal and fetal physiology during pregnancy. The placenta connects to the fetus via the umbilical cord, and on the opposite aspect to the maternal uterus in a species-dependent manner. In humans, a thin layer of maternal decidual (endometrial) tissue comes away with the placenta when it is expelled from the uterus following birth. Placentas are a defining characteristic of placental mammals, but are also found in marsupials and some non-mammals with varying levels of development.

<span class="mw-page-title-main">Menstrual cycle</span> Natural changes in the human female reproductive system

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 makes pregnancy possible. The ovarian cycle controls the production and release of eggs and the cyclic release of estrogen and progesterone. The uterine cycle governs the preparation and maintenance of the lining of the uterus (womb) to receive an embryo. These cycles are concurrent and coordinated, normally last between 21 and 35 days, with a median length of 28 days, and continue for about 30–45 years.

<span class="mw-page-title-main">Blastocyst</span> Structure formed around day 5 of mammalian embryonic development

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 trophectoderm. This layer surrounds the inner cell mass and a fluid-filled cavity known as the blastocoel. In the late blastocyst, the trophectoderm is known as the trophoblast. The trophoblast gives rise to the chorion and amnion, the two fetal membranes that surround the embryo. The placenta derives from the embryonic chorion and the underlying uterine tissue of the mother.

<span class="mw-page-title-main">Trophoblast</span> Early embryonic structure that gives rise to the placenta

The trophoblast 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 placenta. They form during the first stage of pregnancy and are the first cells to differentiate from the fertilized egg to become extraembryonic structures that do not directly contribute to the embryo. After blastulation, the trophoblast is contiguous with the ectoderm of the embryo and is referred to as the trophectoderm. After the first differentiation, the cells in the human embryo lose their totipotency because they can no longer form a trophoblast. They become pluripotent stem cells.

<span class="mw-page-title-main">Decidua</span> Part of uterus modified in pregnancy

The decidua is the modified mucosal lining of the uterus 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 influence of progesterone. Endometrial cells become highly characteristic. The decidua forms the maternal part of the placenta and remains for the duration of the pregnancy. After birth the decidua is shed together with the placenta.

<span class="mw-page-title-main">Cytotrophoblast</span>

"Cytotrophoblast" is the name given to both the inner layer of the trophoblast or the cells that live there. It is interior to the syncytiotrophoblast and external to the wall of the blastocyst in a developing embryo.

<span class="mw-page-title-main">Implantation (embryology)</span> First stage of pregnancy

Implantation, also known as nidation, is the stage in the embryonic development of mammals in which the blastocyst hatches, attaches, 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. An implanted embryo is detected by the presence of increased levels of human chorionic gonadotropin (hCG) in a pregnancy test. The implanted embryo will receive oxygen and nutrients in order to grow.

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 elongated and open on its free surface by funnel-shaped orifices, while their deeper portions are tortuous and dilated into irregular spaces. The interglandular tissue is also increased in quantity, and is crowded with large round, oval, or polygonal cells, termed decidual cells. Their enlargement is due to glycogen and lipid accumulation in the cytoplasm allowing these cells to provide a rich source of nutrition for the developing embryo. Decidual cells are also thought to control the invasion of the endometrium by trophoblast cells.

<span class="mw-page-title-main">Human embryonic development</span> Development and formation of the human embryo

Human embryonic development or human embryogenesis is the development and formation of the human embryo. It is characterised by the processes of cell division and cellular differentiation of the embryo that occurs during the early stages of development. In biological terms, the development of the human body entails growth from a one-celled zygote to an adult human being. Fertilization occurs when the sperm cell successfully enters and fuses with an egg cell (ovum). The genetic material of the sperm and egg then combine to form the single cell zygote and the germinal stage of development commences. Embryonic development in the human, covers the first eight weeks of development; at the beginning of the ninth week the embryo is termed a fetus. The eight weeks has 23 stages.

Arcuate arteries located in the uterus branch out and supply blood to different layers of the uterus. These arteries meet the myometrial-endometrial junction and lead to straight and endometrial arteries. The endometrium receives blood from endometrial arteries which are also called spiral arteries. Endometrial arteries proliferate rapidly and react to different hormones released. These hormones are progesterone and estrogen released by the ovaries and produced by the endocrine system. The endometrial arteries not only supply blood to the endometrium but are also important during pregnancy. They are the initial site of transportation of blood from the mother to the baby.

<span class="mw-page-title-main">Glycodelin</span> Mammalian protein found in Homo sapiens

Glycodelin(GD) also known as human placental protein-14 (PP-14)progestogen-associated endometrial protein (PAEP) or pregnancy-associated endometrial alpha-2 globulin is a glycoprotein that inhibits cell immune function and plays an essential role in the pregnancy process. In humans is encoded by the PAEP gene.

<span class="mw-page-title-main">Homeobox A10</span> Protein-coding gene in humans

Homeobox protein Hox-A10 is a protein that in humans is encoded by the HOXA10 gene.

Reproductive immunology refers to a field of medicine that studies interactions between the immune system and components related to the reproductive system, such as maternal immune tolerance towards the fetus, or immunological interactions across the blood-testis barrier. The concept has been used by fertility clinics to explain fertility problems, recurrent miscarriages and pregnancy complications observed when this state of immunological tolerance is not successfully achieved. Immunological therapy is a method for treating many cases of previously "unexplained infertility" or recurrent miscarriage.

Hormonal regulation occurs at every stage of development. A milieu of hormones simultaneously affects development of the fetus during embryogenesis and the mother, including human chorionic gonadotropin (hCG) and progesterone (P4).

<span class="mw-page-title-main">Chorionic gonadotropin beta</span> Protein-coding gene in the species Homo sapiens

Choriogonadotropin subunit beta (CG-beta) also known as chorionic gonadotrophin chain beta is a protein that in humans is encoded by the CGB gene.

Menstruation is the shedding of the uterine lining (endometrium). It occurs on a regular basis in uninseminated sexually reproductive-age females of certain mammal species.

<span class="mw-page-title-main">Preimplantation factor</span> Peptide involved in placental development

Preimplantation factor(PIF) is a peptide secreted by trophoblast cells prior to placenta formation in early embryonic development. Human embryos begin to express PIF at the 4-cell stage, with expression increasing by the morula stage and continuing to do so throughout the first trimester. Expression of preimplantation factor in the blastocyst was discovered as an early correlate of the viability of the eventual pregnancy. Preimplantation factor was identified in 1994 by a lymphocyte platelet-binding assay, where it was thought to be an early biomarker of pregnancy. It has a simple primary structure with a short sequence of fifteen amino acids without any known quaternary structure. A synthetic analogue of preimplantation factor (commonly abbreviated in studies as sPIF or PIF*) that has an identical amino acid sequence and mimics the normal biological activity of PIF has been developed and is commonly used in research studies, particularly those that aim to study potential adult therapeutics.

<span class="mw-page-title-main">Maternal recognition of pregnancy</span> Crucial aspect of carrying a pregnancy to full term

Maternal recognition of pregnancy is a crucial aspect of carrying a pregnancy to full term. Without maternal recognition to maintain pregnancy, the initial messengers which stop luteolysis and promote foetal implantation, growth and uterine development finish with nothing to replace them and the pregnancy is lost.

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 derive from progenitor cytotrophoblasts (CYTs), as does the other main trophoblast subtype, syncytiotrophoblast (SYN). They are sometimes called intermediate trophoblast.

References

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