Decidualization is a process that results in significant changes to cells 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 layer ...

in preparation for, and during,

pregnancy Pregnancy is the time during which one or more offspring develops ( gestates) inside a woman's uterus (womb). A multiple pregnancy involves more than one offspring, such as with twins. Pregnancy usually occurs by sexual intercourse, but ...

. This includes morphological and functional changes (the decidual reaction) to endometrial stromal cells (ESCs), the presence of decidual

white blood cell White blood cells, also called leukocytes or leucocytes, are the cell (biology), cells of the immune system that are involved in protecting the body against both infectious disease and foreign invaders. All white blood cells are produced and de ...

s (leukocytes), and vascular changes to maternal arteries. The sum of these changes results in the endometrium changing into a structure called 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 ...

. In humans, the decidua is shed during

childbirth Childbirth, also known as labour and delivery, is the ending of pregnancy where one or more babies exits the internal environment of the mother via vaginal delivery or caesarean section. In 2019, there were about 140.11 million births globall ...

. Decidualization plays an important role in promoting placenta formation between a mother and her fetus by mediating the invasiveness of

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 pl ...

cells. It also triggers the production of cellular and molecular factors that result in structural changes, or remodeling, of maternal

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 ...

. Decidualization is required in some mammalian species where embryo implantation and

cell invasion of the endometrium occurs, also known as

hemochorial 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 remov ...

. This allows maternal blood to come into direct contact with the fetal

chorion The chorion is the outermost fetal membrane around the embryo in mammals, birds and reptiles (amniotes). It develops from an outer fold on the surface of the yolk sac, which lies outside the zona pellucida (in mammals), known as the vitelline ...

, 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. In humans, decidualization occurs 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 ...

during 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 ...

. 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 The estrous cycle (, originally ) is the set of recurring physiological changes that are induced by reproductive hormones in most mammalian therian females. Estrous cycles start after sexual maturity in females and are interrupted by anestrous p ...

, absorbed. 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.

Overview

After ovulation, the high 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 ...

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,

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, and

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. These secreted factors will regulate the invasiveness of trophoblast cells that eventually form the placental connection if an embryo implants into the decidua.

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 and some

dendritic cell Dendritic cells (DCs) are antigen-presenting cells (also known as ''accessory cells'') of the mammalian immune system. Their main function is to process antigen material and present it on the cell surface to the T cells of the immune system. ...

s. As the fetus consists of both maternal and paternal DNA, the decidual leukocytes play a role in suppressing the

immune response An immune response is a reaction which occurs within an organism for the purpose of defending against foreign invaders. These invaders include a wide variety of different microorganisms including viruses, bacteria, parasites, and fungi which could ...

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.

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 Epithelium or epithelial tissue is one of the four basic types of animal tissue, along with connective tissue, muscle tissue and nervous tissue. It is a thin, continuous, protective layer of compactly packed cells with a little intercellula ...

cell-like appearance due to the accumulation of

glycogen Glycogen is a multibranched polysaccharide of glucose that serves as a form of energy storage in animals, fungi, and bacteria. The polysaccharide structure represents the main storage form of glucose in the body. Glycogen functions as one o ...

and

lipid Lipids are a broad group of naturally-occurring molecules which includes fats, waxes, sterols, fat-soluble vitamins (such as vitamins A, D, E and K), monoglycerides, diglycerides, phospholipids, and others. The functions of lipids include ...

droplets. Furthermore, they begin secreting cytokines, growth factors, and proteins like

IGFBP1 Insulin-like growth factor-binding protein 1 (IBP-1) also known as placental protein 12 (PP12) is a protein that in humans is encoded by the ''IGFBP1'' gene. Function This gene is a member of the Insulin-like growth factor-binding protein (IGFB ...

and

prolactin Prolactin (PRL), also known as lactotropin, is a protein best known for its role in enabling mammals to produce milk. It is influential in over 300 separate processes in various vertebrates, including humans. Prolactin is secreted from the pit ...

, along with

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 ...

(ECM) proteins such as

fibronectin Fibronectin is a high- molecular weight (~500-~600 kDa) glycoprotein of the extracellular matrix that binds to membrane-spanning receptor proteins called integrins. Fibronectin also binds to other extracellular matrix proteins such as collage ...

and

laminin Laminins are a family of glycoproteins of the extracellular matrix of all animals. They are major components of the basal lamina (one of the layers of the basement membrane), the protein network foundation for most cells and organs. The laminins ...

. 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.

During pregnancy

The decidual reaction is seen in very early pregnancy in the generalized area where 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 ...

contacts the endometrial

. It consists of an increase in secretory functions of the endometrium at the area of implantation, as well as a surrounding stroma that becomes

edema Edema, also spelled oedema, and also known as fluid retention, dropsy, hydropsy and swelling, is the build-up of fluid in the body's Tissue (biology), tissue. Most commonly, the legs or arms are affected. Symptoms may include skin which feels t ...

tous. 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 Ectopic pregnancy is a complication of pregnancy in which the embryo attaches outside the uterus. Signs and symptoms classically include abdominal pain and vaginal bleeding, but fewer than 50 percent of affected women have both of these symptoms. ...

and

hysterectomies Hysterectomy is the surgical removal of the uterus. It may also involve removal of the cervix, ovaries (oophorectomy), Fallopian tubes (salpingectomy), and other surrounding structures. Usually performed by a gynecologist, a hysterectomy may be ...

, implantation can occur anywhere in the abdomino-pelvic cavity.

Role in diseases and disorders

Abnormalities in decidualization have been implicated in diseases such as

endometriosis Endometriosis is a disease of the female reproductive system in which cells similar to those in the endometrium, the layer of tissue that normally covers the inside of the uterus, grow outside the uterus. Most often this is on the ovaries, f ...

, in which impaired decidualization leads to ectopic uterine tissue growth. Lack of decidualization has also been linked to higher rates of

miscarriage Miscarriage, also known in medical terms as a spontaneous abortion and pregnancy loss, is the death of an embryo or fetus before it is able to survive independently. Miscarriage before 6 weeks of gestation is defined by ESHRE as biochemical lo ...

Chronic deciduitis Chronic deciduitis is a type of long-lasting inflammation that arises in pregnancy and affects the endometrial stromal tissue (decidua). It is associated with preterm labour. The diagnosis rests primarily on the presence of plasma cells. Image ...

, a chronic

inflammation Inflammation (from la, wikt:en:inflammatio#Latin, inflammatio) is part of the complex biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or Irritation, irritants, and is a protective response involving im ...

of the decidua, has been linked with

premature birth Preterm birth, also known as premature birth, is the birth of a baby at fewer than 37 weeks gestational age, as opposed to full-term delivery at approximately 40 weeks. Extreme preterm is less than 28 weeks, very early preterm birth is between 2 ...

In research

The decidualization process is initiated by progesterone, but this requires

cyclic adenosine monophosphate Cyclic adenosine monophosphate (cAMP, cyclic AMP, or 3',5'-cyclic adenosine monophosphate) is a second messenger important in many biological processes. cAMP is a derivative of adenosine triphosphate (ATP) and used for intracellular signal transd ...

(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 ''In vitro'' (meaning in glass, or ''in the glass'') studies are performed with microorganisms, cells, or biological molecules outside their normal biological context. Colloquially called "test-tube experiments", these studies in biology an ...

'' decidualization results in similar morphological changes to the human ESCs as well as upregulated production of decidualization markers such as

and

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

References

External links

Implantation stages
Human embryology; developed by the universities of Fribourg, Lausanne and Bern (Switzerland).
Histopathology Uterus – Decidual reaction
Microscopic review of decidualization {{Embryology Human pregnancy Menstrual cycle